June 2007, Volume 30, Number 6 , pp. 1335-1684
Bench to Clinic Symposia:
Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes: Preclinical biology and mechanisms of action Daniel J. Drucker Diabetes Care 2007 30: 1335-1343. Dipeptidyl Peptidase-4 Inhibitors: Clinical data and clinical implications Bo Ahrén Diabetes Care 2007 30: 1344-1350. Original Articles:
Clinical Care/Education/Nutrition:
Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes Roland E. Schmieder, Christian Delles, Albert Mimran, Jean P. Fauvel, and Luis M. Ruilope Diabetes Care 2007 30: 1351-1356. Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes Klas Ekström, Jenny Salemyr, Ingmar Zachrisson, Christine Carlsson-Skwirut, Eva Örtqvist, and Peter Bang Diabetes Care 2007 30: 1357-1363. Initiate Insulin by Aggressive Titration and Education (INITIATE): A randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups Hannele Yki-Järvinen, Leena Juurinen, Michael Alvarsson, Tord Bystedt, Ian Caldwell, Melanie Davies, Sanni Lahdenperä, Gil Nijpels, and Markku Vähätalo Diabetes Care 2007 30: 1364-1369.
Prediction of Severe Hypoglycemia Daniel J. Cox, Linda Gonder-Frederick, Lee Ritterband, William Clarke, and Boris P. Kovatchev Diabetes Care 2007 30: 1370-1373. Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals With Type 2 Diabetes: One-year results of the Look AHEAD trial The Look AHEAD Research Group Diabetes Care 2007 30: 1374-1383. Objectively Measured Light-Intensity Physical Activity Is Independently Associated With 2-h Plasma Glucose Genevieve N. Healy, David W. Dunstan, Jo Salmon, Ester Cerin, Jonathan E. Shaw, Paul Z. Zimmet, and Neville Owen Diabetes Care 2007 30: 1384-1389. A Multicenter Randomized Controlled Trial of Motivational Interviewing in Teenagers With Diabetes Sue J. Channon, Michelle V. Huws-Thomas, Stephen Rollnick, Kerenza Hood, Rebecca L. Cannings-John, Carol Rogers, and John W. Gregory Diabetes Care 2007 30: 1390-1395. Safe at School: A Virginia Experience Martha A. Hellems and William L. Clarke Diabetes Care 2007 30: 1396-1398. Satisfaction and Quality of Life With Premeal Inhaled Versus Injected Insulin in Adolescents and Adults With Type 1 Diabetes Marcia A. Testa and Donald C. Simonson Diabetes Care 2007 30: 1399-1405. Orange Juice or Fructose Intake Does Not Induce Oxidative and Inflammatory Response Husam Ghanim, Priya Mohanty, Ram Pathak, Ajay Chaudhuri, Chang Ling Sia, and Paresh Dandona Diabetes Care 2007 30: 1406-1411. Interindividual Variability and Intra-Individual Reproducibility of Glycemic Index Values for Commercial White Bread Sonia Vega-López, Lynne M. Ausman, John L. Griffith, and Alice H. Lichtenstein Diabetes Care 2007 30: 1412-1417.
Epidemiology/Health Services/Psychosocial Research:
Short-Term Weight Change and the Incidence of Diabetes in Midlife: Results from the Australian Longitudinal Study on Women's Health Gita D. Mishra, Gretchen Carrigan, Wendy J. Brown, Adrian G. Barnett, and Annette J. Dobson Diabetes Care 2007 30: 1418-1424.
Insulin Resistance Is Associated With Hypercortisolemia in Polynesian Patients Treated With Antipsychotic Medication Nicola R. Poa and Paul F. Edgar Diabetes Care 2007 30: 1425-1429. Development of Diabetes in Chinese With the Metabolic Syndrome: A 6-year prospective study Bernard M.Y. Cheung, Nelson M.S. Wat, Yu Bun Man, Sidney Tam, G. Neil Thomas, Gabriel M. Leung, Chun Ho Cheng, Jean Woo, Edward D. Janus, Chu Pak Lau, Tai Hing Lam, and Karen S.L. Lam Diabetes Care 2007 30: 1430-1436. Severe Hypoglycemia and Smoking in a Long-Term Type 1 Diabetic Population: Wisconsin Epidemiologic Study of Diabetic Retinopathy Flavio E. Hirai, Scot E. Moss, Barbara E.K. Klein, and Ronald Klein Diabetes Care 2007 30: 1437-1441. Relationship of Physician Volume With Process Measures and Outcomes in Diabetes Alexander Turchin, Maria Shubina, and Merri L. Pendergrass Diabetes Care 2007 30: 1442-1447. How Doctors Choose Medications to Treat Type 2 Diabetes: A national survey of specialists and academic generalists Richard W. Grant, Deborah J. Wexler, Alice J. Watson, William T. Lester, Enrico Cagliero, Eric G. Campbell, and David M. Nathan Diabetes Care 2007 30: 1448-1453. Diabetes Care in Extended-Care Facilities: Appropriate intensity of care? Rachel M. Holt, Frank L. Schwartz, and Jay H. Shubrook Diabetes Care 2007 30: 1454-1458. Racial and Ethnic Variation in Access to Health Care, Provision of Health Care Services, and Ratings of Health Among Women With Histories of Gestational Diabetes Mellitus Catherine Kim, Brandy Sinco, and Edith A. Kieffer Diabetes Care 2007 30: 1459-1465. The Underuse of Screening Services Among Elderly Women With Diabetes A. Marshall McBean and Xinhua Yu Diabetes Care 2007 30: 1466-1472. A Cohort Study of People With Diabetes and Their First Foot Ulcer: The role of depression on mortality Khalida Ismail, Kirsty Winkley, Daniel Stahl, Trudie Chalder, and Michael Edmonds Diabetes Care 2007 30: 1473-1479.
Emerging Treatments and Technologies:
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy and Safety of Topiramate Controlled Release in the Treatment of Obese Type 2 Diabetic Patients Julio Rosenstock, Priscilla Hollander, Kishore M. Gadde, Xiang Sun, Richard Strauss, Albert Leung for the OBD-202 Study Group Diabetes Care 2007 30: 1480-1486. Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes Dennis Kim, Leigh MacConell, Dongliang Zhuang, Prajakti A. Kothare, Michael Trautmann, Mark Fineman, and Kristin Taylor Diabetes Care 2007 30: 1487-1493.
Pathophysiology/Complications:
Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients: An adaptive phenomenon? Melania Manco, José M. Fernández-Real, Maria E. Valera-Mora, Henri Déchaud, Giuseppe Nanni, Vincenzo Tondolo, Menotti Calvani, Marco Castagneto, Michel Pugeat, and Geltrude Mingrone Diabetes Care 2007 30: 1494-1500. Plasma Resistin, Associated With Single Nucleotide Polymorphism –420, Is Correlated With Insulin Resistance, Lower HDL Cholesterol, and High-Sensitivity C-Reactive Protein in the Japanese General Population Haruhiko Osawa, Yasuharu Tabara, Ryuichi Kawamoto, Jun Ohashi, Masaaki Ochi, Hiroshi Onuma, Wataru Nishida, Kazuya Yamada, Jun Nakura, Katsuhiko Kohara, Tetsuro Miki, and Hideichi Makino Diabetes Care 2007 30: 1501-1506. Accelerated Loss of Skeletal Muscle Strength in Older Adults With Type 2 Diabetes: The Health, Aging, and Body Composition Study Seok Won Park, Bret H. Goodpaster, Elsa S. Strotmeyer, Lewis H. Kuller, Robert Broudeau, Candace Kammerer, Nathalie de Rekeneire, Tamara B. Harris, Ann V. Schwartz, Frances A. Tylavsky, Yong-wook Cho, Anne B. Newman for the Health, Aging, and Body Composition Study Diabetes Care 2007 30: 1507-1512. The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes Su Chi Lim, Nils G. Morgenthaler, Tavintharan Subramaniam, Yew Seng Wu, Siew Kheng Goh, and Chee Fang Sum Diabetes Care 2007 30: 1513-1519.
Cardiovascular and Metabolic Risk:
Abnormal Left Ventricular Energy Metabolism in Obese Men With Preserved Systolic and Diastolic Functions Is Associated With Insulin Resistance Gianluca Perseghin, Georgia Ntali, Francesco De Cobelli, Guido Lattuada, Antonio Esposito, Elena Belloni, Tamara Canu, Federica Costantino, Francesca Ragogna, Paola Scifo, Alessandro Del Maschio, and Livio Luzi Diabetes Care 2007 30: 1520-1526. Association of A1C With Cardiovascular Disease and Metabolic Syndrome in Asian Indians With Normal Glucose Tolerance James Dilley, Anbazhagan Ganesan, Raj Deepa, Mohan Deepa, Gopalakrishnan Sharada, O. Dale Williams, and Viswanathan Mohan Diabetes Care 2007 30: 1527-1532. Relationship Between Metabolic Risk Factor Clustering and Cardiovascular Mortality Stratified by High Blood Glucose and Obesity: NIPPON DATA90, 1990– 2000 Aya Kadota, Atsushi Hozawa, Tomonori Okamura, Takashi Kadowak, Koshi Nakmaura, Yoshitaka Murakami, Takehito Hayakawa, Yoshikuni Kita, Akira Okayama, Yasuyuki Nakamura, Atsunori Kashiwagi, Hirotsugu Ueshima for the NIPPON DATA Research Group Diabetes Care 2007 30: 1533-1538. Exercise Capacity and Body Mass as Predictors of Mortality Among Male Veterans With Type 2 Diabetes Paul A. McAuley, Jonathan N. Myers, Joshua P. Abella, Swee Y. Tan, and Victor F. Froelicher Diabetes Care 2007 30: 1539-1543. What Is the Best Predictor of Future Type 2 Diabetes? Muhammad A. Abdul-Ghani, Ken Williams, Ralph A. DeFronzo, and Michael Stern Diabetes Care 2007 30: 1544-1548. Vitamin D, Parathyroid Hormone Levels, and the Prevalence of Metabolic Syndrome in Community-Dwelling Older Adults Jared P. Reis, Denise von Mühlen, Donna Kritz-Silverstein, Deborah L. Wingard, and Elizabeth Barrett-Connor Diabetes Care 2007 30: 1549-1555. Is There a Single Underlying Factor for the Metabolic Syndrome in Adolescents?: A confirmatory factor analysis Chaoyang Li and Earl S. Ford Diabetes Care 2007 30: 1556-1561. Effect of BMI on Lifetime Risk for Diabetes in the U.S. K.M.V. Narayan, James P. Boyle, Theodore J. Thompson, Edward W. Gregg, and David F. Williamson Diabetes Care 2007 30: 1562-1566.
Strong Association Between Time Watching Television and Blood Glucose Control in Children and Adolescents With Type 1 Diabetes Hanna D. Margeirsdottir, Jakob R. Larsen, Cathrine Brunborg, Leiv Sandvik, Knut Dahl-Jørgensen for the Norwegian Study Group for Childhood Diabetes Diabetes Care 2007 30: 1567-1570. Brief Reports:
Clinical Care/Education/Nutrition:
Adolescents at Risk for MODY3 Diabetes Prefer Genetic Testing Before Adulthood Brita Liljeström, Tiinamaija Tuomi, Bo Isomaa, Leena Sarelin, Katja Aktan- Collan, and Helena Kääriäinen Diabetes Care 2007 30: 1571-1573. Thiazolidinedione Treatment Decreases Bone Mineral Density in Type 2 Diabetic Men Subhashini Yaturu, Barbara Bryant, and Sushil K. Jain Diabetes Care 2007 30: 1574-1576. Prevention of Transition From Incipient to Overt Nephropathy With Telmisartan in Patients With Type 2 Diabetes Hirofumi Makino, Masakazu Haneda, Tetsuya Babazono, Tatsumi Moriya, Sadayoshi Ito, Yasuhiko Iwamoto, Ryuzo Kawamori, Masahiro Takeuchi, Shigehiro Katayama for the INNOVATION Study Group Diabetes Care 2007 30: 1577-1578. Non–Glycemic-Dependent Reduction of Late Pregnancy A1C Levels in Women With Type 1 Diabetes Lucrecia Herranz, Lourdes Saez-de-Ibarra, Cristina Grande, and Luis F. Pallardo Diabetes Care 2007 30: 1579-1580. Reduction of Microalbuminuria in Patients With Type 2 Diabetes: The Shiga Microalbuminuria Reduction Trial (SMART) The Shiga Microalbuminuria Reduction Trial (SMART) Group Diabetes Care 2007 30: 1581-1583. Evaluation of a Teaching and Treatment Program in Over 4,000 Type 2 Diabetic Patients After Introduction of Reimbursement Policy for Physicians Stefan Korsatko, Wolfgang Habacher, Ivo Rakovac, Johannes Plank, Sabine Seereiner, Peter Beck, Robert Gfrerer, Peter Mrak, Bernd Bauer, Manfred Großschädl, and Thomas R. Pieber Diabetes Care 2007 30: 1584-1586. Gain in Patients' Knowledge of Diabetes Management Targets Is Associated With Better Glycemic Control Padmalatha Berikai, Peter M. Meyer, Rasa Kazlauskaite, Barbara Savoy, Kelly Kozik, and Leon Fogelfeld Diabetes Care 2007 30: 1587-1589.
Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism Vassili Valayannopoulos, Martine Vaxillaire, Yves Aigrain, Francis Jaubert, Christine Bellanné-Chantelot, Maria-Joao Ribeiro, Francis Brunelle, Philippe Froguel, Jean-Jacques Robert, Michel Polak, Claire Nihoul-Fékété, and Pascale de Lonlay Diabetes Care 2007 30: 1590-1592.
Epidemiology/Health Services/Psychosocial Research:
Relationship Between BMI and Age at Diagnosis of Type 1 Diabetes in a Mediterranean Area in the Period of 1990–2004 Marga Giménez, Eva Aguilera, Conxa Castell, Nuria de Lara, Joana Nicolau, and Ignacio Conget Diabetes Care 2007 30: 1593-1595. Extended Analyses of the Association Between Serum Concentrations of Persistent Organic Pollutants and Diabetes Duk-Hee Lee, In-Kyu Lee, Michael Steffes, and David R. Jacobs, Jr. Diabetes Care 2007 30: 1596-1598. Maintenance of Glucose Control in Patients With Type 1 Diabetes During Acute Mental Stress by Riding High-Speed Rollercoasters Peter Wiesli, Pierre-Alexandre Krayenbühl, Oranna Kerwer, Burkhardt Seifert, and Christoph Schmid Diabetes Care 2007 30: 1599-1601. Depression Among Type 2 Diabetes Rural Appalachian Clinic Attendees Mary de Groot, Todd Doyle, Erin Hockman, Charles Wheeler, Brenda Pinkerman, Jay Shubrook, Robert Gotfried, and Frank Schwartz Diabetes Care 2007 30: 1602-1604.
Emerging Treatments and Technologies:
Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients With Hypertension Kwang Kon Koh, Michael J. Quon, Sang Jin Lee, Seung Hwan Han, Jeong Yeal Ahn, Jeong-a Kim, Wook-Jin Chung, Yonghee Lee, and Eak Kyun Shin Diabetes Care 2007 30: 1605-1607. Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes Tina Vilsbøll, Milan Zdravkovic, Tu Le-Thi, Thure Krarup, Ole Schmitz, Jean- Pierre Courrèges, Robert Verhoeven, Ingrid Bugánová, and Sten Madsbad Diabetes Care 2007 30: 1608-1610.
Pathophysiology/Complications:
Thyroid Autoimmunity at Onset of Type 1 Diabetes as a Predictor of Thyroid Dysfunction Gemma C. González, Ismael Capel, José Rodríguez-Espinosa, Didac Mauricio, Alberto de Leiva, and Antonio Pérez Diabetes Care 2007 30: 1611-1612. Digenic Inheritance of Hepatocyte Nuclear Factor-1 and -1ß With Maturity-Onset Diabetes of the Young, Polycystic Thyroid, and Urogenital Malformations Beate Karges, Carsten Bergmann, Katrina Scholl, Eberhard Heinze, Franz Maximilian Rasche, Klaus Zerres, Klaus-Michael Debatin, Martin Wabitsch, and Wolfram Karges Diabetes Care 2007 30: 1613-1614. Insulin-Like Growth Factor Binding Protein–Related Protein 1 (IGFBP- rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes Abel López-Bermejo, Javad Khosravi, Wifredo Ricart, Antoni Castro, Vivian Hwa, Katherine L. Pratt, Roser Casamitjana, Ron G. Rosenfeld, and José Manuel Fernández-Real Diabetes Care 2007 30: 1615-1617.
Cardiovascular and Metabolic Risk:
Leisure-Time Physical Activity Is Associated With the Metabolic Syndrome in Type 1 Diabetes: Effect of the PPAR Pro12Ala polymorphism: the FinnDiane Study Johan Wadén, Lena M. Thorn, Carol Forsblom, Timo Lakka, Markku Saraheimo, Milla Rosengård-Bärlund, Outi Heikkilä, Maija Wessman, Joni A. Turunen, Maija Parkkonen, Heikki Tikkanen, Per-Henrik Groop on behalf of the FinnDiane Study Group Diabetes Care 2007 30: 1618-1620. Additive Effects of Obesity and TCF7L2 Variants on Risk for Type 2 Diabetes Among Cardiac Patients Qing Ling Duan, Marie-Pierre Dubé, Nancy Frasure-Smith, Amina Barhdadi, François Lesperance, Pierre Théroux, Judith St-Onge, Guy A. Rouleau, and Jeanne M. McCaffery Diabetes Care 2007 30: 1621-1623. Metabolic Syndrome in Hypertensive Patients: Correlation between anthropometric data and laboratory findings Kelminda Bulhões and Leila Araújo Diabetes Care 2007 30: 1624-1626. C-Reactive Protein Is Independently Associated With Glucose but Not With Insulin Resistance in Healthy Men Anne G. Niehoff, Timon W. van Haeften, N. Charlotte Onland-Moret, Clara C. Elbers, Cisca Wijmenga, and Yvonne T. van der Schouw Diabetes Care 2007 30: 1627-1629. Reviews/Commentaries/ADA Statements:
Standards and Review Criteria:
National Standards for Diabetes Self-Management Education Martha M. Funnell, Tammy L. Brown, Belinda P. Childs, Linda B. Haas, Gwen M. Hosey, Brian Jensen, Melinda Maryniuk, Mark Peyrot, John D. Piette, Diane Reader, Linda M. Siminerio, Katie Weinger, and Michael A. Weiss Diabetes Care 2007 30: 1630-1637.
ADA Workgroup Report:
Computer Modeling of Diabetes and Its Complications: A report on the Fourth Mount Hood Challenge Meeting The Mount Hood 4 Modeling Group Diabetes Care 2007 30: 1638-1646.
Consensus Statements:
Waist Circumference and Cardiometabolic Risk: A Consensus Statement from Shaping America's Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; the American Society for Nutrition; and the American Diabetes Association Samuel Klein, David B. Allison, Steven B. Heymsfield, David E. Kelley, Rudolph L. Leibel, Cathy Nonas, and Richard Kahn Diabetes Care 2007 30: 1647-1652. Use of Insulin Pump Therapy in the Pediatric Age-Group: Consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes Moshe Phillip, Tadej Battelino, Henry Rodriguez, Thomas Danne, Francine Kaufman for the Consensus forum participants Diabetes Care 2007 30: 1653-1662.
Perspectives on the News:
Nonalcoholic Fatty Liver Disease and Insulin Resistance in Youth Zachary T. Bloomgarden Diabetes Care 2007 30: 1663-1669.
Editorials:
Thiazolidinedione Therapy Gets Complicated: Is bone loss the price of improved insulin resistance? Ann V. Schwartz and Deborah E. Sellmeyer Diabetes Care 2007 30: 1670-1671. Point: Recent Long-Term Clinical Studies Support an Enhanced Role for Thiazolidinediones in the Management of Type 2 Diabetes Steven E. Kahn and Bernard Zinman Diabetes Care 2007 30: 1672-1676. Counterpoint: A Diabetes Outcome Progression Trial (ADOPT): Good for Sulfonylureas? Ebaa Al-Ozairi, Latika Sibal, and Philip Home Diabetes Care 2007 30: 1677-1680. Errata:
Errata
Diabetes Care 2007 30: 1683. Errata
Diabetes Care 2007 30: 1684. Online Letters: Observations:
Pioglitazone Rapidly Increases Serum Adiponectin Levels in Men With Normal Glucose Tolerance Yukio Ikeda, Hiroshi Takata, Kosuke Inoue, Masayuki Shinahara, Shojiro Inada, Hiroshi Maruyama, Fumiaki Osaki, Tadashi Suehiro, and Kozo Hashimoto Diabetes Care 2007 30: e48. Online Letters: Comments and Responses:
Cortisol Secretion in Patients With Type 2 Diabetes: Relationship With Chronic Complications: Response to Chiodini et al. Jorge I. Castillo-Quan and Julia M. Pérez-Osorio Diabetes Care 2007 30: e49. Cortisol Secretion in Patients With Type 2 Diabetes: Relationship With Chronic Complications: Response to Castillo-Quan and Pérez-Osorio Iacopo Chiodini, Guido Adda, Paolo Beck-Peccoz, Emanuela Orsi, Bruno Ambrosi, and Maura Arosio Diabetes Care 2007 30: e50. Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women: Response to Juutilainen et al. Giovanni Targher, Lorenzo Bertolini, Giacomo Zoppini, Giuseppe Lippi, and Luciano Zenari Diabetes Care 2007 30: e51. Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women: Response to Targher et al. Auni Juutilainen, Seppo Lehto, Tapani Rönnemaa, Kalevi Pyörälä, and Markku Laakso Diabetes Care 2007 30: e52. IGF-Binding Protein-1 Levels Are Related to Insulin-Mediated Glucose Disposal and Are a Potential Serum Marker of Insulin Resistance: Response to Maddux et al. Timon W. van Haeften, Maria L. Zonderland, Louise W.E. Sabelis, and Jaap van Doorn Diabetes Care 2007 30: e53. IGF-Binding Protein-1 Levels Are Related to Insulin-Mediated Glucose Disposal and Are a Potential Serum Marker of Insulin Resistance: Response to van Haeften et al. Betty A. Maddux, Adeline Chan, Elena A. De Filippis, Lawrence J. Mandarino, and Ira D. Goldfine Diabetes Care 2007 30: e54. Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients: Response to Targher et al. and Hu et al. Manisha Talim Diabetes Care 2007 30: e55. Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients: Response to Talim Gang Hu, Pekka Jousilahti, and Jaakko Tuomilehto Diabetes Care 2007 30: e56. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A Scientific Statement From the American Heart Association and the American Diabetes Association: Response to Buse et al. Antonio Nicolucci, Giorgia De Berardis, Michele Sacco, and Gianni Tognoni Diabetes Care 2007 30: e57. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A Scientific Statement From the American Heart Association and the American Diabetes Association: Response to Nicolucci et al. John B. Buse, Michael P. Pignone for the ADA/AHA Primary Prevention Consensus Panel Diabetes Care 2007 30: e58.
Bench to Clinic Symposia EDITORIAL REVIEW
Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes Preclinical biology and mechanisms of action
DANIEL J. DRUCKER, MD does not appear to be essential for enzy- matic activity or binding of ADA. The cat- alytic region encompasses amino acids ipeptidyl peptidase (DPP)-4 is a demonstrate that GIP and GLP-1 recep- 511–766 and is also present in a soluble complex enzyme that exists as a tor–dependent pathways represent the form of DPP-4 (sDPP-4), which is com- D membrane-anchored cell surface dominant mechanisms transducing the prised of the majority of the extracellular peptidase that transmits intracellular sig- glucoregulatory actions of DPP-4 inhibi- DPP-4 protein (amino acids 39–766) (3). nals via a short intracellular tail and as a tors in vivo. The available preclinical data sDPP-4 is capable of exhibiting enzymatic second smaller soluble form present in suggests that highly selective DPP-4 inhi- activity and interacting with the man- the circulation. DPP-4 cleaves a large bition represents an effective and safe nose-6-phosphate/insulin-like growth number of chemokines and peptide hor- strategy for the therapy of type 2 diabetes. factor II receptor (M6P-IGFIIR) on spe- mones in vitro, but comparatively fewer DPP-4 is a widely expressed cell sur- cific cell types (4). The wide tissue distri- peptides have been identified as endoge- face peptidase that exhibits a complex bi- bution of DPP-4 on numerous cell types nous physiological substrates for DPP-4 ology encompassing cell membrane– and in different vascular beds and its pres- in vivo. Both glucose-dependent insuli- associated activation of intracellular ence as a soluble active enzyme in the cir- notropic polypeptide (GIP) and gluca- signal transduction pathways, cell-cell in- culation ensures that DPP-4–mediated gon-like peptide-1 (GLP-1) are endo- teraction, and enzymatic activity exhib- proteolysis is a common event in most genous physiological substrates for ited by both the membrane-anchored and tissue compartments. DPP-4, and chemical inhibition of DPP-4 soluble forms of the enzyme (1). DPP-4, DPP-4 is a member of a complex gene activity, or genetic inactivation of DPP-4 also originally known as the lymphocyte family (Fig. 1), many members of which in rodents, results in increased levels of cell surface marker CD26, or as the aden- also cleave structurally related peptides intact bioactive GIP and GLP-1. Further- osine deaminase (ADA)-binding protein, (5,6). The DPP-4–related enzymes (Fig. more, mice and rats with genetic inactiva- is a 766–amino acid serine protease that 1) include seprase; fibroblast activation ␣ tion or inhibition of DPP-4 exhibit preferentially cleaves peptide hormones protein ; DPP-6, -8, and -9; attractin; ␣ improved glucose tolerance, elevated lev- containing a position two alanine or pro- N-acetylated- –linked acidic dipepti- els of GLP-1 and GIP, and resistance to line. The human gene encoding DPP has dases I, II, and L; quiescent cell proline diet-induced obesity and hyperglycemia. been localized to chromosome 2 locus dipeptidase; thymus-specific serine pro-  Sustained DPP-4 inhibition lowers blood 2q24.3 (2). The majority of the DPP-4 tease; and DPP-4 (7). ADA immunoaf- glucose via stimulation of insulin and in- protein is extracellular, with a hydropho- finity chromatography, which selectively hibition of glucagon secretion and is asso- bic transmembrane sequence (amino ac- binds and sequesters DPP-4, removed the ciated with preservation of -cell mass in ids 7–28) anchoring the protein in the cell majority (95%) of DPP-4–like enzymatic preclinical studies. Although DPP-4 membrane, followed by a very short six– activity present in human plasma, thereby cleaves dozens of regulatory peptides and amino acid intracellular sequence. DPP-4 identifying DPP-4 as the predominant en- chemokines in vitro, studies of mice with is found on the cell surface as a glycosy- zyme responsible for X-Pro or X-Ala genetic inactivation of incretin receptors lated homodimer; however, glycosylation cleavage in human serum (3). The multi- ple members of the DPP-4 family man- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● date a careful assessment of the selectivity From the Department of Medicine, Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, and specificity of any agent used to inhibit Mount Sinai Hospital, University of Toronto, Ontario, Canada. DPP-4 activity (8). Address correspondence and reprint requests to Dr. Daniel J. Drucker, Mount Sinai Hospital, 600 Uni- versity Ave., Toronto, Ontario, Canada M5G 1X5. E-mail: [email protected]. Received for publication 6 February 2007 and accepted in revised form 11 February 2007. DPP-4 AND THE Published ahead of print at http//:care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc07-0228. D.J.D. has served as an advisor or consultant to Amgen Inc., Amylin Pharmaceuticals, Arisaph Pharma- INACTIVATION OF INCRETIN ceuticals Inc., Bayer Inc., Chugai Inc., Conjuchem Inc., Eli Lilly Inc., Glaxo Smith Kline, Glenmark Phar- HORMONES — Circulating levels of maceuticals, Johnson & Johnson, Merck Research Laboratories, Merck Fr., Novartis Pharmaceuticals, NPS DPP-4 activity have been reported to be Pharmaceuticals Inc., Phenomix Inc., Takeda, and Transition Pharmaceuticals Inc. Neither D.J.D. or his higher in some studies of subjects with family members hold stock directly or indirectly in any of these companies. chronic hyperglycemia and type 2 diabe- Abbreviations: ADA, adenosine deaminase; DFS, des-fluoro-sitagliptin; DPP, dipeptidyl peptidase; GHRH, growth hormone–releasing hormone; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, tes (9,10); however, whether circulating glucagon-like peptide-1; IGF, insulin-like growth factor; M6P-IGFIIR, mannose-6-phosphate/insulin-like DPP-4 activity correlates with the levels of growth factor II receptor; NK, natural killer; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase active plasma GLP-1 in individual human activating peptide; PYY, peptide YY; QPP, quiescent cell proline dipeptidase; SDF, stromal cell–derived subjects is not known. The observation factor; sDPP-4, soluble form of DPP-4; VP, valine pyrrolidide. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion that DPP-4 was capable of cleaving the factors for many substances. incretin peptides GIP and GLP-1 in hu- © 2007 by the American Diabetes Association. man serum in vitro, together with the
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1335 DPP-4 inhibition and treating type 2 diabetes
the DPP-4 gene (27). Nevertheless, DPP-4 inhibition is not capable of exerting sig- nificant antidiabetic actions in all preclin- ical models, as acute VP administration increased plasma levels of intact GLP-1 in older db/db mice but VP did not lower blood glucose in 24-week-old severely hyperglycemic (fasting blood glucose 29 mmol/l) db/db mice (28).
DPP-4 INHIBITORS AND -CELL MASS AND SURVIVAL — DPP-4 inhibitors ex- hibit favorable actions on islet and -cell mass, morphology, and survival. Wistar rats treated with streptozotocin and twice-daily P32/98 for 7 weeks exhibited increased body weight, lowered fed blood glucose, and increased levels of plasma insulin (29). Furthermore, P32/98 im- proved glucose tolerance, enhanced glu- cose-stimulated insulin release in perfused pancreas experiments, and in- Figure 1—Family of DPP-4–related proteases and their substrate specificities. For the majority creased pancreatic insulin content. Histo- of enzymes, the biological roles and identity of endogenous substrates remains poorly understood. APP, aminopeptidase P; FAP, fibroblast activation protein; PEP, prolyl endopeptidase. logical analyses demonstrated an increased number of small islets and a greater proportion of -cells within islets demonstration that chemical inhibitors of DPP-4 INHIBITORS LOWER in rats treated with P32/98 (29). DPP-4 prevented the degradation of GIP BLOOD GLUCOSE — Related stud- The DPP-4 inhibitor des-fluoro- and GLP-1, firmly established the impor- ies examined the effects of chemical in- sitagliptin (DFS) significantly reduced tance of DPP-4 as a critical determinant of hibitors of DPP-4 enzymatic activity on ambient and fed blood glucose and A1C incretin inactivation (11). Subsequent the structure and activity of GLP-1 in nor- levels in diabetic ICR mice, in association studies demonstrated reduced cleavage of mal animals and in experimental models with decreased liver weight and reduced intact GLP-1(7-36)amide and GIP(1-42) of diabetes. The nonselective DPP-4 in- levels of hepatic and plasma triglycerides in serum from DPP-4–deficient rats in hibitor valine pyrrolidide (VP) prevented and plasma free fatty acids (30). Further- vitro or following infusion of the peptides the degradation of GLP-1 and GIP in more DFS-treated animals exhibited in- into DPP-4–deficient rats in vivo, provid- anesthetized pigs and potentiated the in- creased -cell mass and a reduction in the ing complementary evidence for the im- cretin-mediated reduction of plasma glu- ␣-cell–to–-cell ratio. A head-to-head portance of DPP-4 in the control of cose and stimulation of insulin secretion comparison of glipizide and DFS for 10 incretin inactivation (12). Moreover, both in response to an intravenous glucose weeks in diabetic mice demonstrated GLP-1(7-36)amide and the NH2-terminal challenge (16,17). Similarly, VP acutely comparatively greater improvement of DPP-4–generated metabolite GLP-1(9- improved oral glucose tolerance in high- glycemia and A1C in DFS-treated mice, 36)amide were identified in plasma from fat–fed pigs, in association with increased and improvements in pancreatic insulin both fasted and fed humans, and inhibi- levels of intact GLP-1 and increased levels content and relative -cell area were ob- tors of DPP-4 prevented the conversion of of plasma insulin following oral glucose served in mice treated with DFS but not in GLP-1(7-36)amide to GLP-1(9-36)amide loading (18). A series of related studies glipizide-treated animals (30). Further- in human plasma in vitro (13). Similarly, then demonstrated that inhibition of more, islets isolated from DFS-treated the majority of circulating immunoreac- DPP-4 activity preserved levels of intact mice exhibited improved insulin secre- tive GIP in human plasma is the NH2- GLP-1 and improved glucose tolerance in tion in response to KCl or glucose and terminally cleaved GIP(3-42) peptide, normal and diabetic rats and mice (19– increased islet insulin content (30). accounting for Ͼ70% of total plasma GIP 26) in association with enhanced glucose- A comparative study of the DPP-4 in- immunoreactivity in the fasting state and stimulated insulin secretion in islets hibitor vildagliptin versus the GLP-1R ag- 58% of total GIP after meal ingestion (14). isolated from DPP-4 inhibitor–treated onist liraglutide was carried out in candy- Furthermore, exogenous administration mice (25). fed rats for 12 weeks (31). Liraglutide of either GIP or GLP-1 via the subcutane- Verification that DPP-4 was the dom- reduced food intake and attenuated ous or intravenous routes was associated inant molecular target for the glucose weight gain; however, there were no ma- with the rapid degradation of both pep- lowering properties of NVP-DPP728 was jor differences in glucose or A1C in the tides within minutes to the DPP-4 metab- illustrated in studies demonstrating that two treatment arms, whereas plasma in- olites GIP(3-42) and GLP-1(9-36)amide, this compound acutely lowered blood sulin levels were significantly higher in respectively. Hence, DPP-4 is a principal glucose following oral glucose challenge rats treated with vildagliptin (31). Both determinant of the circulating t1/2 of in- in wild-type Wistar rats but not in Fischer vildagliptin- and liraglutide-treated rats tact bioactive GIP and GLP-1 (14,15). 344 rats with an inactivating mutation in exhibited a relative normalization of
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Ϫ Ϫ -cell mass compared with vehicle- 4 / mice. DPP-4–deficient rats exhib- clearly implicate a role for DPP-4 in the con- treated candy-fed rats. ited increased pain sensitivity, reduced trol of immune function, inflammatory re- stress-like responses, and decreased sus- sponses, and behavior. However, whether ROLE OF ENDOGENOUS ceptibility to the sedative effects of etha- these phenotypes can be selectively as- DPP-4 nol (39). Furthermore, splenocytes cribed to loss of the catalytic activity of the isolated from DPP-4–deficient rats ex- enzyme or more generalized loss of DPP-4 Studies in rats and mice with hibited decreased natural killer (NK) cell– function independent of the catalytic activ- inactivating DPP-4 mutations mediated tumor lysis using syngeneic ity cannot yet be determined. The biological importance of DPP-4 has MADB106 tumor cells as antigen (35). been examined in rats with a naturally oc- Modest yet detectable abnormalities in curring loss of function mutation in the immune responses and behavior have Ϫ/Ϫ IMPORTANCE OF DPP-4– DPP-4 gene and in mice with targeted ge- also been described in DPP-4 mice, SELECTIVE INHIBITION — Al- netic inactivation of DPP-4. A strain of including changes in stress-associated though experimental results obtained Fischer 344 (F344) rats originally identi- mobility, curiosity, and exploratory be- using nonselective DPP-4 inhibitors im- fied in Japan harbor a Gly633-Arg muta- haviors (40). In separate studies, the rel- ϩ plicated a role for DPP-4 in the control tion in the DPP-4 gene within the active ative number of CD4 T-cells was lower of immune regulation, transplantation site of the enzyme. The mutant DPP-4 and NK cells higher in spleen cells, and ϩ biology, cancer cell growth, and metas- protein is synthesized appropriately, yet it the numbers of circulating CD4 NK T- Ϫ Ϫ tasis (43,44), there is limited data for is not exported out of the endoplasmic cells were reduced in DPP-4 / mice reticulum and is rapidly degraded with- (41). Furthermore, interleukin-4 produc- similar studies using highly selective out being processed to the mature active tion was significantly reduced, and levels DPP-4 inhibitors that have been gener- enzyme (32–34). Subsequent studies of interleukin-10 and interferon-␥ were ated for the treatment of type 2 diabetes. identified heterogeneity in baseline levels increased following stimulation with More recent experiments comparing the Ϫ Ϫ of DPP-4 activity in different inbred rat pokeweed mitogen in splenic DPP-4 / actions of DPP-4–selective versus strains, emphasizing the importance of lymphocytes. Following immunization –nonselective inhibitors suggest that careful characterization of enzymatic ac- with pokeweed mitogen, serum levels of preferential inhibition of DPP-8/9 and tivity in different rodent models (35). total IgG, IgG1, IgG2, and IgE were sig- quiescent cell proline dipeptidase F344 rats exhibit improved glucose toler- nificantly lower, accompanied by lower (QPP) in vivo was associated with a spe- ance and increased levels of plasma levels of plasma cytokines, in serum from cies- and tissue-specific profile of differ- Ϫ Ϫ GLP-1 and insulin following oral glucose DPP-4 / mice (41). Analysis of nocicep- ent toxicities. Inhibition of DPP-8/9 challenge. Furthermore, high-fat feeding tive responses revealed reduced latencies produced alopecia, thrombocytopenia, of F344 rats for 7 weeks was associated to stimuli such as the hot plate or tail splenomegaly, thrombocytopenia, and with reduced weight gain, increased lev- pinch test, in association with increased multiorgan pathology, leading to death els of intact GLP-1, improved glucose tol- plasma levels of substance P. The abnor- in rats and gastrointestinal toxicity in erance, and enhanced insulin sensitivity mal latencies were abolished following dogs. Moreover, similar toxicities were Ϫ Ϫ Ϫ Ϫ as assessed by homeostatic model assess- treatment of DPP-4 / mice with a sub- observed in wild-type and DPP-4 / ment (36). Hence, loss of DPP-4 activity stance P (neurokinin 1) receptor antago- mice treated with DPP-8/9 inhibitors in rats is associated with potentiation of nist, and administration of two different (8). In contrast, inhibition of the related endogenous GLP-1 action and improve- DPP-4 inhibitors reduced latencies in enzyme QPP produced reticulocytope- ment of glucose tolerance. wild-type mice (41). These findings im- nia in rats, whereas selective inhibition Targeted inactivation of the DPP-4 plicate a role for DPP-4 as a critical regu- of DPP-4 was not associated with de- gene in mice also leads to increased lator of substance P–mediated inflam- tectable toxicity in rats or dogs (8). Sim- plasma levels of GIP, GLP-1, and insulin matory responses in vivo. ilarly, inhibition of DPP-8/9, but not and reduced glycemic excursion follow- A role for DPP-4 in the modulation of DPP-4, was associated with reduction of ing oral glucose challenge (37). Consis- the inflammatory response is suggested mitogen-stimulated proliferation of hu- tent with findings in DPP-4–deficient by differences in the severity of experi- Ϫ Ϫ man mononuclear cells in vitro (8). Cu- rats, DPP-4 / mice exhibit resistance to mental arthritis in wild-type vs. DPP- Ϫ Ϫ riously, some but not all DPP-4 diet-induced obesity, reduced fat accu- 4 / mice. Antigen-induced arthritis and inhibitors have been reported to pro- mulation, decreased plasma levels of lep- plasma levels of the proinflammatory che- tin, and reduced food intake but mokine stromal cell–derived factor duce skin lesions in monkey studies. increased energy expenditure on a high- (SDF)-1 were significantly increased in The extent to which these findings re- Ϫ Ϫ Ϫ Ϫ fat diet (38). DPP-4 / mice appear to be DPP-4 / mice, in association with in- flect differential selectivity of specific more insulin sensitive and fail to develop creased numbers of SDF-1 receptor agents for the monkey enzymes and hyperinsulinemia, hepatic steatosis, or is- (CXCR4)-positive cells infiltrating ar- whether the lesions are completely at- let hyperplasia after high-fat feeding. thritic joints. Furthermore, plasma DPP-4 tributable to non–DPP-4–dependent Ϫ Ϫ Moreover, DPP-4 / mice were resistant activity was reduced in wild-type mice mechanisms remains poorly under- to the development of streptozotocin- with antigen-induced arthritis and in hu- stood. Collectively, these findings illus- induced diabetes following a single injec- man subjects with rheumatoid arthritis, and trate that data obtained using tion of streptozotocin (38). the levels of circulating DPP-4 and DPP-4 nonselective DPP inhibitors needs to be The importance of DPP-4 for control activity were inversely correlated with the interpreted with caution in regard to the of immune function and behavior has also severity of rheumatoid arthritis in affected putative role of DPP-4 in the develop- been examined in F344 rats and DPP- subjects (42). Taken together, the data ment of specific organ pathologies.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1337 DPP-4 inhibition and treating type 2 diabetes
Table 1—DPP-4 peptide substrates DPP-4 in vitro to yield glucagon (3–29), and this cleavage is inhibited by the Pharmacological Physiological DPP-4 inhibitor isoleucine thiazolidide (49); however, increased plasma levels of Aprotinin IP-10 GLP-1 intact versus cleaved glucagon have not Bradykinin MDC GLP-2 been reported following administration of -Casomorphin-2 MCP-1 GIP DPP-4 inhibitors in vivo or in rats or mice CG MCP-2 SDF-1␣/ with inactivating mutations of the DPP-4 CLIP MCP-3 Substance P gene. Endomorphin-2 Tyr-melanostatin GLP-2(1-33) is cleaved by DPP-4 at Enterostatin ␣1-microglobulin the position 2 alanine both in vitro and Eotaxin NPY following exogenous administration in GCP-2 PHM vivo, leading to the generation of GLP- GHRH Prolactin 2(3-33) (50,51). Moreover, DPP-4– GRP PYY resistant GLP-2 analogs exhibit much IGF-1 RANTES greater potency than native GLP-2 in vivo IL-2 Trypsinogen (50). Nevertheless, although DPP-4 inhi- Il-1 Tryspinogen pro-peptide Colipase bition increased the plasma levels of intact Peptides cleaved by DPP4 may be pharmacological or physiological substrates. Physiological peptide sub- nutrient-stimulated GLP-2 (1–33) in rats, strates are defined as those peptides whose endogenous levels of intact to cleaved forms are significantly chronic administration of the DPP-4 in- different following genetic inactivation or chemical inhibition of DPP4 activity in vivo. CG, chromogranin; hibitor VP alone had no effect on intesti- CLIP, corticotropin-like intermediate lobe peptide; GCP-2, granulocyte chemotactic protein-2; GRP, gastrin- releasing peptide; IL-1, interleukin-1; IL-2, interleukin-2; IP-10, interferon-␥–inducible protein 10, also nal growth, a key biological readout of known as CXCL10 or chemokine (C-X-C motif) ligand 10; MCP, monocyte chemotactic protein; MDC, enhanced GLP-2 activity in vivo (52). macrophage-derived chemokine; PHM, peptide histidine methionine; RANTES, regulated on activation Growth hormone–releasing hormone normal T-cell expressed and secreted. (GHRH) was one of the first peptides demonstrated to be a substrate for DPP-4 DPP-4 SUBSTRATES AND tions (37). Similarly, the chemokines (53). Circulating levels of GHRH are low REDUCED DPP-4 ENZYME SDF-1␣ and SDF- are cleaved by DPP-4 and difficult to measure in plasma. Nev- ACTIVITY at the NH2-terminus, and plasma levels of ertheless, increased levels of intact bioac- intact SDF-1␣ (1–67) are increased in tive GHRH in the hypothalamic-pituitary Ϫ Ϫ Physiology versus pharmacology DPP-4 / mice (42). Hence, endogenous axis would be predicted to stimulate Numerous endocrine peptides, chemo- levels of intact SDF-1 are clearly depen- growth hormone secretion, leading to in- kines, and neuropeptides contain an ala- dent on DPP-4 activity. creased circulating levels of insulin-like nine or proline at position 2 and are Substance P may also be a physiolog- growth factor (IGF)-1 and somatic Ϫ Ϫ putative DPP-4 substrates (Table 1). An ical substrate for DPP-4. Levels of tissue growth. However, DPP-4 / mice and endogenous physiological DPP-4 sub- DPP-4 are reduced in nasal tissue of hu- F344 mutant rats do not exhibit increased strate is defined as a peptide whose en- man subjects with chronic rhinosinusitis, body size or organ growth. Furthermore, dogenous circulating levels of intact and the vasodilatory effects of substance P treatment of young pigs for 72 h with a versus NH2-terminally cleaved forms are are attenuated by DPP-4 in vivo (45). sitagliptin analog that produced 90% in- altered following reduction or elimina- Conversely, DPP-4 inhibition potentiates hibition of plasma DPP-4 activity was not tion of DPP-4 activity in vivo. For the ma- the vasodilatory effects of exogenous sub- associated with alterations in the circulat- jority of peptides listed in Table 2, it is stance P, findings consistent with reports ing concentrations of IGF-1 (54). Simi- reasonable to assume that they may be of nasopharyngitis in human subjects larly, 10 days of sitagliptin administration pharmacological substrates, as DPP-4 treated with DPP-4 inhibitors (46,47). to healthy nondiabetic male subjects did produces NH2-terminal cleavage of the Moreover, plasma levels of substance P not produce significant elevations in peptide(s) in vitro. In contrast, there is were more than twofold higher in DPP- IGF-1 or IGF binding protein-3 relative to Ϫ Ϫ ϩ ϩ limited evidence that the majority of these 4 / versus DPP-4 / mice (48). Hence, placebo-treated control subjects (55). peptides are physiological substrates. substance P fulfills the criteria for an en- Hence, DPP-4 inhibition may not always Moreover, even small changes in the ra- dogenous substrate of DPP-4. Whether produce predictable changes in down- tios of intact to cleaved peptide for phys- clinically meaningful increases in the lev- stream biological pathways, despite alter- iological DPP-4 substrates may not always els of SDF-1 or substance P occur in hu- ing the relative levels of intact-to-cleaved be sufficient to produce predicted biolog- mans following partial reduction of peptide substrates. ical changes in specific target tissues, as DPP-4 activity with selective DPP-4 in- Neuropeptide Y (NPY) and peptide discussed below. hibitors remains uncertain. YY (PYY) exert opposing actions on con- Both GIP and GLP-1 are physiological Although the majority of peptide hor- trol of food intake, and both peptides are substrates for DPP-4, as DPP-4 inhibition mones listed in Table 1 may be cleaved by cleaved by DPP-4 in vitro, resulting in the is associated with increased circulating DPP-4 in vitro, the endogenous levels of generation of NH2-terminally truncated levels of intact GIP and GLP-1 in vivo intact-to-cleaved peptide may not be sig- peptides with different receptor affinities. Ϫ Ϫ (16,17), and levels of intact GIP and nificantly different in DPP-4 / versus Inhibition of DPP-4 activity prevents the ϩ ϩ GLP-1 are increased, relative to their DPP-4 / mice or rats or following ad- generation of the anorectic PYY(3-36) NH2-terminally cleaved forms in rats and ministration of DPP-4 inhibitors in vivo. from PYY(1-36), and reduced levels of mice with inactivating DPP-4 gene muta- For example, glucagon is cleaved by PYY(3-36) have been detected following
1338 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Drucker
during tissue hypoxia; however, chron- ically elevated levels of adenosine may be deleterious in experimental models of inflammation. Experimental hypoxia induces the cell surface expression of both ADA and DPP-4 on vascular endo- thelial cells, and ADA activity is also in- creased in plasma from hypoxic human subjects (68). However, there does not seem to be a correlation between the ability of ADA to bind DPP-4 and the development of immunodeficiency in human subjects with ADA mutations (69). Hence, the functional importance, if any, of selective DPP-4 inhibition on ADA binding and activity remains obscure.
Figure 2—The principal biological actions of the active incretin hormones GLP-1(7-36)amide BIOLOGICAL IMPORTANCE and GIP(1-42) and the actions of the peptides GLP-1(9-36)amide and GIP(3-42) generated OF GLP-1(9-36)AMIDE following cleavage by DPP-4. AND GIP(3-42) — Intact GLP-1 and GIP are rapidly cleaved by DPP-4 to yield GLP-1(9-36)amide and GIP(3-42) infusion of PYY(1-36) into rats treated mor growth and enhanced metastatic or (Fig. 2), and the levels of NH2- with a DPP-4 inhibitor (56). Although invasive behavior (59–61). The impor- terminally truncated incretins are DPP-4 is clearly important for cleavage of tance of DPP-4 for retention of chemo- greater than the levels of intact GIP and exogenous PYY(1-36), biologically signif- therapy sensitivity and topoisomerase-2 GLP-1 in both the fasting and postpran- icant alterations in the levels of endoge- expression has been mapped, using site- dial states (13,14). Following sustained nous PYY(1-36)-to-PYY(3-36) have not directed mutagenesis, to a region of the inhibition of DPP-4 activity, plasma lev- yet been described in rodents or humans protein essential for its enzymatic activity els of GLP-1(7-36)amide and GIP(1-42) with reductions in DPP-4 activity. DPP-4 (62,63). DPP-4/CD26 is expressed at low are increased (70), whereas levels of cleavage of NPY(1-36) in vitro leads to the levels on resting T-cells; however, DPP-4 GLP-1(9-36)amide and GIP(3-42) are generation of NPY(3-36), which exhibits expression increases following T-cell acti- substantially decreased. Hence, it seems a markedly reduced affinity for the orexi- vation. DPP-4 functions as a T-cell co- reasonable to consider whether differ- genic Y1 receptor but interacts with the stimulatory molecule that enhances ences in the ratios of intact to cleaved Y2/Y5 receptor. Exogenous administra- antigen-specific T-cell proliferation (64), incretin peptides have biological impli- tion of NPY also exert effects on vasomo- and sDPP-4 enhances T-cell transendo- cations. Although GIP(3-42) may be a tor activity, angiogenesis, and vascular thelial migration in vitro, actions that re- weak GIP receptor antagonist in vitro, it remodeling; however, the importance of quire the catalytic activity of the DPP-4 does not exert glucoregulatory actions endogenous basal levels of NPY(1-36) enzyme and a functional M6P-IGFIIR (4). in vivo (71,72). and NPY(3-36) for control of these activ- DPP-4 also regulates migration of hu- There is considerable evidence that ϩ ities remains uncertain. Although admin- man cord blood CD34 progenitor cells GLP-1(9-36)amide has biological actions in istration of NPY produces potent and the homing and engraftment of he- vivo (Fig. 2). GLP-1(9-36)amide modestly anxiolytic and sedative-like effects in matopoetic stem cells. Inhibition of enhances glucose clearance independent of DPP-4–deficient F344 rats (57), there is DPP-4 enzymatic activity promotes hu- changes in insulin secretion in pigs (73), little evidence that endogenous circulat- man hematopoetic stem cell migration whereas studies in mice show no effect of ing or tissue levels of NPY(1-36) versus and bone marrow engraftment via poten- GLP-1(9-36)amide on insulin secretion or NPY(3-36) are significantly altered fol- tiation of the levels of intact CXCL12/ glucose clearance (74). GLP-1(9-36)amide lowing reduction of DPP-4 activity in SDF-1␣, a physiological substrate for had no effect on glucose clearance or insulin vivo. DPP-4 activity (Table 1) (65,66). Further- secretion in healthy human volunteers fol- more, inhibition of DPP-4 activity en- lowing intravenous glucose infusion (75). BIOLOGICAL ACTIVITIES OF hanced homing and engraftment of bone In contrast, acute infusion of GLP-1(9- DPP-4 NOT RELATED TO marrow cells or enriched hematopoetic 36)amide lowered postprandial glucose fol- CONTROL OF GLUCOSE stem cells in the liver of allogeneic fetal lowing meal ingestion independent of HOMEOSTASIS — DPP-4 has been mice following in utero hematopoetic cell changes in levels of insulin or glucagon or implicated in the control of lymphocyte transplantation (67), likely due to poten- gastric emptying in human subjects (76). and immune function, cell migration, vi- tiation of SDF-1␣ interaction with the Although substantial amounts of GLP-1(9- ral entry, cancer metastasis, and inflam- CXCR4 receptor. 36) are generated following meal ingestion, mation (rev. in 1,58). DPP-4 expression The importance of the interaction of GLP-1(9-36)amide does not appear to an- often varies with the state of cellular dif- human DPP-4 with ADA remains in- tagonize the glucose-lowering properties of ferentiation, and loss of DPP-4 expression completely understood. Adenosine ex- GLP-1(7-36)amide in diabetic human has been associated with changes in tu- erts acute anti-inflammatory effects subjects (77). Remarkably, GLP-1(9-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1339 DPP-4 inhibition and treating type 2 diabetes
drinking water for 8 weeks. Although vildagliptin improved insulin secretion and lowered blood glucose in wild-type mice, no effect of vildagliptin on glucose control or insulin secretion was observed in DIRKO mice (83). Hence, the available preclinical data strongly support the es- sential importance of the GIP and GLP-1 receptors as dominant mediators for the antidiabetic actions of DPP-4 inhibitors.
DPP-4 INHIBITORS
Current concepts and major unanswered questions A large number of actions ascribed to in- hibition of DPP-4 activity were originally delineated in experiments using nonse- lective DPP-4 inhibitors. However, many of these inhibitors were subsequently shown to exhibit inhibitory “off target” ac- tions on related proteases in the absence of DPP-4 activity (8,84). Hence, the avail- able literature on the pleiotropic effects of DPP-4 inhibition using first-generation Figure 3—Four different DPP-4 inhibitors (LAF237/vildagliptin, VP, Syrrx106124, and nonselective inhibitors must be inter- TP8211) acutely lower blood glucose and enhance glucose-stimulated insulin secretion in preted with caution, pending analysis of wild-type mice and in mice with targeted disruption of single incretin receptors (Glp1rϪ/Ϫ data from confirmatory experiments car- and GiprϪ/Ϫ). In contrast, none of the DPP-4 inhibitors lowers blood glucose or stimulates ried out using highly selective inhibitors insulin secretion in mice with genetic disruption of both the GIP and GLP-1 receptors (dual of the DPP-4 enzyme. Similarly, although incretin receptor knockout [DIRKO]). Data shown is from experiments using VP; however, intriguing metabolic, behavioral, and im- identical results were obtained with the three other DPP-4 inhibitors, as described in ref. 82. munologic phenotypes have been de- scribed in rodents with inactivating mutations in the DPP-4 gene, F344 rats Ϫ Ϫ 36)amide increased myocardial glucose insulinotropic response to exogenous and DPP-4 / mice exhibit a complete uptake and improved left ventricular PACAP and GRP in mice in vivo (81). loss of DPP-4 activity. In contrast, there is function in dogs with pacing-induced Hence, it is reasonable to postulate that little data on these parameters following dilated cardiomyopathy (78). The one or more of these peptides, together administration of highly selective DPP-4 mechanisms through which GLP-1(9- with GLP-1 and GIP, contribute to the inhibitors that produce a 50–80% reduc- 36)amide mediates its emerging biolog- reduction in glycemia observed following tion in enzymatic activity. Thus, whether ical actions are currently poorly acute or chronic DPP-4 inhibition. biological results obtained with selective understood and the subject of active In contrast, studies in mice with dis- DPP-4 enzyme inhibitors will be identical investigation. ruption of single incretin receptors, or to data obtained in studies of rodents with analysis of mice with combined genetic complete absence, during both develop- DPP-4 INHIBITION AND disruption of both the GIP and GLP-1 re- ment and adult life, of a multifunctional REDUCTION OF BLOOD ceptors (double incretin receptor knock- DPP-4 protein requires more careful in- GLUCOSE out or DIRKO mice), strongly suggest that vestigation. Furthermore, it will be im- GIP and GLP-1 are the principal peptide portant to monitor DPP-4–treated Mechanisms of action substrates responsible for transducing the human subjects carefully for the develop- A considerable number of glucoregula- glucose-lowering actions of DPP-4 inhib- ment of inflammatory conditions, angio- tory peptides, in addition to GLP-1 and itors (Fig. 3). Although DPP-4 inhibitors edema, rhinitis, and urticaria, given the GIP, have been identified as exogenous lower blood glucose and stimulate insulin potential importance of SDF-1 and/or Ϫ Ϫ Ϫ Ϫ substrates susceptible to DPP-4 cleavage secretion in Gipr / or Glp1r / mice substance P as DPP-4 substrates. (Table 1). For example, DPP-4 cleaves va- (37,82), four different DPP-4 inhibitors Equally compelling questions arise soactive intestinal peptide, pituitary ade- failed to reduce blood glucose following from attempts to understand how DPP-4 nylate cyclase activating peptide acute oral glucose challenge in normogly- inhibitors lower blood glucose in diabetic (PACAP), oxyntomodulin, and gastrin- cemic DIRKO mice (82) (Fig. 3). To de- subjects. The major actions of DPP-4 in- releasing peptide (GRP) (79,80), and dif- termine the importance of GIP and GLP-1 hibitors in vivo include suppression of ferential metabolism of exogenously receptor signaling for the chronic glu- glucagon secretion and enhancement of infused PACAP38 was observed in wild- coregulatory actions of DPP-4 inhibitors, insulin secretion, consistent with the Ϫ Ϫ type versus DPP-4 / mice (80). Further- high-fat–fed DIRKO mice were treated known actions of GLP-1 and GIP. Preclin- more, DPP-4 inhibition potentiates the with vildagliptin continuously in the ical data in rodents with loss of incretin
1340 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Drucker receptor signaling support a critical role Naim HY, Alfalah M, Demuth HU, von tidyl peptidase IV inhibition potentiates for the GLP-1 and GIP receptors for trans- Horsten S: Neuropeptide Y (NPY) cleav- the insulinotropic effect of glucagon-like duction of the antidiabetic actions of ing enzymes: Structural and functional peptide 1 in the anesthetized pig. Diabetes DPP-4 inhibitors (82,83). Nevertheless, homologues of dipeptidyl peptidase 4. 47:764–769, 1998 prolonged DPP-4 inhibition in diabetic Peptides 28:257–268, 2007 17. Deacon CF, Danielsen P, Klarskov L, 7. Busek P, Malik R, Sedo A: Dipeptidyl pep- Olesen M, Holst JJ: Dipeptidyl peptidase human subjects may recruit additional as tidase IV activity and/or structure homo- IV inhibition reduces the degradation and yet unidentified mechanisms that pro- logues (DASH) and their substrates in clearance of GIP and potentiates its insu- mote glucose lowering. Moreover, the cancer. Int J Biochem Cell Biol 36:408– linotropic and antihyperglycemic effects long-term consequences of DPP-4 inhibi- 421, 2004 in anesthetized pigs. Diabetes 50:1588– tion on -cell function and the durability 8. Lankas GR, Leiting B, Roy RS, Eiermann 1597, 2001 of glucose lowering achieved with sus- GJ, Beconi MG, Biftu T, Chan CC, Ed- 18. Ahren B, Holst JJ, Martensson H, Balkan tained DPP-4 inhibition require careful mondson S, Feeney WP, He H, Ippolito B: Improved glucose tolerance and insulin clinical assessment. Taken together, it DE, Kim D, Lyons KA, Ok HO, Patel RA, secretion by inhibition of dipeptidyl pep- seems prudent to pursue additional de- Petrov AN, Pryor KA, Qian X, Reigle L, tidase IV in mice. Eur J Pharmacol 404: tailed studies of the biological role(s) of Woods A, Wu JK, Zaller D, Zhang X, Zhu 239–245, 2000 L, Weber AE, Thornberry NA: Dipeptidyl 19. Pauly RP, Demuth HU, Rosche F, DPP-4 and the consequences and safety peptidase IV inhibition for the treatment Schmidt J, White HA, Lynn F, McIntosh of highly selective DPP-4 inhibition in of type 2 diabetes: potential importance of CH, Pederson RA: Improved glucose tol- experimental and clinical models of selectivity over dipeptidyl peptidases 8 erance in rats treated with the dipeptidyl diabetes. and 9. Diabetes 54:2988–2994, 2005 peptidase IV (CD26) inhibitor Ile-thiazo- 9. Mannucci E, Pala L, Ciani S, Bardini G, lidide. Metabolism 48:385–389, 1999 Pezzatini A, Sposato I, Cremasco F, Og- 20. Pederson RA, White HA, Schlenzig D, Acknowledgments— D.J.D. is supported in nibene A, Rotella CM: Hyperglycaemia in- Pauly RP, McIntosh CH, Demuth HU: Im- part by a Canada Research Chair in Regulatory creases dipeptidyl peptidase IV activity in proved glucose tolerance in Zucker fatty Peptides and operating grants from the Cana- diabetes mellitus. Diabetologia 48:1168– rats by oral administration of the dipepti- dian Diabetes Association, the Juvenile Diabe- 1172, 2005 dyl peptidase IV inhibitor isoleucine thia- tes Research Foundation, and the Canadian 10. Ryskjaer J, Deacon CF, Carr RD, Krarup zolidide. Diabetes 47:1253–1258, 1998 Institutes for Health Research. T, Madsbad S, Holst J, Vilsboll T: Plasma 21. Balkan B, Kwasnik L, Miserendino R, I thank Dr. L. Baggio for critical review of dipeptidyl peptidase-IV activity in pa- Holst JJ, Li X: Inhibition of dipeptidyl the manuscript. tients with type-2 diabetes mellitus corre- peptidase IV with NVP-DPP728 increases lates positively with HbAlc levels, but is plasma GLP-1 (7-36 amide) concentra- not acutely affected by food intake. Eur J tions and improves oral glucose tolerance References Endocrinol 155:485–493, 2006 in obese Zucker rats. Diabetologia 42: 1. Lambeir AM, Durinx C, Scharpe S, De 11. 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Ikushima H, Munakata Y, Iwata S, K, Holst JJ: Degradation of endogenous ML: Chronic inhibition of circulating Ohnuma K, Kobayashi S, Dang NH, Mo- and exogenous gastric inhibitory poly- dipeptidyl peptidase IV by FE 999011 de- rimoto C: Soluble CD26/dipeptidyl peptide in healthy and in type 2 diabetic lays the occurrence of diabetes in male peptidase IV enhances transendothelial subjects as revealed using a new assay for Zucker diabetic fatty rats. Diabetes 51: migration via its interaction with man- the intact peptide. J Clin Endocrinol Metab 1461–1469, 2002 nose 6-phosphate/insulin-like growth 85:3575–3581, 2000 25. Kvist M, Reimer MK, Holst JJ, Ahren B: factor II receptor. Cell Immunol 215: 15. Deacon CF, Nauck MA, Toft-Nielsen M, Long-term inhibition of dipeptidyl pepti- 106–110, 2002 Pridal L, Willms B, Holst JJ: Both subcu- dase IV improves glucose tolerance and 5. Gorrell MD: Dipeptidyl peptidase IV and taneously and intravenously adminis- preserves islet function in mice. 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Hartmann B, Thulesen J, Kissow H, Zycband E, Feng Y, Zhu L, Li C, Howard E: Behavioral characterization of CD26 Thulesen S, Orskov C, Ropke C, Poulsen AD, Moller DE, Thornberry NA, Zhang deficient mice in animal tests of anxiety SS, Holst JJ: Dipeptidyl peptidase IV inhi- BB: Chronic inhibition of dipeptidyl pep- and antidepressant-like activity. Behav bition enhances the intestinotrophic ef- tidase-4 with a sitagliptin analog pre- Brain Res 171:279–285, 2006 fect of glucagon-like peptide-2 in rats and serves pancreatic -cell mass and 41. Yan S, Marguet D, Dobers J, Reutter W, mice. Endocrinology 141:4013–4020, function in a rodent model of type 2 dia- Fan H: Deficiency of CD26 results in a 2000 betes. Diabetes 55:1695–1704, 2006 change of cytokine and immunoglobulin 53. Frohman LA, Downs TR, Heimer EP, Fe- 31. Raun K, von Voss P, Gotfredsen CF, Golo- secretion after stimulation by pokeweed lix AM: Dipeptidyl peptidase IV and tryp- zoubova V, Rolin B, Knudsen LB: Lira- mitogen. 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Morimoto C, Schlossman SF: The struc- 1373–1378, 2006 (Gly6333Arg) of dipeptidyl peptidase IV ture and function of CD26 in the T-cell 55. Bergman AJ, Stevens C, Zhou Y, Yi B, La- causes its retention and rapid degradation immune response. Immunol Rev 161:55– ethem M, De Smet M, Snyder K, Hilliard in the endoplasmic reticulum. Biochemistry 70, 1998 D, Tanaka W, Zeng W, Tanen M, Wang 31:11921–11927, 1992 44. Dang NH, Morimoto C: CD26: an ex- AQ, Chen L, Winchell G, Davies MJ, Ra- 33. Erickson RH, Suzuki Y, Sedlmayer A, panding role in immune regulation and mael S, Wagner JA, Herman GA: Pharma- Kim YS: Biosynthesis and degradation cancer. Histol Histopathol 17:1213–1226, cokinetic and pharmacodynamic pro- of altered immature forms of intestinal 2002 perties of multiple oral doses of sitaglip- dipeptidyl peptidase IV in a rat strain 45. Grouzmann E, Monod M, Landis B, Wilk tin, a dipeptidyl peptidase-IV inhibitor: a lacking the enzyme. J Biol Chem 267: S, Brakch N, Nicoucar K, Giger R, Malis double-blind, randomized, placebo-con- 21623–21629, 1992 D, Szalay-Quinodoz I, Cavadas C, Morel trolled study in healthy male volunteers. 34. Thompson NL, Hixson DC, Callanan H, DR, Lacroix JS: Loss of dipeptidylpepti- Clin Ther 28:55–72, 2006 Panzica M, Flanagan D, Faris RA, Hong dase IV activity in chronic rhinosinusitis 56. Unniappan S, McIntosh CH, Demuth HU, WJ, Hartel-Schenk S, Doyle D: A Fischer contributes to the neurogenic inflamma- Heiser U, Wolf R, Kieffer TJ: Effects of rat substrain deficient in dipeptidyl pep- tion induced by substance P in the nasal dipeptidyl peptidase IV on the satiety ac- tidase IV activity makes normal steady- mucosa. FASEB J 16:1132–1134, 2002 tions of peptide YY. Diabetologia 49: state RNA levels and an altered protein: 46. Charbonnel B, Karasik A, Liu J, Wu M, 1915–1923, 2006 use as a liver-cell transplantation model. Meininger G: Efficacy and safety of the 57. Karl T, Hoffmann T, Pabst R, von Horsten Biochem J 273:497–502, 1991 dipeptidyl peptidase-4 inhibitor sitaglip- S: Behavioral effects of neuropeptide Y in 35. Karl T, Chwalisz WT, Wedekind D, tin added to ongoing metformin therapy F344 rat substrains with a reduced dipep- Hedrich HJ, Hoffmann T, Jacobs R, Pabst in patients with type 2 diabetes inade- tidyl-peptidase IV activity. Pharmacol Bio- R, von Horsten S: Localization, transmis- quately controlled with metformin alone. chem Behav 75:869–879, 2003 sion, spontaneous mutations, and varia- Diabetes Care 29:2638–2643, 2006 58. Aytac U, Dang NH: CD26/dipeptidyl pep- tion of function of the Dpp4 (dipeptidyl- 47. Pi-Sunyer FX, Schweizer A, Mills D, tidase IV: a regulator of immune function peptidase IV; CD26) gene in rats. Regul Dejager S: Efficacy and tolerability of and a potential molecular target for ther- Pept 115:81–90, 2003 vildagliptin monotherapy in drug-naive apy. Curr Drug Targets Immune Endocr 36. Yasuda N, Nagakura T, Yamazaki K, In- patients with type 2 diabetes. Diabetes Res Metabol Disord 4:11–18, 2004 oue T, Tanaka I: Improvement of high Clin Pract 76:132–138, 2007 59. Wesley UV, McGroarty M, Homoyouni A: fat-diet-induced insulin resistance in di- 48. Guieu R, Fenouillet E, Devaux C, Fajloun Dipeptidyl peptidase inhibits malignant peptidyl peptidase IV-deficient Fischer Z, Carrega L, Sabatier JM, Sauze N, Mar- phenotype of prostate cancer cells by rats. Life Sci 71:227–238, 2002 guet D: CD26 modulates nociception in blocking basic fibroblast growth factor
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signaling pathway. Cancer Res 65:1325– hausen J, Ibla J, Rosenberger P, Odegard cretion in humans. Am J Physiol Endocrinol 1334, 2005 KC, Laussen PC, Thompson LF, Colgan Metab 290:E1118–E1123, 2006 60. Pro B, Dang NH: CD26/dipeptidyl pepti- SP: Endothelial catabolism of extracellu- 77. Zander M, Madsbad S, Deacon CF, Holst dase IV and its role in cancer. Histol His- lar adenosine during hypoxia: the role of JJ: The metabolite generated by dipepti- topathol 19:1345–1351, 2004 surface adenosine deaminase and CD26. dyl-peptidase 4 metabolism of glucagon- 61. Kajiyama H, Kikkawa F, Khin E, Shibata Blood 108:1602–1610, 2006 like peptide-1 has no influence on plasma K, Ino K, Mizutani S: Dipeptidyl pepti- 69. Richard E, Arredondo-Vega FX, Santiste- glucose levels in patients with type 2 dia- dase IV overexpression induces up-regu- ban I, Kelly SJ, Patel DD, Hershfield MS: betes. Diabetologia 49:369–374, 2006 lation of E-cadherin and tissue inhibitors The binding site of human adenosine 78. Nikolaidis LA, Elahi D, Shen YT, Shannon of matrix metalloproteinases, resulting in deaminase for CD26/dipeptidyl peptidase RP: Active metabolite of GLP-1 mediates decreased invasive potential in ovarian IV: the Arg142Gln mutation impairs myocardial glucose uptake and improves carcinoma cells. Cancer Res 63:2278– binding to cd26 but does not cause im- left ventricular performance in conscious 2283, 2003 mune deficiency. J Exp Med 192:1223– dogs with dilated cardiomyopathy. Am J 62. Aytac U, Claret FX, Ho L, Sato K, 1236, 2000 Physiol Heart Circ Physiol 289:H2401– Ohnuma K, Mills GB, Cabanillas F, Mori- 70. Mari A, Sallas WM, He YL, Watson C, H2408, 2005 moto C, Dang NH: Expression of CD26 Ligueros-Saylan M, Dunning BE, Deacon 79. Lambeir AM, Durinx C, Proost P, Van and its associated dipeptidyl peptidase IV CF, Holst JJ, Foley JE: Vildagliptin, a Damme J, Scharpe S, De Meester I: Kinetic enzyme activity enhances sensitivity to dipeptidyl peptidase-IV inhibitor, im- study of the processing by dipeptidyl- doxorubicin-induced cell cycle arrest at proves model-assessed {beta}-cell func- peptidase IV/CD26 of neuropeptides in- the G(2)/M checkpoint. Cancer Res 61: tion in patients with type 2 diabetes. J Clin volved in pancreatic insulin secretion. 7204–7210, 2001 Endocrinol Metab 90:4888–4994, 2005 FEBS Lett 507:327–330, 2001 63. Yamochi T, Aytac U, Sato T, Sato K, 71. Gault VA, Parker JC, Harriott P, Flatt PR, 80. 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Christopherson KW 2nd, Hangoc G, RL, D’Alessio DA: Effects of GLP-1-(7- classic incretin receptors for GLP-1 and Mantel CR, Broxmeyer HE: Modulation of 36)NH(2), GLP-1-(7-37), and GLP-1- GIP are essential for the sustained glu- hematopoietic stem cell homing and en- (9-36)NH(2) on intravenous glucose coregulatory actions of vildagliptin in graftment by CD26. Science 305:1000– tolerance and glucose-induced insulin mice (Abstract). Diabetologia 49:107, 1003, 2004 secretion in healthy humans. J Clin En- 2006 67. Peranteau WH, Endo M, Adibe OO, Mer- docrinol Metab 88:1772–1779, 2003 84. Jones B, Adams S, Miller GT, Jesson MI, chant A, Zoltick PW, Flake AW: CD26 76. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1343 Bench to Clinic Symposia EDITORIAL REVIEW
Dipeptidyl Peptidase-4 Inhibitors Clinical data and clinical implications
BO AHREN´ , MD, PHD TWO STRATEGIES FOR GLP-1– BASED THERAPY — To harness the antidiabetic action of GLP-1 and at the he enzyme dipeptidyl peptidase-4 tion and stimulates insulin secretion (1). same time overcome the problem of the (DPP-4) prevents the inactivation of GLP-1 also exhibits strong antidiabetic rapid inactivation of the native hor- T glucagon-like peptide-1 (GLP-1). actions, as initially demonstrated already mone, two strategies have been ex- Since GLP-1–based therapy is a promis- in the early 1990s (2–4). Thus, infusion plored. Both these strategies have been ing novel treatment of type 2 diabetes, the of GLP-1 lowers circulating glucose shown to be successful. One approach strategy to inhibit the enzyme has been through a combination of stimulation of is to use GLP-1 receptor agonists explored. Several DPP-4 inhibitors are in insulin secretion and inhibition of gluca- (GLP-1 mimetics), which are not de- clinical development; these are orally ac- gon secretion. A 6-week study with con- graded by DPP-4. A representative of tive and increase levels of active GLP-1, tinuous subcutaneous infusion of GLP-1 this approach is exenatide (Byetta; Lilly) which in turn increases insulin secretion showed reduction in fasting and prandial (8), which is now approved for use in and reduces glucagon secretion and glycemia along with reduction in A1C the treatment of diabetes both in the U.S. and Europe. Liraglutide (Novo thereby lowers glucose levels. Most expe- and improvement both in insulin secre- Nordisk) is another example of this rience exists for sitagliptin (Merck) and tion and insulin action and reduction in strategy. The other approach for GLP- vildagliptin (Novartis), which both have a body weight, which illustrates the po- 1–based therapy is to inhibit the en- long duration of action, allowing once- tency of GLP-1–based therapy (5). daily administration. In drug-naı¨ve sub- zyme activity of DPP-4 (1,9–13). jects with type 2 diabetes, both sitagliptin and vildagliptin reduce A1C levels by DPP-4 INACTIVATION OF ϳ1% as monotherapy, as demonstrated DPP-4 inhibition as a strategy to GLP-1 — It was early understood that treat diabetes in studies up to 52 weeks. Also in combi- GLP-1 is unattractive as chronic therapy nation with metformin and thiazo- The rationale for the strategy of inhibiting of diabetes because the hormone is rap- DPP-4 in the treatment of type 2 diabetes lidinediones, sitagliptin and vildagliptin idly inactivated by the action of the en- improve glycemic control with reduction is to prevent the inactivation of GLP-1 and ϳ zyme DPP-4 (6). This enzyme is widely therefore to enhance and prolong the ac- of A1C of 1%. Both sitagliptin and expressed in several organs and circulates vildagliptin are safe and tolerable with tion of the endogenously released incretin in a soluble form (7). It acts by cleavage of hormone. This strategy was first summa- low risk of hypoglycemia. They are both the two NH -terminal amino acids of bio- body weight neutral. The studies pre- 2 rized by Holst and Deacon (14), who active peptides, provided that the second showed that DPP-4 inhibition increases sented thus far therefore suggest that amino acid is alanine or proline. Since the DPP-4 inhibition is an efficient treatment circulating levels of GLP-1 in experimen- second NH2-terminal amino acid in tal animals and that the insulinotropic ac- of type 2 diabetes, both as monotherapy GLP-1 is alanine, GLP-1 is cleaved to a and combination therapy. Because of its tion of exogenously administered GLP-1 truncated form [sometimes called GLP-1 efficiency, safety, and tolerability in associ- is augmented by DPP-4 inhibition. Later (9-36)amide] (6). This truncated form of ation with the oral mode of administration, studies demonstrated that the prevention GLP-1 is largely inactive; therefore, the it is expected that DPP-4 inhibition will be a of inactivation of GLP-1 by DPP-4 inhibi- cleavage of GLP-1 by DPP-4 is an inacti- first-line treatment of the early stage of type tion markedly increases the active GLP-1 vation process. The cleavage is rapid, 2 diabetes, particularly in combination with in the circulation. For example, as shown metformin or thiazolidinediones. which is the reason why native GLP-1 has in dogs, the active GLP-1 under fasting a short half-life (Ͻ2 min). Therefore, it is conditions accounts for only ϳ10% of to- GLP-1 AS AN necessary to use multiple daily injections tal GLP-1, whereas after DPP-4 inhibition ANTIDIABETIC HORMONE — of continuous subcutaneous infusion of 99% of GLP-1 is in the active form (15). GLP-1 is one of the important incretin GLP-1 for maintenance of glycemic con- The increase in concentrations of active hormones; it is released after meal inges- trol when using the native GLP-1. GLP-1 following administration of DPP-4 inhibitors has subsequently been con- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● firmed in clinical studies (Fig. 1). It has From the Department of Clinical Sciences, Division of Medicine, Lund University, Lund, Sweden. also been demonstrated that DPP-4 inhi- Address correspondence and reprint requests to Dr. Bo Ahre´n, MD, PhD, Lund University, Division of bition increases not only prandial but also Medicine, B11 BMC, SE-221 84 Lund, Sweden. E-mail: [email protected]. Received for publication 4 February 2007 and accepted in revised form 11 February 2007. fasting levels of active GLP-1 (16). In fact, Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc07-0233. DPP-4 inhibition results in an overall in- B.A. has been a consultant for Novartis and Merck. crease in GLP-1 levels with preserved cir- Abbreviations: DPP-4, dipeptidyl peptidase-4; FDA, Food and Drug Administration; GIP, glucose- cadian rhythm throughout the day (Fig. dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 2). Since DPP-4 is also the inactivation factors for many substances. enzyme for the other incretin hormone, © 2007 by the American Diabetes Association. glucose-dependent insulinotropic
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It was found that following a 4-week treatment period, fasting, prandial, and mean glucose levels were reduced by Ͼ1 mmol/l, and even though the study was only 4 weeks in duration, A1C was low- ered by 0.5%. The treatment was also highly tolerable and safe, suggesting the feasibility of this approach for the treat- ment of type 2 diabetes.
Vildagliptin and sitagliptin Following these initial animal studies and the successful proof-of-concept study in humans, several DPP-4 inhibitors have been developed, which are in different stages in clinical development (Table 1). Vildagliptin (LAF237, Galvus; Novartis) and sitagliptin (MK-0431, Januvia; Merck) have been explored in detail (23– 25). They are orally active and rapidly ab- sorbed, and both efficiently inhibit plasma DPP-4 activity—plasma DPP-4 activity is inhibited by almost 100% al- ready at 15–30 min after oral administra- tion, and Ͼ80% inhibition lasts for Ͼ16 h (26). They are therefore both possible to administer once daily; sitagliptin has been approved by the Food and Drug Admin- istration (FDA) (October 2006), whereas vildagliptin has been applied for ap- proval. Both compounds are planned to be used in a dose of 100 mg once daily. Whereas hepatic insufficiency does not seem to alter pharmacokinetics of the Figure 1—Plasma levels of active GLP-1, glucose, insulin, and glucagon before and after intake compounds, renal insufficiency increases of a standardized breakfast (at time 0) after 4 weeks of treatment with vildagliptin (100 mg daily; circulating sitagliptin (28). Therefore, in n ϭ 18) or placebo (n ϭ 19) in subjects with type 2 diabetes (reproduced with permission from the patients with moderate (creatinine clear- Endocrine Society, ref. 26). ance Ͻ50 ml/min) or severe (creatinine clearance Ͻ30 ml/min) renal insuffi- polypeptide (GIP) (5), the concentrations mean A1C 7.4%, and mean fasting glu- ciency, the dose of sitagliptin should be of active GIP are also increased through- cose 9.0 mmol/l) were treated with the reduced to 50 and 25 mg, respectively, out the 24-h period after DPP-4 inhibition DPP-4 inhibitor NVP-DPP728 (Novartis). and the FDA recommends that renal func- (16). This is, however, probably of less importance for the antidiabetic action of DPP-4 inhibition, since GIP seems to have lost much of its insulinotropic action in diabetes and, furthermore, since GIP stimulates rather than inhibits glucagon secretion (17).
Early studies on DPP-4 inhibition The strategy to inhibit DPP-4 as a treat- ment of diabetes was initially verified in animal studies, which demonstrate that genetic deletion of DPP-4 (18) or pharma- cological inhibition of DPP-4 improves glucose tolerance and insulin secretion in a variety of experimental models (12,19– 21). The final proof-of-concept study in Figure 2—Plasma levels of intact GLP-1 during 13.5-h sampling comprising three standardized humans was published in 2002 (22). Pa- meals the day before and after 28 days’ treatment with vildagliptin (100 mg twice daily) in nine tients with drug-naı¨ve type 2 diabetes drug-naı¨ve patients with type 2 diabetes (reproduced with permission from the Endocrine Society, (mean age 65 years, mean BMI 27 kg/m2, ref. 16).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1345 DPP-4 inhibitors
Table 1—DPP-4 inhibitors in various stages of clinical development according to various pared with treatment with metformin at databases in the public domain 1 g twice daily (n ϭ 254) in subjects with type 2 diabetes (33). The subjects were, Stage in again, drug-naı¨ve patients with a mean Name Company development diabetes duration of 2.4 years, and they had a mean baseline A1C of 8.7%. It was Sitagliptin (Januvia) Merck Approved by FDA found that vildagliptin reduced A1C by Vildagliptin (Galvus) Novartis Filed to FDA 1.0%, whereas metformin reduced A1C Alogliptin Takeda Phase III by 1.4%; hence, although noninferiority Saxagliptin Bristol-Myers Squibb Phase III versus metformin was not reached, vilda- PSN-9301 OSI Pharmaceuticals Phase II gliptin also showed a clinically meaning- R1438 Roche Phase II ful reduction of A1C in this study. Again, TA-6666 Tanabe Phase II vildagliptin was safe and tolerable; three PHX1149 Phenomix Phase II patients reported mild hypoglycemic GRC 8200 Glenmark Pharmaceuticals Phase II events in the vildagliptin plus metformin– SYR-619 Takeda Phase I treated group versus one patient in the TS-021 Taisho Pharmaceuticals Phase I metformin-treated group. SSR 162369 Sanofi-Aventis Phase I Sitagliptin. The first study using sita- ALS 2-0426 Alantos Pharmaceuticals Phase I gliptin as monotherapy evaluated the compound in 743 drug-naı¨ve patients with type 2 diabetes using different doses tion is assessed before start of sitagliptin pendency of the action. Another study for a treatment duration of 12 weeks (34). treatment. No drug interactions have showed that during a 24-week period in The patients had a mean baseline A1C of been observed for the DPP-4 inhibitors 354 drug-naı¨ve patients with type 2 dia- 7.7% and were inadequately treated with and other drugs. betes (baseline A1C 8.4%), A1C was re- diet and exercise. Sitagliptin was given at duced by 0.5% by vildagliptin at 50 mg the doses of 5, 12.5, 25, or 50 mg twice Vildagliptin and sitagliptin as once daily, by 0.7% by vildagliptin at 50 daily. It was found that after 12 weeks, all monotherapy mg twice daily, and by 0.9% by vildaglip- groups given sitagliptin had displayed a Vildagliptin. In the first clinical study tin at 100 mg once daily (31). Vildagliptin significant reduction in A1C in relation to with vildagliptin, 100 mg once daily was was well tolerated in all groups. This placebo, with the largest reduction versus administered to 18 drug-naïve patients shows that 100 mg vildagliptin provides placebo (0.77%) at the dose of 50 mg with type 2 diabetes for 4 weeks and the similar clinical benefit when given as sin- twice daily. In one arm of the study, glipi- effects compared with a placebo- gle dose or divided. zide was given at 5 mg daily with elective administered group (n ϭ 19). The pa- In two studies, vildagliptin as mono- titration to 20 mg daily. In this group, tients had a mean baseline glucose of 8.8 therapy has been compared with other ac- A1C was reduced by 1.0%. Hypoglyce- mmol/l and a mean baseline A1C of 7.2% tive treatment modalities. A 24-week mic events were observed in 17% of pa- (26). It was found that vildagliptin re- study compared the effect of vildagliptin tients given glipizide versus Ͻ1% in the duced fasting glucose by ϳ0.7–0.9 (50 mg twice daily; n ϭ 519) with that of sitagliptin groups. Whereas body weight mmol/l and prandial glucose by 1.5 rosiglitazone (8 mg once daily; n ϭ 267) increased in subjects given glipizide (by mmol/l, and A1C also was significantly in subjects with type 2 diabetes (32). The 1.1 kg), no significant change in body reduced (26). A subsequent study in pa- subjects were drug-naı¨ve patients with a weight was observed in subjects given tients with type 2 diabetes with a mean mean baseline A1C level of 8.7% and a sitagliptin. Another study examined the baseline A1C of 7.7% showed that after mean diabetes duration of 2.4 years. Fol- influence of sitagliptin as monotherapy 12-week treatment with vildagliptin at 50 lowing the 24-week treatment, vildaglip- over 12 weeks versus placebo; a total of or 100 mg once daily, A1C had been re- tin reduced A1C by 1.1%. The reduction 552 patients were included. They were all duced by 0.46 and 0.40%, respectively, was seen during the first 5–10 weeks, and drug-naı¨ve patients and had a mean base- compared with the nonsignificant 0.13% then a sustained effect of vildagliptin was line A1C level of 7.7%. Sitagliptin was reduction of A1C in the placebo group evident. The reduction in A1C was not given at 25, 50, or 100 mg once daily or (29). In a third study, vildagliptin was significantly different from the reduction 50 mg twice daily, and it was found that given as monotherapy at 25 mg twice with rosiglitazone, which was 1.3%. the largest reduction in A1C (by 0.6%) daily for 12 weeks (30). It was demon- Vildagliptin was safe and tolerable and was observed by the dose of 100 mg daily strated that both fasting and prandial glu- showed a lower degree of adverse events (35). This was accompanied by a reduc- cose were reduced and that A1C was than rosiglitazone. One mild hypoglyce- tion in fasting glucose by 0.9 mmol/l. Fur- reduced by 0.6% from a mean baseline of mic event was evident in each group, and thermore, an 18-week study comprising 8.0%. These placebo-controlled studies whereas patients given rosiglitazone ex- 521 patients using sitagliptin at 100 or thus showed that vildagliptin efficiently perienced an increase in body weight by 200 mg once daily as monotherapy versus improved glycemic control. Moreover, 1.6 kg, those given vildagliptin had no placebo in patients with an initial A1C vildagliptin was safe and tolerable with significant change in body weight. The in- level of 8.1% showed a reduction in A1C adverse events of the same degree as in the cidence of edema was greater with rosiglit- by 0.60 and 0.48%, respectively (36; Fig. placebo groups. Furthermore, the num- azone (4.1%) than vildagliptin (2.1%). 3). Finally, a 24-week study using sita- ber of hypoglycemic events was very low, Vildagliptin as monotherapy at 50 mg gliptin at 100 or 200 mg daily in drug- which is expected from the glucose de- twice daily (n ϭ 526) is also being com- naı¨ve patients with type 2 diabetes with a
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metformin when compared with the con- trol group given metformin alone; the re- duction in A1C was 0.7% in the group given 50 mg once daily and 1.1% in the group given vildagliptin at 50 mg twice daily. Vildagliptin has also been examined when used in combination with pioglita- zone in a 6-month study involving 592 patients who were assigned to treatment with vildagliptin alone at 100 mg daily, with vildagliptin at 50 or 100 mg in com- bination with pioglitazone at 15 or 30 mg, respectively, or with pioglitazone alone at 30 mg daily (41). Baseline A1C was 8.7%, and a large reduction in A1C (1.9%) was Figure 3—A1C over time in patients with type 2 diabetes given placebo (E), once-daily sitagliptin observed in the group treated with vilda- at 100 mg ( ), and once-daily sitagliptin at 200 mg (f) (reproduced with permission from gliptin at 100 mg in combination with Springer Verlag, ref. 36). pioglitazone at 30 mg daily. Finally, vilda- gliptin has also been added to insulin in subjects with more advanced type 2 dia- mean baseline A1C of 8.0% showed a re- A1C levels by 0.7% compared with met- betes in a 24-week study (42). In this duction by 0.74 and 0.94%, respectively formin alone. Furthermore, during the study, mean duration of diabetes was (37). In conclusion, studies using vilda- following 40 weeks, A1C increased by 14.6 years and patients had been treated gliptin or sitagliptin as monotherapy in 0.066% per month in patients given met- with insulin for a mean duration of 6.3 patients with type 2 diabetes show good formin alone, whereas in subjects given years. The mean daily insulin dose was 82 efficiency to improve the glycemic control vildagliptin in combination with met- units, and mean baseline A1C was 8.9%; with a reduction in A1C of ϳ0.8–1.1% formin the rate of increase in A1C was this was reduced by 0.5% in the group over 12–52 weeks of treatment. As in only 0.013% per month (Fig. 4). This given vildagliptin with insulin versus most studies in type 2 diabetes, subjects suggests the progressive deterioration in 0.2% in the group given insulin alone. with the highest baseline A1C levels have glycemic control seen in patients treated Hypoglycemic events were less common the largest reduction in A1C; therefore, with metformin was prevented by addi- and less severe in the patients given vilda- when directly comparing the degree of re- tion of vildagliptin. A larger study com- gliptin in combination with insulin (33 duction, this must be taken into account. prising altogether 416 patients examined patients, 113 events, 0 severe events) ver- Finally, in monotherapy there is no indi- the addition of vildagliptin at 50 mg once sus in those given insulin alone (45 pa- cation of differences in efficacy between or twice daily to ongoing treatment with tients, 185 events, 6 severe events). younger and older subjects and no rela- metformin (40). The patients had a mean Hence, in combination with insulin, tion to degree of obesity, although results diabetes duration of 6.2 years and a mean vildagliptin reduced A1C more markedly in these subsets of patients are not always baseline A1C of 8.4%. The results show, than insulin alone, and this was associ- clearly reported. again, a reduction in A1C in the groups ated with a reduced risk of hypoglycemia. given vildagliptin in combination with Also, sitagliptin has been evaluated in Vildagliptin and sitagliptin in combination therapy Vildagliptin. Studies have reported the experience of treatment with a DPP-4 in- hibitor in combination with metformin, a thiazolidinedione, or insulin. The first study with vildagliptin in combination therapy was a 52-week trial in which the compound was added at the dose of 50 mg daily to ongoing treatment with met- formin (39). The patients had a mean age of 57 years, a mean diabetes duration of 5.5 years, a mean of 2.3 years of ongoing treatment with metformin (1.5–3.0 g daily), and a mean baseline A1C of 7.8%. The study was designed as an initial core study for 12 weeks (n ϭ 107), which was followed by a 40-week extension period in a subset of patients (n ϭ 71). The re- sults showed that during the initial 12- Figure 4—Time course of A1C over 52 weeks in subjects with type 2 diabetes treated with week study period, vildagliptin in vildagliptin (50 mg once daily) in combination with metformin (n ϭ 42) versus metformin alone combination with metformin reduced (n ϭ 29) (reproduced with permission from ref. 38).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1347 DPP-4 inhibitors combination with metformin. In a 6-month tion of 2 vs. Ϫ0.3 mmHg in the placebo- Mechanism of action of DPP-4 study comprising 701 patients, sitagliptin administered group; the difference being inhibition (100 mg daily) was added to ongoing met- significant) (40). This deserves further DPP-4 inhibition prevents the inactiva- formin (Ͼ1.5 g daily) in subjects with a study. Furthermore, frequency of electro- tion of GLP-1, and this increases GLP-1 mean baseline A1C of 8.0%. A1C was re- cardiogram abnormalities during treatment levels. The increase in GLP-1 levels is seen duced by 0.65% by sitagliptin compared with DPP-4 inhibitors has not been higher throughout 24 h, i.e., both after meal in- with placebo (43). In another large study than in the placebo-administered groups. gestion and in the fasting state (16). The comprising a total of 1,172 patients, the ef- Moreover, in contrast to the reduction in importance of GLP-1 for the action of fect of sitagliptin (100 mg daily) in combi- body weight seen after treatment with DPP-4 inhibitors is evident from animal nation with metformin was compared with GLP-1 analogs, DPP-4 inhibitors are body studies showing that DPP-4 inhibition glipizide (up to 20 mg daily) as add-on to weight neutral. This body weight neutrality does not improve glucose homeostasis in metformin during a study period of 52 distinguishes this class of compound from mice with genetic deletion of GLP-1 and weeks. The included subjects had a mean the increase in body weight, which is asso- GIP receptors (47). GLP-1 in turn stimu- baseline A1C of 7.5%, and it was reported lates insulin secretion, and it has been ciated with treatment with thiazolidinedi- that in both groups A1C was reduced by documented that acute -cell function is ones and sulfonylureas. 0.67% (44). The study reported two impor- improved also by DPP-4 inhibition. This A potential concern during the devel- tant differences between the groups—the has been documented for vildagliptin as number of hypoglycemic events was strik- opment of DPP-4 inhibition as a novel increased insulin response in relation to ingly higher in the group given glipizide therapy has been the potential of DPP-4 to the glucose response after meal ingestion (32%) than in the group given sitagliptin also cleave other bioactive peptides with (26) and increased estimated insulin se- (4.9%), and body weight increased in sub- alanine or proline as the second amino cretory rate after modeling insulin and C- jects given glipizide (by 1.5 kg) but de- acid from the NH2-terminal end (7). Be- peptide data after meal ingestion (16,48). creased in subjects given sitagliptin (by 1.5 cause these other bioactive peptides may Furthermore, sitagliptin has been shown kg). Sitagliptin (100 mg daily, n ϭ 175) has include neuropeptide Y, gastrin-releasing to increase homeostasis model assess- also been examined versus placebo (n ϭ peptide, substance P, and various chemo- ment-B index (a marker for insulin secre- 178) as add-on to pioglitazone at 30 or 45 kines, this phenomenon may potentially tion) and to reduce proinsulin-to-insulin mg daily for 6 months in patients with a cause adverse events related to increased ratio (a marker for -cell function) (36). diabetes duration of 6.1 years and a mean blood pressure, neurogenic inflamma- Animal studies have also shown im- baseline A1C of 8.0% (45). Compared with tion, and immunological reactions. How- proved chronic -cell function, such as placebo, A1C was reduced by 0.7% by sita- ever, no such adverse events have been increased -cell mass, after DPP-4 inhibi- gliptin in combination with pioglitazone. reported in animal studies or in humans tion (12,19,21). However, no such evi- Sitagliptin was well tolerated, and the pro- using DPP-4 inhibition. It should also be dence exists in humans. insulin-to-insulin ratio was reduced in the emphasized that it has not been demon- Another important mechanism for group treated with sitagliptin. strated that DPP-4 indeed affects the me- improved glycemic control by DPP-4 in- The studies presented thus far with tabolism of these other bioactive peptides hibition is inhibition of glucagon secre- vildagliptin and sitagliptin in combina- in humans; studies referred to previously tion, which is an effect by GLP-1 as well. tion therapy therefore show good efficacy are mainly in vitro studies in test tubes. This was initially demonstrated when in combination with both metformin and vildagliptin at 100 mg once or twice daily thiazolidinediones in studies of at least 6 was given for 4 weeks (26), and it has also months’ duration. Mean A1C levels are DPP-4 inhibitors and lipid levels been shown that the entire 24-h glucagon ϳ reduced by 0.6–1%, with the highest The clinical trials with vildagliptin and profile is reduced by vildagliptin (16). reduction in subjects with highest base- sitagliptin have measured fasting levels of Furthermore, a recent study showed that line A1C levels. lipids, and in general no or very little ef- the reduction in glucagon levels in asso- fects have been found on parameters such ciation with increased insulin secretion by Safety and tolerability of DPP-4 as cholesterol and triglycerides. This administration of 100 mg vildagliptin to inhibitors subjects with type 2 diabetes was accom- would suggest that DPP-4 inhibition does Both vildagliptin and sitagliptin are tolera- panied by inhibition of hepatic glucose not affect lipid metabolism. However, a ble and safe with an adverse events profile production, as determined by clamp tech- recent study (46) showed that vildagliptin similar to that of placebo-administered pa- nique using tracer glucose (49). These tients in clinical studies. Also, the reported largely (by 85%) inhibited the triglyceride findings are of great importance consider- numbers of hypoglycemia are very low dur- response to ingestion of a fat-rich meal ing the inappropriately high glucagon se- ing DPP-4 inhibition, which is expected following a 4-week treatment at 50 mg cretion in subjects with type 2 diabetes from the glucose dependency on the effects twice daily in patients with type 2 diabe- (50). of GLP-1. Reports on effects of DPP-4 inhi- tes. This was seen in association with a Besides the improvement of islet bition on blood pressure are few, and when 91% reduction in chylomicron apoli- function, DPP-4 inhibition may also im- reported, no 24-h measurements have been poprotein B-48 and chylomicron choles- prove insulin sensitivity. This has been undertaken. Most studies report no effect terol. Hence, vildagliptin improves found following treatment with vilda- on blood pressure. However, in one 24- plasma lipids and lipoprotein particle me- gliptin using both an indirect measure week study with vildagliptin in combina- tabolism after a fat-rich meal, which of insulin sensitivity (48) and the hyper- tion with metformin, a slight reduction in would be of importance considering the insulinemic-euglycemic clamp test blood pressure was seen in the group given relevance for prandial lipemia as a marker (51). This may be a consequence of the vildagliptin (systolic blood pressure reduc- for cardiovascular diseases. reduced glucagon levels seen after
1348 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ahre´n
DPP-4 inhibition in association with the long-term durability and long-term tin hormones by inhibition of dipeptidyl improved insulin action due to im- safety as well as action in subsets of pa- peptidase IV suppresses meal-induced in- proved metabolic control. tients, such as in the elderly. cretin secretion in dogs. J Endocrinol 172: In contrast to GLP-1, DPP-4 inhibi- 355–362, 2002 tion does not seem to affect gastric emp- 16. Mari A, Sallas WM, He YL, Watson C, References Ligueros-Seylan M, Dunning BE, Deacon tying, as is evident by the lack of effect of CF, Holst JJ, Foley JE: Vildagliptin, a DPP-4 inhibitors on the rate of increase in 1. Drucker DJ, Nauck MA: The incretin sys- tem: glucagon-like peptide-1 receptor dipeptidyl peptidase-IV inhibitor, im- circulating glucose after meal ingestion. agonists and dipeptidyl peptidase-4 in- proves model-assessed beta-cell function Furthermore, vildagliptin did not affect hibitors in type 2 diabetes. 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tes. J Med Chem 48:141–151, 2005 cacy and tolerability of the dipeptidyl 541, 2006 25. Ahre´n B: Vildagliptin: an inhibitor of peptidase-4 inhibitor sitagliptin as mono- 45. Rosenstock J, Brazg RG, Andryuk PJ, Lu dipeptidyl peptidase-4 with antidiabetic therapy over 12 weeks in patients with K, Stein P: Efficacy and safety of the properties. Exp Opin Invest Drugs 15:431– type 2 diabetes. Int J Clin Pract 61:171– dipeptidyl peptidase-4 inhibitor sitaglip- 442, 2006 180, 2007 tin added to ongoing pioglitazone therapy 26. Ahre´n B, Landin-Olsson M, Jansson PA, 35. Hanefeld M, Herman G, Mickel C, in patients with type 2 diabetes: a 24- Svensson M, Holmes D, Schweizer A: In- McGowan A, Wu M: Zhao P, Stein P. Ef- week, multicenter, randomized, double- hibition of dipeptidyl peptidase-4 re- fect of MK-0431, a dipeptidyl peptidase blind, placebo-controlled, parallel-group duces glycemia, sustains insulin levels IV (DPP-IV) inhibitor, on glycemic con- study. 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Ahre´n B, Gomis R, Standl E, Mills D, Ligueros-Saylan M, Wang Y, He YL, Dar- proved glycaemic control with dipeptidyl Schweizer A: Twelve- and 52-week effi- peptidase-4 inhibition in patients with cacy of the dipeptidyl peptidase IV inhib- land C, Holst JJ, Deacon CF, Cusi K, Mari type 2 diabetes: vildagliptin (LAF237) itor LAF237 in metformin-treated A, Foley JE, DeFronzo RA: The dipeptidyl dose response. Diabet Obes Metab 7:692– patients with type 2 diabetes. Diabetes peptidase IV inhibitor vildagliptin sup- 698, 2005 Care 27:2874–2880, 2004 presses endogenous glucose production 30. Pratley RE, Jauffret-Kamel S, Galbreath E, 40. Bosi E, Camisaca RP, Collober C, Roch- and enhances islet function after single Holmes D: Twelve-week monotherapy otte E, Garber AJ: Effects of vildagliptin on dose administration in type 2 diabetic pa- with the DPP-4 inhbitor vildagliptin im- glucose control over 24 weeks in patients tients. J Clin Endocrinol Metab 92:1249– proves glycemic control in subjects with with type 2 diabetes inadequately con- 1255, 2007 type 2 diabetes. Horm Metab Res 387: trolled with metformin. Diabetes Care 30: 50. Dunning BE, Foley JE, Ahre´n B: Alpha cell 423–438, 2006 890–895, 2007 function in health and disease: influence 31. Pi-Sunyer FX, Schweizer A, Mills D, De- 41. Nathwani A: The use of vildagliptin for of glucagon-like peptide-1. Diabetologia jager S: Efficacy and tolerability of vilda- treatment of patients with type 2 diabetes 48:1700–1713, 2005 gliptin monotherapy in drug-naı¨ve (Abstract). Presented at the 66th Scientific 51. Azuma K, Radikova Z, Mancino JM, To- patients with type 2 diabetes. Diabetes Res Sessions of the American Diabetes Associ- ledo FGS, Thomas E, Lubowsky ND, Clin Pract 76:132–138, 2007 ation, Washington, DC, 9–13 June 2006 Kelkley CA, Kangani CO, Serra D, He Y, 32. Rosenstock J, Baron MA, Dejager S, Mills 42. Fonseca V, DeJager S, Albrecht D, Shirt L, Ligueras-Saylan M, Foley JE, Kelley DE: D, Schweizer A: Comparison of vildaglip- Schweizer A: Vildagliptin as add-on to in- DPP-4 inhibition improves insulin resis- tin and rosiglitazone monotherapy in pa- sulin in patients with type 2 diabetes tance (IR) in type 2 DM (Abstract). Pre- tients with type 2 diabetes: a 24-week, (T2D). Diabetes 55 (Suppl 1.):A111, 2006 sented at the 66th Scientific Sessions of double-blind, randomized trial. Diabetes 43. Charbonnel B, Karasik A, Liu J, Wu M, the American Diabetes Association, Care 30:217–223, 2007 Meininger G: Efficacy and safety of the Washington, DC, 9–13 June 2006 (Late- 33. Dejager S, Lebeaut A, Couturier A, dipeptidyl peptidase-4 inhibitor sitaglip- breaking abstract 5-LB) Schweizer A: Sustained reduction in A1C tin added to ongoing metformin therapy 52. Vella A, Bock G, Giesler PD, Burton DB, during one-year treatment with vildaglip- in patients with type 2 diabetes inade- Rizza RA, Camilleri M: The effect of the tin in patients with type 2 diabetes quately controlled with metformin alone. dipeptidyl peptidase IV inhibitor LAF237 (T2DM) (Abstract). Diabetes 55 (Suppl. Diabetes Care 29:2638–2643, 2006 on gastrointestinal function and glucose 1):A29, 2006 44. Jago C: American Diabetes Association metabolism in type 2 diabetes. Diabetolo- 34. Scott R, Wu L, Sanchez M, Stein P: Effi- 66th Scientific Sessions. IDrugs 9:538– gia 49 (Suppl. 1):26–27, 2006
1350 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes
1 3 ROLAND E. SCHMIEDER, MD, FACC JEAN P. FAUVEL, MD hydraulic pressure, podocyte function, 1 4 CHRISTIAN DELLES, MD LUIS M. RUILOPE, MD electric charge, and increased permeabil- 2 ALBERT MIMRAN, MD ity, provoked by endothelial dysfunction (6). Prospective studies have demon- strated the predictive value of endothelial OBJECTIVE — One of the earliest signs of vascular change is endothelial dysfunction, which dysfunction for future cardiovascular is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this morbid events when assessed in the pe- study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial ripheral and coronary circulation (7–9) function. and most likely, although not yet proven, in the renal circulation. RESEARCH DESIGN AND METHODS — In a multicenter, prospective, double-blind, The endothelium is a major regulator forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate Ͼ80 ml/min, and normo- or microalbuminuria were treated once daily with 40/80 of vascular homeostasis, with functional mg telmisartan or 5/10 mg ramipril for 9 weeks. integrity being essential for the mainte- nance of blood flow and antithrombotic RESULTS — The mean Ϯ SE fall in renal plasma flow (RPF) in response to intravenous activity (10). Nitric oxide (NO), formed G N -monomethyl-L-arginine (L-NMMA), reflecting the magnitude of nitric oxide (NO) activity, from L-arginine in the presence of NO increased with telmisartan from 71.9 Ϯ 9.0 ml/min before therapy to 105.2 Ϯ 9.7 ml/min at the synthase, is released by the vascular en- end of treatment (P Ͻ 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 Ϯ dothelial cells and brings about relaxation 12.2 to 87.8 Ϯ 9.2 ml/min (P ϭ 0.018). The adjusted difference between treatments was Ϫ Ϯ ϭ of vascular tissue and inhibition of plate- 17.1 13.7 ml/min (P 0.214). In accordance, telmisartan increased RPF at rest (i.e., let aggregation and adhesion (11). Endo- without L-NMMA) from 652.0 Ϯ 27.0 to 696.1 Ϯ 31.0 ml/min (P ϭ 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater thelial dysfunction occurs as a result of was the vasodilatory effect on renal vasculature (r ϭ 0.47, P Ͻ 0.001). impairment of NO synthesis or increased NO degradation and has been detected in CONCLUSIONS — In patients with type 2 diabetes, telmisartan and ramipril both increased patients with hypertension, peripheral ar- NO activity of the renal endothelium significantly, which in turn may support the preservation terial occlusive disease, and chronic renal of cardiovascular and renal function. failure (12–15). Angiotensin II, which is widely implicated in endothelial dysfunc- Diabetes Care 30:1351–1356, 2007 tion, increases oxidative stress, which causes stimulation of NO breakdown he close link between cardiovascu- outcome, have now been identified as ex- (16). In the long term, endothelial dys- lar and renal changes due to cardio- cellent predictors of cardiovascular mor- function results in atherosclerosis and T vascular risk factors, such as arterial bidity and mortality (2–4). Most subsequent target-organ damage, leading hypertension and diabetes, has stimu- surprisingly, their predictive power sur- to overt cardiovascular disease and lated increasing interest (1–3). Albumin- passes that of classic risk markers of car- chronic kidney disease (9). Studies in the uria and decreased renal function, which diovascular and atherosclerotic disease forearm vasculature of hypertensive pa- are both primarily known to predict renal (5). Albuminuria is related to intrarenal tients have shown that increased blood ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● pressure correlates with decreased NO ac-
1 tivity (13,15,17) and normalization of From the Department of Nephrology and Hypertension, University of Erlangen-Nu¨ rnberg, Erlangen, Ger- blood pressure with increased NO activ- many; the 2Department of Medicine, University of Montpellier, Montpellier, France; the 3Department of Nephrology and Arterial Hypertension, Hoˆpital E. Herriot, Lyon, France; and the 4Hypertension Unit, 12 de ity (18). Octubre Hospital, Madrid, Spain. In view of the pathogenetic role of the Address correspondence and reprint requests to R.E. Schmieder, Clinical Research Center Medizinische imbalance between angiotensin II and Klinik 4, Universita¨tsklinikum Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: NO in target-organ damage, it is a logical [email protected]. Received for publication 27 July 2006 and accepted in revised form 19 February 2007. approach to target the renin-angiotensin Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-1551. system (RAS). ACE inhibitors prevent the Clinical trial reg. no. NCT00240422, clinicaltrials.gov. formation of angiotensin II from angio- R.E.S. has received an honorarium for serving on an advisory board and for and research grants from tensin I, whereas the angiotensin II recep- Boehringer Ingelheim. Abbreviations: ARB, angiotensin II receptor blocker; DBP, diastolic blood pressure; GFR, glomerular tor blockers (ARBs) specifically prevent G filtration rate; L-NMMA, N -monomethyl-L-arginine; MAP, mean arterial pressure; RAS, renin-angiotensin the binding of angiotensin II to type 1 system; RPF, renal plasma flow; SBP, systolic blood pressure. receptors (19). All of the antihypertensive A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion agents used in this study have been shown factors for many substances. to exert target-organ protection (20–22), © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby but their pharmacologic profiles differ marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. substantially. ACE inhibitors lead to accu-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1351 Renal endothelial function mulation of bradykinin, known to im- atenolol were permitted to avoid uncon- GFR by RPF. Renal vascular resistance prove endothelial function, whereas ARBs trolled blood pressure (mean SBP Ն180 was calculated as mean arterial pressure Ն ϫ Ϫ elicit stimulation of the angiotensin II AT2 mmHg and/or DBP 110 mmHg). At the (MAP) (1 hematocrit)/RPF. receptors and modulate peroxisome pro- end of this period, there was double-blind L-NMMA was administered intrave- liferator–activated receptor-␥ receptors. randomization to once-daily telmisartan nously as a bolus infusion (3 mg/kg over 5 The clinical relevance of these additional or ramipril. For the first 3 weeks of the min) followed by constant infusion (2 effects of ACE inhibitors and ARBs is con- double-blind, double-dummy treatment, mg/kg over 40 min). Thus, the total dose troversial. So far, the effects of ACE inhib- the lower dose of the assigned study drug of L-NMMA was 5 mg/kg (29). Then, L- itors and ARBs have been examined (40 mg telmisartan or 5 mg ramipril) was arginine (L-arginine hydrochloride 6%; mainly in the peripheral circulation. Al- administered. For the subsequent 6 University Hospital Pharmacy, Erlangen, though small sample sizes have been weeks, patients received double-blind, Germany) was administered intrave- used, significant improvement of endo- double-dummy treatment with either 80 nously at a dose of 100 mg/kg over 45 min thelial function has been observed for mg telmisartan or 10 mg ramipril. Add-on (30). Blood samples to determine inulin both compounds used in the current trial. therapy was permitted if blood pressure and p-aminohippurate concentrations Ramipril significantly improved renal en- was inadequately controlled (mean SBP were drawn at 0, 120, 165, and 210 min. dothelial function in normotensive, nor- Ն160 mmHg and/or DBP Ն95 mmHg) at During the last 5 min of each infusion moalbuminuric men with type 1 diabetes the end of the forced-titration period. The step, blood pressure was measured twice, (23), and telmisartan increased endothe- overall goal was to reach a target blood and the mean of these measurements was lial function in treatment-naive hyperten- pressure of Ͻ130/80 mmHg. In fact, in used for analysis. sive patients (24). However, to date, there one patient of each group, 12.5 mg hy- Blood samples for the determination have been no studies and no head-to- drochlorothiazide was added. The study of plasma angiotensin II concentrations head comparisons examining the effects was approved by the local ethic commit- were collected from patients in the supine of RAS blockade on renal endothelial tees in each country, and written in- position after1hofcomplete rest. For function in patients with type 2 diabetes formed consent was obtained. plasma angiotensin II measurements, and hypertension, who are known to have blood was collected into prechilled 10-ml a very high risk of cardiovascular and re- Assessment of renal endothelial syringes prepared with 1.25 mmol EDTA nal morbidity (25,26). function and 26 mmol phenanthrolene to inhibit The change in renal plasma flow (RPF) in ACE. Immunoreactive angiotensin II was G RESEARCH DESIGN AND response to N -monomethyl-L-arginine measured by radioimmunoassay as de- METHODS — Adult (age range (L-NMMA) served as a measure of basal scribed in detail previously (31). 30–80 years) patients of either sex with NO activity in the renal circulation (28– type 2 diabetes who either were not tak- 30). The magnitude of the vasoconstric- Statistical analysis ing metformin or had been receiving a sta- tive response to the blockade of NO The primary objective was to determine ble dose for a minimum of 12 weeks synthesis mirrors the vasodilatory effect whether ACE inhibitors or/and ARBs in- before enrollment were eligible for inclu- of NO at baseline in the renal endothe- crease basal NO activity relative to base- sion in the study. Other inclusion criteria lium. Thus, a greater vasoconstrictive re- line after 9 weeks of treatment. The were normoalbuminuria or microalbu- sponse after L-NMMA application sample size was calculated to be n ϭ 50 minuria; glomerular filtration rate (GFR), indicates a greater blockade of NO. The per group. The secondary objective was determined using the Cockcroft-Gault evaluation of the change in this response to compare these two treatment arms formula (27), Ͼ80 ml/min; and arterial between the end of the placebo phase and with respect to their effect on basal NO hypertension (mean seated systolic blood the end of the 9 weeks’ treatment was the activity. The analysis was conducted us- pressure [SBP] 130–179 mmHg and/or primary objective. ing an ANCOVA with pooled center and diastolic blood pressure [DBP] 80–109 Renal hemodynamic parameters were treatment as main effects and RPF in mmHg or receipt of antihypertensive determined by the constant-infusion in- response to L-NMMA at baseline as co- treatment at stable doses) with mean put-clearance technique with inulin (In- variate in the per protocol set. Adjusted seated SBP Ͻ180 mmHg and/or DBP utest; Fresenius, Linz, Austria) and mean Ϯ SE treatment group differences Ͻ110 mmHg. Patients were excluded if sodium p-aminohippurate (Clinalpha, were determined. any of the following applied: A1C Ͼ9%, Basel, Switzerland) for GFR and RPF, re- receipt of thiazolidinediones, and/or ini- spectively, as previously outlined (28). RESULTS tiation of statins in the 4 weeks before Briefly, after bolus infusion of inulin and randomization; proliferative retinopathy; sodium p-aminohippurate over 15 min Baseline characteristics symptomatic cardiovascular disease; sec- and a subsequent constant infusion over A total of 96 patients were randomly as- ondary hypertension; hepatic dysfunc- 105 min, a steady state between input and signed to treatment, of whom 93 completed tion; renal artery stenosis; electrolyte renal excretion of the tracer substances the study. Premature discontinuation was imbalance; and/or previous intolerance of was reached, and the administration of due to an adverse event in one patient, loss ACE inhibitors or ARBs. experimental substances was started in to follow-up after 38 days of treatment in In this prospective, multicenter, par- addition. Systemic hemodynamic param- another, and elevated lipid levels due to allel-group, double-blind, forced- eters (i.e., blood pressure and heart rate) withdrawal of statin therapy after 11 days of titration, randomized study, there was an were monitored in parallel by means of an treatment in a third patient; all these pa- initial 2-week open-label, placebo run-in oscillometric device (Dinamap 1,846 SX; tients were in the ramipril treatment group. period. During this time, hydrochlorothi- Critikon, Norderstedt, Germany). Filtra- Table 1 summarizes the baseline character- azide and, if required, metoprolol or tion fraction was calculated by dividing istics of the per protocol set; there were no
1352 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Schmieder and Associates
Table 1—Baseline characteristics
Telmisartan Ramipril n 45 42 Male (%) 68.1 71.4 Age (years) 59.6 Ϯ 1.3 (37–75) 58.80.0 Ϯ 1.4 (35–74) Weight (kg) 86.8 Ϯ 2.5 91.3 Ϯ 2.7 BMI (kg/m2) 29.4 Ϯ 0.9 30.7 Ϯ 0.9 Smokers (%) 19.1 22.3 Duration of hypertension (years) 10.0 Ϯ 1.3 (0–9.6) 8.9 Ϯ 1.0 (0–8.4) Duration of diabetes (years) 6.8 Ϯ 1.1 (0.2–29) 5.4 Ϯ 0.8 (0.1–30) SBP (mmHg) 148.0 Ϯ 2.4 150.0 Ϯ 1.9 DBP (mmHg) 85.8 Ϯ 1.3 87.9 Ϯ 1.5 A1C (%) 6.92 Ϯ 0.15 6.62 Ϯ 0.11 Previous ACE inhibitor or ARB use (%) 72.3 63.3 Concomitant therapy (%) ␣-Blockers 10.6 4.1 -Blockers 31.3 36.7 Calcium channel blockers 42.6 28.6 Diuretics 59.6 58.2 Other cardiovascular drugs 25.5 34.2 Oral antiglycemic drugs 74.5 73.6 Fibrates 6.4 2.0 Other drugs 55.3 63.3 Data are means Ϯ SE (range) or %. No significant differences (P Ͼ 0.20) were observed between the two groups. significant differences between the two ramipril Ϫ3.1 Ϯ 11.5% (P ϭ 0.105), re- After adjustment for the decrease in blood treatment groups. After excluding, in total, spectively. No sex-based differences were pressure, the change of RPF from end of nine patients with protocol violations (two present with respect to the primary objec- placebo to end of treatment in response to in the telmisartan group and seven in the tive. No clear relation between a fall in L-NMMA was Ϫ40 Ϯ 11 ml/min for tel- ramipril group, e.g., administration of glita- SBP or glycemic control (A1C) and treat- misartan and – 30 Ϯ 14 ml/min for zone or a statin, which was the case in one ment effects on NO activity was found in ramipril (both P Ͻ 0.01), without any dif- patient each), the per protocol set com- univariate and multivariate analyses (data ference between the two groups. prised 45 patients in the telmisartan treat- not shown). GFR did not change significantly at ment group and 42 patients in the ramipril the end of the 9-week treatment period, treatment group. Secondary efficacy end points and values were similar between the two Before treatment, resting RPF, measured groups (Table 2). As a consequence of the Primary efficacy end point before L-NMMA infusion, was compara- increased RPF, renal vascular resistance At the end of the placebo phase, RPF de- ble in the telmisartan and ramipril groups decreased in the telmisartan group (Table creased in response to L-NMMA by (Table 2). After 9 weeks’ treatment, rest- 71.9 Ϯ 9.0 ml/min in the telmisartan ing RPF measured before L-NMMA infu- group and by 60.1 Ϯ 12.2 ml/min in the sion increased significantly (P ϭ 0.047) ramipril group. After 9 weeks’ active treat- by an adjusted mean of 52.1 Ϯ 25.8 ml/ ment, RPF decreased in response to L- min in the telmisartan group, whereas in NMMA by 105.2 Ϯ 9.7 ml/min in the the ramipril group there was a nonsignif- telmisartan group and by 87.8 Ϯ 9.2 ml/ icant increase (P ϭ 0.221) of 31.0 Ϯ 25.1 min in the ramipril group, without any ml/min, without any significant differ- significant difference between the two ence between the two groups. groups. In the telmisartan group, the ad- MAP before L-NMMA infusion de- justed mean change from end of placebo creased significantly with both telmisar- to end of treatment in response to L- tan and ramipril (telmisartan Ϫ6.02 Ϯ NMMA of Ϫ43.2 Ϯ 10.7 ml/min was sig- 9.3 mmHg and ramipril Ϫ4.75 Ϯ 8.2 nificant (P Ͻ 0.001) (Fig. 1). Similarly, in mmHg, both P Ͻ 0.001 vs. before treat- the ramipril group, the adjusted change of ment). Although numerically greater with Ϫ26.1 Ϯ 10.8 ml/min was significant telmisartan, the difference between the Figure 1—Effects of 40/80 mg telmisartan and (P ϭ 0.018). The difference between the two groups was not significant. Neverthe- Ϯ Ϫ Ϯ 5/10 mg ramipril for 9 weeks on the mean SE two groups of 17.1 13.7 ml/min was less, we analyzed the relation of changes RPF in response to 5 mg/kg L-NMMA infusion not different. The corresponding values in L-NMMA response with changes in compared with pre–L-NMMA infusion values. in percent change were for telmisartan MAP after treatment: No significant cor- , baseline; f, end of treatment. *P ϭ 0.018 Ϫ3.3 Ϯ 9.5% (P ϭ 0.027) and for relation was found (r ϭ 0.13, P ϭ 0.232). vs. baseline; ***P Ͻ 0.001 vs. baseline.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1353 Renal endothelial function
Table 2—Effects of 80 mg telmisartan and 10 mg ramipril on secondary renal end points and MAP
Telmisartan: before Ramipril: after Parameter* treatment treatment P value Before treatment After treatment P value RPF (ml/min) 652 Ϯ 27.0 696 Ϯ 31.0 0.047 631 Ϯ 27.3 658 Ϯ 28.2 0.221 GFR (ml/min) 136.3 Ϯ 3.1 136.4 Ϯ 3.4 0.212 134.3 Ϯ 3.7 133.7 Ϯ 3.8 0.558 Filtration fraction (%) 22.0 Ϯ 0.8 20.6 Ϯ 0.7 0.020 22.2 Ϯ 0.7 21.4 Ϯ 0.7 0.154 MAP (mmHg) 100.0 Ϯ 10.4 93.3 Ϯ 10.8 Ͻ0.001 100.1 Ϯ 9.2 95.4 Ϯ 11.0 0.009 Renal vascular resistance (RU) 96.2 Ϯ 4.2 87.1 Ϯ 4.2 0.010 99.3 Ϯ 4.7 93.7 Ϯ 5.1 0.119 Data are means Ϯ SE. *No significant differences in the changes due to treatment were observed between telmisartan and ramipril. RU, resistance unit.
2). The filtration fraction also decreased Mean serum angiotensin II concen- function have not yet been reported. significantly with telmisartan but remain trations were similar at the end of pla- Thus, this is the first study to analyze the unchanged with ramipril. cebo phase in the telmisartan (3.2 pg/ NO activity in renal circulation in type 2 The increase in resting RPF observed ml) and ramipril (3.4 pg/ml) groups. In diabetes and to compare directly the ef- after 9 weeks’ treatment with telmisartan the telmisartan group, there was a sig- fects of two different classes of agents that was related to improved NO activity (r ϭ nificant increase in angiotensin II con- target the RAS. Endothelial function 0.47, P Ͻ 0.001). This positive relation- centrations to 7.0 pg/ml (P Ͻ 0.001), was determined by the effect of NO ac- ship between change in RPF and NO ac- whereas in the ramipril group the an- tivity on renal perfusion in patients with tivity was found in the whole study giotensin II concentration was halved to type 2 diabetes and hypertension, cohort, as well as in both of the two treat- 1.6 pg/ml after treatment (P Ͻ 0.001). which reflects NO production and re- ment groups, and demonstrates the func- The results confirm the mechanism of lease, as well as the effects of oxidative tional consequences of improved NO action of both drugs and similar angio- stress on NO breakdown. activity. tensin II levels before therapy. The significant increase in RPF in re- The increase in MAP after L-NMMA Adverse events were reported by 12 sponse to L-NMMA at the end of treat- infusion was similar at the end of the pla- patients (25.5%) while receiving telmisar- ment with the ARB telmisartan or the ACE cebo phase and at the end of 9 weeks’ tan and by 12 patients (24.5%) while re- inhibitor ramipril shows that targeting the treatment, as well as between the two ceiving ramipril. The majority of these RAS increases NO activity. Although nu- treatment groups. The adjusted mean dif- events were mild in intensity (nine tel- merically greater with telmisartan, there ferences of MAP response to L-NMMA be- misartan patients and seven ramipril pa- was no statistically significant difference fore versus after therapy were 0.2 Ϯ 1.1 tients). Adverse events considered to be between the effects of telmisartan and mmHg (P ϭ 0.891) for telmisartan and drug related (headache, cough, and two ramipril. Under resting conditions (pre– Ϫ0.2 Ϯ 1.1 mmHg (P ϭ 0.884) for cases of dizziness) were recorded in four L-NMMA infusion), RPF increased signif- ramipril. patients treated with ramipril. There were icantly in the telmisartan group but not in L-Arginine infusion increased the RPF no drug-related adverse events in the the ramipril group, and the greater the at baseline by 6.4 Ϯ 13.7 ml/min com- telmisartan group. improvement of NO activity the greater pared with the pre–L-NMMA infusion was the increase of renal perfusion under value in the telmisartan group, whereas CONCLUSIONS — The impact of resting conditions. This indicates that the the increase was 1.3 Ϯ 13.3 ml/min in the RAS blockers on endothelial function has increase of NO activity after the blockade ramipril group. After 9 weeks’ treatment, been repeatedly examined in hyperten- of the RAS is functionally relevant because there was a significant adjusted mean in- sive patients. With respect to the ACE in- vasodilation became evident in the renal crease in the RPF response to L-arginine in hibitors and ARBs, an improvement in vasculature. Because the effect of L- the telmisartan group of 22.0 Ϯ 22.8 ml/ endothelium-dependent flow-mediated NMMA on systemic MAP did not change min (P ϭ 0.024), whereas the adjusted vasodilation has been observed (32,33). significantly after therapy compared with mean increase of 12.3 Ϯ 23.8 ml/min was The enhancement of endothelial function before therapy with either of the study not significant in the ramipril group (P ϭ has been related to improved cardiovas- drugs and because the decrease of blood 0.075). cular prognosis (34,35). Similarly, a re- pressure after treatment was not related to The adjusted geometric mean albu- duction in albuminuria, which is also the RPF response to L-NMMA, changes in min excretion decreased from 9.0 to 7.2 linked to the integrity of the endothelium, renal perfusion pressure do not appear to mg/24 h at week 9 in the telmisartan results in improved cardiovascular and explain our results. group (P ϭ 0.022) and changed from renal prognosis (36,37). So far, the assess- Our findings in patients with type 2 11.7 to 10.7 mg/24 h in the ramipril ment of endothelial function has been diabetes and hypertension are consistent group (P ϭ 0.961), without any clear dif- mainly carried out in the peripheral cir- with previous observations on the effects ference between the two groups (P ϭ culation (7,13,17,38). However, it is now of enalapril, eprosartan, and valsartan in 0.074). In the subset of patients with al- apparent that the cardiovascular progno- hypertensive patients (30,39). In con- bumin excretion Ͼ10 mg/24 h at the end sis is clearly reflected by renal parameters, trast, opposite effects have been observed of placebo phase, telmisartan and such as GFR, albuminuria, and, poten- with amlodipine in humans, which was ramipril both decreased albumin excre- tially, renal endothelial function (2–4). associated with reduced NO activity in tion significantly to the same extent (tel- Moreover, head-to-head comparisons of the renal vessels (39). Inhibition of NO in misartan, P Յ 0.05; ramipril, P Ͻ 0.05). ARBs and ACE inhibitors on endothelial the kidneys has been found to increase
1354 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Schmieder and Associates glomerular sclerosis, tubular interstitial with a reduction in cardiovascular risk T, Munzel T: Endothelial dysfunction, ox- fibrosis, osteopontin expression, macro- (36,45). idative stress, and risk of cardiovascular phage infiltrations, and proteinuria In summary, targeting the RAS in pa- events in patients with coronary artery (40,41). In accordance with these exper- tients with type 2 diabetes and hyperten- disease. Circulation 104:2673–2678, 2001 sion with ACE inhibitors and ARBs 9. Schachinger V, Britten MB, Zeiher AM: imental data in the kidneys, NO is consid- Prognostic impact of coronary vasodilator ered the ideal antiatherosclerotic substance, showed similar effects on renal endothe- dysfunction on adverse long-term out- and increased NO activity is thought to be lial function, demonstrated by increased come of coronary heart disease. Circula- likely to counteract profibrotic, inflamma- NO activity. tion 101:1899–906, 2000 tory, and proliferative processes in the 10. Brunner H, Cockroft JR, Deanfield J, whole vascular system. Hence, the in- Donald A, Ferrannini E, Halcox J, Kiowski creased NO activity of the endothelium, as Acknowledgments— TRENDY (Telmisartan W, Luscher TF, Mancia G, Natali A, Oliver now documented in type 2 diabetes, might versus Ramipril on Renal Endothelium Func- JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti tion in Type 2 Diabetes) is a stand-alone trial in the long term reduce the development of A, Spieker LE, Takkei S, Webb DJ: Endo- and part of the ongoing PROTECTION (Pro- thelial function and dysfunction. Part II. As- cardiovascular complications. gramme of Research to Show Telmisartan sociation with cardiovascular risk factors Infusion of L-arginine after the inhi- End-Organ Protection) Study Programme (co- and diseases: a statement by the Working bition of NO synthase with L-NMMA re- sponsored by Boehringer Ingelheim, Bayer Group on Endothelins and Endothelial Fac- versed the effects of L-NMMA on RPF. AG, and GlaxoSmithKline). tors of the European Society of Hyperten- The relationship between the L-arginine sion. J Hypertens 23:233–246, 2005 effect and NO release has previously 11. Palmer RM, Ashton DS, Moncada S: Vas- been demonstrated by Schlaich et al. References cular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664– (42). Analysis of the reaction to L- 1. Segura J, Ruilope LM, Zanchetti A: On the arginine showed that, at the end of importance of estimating renal function 666, 1988 12. 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1356 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes
1 1 KLAS EKSTROM¨ , MD CHRISTINE CARLSSON-SKWIRUT, PHD diabetes have GH hypersecretion (10,11) 1 1 JENNY SALEMYR, MD EVA ÖRTQVIST, MD, PHD and markedly subnormal IGF-I levels 1 1,2 INGMAR ZACHRISSON, MD, PHD PETER BANG, MD, PHD, MSCI (12), which further augment their insulin resistance during the period of rapid growth. The relative GH hypersecretion is OBJECTIVE — We sought to test the hypothesis that start of insulin glargine with sustained secondary to decreased negative IGF-I nightly insulin action results in changes in circulating concentrations of IGF-I and IGF binding feedback on pituitary GH secretion (13). proteins (IGFBPs) in adolescents with type 1 diabetes—changes that may support improvement The subnormal IGF-I levels are thought to of A1C. be due to portal insulinopenia and GH receptor (GHR) resistance (14). The start- RESEARCH DESIGN AND METHODS — Twelve pubertal adolescents with type 1 ing of subcutaneous insulin therapy in diabetes and initially on NPH insulin were studied during 12 weeks of intensified treatment with glargine. newly diagnosed type 1 diabetic patients increases IGF-I (15) although direct por- RESULTS — Subnormal IGF-I SD scores on NPH (Ϫ1.8 Ϯ 0.4) rapidly increased and re- tal insulin infusion (16) or intraperitoneal mained 54 Ϯ 9% elevated (P Ͻ 0.001) after 12 weeks on glargine. A1C decreased from 8.3 Ϯ insulin delivery (17) is required to com- 0.6% to a nadir of 6.9 Ϯ 0.3% (P ϭ 0.002) at 6 weeks and correlated with changes in IGF-I (r ϭ pletely restore normal IGF-I concentra- Ϫ0.64, P Ͻ 0.05). The increase in IGF-I did not suppress the mean overnight growth hormone tions. The molecular mechanisms by (GH) secretion at 6 weeks. The mean overnight IGFBP-1 levels decreased (P ϭ 0.035), support- which insulin promotes GH signaling are ing the hypothesis that the nightly hepatic insulin action was increased. Circulating IGF-I not well understood. GH binding protein increased in the absence of changes in both GH secretion and GH receptor numbers (assessed by (GHBP) is the extracellular part of the growth hormone binding protein), indicating that postreceptor mechanisms are involved. IGFBP-3 proteolysis was decreased. GHR that is shredded into the blood- stream after proteolytic degradation. CONCLUSIONS — Increased hepatic insulin action after start of glargine was evident from GHBP may reflect to some extent the he- a decrease in night time IGFBP-1 concentrations. This may improve GH postreceptor signaling, patic GHR number and function. GHBP is resulting in increased circulating IGF-I. We suggest that even in the absence of changes in GH, reduced in pubertal type 1 diabetic pa- increased IGF-I and decreased IGFBP-1 support the improvement of metabolic control. tients (18) and increases during intraperi- toneal insulin delivery (17). Diabetes Care 30:1357–1363, 2007 The functional importance of low IGF-I in type 1 diabetes is suggested by n type 1 diabetes, metabolic control of- fects are not balanced by the insulin-like direct IGF-I effects on glucose metabo- ten deteriorates during puberty. In- effects of IGF-I (5). IGF-I improves insu- lism in type 1 diabetes (8). Adjunctive ad- I creased GH secretion is thought to lin sensitivity directly by stimulating glu- ministration of IGF-I (19) or IGF-I/IGFBP contribute by impairing insulin sensitiv- cose uptake in human muscle ex vivo (IGF binding protein)-3 (13) in type 1 di- ity (1). GH-induced lipolysis, stimulation with the same potency as that of insulin abetic patients decreases insulin require- of hepatic glucose output, and induction (6), and IGF-I administration reduces in- ments and improves insulin sensitivity in of suppressors-of-cytokine-signaling sulin needs in healthy subjects (7). Al- short-term studies. The association of in- (SOCS) expression may be involved (2– though direct IGF-I effects are significant creased IGF-I and improved insulin sen- 4). Even healthy adolescents develop in- (8), IGF-I also reduces GH secretion by sitivity with decreased GH secretion in sulin resistance when GH and IGF-I feedback inhibition and thereby indi- these studies has not been found in longer- increase during the period of rapid longi- rectly increases insulin sensitivity (9). term studies demonstrating improved tudinal growth, suggesting that GH ef- During puberty, patients with type 1 glycemic control (20,21). Direct IGF-I ef- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● fects on glucose metabolism and its neg- ative feedback on GH are modulated by a From the 1Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden; and 2CLINTEC, Karolinska Institute, Stockholm, Sweden. family of six IGFBPs. Circulating IGFBPs Address correspondence and reprint requests to Peter Bang, MD, PhD, Pediatric Endocrinology Unit reduce the glucose-lowering potency of Q2:08, Karolinska Institute, SE-171 76 Stockholm, Sweden. Email: [email protected]. systemically administered IGF-I (22). In- Received for publication 13 November 2006 and accepted in revised form 9 March 2007. sulin deficiency impairs the suppression Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2328. Abbreviations: GH, growth hormone; GHBP, growth hormone binding protein; GHR, growth hormone of hepatic IGFBP-1 production in type 1 receptor; IGFBP, IGF binding protein; IGFBP-3-PA, IGFBP-3 proteolysis; MIT, mealtime insulin therapy; diabetes, and increased IGFBP-1 may at- SOCS, suppressors of cytokine signaling. tribute to attenuation of the insulin-like A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion effects of circulating IGF-I. Hepatic pro- factors for many substances. duction and circulating levels of IGFBP-1 © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby are decreased during hyperinsulinemic marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. clamps in type 1 diabetic patients (23)
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1357 Long-acting insulin effects on the IGF system and even in surgical patients with pe- doses to optimize metabolic control. sured three times during the 24-h study ripheral insulin resistance (24). Thus, Each subject was admitted to our clini- periods (1800, 0600, and 1700 h) at 0 IGFBP-1 is considered to be a marker of cal research unit during 26 h (1600 to and 6 weeks and at 0800 h at 2, 4, 8, and hepatic insulin actions. IGFBP-3 binds 1800 h plus 1 day) before the start of 12 weeks. 95% of circulating IGF-I in a circulating glargine (0 week) and after 6 weeks on GH. GH was analyzed in serum by a ternary complex with an acid labile sub- glargine (Lantus; Sanofi-Aventis). In ad- commercial dissociation-enhanced lan- unit. Proteolysis of IGFBP-3 decreases dition, they were studied in the morn- thanide fluorescence immunoassay from IGF-I affinity and has been shown to ing fasted state after 1, 2, 4, 8, and 12 Perkin Elmer (Turku, Finland) according increase circulating IGF-I activity (25). weeks on glargine. At the first admis- to the manufacturer’s directions. Stan- In adolescent boys with type 1 diabetes, sion, all subjects were on MIT/NPH dards were prepared against World proteolysis of IGFBP-3 is increased, and with NPH insulin twice daily and the Health Organization Reference Prepara- this may partly counteract the effects of rapid-acting insulin analog Lispro or tion 80/505. The intra- and interassay increased IGFBP-1 on circulating IGF-I Aspart at meal- and snack times at 1800, CVs were 3.4 and 5.3%, respectively. GH activity (26). 2100, 0900, 1200, and 1430 h. Bedtime profiles were assessed by a peak detection Intensive insulin treatment is fre- was from 2400 to 0830 h. Following program (Pulsar) from determinations ev- quently based on a basal bolus regimen admission, two peripheral venous cath- ery 30 min. with NPH combined with mealtime insu- eters (antecubital or dorsal hand), as IGFBP-1. The total IGFBP-1 serum lev- lin therapy (MIT) with a rapid-acting in- well as gluteal probes for continuous els were determined by a radioimmuno- sulin analog. It has been shown that the glucose monitoring and microdialysis, assay elsewhere described (34), modified long-acting insulin analog glargine, with were inserted on preanesthetized from ref. 35. The detection limit was 6 sustained delivery of insulin over 24 h (EMLA) locations. Blood samples were g/l, and the intra- and interassay CVs (27), improves A1C (28,29) and reduces drawn at cannulation (1800 h) and then were 5.6 and 11.8%, respectively. the incidence of nocturnal hypoglycemia every 30 min from 2100 to 1700 h the IGFBP-1 was analyzed hourly from 2100 compared with NPH (30). The rather next day. Hormone determinations be- to 1700 h. short duration of the effect of NPH given tween 0000 and 1000 h were defined as IGFBP-3 proteolysis. Serum IGFBP-3 at bedtime contributes to the dawn phe- overnight and the remaining ones as proteolysis (IGFBP-3-PA) was deter- nomenon, with increasing B-glucose lev- daytime. Blood samples were allowed to mined by in vitro degradation of 125I- els in the early morning. It is likely that clot (5°C, 2.0 h), and serum was stored IGFBP-3 as previously described (34). early-morning insulinopenia further con- at Ϫ20°C. All samples were analyzed in Briefly, serum was incubated with 125I- tributes to low IGF-I levels, GH hyperse- the same batch and all samples from labeled glycosylated recombinant human cretion, and insulin resistance. In the each individual within the same assay IGFBP-3 (Upstate, Charlottesville, VA) present study, changes in the GH-IGF- run. for 5 h (37°C). Proteolysis was stopped by IGFBP axis, not previously reported, were The first dose of glargine was given adding SDS sample buffer, and samples assessed in adolescents with type 1 diabe- before dinner immediately after the first were processed overnight (50 V) on 12% tes changing basal insulin from NPH to 24 h of admission. The initial once-daily SDS-PAGE. Gels were dried, exposed to glargine. We report that the increase in glargine dose equaled ϳ80% of the total hyperfilm (Amersham Biosciences, IGF-I and decrease in IGFBP-1 are asso- NPH dose. After 6 weeks on glargine, the Umeå, Sweden), and the optical density of ciated with improvement of A1C, while 24-h blood sampling procedure was re- the bands was quantified using Image J GH secretion is unaffected. peated. At the visits at 1, 2, 4, 8, and 12 (National Institutes of Health). IGFBP- weeks after starting glargine, morning 3-PA was expressed as a percentage of all RESEARCH DESIGN AND fasting samples were obtained and sub- IGFBP-3 fragments relative to the total in- METHODS — We recruited 12 ado- jects were examined and advised to tensity. IGFBP-3-PA was determined ev- lescents, 4 boys and 8 girls, with type 1 change insulin doses to optimize their ery 4 h from 2100 to 1700 h. diabetes from our outpatient clinic. Their metabolic control. GHBP. Serum GHBP was analyzed by mean age was 12.7 years (range 11.1– means of a commercial ELISA (enzyme- 15.0), diabetes duration 3.1 years (1.0– Ethics linked immunoassay) kit (DSL-10- 6.0), BMI 18.6 kg/m2 (15.9–24.7), and All participants and their parents gave 48100; Diagnostic Systems Laboratories) A1C 8.3 Ϯ 0.6% (Mono S standard). They written informed consent. The study was according to the manufacturer’s instruc- were all in puberty, and, according to approved by the local ethics committee of tions. GHBP was determined at 0600 h. Tanner staging (31), the girls were B2–B3 Karolinska Institute, Stockholm, Sweden, A1C. Blood collected on filter paper was and boys G2–G3. The reported total in- No. 2003-006. analyzed for A1C by high-performance Ϫ Ϫ sulin dose was 1.1 IU kg 1 day 1 liquid chromatography (Variant II; Bio- (0.5–2.1). One female patient had a sus- Biochemical methods Rad Laboratories, Hercules, CA). The pected viral infection at the 6-week ad- IGF-I. Serum IGF-I was determined af- normal reference value is Ͻ5.2%. The in- mission and was excluded from ter acid-ethanol extraction in a radio- traassay CV was 2.9%. All values are calculations at that time point. immunoassay using des(1-3)IGF-I as Swedish Mono-S standard (Mono-S ϭ radioligand (32). The intra- and inter- DCCT [Diabetes Control and Complica- Study protocol assay coefficients of variation (CVs) were tions Trial] standard ϫ 1.0678 Ϫ 1.341). Patients underwent a physical examina- 5 and 11%, respectively. tion for Tanner staging ϳ4 weeks before IGF-I SD scores were calculated by Data analysis the start of the study. They were in- adjusting for sex and Tanner stage as pre- Results are expressed as means Ϯ SE if structed to change their current insulin viously described (33). IGF-I was mea- not otherwise stated. Data distribution
1358 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ekstro¨m and Associates was checked for normality and analyzed GH and GHBP by repeated-measures one-way ANOVA The individual GH levels during the ad- with pairwise multiple comparison pro- mission periods at 0 and 6 weeks are cedures (Student-Newman-Keul shown in Fig. 2B. In general, the individ- method), or Student’s paired t test was ual patterns of GH pulses were similar be- used when appropriate, and correla- fore and after glargine. The GH peaks tions were analyzed by linear regression appeared to be equally distributed during (Sigma Stat 2.0; SYSTAT Software, Lon- the day and night, although some patients don, U.K.). P Ͻ 0.05 was considered displayed more normal rhythms with significant. more peaks during the night. There were no significant changes in measures of GH RESULTS secretion (mean, mean overnight, or AUC) or the GH secretory pattern (peak Auxology number, peak height, peak length, or in- During intensified treatment with terpeak interval) after 6 weeks on glargine glargine, body weight increased from (Pulsar analysis, data not shown). The 46.8 Ϯ 2.5 to 48.3 Ϯ 2.5 kg (P ϭ 0.002), mean GHBPs determined at 0 and 6 height from 157.8 Ϯ 2.0 to 158.7 Ϯ 2.0 weeks did not significantly differ (523 Ϯ cm (P ϭ 0.002), and BMI from 18.7 Ϯ 0.8 95 vs. 488 Ϯ 80 pmol/l). to 19.1 Ϯ 0.9 kg/m2 (P ϭ 0.03) in the 11 patients studied at 6 weeks. IGFBP-3-PA Figure 1—IGF-I (A) and A1C (B) on MIT us- The individual IGFBP-3-PA profiles dur- A1C ing basal NPH insulin at baseline (0 weeks) ing the admission periods at 0 and 6 and during 12 weeks on MIT/glargine treat- Intensified treatment with glargine signif- ment in 12 adolescent subjects with type 1 dia- weeks are shown in Fig. 2C. The mean icantly decreased A1C (Mono-S standard) Ͻ Ͻ Ͻ IGFBP-3-PA on glargine was significantly Ϯ Ϯ betes. *P 0.05, **P 0.01, and ***P Ϯ from 8.3 0.6% to a nadir of 6.9 0.3% 0.001. lower than that on NPH (35.2 1.2 vs. at 6 weeks (P Ͻ 0.002, n ϭ 11). The im- 33.3 Ϯ 1.3%, P Ͻ 0.001). Day mean val- provement in A1C was already significant ues were significantly higher than night at 2 weeks (7.5 Ϯ 0.4%, P Ͻ 0.008) and mean values on both NPH and glargine by 54 Ϯ 9% to Ϫ0.55 Ϯ 0.3 (P Ͼ 0.001), was sustained at the end of the 12-week (P ϭ 0.003 and 0.002, respectively). the IGF-I SD score was in the lower nor- study period (7.3 Ϯ 0.3%, P Ͻ 0.008) in mal range in all patients except the one all patients (Fig. 1B). Insulin dosage with a 1.2 score at basal. The mean total insulin dose during the During both admissions, a significant IGF-I first admission was 1.21 Ϯ 0.12 diurnal variation in IGF-I levels was ob- Ϫ Ϫ The mean total IGF-I level increased as IU kg 1 day 1. After 6 weeks, the served, with the lowest values in the early as after 1 week from 231 Ϯ 19 to mean total insulin dose was 1.05 Ϯ 0.11 morning samples. On NPH insulin, IGF-I Ϫ Ϫ 309 Ϯ 17 g/l (P Ͻ 0.001) and was in- IU kg 1 day 1 or 89 Ϯ 6% of the ini- was 249 Ϯ 24 g/l at 1800 h, 231 Ϯ 19 creased by 44 Ϯ 7% at 4 weeks (P Ͻ tially given total dose, although this did g/l at 0600 h, and 248 Ϯ 23 g/l at 0.001) (Fig. 1A). At 6 weeks, on the fast- not reach significance (P ϭ 0.13). Inter- 1700 h (P Ͻ 0.05). After 6 weeks on ing morning, IGF-I was 274 Ϯ 25 g/l estingly, the change in total insulin dose glargine, IGF-I was 307 Ϯ 27, 274 Ϯ 25, (P ϭ 0.022) or 17 Ϯ 9% over the starting and in IGF-I were positively correlated and 286 Ϯ 24 g/l, respectively (P ϭ value. Subsequently, the increase consol- (r ϭ 0.61, P ϭ 0.046). 0.002). idated with a peak value of 347 Ϯ 25 g/l (P Ͻ 0.001) or 54 Ϯ 9% over baseline at CONCLUSIONS — This is the first 12 weeks. A1C at 0 weeks was positively IGFBP-1 study to report that start of intensified correlated with the percentage increase in The individual IGFBP-1 levels during treatment using glargine as basal insulin IGF-I at all time points (r ϭ 0.93, P Ͻ the admission periods at 0 and 6 weeks in adolescents with type 1 diabetes on 0.001 at 6 weeks). The changes in IGF-I are shown in Fig. 2A. In the majority of MIT resulting in improved A1C is associ- mirrored A1C changes as shown in Fig. 1, patients, IGFBP-1 displayed a diurnal ated with markedly increased circulating and the percentage changes in IGF-I and rhythm with higher levels during the IGF-I and decreased nightly IGFBP-1 se- A1C were inversely correlated at 6 weeks night and early morning. On glargine, cretion. Previous studies of newly diag- (r ϭϪ0.64, P ϭ 0.035), at 4 weeks (r ϭ the excursions of IGFBP-1 to higher lev- nosed patients with type 1 diabetes have Ϫ0.64, P ϭ 0.026), and at 8 weeks (r ϭ els in the early morning were sup- demonstrated increased IGF-I levels after Ϫ0.81, P ϭ 0.001). The individual mean pressed. The mean overnight IGFBP-1 the initiation of insulin treatment (15). IGF-I SD score was markedly subnormal concentration decreased significantly However, portal delivery of insulin on NPH at 0 weeks (Ϫ1.8 Ϯ 0.4) with five from 127 Ϯ 21 to 90 Ϯ 12 g/l (P ϭ (16,17) is required to restore normal cir- patients having values below Ϫ2 and only 0.035) but did not reach significance culating IGF-I by improving hepatic GH one patient above 0 (1.2). Individual when evaluated over the total admission sensitivity. The study design of the IGF-I SD scores correlated inversely with periods (P ϭ 0.065). There were no cor- present study does not allow us to sepa- A1C (r ϭϪ0.64, P ϭ 0.025) at 0 weeks. relations between the percentage of rate the effects of the intensified treatment Although 12 weeks of treatment mark- change in IGF-I and IGFBP-1 or in A1C with frequent visits and supervision from edly increased the mean IGF-I SD score and IGFBP-1 from 0 to 6 weeks. a direct role of glargine on improved A1C
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1359 Long-acting insulin effects on the IGF system
Figure 2—Individual IGFBP-1 (A),GH(B), and IGFBP-3 proteolysis (C) profiles during the first admission period on MIT/NPH at 0 weeks (E) and during the second admisson period 6 weeks after start of MIT/glargine (ƒ). and increased IGF-I. Data from adoles- the decrease in the overnight mean production is the major determinant of cent type 1 diabetic patients on insulin IGFBP-1 but not 20-h mean IGFBP-1 af- circulating IGFBP-1 levels. This is also pumps suggest that an intensified treat- ter 6 weeks. This finding suggests that true in subjects with peripheral insulin ment regime improves A1C by reducing glargine, through sustained hepatic deliv- resistance (24), which may be expected in the number of omitted meal doses (36). ery, promotes insulin action during the our patients. At the present time, mea- Therefore, intensified treatment per se night. The use of IGFBP-1 as a marker of surements of the insulin concentration in may be expected to predominantly in- hepatic insulin effects is based on the fact a sample containing several insulin ana- crease daytime insulin action. In favor of a that circulating IGFBP-1 is liver derived logs are not possible. The role of a suffi- specific effect of glargine in our study is and that insulin suppression of IGFBP-1 cient insulin delivery for GH induction of
1360 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ekstro¨m and Associates circulating IGF-I is further emphasized by of GH, particularly in type 1 diabetes. In long-term trials comparing medium long- the positive correlation between the our study, overnight or 20-h GH secre- acting NPH with long-acting insulin ana- change in the total insulin dose and IGF-I, tion did not change despite the marked logs such as glargine and detemir. which suggests that if the insulin dose is increase in IGF-I. Therefore, if IGF-I ac- However, the present study suggests that markedly decreased, an IGF-I increase tually improves A1C in our study, it is it will be important to monitor the GH- cannot be supported. The diurnal rhythm likely to be independent of GH effects on IGF-IGFBP system, which is associated of IGF-I with low levels in the morning is insulin sensitivity. Acute administration with changes in A1C and which may play a new finding in adolescents with type 1 of IGF-I or IGF-I/IGFBP-3 decreases over- a specific role as a marker of future diabe- diabetes and has not been found with night GH secretion and overnight insulin tes complications. It also demonstrates an older IGF-I assay protocols (37). Whether needs (19) (13). IGF-I/IGFBP-3 reduced association between changes in IGF-I and diminished nightly delivery of insulin hepatic glucose output while peripheral the total insulin dose, suggesting that, af- contributes to the decreasing IGF-I levels glucose uptake remained unchanged ter the initial dose titration, one should should be further investigated. Even in (39). In the IGF-I/IGFBP-3 dose-response strive to maintain the total insulin dose. In healthy subjects, the lower insulin secre- study, an IGF-I increase of at least 50% our study of adolescent subjects with tion during overnight fasting may con- was necessary to suppress overnight GH rapid linear growth, minor but significant tribute to their diurnal rhythm (38), and secretion. In our study, IGF-I increased at increases in weight and BMI were ob- the nightly absence of meal insulin in our the most by 50% but only by 17% at 6 served in accord with previous studies patients may explain that depressed weeks when GH was evaluated. In line (44). However, the physiological increase morning IGF-I persists on glargine. The with this finding, the severe IGF-I defi- in BMI in this age-group should also be lack of significant changes in GHBP in our ciency in our patients before glargine considered. study is in contrast with the finding of treatment was only partially normalized. We report that glargine increases cir- increased GHBP in patients on continu- This may explain why GH secretion was culating IGF-I in the absence of changes ous peritoneal insulin delivery (17). not affected in our study or in other long- in insulin dose. This is conceivable with Given the lack of significant changes in er-term studies with adjunctive IGF-I improved hepatic insulin action as dem- the total insulin dose, GH secretion, and treatment of adolescent type 1 diabetic onstrated by increased overnight inhibi- GHBP on glargine, the improved hepatic patients (20,21). Thus, IGF-I feedback in- tion of IGFBP-1 production. The lack of insulin action appears to increase GH sen- hibition of GH secretion may only be sig- significant changes in GH secretion and sitivity and IGF-I generation by post- nificant in individuals with sufficient GHBP suggests that improved GH induc- receptor mechanisms. Whether decreases IGF-I levels. tion of hepatic IGF-I production is due to in cytokines such as interleukin-6 or tu- The direct effects of circulating IGF-I postreceptor mechanisms. Furthermore, mor necrosis factor-␣ via decreased acti- on glucose homeostasis and its ability to our study suggests that IGF-I therapy may vation of SOCS or other hormonal suppress GH secretion are regulated by be needed to fully normalize IGF-I and changes are involved in improved GH high-affinity binding of IGF-I to six prevent adverse effects of GH hypersecre- receptor signaling is currently under IGFBPs. Proteolytic fragmentation of tion on peripheral insulin sensitivity and investigation. IGFBP-3, the major determinant of IGF-I local IGF-I generation. The present study does not allow us turnover in the circulation, is increased in to determine the causal relationship be- midpubertal male patients with type 1 di- tween the increase in circulating IGF-I abetes (26). We hypothesized that Acknowledgments— This work was sup- and the improved A1C. An improvement IGFBP-3-PA was upregulated to increase ported by an unrestricted grant from Sanofi in glycemic control was obtained despite IGF-I bioavailability, and that is further Aventis and grants from the Samariten, Wera the lack of change in insulin dose. It is supported by our present finding of de- Ekstrom, Frimurare Barnhuset, the Swedish possible that the action profile of glargine creased IGFBP-3-PA when total circulat- Society of Medicine, Barnavård, Barndiabetes- fonden, and the Crown Princess Lovisa Society leads to improved nightly glucose ho- ing IGF-I increases on glargine. On the for Medicine. meostasis and, through reduced glucose other hand, the decrease in nighttime IGF-I was provided by Paul Fielder, Genen- toxicity in peripheral tissues, to increased IGFBP-1 secretion on glargine may in- tech Inc., San Francisco, CA. The catching insulin sensitivity and improved A1C. In- crease circulating IGF-I bioavailability in IGF-I monoclonal antibody was a gift from creased hepatic insulin sensitivity may concert with increased total IGF-I. These Novo Nordisk, Denmark. We would like to subsequently result in improved GH gen- changes in IGFBP-3-PA and IGFBP-1 are thank Sten Rosberg, Gothenburg University, eration of IGF-I and increased systemic expected to have opposite effects on the Sweden, for performing the pulsar analysis. IGF-I levels. More likely, increased IGF-I bioavailability of circulating IGF-I. Since levels may depend on a sustained nightly data from our laboratory have questioned hepatic insulin action of glargine, as dem- the validity/relevance of free IGF-I deter- References onstrated by decreased nightly IGFBP-1 minations (40), we decided not to per- 1. Dunger DB, Acerini CL: IGF-I and diabe- secretion, and increased hepatic GH sen- form such determinations. Instead, we tes in adolescence. Diabete Metab 24:101– sitivity. In that case, the improvement in have recently developed a microdialysis 107, 1998 glucose homeostasis and A1C is second- method to probe tissue interstitial free 2. Bajaj M, Suraamornkul S, Romanelli A, ary to increased IGF-I effects on glucose IGF-I concentrations (41). This method Cline GW, Mandarino LJ, Shulman GI, DeFronzo RA: Effect of a sustained re- homeostasis. Exogenous administration should enable future determinations of duction in plasma free fatty acid con- of IGF-I is known to decrease insulin local IGF-I activity in tissues involved in centration on intramuscular long-chain needs in healthy subjects and type 1 dia- diabetes complications (42,43). fatty Acyl-CoAs and insulin action in betic patients (19). However, some of The clinical relevance of the present type 2 diabetic patients. Diabetes 54: these effects are related to a suppression study must await randomized, controlled, 3148–3153, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1361 Long-acting insulin effects on the IGF system
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1363 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Initiate Insulin by Aggressive Titration and Education (INITIATE) A randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups
1 5 HANNELE YKI-J¨ARVINEN, MD, FRCP MELANIE DAVIES, MD espite new guidelines with strict gly- 1,2 6 LEENA JUURINEN, MD SANNI LAHDENPERA¨, MD cemic targets, a recent survey of 3 7 MICHAEL ALVARSSON, MD GIL NIJPELS, MD 3 157,000 type 2 diabetic patients in- ORD YSTEDT MD 8 D T B , MARKKU V¨AHATALO¨ , MD 4 dicated that over two-thirds have A1C con- IAN CALDWELL, MD centrations Ͼ6.5% (1). In the 2005 guidelines by the International Diabetes Federation, insulin therapy is recom- OBJECTIVE — Insulin is often postponed for years because initiation is time-consuming. We mended when A1C exceeds 7.5% despite sought to compare initiation of insulin individually and in groups with respect to change in A1C other therapies (2). This is because large tri- and several other parameters in type 2 diabetic patients. als have shown that it is feasible to achieve an A1C target of 7.0% using insulin combi- RESEARCH DESIGN AND METHODS — A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. nation therapy regimens (3–6). However, Either in groups of 4–8 or individually, using the same personnel and education program, 121 reluctance to initiate insulin is still com- insulin-naive type 2 diabetic patients with an A1C of 7.0–12.0% were randomized to initiate mon, in part because of lack of time and bedtime insulin glargine. The patients visited the treatment center before and at the time of resources. There is thus a need for innova- insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a tive strategies to facilitate the transition to fasting plasma glucose 4.0–5.5 mmol/l. insulin therapy. Simple addition of basal insulin to ex- RESULTS — At 24 weeks, mean Ϯ SE A1C had decreased from 8.7 Ϯ 0.2 to 6.9 Ϯ 0.1% in isting oral agents is an attractive way to start those treated individually and from 8.8 Ϯ 0.2 to 6.8 Ϯ 0.1% in those in groups (not significant Ϯ Ϯ insulin therapy as it involves only one injec- [NS]). Insulin doses averaged 62 5 IU and 56 5 IU at 24 weeks (NS), respectively. The tion of insulin, the dose of which can be frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 Ϯ 0.1 h) was 48% less than in those treated individually adjusted based on measurement of fasting (4.2 Ϯ 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients. plasma glucose (FPG) (4,7–9). In studies where an A1C of ϳ7.0% was achieved, the CONCLUSIONS — Similar glycemic control and treatment satisfaction can be achieved by insulin dose was aggressively titrated by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much daily measurement of FPG and frequent time as individual initiation. self-adjustment of insulin dose (4,6,9). Recent comparison of titration algorithms Diabetes Care 30:1364–1369, 2007 in 4,961 patients with type 2 diabetes showed that a simple subject-administered titration conferred significantly improved glycemic control with a low incidence of severe hypoglycemia compared with phy- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● sician-managed titration (10). From the 1University of Helsinki, Helsinki, Finland, the 2Minerva Institute for Medical Research, Helsinki, Historically, insulin therapy has been Finland, the 3Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, 4 5 started individually in patients with type 2 Stockholm, Sweden; the Swan Lane Medical Centre, Bolton, U.K.; the Leicester Royal Infirmary, Leicester, diabetes. Considering limited resources, the U.K., 6Sanofi-Aventis, Helsinki, Finland; the 7VU University Medical Center, Amsterdam, the Netherlands; and 8Turku Health Center, Turku, Finland. large numbers of patients, and that patients Address correspondence and reprint requests to Hannele Yki-Ja¨rvinen, MD, FRCP, University of Helsinki, with type 2 diabetes by definition “survive P.O. Box 700, Room C426B, FIN-00029 HUCH, Helsinki, Finland. E-mail: [email protected].fi. without insulin,” it would seem worthwhile Received for publication 6 November 2006 and accepted in revised form 13 March 2007. to establish whether insulin can be started Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1357. Clinical trial reg. no. ISRTN09079822, clinicaltrials.gov. in groups. The present study was designed H.Y.-J. has acted as a consultant or speaker for Amylin, Astra-Zeneca, Aventis, Lilly, Merck, MSD, Pfizer, to test in a randomized fashion in poorly and Sanofi-Aventis and has received grant support for investigator-initiated trials from Astra-Zeneca, Aven- controlled insulin-naive patients with type tis, Eli Lilly, Novartis, and Roche. M.D. has acted as a consultant and speaker for Novartis, Novo Nordisk, 2 diabetes whether this is the case. Sanofi-Aventis, and Eli Lilly and has received grants in support of investigator and internal trials from Servier, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis. Abbreviations: ALT, alanine aminotransferase; DTSQ, Diabetes Treatment Satisfaction Questionnaire; RESEARCH DESIGN AND FPG, fasting plasma glucose. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion METHODS factors for many substances. Study design © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby This was a multicenter, open, random- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ized, parallel-group study to compare ini-
1364 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Yki-Ja¨rvinen and Associates tiation of insulin in groups versus age (1ϫ), gender (0.5ϫ), BMI (1.5ϫ), Phone calls at weeks 1, 2, 4, 8, 16, individually in insulin-naive type 2 dia- A1C (1.5ϫ), duration of diabetes (0.5ϫ), and 20 betic patients who were poorly controlled previous oral agents (1ϫ), history of ma- The patients sent FPGs using a modem or on oral hypoglycemic agents. crovascular disease (0.5ϫ), and educa- by mail before calling the study center. The study consisted of a 3- to 14-week tion (1ϫ). During the call, the study nurse reviewed run-in phase and a 24-week treatment glucose measurements received at a Web phase. It was performed in Finland, Swe- site (www.prowellness.com), encouraged den, the U.K., and the Netherlands in accor- Preinitiation visit at ؊2 weeks self-adjustment of insulin dose, and asked dance with the Declaration of Helsinki and (group or individual) for possible adverse events, incidents of good clinical practice (GCP) as described by The group size was four to eight subjects. hypoglycemia, and changes in medication. Note for Guidance CPMP/ICH/135/95. Ap- The same nurse led group and individual proval by institutional ethics committees sessions. After screening visits, education Six-week visit (group or individual) was obtained for each site. All patients pro- was entirely taken care of by the nurse. The patients examined their FPGs, which vided written informed consent before The participants received counseling on had been sent via modem to the treatment study entry. The study design was investi- pathogenesis and treatment (especially center, and discussed self-adjustment of gator-initiated (H.Y.). Sanofi-aventis pro- insulin dose. Body weight and vital signs insulin treatment) of type 2 diabetes. All vided funding and helped in conducting the were recorded, and a blood sample for educational materials for each visit were study according to GCP guidelines (S.L.) measurement of A1C was obtained. Ef- but did not participate in data analysis, in- similar in all centers. The participants fects of insulin therapy on body weight terpretation of the data, or writing the were taught and asked to perform self- and the importance of a healthy lifestyle manuscript. monitoring of FPG every morning and to (diet and exercise) were discussed. Ad- send glucose values to the treatment cen- verse events were recorded. Patients ter using a modem before the next visit. In Male or female patients aged Ն18 years of the U.K., the patients sent glucose values Twelve-week visit (group or age with type 2 diabetes treated with a recorded on a diary card to the study cen- individual) stable dose (any dose) of sulfonylurea and ter by mail. As the 6-week visit. In addition, the im- metformin (Ն1.5 g) or either drug alone portance of A1C measurement and causes for at least 6 months were recruited. Fur- for a variation of insulin requirements in ther inclusion criteria included BMI Ͻ45 Initiation of insulin visit at 0 weeks type 2 diabetes were discussed. kg/m2, A1C between 7.0 and 12%, and (group or individual) willingness and ability to inject insulin, At this visit, participants were taught how Twenty-four–week visit (group or perform self-monitoring of blood glucose, to inject insulin, use the insulin pen (Op- individual, end of study) and share some health information (gly- tiSet; Aventis Pharma, Germany), and As the 6-week visit. In addition, a blood cemic control and body weight) with self-adjust insulin dose. Symptoms and sample for measurement of fasting serum other members. Main exclusion criteria signs of hypoglycemia were discussed. lipids, A1C (central measurement), FPG, were as previously described (9). Treatment satisfaction was assessed by sodium, potassium, creatinine, ALT, and asking the patients to fill in a Diabetes blood counts were obtained. The partici- Screening visit at ؊14 to ؊3 weeks Treatment Satisfaction Questionnaire pants were asked to fill in forms for the (individual) (DTSQ) form (12). The participants were DTSQ, status version, and DTSQ, change Informed consent was obtained, and the told to inject 10 IU s.c. of insulin glargine version (13). inclusion and exclusion criteria were re- (Lantus; Sanofi-Aventis, Germany) daily viewed. After a history and physical ex- at bedtime and to measure FPG every Analytical procedures amination, a fasting blood sample was morning. The patients were asked to in- A1C was measured by high-pressure liq- taken for measurement of A1C (central crease the dose of insulin glargine by 2–4 uid chromatography using the fully auto- measurement), FPG, sodium, potassium, IU when FPG exceeded 5.5 mmol/l for 3 mated Glycosylated Hemoglobin creatinine, alanine aminotransferase Analyzer System (BioRad, CA), traceable consecutive days. The target FPG was (ALT), and blood counts. Body weight to the Diabetes Control and Complica- 4.0–5.5 mmol/l. If FPGs were Ͻ4.0 and height were measured. Other tests in- tions Trial reference method, with a refer- mmol/l and symptomatic hypoglycemia cluded electrocardiogram, urine analysis, ence range of 4.0–6.0%. Lipids, and a pregnancy test. A retinal examina- occurred without an identifiable reason, electrolytes, ALT, blood counts, creati- tion was scheduled if not performed the patients were asked to decrease the nine concentrations, pregnancy tests, and within the last 12 months. Oral antidia- insulin dose by 2 IU/day. Participants urine analyses were performed using betes drugs were continued unchanged. were also asked to record glucose values methods in local laboratories. The importance of dietary and lifestyle and insulin doses daily in a diary to facil- approaches was reinforced. itate self-adjustment. They recorded Statistical analyses After visit 1, eligible patients were symptoms of hypoglycemia and the glu- The primary end point was difference in randomized to either an individual or a cose concentration at the time of hypogly- A1C between the education programs. group education program. Randomiza- cemia in the diary. At this and all The educational programs were defined tion was performed centrally, using the subsequent visits, body weight and blood as equally successful if A1C at the end of minimization of differences method (11). pressure were recorded. A blood sample the study differed by Ͻ0.5%. In a previ- The following variables were included was taken for measurement of serum lip- ous study where insulin regimen con- (relative weight is given in parentheses): ids and A1C. sisted of basal insulin (glargine or NPH)
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1365 Initiation of insulin in groups combined with metformin (9), the A1C at Table 1—Baseline demographics and characteristics of the study groups (intention-to-treat the end of the study averaged 7.19 Ϯ groups) 0.91%. Assuming a common SD of 0.91% Ϫ and a 0.5%, 0.5% equivalence region, Group equivalence between the two education Characteristic Individualized treatment treatment programs can be demonstrated with 53 patients per group at the 0.05 level of sig- Patients (n)6358 nificance and 80% power. The goal was to Sex (male/female) 65/35 59/41 recruit at least 120 patients to allow for Age (years) 58 Ϯ 158Ϯ 1 drop-outs. Weight (kg) 93.8 Ϯ 2.6 90.1 Ϯ 2.8 Secondary objectives included com- BMI (kg/m2) 31.5 Ϯ 0.7 31.2 Ϯ 0.9 parison of the two educational methods Duration of diabetes (years) 8 Ϯ 17Ϯ 1 with respect to the following: 1) time A1C (%) 8.65 Ϯ 0.18 8.79 Ϯ 0.20 spent by a nurse on education, physician’s Complications/other conditions time, and number and duration of phone Hypertension 55 50 calls; 2) change in the concentrations of Macrovascular disease 14 16 serum HDL and LDL cholesterol and se- Microvascular disease 47 55 rum triglycerides; 3) change in body Oral agents before insulin weight and blood pressure; 4) change in Sulfonylurea and metformin 84 79 FPG; 5) insulin dose at study end, 6) Metformin only 10 10 change in subject’s treatment satisfaction; Sulfonylurea only 6 10 and 7) incidence of hypoglycemic epi- Education sodes, as previously defined (9), during Elementary school 41 43 the study. Vocational education 44 48 All statistical analyses were per- Academic 14 9 formed on an intent-to-treat basis, de- Data are means Ϯ SE or percentages unless otherwise indicated. fined as randomized patients who received at least one injection of insulin. Statistical testing was performed at a group formation took too long: n ϭ 1; was 47% by week 12 and 66% by study two-sided significance level of ␣ϭ other: n ϭ 2). A total of 121 patients end in the group treatment arm. The cor- 0.05. The primary end point was evalu- started insulin therapy and comprised responding fractions were 41 and 70% in ated by using an ANCOVA model with the intention-to-treat population. Five the individualized treatment arm (NS be- A1C change from baseline to the end of dropped out from the individual educa- tween arms). the study as a response variable. The tion arm (poor compliance, n ϭ 2; hy- method of education and center were poglycemia, n ϭ 1; protocol violation, Hypoglycemia included as fixed effects, with the base- n ϭ 1; new adverse event, n ϭ 1). No The number of symptomatic hypoglyce- line value of A1C as a covariate in the patients dropped out from the group mia incidents averaged 3.5 and 3.1 epi- ANCOVA model. A similar ANCOVA education arm. The mean group size sodes/patient year in the individual and model was used for LDL and HDL cho- was 5.3 individuals. Of scheduled vis- group treatment arms, respectively (NS). lesterol (log transformed), triglycerides its, 95.6 and 90.3% were attended in The percentage of patients experiencing (log transformed), body weight, blood the individual and the group education symptomatic hypoglycemia was 44 and pressure, and fasting glucose concentra- arms, respectively (NS). Baseline demo- 40%, respectively (NS). Of those experi- tion. The change in a subjects’ treatment graphic and clinical characteristics were encing symptomatic hypoglycemia, 13 satisfaction was compared between the similar between the treatment groups and 10% were nocturnal in the individual groups using Mann-Whitney U test. The (Table 1). and group treatment arms, respectively proportion of patients with hypoglyce- (NS). There were no incidents of severe mic events and the number of events Glycemic control hypoglycemia. The number of fasting hy- were compared using Cochran-Mantel- A1C decreased from 8.65 Ϯ 0.18% at 0 poglycemia incidents, defined as FPG Haenszel test stratified by center. All weeks to 6.89 Ϯ 0.14% at 24 weeks in Ͻ2.5, 3.2, and 4.0 mmol/l, averaged statistical analyses were performed by patients individually treated (P Ͻ 0.001) 0.73, 3.6, and 19.5 episodes/patient-year 4Pharma (Kista, Sweden). and from 8.79 Ϯ 0.20% to 6.81 Ϯ 0.12% in those individually treated and 0.53, in those in the group education arm (P Ͻ 4.4, and 20.1 episodes/patient-year in the RESULTS 0.001), with no difference between the group arm (NS). The percentage of pa- two arms (Fig. 1). tients with FPG Ͻ2.5, 3.2, and 4.0 Patient characteristics FPG averaged 9.0 Ϯ 0.1, 7.1 Ϯ 0.1, mmol/l averaged 13, 33, and 60% in those A total of 128 patients were eligible at and 6.3 Ϯ 0.1 mmol/l in those individu- individually treated and 12, 38, and 66% randomization visit. Seven patients ally treated and 8.7 Ϯ 0.1, 6.9 Ϯ 0.1 and in the group arm (NS) (Fig. 1). dropped out during the recruitment 6.4 Ϯ 0.1 mmol/l in the group treatment phase while waiting for start of insulin patients during weeks 0–7, 8–15, and Insulin dose therapy (metastasis of papillary thyroid 16–23. The cumulative percentage of pa- Insulin doses were similarly titrated by carcinoma, retinal neovascularization, tients achieving target (weekly mean FPG both study arms. At 24 weeks, the insulin and unwillingness to continue: n ϭ 2; within the target range 4.0–5.5 mmol/l) doses averaged 62 Ϯ 5 and 56 Ϯ 5 IU/day
1366 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Yki-Ja¨rvinen and Associates
Figure 1—A1C, serum ALT activities, total diabetes treatment satisfaction score, and the percentage of patients with FPGs Ͻ4.0 mmol/l in the individual and group arms at baseline (0 weeks) and after 24 weeks of treatment. The FPGs Ͻ4.0 mmol/l at 24 weeks denote the percentage of patients during the entire 24-week period. IND, individualized treatment.
(NS) (0.64 Ϯ 0.05 and 0.60 Ϯ 0.05 IU treatment 140 Ϯ 2 vs. 142 Ϯ 3mmHg (49%) in the individual and 28 patients Ϫ Ϫ kg 1 day 1, NS) in the individual and and group treatment 140 Ϯ 2 vs. 142 Ϯ 3 (48%) in the group arms reported at least group treatment arms. mmHg) and diastolic (at 0 vs. 24 weeks, one adverse event. Most common were individual treatment 83 Ϯ 1 vs. 82 Ϯ 1 infections and musculoskeletal disorders, Body weight mmHg and group treatment 85 Ϯ 1 vs. with no differences between the arms. The mean weight gain during 24 weeks 83 Ϯ 1 mmHg) blood pressures remained There was one side effect considered to be was significantly lower in the individual unchanged. Serum ALT decreased highly related to treatment: one injection site re- (2.2 Ϯ 0.4 kg) than in the group (3.7 Ϯ significantly in both the individual and action in the individual treatment arm. 0.6 kg, P Ͻ 0.02) arm. the group education arms (Fig. 1). Four patients (group, n ϭ 1; individual, n ϭ 3) had serious adverse events during Lipids, blood pressure, and liver Treatment satisfaction and time the course of the study. All serious ad- enzymes spent on patient education verse events recovered without sequelae. There were no within–education arm dif- Total treatment satisfaction outcome im- ferences in serum triglycerides, HDL, or proved significantly and similarly in both CONCLUSIONS — The present study LDL cholesterol. Serum triglycerides de- education arms (Fig. 1). There were no is to our knowledge the first attempt to creased from 2.4 Ϯ 0.2 to 1.7 Ϯ 0.1 significant differences between the compare, in a randomized fashion, initia- mmol/l (P Ͻ 0.001 for 24 vs. 0 weeks) in groups in responses to the individual tion of insulin therapy by adding basal in- those individually treated and from 2.1 Ϯ questions of the DTSQ (data not shown). sulin to existing oral agents individually and 0.1 mmol/l to 1.8 Ϯ 0.1 mmol/l (P Ͻ The total time (scheduled and extra) in groups. We found that both education 0.001 for 24 vs. 0 weeks) in the group arm over 24 weeks spent starting insulin was methods were equally effective with re- (NS). Serum HDL cholesterol averaged 48% lower in the group than in the indi- spect to improvement of glycemic con- 1.26 Ϯ 0.05 vs. 1.27 Ϯ 0.04 mmol/l (NS) vidual education arm (Fig. 2). There was trol. There were also no differences in the in those individually treated and 1.28 Ϯ no correlation between class time or total time course of titration of the insulin 0.05 vs. 1.34 Ϯ 0.05 mmol/l (P Ͻ 0.05 for time and the A1C achieved, the change in doses, in symptomatic or biochemical hy- 24 vs. 0 weeks) in the group arm at 0 vs. A1C, or the percentage of decrease in A1C poglycemia, or in treatment satisfaction. 24 weeks (NS). Serum LDL cholesterol (data not shown) within the educational Individual initiation took twice the remained unchanged and averaged arms. amount of the nurse educator’s time com- 2.78 Ϯ 0.10 vs. 2.77 Ϯ 0.10 mmol/l in pared with initiation of insulin in groups. the individual treatment arm and 2.58 Ϯ Adverse events Weight gain was slightly greater when in- 0.12 vs. 2.71 Ϯ 0.11 mmol/l in the group The incidence of adverse events consid- sulin was started in groups compared arm at 0 vs. 24 weeks (NS). ered not to be related to treatment was with patients treated individually. Systolic (at 0 vs. 24 weeks, individual similar between groups: 31 patients We chose to start insulin therapy by
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1367 Initiation of insulin in groups
implies that patients were equally satis- fied with both educational methods, it is not possible to determine why treatment satisfaction improved. We have previ- ously shown that treatment satisfaction improved with combination therapy compared with use of continued oral agents (7), suggesting that improved gly- cemic control rather than simply partici- pating in a study improves general well- being. Of note, treatment satisfaction was similar, although participation in the group arm required more time of the pa- tient than individual education. In conclusion, starting insulin in type Figure 2—Total time spent to initiate insulin during the study. The total (scheduled in-class or 2 diabetes in groups gives as good glyce- over-the-phone and extra) time for the group arm was 2.3 Ϯ 0.1h(n ϭ 58): 1.6 Ϯ 0.1 h for mic control as individual initiation. scheduled visits, 0.59 Ϯ 0.03 h for scheduled phone calls, and 0.73 Ϯ 0.24 h for extra visits (n ϭ Group and individual education also ap- 10) and 0.17 Ϯ 0.05 h for extra phone calls (n ϭ 11). The corresponding times in the individual pear similar with respect to hypoglyce- arm were as follows: 4.4 Ϯ 0.2 (n ϭ 63), 3.6 Ϯ 0.2, 0.59 Ϯ 0.03, 0.59 Ϯ 0.2 (n ϭ 14), and 0.14 Ϯ mia, lipid changes, and insulin doses. 0.03 h (n ϭ 11). Body weight increased more in the group education than in the individual educa- tion arm. Given years of delay in initiating adding basal insulin to existing oral Compared with other studies, this cannot insulin and the growing number of pa- agents, which mostly consisted of sulfo- be attributed to differences in baseline BMI, tients needing intensified treatment, we nylureas combined with metformin. This glycemic control, duration of diabetes, lack recommend initiation of insulin therapy regimen, compared with other options of weight gain during insulin therapy, or using the simple principles of the present such as use of insulin mixtures or multi- choice of oral agents. We attribute the suc- study in groups rather than individually ple insulin injection regimens, requires cess to use of adequate titration of insulin because this saves considerable amount of only one measurement of fasting glucose doses and to not discontinuing the sulfonyl- time and resources. Although not all pa- and one injection of insulin and is associ- urea. In the large treat-to-target study, tients will be eligible for this method of ated with less weight gain and hypoglyce- where basal insulin was added to sulfonyl- education, we believe a substantial pro- mia than multiple insulin injection urea and metformin combination therapy portion of the diabetic population will be regimens (5–8). Recommending only one (4), FPG was higher than in the LANMET eligible. fasting measurement for adjusting a single study (9), where only metformin was injection of insulin also facilitates inter- used—yet A1C was lower. Our patients pretation of glucose values received by were just as obese as those in the study of Acknowledgments— This study was investi- modem (9). One center did not use the Riddle et al. (4) but used 55–62 IU of insu- gator initiated and supported by Sanofi- Aventis. modem but nevertheless managed to lin, while the insulin doses in the latter achieve good glycemic control in both ed- study were 42–47 IU. ucation arms. We found use of the mo- Body weight increased by 3.7 kg in References dem very helpful, as it allows immediate the group arm, which was 1.5 kg more 1. State of diabetes health [article online], visualization of whether the FPG target than in the individual treatment arm. We 2006. Available from www.stateofdiabe- has been reached. The modem also al- have previously shown that for every 1% tes.com/state_compare.htm. Accessed 5 lowed accurate assessment of fasting hy- decrease in A1C, body weight increases March 2006. poglycemia; however, symptomatic by 2 kg (16). This increase reflects the net 2. International Diabetes Federation 2CGT: hypoglycemia is underestimated unless effects of reduction in calories lost in the Insulin therapy. In Global guideline for type 2 diabetes [article online], 2006. patients are strongly encouraged to also urine and of changes in energy expendi- Availablefromhttp://www.idf.org/webdata/ record hypoglycemia on a card. In keep- ture due to an increase in fat-free mass docs/GGT2D%2010%20Insulin% ing with this, we found almost twice the that accompanies weight gain, as well as a 20therapy.pdf. rate of confirmed hypoglycemia (episodes decrease in the energy consumed for glu- 3. Wright A, Burden AC, Paisey RB, Cull CA, Ϫ Ϫ of FPG Ͻ4.0 mmol/l patient 1 year 1) cose production (16). Since A1C de- Holman RR: Sulfonylurea inadequacy: ef- than in the treat-to-target study but less creased by 2% in both arms, one would ficacy of addition of insulin over 6 years in symptomatic hypoglycemia (4). This have predicteda4kgweight gain in both patients with type 2 diabetes in the U.K. could possibly be due to use of the mo- arms, but this was only observed in the Prospective Diabetes Study (UKPDS 57). dem, which allows accurate recording of group arm. The difference in weight gain Diabetes Care 25:330–336, 2002 all measured glucoses. between the two educational arms sug- 4. Riddle MC, Rosenstock J, Gerich JE, the Insulin glargine 4002 Study investigators: The A1C achieved at the end of 24 gests that the patients may have received The treat-to-target trial: randomized addi- weeks in the group education arm (6.8%) is more dietary advice during the individual tion of glargine or human NPH insulin to to our knowledge the best glycemic control education sessions than in the group. oral therapy in type 2 diabetic patients. achieved in any insulin treatment study in Treatment satisfaction improved sim- Diabetes Care 26:3080–3086, 2003 established type 2 diabetes (4–6,9,14–15). ilarly in both educational arms. While this 5. Raskin P, Allen E, Hollander PA, Lewin A,
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1369 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Prediction of Severe Hypoglycemia
1 2 DANIEL J. COX, PHD WILLIAM CLARKE, MD ited to assessment of long-term risk. 1 1 LINDA GONDER-FREDERICK, PHD BORIS P. KOVATCHEV, PHD The Diabetes Control and Complica- 1 LEE RITTERBAND, PHD tions Trial concluded that only ϳ8% of the variance of future (within several months) SH episodes could be ac- OBJECTIVE — Prevention of severe hypoglycemia (SH) is premised partially on the ability to counted for from known variables (4). accurately anticipate its occurrence. This study prospectively tests methods for predicting SH Further studies using a structural equa- using blood glucose meter readings. tion model history of SH, A1C, hypo- glycemia awareness, and autonomic RESEARCH DESIGN AND METHODS — One hundred adults with type 1 diabetes score accounted for 18% of the variance were followed for 6 months, and 79 insulin-using adults with type 2 diabetes were followed for 4 months. During this time, subjects’ routine self-monitored blood glucose (SMBG) readings of future SH (12). In a series of previous were stored on and retrieved from memory meters, and participants were queried biweekly publications, we reported that the low about occurrence of SH. Respective demographics for the two groups were age 40.7 and 50.2 blood glucose index (LBGI; a measure years, duration of diabetes 20.0 and 12.2 years, A1C 7.6 and 8.8%, and male sex 43 and 39%, of the frequency and extent of low self- respectively. monitored blood glucose [SMBG] read- ings) accounts for 40–55% of future RESULTS — Relative risk for SH, quantified by the ratio of an individual’s low blood glucose (within 6 months) SH episodes (13–16). index (LBGI) based on the previous 150 SMBG readings to the LBGI based on recent SMBG Hypoglycemia may lead to a “vi- readings, increased significantly in the 24 h before SH episodes in individuals with type 1 and cious cycle” of recurrent hypoglycemic type 2 diabetes (t ϭ 10.3, P Ͻ 0.0001, and t ϭ 4.2, P Ͻ 0.001, respectively). A sliding algorithm detected 58% of imminent (within 24 h) SH episodes in the type 1 diabetic group and 60% of episodes (17–21). According to the those in the type 2 diabetic group when three SMBG readings were available in the 24 h before concept of hypoglycemia-associated au- an episode. Detection increased to 63 and 75%, respectively, if five SMBG readings were available tonomic failure (22), recent antecedent in the 24 h before an episode. hypoglycemia causes defective counter- regulation and hypoglycemic unaware- CONCLUSIONS — SH often follows a specific blood glucose fluctuation pattern that is ness. Hypoglycemia-associated identifiable from SMBG. Thus, partial prediction of imminent SH is possible, providing a po- autonomic failure is observed in both tential tool to trigger self-regulatory prevention of significant hypoglycemia. type 1 (22) and advanced type 2 (23) diabetes. Considering this, it is reason- Diabetes Care 30:1370–1373, 2007 able to expect that SH episodes are pre- ceded by specific patterns of hormonal lthough achieving the goal of treated with insulin (5). Because SH can disturbances, which in turn are re- nearly normal glycemia amelio- result in cognitive dysfunction (6–8), flected by specific patterns of glycemic A rates much of the risk of hypergly- accidents, coma, and even death (9), disturbance, potentially recognizable cemia-related complications of diabetes hypoglycemia has been identified as the from SMBG. Yet, to the best of our (1–3), achieving such control is often primary barrier to optimization of gly- knowledge, prediction of imminent SH prevented by the occurrence of hypo- cemic control in diabetes (10,11). in the field had not been reported before glycemia, in particular by episodes of Prevention of SH presumes an indi- our finding of specific glucose patterns severe hypoglycemia (SH), as defined vidual can either accurately anticipate preceding SH episodes (24). After this by low blood glucose resulting in stu- when such an event is likely to occur to initial report, we took the next logical por, seizure, or unconsciousness that initiate prophylactic steps or detect step toward detection of imminent hy- precludes self-treatment (4). Although early signs of mild hypoglycemia to ini- poglycemic episodes, developing a slid- common in type 1 diabetes, recent evi- tiate immediate treatment to preclude ing algorithm that uses SMBG data and dence suggests that SH can also be prob- further progression. The prediction of derivatives from the LBGI to identify lematic for patients with type 2 diabetes hypoglycemia has been historically lim- patterns of glycemic disturbances likely ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● to be precursors to SH. From the 1Department of Psychiatry and Neurobehavioral Sciences, University of Virginia Health System, With a large prospective study, we 2 Charlottesville, Virginia; and the Department of Pediatrics, University of Virginia Health System, Char- tested the hypothesis that a vicious cy- lottesville, Virginia. Address correspondence and reprint requests to Daniel J. Cox, PhD, University of Virginia Health System, cle of recurrent low blood glucose can Box 800137, Charlottesville, VA 22908. E-mail: [email protected]. predict imminent SH among individu- Received for publication 3 July 2006 and accepted in revised form 7 March 2007. als with both type 1 and insulin-treated Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-1386. type 2 diabetes using our previously Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ published algorithms. If shown to be dc06-1386. Abbreviations: LBGI, low blood glucose index; SH, severe hypoglycemia; SMBG, self-monitored blood prospectively valid, this algorithm has glucose. the potential to provide an important A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion clinical tool for the prediction and pos- factors for many substances. sible prevention of imminent (within © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 24 h) SH episodes in type 1 and type 2 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. insulin-using patients.
1370 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cox and Associates
Table 1—Demographic characteristics and SMBG frequency of the participants ject has a single sudden low SMBG read- ing exceeding an individual threshold Type 1 Type 2 determined from the subjects’ LBGI from diabetes diabetes the last 150 readings and its SD. If either of these conditions were met, the algo- n 90 70 rithm indicated an increased risk for im- Average age (years) 40.7 Ϯ 11.2 50.2 Ϯ 8.0 minent SH (e.g., raised a binary “flag” Sex (% male) 43 39 indicating that the following 24 h were Caucasian/African American/Hispanic/Native 96/3/1/0 71/27/0/2 risky). To minimize false alarms, the algo- American (%) rithm was individualized so not to signal BMI (kg/m2) 25.3 Ϯ 4.4 36.3 Ϯ 9.2 as risky for imminent SH more than 10% Duration of diabetes (years) 20.0 Ϯ 10.7 12.2 Ϯ 8.5 of the total time of the study. The LBGI is Ϫ Ϫ Insulin (units kg 1 day 1) 0.48 Ϯ 0.26 0.56 Ϯ 0.25 central to the computation of risk for im- A1C (%) 7.6 Ϯ 1.2 8.8 Ϯ 2.0 minent severe hypoglycemia. The formu- Number of SH episodes in the last year (average 1.3 0.3 las for the LBGI have been reported per person) previously (15) and are included in their Percent of subjects who experienced at least one 36 10 entirety in the online appendix (available at SH in the past year (%) http://dx.doi.org/10.2337/dc06-1386). SMBG readings per day during the study 5.4 Ϯ 2.3 3.5 Ϯ 0.8 To assess the predictive ability of this Data are means Ϯ SD, unless otherwise indicated. algorithm, the SMBG data of each subject were matched by date and time to his/her independently reported survey records of RESEARCH DESIGN AND ing in stupor, seizure, or unconsciousness SH episodes. Then we counted the per- METHODS — One hundred adults that precludes self-treatment. Thus, the centage of SH episodes preceded by a hy- with type 1 diabetes and 79 adults with biweekly surveys contained only symp- poglycemia flag within Ͻ24 h for each type 2 diabetes taking insulin were re- tomatic SH episodes, recorded indepen- subject. Because the algorithm develop- cruited through regional advertisements. dently from SMBG. A portion of SH ment was finalized before this study All subjects had been diagnosed for at episodes was confirmed via telephone in- (16,24), this entire data collection is a least 2 years. Exclusion criteria were age terviews with the subject in order to en- prospective validation of the method. The Ͼ65 years, mental retardation, psychosis, sure maximal accuracy of these data. determination of imminent risk was done active substance abuse, or significant de- Except for being provided with free after subjects returned their meter; there- pression as defined by a Beck Depression SMBG supplies and being asked to report fore, subjects were unaware of their high- Inventory score Ͼ16. Ninety subjects occurrence of SH, no other information risk periods as quantified by the with type 1 and 70 with type 2 diabetes (i.e., risk status) or recommendations for algorithm. completed the entire data collection de- changes to the diabetes management rou- scribed below. Table 1 presents demo- tines of the participants were provided. RESULTS graphic data, history of SH, and SMBG This “no intervention” policy was applied frequency of these participants. in order to ensure generalization of the Frequency of SH All subjects signed institutional re- results from the study. During the study, type 1 diabetic subjects view board–approved consent forms and reported a total of 88 SH (0.16 per subject attended orientation meetings where they Data analysis per month) episodes. Twenty percent of completed screening questionnaires and After all SMBG and SH surveys were col- type 1 diabetic subjects reported prospec- had blood drawn for A1C determination. lected, we applied a previously reported tive SH in 6 months, whereas 80% re- Subjects were introduced to the One- sliding algorithm looking for specific ported no episodes. In type 2 diabetic Touch Ultra meter (LifeScan, Milpitas, blood glucose fluctuation patterns in subjects, there were a total of 22 SH epi- CA) and were given test strips for 150 SMBG data that were shown to precede sodes (0.08 per subject per month). Ten SMBG readings. Because the memory of SH episodes (24). This algorithm in- percent of type 2 diabetic subjects re- OneTouch Ultra holds 150 readings, sub- volved sliding across the timeline of indi- ported prospective SH in 4 months, jects notified the researcher when they vidual participants’ SMBG data and whereas 90% reported no episodes. started their last vial of test strips and a continuously computing whether there replacement meter was mailed to them was an elevated long-term (last 150 SMBG patterns preceding SH along with an additional 150 strips. This SMBGs) risk of SH occurrence and then episodes ensured an uninterrupted 6-month (4- superimposing on this long-term risk in- The clearest indicator of upcoming SH month for the type 2 diabetic group) se- dex whether there was sudden relative in- was a highly significant increase in the quence of SMBG readings for each creased risk. This increase in imminent relative risk for hypoglycemia (e.g., the subject. Subjects were also introduced to risk was defined in one of two ways: 1) the ratio of LBGI computed over a 24-h pe- a custom-designed automated e-mail sur- subject’s average LBGI from his/her last riod to LBGI computed from the previous vey system. This system contacted sub- 150 SMBG readings was Ͼ2.5 (moderate 150 SMBG readings). Figure 1 presents jects at 2-week intervals and asked them risk), and both the LBGI and its SD in- the relative imminent SH risk for type 1 to report occurrence of SH, including the creased over the last 50 trials; or 2) the and type 2 diabetic subjects. ANOVA date and time of each episode. SH was subject’s average LBGI from his/her last with contrasts showed that in type 1 dia- defined as severe neuroglycopenia result- 150 SMBG readings is Ͼ2.5, and the sub- betic subjects, the risk ratio (current-to-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1371 Predicting severe hypoglycemia
terns (signatures) in glucose fluctuations that increase risk for imminent SH. This prospective study also provides evidence for the predictive validity of methods pre- viously developed in our laboratory for short-term risk for significant hypoglyce- mia. Using a sliding algorithm, we were able to predict 58–60% of imminent (i.e., within the next 24 h) episodes of SH, with only three preceding SMBG readings. When more readings are available, the ac- curacy of prediction appears to increase. In addition, the accuracy of prediction was somewhat higher in type 2 diabetic subjects. This phenomenon is explained by the significantly lower amplitude and speed of blood glucose fluctuations in type 2 diabetes (25), which result in lower “background noise,” thus making the sig- nature of upcoming hypoglycemia more Figure 1— The ratio of LBGI to its baseline in the 3 days preceding and 2 days following an prominent and easier to detect (Fig. 1). episode of SH for individuals with type 1 (T1DM) and type 2 (T2DM) diabetes. Although these findings provide evi- dence that patterns in SMBG readings that baseline LBGI) increased significantly in in the 24-h period before SH. For exam- are precursors to SH can be detected, this the day before SH (t ϭ 10.3, P Ͻ 0.0001). ple, when four SMBG readings were avail- study also has some methodological lim- In type 2 diabetic subjects, risk ratio (cur- able for the 24 h in the type 1 diabetic itations that should be considered. Per- rent-to-overall LBGI) increased signifi- group, 60% of the episodes were pre- haps the most important is that we do not cantly over the 2 days preceding an dicted. As expected, Table 2 shows that know if subjects took action, based on episode (F ϭ 10.2, P Ͻ 0.001), with the the accuracy of the prediction slightly in- their SMBG readings, which affected their most significant increase the day before creases with the number of SMBG read- risk of SH. Future studies should include SH (t ϭ 4.2, P Ͻ 0.005). The relative risk ings preceding an episode. For example, if measurement of diabetes management increase in type 2 diabetic subjects was an individual performed three versus five behaviors that might reduce or increase higher than in type 1 diabetic subjects due SMBG readings a day, Ͼ58 vs. 63% of SH risk level. In addition, not all SH episodes to a lower baseline risk in the former episodes in the type 1 diabetic group and were predicted, with the number of un- group, which explains the better predic- Ͼ60 vs. 73% of SH episodes in the type 2 predicted episodes ranging from 27 to tion of SH in type 2 diabetes. diabetic group could be predicted and po- 42%, depending on the number of blood tentially avoided. The average warning glucose readings available in the preced- Prediction of imminent (within 24 h) time between a hypoglycemia imminent ing 24 h. This suggests that SH is not al- SH risk increase signal by the algorithm and a ways preceded by glucose disturbances The percent of survey-reported SH epi- subsequent episode of SH was 11 h (SD indicative of increasing risk that occur sodes that were predicted by a significant 8.6) in type 1 and 10.8 h (SD 9.1) in type many hours before the episode, which is increase in the imminent risk algorithm 2 diabetic subjects. Thus, in the majority not surprising. Risk for SH may also in- was then computed. Table 2 presents the of cases sufficient warning time for pre- crease suddenly due to other factors, such accuracy of this short-term prediction for ventative treatment was given. as overbolusing rapid-acting insulin, type 1 and type 2 diabetic subjects and skipping or delaying meals, or intense shows the percent of predicted episodes CONCLUSIONS — Our findings physical activity. when a minimum of three, four, and five demonstrate that episodes of significant The potential, however, to predict SMBG readings (column 2) were available hypoglycemia are often preceded by pat- more than half of imminent episodes of SH based on blood glucose meter data has Table 2—Prediction of upcoming (within 24 h) SH and mild hypoglycemia important clinical implications for help- ing patients to avoid significant hypogly- cemia. If online analysis of SMBG data Minimum number of SMBG were performed by meters, and early readings in the 24 h Percent predicted warnings were provided, individuals preceding the episode SH episodes would be able to take preventives steps to Accuracy in type 1 diabetes 3 58 reduce the imminent risk of SH. These 460steps could include increasing the fre- 560quency of SMBG, being more vigilant for any signs of hypoglycemia, reducing in- Accuracy in type 2 diabetes 3 60 sulin dose by 10%, avoiding strenuous 464exercise without eating extra carbohy- 573drates, and avoiding delayed meals or
1372 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cox and Associates missed snacks. This type of online analy- paired awareness. Diabet Med 20:1016– of severe hypoglycemia in type 1 and type sis of SMBG data to provide such warn- 1021, 2003 2 diabetes using self-monitoring blood ings would be a useful adjunct to other 6. Gold AE, Deary IJ, Frier BM: Recurrent glucose (SMBG) data. Diabetes Technol behavioral interventions, such as blood severe hypoglycaemia and cognitive func- Ther 5:817–828, 2003 glucose awareness training (26) that fo- tion in type I diabetes. Diabet Med 17. White NH, Skor DA, Cryer PE, Levan- 10:503–508, 1993 doski L, Santiago JV: Identification of type cuses on improving detection, treatment, 7. Deary IJ, Crawford JR, Hepburn DA, Lan- I diabetic patients at increased risk for hy- and prevention of extreme blood glucose gan SJ, Blackmore LM, Frier BM: Severe poglycemia during intensive therapy. levels. The next step for clinical investiga- hypoglycemia and intelligence in adult N Engl J Med 308:485–491, 1983 tors is to conduct randomized clinical tri- patients with insulin-treated diabetes. Di- 18. Cryer PE, Gerich JE: Glucose counter- als to determine whether patients can use abetes 42:341–344, 1993 regulation, hypoglycemia, and intensive this information to successfully reduce 8. Lincoln NB, Faleiro RM, Kelly C, Kirk BA, therapy of diabetes mellitus. N Engl J Med the occurrence of SH. Even though it is Jeffcoate WJ: Effect of long-term glycemic 313:232–241, 1985 unlikely that this predictive algorithm, ei- control on cognitive function. Diabetes 19. Amiel SA, Tamborlane WV, Simonson ther alone or in conjunction with behav- Care 19:656–658, 1996 DC, Sherwin RS: Defective glucose coun- ioral interventions, will completely 9. Bloomgarden ZT: International Diabetes terregulation after strict glycemic control Federation meeting, 1997, and Metropol- of insulin-dependent diabetes mellitus. eliminate SH episodes, this approach may itan Diabetes Society of New York meet- N Engl J Med 316:1376–1383, 1987 offer a relatively simple and noninvasive ing, November 1997: approaches to 20. Amiel SA, Sherwin RS, Simonson DC, method to achieve clinically significant treatment and other topics in type 1 dia- Tamborlane WV: Effect of intensive insu- reductions in risk. betes: genetic heterogeneity of diabetes. lin therapy on glycemic thresholds for Diabetes Care 21:658–665, 1998 counterregulatory hormone release. Dia- 10. Cryer PE: Hypoglycemia: the limiting fac- betes 37:901–907, 1988 Acknowledgments— This study was sup- tor in the management of IDDM. Diabetes 21. Cryer PE: Hypoglycemia begets hypogly- ported by National Institutes of Heath Grants 43:1378–1389, 1994 cemia. Diabetes 42:1691–1693, 1993 RO1 DK 28288 and 51562 and by a grant from 11. Cryer PE: Hypoglycaemia: the limiting 22. Dagogo-Jack SE, Craft S, Cryer PE: Hypo- LifeScan. factor in the glycaemic management of glycemia-associated autonomic failure in type I and type II diabetes. Diabetologia insulin dependent diabetes mellitus. J Clin 45:937–948, 2002 Invest 91:819–828, 1993 References 12. Gold AE, Frier BM, MacLeod KM, Deary 23. Segel SA, Paramore DS, Cryer PE: Hypogly- 1. The Diabetes Control and Complica- IJ: A structural equation model for predic- cemia-associated autonomic failure in ad- tions Trial Research Group: The effect of tors of severe hypoglycaemia in patients vanced type 2 diabetes. Diabetes 51:724– intensive treatment of diabetes on the with insulin-dependent diabetes mellitus. 733, 2002 development and progression of long- Diabet Med 14:309–315, 1997 24. Kovatchev BP, Cox DJ, Farhy LS, Straume term complications of insulin-depen- 13. Kovatchev BP, Cox DJ, Gonder-Frederick M, Gonder-Frederick LA, Clarke WL: Ep- dent diabetes mellitus. N Engl J Med LA, Clarke WL: Symmetization of the isodes of severe hypoglycemia in type 1 329:978–986, 1993 blood glucose measurement scale and its diabetes are preceded, and followed, 2. Reichard P, Phil M: Mortality and treat- applications. Diabetes Care 20:1655– within 48 hours by measurable distur- ment side effects during long-term inten- 1658, 1997 bances in blood glucose. J Clin Endocrinol sified conventional insulin treatment in 14. Cox DJ, Kovatchev B, Julian D, Gonder- Metab 85:4287–4292, 2000 the Stockholm Diabetes Intervention Frederick LA, Polonsky WH, Schlundt 25. Kovatchev BP, Cox DJ, Gonder-Frederick Study. Diabetes 43:313–317, 1994 DG, Clarke WL: Frequency of severe hy- LA, Clarke WL: Methods for quantifying 3. U.K. Prospective Diabetes Study Group poglycemia in IDDM can be predicted self-monitoring blood glucose profiles ex- (UKPDS): Intensive blood-glucose con- from self-monitoring blood glucose data. emplified by an examination of blood glu- trol with sulphonylureas or insulin com- J Clin Endocrinol Metab 79:1659–1662, cose patterns in patients with type 1 and pared with conventional treatment and 1994 type 2 diabetes. Diabetes Technol Ther risk of complications in patients with type 15. Kovatchev BP, Cox DJ, Gonder-Frederick 4:295–303, 2002 2 diabetes. Lancet 352:837–853, 1998 LA, Young-Hyman D, Schlundt D, Clarke 26. Cox DJ, Gonder-Frederick LS, Ritterband 4. The Diabetes Control and Complications WL: Assessment of risk for severe hypo- L, Patel K, Scha¨chinger H, Fehm-Wolfs- Trial Research Group: Hypoglycemia in glycemia among adults with IDDM: vali- dorf G, Hermanns N, Snoek F, Zrebiec J, the Diabetes Control and Complications dation of the Low Blood Glucose Index. Polonsky W, Schlundt D, Kovatchev B, Trial. Diabetes 46:271–286, 1997 Diabetes Care 21:1870–1875, 1998 Clarke W: Blood glucose awareness train- 5. Henderson JN, Allen KV, Deary IJ, Frier 16. Kovatchev BP, Cox DJ, Kumar A, Gonder- ing (BGAT): what is it, where is it, and BM: Hypoglycemia in insulin-treated type Frederick LA, Clarke WL: Algorithmic where is it going? Diabetes Spectrum 19: 2 diabetes: frequency, symptoms and im- evaluation of metabolic control and risk 43–49, 2006
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1373 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals With Type 2 Diabetes One-year results of the Look AHEAD trial
THE LOOK AHEAD RESEARCH GROUP* diabetes support and education (DSE). Follow-up of Look AHEAD participants is ongoing and is planned to extend for up OBJECTIVE — The effectiveness of intentional weight loss in reducing cardiovascular disease to 11.5 years. For the study to continue (CVD) events in type 2 diabetes is unknown. This report describes 1-year changes in CVD risk for this period, two feasibility criteria factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on were set by the Look AHEAD study group the incidence of major CVD events. based on 1-year changes: 1) a difference between ILI and DSE participants of Ͼ5 RESEARCH DESIGN AND METHODS — This study consisted of a multicentered, percentage points in the average percent randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45–74 years, with Ͼ 2 Ͼ 2 change in weight from baseline and 2)an BMI 25 kg/m ( 27 kg/m if taking insulin). An intensive lifestyle intervention (ILI) involving average absolute percent weight loss from group and individual meetings to achieve and maintain weight loss through decreased caloric baseline among ILI participants (not us- intake and increased physical activity was compared with a diabetes support and education Ͼ (DSE) condition. ing insulin at baseline) of 5%. This re- port documents the success of Look RESULTS — Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% AHEAD in meeting these 1-year feasibility in DSE group (P Ͻ 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P Ͻ 0.001). criteria and describes changes in the two A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid- groups at the end of the 1st year in fitness, lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P Ͻ 0.001) vs. from 7.3 to 7.2% cardiovascular disease risk factors, and in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to- use of medicines. creatinine ratio improved significantly more in ILI than DSE participants (all P Ͻ 0.01).
CONCLUSIONS — At 1 year, ILI resulted in clinically significant weight loss in people with RESEARCH DESIGN AND type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and METHODS — For inclusion in the reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine study, participants were 45–74 years of whether these changes are maintained and will reduce CVD risk. age (which was changed to 55–74 years Diabetes Care 30:1374–1383, 2007 during the 2nd year of recruitment to in- crease the anticipated cardiovascular event rate), had a BMI Ͼ25 kg/m2 (Ͼ27 ook AHEAD (Action for Health in objective is to determine whether cardio- 2 kg/m if currently taking insulin), A1C Diabetes) is an National Institutes of vascular morbidity and mortality in indi- Ͻ11%, blood pressure Ͻ160 (systolic) L Health–funded clinical trial, con- viduals with type 2 diabetes can be and Ͻ100 (diastolic) mmHg, and triglyc- ducted in 16 centers in the U.S., investi- reduced by long-term weight reduction, erides Ͻ600 mg/dl. gating the long-term health impact of an achieved by an ILI that includes diet, Participants completed maximal intensive lifestyle intervention (ILI) in physical activity, and behavior modifica- graded exercise tests to assess fitness be- 5,145 overweight or obese adults with tion (3). The goal of this intervention is fore randomization. The test consisted of type 2 diabetes. The design and methods for individuals to achieve and maintain a the participant walking on a motorized of this trial have been reported elsewhere loss of at least 7% of initial body weight. treadmill at a constant self-selected walk- (1), as have the baseline characteristics of Results of the ILI group will be compared ing speed (1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 the randomized cohort (2). Its primary with a usual-care condition that includes ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● mph). The elevation of the treadmill was initially set at 0% grade and increased by Address correspondence and reprint requests to Mark Espeland, PhD, Division of Public Health Sciences, 1.0% every minute. Heart rate and rating Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: [email protected]. of perceived exertion (RPE) using the Received for publication 12 January 2007 and accepted in revised form 5 March 2007. Borg 15-category scale (4) were measured Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc07-0048. during the final 10 s of each exercise stage Clinical trial reg. no. NCT00017953, clinicaltrials.gov. and at the point of test termination. To *Authors and members of the Look AHEAD trial are listed in the APPENDIX. Abbreviations: ADA, American Diabetes Association; CVD, cardiovascular disease; DSE, diabetes sup- determine eligibility at baseline, a maxi- port and education; ILI, intensive lifestyle intervention; AHEAD, Action for Health in Diabetes; METS, mal exercise test was performed. For in- metabolic equivalents; RPE, rating of perceived exertion. dividuals not taking prescription medi- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion cine that would affect heart rate response factors for many substances. during exercise (e.g., -blocker), the base- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby line test was considered valid if the individ- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ual achieved at least 85% of age-predicted
1374 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Look AHEAD Research Group maximal heart rate (age-predicted maximal ment components from the Diabetes Pre- were invited to three additional group heart rate ϭ 220 Ϫ age) and a minimum of vention Program (6–8) and the National sessions during the 1st year. A standard 4 metabolic equivalents (METS). For indi- Heart, Lung, and Blood Institute’s clinical protocol was used for conducting these viduals taking prescription medicine that guidelines (9). During months 1–6, par- sessions, which provided information would affect the heart rate response during ticipants were seen weekly with three and opportunities for discussing topics exercise, the baseline test was considered group meetings and one individual ses- related to diet, physical activity, and so- valid if the individual achieved an RPE of at sion per month. During months 7–12, cial support. However, the DSE group least 18 and a minimum of 4 METS. Indi- group sessions were provided every other was not weighed at these sessions and re- viduals not achieving these criteria were not week and the monthly individual session ceived no counseling in behavioral strat- eligible for randomization into Look was continued. Sessions were led by in- egies for changing diet and activity. AHEAD. METS at each exercise stage and at tervention teams that included registered test termination were estimated from a stan- dietitians, behavioral psychologists, and Ongoing clinical care dardized formula that incorporates walking exercise specialists. All participants in the ILI and DSE groups speed and grade (5). Caloric restriction was the primary continued to receive care for their diabe- The goal was to recruit approximately method of achieving weight loss. The ma- tes and all other medical conditions from equal numbers of men and women, with cronutrient composition of the diet was their own physicians. Changes in all med- Ͼ33% from racial and ethnic minority structured to enhance glycemic control icines were made by the participants’ own groups. Informed consent was obtained and to improve CVD risk factors. It in- physicians, except for temporary reduc- from all participants before screening and cluded a maximum of 30% of total calo- tions in hyperglycemia medicines during at enrollment, consistent with the Hel- ries from fat (with a maximum of 10% of periods of intensive weight loss interven- sinki Declaration and the guidelines of total calories from saturated fat) and a tion, which were made by the interven- each center’s institutional review board. minimum of 15% of total calories from tion sites following a standardized After all eligibility criteria were con- protein (10). Participants were prescribed treatment protocol aimed at avoiding firmed, participants were randomly as- portion-controlled diets, which included hypoglycemia. signed with equal probability to either the the use of liquid meal replacements (pro- ILI or the DSE comparison condition. vided free of charge) and frozen food en- Assessments Randomization was stratified by clinical tre´es, as well as structured meal plans Anthropometry. All participants were center. (comprised of conventional foods) for scheduled to attend baseline and 1-year those who declined the meal replace- assessments, at which time measures were Interventions ments. Monthly reviews took place at an collected by staff members who were Before randomization, all study partici- individual session to reassess progress. masked to participants’ intervention as- pants were required to complete a 2-week The physical activity program pre- signments. Weight and height were as- run-in period that included successful scribed in the ILI relied heavily on home- sessed in duplicate using a digital scale self-monitoring of diet and physical activ- based exercise with gradual progression and a standard stadiometer. Seated blood ity, and they were provided an initial ses- toward a goal of 175 min of moderate- pressure was measured in duplicate, us- sion of diabetes education with particular intensity physical activity per week. Al- ing an automated device after a 5-min emphasis on aspects of diabetes care re- though walking was encouraged, rest. Participants brought all prescription lated to the trial such as management of participants were allowed to choose other medicines to the clinic to ensure record- hypoglycemia and foot care. The session types of moderate-intensity physical ac- ing accuracy. History of cardiovascular stressed the importance of eating a tivity, and programs were tailored based disease was based on self-report of myo- healthy diet and being physically active on the results of a baseline physical fitness cardial infarction, stroke, transient isch- for both weight loss and improvement of test and safety concerns. emic event, percutaneous transluminal glycemic control. All individuals who The ILI included a “toolbox” ap- coronary angioplasty, or coronary artery smoked were encouraged to quit and proach, as used in the Diabetes Preven- bypass graft. were provided self-help materials and/or tion Program (6,7), to help participants Fitness. At 1 year, a submaximal exer- referral to local programs as appropriate. achieve and maintain the study’s weight cise test was performed and terminated The weight loss intervention pre- loss and activity goals. Use of the toolbox when the participant first achieved or ex- scribed in the 1st year has been described was based on a preset algorithm and as- ceeded 80% of age-predicted maximal ϭ in detail (3). Briefly, it combines diet sessment of participant progress. After the heart rate (HRMax in beats per min modification and increased physical ac- first 6 months, the toolbox algorithm in- 220 Ϫ age). If the participant was taking a tivity and was designed to induce a min- cluded use of a weight loss medicine (or- -blocker at baseline or 1-year assess- imum weight loss of 7% of initial body listat) and/or advanced behavioral ment, the submaximal test was termi- weight during the 1st year. Individual strategies for individuals who had diffi- nated at the point when the participant participants were encouraged to lose culty in meeting the trial’s weight or ac- first reported achieving or exceeding 16 Ͼ10% of their initial body weight, with tivity goals. Specific protocols were used on the 15-category RPE scale. For partic- the expectation that aiming high would to determine when to initiate medication ipants not taking a -blocker, change in ensure that a greater number of partici- or other approaches, to monitor partici- cardiorespiratory fitness was computed as pants would achieve the minimum 7% pants, and to determine when to stop a the difference in estimated METS be- weight loss. The intervention was mod- particular intervention. tween points during the baseline and eled on group behavioral programs devel- Participants assigned to DSE attended 1-year tests when Ͼ80% of age-predicted oped for the treatment of obese patients the initial prerandomization diabetes ed- maximal heart rate was attained. For par- with type 2 diabetes and included treat- ucation session (described above) and ticipants taking -blockers at either base-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1375 Reduction in weight and CVD risk factors
Figure 1—Enrollment of Look AHEAD participants. line or 1 year, change in cardiorespiratory Disease Control and Prevention reference stolic blood pressure Ͻ80 mmHg, and fitness was computed as the difference in methods. LDL cholesterol was calculated lipid control as LDL cholesterol Ͻ100 estimated METS between points during by the Friedewald equation (11). HDL mg/dl. the baseline and 1-year tests when RPE cholesterol was analyzed by the treatment Ͼ16 was attained. of whole plasma with dextran sulfate mi- Statistical methods ϩ Serum measures. The Central Biochem- nus Mg2 to precipitate all of the apoli- Cross-sectional differences between par- istry Laboratory (Northwest Lipid Re- poprotein B–containing lipoproteins. ticipants assigned to the ILI and DSE con- search Laboratories, University of Albumin and creatinine concentrations ditions were assessed using ANCOVA and Washington, Seattle, WA) conducted were measured from spot urine samples. logistic regression, with adjustment for standardized analyses of shipped frozen Participants were classified as having clinical center (the sole factor used to specimens. A1C was measured by a ded- the metabolic syndrome using the criteria stratify randomization). Changes in out- icated ion exchange high-performance proposed by the National Cholesterol Ed- come measures from baseline to 1 year liquid chromatography instrument (Bio- ucation Program Adult Treatment Pro- were compared using ANCOVA and rad Variant 11). Fasting serum glucose gram III panel (12). They also were Mantel-Haenszel tests. was measured enzymatically on a Hitachi classified according to their success in 917 autoanalyzer using hexokinase and meeting treatment goals published by the RESULTS glucose-6-phosphate dehydrogenase. To- American Diabetes Association (ADA) tal serum cholesterol and triglycerides (13). Glycemic control was defined as Participants’ baseline characteristics were measured enzymatically using A1C Ͻ7.0%, blood pressure control as Figure 1 describes trial enrollment. Of methods standardized to the Centers for systolic blood pressure Ͻ130 and dia- 28,622 individuals who provided infor-
1376 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Look AHEAD Research Group
Table 1—Baseline characteristics of the ILI and DSE groups circumference in the ILI than DSE group, with mean decreases of 6.2 Ϯ 10.2 vs. Ϯ Ͻ Intervention assignment 0.5 8.5 cm (P 0.001). In the ILI group, the average weight Characteristic ILI DSE P value loss among baseline insulin users was 7.6 Ϯ 7.0% compared with 8.7 Ϯ 6.9% in n 2,570 2,575 ϭ Women 1,526 (59.3) 1,537 (59.6) 0.85* nonusers (P 0.002). Insulin users, com- Ethnicity pared with noninsulin users, were less likely to achieve weight losses Ͼ10% African American 399 (15.5) 404 (15.7) Ͼ American Indian/Alaskan Native 130 (5.1) 128 (5.0) (33.5 vs. 38.5%) or 7% (47.8 vs. Asian/Pacific Islander 29 (1.1) 21 (0.8) 0.28* 56.4%). In the DSE group, average weight loss was 0.3 Ϯ 5.1% among insulin users Hispanic/Latino 339 (13.2) 338 (13.2) Ϯ Non-Hispanic white 1,618 (63.1) 1,628 (63.3) versus 0.8 4.7% among noninsulin users. Other/multiple 48 (1.9) 50 (1.9) Age (years) 58.6 Ϯ 6.8 58.9 Ϯ 6.9 0.12† Changes in fitness History of cardiovascular disease‡ 371 (14.4) 351 (13.6) 0.40* Figure 2B illustrates the cumulative dis- Metabolic syndrome 2,406 (93.6) 2,431 (94.4) 0.32* tribution of measured 1-year fitness Use of insulin 381 (14.8) 408 (15.8) 0.31* changes in 4,246 participants who had BMI (kg/m2) repeat testing. Fitness tended to increase Women 36.3 Ϯ 6.2 36.6 Ϯ 6.0 0.15† in both groups; however, increases were Men 35.3 Ϯ 5.7 35.1 Ϯ 5.2 0.41† more prevalent and tended to be larger Weight (kg) among ILI participants; 70.1% of the ILI Women 94.8 Ϯ 17.9 95.4 Ϯ 17.3 0.34† participants had increased fitness at 1 year Men 108.9 Ϯ 19.0 109.0 Ϯ 18.0 0.94† compared with 46.3% of the DSE partic- ipants (P Ͻ 0.001). Fitness increases av- Waist circumference (cm) Ϯ Women 110.5 Ϯ 13.6 111.2 Ϯ 13.2 0.14† eraged 20.9 29.1% among ILI Ϯ Ϯ participants compared with 5.8 Ϯ 22.0% Men 118.7 14.0 118.4 12.9 0.62† Ͻ Fitness (METS) among DSE participants (P 0.001). Women 6.7 Ϯ 1.7 6.6 Ϯ 1.7 0.38† These changes could not be fully ac- Men 7.9 Ϯ 2.1 8.0 Ϯ 2.2 0.89† counted for by changes in weight. After covariate adjustment for weight changes, Data are means Ϯ SD or frequency (%). *2 test. †ANCOVA, adjusted for clinical center. ‡Self-report of prior myocardial infarction, stroke, transient ischemic attack, angioplasty/stent, coronary artery bypass graft, the fitted mean difference in fitness in- carotid endarterectomy, angioplasty of lower extremity, aortic aneurysm repair, or heart failure. creases between groups remained statisti- cally significant (15.9% for ILI vs. 10.8% for DSE, P Ͻ 0.001). mation during prescreening, 15,561 cines. Baseline BMI, weight, waist circum- (54.4%) were found to be eligible for ference, and fitness are given by sex in Changes in medicines and clinic visits to confirm eligibility. The Table 1. A BMI of Ն30.0 kg/m2 was cardiovascular risk factors most common reasons for ineligibility at present in 85.1% of participants. During the 1st year, use of glucose- this stage were related to age (13.5%), lowering medicines among ILI partici- lack of diabetes (8.6%), and the likeli- Weight loss pants decreased from 86.5 to 78.6%, hood that the diabetes was type 1 (4.4%). The 1-year examination was attended by whereas it increased from 86.5 to 88.7% Of 9,045 (58.1%) who attended clinic 2,496 (97.1%) of the ILI and 2,463 among DSE participants (P Ͻ 0.001). As visits, 5,145 (56.9%) were ultimately ran- (95.7%) of the DSE participants (P ϭ shown in Table 2, despite this difference, domized: 2,570 participants were as- 0.004). Among the factors listed in Table mean fasting glucose declined more signed to ILI and 2,575 to DSE. At this 1, only the distribution of baseline insulin among ILI participants compared with stage, individuals were most commonly use significantly varied between nonat- DSE participants (P Ͻ 0.001), as did ineligible due to staff judgment (7.6%), tendees (21.0%) versus attendees mean A1C (P Ͻ 0.001). elevated blood pressure (7.0%), or in- (15.1%) (P ϭ 0.04). Over the 1st year of As described in Table 2, the preva- complete behavioral run ins (4.8%). the trial, the ILI group lost an average of lence of antihypertensive medicine use At baseline, the characteristics of par- (means Ϯ SD) 8.6 Ϯ 6.9% of initial body remained unchanged among ILI partici- ticipants assigned to the two intervention weight compared with 0.7 Ϯ 4.8% in the pants but increased by 2.2% (0.6%) conditions were similar (Table 1). Over- DSE group (P Ͻ 0.001). Figure 2A por- among DSE participants (P ϭ 0.02). all, 14.0% reported a history of cardiovas- trays the cumulative distribution of Mean systolic and diastolic blood pres- cular disease, 94.0% met the National weight changes in the two groups. Within sure levels declined in both groups, but Cholesterol Education Program Adult the ILI group, 37.8% of participants met reductions were significantly greater in Treatment Panel III definition for the met- the individual weight loss goal (Ͼ10% of ILI than in DSE participants (both P Ͻ abolic syndrome (12), 15.3% were taking initial weight) and 55.2% met the group 0.001). insulin, 87.5% were using diabetes med- average goal (Ͼ7%) compared with 3.2 Use of lipid-lowering medicines in- icines (including insulin), 75.3% were us- and 7.0% of DSE participants, respec- creased in both groups; however, the in- ing antihypertensive medicines, and tively. These weight losses were accompa- crease was significantly smaller among ILI 51.0% were using lipid-lowering medi- nied by greater mean reductions in waist participants than in DSE participants
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1377 Reduction in weight and CVD risk factors
Table 2—Changes in measures of diabetes control, blood pressure control, measures of lipid/ creased more among ILI (P Ͻ 0.001). The lipoproteins control, albumin-to-creatinine ratio, and prevalence of metabolic syndrome prevalence of urine albumin-to-creatinine among participants seen at year 1 ratios Ն30.0 g/mg decreased more among ILI participants than DSE partici- ϭ Measure ILI DSE P value pants (P 0.002). n 2,496 2,463 Classification of participants Use of diabetes medicines (%) The percentage meeting criteria for the Baseline 86.5 Ϯ 0.7 86.5 Ϯ 0.7 0.93* metabolic syndrome decreased signifi- Year 1 78.6 Ϯ 0.8 88.7 Ϯ 0.6 Ͻ0.001* cantly more among ILI than DSE partici- Change Ϫ7.8 Ϯ 0.6 2.2 Ϯ 0.5 Ͻ0.001† pants (P Ͻ 0.001). As shown in Table 2, Fasting glucose (mg/dl) the prevalence declined from 93.6 to Baseline 151.9 Ϯ 0.9 153.6 Ϯ 0.9 0.21‡ 78.9% in the ILI group compared with a Year 1 130.4 Ϯ 0.8 146.4 Ϯ 0.9 Ͻ0.001‡ decline of 94.4 to 87.3% in the DSE Change Ϫ21.5 Ϯ 0.9 Ϫ7.2 Ϯ 0.9 Ͻ0.001‡ group. The prevalence of meeting ADA A1C (%) goals for A1C, blood pressure, and LDL Baseline 7.25 Ϯ 0.02 7.29 Ϯ 0.02 0.26‡ cholesterol increased among both ILI and Year 1 6.61 Ϯ 0.02 7.15 Ϯ 0.02 Ͻ0.001‡ DSE participants (Table 3). These in- Difference Ϫ0.64 Ϯ 0.02 Ϫ0.14 Ϯ 0.02 Ͻ0.001‡ creases were greater among ILI partici- Use of antihypertensive medicines (%) pants (P Ͻ 0.001) for A1C and blood Baseline 75.3 Ϯ 0.9 73.7 Ϯ 0.9 0.23* pressure 26.4 Ϯ 1.0% vs. 5.4 Ϯ 1.07% Year 1 75.2 Ϯ 0.9 75.9 Ϯ 0.9 0.54* and 15.1 Ϯ 1.1% vs. 7.0 Ϯ 1.2%, respec- Change Ϫ0.1 Ϯ 0.6 2.2 Ϯ 0.6 0.02† tively (both P Ͻ 0.001), but were of sim- Systolic blood pressure (mmHg) ilar magnitudes for LDL cholesterol. The Baseline 128.2 Ϯ 0.4 129.4 Ϯ 0.3 0.01‡ prevalence simultaneously meeting all Year 1 121.4 Ϯ 0.4 126.6 Ϯ 0.4 Ͻ0.001‡ three goals increased from 10.8 to 23.6% Change Ϫ6.8 Ϯ 0.4 Ϫ2.8 Ϯ 0.3 Ͻ0.001‡ among ILI participants compared with an Diastolic blood pressure (mmHg) increase from 9.5 to 16.0% among DSE Baseline 69.9 Ϯ 0.2 70.4 Ϯ 0.2 0.11‡ participants (P Ͻ 0.001). Year 1 67.0 Ϯ 0.2 68.6 Ϯ 0.2 Ͻ0.001‡ Change Ϫ3.0 Ϯ 0.2 Ϫ1.8 Ϯ 0.2 Ͻ0.001‡ CONCLUSIONS — The present re- Use of lipid-lowering medicines (%) sults show that clinically significant Baseline 49.4 Ϯ 1.0 48.4 Ϯ 1.0 0.52* weight loss is broadly achievable in sub- Year 1 53.0 Ϯ 1.0 57.8 Ϯ 1.0 Ͻ0.001* jects with type 2 diabetes and is associated Change 3.7 Ϯ 0.8 9.4 Ϯ 0.8 Ͻ0.001† with improved cardiovascular risk fac- LDL cholesterol (mg/dl) tors. At 1 year, participants in ILI Baseline 112.2 Ϯ 0.4 112.4 Ϯ 0.6 0.78‡ achieved an average loss of 8.6% of initial Year 1 107.0 Ϯ 0.6 106.7 Ϯ 0.7 0.74‡ body weight and a 21% improvement in Change Ϫ5.2 Ϯ 0.6 Ϫ5.7 Ϯ 0.6 0.49‡ cardiovascular fitness. Separate manu- HDL cholesterol (mg/dl) scripts are underway that will provide de- Baseline 43.5 Ϯ 0.2 43.6 Ϯ 0.2 0.80‡ tails on the relative contributions of Year 1 46.9 Ϯ 0.3 44.9 Ϯ 0.2 Ͻ0.001‡ individual strategies (e.g., meal replace- Change 3.4 Ϯ 0.2 1.4 Ϯ 0.1 Ͻ0.001‡ ment, orlistat) toward this successful out- Triglycerides (mg/dl) come. Even participants on insulin lost an Baseline 182.8 Ϯ 2.3 180.0 Ϯ 2.4 0.38‡ average of 7.6% of initial weight. The ILI Year 1 152.5 Ϯ 1.8 165.4 Ϯ 1.9 Ͻ0.001‡ was associated with an increase from 46 Change Ϫ30.3 Ϯ 2.0 Ϫ14.6 Ϯ 1.8 Ͻ0.001‡ to 73% in the participants who met the Albumin-to-creatinine ratio (Ͼ30.0 ADA goal of A1C Ͻ7% and a doubling in g/mg) (%) the percent of individuals who met all Baseline 16.4 Ϯ 0.7 16.9 Ϯ 0.8 0.69‡ three of the ADA goals for glycemic con- Year 1 12.5 Ϯ 0.7 15.4 Ϯ 0.7 0.005‡ trol, hypertension, and dyslipidemia. Change Ϫ3.9 Ϯ 0.6 Ϫ1.5 Ϯ 0.6 0.002‡ Look AHEAD is the first large clinical Metabolic syndrome (%) trial to compare an intensive weight loss Baseline 93.6 Ϯ 0.5 94.4 Ϯ 0.5 0.23‡ intervention (i.e., ILI) with a support and Year 1 78.9 Ϯ 0.8 87.3 Ϯ 0.7 Ͻ0.001‡ education group (i.e., DSE) in individuals Change Ϫ14.7 Ϯ 0.8 Ϫ7.1 Ϯ 0.7 Ͻ0.001‡ with type 2 diabetes. As expected, partic- Data are means Ϯ SE or % Ϯ SE. *Logistic regression with adjustment for clinical site. †Mantel-Haenszel test ipants in the ILI group had significantly with adjustment for clinical site. ‡ANCOVA, with adjustment for clinical site. greater weight loss and improvement in fitness at 1 year than those in the DSE (P Ͻ 0.001). Mean levels of LDL choles- lesterol levels increased more among ILI group. Moreover, they had a significantly terol declined by similar magnitudes in than DSE participants (P Ͻ 0.001), greater decrease in the number of medi- both groups (P ϭ 0.49). Mean HDL cho- whereas mean triglyceride levels de- cines used to treat their diabetes and
1378 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Look AHEAD Research Group
(14), but their average baseline BMI was higher. Overall, they are healthier than diabetic individuals in the National Health and Nutrition Examination Survey with regard to glucose, A1C, and lipid lev- els and are less likely to smoke. A large percentage was taking medicines for risk factors at study enrollment, and many had a significant history of cardiovascular disease. Despite the level of health of the sample, fewer than half met the ADA goal for A1C and only 10% met all three ADA goals (13). The ILI was extremely effective in increasing the percent of participants who met these goals. At 1 year, 72.7% met the goal for A1C and 23.6% met all three goals, compared with only 50.8 and 16.0%, respectively, for the DSE group. The ILI also was associated with signifi- cantly greater remission of the metabolic syndrome than was the DSE intervention. Several large clinical trials of individ- uals with impaired glucose tolerance (6,15) or hypertension (16,17) have achieved average weight losses of 4–7% at 1 year using intensive lifestyle interven- tions that emphasized behavior change. These weight losses were associated with marked improvement in health status. Al- though a number of smaller studies (18,19) have shown that it is possible, us- ing strong behavioral programs, to pro- duce significant weight loss in patients with type 2 diabetes, most studies of Figure 2—Distribution of 1-year changes in percent weight (A) and fitness (B) (METS) among weight loss in such individuals have had individuals grouped by intervention assignment. Dashed lines are used to indicate the percentages only modest success. It appears that indi- of ILI participants with weight losses exceeding 10, 7, and 5%, respectively. viduals with diabetes (especially those on insulin) may have more difficulty losing blood pressure. Despite the greater reduc- Table 3—Changes in percentage of participants meeting ADA goals for risk factors tions in these medicines, the ILI group showed greater improvements in their Measure ILI DSE P value glycemic control, albumin-to-creatinine ratio, systolic and diastolic blood pres- A1C (Ͻ7%) sure, triglycerides, and HDL cholesterol Baseline 46.3 Ϯ 1.0 45.4 Ϯ 1.0 0.50* than the DSE group. Changes in LDL cho- Year 1 72.7 Ϯ 0.9 50.8 Ϯ 1.0 Ͻ0.001* lesterol were comparable in the two Difference 26.4 Ϯ 1.0 5.4 Ϯ 1.0 Ͻ0.001† groups. Of particular note is that mean Blood pressure (Ͻ130/80 mmHg) (%) A1C fell from 7.2 to 6.6%. Few studies, Baseline 53.5 Ϯ 1.0 49.9 Ϯ 1.0 0.01* even trials of newer diabetes medicines, Year 1 68.6 Ϯ 0.9 57.0 Ϯ 1.0 Ͻ0.001* have achieved levels of A1C of 6.6%. Al- Change 15.1 Ϯ 1.1 7.0 Ϯ 1.2 Ͻ0.001† though the DSE group had smaller bene- LDL cholesterol (Ͻ100 mg/dl) (%) fits than ILI, it is important to recognize Baseline 37.1 Ϯ 1.0 36.9 Ϯ 1.0 0.87* that these participants also experienced Year 1 43.8 Ϯ 1.0 44.9 Ϯ 1.0 0.45* some improvement (not worsening), on Change 6.7 Ϯ 1.0 8.0 Ϯ 1.0 0.34† average, in weight, fitness, and cardiovas- All three goals cular risk factors. Baseline 10.8 Ϯ 0.6 9.5 Ϯ 0.6 0.13* The Look AHEAD participants are of Year 1 23.6 Ϯ 0.8 16.0 Ϯ 0.7 Ͻ0.001* similar ethnic distribution to that ob- Change 12.8 Ϯ 0.9 6.5 Ϯ 0.8 Ͻ0.001† served in the National Health and Nutri- Data are % Ϯ SD. *Logistic regression with adjustment for clinical site. †Mantel-Haenszel test with adjust- tion Examination Survey 1999–2000 ment for clinical site.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1379 Reduction in weight and CVD risk factors weight and then keeping it off than those AHEAD trial is the effect of weight loss on Prevention (to Edward W. Gregg, PhD; David without diabetes (20). For example, the development of cardiovascular dis- F. Williamson, PhD; and Ping Zhang, PhD). among adult Pima Indians receiving stan- ease. Although the difference between the The following organizations have commit- dard clinical care for type 2 diabetes, ILI and DSE groups in the change in risk ted to make major contributions to Look those treated with insulin lost less weight factors at 1-year points to the potential AHEAD: Federal Express, Health Management Resources, Johnson & Johnson, LifeScan, Op- than those treated without drugs or with cardiovascular benefits of the ILI, we will tifast-Novartis Nutrition, Roche Pharmaceuti- oral agents (21). The larger weight losses need several additional years to determine cals, Ross Product Division of Abbott in Look AHEAD than in prior clinical tri- whether the initial weight loss can be Laboratories, and Slim-Fast Foods Company. als may be attributable to the combination maintained, whether weight loss has a of group and individual contact, the long-term effect on the risk factors, and higher physical activity goal that was pre- whether the favorable risk factor changes APPENDIX scribed, and/or the more intense dietary translate into reduced cardiovascular intervention, which included not only events. This is critical information for es- Authors calorie and fat restrictions but also struc- tablishing evidence-based recommenda- Xavier Pi-Sunyer, MD; George Blackburn, tured meal plans, each of which has pre- tions with regard to weight loss for the MD, PhD; Frederick L. Brancati, MD, viously been associated with successful prevention of cardiovascular disease in MHS; George A. Bray, MD; Renee Bright, weight loss and maintenance (22–25). Al- individuals with diabetes. MS; Jeanne M. Clark, MD, MPH; Jeffrey though Look AHEAD participants using M. Curtis, MD, MPH; Mark A. Espeland, insulin achieved less average weight loss PhD; John P. Foreyt, PhD; Kathryn than those not on insulin (7.6 vs. 8.7%), Graves, MPH, RD, CDE; Steven M. Acknowledgments— This study is sup- Haffner, MD; Barbara Harrison, MS; the weight loss of the participants on in- ported by the Department of Health and Hu- sulin demonstrates that use of insulin man Services through the following James O. Hill, PhD; Edward S. Horton, does not prevent successful weight loss. A cooperative agreements from the National In- MD; John Jakicic, PhD; Robert W. Jeffery, recent meta-analysis (26) found that the stitutes of Health: DK57136, DK57149, PhD; Karen C. Johnson, MD, MPH; use of meal replacements increased both DK56990, DK57177, DK57171, DK57151, Steven Kahn, MB, ChB; David E. Kelley, short- and long-term average weight loss DK57182, DK57131, DK57002, DK57078, MD; Abbas E. Kitabchi, MD, PhD; Wil- by ϳ2.5 kg, compared with prescription DK57154, DK57178, DK57219, DK57008, liam C. Knowler, MD, DrPH; Cora E. DK57135, and DK56992. The following fed- of a conventional reducing diet with the Lewis, MD, MSPH; Barbara J. Maschak- eral agencies have contributed support: Na- Carey, MSN, CDE; Brenda Montgomery, same calorie goals. Our findings that par- tional Institute of Diabetes and Digestive and ticipants in the ILI had significant im- RN, MS, CDE; David M. Nathan, MD; Kidney Diseases; National Heart, Lung, and Jennifer Patricio, MS; Anne Peters, MD; J. provements in cardiovascular risk factors Blood Institute; National Institute of Nursing confirms prior studies showing that initial Research; National Center on Minority Health Bruce Redmon, MD; Rebecca S. Reeves, weight loss in type 2 diabetes is associated and Health Disparities; Office of Research on DrPH, RD; Donna H. Ryan, MD; Monika with improved glycemic control and car- Women’s Health; and the Centers for Disease Safford, MD; Brent Van Dorsten, PhD; diovascular risk factors at 1 year (27,28). Control and Prevention. This research was Thomas A. Wadden, PhD; Lynne Wagen- However, the long-term impact of such supported in part by the Intramural Research knecht, DrPH; Jacqueline Wesche- weight losses remains unclear. Program of the National Institute of Diabetes Thobaben, RN, BSN, CDE; Rena R. Wing, and Digestive and Kidney Diseases. PhD; Susan Z. Yanovski, MD. Estimated fitness improved in both Additional support was received from the groups over the year, but it improved sig- Johns Hopkins Medical Institutions Bayview nificantly more in the ILI group. It is un- General Clinical Research Center Clinical sites known how much of the improvement in (M01RR02719); the Massachusetts General The Johns Hopkins Medical Institutions: either treatment group was due to mea- Hospital Mallinckrodt General Clinical Re- Frederick L. Brancati, MD, MHS; Jeff Ho- surement variability and greater familiar- search Center (M01RR01066); the University nas, MS; Lawrence Cheskin, MD; Jeanne ity with the testing procedure at the of Colorado Health Sciences Center General M. Clark, MD, MPH; Kerry Stewart, EdD; 1-year visit and how much represented Clinical Research Center (M01RR00051) and Richard Rubin, PhD; Jeanne Charleston, physiologic change. The difference in im- Clinical Nutrition Research Unit (P30 RN; Kathy Horak, RD. provement between the ILI and DSE DK48520); the University of Tennessee at Pennington Biomedical Research Memphis General Clinical Research Center groups, however, can be taken as a mea- (M01RR0021140); the University of Pitts- Center: George A. Bray, MD; Kristi Rau; sure of the ILI treatment effect. This treat- burgh General Clinical Research Center Allison Strate, RN; Brandi Armand, LPN; ment effect persisted even after (M01RR000056 44); National Institutes of Frank L. Greenway, MD; Donna H. Ryan, adjustment for the 1-year weight change. Health Grant DK 046204; the University of MD; Donald Williamson, PhD; Amy Bac- The changes in fitness compared favor- Washington/VA Puget Sound Health Care Sys- hand; Michelle Begnaud; Betsy Berhard; ably with those observed in prior studies tem Medical Research Service, Department of Elizabeth Caderette; Barbara Cerniaus- with both diabetic (29,30) and nondia- Veterans Affairs; and Frederic C. Bartter Gen- kas; David Creel; Diane Crow; Helen betic (29,31,32) participants. Thus, the eral Clinical Research Center (M01RR01346). Guay; Nancy Kora; Kelly LaFleur; Kim modest increase in physical activity, pri- Federal support: National Institute of Dia- Landry; Missy Lingle; Jennifer Perault; marily walking, had a very beneficial ef- betes and Digestive and Kidney Diseases (to Mandy Shipp, RD; Marisa Smith; Eliza- Barbara Harrison, MS; Van S. Hubbard, MD fect. This may translate into a lower rate of PhD; and Susan Z. Yanovski, MD); the Na- beth Tucker. cardiovascular events, including mortal- tional Heart, Lung, and Blood Institute (to The University of Alabama at Bir- ity, as suggested in some observational Lawton S. Cooper, MD, MPH; Jeffrey Cutler, mingham: Cora E. Lewis, MD, MSPH; studies (33,34). MD, MPH; and Eva Obarzanek, PhD, MPH, Sheikilya Thomas, MPH; Monika Safford, The primary outcome of the Look RD); and the Centers for Disease Control and MD; Vicki DiLillo, PhD; Charlotte Bragg,
1380 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Look AHEAD Research Group
MS, RD, LD; Amy Dobelstein; Stacey Gil- elle Chan, BS; Kati Konersman, MA, RD, Barbara Bancroft, RN, MS; Anna Ber- bert, MPH; Stephen Glasser, MD; Sara CDE; Magpuri Perpetua, RD. torelli, MBA, RD; Richard Carey, BS; Ta- Hannum, MA; Anne Hubbell, MS; Jen- The University of Tennessee Health tum Charron, BS; Heather Chenot, MS; nifer Jones, MA; DeLavallade Lee; Ruth Science Center: Karen C. Johnson, MD, Kimberley Chula-Maguire, MS; Pamela Luketic, MA, MBA, MPH; Karen Marshall; MPH; Helen Lambeth, RN, BSN; Carolyn Coward, MS, RD; Lisa Cronkite, BS; Julie L. Christie Oden; Janet Raines, MS; Cathy M. Gresham, RN; Abbas E. Kitabchi, MD, Currin, MD; Maureen Daly, RN; Caitlin Roche, RN, BSN; Janet Truman; Nita PhD; Stephanie A. Connelly, MD, MPH; Egan, MS; Erica Ferguson, BS, RD; Linda Webb, MA; Audrey Wrenn, MAEd. Lynne Lichtermann, RN, BSN. Foss, MPH; Jennifer Gauvin, BS; Don Harvard center: Massachusetts Gen- University of Minnesota: Robert W. Kieffer, PhD; Lauren Lessard, BS; Debo- eral Hospital: David M. Nathan, MD; Jeffery, PhD; Carolyn Thorson, CCRP; rah Maier, MS; J.P. Massaro, BS; Tammy Heather Turgeon, RN, BS, CDE; Kristina John P. Bantle, MD; J. Bruce Redmon, Monk, MS; Rob Nicholson, PhD; Erin Schumann, BA; Enrico Cagliero, MD; MD; Richard S. Crow, MD; Scott Crow, Patterson, BS; Suzanne Phelan, PhD; Hol- Linda Delahanty, MS, RD; Kathryn Hay- MD; Susan K. Raatz, PhD, RD; Kerrin lie Raynor, PhD, RD; Douglas Raynor, ward, MD; Ellen Anderson, MS, RD; Lau- Brelje, MPH, RD; Carolyne Campbell; PhD; Natalie Robinson, MS, RD; Deborah rie Bissett, MS, RD; Richard Ginsburg, Jeanne Carls, MEd; Tara Carmean-Mihm, Robles; Jane Tavares, BS. PhD; Valerie Goldman, MS, RD; Virginia BA; Emily Finch, MA; Anna Fox, MA; The University of Texas Health Sci- Harlan, MSW; Charles McKitrick, RN, Elizabeth Hoelscher, MPH, RD, CHES; La ence Center at San Antonio: Steven M. BSN, CDE; Alan McNamara, BS; Theresa Donna James; Vicki A. Maddy, BS, RD; Haffner, MD; Maria G. Montez, RN, Michel, DPT, DSc, CCS; Alexi Poulos, BA; Therese Ockenden, RN; Birgitta I. Rice, MSHP, CDE; Carlos Lorenzo, MD. Barbara Steiner, EdM; Joclyn Tosch, BA. MS, RPh CHES, BS; Ann D. Tucker, BA; University of Washington/VA Puget Joslin Diabetes Center: Edward S. Hor- Mary Susan Voeller, BA; Cara Walcheck, Sound Health Care System: Steven Kahn ton, MD; Sharon D. Jackson, MS, RD, BS, RD. MB, ChB; Brenda Montgomery, RN, MS, CDE; Osama Hamdy, MD, PhD; A. En- St. Luke’s Roosevelt Hospital Center: CDE; Robert Knopp, MD; Edward Lipkin, rique Caballero, MD; Sarah Bain, BS; Eliz- Xavier Pi-Sunyer, MD; Jennifer Patricio, MD; Matthew L. Maciejewski, PhD; Dace abeth Bovaird, BSN, RN; Ann Goebel- MS; Stanley Heshka, PhD; Carmen Pal, Trence, MD; Terry Barrett, BS; Joli Bartell, Fabbri, PhD; Lori Lambert, MS, RD; Sarah MD; Lynn Allen, MD; Diane Hirsch, RNC, BA; Diane Greenberg, PhD; Anne Murillo, Ledbury, MEd, RD; Maureen Malloy, BS; MS, CDE; Mary Anne Holowaty, MS, CN. BS; Betty Ann Richmond, MEd; April Kerry Ovalle, MS, RCEP, CDE. Beth Israel University of Pennsylvania: Thomas Thomas, MPH, RD. A. Wadden, PhD; Barbara J. Maschak- Southwestern American Indian Cen- Deaconess Medical Center: George Black- Carey, MSN, CDE; Stanley Schwartz, ter, Phoenix, Arizona, and Shiprock, New burn, MD, PhD; Christos Mantzoros, MD, MD; Gary D. Foster, PhD; Robert I. Mexico: William C. Knowler, MD, DrPH; DSc; Kristina Day, RD; Ann McNamara, Berkowitz, MD; Henry Glick, PhD; Paula Bolin, RN, MC; Tina Killean, BS; RN. Shiriki K. Kumanyika, PhD, RD, MPH; Jonathan Krakoff, MD; Jeffrey M. Curtis, University of Colorado Health Sci- Johanna Brock; Helen Chomentowski; MD, MPH; Justin Glass, MD; Sara ences Center: James O. Hill, PhD; Marsha Vicki Clark; Canice Crerand, PhD; Michaels, MD; Peter H. Bennett, MB, Miller, MS, RD; JoAnn Phillipp, MS; Rob- Renee Davenport; Andrea Diamond, FRCP; Tina Morgan; Shandiin Begay, ert Schwartz, MD; Brent Van Dorsten, MS, RD; Anthony Fabricatore, PhD; MPH; Bernadita Fallis, RN, RHIT, CCS; PhD; Judith Regensteiner, PhD; Salma Louise Hesson, MSN; Stephanie Jeanette Hermes, MS, RD; Diane F. Hol- Benchekroun, MS; Ligia Coelho, BS; Pau- Krauthamer-Ewing, MPH; Robert Kueh- lowbreast; Ruby Johnson; Cathy Manus, lette Cohrs, RN, BSN; Elizabeth Daen- nel, PhD; Patricia Lipschutz, MSN; LPN; Maria Meacham, BSN, RN, CDE; inck, MS, RD; Amy Fields, MPH; Susan Monica Mullen, MS, RD; Leslie Julie Nelson, RD; Carol Percy, RN; Patri- Green; April Hamilton, BS, CCRC; Jere Womble, PhD, MS; Nayyar Iqbal, MD. cia Poorthunder; Sandra Sangster; Nancy Hamilton, BA; Eugene Leshchinskiy; Mi- University of Pittsburgh: David E. Scurlock, MSN, ANP-C, CDE; Leigh A. chael McDermott, MD; Lindsey Munk- Kelley, MD; Jacqueline Wesche- Shovestull, RD, CDE; Janelia Smiley; Ka- witz, BS; Loretta Rome, TRS; Kristin Thobaben, RN, BSN, CDE; Lewis Kuller, tie Toledo, MS, LPC; Christina Tomchee, Wallace, MPH; Terra Worley, BA. MD, DrPH; Andrea Kriska, PhD; Janet BA; Darryl Tonemah, PhD. Baylor College of Medicine: John P. Bonk, RN, MPH; Rebecca Danchenko, BS; University of Southern California: Foreyt, PhD; Rebecca S. Reeves, DrPH, Daniel Edmundowicz, MD; Mary L. Anne Peters, MD; Valerie Ruelas, MSW, RD; Henry Pownall, PhD; Ashok Balasu- Klem, PhD, MLIS; Monica E. Yamamoto, LCSW; Siran Ghazarian Sengardi, MD; bramanyam, MBBS; Peter Jones, MD; DrPH, RD, FADA; Barb Elnyczky, MA; Kathryn Graves, MPH, RD, CDE; Kati Michele Burrington, RD; Chu-Huang George A. Grove, MS; Pat Harper, MS, Konersman, MA, RD, CDE; Sara Serafin- Chen, MD, PhD; Allyson Clark, RD; RD, LDN; Janet Krulia, RN, BSN, CDE; Dokhan. Molly Gee, MEd, RD; Sharon Griggs; Juliet Mancino, MS, RD, CDE, LDN; Anne Michelle Hamilton; Veronica Holley; Mathews, MS, RD, LDN; Tracey Y. Mur- Coordinating center Jayne Joseph, RD; Patricia Pace, RD: ray, BS; Joan R. Ritchea; Jennifer Rush, Wake Forest University: Mark A. Es- Julieta Palencia, RN; Olga Satterwhite, MPH; Karen Vujevich, RN-BC, MSN, peland, PhD; Judy L. Bahnson, BA; Lynne RD; Jennifer Schmidt; Devin Volding, CRNP; Donna Wolf, MS. Wagenknecht, DrPH; David Reboussin, LMSW; Carolyn White. The Miriam Hospital/Brown Medical PhD; W. Jack Rejeski, PhD; Alain Bertoni, University of California at Los Ange- School: Rena R. Wing, PhD; Renee Bright, MD, MPH; Wei Lang, PhD; Gary Miller, les School of Medicine: Mohammed F. MS; Vincent Pera, MD; John Jakicic, PhD; PhD; David Lefkowitz, MD; Patrick S. Saad, MD; Siran Ghazarian Sengardi, MD; Deborah Tate, PhD; Amy Gorin, PhD; Reynolds, MD; Paul Ribisl, PhD; Mara Vi- Ken C. Chiu, MD; Medhat Botrous; Mich- Kara Gallagher, PhD; Amy Bach, PhD; tolins, DrPH; Michael Booth, MBA; Kathy
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1381 Reduction in weight and CVD risk factors
M. Dotson, BA; Amelia Hodges, BS; Carrie tion or metformin. N Eng J Med 346:393– trolled trial of nonpharmacologic inter- C. Williams, BS; Jerry M. Barnes, MA; Pa- 403, 2003 ventions in the elderly (TONE). JAMA 279: tricia A. Feeney, MS; Jason Griffin, BS; Lea 7. The Diabetes Prevention Program Re- 839–846, 1998 Harvin, BS; William Herman, MD, MPH; search Group: The Diabetes Prevention 17. Trials of Hypertension Prevention Collab- Patricia Hogan, MS; Sarah Jaramillo, MS; Program (DPP): description of the lifestyle orative Research Group: Trials of Hyper- intervention. Diabetes Care 25:2165– tension Prevention: phase II. Effects of Mark King, BS; Kathy Lane, BS; Rebecca 2171, 2002 weight loss and sodium reduction inter- Neiberg, MS; Andrea Ruggiero, MS; 8. Wing RR, Hamman RF, Bray GA, Dela- vention on blood pressure and hyperten- Christian Speas, BS; Michael P. Walkup, hanty L, Edelstein SL, Hill JO, Horton ES, sion incidence in overweight people with MS; Karen Wall, AAS; Michelle Ward; De- Hoskin MA, Kriska A, Lachin J, Mayer- high-normal blood pressure. Arch Int Med lia S. West, PhD; Terri Windham. Davis EJ, Pi-Sunyer X, Regensteiner JG, 157:657–667, 1997 Venditti B, Wylie-Rosett J, the Diabetes 18. Wolf AM, Conaway MR, Crowther JQ, Central resources centers Prevention Program Research Group: Hazen KY, L Nadler J, Oneida B, Bovbjerg Achieving weight and activity goals VE, the Improving Control with Activity Dual-Energy X-Ray Absorptiometry among Diabetes Prevention Program life- and Nutrition (ICAN) Study: Translating Reading Center, University of California style participants. Obes Res 12:1426– lifestyle intervention to practice in obese at San Francisco: Michael Nevitt, PhD; 1434, 2004 patients with type 2 diabetes: Improving Susan Ewing, MS; Cynthia Hayashi; Jason 9. 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Guare JC, Wing RR, Grant A: Comparison abetes and Digestive and Kidney Diseases: of obese NIDDM and nondiabetic wom- EPICARE, Wake Forest University School Look AHEAD: Action for Health in Dia- en: short- and long-term weight loss. Obes of Medicine: Ronald J. Prineas, MD, PhD; betes. Available from www.niddk.nih. Res 3:329–335, 1995 Teresa Alexander; Lisa Billings; Charles gov/patient/SHOW/LookAHEAD.htm. 21. Looker HC, Knowler WC, Hanson RL: Campbell, AAS, BS; Sharon Hall; Susan Accessed 6 May 2005 Changes in body mass index and weight Hensley; Yabing Li, MD; Zhu-Ming 11. Friedewald WT, Levy RI, Fredrickson DS: before and after the development of type 2 Zhang, MD. Estimation of the concentration of low- diabetes. Diabetes Care 24:1917–1922, Diet Assessment Center, University of density lipoprotein cholesterol in plasma, 2001 South Carolina, Arnold School of Public without use of the preparative ultracentri- 22. 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29. Walker KZ, Piers LS, Putt RS, Jones JA, overweight, sedentary women: a random- cular disease in men and women in the O’Dea K: Effects of regular walking on ized trial. JAMA 290:1323–1330, 2003 lipid research clinics study. Am J Epide- cardiovascular risk factors and body com- 32. Donnelly JE, Hill JO, Jacobsen DJ, Pot- miol 56:832–841, 2002 position in normoglycemic women and teiger J, Sullivan DK, Johnson SL, Heelan 34. Lee CD, Blair SN, Jackson AS: Cardiore- women with type 2 diabetes. Diabetes K, Hise M, Fennessey PV, Sonko B, Sharp spiratory fitness, body composition, and Care 22:555–561, 1999 T, Jakicic JM, Blair SN, Tran ZV, Mayo M, all-cause and cardiovascular disease mor- 30. Goodpaster BH, Katsiaras A, Kelley DE: Gibson C, Washburn RA: Effects of a 16- tality in men. Am J Clin Nutr 69:373–380, Enhanced fat oxidation through physical month randomized controlled exercise 1999 activity is associated with improvements trial on body weight and composition in 35. Wei M, Gibbons LW, Kampert JB, Nicha- in insulin sensitivity in obesity. Diabetes young, overweight men and women. Arch man MZ, Blair SN: Low cardiorespiratory 52:2191–2197, 2003 Int Med 163:1343–1350, 2003 fitness and physical inactivity as predic- 31. Jakicic JM, Marcus BH, Gallagher KI, Na- 33. Stevens J, Cai J, Evenson KR, Thomas R: tors of mortality in men with type 2 politano M, Lang W: Effect of exercise du- Fitness and fatness as predictors of mor- diabetes. Ann Intern Med 132:605–611, ration and intensity on weight loss in tality from all causes and from cardiovas- 2000
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1383 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Objectively Measured Light-Intensity Physical Activity Is Independently Associated With 2-h Plasma Glucose
1 2 GENEVIEVE N. HEALY, MPH JONATHAN E. SHAW, MD Physical activity is one of the key 2 2 DAVID W. DUNSTAN, PHD PAUL Z. ZIMMET, MD modifiable risk factors for hyperglycemia. 3 1 JO SALMON, PHD NEVILLE OWEN, PHD 4 Evidence from population-based cross- ESTER CERIN, PHD sectional studies indicates that both phys- ical activity and sedentary behavior (particularly television viewing time) are OBJECTIVE — We examined the associations of objectively measured sedentary time, light- independently associated with blood glu- intensity physical activity, and moderate- to vigorous-intensity activity with fasting and 2-h cose in adults without known diabetes postchallenge plasma glucose in Australian adults. (6–8). However, the physical activity and sedentary time variables in these studies RESEARCH DESIGN AND METHODS — A total of 67 men and 106 women (mean have typically been derived from self- age Ϯ SD 53.3 Ϯ 11.9 years) without diagnosed diabetes were recruited from the 2004–2005 Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Physical activity was measured by report measures, generally a 1-week re- Actigraph accelerometers worn during waking hours for 7 consecutive days and summarized as call. In addition to the imprecision sedentary time (accelerometer counts/min Ͻ100; average hours/day), light-intensity (counts/ associated with such measures, it is also min 100-1951), and moderate- to vigorous-intensity (counts/min Ն1,952). An oral glucose difficult to accurately capture light- tolerance test was used to ascertain 2-h plasma glucose and fasting plasma glucose. intensity physical activity or total seden- tary behavior (rather than components of RESULTS — After adjustment for confounders (including waist circumference), sedentary leisure-time sedentary behavior) by ques- time was positively associated with 2-h plasma glucose (b ϭ 0.29, 95% CI 0.11–0.48, P ϭ tionnaire (9). Light-intensity activity, 0.002); light-intensity activity time (b ϭϪ0.25, Ϫ0.45 to Ϫ0.06, P ϭ 0.012) and moderate- to ϭϪ Ϫ Ϫ ϭ which includes activities such as washing vigorous-intensity activity time (b 1.07, 1.77 to 0.37, P 0.003) were negatively dishes, ironing, and other routine domes- associated. Light-intensity activity remained significantly associated with 2-h plasma glucose following further adjustment for moderate- to vigorous-intensity activity (b ϭϪ0.22, Ϫ0.42 to tic or occupational tasks (10), is the pre- Ϫ0.03, P ϭ 0.023). Associations of all activity measures with fasting plasma glucose were dominant determinant of variability in nonsignificant (P Ͼ 0.05). total daily energy expenditure (11). Clin- ical studies have demonstrated associa- CONCLUSIONS — These data provide the first objective evidence that light-intensity phys- tions between nonexercise activities ical activity is beneficially associated with blood glucose and that sedentary time is unfavorably (“nonexercise activity thermogenesis”) associated with blood glucose. These objective data support previous findings from studies using and obesity risk (12); however, there is self-report measures, and suggest that substituting light-intensity activity for television viewing limited evidence on the extent to which or other sedentary time may be a practical and achievable preventive strategy to reduce the risk such light-intensity activities are associ- of type 2 diabetes and cardiovascular disease. ated with other health outcomes (13,14). Diabetes Care 30:1384–1389, 2007 Given the challenge of assessing physical activity across the continuum of varying intensities, accurate measures of hronic high blood glucose concen- tes and impaired glucose tolerance (2– free-living physical activities (sedentary, trations (hyperglycemia) are both 5). Understanding the association of light, moderate, and vigorous) are re- C a characteristic and a precursor of modifiable type 2 diabetes risk factors quired. Using accelerometers, we exam- type 2 diabetes (1). Hyperglycemia is with blood glucose across the glucose ined the associations of objectively also associated with an increased risk of range can inform the development of measured sedentary time, light-intensity cardiovascular disease and premature population strategies for reducing the activity, and moderate- to vigorous- mortality, and this association persists risk of diabetes and other cardiovascu- intensity activity with fasting and 2-h below the categorical cutoffs for diabe- lar diseases. postchallenge plasma glucose in Austra- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● lian adults without diagnosed diabetes. From the 1Cancer Prevention Research Centre, School of Population Health, The University of Queensland, Brisbane, Australia; the 2International Diabetes Institute, Melbourne, Australia; the 3Deakin University, Melbourne, Australia; and the 4The University of Hong Kong, Hong Kong, China. RESEARCH DESIGN AND Address correspondence and reprint requests to Genevieve Healy, MPH, Cancer Prevention Research METHODS — Participants for this Centre, School of Population Health, The University of Queensland, Herston, Queensland, Australia 4006. cross-sectional observational study were E-mail: [email protected]. Received for publication 18 January 2007 and accepted in revised form 12 March 2007. recruited between October and Decem- Published ahead of print at http://care.diabetesjournals.org on 1 May 2007. DOI: 10.2337/dc07-0114. ber 2005 from attendees at five Queens- Abbreviations: AusDiab; Australian Diabetes, Obesity, and Lifestyle; FPG, fasting plasma glucose. land testing sites of the population-based A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Australian Diabetes, Obesity and Lifestyle factors for many substances. (AusDiab) Study (15–17). Recruitment © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby for the present study was contingent on marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. accelerometer availability and the timing
1384 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Healy and Associates
Table 1—Sex-specific demographic, biological, physical activity, and behavioral characteristics of study participants
P for sex Characteristic Men Women Total difference n 67 106 173 Age (years) 52.7 (49.7–55.7) 53.6 (51.4–55.9) 53.3 (51.5–55.1) 0.628 BMI (kg/m2) 27.8 (26.8–28.7) 26.8 (25.9–27.8) 27.2 (26.5–27.9) 0.187 Waist circumference (cm) 98.2 (95.6–100.9) 87.0 (84.8–89.2) 91.4 (89.5–93.2) Ͻ0.001 Height (cm) 176.3 (175.0–177.6) 163.4 (162.1–164.6) 168.4 (167.1–169.7) Ͻ0.001 FPG (mmol/l) 5.4 (5.2–5.5) 5.1 (5.0–5.2) 5.2 (5.1–5.3) Ͻ0.001 2-h plasma glucose (mmol/l) 6.0 (5.5–6.5) 5.6 (5.3–5.8) 5.7 (5.5–6.0) 0.055 Plasma glucose status Normal glucose tolerance 53 (79) 96 (91) 149 (86) Isolated IFG 1 (2) 1 (1) 2 (1) Isolated IGT 9 (13) 8 (8) 17 (10) IFG and IGT 1 (2) 1 (1) 2 (1) Newly diagnosed diabetes 3 (5) 0 (0) 3 (2) Accelerometer-derived variables (average daily time in h) Time accelerometer worn 14.8 (14.5–15.1) 14.8 (14.6–15.1) 14.8 (14.6–15.0) 0.840 Sedentary time* 8.5 (8.2–8.8) 8.3 (8.1–8.6) 8.4 (8.2–8.6) 0.283 Light-intensity activity* 5.6 (5.3–6.0) 6.1 (5.8–6.3) 5.8 (5.7–6.0) 0.045 Moderate- to vigorous-intensity 0.7 (0.6–0.8) 0.5 (0.4–0.5) 0.6 (0.5–0.6) Ͻ0.001 activity* Moderate- to vigorous-intensity activity 0.8 (0.7–0.9) 0.5 (0.5–0.6) 0.6 (0.6–0.7) Ͻ0.001 by accelerometer and diary* Percent time at each activity level while accelerometer worn (%) Sedentary time 57.2 (54.9–59.5) 55.9 (54.2–57.6) 56.6 (55.2–58.0) 0.328 Light-intensity activity 23.0 (21.7–24.3) 24.5 (23.5–25.5) 23.8 (23.0–34.6) 0.063 Moderate- to vigorous-intensity activity 4.5 (4.0–5.1) 3.2 (2.8–3.6) 3.9 (3.5–4.2) Ͻ0.001 Moderate- to vigorous-intensity activity 5.2 (4.5–5.8) 3.5 (3.1–4.0) 4.3 (4.0–4.7) Ͻ0.001 by accelerometer and diary Current smokers 1 (2) 2 (2) 3 (2) 0.828 Family history of diabetes 11 (16) 28 (26) 39 (22) 0.130 University/further education 44 (66) 52 (49) 96 (56) 0.038 Moderate/heavy alcohol drinkers 30 (45) 24 (3) 54 (31) 0.007 Full-time employment 53 (79) 42 (40) 95 (55) Ͻ0.001 Household income Ն$1500/week 35 (52) 32 (30) 67 (39) 0.005 Data are means (95% CI) or n (%). *Means adjusted for time accelerometer worn; statistical comparisons are adjusted for age. Sedentary time (Ͻ100 counts/min), light-intensity activity (100–1,951 counts/min), and moderate- to vigorous-intensity activity (Ն1,952 counts/min). IFG, impaired fasting glucose; IGT, impaired glucose tolerance. of examination procedures of the main fast (minimum of 9 h), an oral glucose right anterior axillary line, were used to study; those with known diabetes, with tolerance test was performed using World measure physical activity. Participants visible limitations to mobility, and preg- Health Organization specifications (19). were instructed to wear the accelerometer nant women were not approached. Of The outcome variables of fasting plasma during all waking hours for a continuous those available and eligible, all were ap- glucose (FPG) and 2-h plasma glucose period of 7 days and to provide details on proached, with the recruitment rate ex- levels were determined by a spectropho- activity duration, type, and intensity dur- ceeding 80% at each site. Each participant tometric-hexokinase method (Roche ing nonwearing/nonsleep periods. Physi- gave informed consent to participate, and Modular; Roche Diagnostics, Indianapo- cal activity diaries supplemented the ethics approval was obtained from the In- lis, IN). Demographic and behavioral at- accelerometer data by recording nonam- ternational Diabetes Institute and from tributes were assessed using interviewer- bulatory activities as well as on/off times the University of Queensland. administered questionnaires; height, of the accelerometer. On the day of recruitment, partici- weight, and waist circumference were pants underwent biochemical, anthropo- measured. Statistical analysis metric, and behavioral assessments as Uniaxial Actigraph accelerometers In line with previous research reporting part of the larger set of AusDiab survey (formerly known as the CSA activity mon- the reliability and validity of the Interna- procedures. The detailed methods of this itor model WAM 7164; http://www. tional Physical Activity Questionnaire protocol have been previously published theactigraph.com/), fitted firmly around (20), a pragmatic cutoff of Ͻ100 counts/ (16–18). In brief, following an overnight the participant’s trunk and placed on the min was chosen to categorize sedentary
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1385 Objectively measured activity and blood glucose
Table 2—Regression analysis of physical activity measures with 2-h postchallenge plasma glucose
B 95% CI P Adjusted R2 Model 1 Sedentary time 0.35 0.17 to 0.53 Ͻ0.001 0.13 Light-intensity activity Ϫ0.30 Ϫ0.49 to Ϫ0.12 0.002 0.11 Moderate- to vigorous-intensity activity Ϫ1.08 Ϫ1.76 to Ϫ0.41 0.002 0.11 Model 2 Sedentary time 0.29 0.11 to 0.48 0.002 0.16 Light-intensity activity Ϫ0.25 Ϫ0.45 to Ϫ0.06 0.012 0.14 Moderate- to vigorous-intensity activity Ϫ1.07 Ϫ1.77 to Ϫ0.37 0.003 0.15 Model 3 Sedentary time* 0.23 0.04 to 0.42 0.019 0.18 Light-intensity activity* Ϫ0.22 Ϫ0.42 to Ϫ0.03 0.023 0.17 Moderate- to vigorous-intensity activity† Ϫ0.81 Ϫ1.53 to Ϫ0.09 0.029 0.18 Model 4 (sex interactions; male ref.) Sedentary time Ϫ0.22 Ϫ0.52 to 0.08 0.148 0.16 Light-intensity activity 0.27 Ϫ0.13 to 0.66 0.181 0.14 Moderate- to vigorous-intensity activity 0.52 Ϫ0.81 to 1.84 0.445 0.15 Activity measured as hours per day. Model 1 was adjusted for age, sex, and time accelerometer worn. Model 2 was adjusted for age, sex, height, waist circumference, time accelerometer worn, accelerometer unit, family history of diabetes, alcohol intake, education, income, and smoking status. Model 3 was adjusted for above covariates and moderate-to-vigorous physical activity (*) or sedentary time (†). Model 4 was adjusted for the same covariates as Model 2 and examined the sex interaction. time, which includes activities such as sit- models then examined the associations of graphic and behavioral characteristics are ting or working quietly (e.g., reading, typ- physical activity with blood glucose mea- listed in Table 1. ing). The widely utilized Freedson’s sures. Models were initially adjusted for Consistent with previous findings cutoffs (21) were then used to differenti- the potential confounders of age (years), (1,7,8), men had significantly higher FPG ate moderate- to vigorous-intensity activ- sex, and time accelerometer worn (h), readings and waist circumference and ity (counts/min Ն1,952) from light- with further adjustment for height (cm), spent more time in moderate- to vigor- intensity activity (100–1,951 counts/ waist circumference (cm), accelerometer ous-intensity activity compared with min). A criterion of at least 20 min of unit number, alcohol intake (self- women. Additionally, a higher propor- continuous 0 counts, as well as diary in- reported as none, light, and moderate-to- tion of men worked full-time compared formation, identified nonwearing peri- heavy), education (attended university or with women. Compared with the broader ods. Average daily time (h) was used to further education, yes/no), income AusDiab Study population, participants summarize the time spent in moderate- to (household income Ն$1,500/week, yes/ in this substudy were slightly younger vigorous-intensity, light-intensity, and no), smoking status (current or ex/ (53.0 vs. 56.6 years, P Ͻ 0.001) but had a sedentary activity. nonsmoker), and family history of similar mean BMI (27.2 vs. 27.7 kg/m2, To be included in the analysis, partic- diabetes (8). Sex and age (Ͻ60 and Ն60 P ϭ 0.683), self-reported physical activity ipants were required to wear the acceler- years) differences in the associations be- (5.2 vs. 4.8 h/week, P ϭ 0.372), and self- ometer for at least 5 valid days, including tween the physical activity and blood glu- reported television viewing time (13.3 vs. at least 1 weekend day, where a valid day cose measures were tested for by adding 13.7 h/week, P ϭ 0.628). was at least 10 h of recorded activity (us- interaction terms to the model. Statistical Table 2 shows that after adjustment ing both accelerometer and diary data). significance was set at P Ͻ 0.05 for the for potential confounders, higher seden- Of the 204 originally recruited, there were main effects, and P Ͻ 0.1 for the interac- tary time was associated with significantly 9 withdrawals, 6 cases where the acceler- tion effects. Analyses were conducted us- higher 2-h plasma glucose, while higher ometer download was faulty and 11 cases ing Stata version 9.0 (22). moderate- to vigorous-intensity and in- where the participant did not meet the creased light-intensity physical activity compliance criteria, leaving a total of 178 time were associated with significantly (70 men, 108 women) who met the inclu- RESULTS — The age of the partici- lower 2-h plasma glucose. Although at- sion criteria. Blood glucose measures pants ranged from 30 to 87 years (mean tenuated, these significant associations were available for 173 of these partici- 53.3 years), and the majority (86%) had persisted after adjusting for other physical pants (67 men, 106 women). Data were blood glucose readings within the “nor- activity measures. Figure 1 highlights complete for all other variables. Of the mal” range (Ͻ6.1 mmol/l for FPG and these significant adjusted associations 173, 6 (3.5%) had 5 days of valid physical Ͻ7.8 mmol/l for 2-h plasma glucose); with 2-h plasma glucose across sex- activity data, with the majority (80.3%) 47.4% were overweight (BMI 25.0–29.9 specific quartiles of sedentary time, light having 7 days of valid data. kg/m2), and 21.4% were obese (BMI Ն30 intensity, and moderate- to vigorous- Univariate analyses were used to kg/m2). The majority (98.8%) spoke En- intensity physical activity. compare sex differences for descriptive glish at home, while 38 women (35.5%) The significant association of moder- and physical activity characteristics of the had either gone through or were now go- ate- to vigorous-intensity physical activity sample. Forced-entry linear regression ing through menopause. Sociodemo- with 2-h plasma glucose persisted when
1386 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Healy and Associates
though attenuated, the direction of the ef- that were based on self-reported physical fect remained the same when only those activity and sedentary behavior (6,8,18). with 7 days of complete data were ana- A major finding of this study is the lyzed (n ϭ 139), with nonstandardized significant association of light-intensity regression coefficients of 0.17 (P ϭ physical activity with 2-h plasma glucose, 0.088), Ϫ0.14 (P ϭ 0.162), and Ϫ0.42 independent of moderate- to vigorous- (P ϭ 0.271) for sedentary time, light- intensity physical activity time. Light- intensity activity, and moderate- to vigor- intensity physical activities are reported ous-intensity activity, respectively. A to be the most prevalent form of activity in similar pattern was also observed when a the general North-American population; more generalized measure of obesity, however, this intensity level is particu- BMI, was included in the models instead larly difficult to detect and assess (9). of waist circumference, with nonstand- Consequently, there is limited epidemio- ardized regression coefficients of 0.31 logical evidence on the association be- (P ϭ 0.001), Ϫ0.27 (0.006), and Ϫ1.09 tween light-intensity physical activity and (0.002) for the three intensity levels (sed- health outcomes (13,14). The majority of entary time, light, and moderate to vigor- participants in our study had normal glu- ous, respectively). Similarly, when the cose tolerance and, therefore, would be data were reanalyzed for full-time work- considered to have a lower risk for hyper- ers only (n ϭ 95), the nonstandardized glycemia-induced complications com- regression coefficients were 0.32 (P ϭ pared with those with impaired glucose 0.018), Ϫ0.28 (P ϭ 0.064), and Ϫ1.09 tolerance. However, a recent meta- (P ϭ 0.014) for sedentary time, light- analysis of 38 prospective studies re- intensity activity, and moderate- to vigor- ported a continuous linear association ous-intensity activity, respectively. between increasing 2-h plasma glucose For FPG, Table 3 shows that the only and risk of all-cause and cardiovascular significant association observed was with disease mortality, with no apparent risk sedentary time, adjusted for age, sex, and threshold (4). Thus, even apparently time accelerometer worn. However, the small shifts in 2-h plasma glucose may association became nonsignificant follow- have important clinical implications. ing further adjustment for potential con- On average, participants spent only a founders, including waist circumference. small proportion of waking hours in mod- There were no statistically significant sex erate- to vigorous-intensity activity (4%). or age interactions observed for the asso- Most activity during waking hours can thus ciations between the physical activity be categorized broadly into two distinct measures and blood glucose (P Ͼ 0.1). modes: light-intensity physical activity and sedentary time. Those who spend more time in light-intensity activity must there- CONCLUSIONS — Previous research fore spend less time in sedentary behaviors. in this study population has reported signif- The beneficial association of light-intensity icant dose-response associations of seden- physical activity with 2-h plasma glucose, as Figure 1—Associations of 2-h plasma glucose tary behavior (television viewing time) and opposed to the detrimental association of with quartiles of percentage of waking hours moderate-to-vigorous physical activity sedentary time with 2-h plasma glucose, has spent in sedentary time (A), light-intensity ac- with 2-h plasma glucose, but not FPG, important implications for lifestyle inter- tivity (B), and moderate- to vigorous-intensity using self-report measures (6,8). Our ventions. Although moderate- to vigorous- activity (C). A: The cut points for men were study extends these findings and is the intensity physical activity is an important 51.19, 58.44, and 64.05; for women, they were first to examine the associations of objec- component of the healthy lifestyle message, 51.05, 55.55, and 62.85. B: The cut points for tively measured intensity of physical ac- practically, intervention studies that target men were 19.26, 22.65, and 26.27; for women, tivity and sedentary time with blood reducing sedentary behavior by the substi- they were 20.19, 24.47, and 27.54. C: The cut points for men were 2.94, 5.03, and 6.96; for glucose measures in adults. Following ad- tution of light-intensity activities may have a women, they were 1.90, 2.91, and 4.72. Mar- justment for potential confounders, in- higher success rate, particularly given that ginal means (95% CI) were adjusted for age, cluding waist circumference, significant more than one-half of the population fails to sex, height, waist circumference, family history dose-response associations of sedentary participate in adequate amounts of physical of diabetes, alcohol intake, education level, in- time and moderate- to vigorous-intensity activity to benefit their health (6). Light- come, smoking status, accelerometer unit, and physical activity were observed with 2-h intensity physical activity interventions may percent moderate- to vigorous-intensity activ- plasma glucose, but not FPG, with the also be more likely to succeed across a vari- ity (sedentary and light intensity) or percent magnitude of the associations greater than ety of settings, including the workplace. sedentary (moderate to vigorous intensity). that previously reported (6,8,23). Given The only significant association ob- that the characteristics of our sample are served for FPG was for sedentary time, the diary data were excluded from the similar to the participant characteristics of unadjusted for waist circumference. This analysis (b ϭϪ1.07 [95% CI Ϫ1.86 to the overall AusDiab sample, these results concurs with previous population-based Ϫ0.28] P ϭ 0.008). Additionally, al- increase our confidence in earlier findings research using self-reported television
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1387 Objectively measured activity and blood glucose
Table 3—Regression analysis of physical activity measures with fasting plasma glucose
B 95% CI P Adjusted R2 Model 1 Sedentary time 0.05 0.00 to 0.11 0.046 0.13 Light-intensity activity Ϫ0.04 Ϫ1.00 to 0.11 0.117 0.12 Moderate- to vigorous-intensity activity Ϫ0.15 Ϫ0.35 to 0.05 0.141 0.12 Model 2 Sedentary time 0.04 Ϫ0.02 to 0.09 0.163 0.15 Light-intensity activity Ϫ0.03 Ϫ0.09 to 0.02 0.248 0.15 Moderate- to vigorous-intensity activity Ϫ0.08 Ϫ0.29 to 0.13 0.439 0.15 Model 3 Sedentary time* 0.04 Ϫ0.02 to 0.09 0.224 0.15 Light-intensity activity* Ϫ0.03 Ϫ0.09 to 0.03 0.281 0.15 Moderate- to vigorous-intensity activity† Ϫ0.04 Ϫ0.26 to 0.09 0.706 0.15 Model 4 (sex interactions; male ref.) Sedentary time Ϫ0.03 Ϫ0.12 to 0.06 0.549 0.15 Light-intensity activity 0.03 Ϫ0.09 to 0.15 0.613 0.15 Moderate- to vigorous-intensity activity 0.03 Ϫ0.37 to 0.42 0.898 0.14 Activity measured as hours per day. Model 1 was adjusted for for age, sex, and time accelerometer worn. Model 2 was adjusted for age, sex, height, waist circumference, time accelerometer worn, accelerometer unit, family history of diabetes, alcohol intake, education, income, and smoking status. Model 3 was adjusted for above covariates and moderate-to-vigorous physical activity (*) or sedentary time (†). Model 4 was adjusted for the same covariates as Model 2 and examined the sex interaction. time as an estimate of sedentary behavior fluenced their physical activity behavior. register a quite low average of 60 counts/ (7,8,24). These findings emphasize the The 7-day collection of physical activity min (28). Also, there is some evidence important physiological differences be- data occurred after the blood glucose that the relationship between accelerom- tween FPG and 2-h plasma glucose in measure was taken. Given that there are eter counts and physical activity intensity their relationship with physical activity acute effects of physical activity on blood varies across individuals (29). Future re- and highlight that lifestyle interventions glucose, the results of this study are there- search, using shorter epoch lengths, addressing increasing physical activity fore reliant on the extent to which par- should utilize recently published regres- and reducing sedentary time need to mea- ticipants engaged in a typical week of free- sion equations that more accurately cap- sure 2-h plasma glucose, rather than FPG, living physical activity behavior. Addi- ture free-living physical activity (28). as the primary outcome. tionally, the beneficial association of Our study adds to the broader evi- This is the first study to examine as- moderate-to-vigorous physical activity on dence base on not only the importance of sociations of objectively assessed inten- 2-h plasma glucose may have been under- increasing moderate-to-vigorous physical sity of free-living physical activity and estimated, as placing moderate- to vigor- activity but also reducing sedentary be- sedentary time with standard blood glu- ous-intensity physical activity into a havior in adult populations where the cose measures. The study was conducted single category does not take into account prevalence of type 2 diabetes is increas- in a nonclinical population that was rep- the strong influence on insulin action of ing. Our data provide the first objective resentative of the broader AusDiab study vigorous-intensity activity compared with evidence that light-intensity physical ac- population. Additional strengths of the moderate-intensity activity (26). Limita- tivity is beneficially associated with blood study include the detailed sociodemo- tions are inherent in all cut points used to glucose and that sedentary time is unfa- graphic, medical, and behavioral data ob- summarize accelerometer data (27). vorably associated with blood glucose. tained. There was high compliance with Freedson’s cut points were used in this Substituting light-intensity activity for the study protocol, and the study fol- study, and although they are one of the television viewing or other sedentary time lowed recommendations for best practice more commonly reported cut points used may be a practical and achievable preven- for the use of accelerometers in field work in accelerometer studies of physical activ- tive strategy. (25). Measurement of physical activity ity, they were originally derived using a and sedentary time was not limited to lei- young adult population (21), and the in- Acknowledgments— The following pro- sure-time activities, while the combined tensity values that represent light and vided financial support: the National Health use of accelerometers and physical activ- moderate-to-vigorous may not reflect the and Medical Research Council (grant ity diaries ensured that a broad range of self-reported intensity level in this older 233200); the Australian Government Depart- physical activities could be captured and adult population. Similarly, in line with ment of Health and Ageing; Abbott Austral- analyzed. previous research (20), a relatively high asia; Alphapharm; AstraZeneca; Aventis There are some potential limitations cut point of Ͻ100 counts/min was chosen Pharma; Bristol-Myers Squibb; City Health of our findings. The cross-sectional na- for sedentary time. Although it is unlikely Centre, Diabetes Service, Canberra, Australia; Department of Health and Community Ser- ture of the data limits inference about cau- to change the direction of the findings, a vices, Northern Territory; Department of sality, though considering that those with lower cut point for sedentary time may be Health and Human services, Tasmania; De- known diabetes were excluded from the more appropriate, given the recent evi- partment of Health, New South Wales; De- study, it is unlikely that the blood glucose dence that nonambulatory standing activ- partment of Health, Western Australia; levels of our participants could have in- ities, such as the filing of paperwork, can Department of Health, South Australia; De-
1388 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Healy and Associates partment of Human Services, Victoria; Diabe- ing blood glucose in Australian adults: the lence of diabetes and impaired glucose tes Australia; Diabetes Australia Northern AusDiab study. Diabetes Care 29:2598– tolerance: the Australian Diabetes, Obe- Territory; Eli Lilly Australia; the estate of the 2604, 2006 sity and Lifestyle Study. Diabetes Care 25: late Edward Wilson; GlaxoSmithKline; Jack 7. Kronenberg F, Pereira MA, Schmitz MK, 829–834, 2002 Brockhoff Foundation; Janssen-Cilag; Kidney Arnett DK, Evenson KR, Crapo RO, 17. Dunstan DW, Zimmet PZ, Welborn TA, Health Australia; Marian and F.H. Flack Trust; Jensen RL, Burke GL, Sholinsky P, Ellison Cameron AJ, Shaw J, de Courten M, Jolley Menzies Research Institute; Merck Sharp and RC, Hunt SC: Influence of leisure time D, McCarty DJ: The Australian Diabetes, Dohme; Novartis Pharmaceuticals; Novo physical activity and television watching Obesity and Lifestyle Study (AusDiab)– Nordisk Pharmaceuticals; Pfizer; the Pratt on atherosclerosis risk factors in the methods and response rates. Diabetes Res Foundation; Queensland Health; Roche Diag- NHLBI Family Heart Study. Atherosclero- Clin Pract 57:119–129, 2002 nostics Australia; Royal Prince Alfred Hospital, sis 153:433–443, 2000 18. Dunstan DW, Salmon J, Owen N, Arm- Sydney; and Sanofi Synthelabo. 8. Dunstan DW, Salmon J, Healy GN, Shaw strong T, Zimmet PZ, Welborn TA, Cam- G.N.H. is supported by Queensland Gov- JE, Jolley D, Zimmet PZ, Owen N: Asso- eron AJ, Dwyer T, Jolley D, Shaw JE: ernment Growing the Smart State PhD fund- ciation of television viewing with fasting Physical activity and television viewing in ing and an Australian Postgraduate Award. and 2-hr post-challenge plasma glucose relation to risk of undiagnosed abnormal N.O. is supported by a Queensland Health levels in adults without diagnosed diabe- glucose metabolism in adults. Diabetes Core Research Infrastructure grant and by Na- tes. Diabetes Care 30:516–522, 2007 Care 27:2603–2609, 2004 tional Health and Medical Research Council 9. Shephard RJ: Limits to the measurement 19. World Health Organization: Definition, program grant funding (no. 301200). D.W.D. of habitual physical activity by question- Diagnosis and Classification of Diabetes Mel- and J.S. are supported by a Victorian Health naires. Br J Sports Med 37:197–206, 2003 litus and its Complications: Report of a WHO Promotion Foundation Public Health Re- 10. Ainsworth BE, Haskell WL, Whitt MC, Ir- Consultation. Part 1. Diagnosis and classifi- search Fellowship. win ML, Swartz AM, Strath SJ, O’Brien cation of diabetes mellitus. Geneva,World We thank A. Allman, B. Atkins, S. Bennett, S. WL, Bassett DR Jr, Schmitz KH, Emplain- Health Org., 1999 Chadban, S. Colagiuri, M. de Courten, M. Dal- court PO, Jacobs DR Jr, Leon AS: Com- 20. Craig CL, Marshall AL, Sjostrom M, Bau- ton, M. D’Embden, T. Dwyer, D. Jolley, I. Kemp, pendium of physical activities: an update man AE, Booth ML, Ainsworth BE, Pratt P. Magnus, J. Mathews, D. McCarty, A. Meehan, of activity codes and MET intensities. Med M, Ekelund U, Yngve A, Sallis JF, Oja P: K. O’Dea, P. Phillips, P. Popplewell, C. Reid, A. Sci Sports Exerc 32:S498–S504, 2000 International physical activity question- Stewart, R. Tapp, H. Taylor, T. Welborn, and F. 11. Donahoo WT, Levine JA, Melanson EL: naire: 12-country reliability and validity. Wilson for their invaluable contribution to the Variability in energy expenditure and its Med Sci Sports Exerc 35:1381–1395, 2003 set up and field activities of AusDiab; M. Lee for components. Curr Opin Clin Nutr Metab 21. Freedson PS, Melanson E, Sirard J: Cali- for her assistance with recruitment and data col- Care 7:599–605, 2004 bration of the Computer Science and Ap- lection; and we are especially grateful to the par- 12. Levine JA, Eberhardt NL, Jensen MD: Role plications, Inc. accelerometer. Med Sci ticipants for volunteering their time to be of nonexercise activity thermogenesis in Sports Exerc 30:777–781, 1998 involved in this study. resistance to fat gain in humans. Science 22. Stata Corp: Statistical Software: Release 283:212–214, 1999 8.0. College Station, TX, Stata Corpora- 13. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1389 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
A Multicenter Randomized Controlled Trial of Motivational Interviewing in Teenagers With Diabetes
1 3 SUE J. CHANNON, D CLIN PSYCH REBECCA L. CANNINGS-JOHN, MSC was a need for more well-designed trials 2 5 MICHELLE V. HUWS-THOMAS, MSC CAROL ROGERS, RGN of such interventions, particularly in the 3 5 STEPHEN ROLLNICK, PHD JOHN W. GREGORY, MD 4 U.K. health care context. Motivational in- KERENZA HOOD, PHD terviewing, a counseling approach to fa- cilitate behavioral change (5), has been demonstrated as effective in adults in OBJECTIVE — We sought to examine the efficacy of motivational interviewing with teenag- some health care settings (6,7), and there ers aged 14–17 years with type 1 diabetes. is preliminary evidence of its effectiveness in improving glycemic control and psy- RESEARCH DESIGN AND METHODS — In a randomized controlled trial analyzed by chological well-being in teenagers with intention to treat, 66 teenagers with type 1 diabetes attending diabetes clinics in South Wales, type 1 diabetes in short-term, uncon- U.K., were randomly assigned to the intervention group (38) and control group (28). Teenagers in the intervention group received motivational interviewing, and the control group received trolled trials (8,9). The multicenter ran- support visits. All participants received individual sessions over 12 months. The main outcome domized controlled trial reported here measures assessed at baseline, 6, 12, and 24 months were serum A1C and psychosocial self- was developed to replicate and extend the report questionnaires including quality of life and well-being measures. findings of the pilot study (8), employing a fully powered design and an evaluation RESULTS — At 12 months, 60 patients had complete data. At the end of the intervention (12 of longer-term outcomes. months), the mean A1C in the motivational interviewing group was significantly lower than in the control group (P ϭ 0.04), after adjusting for baseline values. At 24 months (when n ϭ 47), ϭ RESEARCH DESIGN AND this difference in A1C was maintained (P 0.003). There were differences in psychosocial METHODS variables at 12 months, with the motivational interviewing group indicating more positive well-being, improved quality of life, and differences in their personal models of illness (all P Ͻ 0.01). Some of these differences were maintained at 24 months. Aims and hypotheses The aim of this study was to examine the CONCLUSIONS — Motivational interviewing can be an effective method of facilitating be- impact of motivational interviewing, havioral changes in teenagers with type 1 diabetes with subsequent improvement in their gly- compared with the control intervention cemic control. of support visits, on serum A1C concen- trations and psychosocial functioning in Diabetes Care 30:1390–1395, 2007 adolescents with type 1 diabetes. We hy- pothesized that, compared with the con- ype 1 diabetes is the third most com- documented (3). However, recognition of trol group, motivational interviewing mon chronic illness in teenagers (1). the impact of psychosocial factors on self- would improve psychosocial functioning T It imposes physical and emotional care during adolescence has led to a focus and reduce A1C concentrations. burdens on young people and their fami- on psychosocial interventions to improve lies (1) and can have a profound effect on outcomes. Design and participants quality of life (2). The beneficial effects of A review of educational and psychos- This study was designed as a multicenter favorable glycemic control in the preven- ocial interventions for adolescents with trial of a complex intervention, providing tion of long-term complications are well type 1 diabetes (4) concluded that there a phase II level of evidence of efficacy ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● (10). Each intervention was delivered by From the 1Department of Child Psychology, Cardiff and Vale NHS Trust, Wales, U.K.; the 2School of Nursing one person for all participants in their arm and Midwifery studies, Cardiff University, Wales, U.K.; the 3Department of General Practice, Cardiff Uni- of the study. Following randomization, versity, Wales, U.K.; the 4South East Wales Trial Unit, Cardiff University, Wales, U.K.; and the 5Department participants received either motivational of Child Health, Cardiff University, Wales, U.K. interviewing or support visits for 1 year Address correspondence and reprint requests to S. Channon, Child Clinical Psychology Department, with a 12-month follow-up. The inter- Children’s Centre, St. David’s Hospital, Canton, Cardiff CF11 9XB, U.K. E-mail: sue.channon@ cardiffandvale.wales.nhs.uk. ventionists worked independently from Received for publication 7 November 2006 and accepted in revised form 20 February 2007. the diabetes clinics. Clinic staff were un- Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2260. aware of which children were participat- Clinical trial reg. no. NCT00326573, clinicaltrials.gov. ing in the study, and participants were Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ dc06-2260. unaware to which arm of the trial they had S.J.C. is currently affiliated with the Child Clinical Psychology Department, Children’s Centre, St. David’s been randomized. The study received Hospital, Wales, U.K. ethical approval from the local research A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ethics committees. factors for many substances. Participants were recruited from five © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby diabetes services between January and marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. September 2002. The centers with diabe-
1390 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Channon and Associates tes clinics ranging between 49 and 220 change against the personal costs, which etc., and lasting between 20 and 60 min. patients were all in the industrially devel- may be social, emotional, or financial. Interviews finished after a maximum of oped region of South Wales. All individ- Their ambivalence about making that 12 months’ contact for each individual. uals aged between 14 and 17 years with change reflects the balance of those ben- The mean number of visits was six for the type 1 diabetes, regardless of glycemic efits and costs; the clinician’s role is to control group participants and four control, attending diabetes clinics in the elicit them and increase the patient’s within the motivational interviewing participating centers were eligible, with awareness of them. group. the following exceptions: those with Ͻ1 Alternatives. Once the patients are more year since diagnosis, learning disabilities, aware of the costs and benefits of their Primary and secondary outcome other medical conditions affecting diabe- behavior, alternatives to the current be- measures tes management, medical care predomi- haviors are considered. The primary outcome measure was mean nantly managed elsewhere, or accom- Problem solving. Having identified al- serum A1C concentration, measured at modation by social services. ternative behaviors, the costs and benefits baseline, 6, 12, and 24 months. The sec- The diabetes nurse specialists for each of the different options are discussed. ondary outcome measures were psycho- center sent information about the study to Making choices. The selection of an al- social questionnaires completed inde- all eligible patients and to their parent/ ternative behavior to implement rests pendently by the participants. The mea- guardian. Following consent to contact, with the patient. sures used (and domains they measured) the patients were seen by the researcher Goal setting. Once the alternative be- were as follows: 1) The Diabetes Quality and given further information about the havior has been chosen, the clinician and of Life Measure for Youths (14) measured study. Informed consent was obtained patient set a goal that is realistic and life satisfaction, disease impact, and dis- both from the patients and their parent/ achievable in the time between appoint- ease-related worries. 2) The Child Health guardian before randomization. ments. Locus of Control (15) studied the locus of In order to detect a difference of 1% in Avoidance of confrontation. One of the control in relation to health issues. 3) The mean A1C (SD ϭ 1.2%) at a 5% signifi- central tenets of motivational interview- Modified Health Care Climate Question- cance level with 90% power, 30 patients ing is avoidance of confrontation, to re- naire (16) assessed perceptions of the de- per group would be required. To allow for duce resistance and argumentation. gree of autonomy support from health a loss to follow-up rate of 25%, we aimed Instead the style is one of eliciting, using care providers. 4) The Diabetes Knowl- to recruit 80 patients. open-ended questions to encourage par- edge Scale (17) measured knowledge ticipants to articulate their concerns and about diabetes. 5) The Self-Efficacy for Randomization goals. Diabetes Scale (18) assessed self-efficacy Participants for each center were all re- The control intervention was nondi- beliefs. 6) The Well-being Questionnaire cruited and completed the baseline as- rective psychological support with the (19) assessed depressed mood, anxiety, sessments before being randomized into aim of providing support, information, and positive well-being. 7) The Diabetes one of two groups using randomly per- and education in a patient-centered style. Family Behavior Scale (20) studied diabe- muted blocks of four. One group received Both interventionists received fortnightly tes-specific family support. 8) The Per- motivational interviewing, and, to control supervision to ensure quality control and, sonal Models of Diabetes Scale (21) for the effect of additional contact, the where possible, interviews were record- looked at personal beliefs and models of control group received support visits. ed via audiotape. A sample of the moti- illness. All the questionnaires were com- Randomization was completed indepen- vational interviewing tapes was also pleted at baseline and 12 months, with dently and remotely stratified by sex and reviewed by external motivational inter- the Diabetes Quality of Life Measure for clinic. viewing trainers to ensure fidelity of the Youths and Well-Being Questionnaire method to the tenets of motivational in- also completed at 24 months. Interventions terviewing. In neither group was advice There were two female interventionists, given regarding changes in insulin regi- Data collection and collation both with a nursing background. The mo- men; all these issues were directed to the The baseline A1C and psychosocial data tivational interviewing interventionist participant’s diabetes team. collection was completed before the start was in training as a health psychologist. For participants in the motivational of the intervention. All capillary blood The motivational interviewing interven- interviewing group, the frequency and lo- samples for A1C measurement were tion (described in Channon et al. [11]) cation of appointments was determined mailed to a single independent clinical used the “menu of strategies” approach by the participants to fit with the patient- biochemistry department and analyzed (12,13), eliciting patient views and then driven principles of motivational inter- by high-pressure chromatography. The exploring discrepancies between beliefs viewing. In the control group, the pattern coefficients of variation (CVs) within and and behavior. While no two motivational of visits was more structured, with ap- between the A1C assays were Ͻ1.15 and interviewing sessions will be the same, as pointments arranged every 6–8 weeks, a Ͻ1.75%, respectively. Questionnaire they are patient driven, they are likely to frequency based on contact data from the data were collated and coded onto SPSS include the following aspects. pilot study, to control for anticipated level Software, version 11. Follow-up data Awareness building. The clinician’s role of contact in the motivational interview- were collected between June and Septem- is to help the patients articulate their si- ing group. ber 2004. multaneously held but conflicting beliefs Intervention delivery took place be- about behavioral change. In making deci- tween July 2002 and September 2003, Statistical analysis sions about changing behavior, individu- mostly in participants’ homes, with some To compare the two groups, a repeated- als weigh up the benefits of making the interviews conducted in cafes or parks, measures ANCOVA was performed with
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1391 Motivational interviewing with teenagers
A1C concentrations at 6, 12, and 24 months and the baseline measurement treated as the covariate. Analysis is pre- sented for the effect of the intervention immediately postintervention, as well as the overall analysis across all time points. For each of the psychological scales, participants with Յ20% of scale items missing were imputed by using the mean values of the remaining items. ANCOVA was used to compare the groups with re- spect to their individual psychosocial measurements at 12 and 24 months, again using baseline as the covariate. To allow for multiple comparisons, a Bonfer- roni correction was used. Exploratory analysis of the associa- tions between changes in key psychoso- cial outcomes during treatment (0–12 months) with subsequent changes in A1C (12–24 months) was conducted within groups using Pearson’s correlation coeffi- cients. All analyses were carried out on an intention-to-treat basis.
RESULTS — The flow diagram (Fig. 1) shows the trial profile. Of the original 169 eligible patients, 80 agreed to participate and were randomly allocated to either motivational interviewing (n ϭ 43) or support visits (n ϭ 37). One participant randomized to the control group was in- eligible. A total of 13 patients (5 in the motivational interviewing group and 8 in the control group) declined to participate after randomization but before the first visit. Analyses were based on the remain- ing 66 participants, of whom 60 had com- plete A1C data at 12 months.
Demographic characteristics Figure 1—Flow chart of participants through each stage of the trial Participants in the motivational inter- viewing and control groups were well Attrition adjusting for baseline. This effect was Ϯ Ϯ matched for age (15.3 0.97 and 15.4 More participants withdrew from the mo- maintained 1 year after completion of the 1.19 years, respectively), duration of dia- tivational interviewing intervention in the intervention, 24 months after starting the Ϯ Ϯ betes (9.2 1.96 and 9.1 1.47 years), first 6 months (n ϭ 10) than from the study (F ϭ 9.707, P ϭ 0.003). ethnicity (all Caucasian), sex (47 and 50% control group (n ϭ 4), but this was not Although every effort was made to en- male) and socioeconomic status (median statistically significant (P ϭ 0.24). There sure a complete A1C dataset for each par- group 4 and 3). There were no significant were no significant differences between ticipant, this was not achieved because of differences between the two groups with these participants and those who contin- lost or insufficient samples or participants respect to the baseline characteristics of ued with respect to baseline characteris- discontinuing the study or being unavail- age, duaration of diabetes, sex, and A1C. tics, A1C, or psychological outcomes. able for sampling. The analysis of the The mean A1C for the five participating mean A1C concentrations in the 47 par- centers ranged from 8.4 to 10.0%, and for Primary outcome measure: serum ticipants with a complete dataset (i.e., the participants the range was 8.8 to A1C concentration four measurements) is shown in Table 1. 10.3%. There were a variety of insulin At the end of the year-long interventions, The patterns of change were similar to regimens across both groups, with partic- the mean A1C concentrations between those seen when all participants’ data, in- ipants all injecting insulin 2–4 times the two groups were significantly differ- cluding those with incomplete data, were daily. ent (F ϭ 4.276, P ϭ 0.04) (Table 1) after analyzed.
1392 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Channon and Associates
Table 1—A1C levels at baseline, 6, 12, and 24 months for participants with complete data
Time point MI group (n ϭ 27) Control group (n ϭ 20) Difference between groups Baseline 9.3 Ϯ 2.11 9.0 Ϯ 1.56 0.3 Ϯ 1.90 (Ϫ0.80 to 1.40) 6 months 9.0 Ϯ 1.63 9.5 Ϯ 1.93 Ϫ0.5 Ϯ 1.76 (Ϫ1.52 to 0.52) 12 months 8.7 Ϯ 1.84 9.2 Ϯ 1.78 Ϫ0.5 Ϯ 1.81 (Ϫ1.55 to 0.55) 24 months 8.7 Ϯ 1.88 9.1 Ϯ 1.51 Ϫ0.4 Ϯ 1.73 (Ϫ1.40 to 0.60) Data are means Ϯ SD (95% CI). MI, motivational interviewing.
Secondary outcome measures: nificant differences were still found respectively), and the directions of asso- psychosocial questionnaires between the two groups with respect to ciation were the opposite of those found There were no baseline differences be- life worry and anxiety (F ϭ 17.795, P ϭ in the motivational interviewing group. tween groups in any of the psychosocial 0.001 and F ϭ 18.908, respectively; P Ͻ measures. Differences were found be- 0.001). Differences in satisfaction and im- CONCLUSIONS — The results of tween groups in well-being, quality of life, pact were also significant at 24 months this study show that motivational inter- and personal models of illness after 12 (F ϭ 7.007, P ϭ 0.012 and F ϭ 8.129, viewing can be an effective method of months (all P Ͻ 0.001) (Table 2). Com- respectively; P ϭ 0.008). working with teenagers with diabetes, pared with the control group, the motiva- Exploratory analysis of the associa- producing long-term improvements in tional interviewing group had higher life tions between changes on key psychoso- glycemic control, psychological well- satisfaction, lower life worry, experienced cial measures during the intervention being, and quality of life. Their personal less anxiety, and had more positive well- phase and subsequent levels of glycemic models of illness indicated a stronger be- being. The motivational interviewing control showed that increasing worry and lief that self-care could make a difference group also perceived their diabetes to be reduction in satisfaction from 0 to 12 to diabetes outcomes. more serious and placed greater impor- months in the motivational interviewing The study reported here is the first tance on controlling it. They had stronger group were significantly associated with randomized controlled trial of motiva- beliefs that certain actions were more improvements in A1C from 12 to 24 tional interviewing in childhood diabetes. likely to help prevent future complica- months (r ϭϪ0.40, P ϭ 0.03 and r ϭ It extends the evidence and confirms the tions of diabetes and perceived it to have a Ϫ0.61, P Ͻ 0.001, respectively). There beneficial impact of psychosocial inter- smaller degree of impact on their lives. were no significant associations between ventions based on the principles of moti- At 24 months, although fewer ques- these measures and subsequent control in vational interviewing that have been tionnaires were completed (n ϭ 34), sig- the support group (r ϭ 0.31 and r ϭ 0.22, previously reported in smaller-scale stud-
Table 2—Psychosocial measures at 12 months
Measure Intervention group Control group FP DQoLY Satisfaction* 33.28 Ϯ 9.88 45.55 Ϯ 10.79 31.769 Ͻ0.001 Impact* 50.49 Ϯ 12.05 61.05 Ϯ 18.48 9.553 0.003 Worries* 17.71 Ϯ 7.15 30.23 Ϯ 11.59 22.209 Ͻ0.001 CHLC 15.88 Ϯ 2.59 16.40 Ϯ 1.95 0.034 NS HCCQ 78.06 Ϯ 20.34 84.25 Ϯ 13.30 0.010 NS DKN 11.16 Ϯ 1.86 11.75 Ϯ 1.77 1.406 NS SEDS 175.92 Ϯ 22.73 169.85 Ϯ 27.45 0.733 NS WBQ Depression 10.08 Ϯ 2.25 11.85 Ϯ 1.81 4.326 0.044 Anxiety 6.03 Ϯ 2.23 11.55 Ϯ 3.69 41.267 0.001 Energy 6.19 Ϯ 1.86 7.20 Ϯ 2.31 2.086 0.156 Positive well-being 14.48 Ϯ 3.20 10.24 Ϯ 3.27 22.923 Ͻ0.001 Total well-being 40.56 Ϯ 4.51 30.31 Ϯ 5.90 39.419 Ͻ0.001 DFBS 145.56 Ϯ 20.64 155.57 Ϯ 16.45 1.162 NS PMDQ Importance 32.58 Ϯ 5.06 22.84 Ϯ 4.02 64.776 Ͻ0.001 Likely 41.46 Ϯ 6.25 29.52 Ϯ 5.54 59.056 Ͻ0.001 Worry 33.19 Ϯ 8.76 24.78 Ϯ 5.98 13.605 Ͻ0.001 Agree/disagree 28.32 Ϯ 5.66 34.52 Ϯ 6.23 13.845 Ͻ0.001 Total 135.55 Ϯ 15.30 111.66 Ϯ 10.97 44.642 Ͻ0.001 Data are means Ϯ SD unless otherwise indicated. *Lower score indicates higher quality of life. CHLC, Child Health Locus of Control; DFBS, Diabetes Family Behavior Scale; DKN, Diabetes Knowledge Scale; DQoLY, Diabetes Quality of Life Measure for Youths; HCCQ, Modified Health Care Climate Questionnaire; PMDQ, Personal Models of Diabetes Scale; SEDS, Self-Efficacy for Diabetes Scale; WBQ, Well-Being Questionnaire.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1393 Motivational interviewing with teenagers ies (8,9). Furthermore, this study is one of tically would be the target for the clinical whether the independence of the inter- very few that demonstrate, using a ran- teams. vention from the clinic, both in terms of domized control study design, the poten- The results show a rise, albeit statisti- venue and practitioners, is essential to its tial of a psychosocial intervention to cally nonsignificant, in A1C concentra- success. Furthermore, to maximize the improve glycemic control in children tions in the control group during the first value of this intervention, it would be im- with diabetes over a time period as long as six months with a return to baseline levels portant for the intervention to be part of two years (4). Given the potential benefit after one year. This phenomenon persists routine care. Given the shortage of skilled of improved glycemic control on the fu- whether data for all participants or only child psychologists and psychiatrists ture risks of developing microvascular those with complete data sets are ana- available to support pediatric diabetes complications of diabetes (3), our results lyzed and was not seen in those receiving services, the next research priority is to suggest that psychosocial interventions motivational interviewing. A possible ex- identify the key components of motiva- such as motivational interviewing may be planation for this rise is a seasonal effect as tional interviewing that successfully re- of value in addition to pharmacological this data period coincided with winter, sult in behavioral changes in teenagers, developments in reducing the longer- when glycemic control is known to dete- with a view to developing training of cli- term adverse consequences of diabetes. riorate in children, presumably because nicians working in pediatric diabetes ser- This was a robust study across centers of decreased levels of physical activity vices to use these skills as part of everyday representing a variety of demographic (22). clinical care. and clinical contexts with high-quality in- The results of our study demonstrate tervention delivery, closely monitored to an association between changes in certain ensure adherence to the documented psychological variables and changes in Acknowledgments— We are grateful to Dia- approaches. However, there were also A1C, the latter increasing in significance betes UK, who funded the study (research some recognized weaknesses. By using with time. Although cause and effect can- grant BDA RD01/0002113), and to the teen- two interventionists, the outcome could not be assumed, if psychological factors agers and their families who took part. We wish to thank Professor Ian Russell for be interpreted as therapist effect rather were to impact A1C, it might be antici- his constructive comments on our study de- than resulting from motivational inter- pated that such psychological changes sign and the Brecon Group for facilitating re- viewing. However, both intervention- would precede changes in self-care, cruitment of patients from their clinical ists were closely supervised to ensure which consequently led to changes in services. fidelity to the method of their respective A1C concentrations. Our analyses sug- interventions, and this design was se- gest that motivational interviewing might lected as the best possible for this phase highlight concerns (with the reduction in References of intervention development. The next satisfaction between baseline and 12 1. Porter J, Kirk J, Hocking M, Barrett T: phase would be a multicenter trial with months) but also facilitate the patients’ Measuring psychological adjustment to multiple interventionists. perception that they had the capacity to diabetes in adolescence. Diabetes Today 4: Another possible explanation for the make changes that in turn would lead to 132–136, 2001 improvement in glycemic control in those reduction in A1C. One possible theoreti- 2. Edgar KA, Skinner TC: Illness representa- receiving motivational interviewing may cal explanation for these results could be tions and coping as predictors of emo- relate to changes in insulin regimen. Un- taken from the work by Draycott and tional well being in adolescents with type 1 diabetes. J Paediatr Psychol 28:485–493, fortunately, these data were not collected Dabbs (23,24), who mapped the princi- 2003. during the trial, but a retrospective anal- ples of cognitive dissonance onto the 3. Diabetes Control and Complications Trial ysis of a subsample of participants shows principles and method of motivational in- Research Group: The effect of intensive no evidence of a difference in frequency of terviewing. The method of motivational treatment of diabetes on the development change in insulin regimen between interviewing incorporates the principle of and progression of the long term compli- groups (data not shown). This would be a “deploying discrepancy” in which the pa- cations in insulin dependent diabetes melli- measure that would need to be incorpo- tients’ core values and personal aspira- tus. N Engl J Med 329:977–985, 1994. rated into any larger-scale trial. tions are contrasted, through empathic 4. Hampson SE, Skinner TC, Hart J, Storey Some attrition was inevitable in a listening, with the behavioral problem L, Gage H, Foxcroft D, Kimber A, Shaw K, multicenter clinical trial with a 2-year pe- under discussion. It is hypothesized that Walker J: Effects of educational and psy- chosocial interventions for adolescents riod of data collection. The volume of this experience of discrepancy could trig- with diabetes mellitus: a systematic re- questionnaires was overwhelming for ger the motivation to change behavior. view. Health Technol Assess 5:1–79, 2001. participants, leading to the decision at 24 A systematic review of the literature of 5. Motivational Interviewing: Preparing People months to collect psychosocial data only psychosocial interventions in childhood for Change. 2nd ed. Miller W, Rollnick S, on well being and quality of life to avoid diabetes concluded that well-designed Eds. London, Guildford Press, 2002 the risk of losing all the follow-up data. studies of such interventions are required 6. Burke B, Arkowitz H, Menchola M: The There were few exclusion criteria, and as a (4), and our study meets many of their efficacy of motivational interviewing: a result we recruited some participants who criteria. It has demonstrated that a psy- meta-analysis of controlled clinical trials. J already experienced good glycemic con- chosocial intervention can have a signifi- Consult Clin Psychol 71:843–61, 2003 trol in whom behavior change may have cant impact on psychosocial variables and 7. Hettema J, Steele J, Miller WR: A meta-anal- ysis of research on motivational interview- been unrealistic. Within a service setting, A1C concentrations in a representative ing treatment effectiveness (MARMITE). it might be more appropriate to focus this group of teenagers. Further work is re- Annu Revi Clin Psychol 1:91–111, 2005 intervention on young people with A1C quired to determine whether motiva- 8. Channon S, Smith V, Gregory JW: A pilot Ͼ8%, in whom there was a degree of tional interviewing is more suitable for study of motivational interviewing in ad- readiness to change—a group who realis- certain subgroups of children and olescents with type 1 diabetes. Arch Dis
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Child 88:680–683, 2003 properties. Diabetes Educ 17:114–118, 20. McKelvey J, Waller D, North A, Marks J, 9. Viner RM, Christie D, Taylor V, Hey S: 1991 Schreiner B, Travis L, Murphy J: Reliabil- Motivational/solution-focused interven- 15. Wallston B: Children’s health locus of con- ity and validity of the Diabetes Family Be- tion improves A1C in adolescents with trol. J Consult Clin Psychol 44:680–689, haviour Scale (DFBS). Diabetes Educ 19: type 1 diabetes: a pilot study. Diabetes 1976 125–132, 1993 Med 20:739–742, 2003 16. Williams G, Freedman ZR, Deci EL: Sup- 21. Hampson SE, Glasgow RE, Foster LS: Per- 10. Campbell M, Fitzpatrick R, Haines A, porting autonomy to motivate patients sonal models of diabetes among older Kinmonth AL, Sandercock P, Spielgelhal- with diabetes for glucose control. Diabetes adults: relationship to self-management ter D, Tyrer P: Framework for design and Care 21:1644–1651, 1998 and other variables. Diabetes Educ 21: evaluation of complex interventions to 17. Dunn SM, Bryson JM, Hoskin PL, Alford 300–307, 1995 improve health. BMJ 321:694–696, 2000 JB, Handelsman DJ, Turtle JR: Develop- 22. Hinde FR, Standen PJ, Mann NP, 11. Channon S, Huws-Thomas MV, Gregory ment of the Diabetes Knowledge (DKN) Johnston DI: Seasonal variation of haemo- JW, Rollnick S: Motivational interviewing Scales: forms DKNA, DKNB, and DKNC. globin A1 in children with insulin-depen- with teenagers with diabetes. Clin Child Diabetes Care 7:36–41, 1984 dent diabetes mellitus. Eur J Pediatr 148: Psychol Psychiat 10:43–51, 2005 18. Grossman H: Self-efficacy in adolescent 597–599, 1989 12. Rollnick S, Heather N, Bell A: Negotiating girls and boys with insulin dependent di- 23. Draycott S, Dabbs A: Cognitive disso- behaviour change in medical settings: the abetes mellitus. Diabetes Care 10:324– nance. 1. An overview of the literature development of brief motivational inter- 329, 1987 and its integration into theory and prac- viewing. J Mental Health 1:25–37, 1992 19. Bradley C: The Well-Being Question- tice in clinical psychology. Br J Clin Psy- 13. Rollnick S, Mason P, Butler C: Health Be- naire. In Handbook of Psychology and Dia- chol 37:341–353, 1998 haviour Change: A Guide for Practitioners. betes: A Guide to Psychological Measure- 24. Draycott S, Dabbs A: Cognitive disso- London, Churchill Livingstone, 1999 ment in Diabetes Research and Practice. nance. 2. A theoretical grounding of mo- 14. Ingersoll G, Marrero R: A modified quality Bradley C, Ed. Chur, Switzerland, Har- tivational interviewing. Br J Clin Psychol of life measure for youths: psychometric wood, 1994, p. 89–109 37:355–364, 1998
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1395 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Safe at School: A Virginia Experience
1 MARTHA A. HELLEMS, MD, MS Written authorization for the routine ad- 2 WILLIAM L. CLARKE, MD ministration of insulin and emergency ad- ministration of glucagon from a health care provider is required, as is parental OBJECTIVE — The Commonwealth of Virginia passed legislation in 1999 requiring non- consent. medical school personnel to assist students with the management of type 1 diabetes when school We recently surveyed families of stu- nurses were unavailable. This study was designed to determine which school personnel in dents with type 1 diabetes attending pub- Virginia currently assist type 1 diabetic students with insulin administration and management of lic school in Virginia to determine which hypoglycemia and to determine if these students are being cared for in a safe manner. school personnel currently assist students with insulin administration and manage- RESEARCH DESIGN AND METHODS — Parents of children with type 1 diabetes who ment of hypoglycemia and to evaluate attended public school in Virginia during the previous year and who were receiving their diabetes care at the University of Virginia diabetes clinics were asked to participate in an anon- whether students are cared for in a safe ymous survey. The survey asked parents which school personnel were responsible for their manner while in attendance at school. child’s diabetes care while at school and which persons helped with specific care tasks including Such information could be extremely im- blood glucose monitoring, insulin administration, and assistance with treatment of hypoglyce- portant to advocacy groups such as the mia. Questions were asked regarding the occurrence and treatment of hypoglycemia and any Safe at School Task Force of the American adverse effects of such treatment. Diabetes Association or to legislators from states without laws to protect and assist RESULTS — A total of 185 parents whose children attended 153 different schools responded, students with type 1 diabetes. 69% of whom reported that a full-time school nurse was assigned to their child’s school. In other schools, teachers, administrators, coaches, and cafeteria workers supplemented part-time nurses in assisting students with diabetes management tasks. Although hypoglycemia was not a rare RESEARCH DESIGN AND event (75% of students experienced a median of five episodes per year), only one severe event METHODS — Parents of children with requiring the use of glucagon was reported. In that case, glucagon was administered appropri- type 1 diabetes attending the University ately by a part-time school nurse, and the student experienced no adverse effects related to the of Virginia diabetes clinics and who at- treatment. tended public schools in Virginia during the previous year were asked to partici- CONCLUSIONS — Students with type 1 diabetes can be cared for safely during the school day by a variety of trained medical and nonmedical personnel. The occurrence of one severe pate in an anonymous survey. The survey hypoglycemic event among 185 students suggests that as many as 3% of students could expe- was approved by the University of Vir- rience severe hypoglycemia in a given school year. Legislation that permits nonmedical school ginia Institutional Review Board, and in- personnel to assist students with their diabetes management could make the diabetic children’s formed consent was obtained in every school day safer and improve their overall glucose control. case. The survey was administered Sep- tember through December 2005. Demo- Diabetes Care 30:1396–1398, 2007 graphic information including child’s age, grade in school, school name, and school n 1999, the Virginia General Assembly nurse, physician, physician assistant, or district was requested. Parents were asked passed legislation providing for the nurse practitioner was present. The legis- which person(s) were responsible for I care of public school students diag- lation further provided immunity from li- their child’s diabetes care while at school nosed with type 1 diabetes (1). This leg- ability to such nonmedical personnel and which person(s) helped with specific islation directed that any public school in under the Good Samaritan law and ex- care tasks including blood glucose moni- the state, regardless of size, having one or empted these persons from the nursing toring, insulin administration, and the more students with type 1 diabetes in at- and medical practice acts when perform- treatment of low blood glucose. Parents tendance, must have at least two instruc- ing such diabetes treatment. The Virginia were asked also whether the student per- tional, administrative, or other employees Board of Nursing was directed to develop, forms aspects of diabetes care such as instructed in the administration of insulin in coordination with the boards of medi- blood glucose monitoring and insulin ad- and glucagon. These nonmedical person- cine and education, guidelines for the ministration his- or herself while at nel would act only when no registered training of the nonmedical personnel. school. Specific questions regarding the occurrence and treatment of mild or se- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● vere (loss of consciousness, inability to From the 1Division of General Pediatrics, Department of Pediatrics, University of Virginia, Charlottesville, treat oneself) hypoglycemia were asked. If Virginia; and the 2Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia, a hypoglycemic episode had required the Charlottesville, Virginia. administration of glucagon, information Address correspondence and reprint requests to William L. Clarke, MD, Box 800386, University of Virginia, Charlottesville, VA 22908. E-mail: [email protected]. regarding its administration and adverse Received for publication 19 January 2007 and accepted 27 February 2007. effects was obtained. Finally, parents Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc07-0121. were allowed to respond to an open- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ended question that allowed them to ex- factors for many substances. plain any concerns they may have had © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby regarding their child’s diabetes manage- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ment at school. The survey responses
1396 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Hellems and Clarke
Table 1—Personnel participating in different aspects of diabetes care
Medical Teachers and Other school Diabetes management Grade personnel administrators personnel Parent No one Who is responsible for your child’s K–5 88 64 21 16 0 diabetes care during the school day? 6–8 97 43 30 15 0 9–12 81 25 12 6 9 Who provides diabetes care to your K–5 26 40 2 71 2 child during after-school activities? 6–8 25 37 10 52 18 9–12 6 16 22 25 46 Who helps your child with blood K–5 84 40 2 19 3 glucose monitoring? 6–8 85 12 0 30 15 9–12 33 6 0 13 54 Who helps your child with insulin K–5 74 29 2 24 7 (calculating dose, drawing it up, and/ 6–8 53 8 0 32 22 or injecting boluses)? 9–12 12 1 0 15 75 Who helps treat your child’s low blood K–5 88 53 14 24 2 glucose episodes? 6–8 95 27 17 23 5 9–12 75 27 10 19 18 Data are percentages unless otherwise indicated. K, kindergarten. were compiled to conduct a descriptive (school nurses and clinic assistants) but high school students injected their own analysis of diabetes management in Vir- was shared by teachers and administra- insulin, and 25% received assistance. ginia schools. tors, other school personnel (including Parents of 75% of students reported secretaries, cafeteria workers, coaches or that their child had experienced low RESULTS — Surveys were completed gym teachers, and bus drivers), and par- blood glucose requiring treatment while by parents of 185 children living in cen- ents (Table 1). For a substantial number at school during the previous school year, tral Virginia, a geographic area of about of children, administrators and teachers with a median of five episodes per stu- 60,000 square miles in which there are no assumed responsibility for diabetes man- dent. These episodes of hypoglycemia metropolitan areas with populations agement at least part of the time. Of the were usually treated by medical person- greater than 200,000 people. The respon- nonmedical personnel responsible for the nel, but teachers, administrators, and dents represent approximately nine per- children’s diabetes care, 63% were other school personnel also assisted with cent of children with type 1 diabetes in trained by the school nurse, 35% by a par- treatment for a substantial proportion of Virginia. The children attended kinder- ent, and 15% by a trained diabetes spe- children. Parents of 22% of children of all garten through 12th grade at 153 public cialist. A small number of parents of high grade levels reported that they themselves schools located in 62 different school dis- school students (9%) responded that “no treated their child’s low blood glucose at tricts. Children’s grade levels were ap- one” had responsibility for their child’s school. Of parents who reported that their proximately evenly divided between care during school. children experienced hypoglycemia after lower elementary school grades (kinder- Assistance with blood glucose moni- receiving insulin at school, only 14% re- garten through 5th, n ϭ 58 [31%]), mid- toring varied from elementary to high ported that their children became symp- dle school grades (6th through 8th, n ϭ school, with younger children receiving tomatic. Most reported lethargy, and 60 [32%]), and high school grades (9th more help with this task from medical and none reported seizure or loss of con- through 12th , n ϭ 67 [36%]). nonmedical personnel than older stu- sciousness. Most episodes of hypoglyce- Parents of 95% of the children re- dents. Forty-nine percent of parents re- mia were treated with rapid-acting oral ported that there was a school nurse as- ported that of their children were carbohydrates. One student did require signed to their child’s school, while 69% permitted to check their own blood glu- glucagon administration at school during stated that the nurse was assigned full cose in the classroom (elementary school the previous year. This student, a high time to their child’s school. The part-time 41%, middle school 28%, and high school sophomore who received insulin school nurses were available for a median school 74%), and 54% of high school stu- via an insulin infusion pump, was ner- of 3.25 h/day. A paid health clinic assis- dents received no assistance with their vous because of a morning exam and did tant was available in the schools of five of blood glucose monitoring. not check her blood glucose or eat before the nine children who attended a school Parents of 89% of the children re- going to school. Her school had a part- without a school nurse. Only 20% of the ported that their child required insulin time school nurse who was available that children whose schools had a part-time administration at school during the pre- day and who administered the glucagon. nurse had a health clinic assistant to assist vious year; 79% of children injected their The student experienced no adverse ef- in their care when the school nurse was own insulin. Of children in elementary fects related to the glucagon administra- absent. school grades, 41% injected their own in- tion. A rate of 1 in 185 children Responsibility for the student’s diabe- sulin doses, and most (74%) received as- experiencing severe hypoglycemia re- tes care during the school day was not sistance from a school nurse or other quiring glucagon suggests that as many as limited solely to school medical personnel medical personnel. In contrast, 74% of 3% of diabetic children could experience
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1397 Management of type 1 diabetes at school serious hypoglycemia in a given school ing (62% of all Virginia school districts) Our study has several limitations. The year (95% CI, exact binomial test). stated that a school nurse had primary survey instrument was not validated and responsibility for treating hypoglycemia relied on parental recall of events from the CONCLUSIONS — These data show in students with type 1 diabetes. How- previous school year. We have sampled that children with type 1 diabetes can be ever, less than one-half of those school students in only one region of Virginia, safely cared for during the school day by a districts had a school nurse present in and schools might provide different dia- variety of medical and nonmedical per- each school, and nearly 10% of the school betes care in different regions. Severe ad- sonnel. They also demonstrate that blood systems stated that the child with diabetes verse events are, fortunately, rare, and glucose monitoring, insulin administra- had primary responsibility for treating although our sample represents about tion, and the treatment of low blood glu- his/her own hypoglycemia. Thus, it is rea- nine percent of the state’s diabetic school cose episodes are not rare events in the sonable to infer that the number of children, this sample is not powered to lives of students with type 1 diabetes dur- schools employing school nurses has in- predict the frequency of rare events with ing the school day. The need for assis- creased significantly over the past 16 any precision. tance with monitoring and insulin and/or years and that there is significantly more The American Diabetes Association rapid-acting glucose treatment varies medical care available to these children. has developed the Safe at School State- across age groups, with older children This is an important finding, since there ment of Principles (3), which encourages more independent at these tasks. How- was initially great concern that the Vir- all school districts to identify individuals ever, the single occurrence of severe hy- ginia legislation might encourage school who will be responsible for the safe man- poglycemia among the students whose districts not to hire nurses since nonmed- agement of students with type 1 diabetes parents completed this survey occurred in ical personnel would be trained to assist during attendance at school. Ideally, a high school sophomore who could be in at least some of the medical care of their presumed to be more independent in her students; clearly, such has not been the those responsible persons would be monitoring and insulin administration case. school nurses trained in the management than some of the younger children. In ad- It is interesting to note the numbers of of type 1 diabetes. In those situations dition, she attended a school that only parents of children of all ages who re- where school nurses are unavailable, the had a part-time school nurse. This under- sponded that “no one” at the school is Virginia legislation has been suggested as scores the importance of training non- responsible for their child’s medical care a model of how nonmedical personnel medical school personnel in the during the school day or that they them- could be trained and codified to assist recognition and treatment of hypoglyce- selves assist with blood glucose monitor- these children with day-to-day and emer- mia and affirms the importance of the leg- ing, insulin administration, and treatment gency treatment of diabetic students. Al- islation passed by the Virginia General of low blood glucose episodes. As a child though the data presented above suggests Assembly in 1999. with diabetes matures and becomes more that this is both a practical and safe alter- Several years ago, we surveyed school independent, it seems reasonable that native, more research is needed to ade- districts in Virginia to determine which day-to-day management tasks would be quately assess the abilities of nonmedical personnel treated low blood glucose in assumed by that child, especially during personnel to assist students in the school students with type 1 diabetes attending the school day. However, although 92% day management of diabetes. their schools, and whether or not their of respondents indicated that they feel schools employed school nurses (2). Al- their child is safely cared for at school, a though the respondents to that survey surprising number of parents of younger were also from central Virginia, the study children responding to the survey stated References population did not necessarily coincide that they themselves were responsible for 1. Senate Bill 889, Amending Virginia Code with that of the current study. The previ- their child’s care during the school day. §§ 8.01–225,22.1–275.1, 54.1–2901, 54.1–3001, 54.1–3005, and 54.1–3408, ous study was a survey of school districts, Those responses may reflect insecurity 1999 while the current study is a survey of par- with the medical care available in their 2. Clarke W, Snyder A: Hypoglycemia: can ents of children with type 1 diabetes. De- child’s school and suggest that parents the school respond? Diabetes Care 13: spite these obvious differences in study need to be involved in the planning for 1097–1098, 1990 populations, the results of the previous their child’s attendance at school and in 3. American Diabetes Association: Diabetes survey have important relevance to the discussions with school personnel re- care in the school and day care setting current information reported above. In garding medical support available during (Position Statement). Diabetes Care 30 1989, Ͻ39% of school districts respond- the school day. (Suppl. 1): S66–S73, 2007
1398 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Satisfaction and Quality of Life With Premeal Inhaled Versus Injected Insulin in Adolescents and Adults With Type 1 Diabetes
1 MARCIA A. TESTA, MPH, PHD ceptance of basal/bolus insulin regimens 2 DONALD C. SIMONSON, MD, MPH, SCD is hindered by the burden of multiple in- jections (3–6). Clinical trials have demonstrated that OBJECTIVE — We sought to compare and evaluate the impact of inhaled versus injected inhaled insulin is comparable with in- insulin on potential mediators of patient acceptance of insulin therapy while maintaining com- jected insulin in lowering A1C in individ- parable A1C levels. uals with type 1 (7,8) and type 2 (9) diabetes. However, the clinical rationale RESEARCH DESIGN AND METHODS — During a noninferiority efficacy trial con- for its use is based on the belief that mul- ducted in 40 centers in the U.S., we surveyed treatment satisfaction, quality of life, and adherence Ϫ Ϫ tiple inhalations will be more acceptable barriers at weeks 4, 1, 6, 12, 20, and 24 in adolescents aged 12–17 years and adults with type to patients, thereby promoting increased 1 diabetes who received premeal regular plus twice-daily NPH insulin during a 4-week run-in; then, subjects were randomized to premeal inhaled human insulin plus twice-daily NPH (adults, adherence to intensive insulin regimens. n ϭ 102; adolescents, n ϭ 60) (inhaled) or remaining on run-in therapy (n ϭ 105 and 60, However, evidence of this causal relation- respectively) (subcutaneous injection). ship has not been empirically established during clinical trials of efficacy since ad- RESULTS — Overall treatment satisfaction (0–100) increased by 13.2 Ϯ 1.1 units for inhaled herence to treatment and A1C goals are insulin (baseline ϭ 63.3 Ϯ 1.2) compared with 1.7 Ϯ 0.8 for subcutaneous insulin injection strictly enforced for all patients. Addition- (baseline ϭ 64.1 Ϯ 1.2, P Ͻ 0.0001). All 12 satisfaction subscales favored inhaled insulin (all ally, real-world clinical experience with P Ͻ 0.01), and effects did not vary by age or sex. Despite similar baseline-adjusted end point A1C the only form of inhaled insulin approved Ϯ Ϯ for inhaled (7.7 0.1%) and subcutaneous (7.9 0.1%) regimens, quality-of-life scales of by the U.S. Food and Drug Administra- mental health, symptoms, health status, cognitive functioning, and adherence barriers during tion is lacking since it has just recently treatment were more favorable for inhaled insulin (all P Ͻ 0.05). Greater satisfaction was associated with fewer barriers to insulin adherence (rho ϭϪ0.78, P Ͻ 0.0001) and a greater become available. reduction in A1C (rho ϭϪ0.18, P Ͻ 0.001). While empirical data documenting the relationship between greater accep- CONCLUSIONS — Treatment satisfaction was substantially more favorable, adherence bar- tance and superior glycemic control is not riers moderately lower, and quality of life moderately higher for inhaled compared with subcu- available, mediators in the pathway— taneous regimen. It remains to be demonstrated whether these patient-reported outcomes will namely, treatment satisfaction, quality of translate into improved adherence and glycemic control. life, and barriers to insulin adherence— can be evaluated. Such measures could Diabetes Care 30:1399–1405, 2007 provide valuable insight when weighing the risks and benefits of incorporating in- aintaining A1C levels Ͻ7% in in- quires either an insulin pump or a basal/ haled insulin delivery as part of intensive dividuals with type 1 diabetes has bolus multiple-injection insulin regimen. insulin regimens. The purpose of our M been shown to reduce microvas- However, use of the pump has been lim- study was to compare the impact of in- cular and some macrovascular complica- ited by its cost, required technical exper- haled versus injected insulin on potential tions (1,2). Reaching A1C goals by tise, and the relative paucity of health care mediators of adherence during a clinical intensifying the insulin regimen often re- providers trained in its use, and the ac- trial (8) that previously reported that in- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● haled human insulin has comparable From the 1Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; and the safety and efficacy to injected insulin in 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. type 1 diabetic patients currently using Address correspondence and reprint requests to Marcia A. Testa, MPH, PhD, Department of Biostatistics, multiple daily injections. Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115. E-mail: testa@hsph. harvard.edu. Received for publication 20 July 2006 and accepted in revised form 16 February 2007. RESEARCH DESIGN AND Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-1497. METHODS — A detailed description Clinical trial reg. no. NCT00424333, clinicaltrials.gov. of the clinical results of the parent proto- M.A.T. and D.C.S. have received research grants and honoraria from Pfizer. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ col was published previously (8). Briefly, dc06-1497. this open-label, randomized, multicenter Abbreviations: FPG, fasting plasma glucose. trial consisted of a screening visit, 4-week A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion lead-in, and 24-week treatment phase. A factors for many substances. total of 419 individuals with type 1 dia- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby betes for at least 1 year were screened at marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 40 centers in the U.S. and Canada. Inclu-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1399 Satisfaction with inhaled insulin in type 1 diabetes
Table 1—Demographic and clinical characteristics of study groups at randomization
Inhaled insulin regimen Subcutaneous regimen Adolescents Adults Adolescents Adults n 60 102 60 105 Male 31 (51.7) 53 (52.0) 30 (50.0) 59 (56.2) Married 0 (0.0) 66 (64.7) 0 (0.0) 65 (62.5)* Caucasian 52 (86.7) 87 (85.3) 54 (90.0) 98 (93.3) Occupation Paid employment 0 (0.0)* 82 (81.2)* 1 (1.7) 90 (85.7) Retired — 2 (2.0)* — 3 (2.9) Student 59 (100.0)* 5 (5.0)* 58 (96.7) 4 (3.8) Age (years) 13.8 Ϯ 1.4 (12–17) 38.2 Ϯ 10.6 (19–65) 14.1 Ϯ 1.7 (11–17) 38.6 Ϯ 11.0 (19–65) Duration of diabetes (years) 5.5 Ϯ 3.5 (1.0–13.7) 17.0 Ϯ 10.6 (2.2–50.0) 6.1 Ϯ 3.5 (1–13.6) 19.4 Ϯ 11.2 (1.5–49.0) BMI (kg/m2) 22.4 Ϯ 3.4 (16.9–30.0) 25.4 Ϯ 2.9 (18.0–32.0) 22.0 Ϯ 3.2 (15.0–30.0) 25.7 Ϯ 3.3 (17.4–35.0) A1C (%) 8.3 Ϯ 0.9 (6.3–10.6) 7.8 Ϯ 0.9 (6.2–10.5) 8.3 Ϯ 0.9 (6.3–10.6) 7.8 Ϯ 1.0 (5.9–10.5) C-peptide (pmol/ml) 0.08 Ϯ 0.06 (0.07–0.40) 0.07 Ϯ 0.03 (0.07–0.20) 0.08 Ϯ 0.03 (0.07–0.20) 0.07 Ϯ 0.03 (0.07–0.23) Data are n (%) or means Ϯ SD (range). *Missing data on one individual. sion criteria were age 12–65 years, stable Assessments Bonferroni’s adjustment for type I error on an insulin regimen of at least two in- Clinical. A1C was measured at baseline for multiple end points is provided jections daily for 2 months before screen- (week Ϫ1 to 0) and end point (week 24 or (22,23). Correlation analysis (Pearson r ing, baseline A1C between 6 and 11% last visit), and fasting plasma glucose and Spearman’s rho) and multiple regres- inclusive, fasting plasma C-peptide Յ0.2 (FPG) was recorded at each visit. sion were used to examine the relation- pmol/ml, and BMI Յ30 kg/m2. Exclusion Patient-reported questionnaires. At ships between treatment, glycemic criteria included poorly controlled week Ϫ4 (screening); week Ϫ1 (base- control, satisfaction, adherence barriers, asthma, recent smoking, and significant line); weeks 6, 12, 20, and 24; and early and quality of life. Data are given as laboratory abnormalities. The protocol withdrawal, questionnaires were sent di- means Ϯ SE unless specified otherwise. was approved by the institutional review rectly from clinical sites to the central sur- board, and informed consent was ob- vey laboratory. Validated instruments of tained from all subjects. treatment satisfaction, quality of life, and To standardize baseline assessments barriers to insulin adherence were used RESULTS during the 4 weeks before randomization, (10,11) (see online appendix available at Study accrual, withdrawals, and all patients were switched to subcutane- http://dx.doi.org/10.2337/dc06-1497). baseline characteristics ous premeal regular insulin plus twice- These measures are responsive to the ef- In total, 120 adolescents aged 12–17 daily NPH insulin administered in four fects of therapeutic interventions (12– years were randomized to the inhaled subcutaneous injections daily (subcuta- 14), the impact of side effects of ϭ ϭ neous regimen). Target glucose ranges medication (15), symptoms of diabetes (n 60) and subcutaneous (n 60) reg- (16–18), and changes in A1C (19–21). imens, and 207 adults were randomized were 80–120 mg/dl (4.4–6.7 mmol/l) ϭ An age-appropriate parallel version of the to inhaled (n 102) and subcutaneous before meals and 100–140 mg/dl (5.6– ϭ 7.8 mmol/l) before bedtime. A total of 162 adult questionnaire was used for adoles- (n 105) regimens. For the 160 patients individuals were randomized to insulin cents aged 12–17 years. All scales were on inhaled regimen who completed base- human (rDNA origin) Inhalation Powder coded such that higher scores reflected line questionnaires, 154 (96.3%) com- (Exubera; Pfizer and Nektar Therapeu- the more favorable response, i.e., higher pleted the week 24 questionnaire and 159 tics) and twice-daily NPH insulin (in- satisfaction, better quality of life, and re- (99.4%) completed week 12 or later; for haled regimen); 165 individuals were duced barriers to adherence. the 162 subcutaneous regimen baseline instructed to continue on their preran- completers, corresponding values were domization subcutaneous regimen. In- 152 (93.8%) and 155 (95.7%), respec- haled insulin was administered as one to Statistical methods tively. Baseline demographics, clinical two inhalations within 10 min of starting Treatment satisfaction and quality of life characteristics, and insulin treatments are each meal. The insulin powder was pack- during treatment at weeks 6, 12, 20, and summarized in Table 1. Baseline satisfac- aged in foil blisters of 1- and 3-mg doses, 24 were evaluated using linear mixed tion scores indicated moderate satisfac- which are approximately equivalent to 3 models with fixed (treatment) and base- tion with the run-in subcutaneous insulin IU and 8 IU of subcutaneous insulin, re- line covariate effects. In addition, changes treatment (Table 2) (scale range was 0 spectively. Insulin doses were adjusted from baseline to end point (week 24 or [greatest dissatisfaction] to 100 [highest weekly by the investigator to achieve tar- last visit) satisfaction were compared us- satisfaction]). The one exception was the get premeal glucose levels, and patients ing ANCOVA (adjusted for baseline). All low score of 35 for the preference scale, adjusted doses according to diet and ex- P values report nominal significance lev- suggesting patients had a desire to seek ercise requirements. els at ␣ϭ0.05. For reference, a partial new treatments.
1400 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Testa and Simonson
Table 2—Diabetes treatment satisfaction scores: baseline, end point (last observation carried forward), and change from baseline for inhaled insulin and subcutaneous regimen treatment groups
Baseline End point Change Tests Scaled (n of items) Group n Mean SE Mean SE Mean SE P* P† Regimen Burden (14) INH 159 69.6 1.6 79.4 1.4 9.9 1.3 Ͻ0.0001 Ͻ0.0001 SC 158 71.9 1.4 74.2 1.6 2.3 1.0 0.018 Convenience (6) INH 160 61.4 1.5 74.0 1.5 12.6 1.6 Ͻ0.0001 Ͻ0.0001 SC 159 60.8 1.5 62.0 1.6 1.2 1.1 0.27 Flexibility (4) INH 160 60.5 1.6 72.7 1.6 12.2 1.4 Ͻ0.0001 Ͻ0.0001 SC 159 62.0 1.7 63.6 1.8 1.6 1.3 0.21 Hassle (8) INH 160 67.3 1.6 77.0 1.5 9.7 1.2 Ͻ0.0001 0.003 SC 159 67.7 1.6 72.0 1.7 4.4 1.2 Ͻ0.0001 Interference (11) INH 160 70.8 1.7 80.6 1.5 9.8 1.2 Ͻ0.0001 0.005 SC 159 71.0 1.8 76.1 1.8 5.1 1.2 Ͻ0.0001 Pain (3) INH 160 70.9 1.7 85.2 1.4 14.2 1.5 Ͻ0.0001 Ͻ0.0001 SC 159 72.7 1.7 73.5 1.6 0.8 1.2 0.521 Social (9) INH 158 72.5 1.7 82.4 1.4 9.9 1.2 Ͻ0.0001 Ͻ0.0001 SC 159 74.7 1.6 76.2 1.7 1.5 1.0 0.141 Outcomes Perceived efficacy (3) INH 160 54.2 1.5 68.1 1.5 13.9 1.7 Ͻ0.0001 Ͻ0.0001 SC 159 55.3 1.4 58.1 1.7 2.9 1.5 0.051 Side effects (5) INH 159 73.4 1.2 76.8 1.4 3.4 1.2 0.004 Ͻ0.0001 SC 159 73.2 1.3 70.6 1.5 Ϫ2.6 1.2 0.034 Net benefit General satisfaction (5) INH 160 58.7 1.7 77.0 1.7 18.3 2.2 Ͻ0.0001 Ͻ0.0001 SC 159 59.2 1.8 59.4 1.9 0.3 1.6 0.855 Preference (2) INH 158 34.7 1.4 62.0 1.8 27.4 2.1 Ͻ0.0001 Ͻ0.0001 SC 159 35.2 1.9 36.9 1.9 1.7 1.5 0.251 Advocacy (2) INH 158 65.2 1.6 81.5 1.5 16.3 2.0 Ͻ0.0001 Ͻ0.0001 SC 156 66.3 1.9 66.5 2.0 0.2 1.8 0.922 Total score Overall satisfaction (72) INH 160 63.3 1.2 76.4 1.2 13.2 1.1 Ͻ0.0001 Ͻ0.0001 SC 159 64.1 1.2 65.8 1.4 1.7 0.8 0.036 All scales range from 0 to 100, and higher scores reflect better or more favorable satisfaction. n is less than total due to missing values and/or questionnaires. *Nominal P value for paired t test (baseline Ϫ end point) ϭ 0. †Nominal P value for mean treatment differences between changes from baseline by ANCOVA with baseline score as covariate. Treatment effects for the corresponding linear mixed-model analyses (weeks 6, 12, 20, and 24 assessments) adjusted for baseline (week Ϫ1) were significant at P Ͻ 0.0001 for all scales. For the 12 baseline to end point treatment satisfaction difference scores with mean correlation coefficient r ϭ 0.59, compare nominal P values to a reduced Bonferroni-corrected ␣ of 0.018/0.0036/0.0003 to achieve significance at ␣Ͻ0.05/0.01/0.001. INH, inhaled insulin; SC, subcutaneous.
Changes in glycemic control Patient-reported outcomes the overall treatment satisfaction scale in- Baseline-adjusted A1C at final visit was Diabetes treatment satisfaction. Base- creased to 75.3 Ϯ 1.1 by week 6 and re- 7.7 Ϯ 0.1% for inhaled insulin and 7.9 Ϯ line to end point changes across all 12 mained constant at that level until end 0.1% for subcutaneous regimens (base- satisfaction subscales were more favor- point, whereas subcutaneous regimen did line ϭ 8.0 Ϯ 0.1% for both groups, P ϭ able for inhaled insulin (Table 2). For the not change. Subgroup treatment compar- 0.066 between treatment-adjusted A1C seven regimen-related subscales, im- isons by age-group and sex are shown in baseline to end point change). ANCOVA provements for inhaled insulin were sub- Fig. 1. None of the two- and three-way showed an overall age effect (P ϭ 0.002); stantially greater than for subcutaneous interactions from ANCOVA were statisti- however, tests of the interactions indi- regimen. The two outcome-related sub- cally significant, indicating that differ- cated that the treatment impact on A1C scales, satisfaction with glycemic control ences between inhaled insulin and did not vary by age (P ϭ 0.59), sex (P ϭ and side effects (primarily weight gain subcutaneous regimens were comparable 0.92), or age and sex (P ϭ 0.94). The and hypoglycemia), also were more favor- across these demographic subgroups. 24-week change in FPG for inhaled insu- able for inhaled insulin. The three “net Quality of life during treatment. Be- lin was Ϫ1.9 mmol/l (Ϫ35 mg/dl), benefit” measures of preference (desire to tween screening and baseline there was whereas the subcutaneous group in- seek alternative diabetes treatment), ad- 0.4% decrease in A1C (P Ͻ 0.001) with a creased by 0.2 mmol/l (ϩ4 mg/dl), with vocacy (would recommend treatment), corresponding improvement in overall an adjusted treatment group difference of and general satisfaction confirmed that quality of life (P ϭ 0.024) for both groups Ϫ2.2 mmol/l (Ϫ40 mg/dl) (95% CI Ϫ3.2 patients found inhaled insulin more ac- combined. Overall quality of life (abso- mmol/l [Ϫ58 mg/dl] to Ϫ1.2 mmol/l ceptable after balancing regimen pro- lute scale range of 500 units and operative [Ϫ22 mg/dl]). cesses and outcomes. For inhaled insulin, range of ϳ64 units [17]) improved at end
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1401 Satisfaction with inhaled insulin in type 1 diabetes
tress scale). Forty symptom scores were less distressing for the inhaled insulin group. For symptom distress treatment differences Ͼ0.10–0.19 SD responsive- ness units, 13 were more favorable for in- haled insulin and 1 was more favorable for subcutaneous regimen. All seven symptom distress treatment differences Ͼ0.20 SD responsiveness units, a typical threshold for clinically important differ- ences (10,11,17,21), favored inhaled in- sulin, including general weakness or fatigue (ϩ0.21), sugar in urine (ϩ0.23), feelings of high blood glucose (ϩ0.27), impaired or worsening vision (ϩ0.27, P Ͻ 0.05), lethargy, no energy to do things (ϩ0.36, P Ͻ 0.001), tired, feeling weary (ϩ0.36, P Ͻ 0.001), and feeling overweight (ϩ0.37, P Ͻ 0.01). Adult fe- male subjects on inhaled insulin had a de- crease in weight of 0.4 Ϯ 0.3 kg, while those on subcutaneous regimen gained 0.6 Ϯ 0.3 kg (difference of Ϫ1.0 Ϯ 0.4 kg, P ϭ 0.01). The reduction in distress Figure 1—Mean baseline-adjusted change in overall treatment satisfaction for inhaled insulin regimen ( ) and subcutaneous regimen ( ) evaluated at baseline score of 63.7. §P Ͻ 0.0001 and with feeling overweight was attributed Ͻ primarily to adult female subjects (treat- ‡P 0.01 versus inhaled insulin. A1C treatment changes were not statistically significantly ϩ different between inhaled insulin and subcutaneous regimens within the age- and sex-specific ment difference of 0.71 SD units), and subgroups. actual weight loss was associated with less distress (r ϭ 0.30, P Ͻ 0.001). Comparative treatment preference and point by 12.2 Ϯ 3.3 units for inhaled in- vary by age. There was no difference with associations between treatment satis- sulin and 2.6 Ϯ 3.4 units for subcutane- regard to self-consciousness when using faction, quality of life, adherence barri- ous regimens (P ϭ 0.043), representing a insulin away from home. Six questions ers, and glycemic control. Preference 15% difference in the operative range addressing barriers specific to injectable choices are shown in Table 3, and, except (0.31 Ϯ 0.15 SD responsiveness units). insulin revealed that inhaled insulin rated for “easier to adjust dose,” all favored in- This difference is within the range of val- fewer barriers with insulin (regardless of haled insulin. Analyses between end ues that are likely to be clinically relevant delivery) (total score 74.2 Ϯ 1.4 for in- point overall treatment satisfaction and (10,11,17,21). As shown in Table 3, treat- haled insulin vs. 67.0 Ϯ 1.6 for subcuta- insulin adherence barriers demonstrated ment differences in the quality-of-life neous regimens [higher score reflects greater satisfaction with lower barriers scales were more favorable for inhaled in- fewer/lower barriers], P ϭ 0.001). An- (rho ϭϪ0.78, P Ͻ 0.0001). A1C and sulin, including symptom distress, symp- swers to the 12 inhaler device–specific in- overall treatment satisfaction correlation tom interference in daily activities, sulin questions confirmed positive analysis indicated that better glycemic cognitive functioning, and general health. endorsement for the inhaler device itself, control was only weakly associated with The more positive mental and emotional with the highest endorsement rating of higher satisfaction (rho ϭϪ0.18, P Ͻ health scores were driven primarily by 94.9 Ϯ 1.0 (on a scale of 0–100) for re- 0.001) since the lack of change in A1C in improvements in anxiety and behavioral duced pain. All ratings were significantly this noninferiority design limited the abil- and emotional control. Both age and sex higher than a neutral endorsement score ity to detect an association. modified the treatment effect on mental of 50.0 (P Ͻ 0.0001), and the average health (treatment interactions with age- total rating was 78.3 Ϯ 1.4 (P Ͻ 0.0001 CONCLUSIONS — For individuals group [P ϭ 0.001], sex [P ϭ 0.002], and vs. 50.0). Inhaled insulin patients rated with type 1 diabetes treated with two or age-group by sex [P Ͻ 0.0001]). Adult the bother and hassle associated with more daily injections of regular/NPH in- female subjects showed the largest in- their inhaler device consistently lower at sulin and moderately satisfied with their haled insulin regimen gain in mental weeks 6, 12, 20, and 24 ([mean Ϯ SE] current therapy, there is opportunity to health (ϩ10.9 units) in contrast to adult 83.3 Ϯ 1.9, 82.2 Ϯ 2.0, 80.3 Ϯ 2.1, and improve their experience with insulin male (Ϫ3.6 units), adolescent male (ϩ5.9 82.4 Ϯ 2.0, respectively) than their NPH therapy. Inhaled insulin patients reported units), and adolescent female (ϩ5.4 injections (68.6 Ϯ 2.0, 68.4 Ϯ 2.1, substantial and stable improvement in units) subjects. 66.1 Ϯ 2.1, and 67.6 Ϯ 2.3, respectively, their satisfaction ratings between weeks 6 Adherence barriers to insulin use. As P Ͻ 0.001). and 24 in contrast to no change for those shown in Table 3, the inhaled insulin Symptom distress. Of the 53 patient- remaining on the run-in subcutaneous group scored more favorably on six of the reported symptoms, the inhaled insulin regimen. These findings are consistent seven questions relating to barriers to in- group reported less symptom distress and with other recent studies suggesting that sulin adherence, and these effects did not severity overall (Table 3, symptom dis- ease of use, convenience, social comfort,
1402 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Testa and Simonson
Table 3—Quality of life, barriers to insulin adherence, and comparative preference during treatment (weeks 6, 12, 20, and 24 assessments) adjusted for baseline (week ؊1) for the inhaled insulin and subcutaneous insulin groups
Mean treatment difference Baseline week Ϫ1 Inhaled Subcutaneous (ϩ, favors inhaled P treatment covariate score† insulin insulin insulin) main effect† QOL scales and subscales (n of items)* Overall mental health 482.4 491.1 Ϯ 1.8 486.2 Ϯ 1.8 ϩ5.1 (0.8 to 10.2) 0.047 Psychological distress 515.9 523.4 Ϯ 1.8 523.4 Ϯ 1.8 ϩ5.5 (0.5 to 10.4) 0.031 Psychological well being (total subscale) 426.4 437.7 Ϯ 2.5 433.7 Ϯ 2.5 ϩ4.0 (Ϫ2.8 to 10.9) 0.248 General health status (3) 500.1 509.4 Ϯ 2.4 502.3 Ϯ 2.4 ϩ7.1 (0.3 to 13.9) 0.039 Symptom distress (53 Items) 580.6 583.8 Ϯ 0.8 579.1 Ϯ 0.8 ϩ4.7 (2.4 to 7.0) Ͻ0.0001 Cognitive functioning (total scale) 422.6 427.1 Ϯ 1.4 421.3 Ϯ 1.4 ϩ5.8 (2.0 to 9.6) 0.003 (100–500) Diabetes symptom interference (7) 546.5 556.9 Ϯ 2.6 547.7 Ϯ 2.7 ϩ9.2 (1.8 to 16.5) 0.015 Barriers to insulin adherence‡ I find it difficult to take every dose of insulin 75.6 82.9 Ϯ 1.8 74.4 Ϯ 1.8 ϩ8.4 (3.4 to 13.4) 0.001 recommended. I find it difficult to take insulin away from 70.1 76.4 Ϯ 2.0 70.7 Ϯ 2.0 ϩ5.7 (0.3 to 11.2) 0.04 home. I find it easy to travel for a few days and take all 66.9 76.8 Ϯ 2.0 66.9 Ϯ 2.0 ϩ9.9 (4.4 to 15.4) 0.0005 my doses of insulin. I find it convenient to take insulin. 56.4 70.0 Ϯ 2.0 60.1 Ϯ 2.0 ϩ9.9 (4.4 to 15.5) 0.0005 The time I spend taking each dose of insulin is 69.3 77.5 Ϯ 1.5 68.7 Ϯ 1.5 ϩ8.8 (4.5 to 13.1) 0.00010 acceptable. I am self-conscious taking insulin away from 59.3 62.8 Ϯ 2.4 65.1 Ϯ 2.4 Ϫ2.4 (Ϫ4.4 to 9.2) 0.49 home. Overall, I am satisfied with my current way of 60.1 75.4 Ϯ 1.8 61.7 Ϯ 1.8 ϩ13.7 (8.7 to 18.7) Ͻ0.0001 taking insulin. Insulin adherence barriers (total score) 65.5 74.7 Ϯ 1.3 66.7 Ϯ 1.3 ϩ8.0 (4.4 to 11.6) Ͻ0.0001
Adolescents Adults Comparative preference ratings§ ͓%(n/total)͔ʈ P¶ ͓%(n/total)͔ʈ P¶ Is easier to use? 93.0 (53/57) Ͻ0.0001 83.5 (81/97) Ͻ0.0001 Is more convenient? 87.7 (50/57) Ͻ0.0001 77.1 (74/96) Ͻ0.0001 Allows more flexibility in daily activities? 83.9 (47/56) Ͻ0.0001 81.1 (77/95) Ͻ0.0001 Causes fewer episodes of low blood sugar? 80.0 (44/55) Ͻ0.0001 71.6 (63/88) Ͻ0.0001 Is more comfortable to use in public? 82.1 (46/56) Ͻ0.0001 79.4 (77/97) Ͻ0.0001 Is easier to adjust dose? 39.3 (22/56) 0.14 27.4 (26/95) Ͻ0.0001 Allows easier disposal of medication supplies? 83.9 (47/56) Ͻ0.0001 95.9 (93/97) Ͻ0.0001 Allows more flexibility in scheduling meals? 83.6 (46/55) Ͻ0.0001 78.7 (74/94) Ͻ0.0001 Is more convenient when traveling? 84.2 (48/57) Ͻ0.0001 81.1 (77/95) Ͻ0.0001 Gives you better glucose control? 70.4 (38/54) Ͻ0.0001 69.3 (61/88) 0.0004 Would you choose if both were the same price? 86.0 (49/57) Ͻ0.0001 82.5 (80/97) Ͻ0.0001 Makes you feel better about yourself? 90.6 (48/53) Ͻ0.0001 64.6 (77/91) Ͻ0.0001 Overall is the one you prefer? 87.7 (50/57) Ͻ0.0001 82.5 (80/97) Ͻ0.0001 Data are means Ϯ SE or mean (95% CI) unless otherwise indicated. Higher scores reflect better quality of life, less symptom distress, and lower barriers to adherence. *All scaled 100–600 unless noted otherwise, and higher scores represent higher quality of life (QOL). †Treatment mean differences adjusted at baseline covariate score using linear mixed-models analysis. Baseline-adjusted treatment means (weeks 6, 12, 20, and 24) are calculated at mean baseline score (week Ϫ1). For the 10 mutually exclusive quality-of-life scores tested (sexual functioning, general symptom life interference, and health limitation were not statistically different and are not shown) with mean correlation coefficient r ϭ 0.49, compare nominal P values with a reduced Bonferroni-corrected ␣ of 0.0003/0.003/0.016 to achieve significance at ␣Ͻ0.001/0.01/0.05, respectively. For the seven adherence barriers, compare with 0.0004/0.004/0.018. ‡All scaled 0–100, and higher scores represent lower barriers and great ease. §Percent in the inhaled insulin group reporting a preference for the inhaler compared with injections at week 24. ʈTotal number who declared a preference. ¶Binomial test, P ϭ 0.5. and flexibility of the treatment process are glycemic control, side effects, cognitive that our comparative findings may not ap- important issues to both type 1 and type 2 function, and physical and psychological ply to other insulin regimens. diabetic patients for insulin administra- well being accompanied the higher satis- Although inhaled insulin is not ap- tion (24,25). Our findings also docu- faction ratings for patients on the inhaled proved for individuals aged Յ17 years, mented that more positive perceptions of insulin regimen. It is important to note our study demonstrates its impact on sat-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1403 Satisfaction with inhaled insulin in type 1 diabetes isfaction and quality of life in a younger with insulin is a significant barrier to ad- litus. N Engl J Med 329:977–986, 1993 adolescent population with an average hering to insulin regimens, especially in 2. Reichard P, Nilsson BY, Rosenqvist U: The age of 14 years. Using age-appropriate in- women. effect of long-term intensified insulin struments, improvements with inhaled Because of the noninferiority design treatment on the development of micro- insulin were found to be similar to adults of this trial, during which adherence was vascular complications of diabetes melli- tus. N Engl J Med 329:304–309, 1993 among both male and female subjects. In purposely and strictly enforced in both 3. Zgibor JC, Songer TJ, Kelsey SF, Weiss- this age-group, most patient-reported groups, there was little opportunity to ob- feld J, Drash AL, Becker D, Orchard TJ: outcome studies evaluating intensive in- serve differences in A1C resulting from The association of diabetes specialist care sulin regimens have focused on compar- differences in adherence. As such, we with health care practices and glycemic ing insulin pumps with multiple daily chose to focus assessment on patient rat- control in patients with type 1 diabetes: a injections. Results have varied depending ings of barriers to insulin adherence such crosssectional analysis from the Pitts- on the responsiveness and sensitivity of as “how much difficulty they had taking burgh Epidemiology of Diabetes Compli- the patient-reported measures used and every dose of insulin as recommended.” It cations Study. Diabetes Care 23:472–476, the study design used, but improvement was not surprising that individuals who 2000 in patient satisfaction and ability to ad- expressed the most difficulty had the low- 4. Muller UA, Femerling M, Reinauer KM, RisseA, Voss M, Jorgens V, Berger M, here to intensive regimens are typically est overall satisfaction with treatment. Muhlhauser I: Intensified treatment and higher for the pump. Our study used very Since it has been previously observed that education of type 1 diabetes as clinical sensitive measures and a longitudinal de- clinical trials substantially underestimate routine: a nationwide quality-circle expe- sign during which patients answered discontinuation with drug therapy and rience in Germany: ASD (the Working nearly 2,400 questions over 6 months. As overestimate adherence and that quality Group on Structured Diabetes Therapy of such, we were able to detect improve- of life may better predict outcomes in ac- the German Diabetes Association). Diabe- ments in many domains of satisfaction, tual practice (26,27), we might anticipate tes Care 22 (Suppl. 2):B29–B34, 1999 quality of life, and barriers to adherence that the more favorable satisfaction and 5. Zambanini A, Newson RB, Maisey M, Fe- for the inhaled insulin group. While the quality-of-life outcomes observed for in- her MD: Injection related anxiety in insu- stability and durability of the satisfaction haled insulin might translate into greater lin-treated diabetes. Diabetes Res Clin scores argue against a novelty effect, we acceptance and better adherence with in- Pract 46:239–246, 1999 6. Mollema ED, Snoek FJ, Heine RJ, van der cannot rule out that openly positive or sulin therapy in clinical practice. Ploeg HM: Phobia of self-injecting and negative reactions of the clinic staff to the The barriers to effective diabetes self-testing in insulin-treated diabetes pa- inhaler device could have impacted pa- management are multifactorial, but our tients: opportunities for screening. Diabet tient attitudes. study supports the belief that psycholog- Med 18:671–674, 2001 The reasons for the positive effects of ical, behavioral, and attitudinal factors 7. Quattrin T, Belanger A, Bohannon NJ, inhaled insulin on the quality-of-life out- play a role in patient satisfaction with in- Schwartz SL, Exubera Phase III Study comes are uncertain; however, it is possi- sulin therapy. The use of inhaled insulin Group: Efficacy and safety of inhaled in- ble that the rapidly acting premeal in type 1 diabetic patients should proceed sulin (Exubera) compared with subcuta- inhaled insulin resulted in a more favor- with caution since the long-term conse- neous insulin therapy in patients with able metabolic profile that mediated these quences (both positive and negative) will type 1 diabetes: results of a 6-month, ran- domized, comparative trial. Diabetes Care improvements. Also, FPG was lower by not be known until real-world use, and 27:2622–2627, 2004 40 mg/dl, and the inhaled insulin group experience yields the long-term safety and 8. Skyler JS, Weinstock RS, Raskin P, Yale reported “better glycemic control” even efficacy data that only postmarketing sur- JF, Barrett E, Gerich JE, Gerstein HC, In- though both groups had statistically com- veillance can provide. Communication haled Insulin Phase III Type 1 Diabetes parable A1C. A1C might be too insensi- between physicians and patients pertain- Study Group: Use of inhaled insulin in a tive a measure to detect quality-of-life ing to these patient-centered factors, es- basal/bolus insulin regimen in type 1 dia- improvements that are important and sa- pecially in individuals failing to intensify betic subjects: a 6-month, randomized, lient to patients. Indeed, the higher symp- or maintain their insulin regimen, might comparative trial. Diabetes Care 28:1630– tom distress reported by patients on the better inform the clinical decision process 1635, 2005 subcutaneous regimen were for thirst, when weighing risks and benefits of alter- 9. Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, Chiasson JL, general weakness or fatigue, impaired or native methods of delivering intensive in- Levin SR: Efficacy and safety of inhaled worsening vision, lethargy, no energy to sulin regimens. insulin (Exubera) compared with subcu- do things, tiredness, and feeling weary, all taneous insulin therapy in patients with of which are associated with hyperglyce- type 2 diabetes: results of a 6-month, ran- mia. Acknowledgments— We thank the investi- domized, comparative trial. Diabetes Care One of the most intriguing findings gators (see ref. 8 for a complete list), Ralph R. 27:2356–2362, 2004 was that out of 53 symptoms, the symp- Turner, PhD, MPH; Johanna F. Hayes, ScM; 10. Testa MA, Simonson DC: Assessing qual- tom that was ameliorated most by inhaled Sharon Murphy; and the staff at Phase V Tech- ity-of-life outcomes. N Engl J Med 334: nologies, Inc., for managing the survey data. insulin was “feeling overweight.” Al- 835–840, 1996 though it was previously reported that 11. Testa MA: Interpretation of quality of life body weight increased comparably in outcomes: issues that affect magnitude References and meaning. Medical Care 38:II-166–II- both groups (8), the gains were predom- 1. Diabetes Control and Complications Trial 174, 2000 inant in the growing adolescent subjects, Research Group: The effect of intensive 12. Testa MA, Turner RR, Krafcik MB, Simon- which masked the treatment differential treatment of diabetes on the development son DC, Calvo C, Luque-Otero M, the Ni- in adult female subjects who were most and progression of long-term complica- fedipine GITS Study Group: Quality of distressed by weight gain. Weight gain tions in insulin-dependent diabetes mel- life and calcium channel blockade with
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nifedipine GITS versus amlodipine in hy- distress checklists as a component of tional Biometrics Conference, Seattle, pertensive patients in Spain. J Hypertens quality-of life measurement: comparing Washington, 1986 16:1839–1847, 1998 prompted reports by patient and physi- 24. Weintrob N, Benzaquen H, Galatzer A, 13. Testa MA, Anderson RB, Nackley JF, Hol- cian with concurrent adverse event re- Shalitin S, Lazar L, Fayman G, Lilos P, lenberg NK: Quality of life and antihyper- ports via the physician. Drug Inf J 28:89– Dickerman Z, Phillip M: Comparison of tensive therapy in men: a comparison of 114, 1994 continuous subcutaneous insulin infu- captopril with enalapril. N Engl J Med 328: 19. Testa MA, Turner RR, Simonson DC: Ef- sion and multiple daily injection regimens 907–913, 1993 fects of lower blood glucose and reduced in children with type 1 diabetes: a ran- 14. Testa MA, Hollenberg NK, Anderson RA, inter-day glucose variability on quality of domized open crossover trial. Pediatrics Williams GH: Assessment of quality of life life in type 2 diabetes (Abstract). Diabetes 112:559–564, 2003 by patient and spouse during antihyper- 52 (Suppl. 1):A420, 2003 25. Herman WH, Ilag LL, Johnson SL, Martin tensive therapy with atenolol and nifedi- 20. Testa MA, Hayes JF, Turner RR, Simon- CL, Sinding J, Al Harthi A, Plunkett CD, pine GITS. Am J Hypertens 4:363–373, son DC: Improved quality of life is asso- LaPorte FB, Burke R, Brown MB, Halter 1991 ciated with improved glycemic control in JB, Raskin P: A clinical trial of continuous 15. Anderson RB, Nackley JF, Testa MA: type 2 diabetes: an international, multi- subcutaneous insulin infusion versus Symptom distress check lists as a compo- cultural, multi-center, placebo-control multiple daily injections in older adults nent of quality of life measurement: com- clinical trial (Abstract). Diabetes 49 paring symptom reports with responses (Suppl. 1):A73, 2000 with type 2 diabetes. Diabetes Care 28: to multiple choice questionnaires. Drug 21. Testa MA: Quality-of-life assessment in 1568–1573, 2005 Inf J 29:1689S–1707S, 1995 diabetes research: interpreting the magni- 26. Croog SH, Levine S, Testa MA, Brown B, 16. Testa MA, Simonson DC: Measuring qual- tude and meaning of treatment effects. Di- Bulpitt CJ, Jenkins CD, Klerman GL, Wil- ity of life in hypertensive patients with di- abetes Spectrum 13:36–41, 2000 liams GH: The effects of antihypertensive abetes. Postgrad Med J 64 (Suppl. 3):50– 22. Dubey SD: Adjustment of p-values for therapy on the quality of life. N Engl J Med 58, 1988 multiplicities of intercorrelating symp- 314:1657–1664, 1986 17. Testa MA, Simonson DC, Turner RR: Val- toms. Proceedings of the VIth Interna- 27. Andrade SE, Walker AM, Gottlieb LK, uing quality of life and improvements in tional Society for Clinical Biostatisticians, Hollenberg NK, Testa MA, Saperia GM, glycemic control in people with type 2 Du¨ sseldorf, Germany, 1985 Platt R: Discontinuation of antihyperlipi- diabetes. Diabetes Care 21 (Suppl. 3): 23. Armitage P, Parmar M: Some approaches demic drugs: do rates reported in clinical C44–C52, 1998 to the problem of multiplicity in clinical trials reflect rates in primary care settings? 18. Anderson RB, Testa MA: Symptom trials. Proceedings of the XIIth Interna- N Engl J Med 332:1125–1131, 1995
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1405 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Orange Juice or Fructose Intake Does Not Induce Oxidative and Inflammatory Response
HUSAM GHANIM, PHD AJAY CHAUDHURI, MD proteinase (MMP)-2, MMP-9, tissue fac- PRIYA MOHANTY, MD CHANG LING SIA, BSC tor, and plasminogen activator RAM PATHAK, MD PARESH DANDONA, MD, PHD inhibitor-1 in normal subjects (5) and in vitro (6,7). This raises the question whether ca- OBJECTIVE — We have previously shown that 300 kcal from glucose intake induces a loric intake in any form induces oxida- significant increase in reactive oxygen species (ROS) generation and nuclear factor-B (NF-B) tive stress and inflammation and binding in the circulating mononuclear cells in healthy normal subjects. We hypothesized that whether the type of response is deter- the intake of 300 calories as orange juice or fructose, the other major carbohydrate in orange mined by the source of these calories. juice, would induce a significantly smaller response than that of glucose. This is important since obesity, the re- sult of excessive macronutrient intake, RESEARCH DESIGN AND METHODS — Four groups (eight subjects each) of nor- mal-weight subjects were given a 300-cal drink of glucose (75 g), fructose (75 g), or orange juice is characterized by an excess of oxida- or water sweetened with saccharin (control group) to drink, and then blood samples were tive stress and inflammation (8–10). collected. Furthermore, the restriction of caloric intake in obese subjects results in a re- RESULTS — There was a significant increase in ROS generation by mononuclear cells (by duction of oxidative stress (8,9) and in- 130 Ϯ 18%, P Ͻ 0.001), polymorph nuclear cells (by 95 Ϯ 22%, P Ͻ 0.01), and in NF-B flammatory mediators. A 48-h fast in binding in mononuclear cells by 82 Ϯ 16% (P Ͻ 0.01) over the baseline after2hofglucose normal subjects results in a 35% reduc- intake. These changes were absent following fructose, orange juice, or water intake. There was tion in ROS generation in 24 h and significantly lower ROS generation and NF-B binding following orange juice, fructose, and Ͼ Ͻ 50% reduction in 48 h (11). Clearly, water compared with glucose (P 0.001 for all). Furthermore, incubation of mononuclear cells therefore, caloric intake is a major in vitro with 50 mmol/l of the flavonoids hesperetin or naringenin reduced ROS generation by 52 Ϯ 7% and 77 Ϯ 8% (P Ͻ 0.01), respectively, while fructose or ascorbic acid did not cause any source of oxidative and inflammatory change. stress. Since atherosclerosis, the major cause of cardiovascular death, is associ- CONCLUSIONS — Caloric intake in the form of orange juice or fructose does not induce ated with oxidative stress and inflam- either oxidative or inflammatory stress, possibly due to its flavonoids content and might, there- mation in the arterial wall (12), the fore, represent a potentially safe energy source. search for foods that are least likely to cause oxidative stress and inflammation Diabetes Care 30:1406–1411, 2007 must be pursued. Citrus juices, especially orange juice, ur previous work has shown that nase (IKK)␣ and IKK expression and have been recommended by several the intake of glucose (75 g ϭ 300 IKK activity (1–3). Intravenous infusion health and nutrition groups as a healthy O kcal), cream (33 g ϭ 300 kcal), and of glucose also results in an increase in source of calories, and their intake is as- a fast-food meal (900 kcal) induce an in- proinflammatory cytokines, if endoge- sociated with improved lipid profile and a crease in reactive oxygen species (ROS) nous insulin secretion is inhibited con- reduced risk of cardiovascular disease generation by peripheral blood mononu- comitantly with somatostatin (4). (13,14). Furthermore, orange juice is a clear cells in parallel with an increase in Glucose intake also results in an increase rich source of flavonoids and vitamin C intranuclear nuclear factor-B (NF-B) in proinflammatory transcription factors, (15,16), which may suppress ROS gener- DNA binding, a decrease in inhibitor AP-1 and Egr-1, and the corresponding ation and inflammatory processes. It is B␣, and an increase in inhibitor B ki- genes activated by them: matrix metallo- also possible that flavonoids contained in ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● orange juice may reduce or prevent oxi- From the Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and dative stress and inflammation induced Kaleida Health, Buffalo, New York. by macronutrients like glucose, fructose, Address correspondence and reprint requests to Paresh Dandona, BSc, MB, BS, DPhil, FRCP, Director, and sucrose contained in it. Therefore, we Diabetes-Endocrinology Center of Western NY, Chief of Endocrinology, State University of New York at Buffalo, 3 Gates Circle, Buffalo, NY 14209. E-mail: [email protected]. hypothesized that orange juice intake in- Received for publication 11 July 2006 and accepted in revised form 10 March 2007. duces less oxidative stress and inflamma- Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1458. tion than an equicaloric amount of Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ glucose. dc06-1458. Abbreviations: CRP, C-reactive protein; IKK, inhibitor B kinase; NF-B, nuclear factor-B; ROS, reac- tive oxygen species. RESEARCH DESIGN AND A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion METHODS — Four groups, eight factors for many substances. each, of healthy normal-weight subjects © 2007 by the American Diabetes Association. 2 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby (BMI 20–25 kg/m ), aged 20–40 years, marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. were recruited for this study. Three
1406 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ghanim and Associates
groups were given a single 300-kcal chal- OH), and insulin was measured by an en- http://dx.doi.org/10.2337/dc06-1458]). lenge of glucose, fructose, or orange juice, zyme-linked immunosorbent assay kit (Di- There was no significant difference in glu- whereas subjects from the fourth group agnostics Systems Laboratories, Webster, cose values between glucose and orange were given only water sweetened with TX). Serum C-reactive protein (CRP) was juice intake. There was no significant saccharin. All subjects were given 10 min measured using an enzyme-linked immu- change in glucose concentration follow- to finish their drinks. A fasting blood sam- nosorbent assay kit from Alpha Diagnostic ing fructose or water intake. Plasma insu- ple was collected before and at 1, 2, and International (San Antonio, TX). lin concentrations increased from 9.5 Ϯ 3 h following the drink intake. An insti- 2.44 U/ml to 47.0 Ϯ 8.3, 20.5 Ϯ 8.3, tutional review board–approved consent ROS generation by mononuclear cell and 13.6 Ϯ 5.6 U/mlat1,2,and3h, form was obtained from all subjects. in vitro respectively, following glucose and from Freshly isolated mononuclear cells from 6.1 Ϯ 1.8 U/ml to 50.3 Ϯ 13.1, 19.6 Ϯ Mononuclear cell isolation fasting normal subjects were incubated 12.4, and 4.3 Ϯ 1.5 U/mlat1,2,and Blood samples were collected in Na- for 1 h in PBS containing 5 mmol/l glu- 3 h, respectively, following orange juice EDTA as an anticoagulant. Anticoagu- cose with either fructose (5 mmol/l), vita- (P Ͻ 0.001 repeated-measures ANOVA lated blood samples (3.5 ml) were min C (0.250 mmol/l ascorbic acid), or for both) (online appendix Fig. 2). Fruc- carefully layered over 3.5 ml of Lym- the flavonoids hespertin (50 mol/l) and tose intake increased insulin concentra- pholyte medium (Cedarlane Laborato- naringenin (50 mol/l) dissolved in tions from 8.8 Ϯ 1.3 U/ml to 17.0 Ϯ ries, Hornby, ON, Canada) and DMSO. Cells were washed once, and ROS 5.2, 13.1 Ϯ 3.9, and 8.9 Ϯ 1.8 U/ml at centrifuged to separate the cells. A top assay was carried as previously described. 1, 2, and 3 h, respectively (P Ͻ 0.01 re- band consisting of mononuclear cells and Controls included cells incubated with peated-measures ANOVA). There was no a bottom consisting of polymorph nuclear glucose with or without DMSO. This ex- difference in the change in insulin values cells were collected. This method yields periment was repeated four times, and following glucose and orange juice intake Ͼ95% pure polymorph nuclear cell and data represent the means Ϯ SE. Inhibition when compared by two-factor repeated- mononuclear cell suspensions. of ROS generation by mononuclear cells measures ANOVA, but, when compared was evaluated by incubating freshly iso- with fructose, changes in insulin concen- ROS generation measurement by lated mononuclear cells with the NADPH trations following both glucose and or- chemiluminescence oxidase inhibitor DPI (Sigma, San Anto- ange juice were significantly greater (P Ͻ Polymorph nuclear cells (500 l) or nio, TX) at a concentration of 10–1,250 0.05). There was a trend toward a greater 5 mononuclear cells (2 ϫ 10 cells) were nmol/l for 30 min. Cells were washed once insulin concentration following orange delivered into a Chronolog Lumiaggre- and ROS generation measured. juice for a given glucose concentration gometer cuvette. Luminol was then compared with glucose intake. This was added, followed by 1.0 l of 10 mmol/l Statistical analysis best expressed as a ratio between the in- formylmethionyl leucinyl phenylalanine. Statistical analysis was conducted using crease in insulin and glucose concentra- In this assay system, the release of super- SigmaStat software (SPSS, Chicago, IL). tions at 1 h. This ratio was significantly ⌬ oxide radical as measured by chemilumi- All the data are represented as means Ϯ greater following orange juice ( insulin- ⌬ ϭ Ϯ nescence has been shown to be linearly SE. Statistical analysis from baselines was to- glucose ratio at 1 h 1.77 0.32 vs. Ϯ ϭ correlated with that measured by the fer- carried out using Holm-Sidak one-way 1.12 0.25; P 0.033 unpaired t test). ricytochrome C method. The interassay repeated-measures ANOVA. Dunnett’s coefficient of variation of this assay is 8%. two-factor ANOVA method was used for We have further established that the bio- all multiple comparisons between differ- Effect of the different treatments on logical variation in ROS generation in ent groups. Student’s t tests for impaired ROS generation by mononuclear and ϳ normal subjects is 6% for readings ob- data were used to compare ⌬glucose-to- polymorph nuclear cells tained 1–2 weeks apart. ⌬insulin ratio 1 h after glucose or orange There was a significant increase in ROS juice intake. ROS generation from the in generation by mononuclear and poly- Ϯ Ͻ NF- B DNA binding activity vitro experiment was compared between morph nuclear cells by 130 18% (P Nuclear NF- B DNA binding activity was the treatments using paired t test analysis. 0.001 repeated-measures ANOVA) (Fig. measured by electrophoretic mobility 1A) and 95 Ϯ 22% (P Ͻ 0.01 repeated- shift assay. Nuclear extracts were pre- measures ANOVA) (Fig. 1B), respec- pared from mononuclear cells and by RESULTS tively, over the baseline within2hof high-salt extraction. The specificity of the glucose intake. There was no significant bands was confirmed by supershifting Effect of the different treatments on change in ROS generation by mononu- these bands with specific antibodies plasma glucose and insulin clear or polymorph nuclear cells follow- against Rel-A (p65) and p50 (Santa Cruz concentrations ing fructose, orange juice, or water intake. Biotechnology, Santa Cruz, CA) and by Plasma glucose concentrations increased When ROS generation was compared be- competition with cold oligonucleotides. from a mean of 94 Ϯ 6 mg/dl to 129 Ϯ 21, tween the groups, there was a significant 109 Ϯ 20, and 94 Ϯ 10 mg/dl at 1, 2, and difference between glucose intake and all Measurement of plasma glucose, 3 h, respectively, after glucose intake and of orange juice, fructose, and water intake insulin, and C-reactive protein from 90 Ϯ 4 mg/dl to 116 Ϯ 9, 102 Ϯ 5, (P Ͻ 0.01 for all, two-factor repeated- concentrations and 92 Ϯ 5 mg/dl at 1, 2, and 3 h, respec- measures ANOVA). There was no signifi- Glucose levels were measured in plasma by tively, following orange juice (P Ͻ 0.001 cant difference in ROS generation YSI 2300 STAT Plus glucose analyzer (Yel- repeated-measures ANOVA for both) between orange juice, fructose, and water low Springs Instruments, Yellow Springs, (online appendix Fig. 1 [available at intake.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1407 Orange juice and oxidative stress and inflammation
to orange juice, fructose, and water intake (P Ͻ 0.01 for all, two-factor repeated- measures ANOVA). There was no signifi- cant difference in NF-B binding between orange juice, fructose, and water intake.
Effect of 300-kcal intake on plasma CRP concentration Although none of the challenges induced a significant change in plasma concentra- tions of CRP over the 3-h observation pe- riod, there was a trend toward a fall (P Ͻ 0.1 repeated-measures ANOVA) and a significant fall in CRP concentrations within1hoforange juice intake (1,305 Ϯ 375 vs. 1,219 Ϯ 321 ng/ml, P ϭ 0.044 paired t test) (Fig. 3). The change in CRP concentrations following orange juice was also significantly different compared with water intake (P Ͻ 0.01 two-factor repeated-measures ANOVA).
Effect of orange juice components on ROS generation by mononuclear cells in vitro ROS generation by mononuclear cells freshly isolated from normal subjects was measured individually following a 1-h incu- bation with various components or orange juice. There was no significant change in ROS generation by mononuclear cells fol- lowing incubation with 5 mmol/l fructose or 0.25 mmol/l ascorbic acid when com- pared with control cells incubated with glu- cose alone. ROS generation was significantly lower when mononuclear cells were incubated with hesperetin (by 52 Ϯ 7%, P ϭ 0.004) or naringenin (by 77 Ϯ 8%, P ϭ 0.002), the two major falvonoids in orange juice, when compared with control cells incubated with glucose and DMSO alone (Fig. 4).
Effect of NADPH inhibition on ROS generation by mononuclear cells in vitro There was a significant dose-dependent inhibition of ROS generation by mononu- clear cells following 30 min of incubation in 5 mmol/l glucose with increasing con- Figure 1—ROS generation by mononuclear cells (MNC) (A) and polymorph nuclear cells (PMN) centrations (10–1,250 nmol/l) of the (B) following glucose, fructose, orange juice, and water ingestion. *P Ͻ 0.01 repeated-measures NADPH oxidase inhibitor DPI in DMSO ANOVA for glucose; $P Ͻ 0.01 two-factor repeated-measures ANOVA between glucose and all (online appendix Table 1) compared with ϭ other groups. n 8 for all. control cells incubated with glucose and DMSO alone. This experiment was re- Effect of the different treatments on There was no significant increase in peated three times on mononuclear cells NF-B DNA binding in the NF-B binding following fructose, orange from three different normal subjects. mononuclear cells juice, or water intake. When NF-B DNA NF-B DNA binding was increased signif- binding changes were compared between CONCLUSIONS — Our data con- icantly by 82 Ϯ 16% over the baseline the groups, there was a significant differ- firm that the intake of 75 g glucose in- (P Ͻ 0.01 repeated-measures ANOVA) ence in NF-B binding following glucose duces a significant increase in ROS (Fig. 2) within2hofglucose intake. intake when compared with baseline and generation and NF-B binding by mono-
1408 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ghanim and Associates
shown that superoxide dismutase also markedly suppresses ROS generation in this system. It is intriguing that the absence of an increase in ROS generation and NF-B binding following orange juice intake was observed inspite of an increase in plasma glucose concentration, which was not sig- nificantly different from that observed fol- lowing glucose. This raised the question whether the presence of flavonoids and vitamin C exerted an ROS and NF-B binding suppressive effect or that fruc- tose, the other major sugar in orange juice, may be suppressive of ROS genera- tion and NF-B binding. Therefore, we tested these possibilities in a separate se- ries of experiment conducted in vitro. We were able to demonstrate that fructose and ascorbic acid did not suppress ROS generation, whereas hesperetin and nar- ingenin inhibited ROS generation by 52 and 77%, respectively, at micromolar Figure 2—Change in intranuclear NF-B binding activity following glucose, fructose, orange concentrations. Clearly, therefore, the juice, and water ingestion. *P Ͻ 0.01 repeated-measures ANOVA for glucose; $P Ͻ 0.01 two- two major flavonoids in orange juice factor repeated-measures ANOVA between glucose and all other groups. n ϭ 8 for all. MNC, might mediate the suppression of glu- mononuclear cells. cose-induced ROS generation. This area requires further investigation including work in vivo. nuclear cells at 1 and 2 h after intake. In its the ROS generation in a cell-based as- Since fructose is a major sugar in contrast, equivalent amounts (300 cal) of say system like ours implies that the fruits and other vegetable products, it either orange juice or fructose did not in- majority of ROS detected in our system would be worth investigating the poten- duce a change in either ROS generation or are the products of NADPH oxidase. Sup- tial anti-inflammatory effect of food prod- NF-B binding. These data are important porting this concept, we have previously ucts rich in fructose. It is also of interest since they show for the first time that “safe” nutritional choices on the basis of minimizing postprandial oxidative and inflammatory stress can be made. It is rel- evant that alcohol intake (300 cal) also does not result in increased ROS genera- tion or NF-B binding as previously re- ported by us (17). However, alcohol cannot and should not be recommended as a major macronutrient source. We have previously shown that the diphenylene iodonium (DPI), a specific inhibitor of NADPH oxidase (18), com- pletely inhibits ROS generation by leuko- cytes in a dose-dependent manner (19). Our repeat experiments confirm this, as presented here. This indicates that in our assay system, ROS generation is mainly due to the activation of the NADPH oxi- dase, which is located mainly in the leu- kocyte membrane, in order to assist in bacterial killing following phogocytosis. Further testing with specific inhibitors of the mitochondrial electron transport chain is needed to totally exclude possible contribution of the mitochondria to ROS Figure 3—Change in plasma CRP concentrations following glucose, fructose, orange juice, and generation in our assay system. However, water ingestion. #P Ͻ 0.05 paired t test for orange juice; $P Ͻ 0.01 two-factor repeated-measures the fact that DPI dose-dependently inhib- ANOVA between orange juice and water. n ϭ 8 for all.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1409 Orange juice and oxidative stress and inflammation
the effect of water and orange juice on CRP concentrations following their in- take. The clinical significance of a fall of CRP by 10–15% for a period of 2–3 h following orange juice is not clear. Studies on the long-term effect of orange juice in- take in high-risk groups are necessary to evaluate the clinical implications of a fall in CRP. Our data are relevant to patients with diabetes since oxidative (24) and inflam- matory (25) stress are markedly increased in this condition and may contribute to accelerated atherosclerosis. Clearly, the choice of foods that either do not increase or actually decrease oxidative and inflam- matory stress in diabetic subjects is im- portant. Our findings also raise the issue of whether hypoglycemia in diabetic pa- tients should be treated with glucose or orange juice. Further studies are required. In conclusion, 1) orange juice or fruc- tose taken in equicaloric amounts to 75 g glucose does not cause either oxidative stress or inflammation in contrast to glu- cose; 2) the two flavonoids hesperetin and naringenin have a ROS-suppressive effect Figure 4—ROS generation by mononuclear cells (MNC) in vitro following1hofincubation with in vitro, which needs to be confirmed in orange juice components (fructose [5 mmol/l], vitamin C [0.25 mmol/l ascorbic acid], hespertin vivo; 3) ascorbic acid does not exert this [50 mo/l], and naringenin [50 mol/l]). Control cells were incubated for 1 h with 5 mmol/l glucose alone or with DMSO. *P Ͻ 0.01 paired t test. n ϭ 4; data represents means Ϯ SE. effect; and 4) there are ways of avoiding postprandial oxidative stress and inflam- mation by making appropriate choices. that 75 g fructose did not alter plasma lated as ⌬insulin-to-⌬glucose ratio at 1 h The search for safe noninflammatory glucose concentrations significantly, for each subject was significantly higher foods and diets must continue. while it did induce a small but significant following orange juice intake. This sug- increase in plasma insulin concentrations gests that orange juice may be more insu- at 1 h. It is possible that fructose is taken linogenic compared with glucose and that  References up and metabolized by the -cell, result- changes in glucose concentrations might 1. Mohanty P, Hamouda W, Garg R, Aljada ing in a small release of insulin in fashion not always totally predict plasma insulin A, Ghanim H, Dandona P: Glucose chal- similar to that observed with glucose. The response. Similar observations have been lenge stimulates reactive oxygen species absence of oxidative and inflammatory reported following the intake of orange (ROS) generation by leucocytes. J Clin En- stress following fructose is intriguing juice and other fruit juices in terms of docrinol Metab 85:2970–2973, 2000 since fructose diets in animals induce in- plasma glucose and insulin responses in 2. Mohanty P, Ghanim H, Hamouda W, Al- sulin resistance. However, the quantities type 2 diabetic patients (21). 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Sucrose is hydrolyzed in the in vivo (22,23). crease in intranuclear nuclear factor kap- gastrointestinal tract by disaccharidases The data on the effect of orange juice paB and decrease in inhibitor kappaB in into an equal number of glucose and fruc- on plasma CRP concentrations are inter- mononuclear cells after a mixed meal: ev- tose molecules. Thus, for all practical pur- esting. Although orange juice did not in- idence for a proinflammatory effect. Am J poses, orange juice has glucose and duce a significant fall in CRP over the Clin Nutr 79:682–690, 2004 fructose as the two major sugars in equal observation period of 3 h, there was a 4. Esposito K, Nappo F, Marfella R, Giugli- amounts. It is, therefore, intriguing that trend (P ϭ 0.1 repeated-measures ano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D: Inflammatory although the average increase in glucose ANOVA) toward a reduction and a signif- Ͻ cytokine concentrations are acutely in- and insulin concentrations following or- icant fall at1h(P 0.05 paired t test) creased by hyperglycemia in humans: role ange juice are not significantly different from baseline. There was also a highly sig- of oxidative stress. Circulation 106:2067– from those following glucose, the average nificant (P Ͻ 0.01 two-factor repeated- 2072, 2002 increase in insulin concentrations calcu- measures ANOVA) difference between 5. Aljada A, Ghanim H, Mohanty P, Syed T,
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Bandyopadhyay A, Dandona P: Glucose mononuclear cells in the obese are in a diphenyleneiodonium and its analogues intake induces an increase in activator proinflammatory state. Circulation 110: of superoxide generation by macro- protein 1 and early growth response 1 1564–1571, 2004 phages. Biochem J 242:103–107, 1987 binding activities, in the expression of tis- 11. Dandona P, Mohanty P, Hamouda W, 19. Nicotera T, Thusu K, Dandona P: Ele- sue factor and matrix metalloproteinase in Ghanim H, Aljada A, Garg R, Kumar V: vated production of active oxygen in mononuclear cells, and in plasma tissue Inhibitory effect of a two day fast on reac- Bloom’s syndrome cell lines. Cancer Res factor and matrix metalloproteinase con- tive oxygen species (ROS) generation by 53:5104–5107, 1993 centrations. Am J Clin Nutr 80:51–57, leucocytes and plasma ortho-tyrosine and 20. Li BW, Schuhmann PJ: Sugar analysis of 2004 meta-tyrosine concentrations. J Clin Endo- fruit juices: content and method. J Food 6. Srinivasan S, Hatley ME, Bolick DT, crinol Metab 86:2899–2902, 2001 Sci 48:633–635, 1983 Palmer LA, Edelstein D, Brownlee M, 12. Ross R: Atherosclerosis–an inflammatory 21. Gannon MC, Nuttall FQ, Krezowski PA, Hedrick CC: Hyperglycaemia-induced disease. N Engl J Med 340:115–126, 1999 Billington CJ, Parker S: The serum insulin superoxide production decreases eNOS 13. Kurowska EM, Spence JD, Jordan J, Wet- and plasma glucose responses to milk and expression via AP-1 activation in aortic more S, Freeman DJ, Piche LA, Serratore fruit products in type 2 (non-insulin-de- endothelial cells. Diabetologia 47:1727– P: HDL-cholesterol-raising effect of or- pendent) diabetic patients. Diabetologia 1734, 2004 ange juice in subjects with hypercholes- 29:784–791, 1986 7. Guha M, Bai W, Nadler JL, Natarajan R: terolemia. Am J Clin Nutr 72:1095–1100, 22. Dandona P, Aljada A, Mohanty P, Ghanim Molecular mechanisms of tumor necrosis 2000 H, Hamouda W, Assian E, Ahmad S: In- factor alpha gene expression in monocytic 14. Liu S, Manson JE, Lee IM, Cole SR, Hen- sulin inhibits intranuclear nuclear factor cells via hyperglycemia-induced oxidant nekens CH, Willett WC, Buring JE: Fruit kappaB and stimulates IkappaB in mono- stress-dependent and -independent path- and vegetable intake and risk of cardio- nuclear cells in obese subjects: evidence ways. J Biol Chem 275:17728–17739, vascular disease: the Women’s Health for an anti-inflammatory effect? J Clin En- 2000 Study. Am J Clin Nutr 72:922–928, 2000 docrinol Metab 86:3257–3265, 2001 8. Dandona P, Mohanty P, Ghanim H, Al- 15. Squires SR, Hanna JG: Concentration and jada A, Browne R, Hamouda W, Prabhala stability of ascorbic acid in marketed re- 23. Chaudhuri A, Janicke D, Wilson MF, A, Afzal A, Garg R: The suppressive effect constituted orange juice. J Agric Food Tripathy D, Garg R, Bandyopadhyay A, of dietary restriction and weight loss in Chem 27:639–641, 1979 Calieri J, Hoffmeyer D, Syed T, Ghanim the obese on the generation of reactive ox- 16. Nelson EW, Streiff RR, Cerda JJ: Compar- H, Aljada A, Dandona P: Anti-inflam- ygen species by leukocytes, lipid peroxi- ative bioavailability of folate and vitamin matory and profibrinolytic effect of dation, and protein carbonylation. J Clin C from a synthetic and a natural source. insulin in acute ST-segment-elevation Endocrinol Metab 86:355–362, 2001 Am J Clin Nutr 28:1014–1019, 1975 myocardial infarction. Circulation 109: 9. Davi G, Guagnano MT, Ciabattoni G, Ba- 17. Dhindsa S, Tripathy D, Mohanty P, Gha- 849–854, 2004 sili S, Falco A, Marinopiccoli M, Nutini M, nim H, Syed T, Aljada A, Dandona P: Dif- 24. Dandona P, Thusu K, Cook S, Snyder B, Sensi S, Patrono C: Platelet activation in ferential effects of glucose and alcohol on Makowski J, Armstrong D, Nicotera T: obese women: role of inflammation and reactive oxygen species generation and in- Oxidative damage to DNA in diabetes oxidant stress. JAMA 288:2008–2014, tranuclear nuclear factor-kappaB in mellitus. Lancet 347:444–445, 1996 2002 mononuclear cells. Metabolism 53:330– 25. Dandona P: Endothelium, inflammation, 10. Ghanim H, Aljada A, Hofmeyer D, Syed T, 334, 2004 and diabetes. Curr Diab Rep 2:311–315, Mohanty P, Dandona P: Circulating 18. Hancock JT, Jones OT: The inhibition by 2002
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1411 Clinical Care/Education/Nutrition ORIGINAL ARTICLE
Interindividual Variability and Intra- Individual Reproducibility of Glycemic Index Values for Commercial White Bread
1 2 SONIA VEGA-L´OPEZ, PHD JOHN L. GRIFFITH, PHD The glycemic index value of a given 1 1 LYNNE M. AUSMAN, DSC ALICE H. LICHTENSTEIN, DSC food is determined by monitoring the incre- mental area under the curve (AUC) for blood glucose response over a 2-h period OBJECTIVE — We sought to assess the intra- and interindividual variability of glycemic after feeding a 50-g carbohydrate portion of index value determinations for white bread using glucose as the reference food. both a test food and standard food (50 g glucose or a 50-g carbohydrate portion of RESEARCH DESIGN AND METHODS — A total of 23 healthy adults (aged 20–70 white bread) and expressing the data on a years) completed up to three sets of two visits per set. Each pair of visits assessed the glycemic percentage of the test food relative to the response to 50 g available carbohydrates from commercial white bread and glucose, adminis- standard food (6,10). By definition, any tered in random order. Glycemic index values were calculated by dividing the 2-h incremental area below the fasting glucose concentra- area under the serum glucose response curve after each commercial white bread challenge by the mean area under the curve (AUC) for glucose. tion is not included in the AUC value. If white bread is used as the standard food, the RESULTS — The mean Ϯ SE ratio of the AUC after white bread intake by the AUC after glycemic index value for the test food is fre- glucose intake for the first set of determinations was 78 Ϯ 15 (n ϭ 23; coefficient of variation quently corrected to glucose using a factor [CV] 94%). When using glycemic index values calculated with the subset of participants who of 1.4 (6,10). An extensive compilation of completed three sets of tests (n ϭ 14), glycemic index values for each of the three sets of glycemic index and glycemic load values determinations were 78 Ϯ 10, 60 Ϯ 5, and 75 Ϯ 10, respectively. CVs were 50, 28, and 50%, derived from different laboratories world- respectively. The mean glycemic index value of these three sets was 71 Ϯ 6, with a CV of 30%. wide is currently available (10,11). When an ANOVA approach was applied to these data, the interindividual CV was 17.8%, and the Implicit in the recommendation to for- intra-individual variation was 42.8%. malize glycemic index as a dietary guidance CONCLUSIONS — These data suggest that in response to a challenge of white bread relative tool is the assumption that the glycemic re- to glucose, within-individual variability is a greater contributor to overall variability than among- sponse an individual has to a given food is individual variability. Further understanding of all the sources of variability would be helpful in similar among individuals regardless of better defining the utility of glycemic index values. metabolic and physiological factors. Guide- lines for the determination of glycemic in- Diabetes Care 30:1412–1417, 2007 dex values recommend that it be determined in six or more subjects and the t has been recognized for the past 3 choices to reduce chronic disease risk by values averaged (6). It is additionally rec- decades that carbohydrate-containing some individuals and organizations ommended that the glycemic index value I foods elicit widely different postpran- (4–6) but not by others (7–9). Reluctance for more than one food “. . . be determined dial blood glucose responses (1,2). A sys- to universally recommend the system for in one series of tests, for example, each sub- tem to classify foods on the basis of use in formulating dietary guidance stems ject might test four foods once each and the glycemic response, termed glycemic in- from a number of issues, some relating to standard food three times for a total of seven dex, emerged to capture this information uncertainties in reproducibility among tests in random order on separate days.” It is (3). The classification system has been en- people and variability in the composition further recommended that subjects should dorsed for use as a tool to guide food and preparation of individual foods. be studied on separate days in the morning ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● after a 10–12 h overnight fast and a stan- dard drink of water, tea, or coffee be given From the 1Cardiovascular Nutrition Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutri- tion Research Center on Aging, Tufts University, Boston, Massachusetts; and the 2Biostatistics Research with each test meal. Center, Tufts New England Medical Center, Boston, Massachusetts. There are limited data that have ad- Address correspondence and reprint requests to Alice H. Lichtenstein, DSC, Cardiovascular Nutrition dressed the issue of reproducibility. There- Laboratory, J.M. USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., fore, the current study was carried out to Boston, MA 02111. E-mail: [email protected]. Received for publication 28 July 2006 and accepted in revised form 13 March 2007. assess the interindividual variability (among Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1598. individuals) and intra-individual reproduc- Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ ibility (within the same individual, when re- dc06-1598. peatedly measured) of glycemic index This article is based on work supported by the U.S. Department of Agriculture under agreement no. values for white bread, using glucose as the 58-1950-4-401. Any opinions, findings, conclusions, or recommendations expressed in this article are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. standard food, determined under con- Abbreviations: AUC, area under the curve; GRR, glycemic response ratio. trolled conditions. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. RESEARCH DESIGN AND © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby METHODS — A total of 25 adults marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. (aged 20–70 years) were recruited from
1412 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Vega-Lo´pez and Associates the greater Boston area. Exclusion criteria ipants remained in the Metabolic Research food (glucose) was used instead of the were as follows: 1) known chronic dis- Unit under observation and were restricted mean of three values, used for the stan- eases, including diabetes, untreated hy- to sedentary activities in their rooms. dard method (3,6). pertension, irritable bowel syndrome or For each set of visits, participants The evaluation of the interindividual malabsorptive disorder, or established consumed 500 ml glucose solution (100 variability (among individuals) and intra- cardiovascular, kidney, or liver disease; 2) g/l; 50 g carbohydrate) and 96 g (50 g individual variability (within the same in- smoking; 3)BMIϾ35 kg/m2; 4) fasting available carbohydrate) commercial dividual when repeatedly measured) of glucose Ն7 mg/dl; 5) abnormal blood white bread (Original White Bread; the glycemic index determination was as- chemistry or complete blood count; 6) Pepperidge Farm, Norwalk, CT) with sessed by comparing data from the subset pregnancy or breastfeeding; 7) alcohol 500 ml water, in random order. Water, of participants who were tested three consumption at Ͼ7 drinks/week; 8) use ad libitum, was available throughout times (n ϭ 14). Glycemic index values of medications known to affect glucose the test period. were calculated by dividing the AUC metabolism (insulin, sulfonylureas, met- value for the glycemic response to the first formin, glucosidase inhibitors, thiazo- Biochemical measures white bread challenge by the mean of the lidinedione insulin sensitizers); 9) weight Blood was allowed to clot at room tem- three AUC values after glucose intake. gain or loss Ն7 kg within 6 months before perature for 20 min, and serum was sub- Glycemic index values for these compar- enrollment; and 10) unwillingness to ad- sequently separated by centrifugation at isons were calculated by the standard pro- here to study protocol. Subject identifica- 1,100g at 4°C for 20 min. Glucose was cedures using separate individual AUC tion numbers were assigned sequentially measured using an enzymatic method values for the glycemic response to white in the order in which participants were (Olympus America, Melville, NY). The bread divided by the mean of the three enrolled. All study participants gave writ- CV for the glucose determinations was AUC values after glucose intake, as previ- ten informed consent. The study protocol 2%. Insulin was measured using a human ously described (3,6). was approved by the Human Investiga- insulin–specific radioimmunoassay kit tion Review Committee of Tufts Universi- (Linco Research, St. Louis, MO) (13). The Statistical analyses ty-New England Medical Center. CV for the insulin determinations was The data were entered into a spreadsheet All participants completed one set of 5%. To characterize the study partici- and analyzed using SAS for Windows two visits. A subset of participants com- pants, baseline total, LDL, and HDL cho- (version 9.1; SAS Institute, Cary, NC). pleted three replicate sets (n ϭ 14). Each lesterol and triglyceride concentrations Descriptive statistics and graphs (PROC set, or pair of visits, was used to assess the were measured on a Hitachi 911 auto- UNIVARIATE and PROC MEANS) were glycemic response to white bread and glu- mated analyzer (Roche Diagnostics, Indi- used to summarize the overall effects of cose, administered in random order. Visits anapolis, IN) using enzymatic reagents tests and distributions of the outcome within the same set were conducted no (14). The lipid assays were standardized measures. The overall intra- and interin- more than 7 days apart. One participant was through the Lipid Standardization Pro- dividual variation was calculated through withdrawn from the study because of poor gram of the Centers for Disease Control a variance component model (PROC venous access, whereas one participant was and Prevention, Atlanta, GA. VARCOMP). Data are presented in text unable to complete a set of visits within 7 and tables as means Ϯ SD or SE, as indi- days because of unanticipated scheduling Glycemic index calculations cated. Baseline characteristics of male and conflicts and was excluded from the analy- The incremental blood glucose AUC was female participants were compared using sis. During the testing period, participants determined as previously described (12) independent samples t tests. Analyses were requested to maintain their habitual by calculating the geometric sum of the were conducted at the 0.05 ␣ level. diet and physical activity patterns. Before areas of the triangles and trapezoids for each test day, participants were asked to fast the response over 2 h, excluding area that RESULTS — At baseline, blood pres- and refrain from exercising 12 h before ar- fell below initial fasting glucose concen- sure, anthropometric measures, and insu- rival at the Metabolic Research Unit at the trations. Glucose was used as the refer- lin and lipoprotein concentrations were Human Nutrition Research Center. At the ence food to calculate the glycemic index similar between male and female partici- beginning of the first test day, blood pres- of white bread. Glycemic index values pants (Table 1), whereas waist circumfer- sure, body height and weight, and waist and were calculated by dividing the AUC ob- ence, fasting glucose, and LDL cholesterol hip circumferences were measured using tained after the white bread challenge by were greater in male than in female sub- standardized procedures. Immediately that obtained after glucose intake, as pre- jects (P Ͻ 0.05). thereafter, an intravenous indwelling cath- viously described (3,6). Figure 1 depicts the glycemic re- eter was placed in the forearm for blood The evaluation of the variability of the sponse ratios to white bread and glucose drawing purposes, and a fasting blood sam- glycemic response to white bread and glu- during the first set of tests for each partic- ple was obtained. The test food (described cose was assessed by comparing the data ipant (n ϭ 23). Panels represent the re- below) was provided, and the participant obtained from the first set of tests for all sponse of each participant and are was requested to consume the food within a participants (n ϭ 23). Glycemic response arranged in order of increasing GRR value period of 5 min, under observation, to ratio (GRR) values were calculated by di- from left to right and top to bottom. The mimic a bolus administration of the test viding the AUC value for the glycemic re- mean GRR value was 78 Ϯ 73 (SEM ϭ 15; food. Consistent with the recommended sponse to the first white bread challenge n ϭ 23) with an interindividual CV of standardized protocol for nondiabetic indi- by the AUC value for the glycemic re- 94%. The mean serum glucose AUC for viduals (3,6,12), additional blood samples sponse to the first glucose challenge. GRR the white bread challenge was 2,135 Ϯ were obtained 15, 30, 45, 60, 90, and 120 values differ from glycemic index values 1,175 (SEM ϭ 245; CV ϭ 55%; n ϭ 23), min thereafter. During the test time, partic- in that only one AUC for the reference and the mean serum glucose AUC for the
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1413 Glycemic index variability
Table 1—Baseline characteristics of participants
Variable All participants Male subjects Female subjects P n 23 10 13 Age (years) 42 Ϯ 15 (23–70) 47 Ϯ 14 (30–69) 38 Ϯ 15 (23–70) NS Blood pressure (mmHg) — — — — Systolic 116 Ϯ 13 (89–142) 121 Ϯ 12 (101–137) 112 Ϯ 13 (89–142) NS Diastolic 71 Ϯ 7 (54–81) 72 Ϯ 8 (54–81) 71 Ϯ 6 (62–80) NS BMI (kg/m2) 25.8 Ϯ 3.8 (20.3–32.5) 26.2 Ϯ 3.2 (21.4–29.5) 25.8 Ϯ 4.3 (20.3–32.5) NS Waist circumference (cm) 89 Ϯ 13 (67–117) 96 Ϯ 11 (80–117) 82 Ϯ 11 (67–99) 0.02 Hip circumference (cm) 103 Ϯ 9 (83–119) 102 Ϯ 9 (91–119) 103 Ϯ 10 (83–116) NS Fasting glucose (mmol/l) 4.8 Ϯ 0.5 (3.8–6.0) 5.1 Ϯ 0.4 (4.7–6.0) 4.5 Ϯ 0.4 (3.8–5.2) 0.002 Fasting insulin (pmol/l) 67 Ϯ 32 (10–171) 61 Ϯ 22 (24–100) 72 Ϯ 39 (10–171) NS HOMA* 2.06 Ϯ 1.07 (0.27–5.58) 2.01 Ϯ 0.79 (0.73–3.45) 2.09 Ϯ 1.28 (0.27–5.58) NS Cholesterol (mmol/l) — — — — Total 4.62 Ϯ 0.83 (2.90–6.62) 4.76 Ϯ 0.65 (3.85–5.79) 4.52 Ϯ 0.97 (2.90–6.62) NS LDL 2.79 Ϯ 0.67 (1.32–4.32) 3.06 Ϯ 0.47 (2.30–3.85) 2.58 Ϯ 0.74 (1.32–4.32) 0.01 HDL 1.45 Ϯ 0.29 (1.07–2.15) 1.25 Ϯ 0.13 (1.07–1.45) 1.60 Ϯ 0.30 (1.11–2.15) NS Triglyceride (mmol/l) 0.86 Ϯ 0.42 (0.45–2.09) 1.00 Ϯ 0.40 (0.45–1.69) 0.76 Ϯ 0.42 (0.49–2.09) NS Data are means Ϯ SD (range) unless otherwise indicated. An unpaired t test was conducted for the comparison of male vs. female subjects. *Homeostasis model assessment (HOMA) ϭ glucose (mmol/l) ϫ͓insulin (U/ml)/22.5͔. glucose challenge was 3,556 Ϯ 1,686 calculate an estimate, we have averaged type 1 diabetes. Similarly, from a compar- (SEM ϭ 351; CV ϭ 47%; n ϭ 23). The the individual CV from each subject ison of glycemic index values from differ- mean serum insulin AUC for the white (ranging between 7 and 75%). ent pasta foods in a sample of subjects bread challenge was 2,532 Ϯ 1,591 To assess the components of variance with type 1 (57 Ϯ 20, n ϭ 6, CV ϭ 34%) (SEM ϭ 332; CV ϭ 63%; n ϭ 23), and the within these tests, the overall interindi- and type 2 (49 Ϯ 23, n ϭ 11, CV ϭ 47%) mean serum insulin AUC for the glucose vidual variation was obtained from the diabetes, CVs were 34 and 47%, respec- challenge was 2,945 Ϯ 1,553 (SEM ϭ PROC VARCOMP routine using the fol- tively (19). In another report (20), the 324; CV ϭ 53%; n ϭ 23) (see online ap- lowing model: Y (ij) ϭ u ϩ S(i) ϩ R(ij), mean among-subject CV of the AUC of pendix, located at http://dx.doi.org/ where replicates (R) are nested within the glycemic response was 25% for sub- 10.2337/dc06-1598). subjects (S). When the square root of the jects with type 2 diabetes and 38% for Figure 2 shows individual mean gly- subject variance (͌159.62) is divided by subjects with type 1 diabetes. cemic index values calculated for the sub- the mean glycemic index (70.69), the in- The CV when the test was performed set of participants who were tested three terindividual CV is 17.8%. The intra- in triplicate ranged from 4 to 75%. Ram- times (n ϭ 14). The mean glycemic index individual variation was assessed using dath et al. (21) found significant differ- value for white bread calculated using the same PROC VARCOMP routine, us- ences (P Ͻ 0.001) in glucose AUC AUC values from the first time in which ing the square root of the error term responses to white bread when the mea- white bread was consumed was 78 Ϯ 39 (͌913.56) divided by the mean glycemic sure was repeated on three different occa- (SEM ϭ 10; CV ϭ 50%; n ϭ 14) (Table index to yield an intra-individual variabil- sions in subjects participating in a two- 2). The CV was smaller when the white ity of 42.8%. center study. In one of the few studies that bread was tested more than once (25% reported repeated measurements (four when tests one and two were included CONCLUSIONS — Despite the times) within the same subject, the CV for and 30% when the three tests were in- range of responses observed for individ- white bread ranged between 4 and 46% cluded). However, the range of glycemic ual subjects, the mean glycemic index (22). It has also been reported that the index values obtained was broad (42–106 value for white bread observed in the cur- mean within-subject CV for the AUC of for the mean of tests one and two; 44–132 rent study was 71 Ϯ 22 (SEM ϭ 6; CV ϭ the glycemic response is 16% for patients for the mean of the three tests) (Table 2, 30%, n ϭ 14) (Table 2), which is virtually with type 2 diabetes and 24 to 29% for Fig. 2), suggesting that although the val- identical to the mean value used for refer- patients with type 1 diabetes (20,23). The ues may be valid for groups of people, ence purposes (10). However, the glyce- within-subject CV reported for the glyce- there is some uncertainty when applying mic index values for white bread ranged mic index value was of similar magnitude them to individuals, and it would be help- from 44 to 132, with a CV of 30%. This (16% for patients with type 2 and 25% for ful to understand more about what con- value is consistent with the calculated patients with type 1 diabetes). tributes to this level of variability. CVs from other reports with healthy vol- In a study that assessed the variability As shown in Table 2, there exists sub- unteers, which ranged from 12 to 53% in glycemic index value determinations stantial variation in glycemic index values (3,15–17). From a report evaluating the among seven laboratories in normoglyce- within each individual. For the mean of glycemic response to white bread (18), mic volunteers (24), the CV of the mean three tests, 50% (7 of 14) were at least 10 the mean among-subject CV for the AUC glycemic index value for white bread units away from the overall mean of 71, was calculated as 33% for subjects with ranged between 5 and 85%. Some sources and 29% (4 of 14) at least 15. However, to type 2 diabetes and 39% for subjects with of variability among laboratories in the
1414 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Vega-Lo´pez and Associates
Figure 1—Glycemic (postprandial glucose) response curves to white bread (Œ) or glucose (E). Individual graphs arranged by increasing white bread GRR, denoted in upper right corner of each panel, from left to right and top to bottom. Participant number is denoted in upper-left corner of each panel. GRR ϭ 78 Ϯ 73 (SEM ϭ 15; CV ϭ 94%; n ϭ 23). F, female; M, male.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1415 Glycemic index variability
Figure 2—Individual glycemic index values calculated for the subset of participants who were tested three times (n ϭ 14). ᭜ represent the mean of three glycemic index determinations; horizontal lines represent Ϯ SD. glycemic index value determinations to an oral glucose challenge. Due to con- sity, no significant associations were iden- noted were source of blood (venous vs. cern about reproducibility (25,26), in the tified (26). capillary), biological sample (whole early 1990s, the American Diabetes Asso- The limitations of the current work blood vs. plasma), and method used for ciation shifted their recommendations are that the meals before the tests were not the glucose determinations (24). The and currently endorses the use of fasting controlled, these initial studies did not as- former factor may have contributed to the plasma glucose concentrations for the di- sess a wider range of foods, and the habit- CV observed in the current study. agnosis of insulin resistance and diabetes ual diet of the volunteers before the test The oral glucose tolerance test, in the clinical setting (27). When variabil- days was not controlled. Variability may widely used as an aid for diagnosis of di- ity of oral glucose tolerance test data were have inadvertently been introduced by abetes, is also based on glycemic response evaluated on the basis of age, sex, or obe- using venous instead of capillary blood.
Table 2—Glycemic index values for white bread and mean AUC for bread and glucose determined by measuring its glycemic response on three separate occasions
Mean of tests Mean Ϯ SEM CV(%) of Test 1 Test 2 Test 3 1 and 2 of 3 tests 3 tests Individual values — — — — — — Participant 1 (M) 154 58 185 106 132 Ϯ 38 51 Participant 2 (M) 89 53 40 71 61 Ϯ 15 41 Participant 3 (M) 59 45 70 52 58 Ϯ 722 Participant 4 (F) 126 44 64 85 78 Ϯ 25 55 Participant 5 (M) 78 92 82 85 84 Ϯ 48 Participant 8 (M) 86 52 25 69 54 Ϯ 17 56 Participant 13 (F) 76 67 70 71 71 Ϯ 37 Participant 15 (M) 81 37 70 59 63 Ϯ 13 37 Participant 18 (F) 25 61 47 43 44 Ϯ 11 41 Participant 19 (F) 56 77 89 67 74 Ϯ 10 23 Participant 21 (F) 7 77 60 42 48 Ϯ 21 75 Participant 22 (F) 121 33 99 77 84 Ϯ 26 55 Participant 23 (F) 72 70 62 71 68 Ϯ 37 Participant 24 (M) 56 75 81 65 71 Ϯ 818 Mean Ϯ SEM of GI 78 Ϯ 10 (50) 60 Ϯ 5 (28) 75 Ϯ 10 (50) 69 Ϯ 5 (25) 71 Ϯ 6 (30) M subjects 86 Ϯ 12 (38) 59 Ϯ 7 (32) 79 Ϯ 19 (65) 73 Ϯ 7 (25) 75 Ϯ 10 (36) F subjects 69 Ϯ 17 (65) 61 Ϯ 6 (27) 70 Ϯ 7 (26) 65 Ϯ 6 (25) 67 Ϯ 6 (23) Data are means Ϯ SEM or means Ϯ SEM (CV) unless otherwise indicated; n ϭ 14. Data obtained from participants who attended three sets of tests. CV values in the last column were calculated for the mean of the three tests. All values were calculated by dividing individual glycemic responses to white bread (AUC) by the mean glycemic response to three glucose challenges. GI, glycemic index; F, female; M, male.
1416 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Vega-Lo´pez and Associates
Nonetheless, the conditions mimicked hydrates. Diabetes 26:1178–1183, 1977 Glycaemic index of 102 complex carbo- the standard protocol currently in use 3. Jenkins DJA, Wolever TMS, Taylor RH, hydrate foods in patients with diabetes. (3,6). The strengths of the current report Barker H, Fielden H, Baldwin JM, Bowling Nutr Res 14:651–669, 1994 are that the glycemic index value determi- AC, Newman HC, Jenkins AL, Goff DV: 17. Bornet FRJ, Costagliola D, Rizkalla SW, nations were conducted using a single Glycemic index of foods: a physiological Blayo A, Fontvieille A-M, Haardt M-J, basis for carbohydrate exchange. Am J Letanoux M, Tchobroutsky G, Slama G: type and lot of white bread and followed a Clin Nutr 34:362–366, 1981 protocol that was as consistent as possible Insulinemic and glycemic indexes of six 4. Ludwig DS: The glycemic index: physio- starch-rich foods taken alone and in a among volunteers. This included con- logical mechanisms relating to obesity, di- mixed meal by type 2 diabetics. Am J Clin tracting the time during which the sub- abetes, and cardiovascular disease. JAMA Nutr 45:588–595, 1987 jects consumed the 50 g carbohydrate; 287:2414–2423, 2002 18. Wolever TMS, Jenkins DJA, Josse RG, limiting the type of beverage that partici- 5. Augustin LSA, Franceschi S, Jenkins DJ, Wong GS, Lee R: The glycemic index: pants were allowed to consume during Kendall CWC, La Vecchia C: Glycemic in- similarity of values derived in insulin-de- the test period (water) and the physical dex in chronic disease: a review. Eur J Clin pendent and non-insulin-dependent dia- activities permitted during the 12 h before Nutr 56:1049–1071, 2002 betic patients. J Am Coll Nutr 6:295–305, 6. Food and Agriculture Organization: Car- and during the test period; conditions of 1987 bohydrates in Human Nutrition: A Summary 19. Wolever TMS, Jenkins DJA, Kalmusky J, blood collection, processing, and analy- of the Joint FAO/WHO Expert Consultation, Giordano C, Giudici S, Jenkins AL, sis; and the general surrounds of environ- 1997. Rome, Italy, Food and Agriculture ment of the test area (private room). Organization (United Nations), 1997 Thompson LU, Wong GS, Josse RG: Gly- In conclusion, the level of interindi- 7. Pi-Sunyer FX: Glycemic index and dis- cemic response to pasta: effect of surface vidual variability and intra-individual re- ease. Am J Clin Nutr 76:290S–298S, 2002 area, degree of cooking, and protein en- producibility observed when the 8. American Diabetes Association: Nutrition richment. Diabetes Care 9:401–404, 1986 glycemic index for white bread was deter- principles and recommendations in dia- 20. Wolever TMS, Csima A, Jenkins DJA, Wong GS, Josse RG: The glycemic index: mined under controlled conditions was betes (Position Statement). Diabetes Care 27:S36–S46, 2004 variation between subjects and predictive high despite efforts to standardize the difference. J Am Coll Nutr 8:235–247, 1989 study conditions and protocol as much as 9. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, 21. Ramdath DD, Isaacs RLC, Teelucksingh possible, yet the mean value was compa- Franklin B, Kris-Etherton P, Harris WS, S, Wolever TMS: Glycaemic index of se- rable with that previously published. Howard B, Karanja N, Lefevre M, Rudel L, lected staples commonly eaten in the Ca- When the intra- and interindividual vari- Sacks F, Van Horn L, Winston M, Wylie- ribbean and the effects of boiling v. abilities were calculated using an ANOVA Rosett J: Diet and lifestyle recommenda- crushing. British J Nutr 91:971–977, 2004 approach, it appears that the within- tions revision 2006: a scientific statement 22. Wolever TMS, Jenkins DJA, Vuksan V, individual variability of 43% has a greater from the American Heart Association Nu- Josse RG, Wong GS, Jenkins AL: Glyce- contribution to the overall observed vari- trition Committee. Circulation 114:82– mic index of foods in individual subjects. ability than the among-individual vari- 96, 2006 Diabetes Care 13:126–132, 1990 ability of 18%. These data suggest that 10. Foster-Powell K, Holt SH, Brand-Miller 23. Wolever TMS, Nuttall FQ, Lee R, Wong despite a reduction in the CV with repli- JC: International table of glycemic index GS, Josse RG, Csima A, Jenkins DJA: Pre- and glycemic load values: 2002. Am J Clin cate testing, glycemic responses to a single diction of the relative blood glucose re- Nutr 76:5–56, 2002 sponse of mixed meals using the white food, white bread, can be inconsistent, 11. Denyer G, Dickinson S, Brand-Miller bread glycemic index. Diabetes Care and a better understanding of the sources JC: Home of the Glycemic Index [Inter- 8:418–428, 1985 of this variability would be helpful in de- net], 2006. Available from http://www. 24. Wolever TMS, Vorster HH, Bjo¨rck I, fining the utility of glycemic index values. glycemicindex.com/. Accessed 27 April Brand-Miller JC, Brighenti F, Mann JI, 2007 Ramdath DD, Granfeldt Y, Holt SH, Perry 12. Wolever TMS, Jenkins DJA: The use of the TL, Venter C, Xiaomei W: Determination Acknowledgments— This study was sup- glycemic index in predicting the blood of the glycaemic index of foods: interlabo- ported by a grant from U.S. Department of glucose response to mixed meals. Am J ratory study. Eur J Clin Nutr 57:475–482, Agriculture to Tufts University under agree- Clin Nutr 43:167–172, 1986 2003 ment no. 58-1950-4-401. 13. Morgan CR, Lazarow A: Immunoassay of 25. Ko GT, Chan JC, Woo J, Lau E, Yeung VT, The authors acknowledge the assistance of insulin: two antibody system: plasma in- Chow CC, Cockram CS: The reproduc- Gerard Dallal, PhD, with the algorithm for sulin levels in normal, subdiabetic and di- ibility and usefulness of the oral glucose AUC calculations, and the cooperation of abetic rats. Diabetes 12:115–126, 1963 study participants and Medical Research Unit 14. Lichtenstein AH, Matthan NR, Jalbert SM, tolerance test in screening for diabetes and Nutrition Evaluation Laboratory staff at Resteghini NA, Schaefer EJ, Ausman LM: and other cardiovascular risk factors. Ann the Human Nutrition Research Center at Tufts Novel soybean oils differing in fatty acid Clin Biochem 35:62–67, 1998 University. profile alter cardiovascular disease risk 26. Mooy JM, Grootenhuis PA, de Vries H, factors in moderately hyperlipidemic sub- Kostense PJ, Popp-Snijders C, Bouter LM, jects. Am J Clin Nutr 84:497–504, 2006 Heine RJ: Intra-individual variation of References 15. Jenkins DJA, Wolever TMS, Jenkins AL, glucose, specific insulin and proinsulin 1. Crapo PA, Reaven GM, Olefsky JM: Thorne MJ, Lee R, Kalmusky J, Reichert R, concentrations measured by two oral glu- Plasma glucose and insulin responses to Wong GS: The glycaemic index of foods cose tolerance tests in a general Caucasian orally administered simple and complex tested in diabetic patients: a new basis for population: the Hoorn Study. Diabetolo- carbohydrates. Diabetes 25:741–747, carbohydrate exchange favouring the use gia 39:298–305, 1996 1976 of legumes. Diabetologia 24:257–264, 27. American Diabetes Association: Diagnosis 2. Crapo PA, Reaven GM, Olefsky JM: Post- 1983 and Classification of Diabetes Mellitus prandial plasma-glucose and -insulin 16. Wolever TMS, Katzman-Relle L, Jenkins (Position Statement). Diabetes Care 29: responses to different complex carbo- AL, Vuksan V, Josse RG, Jenkins DJA: S43–S48, 2006
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1417 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Short-Term Weight Change and the Incidence of Diabetes in Midlife Results from the Australian Longitudinal Study on Women’s Health
1 1 GITA D. MISHRA, PHD ADRIAN G. BARNETT, PHD the Australian urban population has risen 1 1 GRETCHEN CARRIGAN, BSC, BECON ANNETTE J. DOBSON, PHD from 7.1 to 18.4% (5). This represents a 2 WENDY J. BROWN, PHD 2.5-fold increase over the last 20 years (5). Absolute weight gain in the last two decades has also been substantial. Austra- OBJECTIVE — Although there is consensus that excess adiposity is strongly associated with lian prospective studies have consistently type 2 diabetes, its relationship with weight change is less clear. This study investigates the demonstrated that, on average, middle- relative impact of BMI at baseline and short-term (2- or 3-year) weight changes on the incidence aged women are currently gaining ap- of diabetes. proximately one-half kilogram per year (6,7). RESEARCH DESIGN AND METHODS — Prospective data were collected from a pop- There are well-established associa- ulation-based cohort of middle-aged women participating in the Australian Longitudinal Study on Women’s Health (n ϭ 7,239 for this report). To date, participants have completed four mailed tions between being overweight or obese surveys (S1, 1996; S2, 1998; S3, 2001; and S4, 2004). Generalized estimating equations were and type 2 diabetes (2,8). The risk ap- used to model binary repeated-measures data to assess the impact of BMI at S1 and weight change pears to increase with the duration of obe- (S1 to S2; S2 to S3) on 3-year incidence of diabetes at S3 and S4, respectively, adjusting for sity (9,10). There is also evidence for an sociodemographic and lifestyle factors. independent effect of weight change, par- ticularly weight gain, on an increased risk RESULTS — BMI at S1 was strongly associated with the development of diabetes by S3 or S4. of diabetes, whereas weight loss is fol- 2 2 Compared with women who had a BMI Ͻ25 kg/m , those with BMI Ն25 kg/m had higher lowed by a reduced risk of type 2 diabetes incidence of diabetes (P Ͻ 0.0001), with odd ratios reaching 12.1 (95% CI 7.6–19.3) for women Ն 2 over periods of 5–10 years (10–12). In in the very obese group (BMI 35 kg/m ). There was no association between shorter-term the U.S. Nurses’ Health Study, weight weight gain or weight loss on first-reported diagnosis of diabetes (P ϭ 0.08). gain during adulthood, even at modest Ͻ CONCLUSIONS — Because women’s risk of developing type 2 diabetes in midlife is more levels (e.g., 5 kg), was associated with closely related to their initial BMI (when aged 45–50 years) than to subsequent short-term weight increased risk of diabetes, independent of change, public health initiatives should target the prevention of weight gain before and during initial body weight. In contrast, women early adulthood. who lost Ͼ5 kg reduced their risk for di- abetes by 50% (11). Diabetes Care 30:1418–1424, 2007 Far less is known about short-term weight change and the time lags between ver recent decades, the number of diabetic neuropathy, amputation, renal incremental weight gain during midlife cases of type 2 diabetes worldwide failure, and blindness will result in excess and its impact on the risk of diabetes. Pro- O has increased rapidly from ϳ30 morbidity and mortality, as well as having spective cohort studies can provide valu- million in 1985 to 194 million in 2003. By a significant economic cost (1). able evidence on the time course of the year 2025, the figure is predicted to This epidemic of diabetes closely par- changes in weight and the onset of rise to 330 million (1). In Australia it was allels the worldwide obesity epidemic (2), weight-related health conditions. In this estimated that 854,400 adults, or 6.3% of with Australia being one of the worst- article, we use data from the first four sur- the population, had diabetes in 2003 (1). affected nations (3). There are major con- veys of the midage cohort of the Austra- This is expected to rise to almost 1.3 mil- cerns about the health consequences of lian Longitudinal Study on Women’s lion by the year 2025, or an estimated obesity, including the growing burden of Health. The objective is to examine the prevalence of 7.6% (1). The consequent chronic diseases and an escalation of fu- relative importance of initial BMI and of complications such as coronary artery ture costs of health services (4). From short-term weight change (over 2 or 3 and peripheral vascular disease, stroke, 1980 to 2000, the prevalence of obesity in years) on the incidence of diabetes. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1School of Population Health, University of Queensland, Queensland, Australia; and the 2School RESEARCH DESIGN AND of Human Movement Studies, University of Queensland, Queensland, Australia. METHODS Address correspondence and reprint requests to Gita Mishra, PhD, School of Population Health, Univer- sity of Queensland, Herston 4006, Australia. E-mail: [email protected]. Received for publication 24 October 2006 and accepted in revised form 15 February 2007. The Australian Longitudinal Study Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2187. on Women’s Health Abbreviations: ALSWH, Australian Longitudinal Study on Women’s Health. The Australian Longitudinal Study on A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Women’s Health (ALSWH) is a prospec- factors for many substances. tive study of factors affecting the health © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby and well-being of three cohorts of women marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. aged 18–23 years (young), 45–50 years
1418 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Mishra and Associates
(middle aged), and 70–75 years (older) at fined as the proportion of these women ferent menstrual frequency compared the time of the initial surveys in 1996. who reported at this survey or a previous with the previous year were classified as Women were selected randomly from the survey that they had been told they had perimenopausal. Those with menstrual National Medicare Health Insurance Da- diabetes. bleeding in the last 3 months and in the tabase (which includes all permanent res- last 12 months and with the same fre- idents of Australia regardless of age, BMI and weight change quency as in the year before were classi- including immigrants and refugees) with Women were asked to report their height fied as premenopausal. Women who had intentional overrepresentation of women and weight at each survey. Self-reported a hysterectomy were classified as having living in rural and remote areas. Further heights from the first three surveys were surgical menopause. details of the recruitment methods and used to obtain a single estimated value for response rates have been described else- each woman by averaging the available Social and lifestyle factors where (13). The study collects self- data. BMI for each woman at S1 was cal- Social and behavioral factors were based reported data using mailed surveys at 2- culated as self-reported weight (kg) at S1 on information collected at S1. Educa- to 3-year intervals from ϳ40,000 women divided by the square of estimated height tional qualifications were categorized as living in all states and territories of Aus- (m2). BMI was categorized as under- “no formal qualifications;” “school certif- tralia. The surveys include questions weight (Ͻ18.5 kg/m2), healthy weight icate;” “higher school certificate;” “trade about health conditions, symptoms, and (18.5 to Ͻ25 kg/m2), overweight (25 to apprenticeship, certificate, or diploma;” diagnoses; use of health services; health- Ͻ30 kg/m2), obese (30 to Ͻ35 kg/m2), or or “university degree or higher degree.” related quality of life; social circum- very obese (Ն35 kg/m2) according to the Area of residence was categorized as “ur- stances, including work and time use; World Health Organization classification ban,” “large rural center,” “small rural demographic factors; and health behav- (4). Fewer than 2% of women were clas- center,” or “other rural or remote area” iors. Complete details of each survey are sified as underweight at S1, so this cate- (14). on the study website (available at http:// gory was combined with the healthy Participants were asked to report fre- www.alswh.org.au). weight group for the analysis. The average quency of engaging in vigorous (e.g., aer- Informed consent was obtained from percentage of annual weight change was obics, jogging) and less vigorous (e.g., all participants in 1996, with ethical calculated by subtracting self-reported walking and swimming) exercise lasting clearance obtained from the University of weight at successive surveys and dividing for Ն20 min in a normal week (15). Re- Newcastle. This article only includes data by weight at the earlier survey and the sponses were scored using approximate from the middle-aged cohort. There were number of years between the surveys. (S1 weekly frequencies of exercise (never ϭ four waves of data collection from 1996 to and S2 were 2 years apart, whereas S2 and 0, once a week ϭ 1, 2 or 3 times per 2004 (S1, 1996; S2, 1998; S3, 2001; and S3 were 3 years apart). Average percent- week ϭ 2.5, 4–6 times per week ϭ 5, S4, 2004). age of annual weight change was catego- every day ϭ 7, and more than once a A total of 13,716 middle-aged women rized as high loss (ՅϪ5%), moderate loss day ϭ 10) and then weighted to reflect the agreed to participate at S1, and by S4 (Ϫ5toՅϪ2.5%), small loss (Ϫ2.5 to intensity of the activity (vigorous ϭ 5 and 10,905 women remained in the study ՅϪ1.5%), stable (Ϫ1.5 to Յϩ1.5%), less vigorous ϭ 3). The resulting physical (79.5%), 204 (1.5%) had died, 636 small gain (ϩ1.5 to Յϩ2.5%), moderate activity scores ranged from 0 to 80 and (4.6%) had withdrawn from the study, gain (ϩ2.5 to Յϩ5%.), or high gain were categorized as “none (Ͻ5),” “low (5 and the remainder did not participate in (Ͼϩ5%). As an indication of absolute to Ͻ15),” “moderate (15 to Ͻ25),” or at least one of S2, S3, and S4, generally weight gain, for a woman in the healthy “high (Ն25).” A score of 15 is commen- because they could not be contacted. weight range with BMI 22 kg/m2 and surate with the current recommendation height 1.65 m, 5% weight gain equates to of moderate intensity activity on most Diabetes 3 kg per year, whereas for a very obese days of the week. This measure is de- At each survey women were asked if they woman with BMI 37 kg/m2 and height scribed in more detail elsewhere (7,16) had been told by a doctor that they had 1.65 m, 5% weight gain equates to 5 kg and has previously been shown to have diabetes. At S1 they were asked if they had per year. acceptable test-retest reliability (17). ever had a diagnosis of diabetes. At S2, S3, Data needed to calculate BMI at S1 Standard questions were used to catego- and S4 they were asked whether they had were missing for 696 women. In addition, rize respondents as never-smoker, ex- been diagnosed with diabetes in the time data needed to calculate average percent- smoker, or current smoker. period that had elapsed since the previous age of annual weight change between S1 survey. For the analysis, there was a defi- and S2 or between S2 and S3 were miss- Statistical analysis nitional issue that had to be considered: ing for 2,503 women. Thus, we had data Predictors of 3-year incidence of diabetes diagnosis of diabetes was not differenti- on diabetes, BMI, and weight change for were examined using repeated-measures ated into type 1 or type 2 at S1 and S4. 7,875 women. data, with weight change between S1 and Because the number of new cases of type 1 S2 used to predict incidence between S2 diabetes was small (n ϭ 5atS2andn ϭ 12 Menopause status and S3 and weight change between S2 at S3), these were combined with the type Menopause status at S1 was defined on and S3 used to predict incidence between 2 diabetic cases, so that the data reported the basis of self-reported menstrual bleed- S3 and S4. These time lags were used to here are for both type 1 and type 2 diabe- ing. Women who reported no menstrual minimize the possibility of reverse causal- tes and referred to simply as “diabetes.” bleeding in the last 12 months were clas- ity from weight loss due to behavioral in- Diabetes status could be determined at all sified as postmenopausal. Those with tervention or treatment as a consequence four surveys for 10,629 women. Preva- menstrual bleeding in the last 12 months of the diabetes diagnosis or due to weight lence of diabetes at each survey was de- but not in the last 3 months or with dif- changes induced by the disease (18).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1419 Diabetes and weight change in midlife
Figure 1—Trends in prevalence of diabetes in middle-aged women grouped according to BMI at the first survey of the ALSWH. f, healthy (n ϭ 5,252); , overweight (n ϭ 2,858); F, obese (n ϭ 1,178); Œ, very obese (n ϭ 612).
Women who first reported a diagnosis of tor variables. For multivariable analysis a cent weight change was only a statistically diabetes at S1 or S2 were excluded from model was fitted with all the predictors, significant risk factor for those with mod- this analysis (n ϭ 406). Data for women then those that were not statistically sig- erate weight loss (Ϫ5toՅϪ2.5%) (P ϭ who first reported a diagnosis of diabetes nificant at the 5% level were omitted, and 0.02) and for those in the high-gain at S3 were not included for the subse- a final parsimonious model was fitted. (Ͼϩ5%) group (P ϭ 0.05) compared quent time period (n ϭ 119). Data from with the stable group. Similarly, physical S1 were used for all other predictor vari- RESULTS — The prevalence of diabe- activity was only associated with a lower ables: BMI, menopausal status, area of tes at each survey among women catego- incidence of diabetes for those in the residence, education level, physical activ- rized by BMI at S1 is shown in Fig. 1. At high-activity group (P ϭ 0.05) compared ity level, and smoking status. S1, prevalence ranged from 1.3% in the with the least active group (Table 1). Incidence of diabetes from S2 to S3 or healthy weight category to 10.9% among In the fully adjusted model (Table 2), from S3 to S4 was modeled using gener- the very obese women. Over time, the BMI at S1 remained most strongly associ- alized estimating equations for binary re- prevalence increased in all four BMI ated with incidence of diabetes. There was peated-measures data (19). The groups with greater increases in the more a significant increase in the incidence of regression coefficients obtained from gen- overweight groups. reported diabetes across BMI groups at S1 eralized estimating equations reflect the Three-year incidence rates from S2 compared with women in the healthy BMI relationship between the incidence of di- (1998) to S3 (2001) and from S3 to S4 Ͻ abetes and the corresponding predictor (2004) and crude odds ratios for develop- group (P 0.0001 for linear trend). Age variables using all longitudinal data avail- ing diabetes, by each of the weight and was positively associated with the inci- able (20). The within-subject correlation other variables, are shown in Table 1. In- dence of diabetes, with an odds ratio of structures were assumed to be exchange- cidence rates were highest for women 1.11 per year increase in age. Ex-smokers able; that is, the correlations between re- who were obese at S1, were oldest (age 50 were 1.5 times more likely to develop di- peated measurements were assigned as at S1), reported none or low levels of abetes than never-smokers. Annual being equal. The analyses were performed physical activity, or were ex-smokers. In weight change and activity level were not using SAS, version 9.1.3 (21) using PROC the univariate (unadjusted) models, BMI, statistically significant factors in the fully GENMOD with the options TYPE ϭ age, smoking status, educational qualifi- adjusted model, nor were there any sig- EXCH and D ϭ Binomial and Link ϭ cations, and menopausal status were all nificant interactions between weight logit. For univariate analyses, separate statistically significantly associated with change and BMI groups (results not models were fitted for each of the predic- the development of diabetes. Annual per- shown).
1420 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Mishra and Associates
Table 1—Number of women and 3-year incidence (%) of diabetes at S3 (2001) and S4 (2004), with odds ratios for developing diabetes from S2 (1998) to S3 (2001) and from S3 to S4 (2004) for 7,239 middle-aged women: results from univariate analyses
S3 S4 Number of women Number of women Odds ratio P value (for the variable Characteristics at S1 in 1996 (diabetes incidence %) (diabetes incidence %) (95% CI) and for each category) BMI (kg/m2) Ͻ0.0001 Healthy (Ͻ25)* 3,985 (0.5) 3,965 (0.5) 1.00 Overweight (25 Յ BMI Ͻ 30) 2,064 (1.0) 2,044 (2.1) 3.16 (2.12–4.72) Ͻ0.0001 Obese (30Յ BMI Ͻ 35) 815 (3.1) 790 (4.4) 7.88 (5.25–11.83) Ͻ0.0001 Very obese (Ն35) 375 (6.1) 352 (5.7) 12.75 (8.21–19.81) Ͻ0.0001 Annual percent weight change 0.3 High loss (ՅϪ5%) 246 (0.8) 108 (2.8) 1.11 (0.45–2.76) 0.82 Moderate loss (Ϫ5toՅϪ2.5%) 565 (1.2) 412 (3.6) 1.79 (1.12–2.87) 0.02 Small loss (Ϫ2.5 to ՅϪ1.5%) 503 (1.2) 475 (0.8) 0.80 (0.42–1.55) 0.51 Stable (Ϫ1.5 to Յϩ1.5%) 3,151 (1.3) 3,778 (1.2) 1.00 Small gain (ϩ1.5 to Յϩ2.5%) 993 (1.2) 1,017 (2.0) 1.26 (0.84–1.89) 0.27 Moderate gain (ϩ2.5 to Յϩ5%) 1,167 (0.9) 1,059 (1.7) 1.03 (0.67–1.57) 0.90 High gain (Ͼϩ5%) 614 (1.5) 302 (3.3) 1.65 (1.00–2.72) 0.05 Age (per year) 1.14 (1.03–1.25) 0.01 Physical activity level 0.09 None 1,804 (1.4) 1,778 (2.0) 1.00 Low 2,258 (1.3) 2,228 (1.8) 0.93 (0.66–1.31) 0.7 Moderate 1,967 (1.1) 1,945 (1.3) 0.70 (0.48–1.03) 0.07 High 1,210 (0.8) 1,200 (1.3) 0.63 (0.40–1.00) 0.05 Smoking status 0.04 Never-smoker 4,015 (1.0) 3,974 (1.4) 1.00 Ex-smoker 2,133 (1.7) 2,097 (2.0) 1.51 (1.12–2.04) 0.007 Current smoker 1,091 (1.0) 1,080 (1.9) 1.18 (0.79–1.77) 0.4 Education 0.04 No formal 1,048 (1.2) 1,035 (2.3) 1.00 School certificate 2,327 (1.6) 2,290 (1.6) 0.90 (0.61–1.34) 0.6 Higher school certificate 1,217 (1.2) 1,203 (2.1) 0.91 (0.58–1.42) 0.7 Trade apprentice/certificate 1,501 (1.1) 1,485 (1.1) 0.62 (0.39–0.99) 0.05 diploma University/higher degree 1,146 (0.7) 1,138 (1.2) 0.54 (0.32–0.91) 0.02 Menopause status 0.009 Premenopausal 3,159 (0.9) 3,130 (1.4) 1.00 Perimenopausal 2,097 (1.5) 2,065 (1.0) 1.06 (0.74–1.52) 0.7 Postmenopausal 415 (0.7) 412 (2.2) 1.24 (0.67–2.28) 0.5 Surgical menopause 1,568 (1.5) 1,544 (2.8) 1.85 (1.33–2.58) 0.0003 Area of residence 0.5 Urban 2,256 (1.3) 2,524 (1.4) 1.00 Large rural center 1,073 (1.2) 1,060 (1.4) 0.98 (0.63–1.53) 0.9 Small rural center 1,042 (1.0) 1,032 (1.6) 0.94 (0.59–1.47) 0.8 Other rural/remote 2,568 (1.3) 2,535 (2.0) 1.22 (0.88–1.68) 0.3 *As only 118 women had BMI Ͻ18.5 kg/m2, their data are included in the healthy weight category. Italicized P values are for test for linear trend across each variable.
CONCLUSIONS — Overweight and ings indicate that initial BMI at S1 was other studies, including the U.S. Nurses’ obesity are becoming increasingly seri- much more strongly associated with the Health Study, in which 61% of type 2 di- ous problems in Australia and through- development of diabetes than shorter- abetes cases could be attributed to over- out the world (4,5). Although there is term weight changes (losses or gains) weight and obesity (22). Similarly in the consensus that excess adiposity is over the 2–3 years before the diagnosis. Women’s Health Study, the relative risk strongly associated with the develop- This study shows that compared with for developing type 2 diabetes was 9 for ment of type 2 diabetes, the association women in the healthy weight range, those obese women compared with healthy between incidence of diabetes with who were overweight or obese at S1 had weight women (8). The magnitude of the weight change is less clear. Prospective substantially higher incidence of diabetes association with BMI was much stronger data from middle-aged women partici- in subsequent surveys, with odds ratios in than with physical activity, confirming a pating in this longitudinal study were the obese group reaching Ͼ12. These finding among Finnish men and women used to investigate this issue. Our find- findings support those from a number of (23).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1421 Diabetes and weight change in midlife
Table 2—Odds ratios for incidence of diabetes: results from a fully adjusted model and a parsimonious model that includes only those variables that were statistically significant at the 5% level in the fully adjusted model
Fully adjusted model* Parsimonious model† OR (95%CI) P value OR (95%CI) P value BMI (kg/m2) Ͻ0.0001 Ͻ0.0001 Healthy (Ͻ25)‡ 1.00 1.00 Overweight (25 Յ BMI Ͻ 30) 3.00 (2.00–4.50) Ͻ0.0001 3.08 (2.06–4.60) Ͻ0.0001 Obese (30 Յ BMI Ͻ 35) 7.32 (4.81–11.14) Ͻ0.0001 7.77 (5.18–11.66) Ͻ0.0001 Very obese (Ն35) 12.48 (7.84–19.88) Ͻ0.0001 12.59 (8.10–19.55) Ͻ0.0001 Percent weight change per year 0.08 High loss (ՅϪ5%) 0.56 (0.22–1.41) 0.2 Moderate loss (Ϫ5toՅϪ2.5%) 1.32 (0.82–2.14) 0.3 Small loss (Ϫ2.5 to ՅϪ1.5%) 0.63 (0.32–1.21) 0.2 Stable (Ϫ1.5 to Յϩ1.5%) 1.00 Small gain (ϩ1.5 to Յϩ2.5%) 1.24 (0.82–1.87) 0.3 Moderate gain (ϩ2.5 to Յϩ5%) 0.93 (0.60–1.42) 0.7 High gain (Ͼϩ5%) 1.54 (0.92–2.56) 0.1 Age 1.11 (1.00–1.23) 0.04 1.11 (1.01–1.23) 0.03 Physical activity level 0.6 None 1.00 Low 1.12 (0.79–1.59) 0.5 Moderate 0.88 (0.59–1.31) 0.5 High 0.90 (0.56–1.45) 0.7 Smoking status 0.04 0.04 Never-smoker 1.00 1.00 Ex-smoker 1.50 (1.11–2.03) 0.009 1.48 (1.09–2.01) 0.01 Current smoker 1.25 (0.83–1.90) 0.3 1.31 (0.87–1.97) 0.2 Education 0.4 No formal qualifications 1.00 School certificate 1.13 (0.74–1.70) 0.6 Higher school certificate 1.31 (0.81–2.10) 0.3 Trade apprentice/certificate/diploma 0.88 (0.53–1.44) 0.6 University/higher degree 0.86 (0.49–1.49) 0.6 Menopause status 0.3 Premenopausal 1.00 Perimenopausal 0.96 (0.67–1.37) 0.8 Postmenopausal 1.03 (0.55–1.93) 0.9 Surgical menopause 1.37 (0.97–1.94) 0.08 Area of residence 0.7 Urban 1.00 Large rural center 0.92 (0.59–1.44) 0.7 Small rural center 0.83 (0.52–1.33) 0.4 Other rural/remote 1.06 (0.76–1.48) 0.8 *Adjusted for all factors listed. †Only including significant variables (P Յ 0.05) from the fully adjusted model. ‡Only 118 women had BMI Ͻ18.5 kg/m2 so we have included them in the healthy weight category. Italicized P values are for test for linear trend across each variable.
The strong association with initial U.S. Nurses’ Health Study, there was a kg, 6–8 kg, and Ն9 kg, respectively, in BMI at S1 found in this study may reflect strong independent effect of initial BMI the 10 years before the incidence of dia- at least three underlying issues: the role of on predicting risk of type 2 diabetes; a betes (12). duration of obesity as a risk factor for di- weight gain of 8–10.9 kg (from age 18 In the U.S. Diabetes Prevention Pro- abetes; the timing of weight change dur- until 1976 when the women were aged gram, weight loss was associated with a ing a critical period before S1, such as between 30 and 55 years) was associated 16% reduction in risk of diabetes. As the during early adulthood; and the latency of with a relative risk of type 2 diabetes of participants were in the intensive lifestyle the effect of weight gain on diabetes. Pre- 2.7, whereas those who gained Ն20 kg intervention arm of the program, they ex- vious studies have found that weight had a relative risk of 12.3 (11). Results perienced much greater weight loss than change during adulthood over longer pe- from the Health Professionals Follow-Up women in our study (mean change of riods than those considered in this study Study have also shown that among men 5.8% per year compared with 0.7% per is associated with incidence of type 2 di- the relative risks of type 2 diabetes were year in our study) (25). abetes (12,11,24). For example, in the 1.4, 1.6, and 2.1 for those who gained 3–5 A Danish longitudinal study fol-
1422 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Mishra and Associates lowed-up two groups of men, one with to gain weight (Ͼ5 kg in 5 years) than ficient to resist the push of environmental juvenile-onset diabetes and obesity and those who did not (7,26). factors toward weight gain.” These changes the other a randomly selected comparison The most obvious limitation of this are required during early adulthood, so that group, who were weighed at average ages study is that all the data are self-reported. young adults do not develop overweight or of 20, 33, 44, and 51 years. The study Previous studies have shown that women obesity as they approach middle age and found that the risk of type 2 diabetes in- are likely to understate their weight and increase their risk of early development of creased with weight gain in early adult life overstate their height (27), so that BMI is diabetes and other chronic illness. but not with weight changes in the late more likely to be underestimated than 30s and the 40s (18). This finding sup- overestimated. However, in a validity ports our results of no association be- study with 200 women from the ALSWH, Acknowledgments— The ALSWH, which tween percentage of change in weight we found 82% agreement on BMI catego- was conceived and developed by groups of in- terdisciplinary researchers at the Universities during middle age and the development ries from self-reported and measured BMI (ϭ0.72), with approximately equal of Newcastle and Queensland, is funded by of diabetes. the Australian Government Department of A reduced risk of developing diabetes proportions of women with underesti- Health and Ageing. with increased activity has been demon- mated (9.4%) and overestimated (8.8%) We thank all the participants for their valu- strated in several prospective studies (2). BMI, so this may not be a major bias in the able contribution to this project. In most of these, a significant inverse as- study as a whole. On the other hand, un- sociation between physical activity and diagnosed cases of diabetes would not be diabetes remained even after adjustment identified, and the effect would be to re- References for BMI. The few studies that have inves- duce the estimated incidence rates and 1. International Diabetes Federation: Preva- tigated the impact of weight change on their associations with weight. lence of diabetes. [article online], 2006. the incidence of diabetes have not focused This study has a number of strengths. Available from http://www.eatlas.idf.org/ on physical activity and diabetes in their It has a community-based sample rather prevalence/. Accessed 18 July 2006 2. Schulze MB, Hu FB: Primary prevention major hypotheses or have not reported than clinical groups of women. The large sample size means that it is possible to of diabetes: what can be done and how the results (12). We found that physical much can be prevented? Annu Rev Public activity level at S1 was not associated with obtain reasonably stable estimates of inci- dence rates between successive surveys. Health 26:445–467, 2005 the incidence of diabetes over surveys 3. Dixon T, Waters AM: A Growing Prob- 2–4. This may be explained by lack of an In a previous article, we have shown that lem: Trends and Patterns in Overweight and weight gain in this cohort was associated effect or by inadequate measurement of Obesity Among Adults in Australia. Can- with quitting tobacco smoking and with physical activity, as we did not ask the berra, Australia, Australian Institute of menopause, so it was important to in- women to report duration of activities in Health and Welfare, 2003 clude these factors in the analyses (7). 4. World Health Organization: Obesity: Pre- S1. In general, strategies for weight loss as venting and Managing the Global Epidemic. Our results revealed that ex-smokers a treatment for adult obesity have met Geneva, World Health Org., 2000 were at a greater risk of developing diabe- with limited success, and lost weight is 5. Cameron AJ, Welborn TA, Zimmet PZ, tes than never-smokers, whereas there usually regained within 2 years (28). The Dunstan DW, Owen N, Salmon J, Dalton was no statistically significant effect for results presented here and supported by M, Jolley D, Shaw JE: Overweight and obesity in Australia: the 1999–2000 Aus- smokers. One reason for this increased previous studies (8,18,22) seem to indi- risk among ex-smokers could be the tralian Diabetes, Obesity and Lifestyle cate that the risk of developing type 2 di- Study (AusDiab). Med J Aust 178:427– higher rate of weight gain in this group abetes in midlife is more closely related to before S1. Previous research with this co- 432, 2003 initial BMI than to subsequent short-term 6. Ball K, Crawford D, Ireland P, Hodge A: hort has shown that the odds of gaining weight change. Moreover, our previous Patterns and demographic predictors of weight in the 5-year period from S1 to S3 work with both the middle-aged and 5-year weight change in a multi-ethnic co- were much higher among women who younger cohorts of the ALSWH indicates hort of men and women in Australia. Pub- quit smoking than in current smokers or that women who are overweight or obese lic Health Nutr 6:269–281, 2003 never-smokers (7). are more likely to gain weight over subse- 7. Brown WJ, Williams L, Ford JH, Ball K, The attenuation of the effects of quent surveys than their counterparts Dobson AJ: Identifying the energy gap: magnitude and determinants of 5-year menopause status (primarily hysterec- who remain in the healthy weight range tomy) in the adjusted model may be due weight gain in midage women. Obes Res (7,29). 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1424 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Insulin Resistance Is Associated With Hypercortisolemia in Polynesian Patients Treated With Antipsychotic Medication
NICOLA R. POA, PHD tion (5). This suggests that environmental PAUL F. EDGAR, MBCHB, PHD or genetic factors may also be important in the development of insulin resistance in psychiatric patients. OBJECTIVE — Type 2 diabetes is more prevalent in the indigenous Polynesian population of Type 2 diabetes affects 21.1% of the New Zealand (Maori) than in Europeans. The aim of this study was to determine whether insulin indigenous, Polynesian population of resistance in Maori psychiatric patients was associated with antipsychotic treatment and to New Zealand (Maori) compared with investigate the mechanism of an association. only 7.5% of New Zealand Europeans (6,7). Therefore, type 2 diabetes is a major RESEARCH DESIGN AND METHODS — Thirty adult Maori psychiatric patients re- Ͼ cause of morbidity and mortality in Maori ceiving antipsychotic medication for 6 months and 30 healthy, age-, sex-, and BMI-matched (6), and Maori may be vulnerable to the control subjects were enrolled. Early morning fasting blood samples were analyzed for plasma levels of glucose, insulin, A1C, triglycerides, total cholesterol, IGF-1, cortisol, cortisol-binding effects of antipsychotic medication on globulin (CBG), and adiponectin. glucose metabolism. In our study, both patients and control subjects were drawn RESULTS — The patient group had significantly higher median fasting insulin plasma levels from the Maori population to determine than the control group (P ϭ 0.002), which were independent of BMI, age, and sex. In addition, whether treatment with antipsychotic the patient group had significantly higher total cortisol (P ϭ 0.03) and lower CBG levels (P ϭ medication was associated with an in- 0.004) than the control group, resulting in significantly higher levels of free cortisol (P ϭ 0.004). crease in insulin resistance in this popu- The patient group was also significantly more hypoglycemic (P ϭ 0.026) and hypertriglyceri- lation. We also investigated possible ϭ demic (P 0.028) than the control group. There was no significant difference in BMI, waist mechanisms by measuring plasma factors circumference, A1C, total cholesterol, IGF-1, or adiponectin levels between the two groups. that have previously been implicated in CONCLUSIONS — An increase in insulin resistance is seen in Maori psychiatric patients the development of insulin resistance, treated with antipsychotic medication. Therefore, Polynesian ethnicity should be considered in i.e., IGF-1, adiponectin, and cortisol. prescribing practice and general care of this group. In addition, the hypothalamic-pituitary- adrenal axis may have an important role in the mechanism by which this insulin resistance RESEARCH DESIGN AND develops. METHODS — Before carrying out this study, written informed consent was ob- Diabetes Care 30:1425–1429, 2007 tained from each individual as approved by the Canterbury Ethics Committee. ntipsychotic medications are used tion (1). Unfortunately, many studies Ethnicity was assessed by self-report ac- to treat the symptoms of psychosis, have associated the treatment of patients cording to the 1996 New Zealand census A such as delusions, perceptual dis- with antipsychotic medication with the question (8), and each subject had at least turbance, thought disorder, and disorga- development of impaired glucose toler- one Maori parent. nized behavior. Psychosis is common in ance, insulin resistance, and type 2 diabe- The patient group consisted of 30 schizophrenia and bipolar disorder and is tes (2–4), but the mechanism underlying Maori psychiatric patients recruited from also seen in major depressive disorder, this association is not known. However, both acute inpatient psychiatric wards dementia, and some personality disor- before the advent of antipsychotic medi- and community outpatient psychiatric ders. In New Zealand, in 2005, 8,750 pre- cation in the 1960s, studies indicated that clinics. All patients had a psychotic illness scriptions for antipsychotic medication patients with schizophrenia had higher (according to the Diagnostic and Statistical were written for every 100,000 popula- rates of diabetes than the normal popula- Manual of Mental Disorders, 4th edition, ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● text revision [DSM-IV-TR]: diagnoses of schizophrenia, DSM-IV-TR 295.0 (n ϭ From the Molecular Psychiatry Research Group, Christchurch School of Medicine and Health Science, 24), schizoaffective disorder, DSM-IV-TR University of Otago, Christchurch, New Zealand. ϭ Address correspondence and reprint requests to Nicola R. Poa, Molecular Psychiatry Research Group, 295.7 (n 3), bipolar I disorder, DSM- Christchurch School of Medicine and Health Science, University of Otago, Christchurch, New Zealand. IV-TR 296.7 (n ϭ 2), and psychotic dis- E-mail: [email protected]. order NOS [not otherwise specified], Received for publication 4 October 2006 and accepted in revised form 12 March 2007. DSM-IV-TR 298.9 (n ϭ 1). Patients were Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2057. Abbreviations: CBG, cortisol-binding globulin; CVD, cardiovascular disease; DSM-IV-TR, Diagnostic and included if they were aged between 18 Statistical Manual of Mental Disorders, 4th edition, text revision; HOMA, homeostasis model of assessment; and 60 years, did not have a prior diagno- HOMA%S, HOMO percentage sensitivity. sis of type 2 diabetes, had received anti- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion psychotic medication for Ͼ6 months, and factors for many substances. were not treated with other medications © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby known to affect weight, such as sodium marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. valproate. Patients had been treated with
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1425 Insulin resistance and antipsychotic medication
Table 1—Clinical characteristics of subjects
Parameters Patient group Control group P value n 30 30 Sex (male/female) 26/4 26/4 Age (years) 32.5 (25.0–41.5) 37.7 (25.8–45.2) 0.095 BMI (kg/m2) 29.5 (25.5–33.1) 30.6 (26.7–32.9) 0.199 Waist (cm) 96.3 (90.0–105.5) 100 (92.3–106.3) 0.393 Fasting insulin (pmol/l) 84.0 (44.8–190.0) 38.5 (28.9–78.0) 0.002* HOMA%S 52.9 (25.5–108.9) 117.2 (58.4–156.7) 0.006* Triglycerides (mmol/l) 1.7 (1.3–2.6) 1.25 (0.9–1.8) 0.028* Fasting glucose (mmol/l) 4.6 (4.1–5.0) 5.1 (4.7–5.4) 0.026* Total cortisol (nmol/l) 436.5 (370.3–510.3) 374.5 (323.3–449.3) 0.03* CBG (nmol/l) 447.5 (349.3–580.8) 580.5 (528.3–707.5) 0.004* Free cortisol (nmol/l) 54.4 (43.7–74.4) 33.6 (22.0–46.7) 0.004* A1C (%) 5.7 (5.4–6.0) 5.6 (5.3–5.8) 0.124 Total cholesterol (mmol/l) 4.9 (3.9–5.5) 5.1 (4.4–5.8) 0.107 IGF-1 (g/l) 197.0 (138.3–251.0) 201 (146.3–228.0) 0.861 Adiponectin (g/l)) 3.6 (2.5–6.2) 5.2 (2.6–8.6) 0.061 Data are median (lower quartile–upper quartile). Subjects were matched for measured variables above the line, i.e., sex, age, and BMI.*P Ͻ 0.05 are considered statistically significant. the antipsychotic medications clozapine Laboratory procedures significantly lower in the patient group (n ϭ 10), olanzapine (n ϭ 12), risperi- Plasma levels of glucose, total cholesterol, (52.9 [25.5–108.9]) than in the control done (n ϭ 6), quetiapine (n ϭ 1), and and triglycerides were determined using group (117.2 [58.4–156.7]; P ϭ 0.006) flupentixol (n ϭ 1). The median time an Aeroset analyzer (Abbott, North Chi- (Table 1). Plasma triglyceride levels were span for treatment was 6.5 months (range cago, IL). A1C was measured using the significantly higher in the patient group 6–11 months). Bio-Rad Variant II high-performance liq- (1.7 mmol/l [1.3–2.6]) than in the control The control subjects (n ϭ 30) were uid chromatography system. Insulin lev- group (1.25 mmol/l [0.9–1.8]; P ϭ drawn from a group of Maori (n ϭ 40) els were measured using an immunoassay 0.028). Median fasting plasma glucose who had responded to an offer of free test- analyzer (IMX; Abbott). Total cortisol and levels were lower in the patient group (4.6 ing for diabetes and volunteered for the cortisol-binding globulin (CBG) levels mmol/l [4.1–5.0]) than in the control study. Maori volunteers were excluded if were measured in-house by radioimmu- group (5.1 mmol/l [4.7–5.4]; P ϭ 0.026); they were familially related to other sub- noassay and enzyme-linked immunosor- however, levels for both groups were in jects, had a prior diagnosis of type 2 dia- bent assay, respectively (12). Plasma the clinically healthy range. betes, or reported a significant current or IGF-1 concentrations were measured, in Plasma total cortisol was significantly chronic illness. Members of the patient duplicate, using a radioimmunoassay (Di- higher in the patient group (436.5 nmol/l group were pair wise matched with the agnostic System Laboratories). Plasma [interquartile range 370.3–510.3]) than volunteer who was closest in age, sex, and adiponectin concentrations were mea- in the control group (374.5 nmol/l BMI. sured, in duplicate, by radioimmunoas- [323.3–449.3]; P ϭ 0.03). Plasma CBG say (LINCO Research, St. Charles, MO). levels were significantly lower in the pa- Clinical measurements and tient group (447.5 nmol/l [349.3–580.8]) Statistical analysis than in the control group (580.5 nmol/l procedures ϭ Participants were asked to fast for 12 h be- The Wilcoxon signed-rank test for non- [528.3–707.5]; P 0.004). Therefore, fore giving a blood sample between 0730 parametric data was used to compare the median plasma free cortisol level was and 0900 h. Glucose tolerance status was the patient and control groups, and re- significantly higher in the patient group sults are presented as medians [inter- (54.4 nmol/l [43.7–74.4]) than in the determined using World Health Organiza- Յ tion criteria (9). Insulin resistance was de- quartile range]. A value of P 0.05 was control group (33.6 nmol/l [22.0–46.7]; ϭ termined using the homeostasis model of considered to be statistically significant. P 0.004). assessment (HOMA) computer model with To examine the relationships between There was no significant difference in results expressed as percentage sensitivity measured variables, Spearman’s corre- BMI or waist circumference between the (HOMA%S) (10). Free cortisol was deter- lation coefficients were determined. groups; however, both the patient and mined according to Coolens et al. (11). The control groups were overweight (13). height and weight of subjects were mea- RESULTS — Median fasting plasma There was no significant difference in sex, sured to the nearest 0.5 cm and 0.1 kg, re- insulin levels were significantly higher in age, A1C, cholesterol, IGF-1, and adi- spectively. BMI was calculated as weight in the patient group (84 pmol/l [interquar- ponectin between the two groups (Table kilograms divided by the square of height in tile range 44.8–190]) than in the control 1). In addition, there was no significant meters (2) and was used as an estimate of group (38.5 pmol/l [28.9–77.0]; P ϭ difference between patients subgrouped overall adiposity. 0.002) (Table 1). HOMA%S values were according to whether they were taking
1426 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Poa and Edgar olanzapine (n ϭ 12) clozapine (n ϭ 10), matched for BMI, which indicated that CBG binds 75% of circulating cortisol or risperidone (n ϭ 6) with respect to free the increased insulin resistance is addi- in plasma and is produced by the liver. cortisol (P ϭ 0.49), CBG (P ϭ 0.29), and tional to that conferred by weight gain. Total plasma cortisol is made up of both insulin (P ϭ 0.35). The increased insulin resistance was also bound and free fractions, and free cortisol Free cortisol positively correlated independent of age or sex. is the form that is active, because it crosses ϭ with plasma insulin levels (rs 0.262, In our study, Maori patients treated cell membranes and interacts with recep- P ϭ 0.043) and negatively with fasting with antipsychotic medication had tors. Therefore, measuring both plasma ϭϪ ϭ plasma glucose levels (rs 0.366, P HOMA%S values similar to those re- CBG levels and total plasma cortisol levels 0.004). The correlation between free cor- ported in Northern Europeans treated allows free plasma cortisol to be esti- tisol and insulin in patients did not differ with antipsychotic medication (23,24). mated, which is a better measure of corti- significantly from the correlation in con- This finding suggested that individual sol activity than the measurement of total trol subjects (P ϭ 0.058). Maori are not more prone to antipsy- plasma cortisol alone (29). Our results in- chotic medication–associated insulin re- dicated that both total cortisol and free CONCLUSIONS — A number of eth- sistance than individual Europeans. cortisol levels were higher in the plasma nic groups, such as the Pima Indians of The majority of the patient group were of the patient group than in the plasma of Arizona and the Polynesians of the Pacific, treated with a dibenzodiazapine antipsy- the control group. In addition, free corti- have a much higher risk for type 2 diabe- chotic medication (clozapine or olanzapine, sol positively correlated with plasma in- tes than do Caucasians (6,14). The total 70%) and had schizophrenia (80%), reflect- sulin levels, which is consistent with a Polynesian population worldwide is ing their recruitment from inpatient and cause-and-effect relationship. This find- about 1.5 million (15,16) and includes outpatient psychiatric units, which in New ing suggested that factors such as antipsy- native Hawaiians, Tongans, Samoans, Zealand are tasked with the treatment of se- chotic medication or stress could directly and New Zealand Maori. Maori comprise vere mental illness. Both clozapine and reduce CBG plasma levels, leading to hy- ϳ15% (600,000) of the total New Zea- olanzapine have been suggested by others percortisolemia, and subsequent in- land population (8) and arrived in New to be more diabetogenic and obesogenic creased insulin resistance. However, total Zealand, from Southeast Asia via the than other antipsychotic medications daily exposure to cortisol may not be ac- South Pacific, ϳ900 years ago. Type 2 di- (3,23,25). Our study was insufficiently curately reflected by a single morning abetes affects 21.1% of Maori compared powerful to determine significant differ- measurement, and obtaining samples at with only 7.5% of New Zealand Europe- ences in effects among individual antipsy- other times of the day could add to the ans (6,7), and insulin-resistant diabetic chotic medications. validity of this relationship. subjects are two to five times more likely Glucocorticoid hormones (mainly The insulin receptor/insulin receptor to die from cardiovascular disease (CVD) cortisol in humans) are so named be- substrate-1/phosphoinositol 3-kinase sig- than those without diabetes (17–19). In cause it was recognized long ago that naling system has been implicated in the addition, increased triglyceride concen- one of their actions is on carbohydrate mechanism of corticosteroid-induced insu- trations found in populations in the Asia- metabolism (26). These hormones are lin resistance. In liver and muscle, dexa- Pacific region increased the relative risk produced in the adrenal cortex under methasone treatment resulted in a for coronary heart disease by 1.33-fold the control of the hypothalamic- reduction in insulin-stimulated insulin re- (20). Therefore, the overall health of pituitary-adrenal axis and at times of ceptor substrate-1–associated phosphoino- Polynesians is vulnerable to any addi- stress provide a longer-term signal to sitol 3-kinase, suggesting that it may play a tional factors that could increase the de- damp many of the acute responses to role in the pathogenesis of insulin resistance velopment of type 2 diabetes. illness and “reset” metabolism in favor at the cellular level in an animal model Excess body mass, insulin resistance, of providing substrates for oxidative (30,31). However, it remains possible that and elevated triglycerides are determining metabolism. In a recent study of anti- the environmental stress resulting from psy- factors for the metabolic syndrome psychotic-naive patients with schizo- chotic episodes or unknown genetic varia- (9,21), which in turn is associated with an phrenia, it was found that these patients tions peculiar to individuals susceptible to increased risk for diabetes (22). Both the were more insulin resistant and also psychotic episodes is the primary cause of patient and control groups in our study more hypercortisolemic than healthy low CBG and hypercortisolemia rather than were classed as overweight, which is con- age- and sex-matched control subjects direct effects of antipsychotic medication. sistent with previous reports that in- (27). Because hypercortisolemia (Cush- The glycemic effects of having psychotic ep- creased BMI is more prevalent in Maori ing’s syndrome) leads to insulin resis- isodes versus the effects of antipsychotic (63%) than in Europeans (21%) (6). tance, glucose intolerance, high blood medication could be examined by deter- However, the patient group was more in- pressure, and triglyceridemia, the au- mining whether the prevalence of insulin sulin resistant and hypertriglyceridemic thors suggested that hypercortisolemia resistance is as common in patients with than the control group, implying addi- could be the primary defect that leads to psychotic illness treated with antipsychotic tional risks of future diabetes and CVD for the development of the insulin resis- medication as in patients with nonpsy- Maori treated with antipsychotic medica- tance in antipsychotic-naive patients chotic psychiatric illness treated with anti- tion. It has been suggested that the asso- with schizophrenia (27). However, in psychotic medication. In an animal study, ciation of antipsychotic treatment with studies examining the effects of antipsy- dogs challenged with antipsychotic medica- both weight gain and diabetes in patients chotic medication on patients with tion developed insulin resistance, which in- is confounded by the lack of exercise and schizophrenia, changes in total plasma dicated that the association of insulin alterations in diet common to psychiatri- cortisol levels have generally not been resistance and antipsychotic medication is cally ill patients. However, in our study, measured or have been an inconsistent unlikely to be entirely related to a psychotic patients and control subjects were finding (27,28). illness (32).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1427 Insulin resistance and antipsychotic medication
The lower median value for glucose in velopment of insulin resistance in 202, 1987 the patient group was surprising but was patients with a psychotic illness who are 12. Lewis J, Lewis M, Elder P: An enzyme- within the healthy range (Ͻ7 mmol/l). In given antipsychotic medication. linked immunoassay for corticosteroid- addition, there was no significant differ- binding globulin using monoclonal and ence in A1C levels between patients and polyclonal antibodies: decline in CBG fol- Acknowledgments— This work was sup- lowing synthetic ACTH. Clin Chim Acta control subjects, and the trend was in the 328:121–128, 2003 expected direction (slightly higher A1C ported by grants from the Health Research Council of New Zealand (04/141R) and the 13. Swinburn BA, Ley SJ, Carmichael HE, levels in patients). Schizophrenia Fellowship of New Zealand (to Plank LD: Body size and composition in There was no difference in IGF-1 lev- P.F.E. and N.R.P.). Polynesians. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1429 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Development of Diabetes in Chinese With the Metabolic Syndrome A 6-year prospective study
1 1 BERNARD M.Y. CHEUNG, PHD CHUN HO CHENG, FRCP causative role. Because insulin resistance, 1 4 NELSON M.S. WAT, FRCP JEAN WOO, MD together with hyperinsulinemia, is a fun- 1 5 YU BUN MAN, MPHIL EDWARD D. JANUS, MD 2 1 damental metabolic abnormality in type 2 SIDNEY TAM, FACB CHU PAK LAU, MD 3 3 diabetes, the metabolic syndrome may be G. NEIL THOMAS, PHD TAI HING LAM, MD 3 1 expected to be a good predictor of the GABRIEL M. LEUNG, MD KAREN S.L. LAM, MD development of the latter. Asians are thought to have a higher body fat percent- age and cardiovascular risks than Cauca- OBJECTIVE — We investigated the association of the metabolic syndrome with new-onset sians at a given BMI (8). These factors diabetes in the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort. raise concerns that definitions of the met- abolic syndrome for Caucasians, when RESEARCH DESIGN AND METHODS — We followed up on 1,679 subjects without diabetes at baseline. Those with a previous diagnosis of diabetes or those who were receiving applied to Asian populations, would un- drug treatment were considered to be diabetic. The remaining subjects underwent a 75-g oral derestimate the population at risk of de- glucose tolerance test (OGTT). Diabetes was defined by plasma glucose Ն7.0 mmol/l with fasting veloping adverse outcomes such as type 2 and/or Ն11.1 mmol/l at 2 h. diabetes, cardiovascular disease, and mortality. Therefore, validation of the RESULTS — The prevalences of the metabolic syndrome at baseline were 14.5 and 11.4%, predictive value of the metabolic syn- respectively, according to U.S. National Cholesterol Education Program (NCEP) and Interna- drome needs to be established in popula- tional Diabetes Federation (IDF) criteria. After a median of 6.4 years, there were 66 and 54 new tion-based cohorts of different ethnicities. cases of diabetes in men and women, respectively. The metabolic syndrome at baseline predicted The International Diabetes Federation incident diabetes. Hazard ratios (HRs) for the NCEP and IDF definitions of the syndrome were (IDF) proposed a new definition of the 4.1 [95% CI 2.8–6.0] and 3.5 [2.3–5.2], respectively. HRs for fasting plasma glucose (FPG) Ն6.1 or 5.6 mmol/l were 6.9 [4.1–11.5] and 4.1 [2.8–6.0], respectively. The NCEP and IDF metabolic syndrome, which uses ethnic- criteria had 41.9 and 31.7% sensitivity and 87.5 and 90.2% specificity, respectively. Their specific central obesity criteria as a pre- positive predictive values were low, ϳ20%, but their negative predictive values were ϳ95%. requisite for diagnosis of the syndrome (4). The American Heart Association/ CONCLUSIONS — The metabolic syndrome, particularly its component, elevated FPG, National Heart, Lung, and Blood Institute predicts diabetes in Chinese. An individual without the metabolic syndrome is unlikely to update of the U.S. National Cholesterol develop diabetes, but one who has it should practice therapeutic lifestyle changes and have Education Program (NCEP) Adult Treat- periodic FPG measurements to detect new-onset diabetes. ment Panel III guidelines also recom- mended similar criteria for central obesity Diabetes Care 30:1430–1436, 2007 in Asians (3). In the present study, we sought to examine the predictive ability of he metabolic syndrome has been produce diagnostic criteria for the syn- the metabolic syndrome for the develop- promoted as a clinical tool for iden- drome, but there is still some controversy. ment of diabetes in a population-based T tifying individuals predisposed to The pathogenetic mechanism underlying cohort of nondiabetic Chinese men and diabetes and/or adverse cardiovascular the metabolic syndrome remains uncer- women, who were followed-up for a me- outcomes (1–7). Attempts have been tain, although central obesity and insulin dian of 6.4 years. We compared two def- made by different consensus groups to resistance have been proposed to play a initions of the metabolic syndrome: the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● updated NCEP definition (3) and the IDF From 1Department of Medicine, University of Hong Kong, Hong Kong, China; 2Department of Clinical definition (4). We also sought to identify Biochemistry Unit, Queen Mary Hospital, Hong Kong, China; 3Department of Community Medicine, Uni- the components of the metabolic syn- 4 versity of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University drome that were predictive of the devel- of Hong Kong, Hong Kong, China; and 5Department of Medicine, University of Melbourne, Western Hos- pital, Footscray, Victoria, Australia. opment of diabetes. Address correspondence and reprint requests to Prof. Bernard M.Y. Cheung, University Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong, China. E-mail: [email protected]. Received for publication 30 August 2006 and accepted in revised form 18 February 2007. RESEARCH DESIGN AND Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-1820. METHODS — The Hong Kong Car- Abbreviations: CRISPS, Hong Kong Cardiovascular Risk Factor Prevalence Study; FPG, fasting plasma glucose; IDF, International Diabetes Federation; IFG, impaired fasting glucose; HOMA-IR, homeostasis diovascular Risk Factor Prevalence Study model assessment estimate of insulin resistance; NCEP, National Cholesterol Education Program; OGTT, (CRISPS) was a cohort study of cardiovas- oral glucose tolerance test; ROC, receiver operating characteristic. cular risk factors in Hong Kong Chinese. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion In 1995–1996, a random sample of 2,895 factors for many substances. Hong Kong Chinese (1,412 men and © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 1,483 women, aged 25–74 years) was re- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cruited from the general population using
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to a standardized protocol. Subjects were seated at rest for at least 10 min, and three measurements were taken at 5-min inter- vals. The Korotkoff V sound was used to determine diastolic blood pressure. Ve- nous blood (20 ml) was taken for blood biochemistry and lipid profile analysis. Lipids were measured on a Hitachi 912 analyzer as described previously (12). LDL cholesterol was calculated using Friedewald’s equation if the total triglyc- eride concentration was not Ͼ4.5 mmol/l. Otherwise, LDL was determined by a direct assay using selective micellar solubilization of LDL by a nonionic deter- gent in an enzyme-coupled colorimetric assay automated on the Hitachi 912 ana- lyzer. Glucose was measured by the hex- okinase method on the Hitachi 912 analyzer. Insulin was measured by micro- particle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan). The ho- meostasis model assessment estimate of insulin resistance (HOMA-IR), a simple assessment of insulin sensitivity, was cal- culated using the following formula: fast- ing plasma glucose (FPG) (millimoles per liter) ϫ fasting insulin (microunits per milliliter)/22.5 (15). Diabetes was defined as FPG Ն7.0 mmol/l (126 mg/dl) or 2-h plasma glu- cose Ն11.1 mmol/l (200 mg/dl) or both (16). Impaired fasting glucose (IFG) was Figure 1—Flow of study subjects. defined as FPG of 5.6–6.9 mmol/l (100– 125 mg/dl) (16). For comparison, the cut random telephone numbers (9–14). This smokers (77% vs. 70%) (P Ͻ 0.001). point of 6.1 mmol/l (110 mg/dl) for IFG method had been validated locally; those They were less likely to be diabetic at was also analyzed. enrolled at baseline were representative of baseline (9% vs. 12%, P ϭ 0.04). The NCEP criteria for the metabolic the general population (12). In 2000– The follow-up visits took place in the syndrome are fulfilled if an Asian individ- 2004, the subjects in this cohort were in- morning after overnight fasting. Demo- ual has three or more of the following: 1) vited for follow-up in the Hong Kong graphic data, including sex, age, occupa- waist circumference Ն90 cm (35 inches) CRISPS2. Completion of enrollment was tion, smoking and drinking habits, and in men and Ն80 cm (31 inches) in delayed because of the outbreak of severe history of cardiovascular diseases, hyper- women, 2) triglyceride concentration acute respiratory syndrome in 2003. tension, and diabetes, were recorded. Ն150 mg/dl (1.7 mmol/l), 3) HDL cho- The study protocol was approved by Subjects underwent a brief physical ex- lesterol Ͻ40 mg/dl (1.03 mmol/l) in men the Ethics Committee of the University of amination that included measurement of and Ͻ50 mg/dl (1.29 mmol/l) in women, Hong Kong. All subjects gave written con- height, weight, and waist and hip circum- 4) blood pressure Ն130/85 mmHg, or 5) sent. The flow of subjects is shown in Fig. ference. Height was measured to the near- fasting glucose Ն100 mg/dl (5.6 mmol/l) 1. Of the 2,895 subjects who initially par- est 0.5 cm and weight to the nearest 0.1 (3,17). Receiving specific treatment for a ticipated (CRISPS1), 1,944 (901 men and kg (Detecto Instrument, Webb City, MO). criterion is counted as fulfilling the crite- 1,043 women; aged 52 Ϯ 12 years; re- BMI was calculated as weight in kilograms rion. In the original NCEP Adult Treat- sponse rate ϭ 67.2%) enrolled in the fol- divided by the square of height in centi- ment Panel III definition, the fasting low-up study (CRISPS2). The baseline meters (2). Waist and hip circumferences glucose cut point was Ն110 mg/dl (Ն6.1 characteristics of the 1,944 participants in were measured twice to the nearest 0.5 mmol/l) (1). This was later revised to CRISPS2 were comparable to those of the cm, and the arithmetic means were used. Ն100 mg/dl (5.6 mmol/l) (2). 951 nonparticipants in terms of age, BMI, Waist circumference was measured half- The IDF criteria for the metabolic LDL cholesterol, drinking habits, and the way between the xiphisternum and the syndrome are similar to the NCEP criteria frequency of hypertension, stroke, and umbilicus, whereas hip circumference except that central obesity, defined using ischemic heart disease. However, those was measured at the level of the greater sex- and ethnic-specific criteria (waist cir- subjects who reenrolled were more likely trochanters. cumference Ն90 cm in Chinese men and to be female (54% vs. 47% in nonpartici- Blood pressure was measured using a Ն80 cm in Chinese women), is a prereq- pants), married (85% vs. 77%), and non- mercury sphygmomanometer according uisite (4).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1431 Diabetes in Chinese with metabolic syndrome
Table 1—Baseline characteristics of subjects with no history of diabetes stratified by metabolic syndrome status
Metabolic syndrome, Metabolic syndrome, NCEP criteria (3) IDF criteria (4) Total Without With Without With n 1,679 1,511 168 1,488 191 Age (years) 45.1 Ϯ 11.9 43.6 Ϯ 11.4 51.2 Ϯ 11.1* 44.1 Ϯ 11.6 53.2 Ϯ 11.5* Male (%) 46.6 45.9 50.6 46.6 46.6 Diabetes in either parent (%) 16.4 15.7 20.1 15.9 20.0 BMI (kg/m2) 24.0 Ϯ 3.5 23.3 Ϯ 3.2 27.6 Ϯ 3.5* 23.4 Ϯ 3.2 28.6 Ϯ 3.0* Waist circumference (cm) 78.2 Ϯ 9.7 76.4 Ϯ 8.7 88.6 Ϯ 8.7* 76.5 Ϯ 8.5 91.7 Ϯ 7.1* Waist-to-hip ratio 0.83 Ϯ 0.08 0.82 Ϯ 0.08 0.90 Ϯ 0.07* 0.82 Ϯ 0.08 0.92 Ϯ 0.07* Systolic blood pressure (mmHg) 117.8 Ϯ 18.5 114.6 Ϯ 15.7 137.6 Ϯ 20.4* 115.4 Ϯ 16.7 136.6 Ϯ 21.2* Diastolic blood pressure (mmHg) 74.1 Ϯ 10.4 72.6 Ϯ 9.2 84.3 Ϯ 10.9* 72.9 Ϯ 9.8 83.5 Ϯ 10.7* Fasting glucose (mmol/l) 5.1 Ϯ 0.5 5.0 Ϯ 0.5 5.5 Ϯ 0.5* 5.1 Ϯ 0.5 5.4 Ϯ 0.5* OGTT 2-h glucose (mmol/l) 6.1 Ϯ 1.6 5.9 Ϯ 1.5 7.4 Ϯ 1.7* 6.0 Ϯ 1.6 7.4 Ϯ 1.7* Total cholesterol (mmol/l) 5.0 Ϯ 0.9 4.9 Ϯ 0.9 5.5 Ϯ 1.0* 5.0 Ϯ 0.9 5.4 Ϯ 0.9* Triglycerides (mmol/l) 1.1 Ϯ 0.7 1.0 Ϯ 0.5 2.0 Ϯ 0.9* 1.0 Ϯ 0.6 1.9 Ϯ 0.8* HDL cholesterol (mmol/l) 1.3 Ϯ 0.3 1.3 Ϯ 0.3 1.0 Ϯ 0.2* 1.3 Ϯ 0.3 1.0 Ϯ 0.2* HOMA-IR 1.1 (0.7–1.7) 1.0 (0.7–1.5) 1.9 (1.3–2.7)* 1.0 (0.7–1.5) 2.0 (1.3–2.7)* Fasting insulin (mIU/l) 4.8 (3.1–7.1) 4.4 (3.0–6.7) 7.9 (5.7–11.2)* 4.4 (3.0–6.5) 8.2 (5.8–11.0)* Tobacco use† Male (%) 46.2 46.1 46.7 45.4 52.8 Female (%) 3.7 3.4 5.0 3.5 4.9 Regular alcohol consumption‡ Male (%) 28.5 28.9 26.5 28.9 27.4 Female (%) 5.3 5.7 2.3 5.7 2.5 Physically active§ 36.7 36.5 36.8 36.5 38.2 Data are shown as means Ϯ SD, median (interquartile range), or %. Student’s unpaired t test, Mann-Whitney test, and Fisher’s exact test were used as appropriate. *P Ͻ 0.001. †Ever been a smoker. ‡At least once a week. §Taking exercise at least once a week in the past month.
Statistical analysis jects who participated in the follow-up tes in subjects with or without the meta- Baseline characteristics were compared study (CRISPS2), there were 1,679 sub- bolic syndrome at baseline with 95% CIs between groups using Student’s unpaired jects who did not have type 2 diabetes were assessed. Cox proportional hazards t test, Mann-Whitney test, McNemar test, initially and were thus included in the regression was used to estimate the age- or Fisher’s exact test. Of the 1,944 sub- present analysis. Incidence rates of diabe- adjusted hazard ratios (HRs) and 95% CI
Table 2—Association of the metabolic syndrome and its components with the risk of incident diabetes
Incidence of diabetes per 1,000 person-years (%) Prevalence at Adjusted HR (95% CI) baseline (%) Without With for incident diabetes* Metabolic syndrome (original NCEP criteria) (1) 7.5 8.9 42.2 4.2 (2.7–6.5) Metabolic syndrome (FPG Ն5.6 mmol/l) (2) 10.0 8.1 41.0 4.5 (3.0–6.8) Metabolic syndrome (FPG Ն5.6 mmol/l and 14.5 7.3 31.3 4.1 (2.8–6.0) Asian cut points for waist circumference) (3) Metabolic syndrome (IDF criteria) (4) 11.4 8.6 29.2 3.5 (2.3–5.2) Central obesity (original NCEP criteria) (1) 4.8 9.7 43.8 5.1 (3.0–8.7) Central obesity (Asian criteria) (3,4) 22.6 7.2 25.6 3.3 (2.2–4.8) High blood pressure 25.6 7.8 21.9 2.3 (1.6–3.5) Hyperglycemia (Ն5.6 mmol/l) 15.0 7.5 33.2 4.1 (2.8–6.0) Hyperglycemia (Ն6.1 mmol/l) 3.2 9.6 66.8 6.9 (4.1–11.5) Hypertriglyceridemia 15.1 9.0 24.4 2.6 (1.7–3.8) Low HDL cholesterol 39.4 8.1 16.0 2.0 (1.4–2.9) Components of the metabolic syndrome are defined as follows: central obesity (original NCEP criteria): waist circumference Ͼ102 cm in men or Ͼ88 cm in women; central obesity (Asian criteria): waist circumference Ն90 cm in men or Ն80 cm in women; high blood pressure: systolic/diastolic blood pressure Ն130/85 mmHg or taking blood pressure–lowering medication; hyperglycemia: FPG Ն5.6 mmol/l; hypertriglyceridemia: fasting triglycerides Ն1.69 mmol/l; low HDL cholesterol: fasting HDL cholesterol Ͻ1.03 or Ͻ1.29 mmol/l in men and women, respectively. *HRs are adjusted for age, sex, tobacco use (never/ever), alcohol consumption (never/occasional/at least once a week), and physical activity (Ͻ1 episode/at least 1 episode a week in the past month).
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Table 3—Sensitivity, specificity, and positive and negative predictive value of the different definitions of the metabolic syndrome and compo- nents with respect to the incidence of diabetes over the follow-up period
Positive predictive Negative predictive Sensitivity (%) Specificity (%) value (%) value (%) Definitions of metabolic syndrome Metabolic syndrome (original NCEP criteria) (1) 25.8 93.9 24.6 94.3 Metabolic syndrome (FPG Ն5.6 mmol/l) (2) 34.2 91.9 24.4 94.8 Metabolic syndrome (FPG Ն5.6 mmol/l and 41.9 87.5 20.5 95.1 Asian cut points for waist circumference) (3) Metabolic syndrome (IDF criteria) (4) 31.7 90.2 19.9 94.5 Components of metabolic syndrome Central obesity (original NCEP criteria) (1) 16.7 96.2 25 93.8 Central obesity (Asian criteria) (3,4) 49.2 79.5 15.6 95.3 High blood pressure 47.5 76.1 13.3 95.0 Hyperglycemia (Ն5.6 mmol/l) 42.5 87.1 20.2 95.2 Hyperglycemia (Ն6.1 mmol/l) 16.7 97.8 37.0 93.9 Hypertriglyceridemia 31.7 86.2 15.0 94.2 Low HDL cholesterol 55.8 61.8 10.1 94.8 See Table 2 for definitions of components of the metabolic syndrome. for the development of diabetes associ- diabetes in men and women, respectively. cut points for central obesity (waist cir- ated with the metabolic syndrome. Sensi- The incidence of diabetes was markedly cumference) and hyperglycemia (FPG) tivities, specificities, and positive and higher in subjects with the metabolic syn- were examined (Table 3). The Asian cri- negative predictive values for the different drome at baseline than in those without teria for central obesity and FPGՆ5.6 definitions of the metabolic syndrome the syndrome (Table 2). The incidence mmol/l had higher sensitivities but lower were determined. Receiver-operating rate was similar for either the NCEP (3) or positive predictive values. characteristic (ROC) curves were drawn the IDF (4) definition of the metabolic ROC curves for the prediction of the for the predictors of diabetes. Analyses syndrome. The HRs associated with the development of diabetes using baseline were performed with SPSS 11.0 for Win- NCEP and the IDF definitions of the met- parameters are shown in Fig. 2. For the dows (SPSS, Chicago, IL); P Ͻ 0.05 (two- abolic syndrome were 4.1 [95% CI 2.8– sake of clarity, not all curves are plotted. Ϯ sided) was considered statistically 6.0] and 3.5 [2.3–5.2], respectively. For men, the areas SE under the ROC Ϯ significant. HRs for diabetes associated with the curves were 0.67 0.03 for waist-to-hip Ϯ components of the metabolic syndrome ratio, 0.70 0.03 for waist circumfer- Ϯ Ϯ are shown in Table 2. Among the indi- ence, 0.75 0.03 for BMI, 0.76 0.03 RESULTS — Baseline characteristics Ϯ vidual components of the metabolic for FPG, and 0.76 0.03 for the plasma of the 1,679 subjects who had no his- syndrome, hyperglycemia and central glucose at2hinanOGTT. For women, tory of diabetes at baseline are shown in Ϯ obesity were more strongly associated the respective areas SE under the ROC Table 1. At baseline, 168 and 191 sub- curves were 0.74 Ϯ 0.03, 0.74 Ϯ 0.03, jects had the metabolic syndrome ac- with incident diabetes than the other Ϯ Ϯ Ϯ components. The HRs for an FPG Ն6.1 0.74 0.03, 0.75 0.03, and 0.82 cording to the NCEP and IDF criteria, Ն 0.03. respectively. As expected, subjects with or 5.6 mmol/l ( 110 or 100 mg/dl) the metabolic syndrome were more were 6.9 [95%CI 4.1–11.5] and 4.1 obese, had higher blood pressure, FPG, [2.8–6.0], respectively. CONCLUSIONS — In recent years, and plasma triglycerides, and had lower Sensitivity, specificity, and positive there has been an alarming increase in di- HDL cholesterol. They also tended to be and negative predictive values for the abetes and the metabolic syndrome in older. However, there were no signifi- metabolic syndrome and its components Asia (17–19). The prevalence of the met- cant differences in sex ratio, tobacco are shown in Table 3. Different definitions abolic syndrome (by NCEP criteria using use, alcohol use, or exercise habit. Insu- of the metabolic syndrome (1–4) are waist circumference criteria for Asians) lin resistance, as indicated by HOMA- shown for comparison. All the definitions stands at 11% in Koreans, 14–24% in IR, was significantly associated with the were highly specific but not sensitive. The Chinese, and 29% in Indians (9,19,20). metabolic syndrome. The prevalences positive predictive values were low, rang- These are not low compared with the of the metabolic syndrome defined by ing from 19.9 to 24.6%, but the negative prevalence of 33.6% in the United States the NCEP criteria were 15.6 and 13.4% predictive values were close to 95%. In (21). Our prospective study confirms that for nondiabetic men and women, re- this population, the updated NCEP defi- the metabolic syndrome predicts the de- spectively, and were 11.3 and 11.4% nition (3) had a higher sensitivity than velopment of diabetes in urbanized Chi- (McNemar test P Ͻ 0.001), respec- previous NCEP definitions (1,2) and the nese as much as in Americans (6,7). The tively, if the IDF definition was applied. IDF definition (4). However, IFG alone HR for the development of diabetes asso- During a median follow-up of 6.4 has a similar sensitivity, but the positive ciated with the metabolic syndrome is years, there were 66 and 54 new cases of predictive value tends to be higher. Two quite variable, depending on the popula-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1433 Diabetes in Chinese with metabolic syndrome
tion studied (22–24). The hazard of de- veloping diabetes associated with the NCEP definition of the metabolic syn- drome is 4.1 in our population, compara- ble to the odds ratios of 3.3 and 5.0 reported for the U.S. and Finland, respec- tively (6,23). In the San Antonio Heart Study, which followed-up on 1,734 participants after 7–8 years, the original NCEP defini- tion (1) performed better than the World Health Organization definition, but low- ering the FPG cutoff to 5.4 mmol/l im- proved the prediction further (6). Interestingly, in our population, an FPG of ϳ5.2 mmol/l had a sensitivity and specificity of ϳ70%. Thus, our results support the change in cut point for IFG from 6.1 to 5.6 mmol/l, because of the Ͼ1-fold gain in sensitivity. However, this gain must be balanced against the lower cardiovascular risk of those who have the mildest hyperglycemia, the paucity of ev- idence of benefit in treating such individ- uals, and the negative consequences of labeling someone as having a disease. We compared the IDF definition of the metabolic syndrome with the NCEP criteria in terms of prediction of new- onset diabetes. The IDF criteria include abdominal obesity as a prerequisite and have different cutoffs for waist circumfer- ence for different ethnic groups (4). In the Insulin Resistance Atherosclerosis Study, the predictive values of the NCEP and IDF criteria were similar (7). In our popula- tion, the updated NCEP (3) and IDF (4) criteria have similar positive and negative predictive values, but the sensitivity of the NCEP criteria tended to be higher. We investigated which component of the metabolic syndrome was more pre- dictive of diabetes. We found that IFG conferred a high risk of subsequent devel- opment of diabetes, as in our previous ob- servations in this cohort after 2 years of follow-up (13). Indeed, IFG was as good as any of the definitions of the metabolic syndrome in predicting the development of diabetes. However, whether IFG is as Figure 2—ROC curves showing the ability of the baseline waist circumference (solid line), FPG strong a predictor as the metabolic syn- (light dotted line), and plasma glucose at2hinanOGTT (dark dotted line) to predict the drome for cardiovascular mortality was development of diabetes in men and women after an interval of 6.4 years. Diagonal segments are not addressed in our study. In our ROC produced by ties. The values were adjusted for age, tobacco use, alcohol consumption, and physical ϩ analysis, waist circumference was as good activity. The sensitivities and specificities of the NCEP ( ) and IDF (*) definitions of the meta- a predictor as FPG in predicting diabetes bolic syndrome (3,4) are shown for comparison. For men, the points on the ROC curves closest to the ideal were 79.4 cm for waist circumference (sensitivity 0.73% and specificity 0.63%), 5.2 in women, but the other components of mmol/l for FPG (sensitivity 0.72% and specificity 0.69%), and 5.8 mmol/l for the 2-h plasma the metabolic syndrome, such as elevated glucose (sensitivity 0.77% and specificity 0.67%). For women, the points on the ROC curves closest blood pressure, were less predictive. In to the ideal were 76.1 cm for waist circumference (sensitivity 0.74% and specificity 0.65%), 5.2 women, the 2-h plasma glucose value in mmol/l for FPG (sensitivity 0.74% and specificity 0.72%), and 6.45 mmol/l for the 2-h plasma an OGTT was an even better predictor of glucose (sensitivity 0.87% and specificity 0.67%). the development of diabetes. Neverthe- less, FPG is easier to obtain than an OGTT
1434 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cheung and Associates test and is therefore the measurement of appropriate for the prediction of diabe- ity associated with the metabolic syn- choice for practical reasons. tes in this population. The absence of drome. Diabetes Care 24:683–689, 2001 If FPG is as good as the metabolic syn- the metabolic syndrome strongly pre- 6. Lorenzo C, Okoloise M, Williams K, Stern drome in predicting the development of dicts the absence of future diabetes. In- MP, Haffner SM: The metabolic syndrome diabetes in the future, the extra effort and terventions targeted to improve FPG as predictor of type 2 diabetes: the San Antonio Heart Study. Diabetes Care 26: costs to diagnose the metabolic syndrome and central obesity will be most useful 3153–3159, 2003 may need to be justified if the objective is for preventing diabetes in our popula- 7. Hanley AJG, Karter AJ, Williams K, Festa solely to predict the development of dia- tion. The presence of the metabolic syn- A, D’Agostino Jr RB, Wagenknecht LE, betes. On the other hand, the process of drome in someone without diabetes is a Haffner SE: Prediction of type 2 diabetes diagnosing the metabolic syndrome may strong warning signal; periodic mea- mellitus with alternative definitions of the lead to the identification of associated car- surement of FPG should be performed metabolic syndrome: the Insulin Resis- diometabolic risk factors such as high to detect progression to diabetes, and tance Atherosclerosis Study. Circulation blood pressure and dyslipidemia that are lifestyle modifications, including 112:3713–3721, 2005 of significant magnitude to justify inter- healthy diet, weight control, and regu- 8. WHO Expert Consultation: Appropriate vention for the prevention of cardiovascu- lar physical activity, should be strongly body-mass index for Asian populations and its implications for policy and inter- lar disease. encouraged. vention strategies. Lancet 363:157–163, For Hong Kong Chinese, the Asian 2004 cut points for central obesity, compared 9. Thomas GN, Ho SY, Janus ED, Lam KS, with the cut points for white Americans, Acknowledgments— The Hong Kong Hedley AJ, Lam TH, Hong Kong Cardio- have higher sensitivity, but the positive CRISPS2 was supported by a Hong Kong Re- vascular Risk Factor Prevalence Study predictive value is slightly lower. Re- search Grants Council grant (7229/01M) and Steering Committee: The U.S. National sults of the ROC analysis are also sup- the Sun Chieh Yeh Heart Foundation. The Cholesterol Education Programme Adult project titled “Impaired Glucose Tolerance as a Treatment Panel III (NCEP ATP III) prev- portive of the use of the lower cut points Precursor of Diabetes and Hypertension in for central obesity in both sexes in our alence of the metabolic syndrome in a Hong Kong Chinese” was supported by a Chinese population. Diabetes Res Clin Asian population. Further studies on Health Care and Promotion Fund Committee the appropriate cut points for different Pract 67:251–257. 2005 Research Grant (212907). 10. Janus ED, Watt NM, Lam KS, Cockram parameters are needed to formulate G. Cheung, J.L.F. Lo, D.F.Y. Chau, and C.Y. CS, Siu ST, Liu LJ, Lam TH: The preva- public health policy for controlling di- Law were the research nurses involved with lence of diabetes, association with cardio- abetes in the community. the clinical study of the subjects. vascular risk factors and implications of The positive predictive value of the diagnostic criteria (ADA 1997 and WHO metabolic syndrome is low because the 1998) in a 1996 community-based popu- majority of people with it will not develop References lation study in Hong Kong Chinese: Hong new-onset diabetes within 6 years. How- 1. Executive summary of the Third Report Kong Cardiovascular Risk Factor Steering ever, the hazard associated with it is not of the National Cholesterol Education Committee. Diabet Med 17:741–745, 2000 low, which means that an individual with Program (NCEP) Expert Panel on De- 11. Lam TH, Liu LJ, Janus ED, Lam KS, Hed- the metabolic syndrome but not diabetes tection, Evaluation, and Treatment of ley AJ, Hong Kong Cardiovascular Risk Factor Prevalence Study Steering Com- should have periodic measurements of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486– mittee: Fibrinogen, other cardiovascular FPG to detect the onset of diabetes. On 2497, 2001 risk factors and diabetes mellitus in Hong the other hand, the metabolic syndrome 2. Grundy SM, Brewer HB Jr, Cleeman JI, Kong: a community with high prevalence has a very high negative predictive value Smith SC Jr, Lenfant C, American Heart of type 2 diabetes mellitus and impaired for future diabetes, which means that an Association, National Heart, Lung, and glucose tolerance. 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1436 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Severe Hypoglycemia and Smoking in a Long-Term Type 1 Diabetic Population Wisconsin Epidemiologic Study of Diabetic Retinopathy
1,2 1 FLAVIO E. HIRAI, MD, MPH BARBARA E.K. KLEIN, MD, MPH RESEARCH DESIGN AND 1 1 SCOT E. MOSS, MA RONALD KLEIN, MD, MPH METHODS — This study was a cross-sectional analysis of the popula- tion seen in the last examination OBJECTIVE — The purpose of this study was to evaluate the relationship of severe hypogly- (2000–2001) of the Wisconsin Epide- cemia and smoking in a population-based cohort of individuals with long-term type 1 diabetes. miologic Study of Diabetic Retinopathy (WESDR). The WESDR is an ongoing RESEARCH DESIGN AND METHODS — This was a cross-sectional analysis of the prospective population-based cohort population-based cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The study initiated in 1980–1982 of indi- analyses in this report were limited to 537 type 1 diabetic individuals with complete data who viduals with type 1 and 2 diabetes living participated in the last examination phase (2000–2001). Severe hypoglycemia was defined as in 11 counties of Wisconsin (9). Partic- having one or more episodes of loss of consciousness or overnight hospitalization attributable to ϭ hypoglycemia in a 1-year period before the examination. ipants were examined at baseline (n 996) and every 4–6 years. The last ex- RESULTS — The prevalence of severe hypoglycemia in this population was 14.3%. In uni- amination phase (2000–2001) was re- variate analysis, current smokers had a greater chance of having severe hypoglycemia compared stricted to individuals (n ϭ 652) with with never smokers (odds ratio 2.40 [95% CI 1.30–4.40]). When we controlled for relevant type 1 diabetes. Detailed protocols used confounders such as age, sex, A1C, waist-to-hip ratio, orthostatic hypotension, alcohol con- in this period were published elsewhere sumption, intensive insulin treatment, past history of severe hypoglycemia, and late complica- (10,11). Briefly, relevant evaluations in- tions of diabetes (nephropathy, neuropathy, and retinopathy), the association remained cluded history of hypoglycemic reac- ϳ statistically significant, with current smoking presenting 2.6 times greater odds of developing tions, neuropathy, nephropathy, severe hypoglycemia. cigarette smoking, and alcohol con- CONCLUSIONS — Current smokers with type 1 diabetes have higher odds of severe hypo- sumption; measurements of blood pres- glycemia episodes. sure in supine and standing positions, A1C, height, weight, and hip and waist Diabetes Care 30:1437–1441, 2007 circumference; and fundus photogra- phy graded for diabetic retinopathy. ver the last few decades, new ther- been described previously as factors as- apeutic agents have been intro- sociated with this complication (1–5). Definitions duced to improve glycemic Smoking has been reported to be asso- O Severe hypoglycemia was defined as control and reduce complications of ciated with hypoglycemia in previous having one or more episodes of loss of type 1 diabetes. The Diabetes Control clinical studies (6–8), and it has been consciousness or overnight hospitaliza- and Complications Trial showed the studied but not related to severe hypo- tion caused by hypoglycemia in a 1-year benefits of tight glycemic control, but it glycemia in population-based studies. period before the examination. There- also showed that individuals receiving Smoking, through its effect on hormone fore, two groups (with and without se- intensive insulin treatment had an in- regulation and insulin clearance, has vere hypoglycemia) were defined and creased risk of developing severe hypo- been hypothesized to result in severe compared for the purpose of this study. glycemia. Thus, this complication hypoglycemia (6–8). The purpose of Participants were considered to be remains a major challenge in treatment this study was to evaluate the relation- never smokers if they had smoked of diabetic patients (1–5). Age, diabetes ship of severe hypoglycemia and smok- Ͻ100 cigarettes in their lifetime, cur- duration, history of previous episodes ing in a population-based study of rent smokers if they had smoked Ͼ100 of hypoglycemia, intensive insulin individuals with long-term type 1 cigarettes and continue to smoke, and treatment, and lower levels of A1C have diabetes. past smokers if they had smoked Ͼ100 ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● cigarettes but had stopped. All individ- From the 1Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, uals classified as past smokers had Wisconsin; and 2Department of Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil. stopped smoking for at least 12 months Address correspondence to Ronald Klein, MD, MPH, 610 N. Walnut St., #417, WARF Office Building, in this study. Intensive insulin treat- Madison, WI 53705-2397. E-mail: [email protected]. Received for publication 3 November 2006 and accepted in revised form 10 March 2007. ment was defined as the use of three or Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2264. more insulin injections per day or use of Abbreviations: WESDR, Wisconsin Epidemiologic Study of Diabetic Retinopathy. a continuous insulin pump. The defini- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tion of past history of severe hypoglyce- factors for many substances. mia only included positive history of © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby hospitalization due to hypoglycemia in marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. previous WESDR examinations because
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1437 Hypoglycemia and smoking in type 1 diabetes information about loss of consciousness levels of A1C and lower waist-to-hip ra- independent factor associated with se- due to hypoglycemia was only obtained tios and tested their blood glucose more vere hypoglycemia, attributing this to in this last examination phase. Ortho- frequently each day (data not shown). differences in lifestyle, carbohydrate static hypotension was defined as a de- The mean Ϯ SD age of this population metabolism, and neuropathy (8). The crease in systolic or diastolic blood was 45.3 Ϯ 9.9 years, duration of dia- relation of smoking to severe hypogly- pressure of at least 20 or 10 mmHg, re- betes was 31.3 Ϯ 7.9 years, and A1C cemia may be due to an effect of smok- spectively, after changing from supine was 7.8 Ϯ 1.4%. Regarding insulin ing on insulin clearance, leading to to standing positions. Neuropathy was treatment, 44.8% took insulin Ն3 hyperinsulinemia, increasing the risk of defined by positive history of tingling or times/day, 90.1% tested their glucose postprandial hypoglycemia, and wors- numbness in the hands, loss of tactile levels using blood from a fingerstick ening metabolic control; such an effect sensation, or loss of temperature sensi- specimen (mean Ϯ SD 3.6 Ϯ 2.1 tests/ was found in individuals with type 2 tivity. Nephropathy was diagnosed if day), and 88.8% adjusted insulin as a diabetes (13). In addition, smoking has the participant had been undergoing re- result of these glucose tests. The use of a been shown to increase the secretion of nal dialysis, had renal transplantation, continuous insulin pump was observed hormones (i.e., growth hormone, argi- or had gross proteinuria. Diabetic reti- in 20.5% of this population. Most of the nine vasopressin, and cortisol) that nopathy was assessed by fundus photo- participants were never smokers counteract insulin action, leading to an graphs and classified according to a (57.7%), 27.0% were past smokers, and increased insulin requirement (14). modified Early Treatment Diabetic Ret- 15.3% were current smokers. Smoking Smokers have been found to require inopathy Study protocol (12). It was status was similar in men and women; more insulin than nonsmokers to categorized into three groups: none to pack-year history was 1.4 times higher achieve the same level of glycemic con- mild nonproliferative, moderate to se- in men than women, although not sta- trol in some, but not all, studies (15– vere nonproliferative, and proliferative tistically significant (P ϭ 0.11). Seven- 17). This increased insulin requirement retinopathy. ty-eight individuals (14.5%) reported may also account for the higher suscep- one or more episodes of severe hypogly- tibility to severe hypoglycemia in smokers. cemia in a period of 1 year. Table 1 Although the WESDR provided a Data analysis shows the characteristics of the WESDR unique opportunity to analyze data Statistical analysis consisted of univari- cohort in the 2000–2001 follow-up ac- from a large population-based cohort of ate analysis of continuous and categor- cording to severe hypoglycemia status. type 1 diabetic individuals, there are ical data using Student’s t test and 2 In the univariate analysis, smoking some limitations that should be consid- test, respectively. Multivariate analysis was significantly associated with the de- ered. First, the definition of a history of using logistic regression was performed velopment of severe hypoglycemia (Ta- severe hypoglycemia included only to adjust for several confounders: age, ble 2). Current smokers were more those who lost consciousness or were sex, A1C, alcohol consumption, waist- likely to report a history of severe hypo- hospitalized, whereas other studies to-hip ratio, orthostatic hypotension, glycemia compared with never smokers used a broader definition including all intensive insulin treatment, and history (OR 2.40 [95% CI 1.30–4.40]). In mul- individuals who had episodes of hypo- of severe hypoglycemia. Three different tivariable analysis (Table 3), smoking glycemia that required help from an- regression models were built. Each remained significantly associated with other individual (1,2,5,8). This model contained the same confounders; severe hypoglycemia while controlling difference might be reflected in the the only difference among them was the for confounders in two models. ORs for prevalence found in our study (14.5%), presence of one of the variables related comparisons of current to never smok- which approximates more the lower to long-term complications of diabetes ers were 2.65 (1.20–5.82), 2.68 (1.21– end of prevalence values found by oth- (nephropathy, neuropathy, and reti- 5.92), and 2.10 (0.90–5.01) for the ers (4–40%) (2,5,8,18). Differences nopathy). These variables were ana- models including nephropathy, neu- might also be due to higher frequencies lyzed separately because of possible ropathy, and retinopathy, respectively. of intensive insulin treatment in some correlations among them. Odds ratios No interactions were observed (with specialty clinics than in the general pop- (ORs) with 95% CIs were estimated, age, sex, duration of diabetes, or inten- ulation of individuals with type 1 dia- and P Ͻ 0.05 was considered signifi- sive insulin treatment). betes. Second, the history of severe cant. Analyses were performed in SAS hypoglycemia was not validated by ex- (SAS Institute, Cary, NC) amination of medical records or mea- The institutional review board ap- CONCLUSIONS — The relation- surement of glycemia during the proved the study, and all participants pro- ship of smoking and low blood glucose episodes. Therefore, severe hypoglyce- vided consent. This research was was described in the 1950s when Bohan mia might have been misclassified in conducted in accordance with the princi- and Berry (7) and Berry (6) published a some participants in our study. In addi- ples of the Declaration of Helsinki. series of cases in which individuals with tion, our assessment of smoking was type 1 diabetes had fewer hypoglycemic based on cigarette smoking only. There episodes after smoking cessation. In our were no questions regarding the use of RESULTS — A total of 537 individu- study, current smokers were 2.6 times smokeless tobacco or other sources of als presenting complete data on insulin as likely to report at least one episode of nicotine or exposure to passive smoking reaction were included in the current severe hypoglycemia compared with in our questionnaire. Third, it is possi- analysis. Compared with those who nonsmokers after controlling for rele- ble that excessive exogenous insulin use were excluded because of incomplete vant confounders. One study in Den- may have resulted in residual con- data (n ϭ 115), this group had lower mark also showed that smoking was an founding. However, we feel it was un-
1438 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Hirai and Associates
Table 1—Clinical characteristics of participants of the WESDR according to severe hypoglycemia status
Severe hypoglycemia All Yes No n 537 78 459 Women (%) 49.9 51.3 49.6 Age (years) 45.3 Ϯ 9.9 44.1 Ϯ 10.7 45.5 Ϯ 9.7 BMI (kg/m2) 27.5 Ϯ 4.7 26.7 Ϯ 4.9 27.7 Ϯ 4.7 Waist-to-hip ratio 0.86 Ϯ 0.09 0.84 Ϯ 0.08* 0.86 Ϯ 0.09* A1C (%) 7.8 Ϯ 1.4 7.8 Ϯ 1.6 7.8 Ϯ 1.4 Diabetes duration (years) 31.3 Ϯ 7.9 31.4 Ϯ 9.5 31.2 Ϯ 7.7 Intensive insulin treatment (%) 65.3 68.4 64.7 Number of times/day taking insulin 2.8 Ϯ 0.9 2.8 Ϯ 0.8 2.8 Ϯ 1.0 Test blood glucose by fingerstick (%) 90.1 97.4* 88.9* Number of tests/day 3.6 Ϯ 2.1 4.0 Ϯ 2.2 3.6 Ϯ 2.1 Use of continuous pump (%) 20.5 23.7 19.9 Triglycerides (mg/dl) 99.5 Ϯ 68.8 100.04 Ϯ 68.7 99.45 Ϯ 68.9 Cholesterol (mg/dl) 179.2 Ϯ 35.2 185.6 Ϯ 35.5 178.1 Ϯ 35.0 LDL cholesterol (mg/dl) 102.8 Ϯ 30.9 106.2 Ϯ 33.4 102.2 Ϯ 30.4 HDL cholesterol(mg/dl) 56.8 Ϯ 15.9 59.4 Ϯ 15.9 56.3 Ϯ 15.9 Orthostatic hypotension (%) 16.5 15.8 16.7 Alcohol consumption (ounces/day) 0.17 Ϯ 0.4 0.17 Ϯ 0.5 0.17 Ϯ 0.3 Smoking (%) Never 57.7 47.4 59.4 Past 27.0 26.9 27.1 Current 15.3 25.7† 13.5† Past severe hypoglycemia (%) 4.6 7.9 4.1 Nephropathy (%) 25.1 28.2 24.6 Neuropathy (%) 47.2 52.6 46.3 Retinopathy (%) None to mild NPDR 42.4 51.1 41.2 Moderate to severe NPDR 18.8 15.6 19.2 Proliferative 38.8 33.3 39.6 Data are means Ϯ SD or percent. *P Ͻ 0.05; †P Ͻ 0.01. NPDR, nonproliferative diabetic retinopathy.
Table 2—ORs and 95% CI in univariate analysis of factors related to severe hypoglycemia
OR (95% CI) P value Sex, male vs. female 1.07 (0.67–1.72) 0.79 Age, 1 year increase 0.98 (0.96–1.01) 0.24 A1C, 1 SD increase 0.99 (0.79–1.25) 0.95 Waist-to-hip ratio, 1 SD increase 0.72 (0.54–0.96) 0.02 Orthostatic hypotension, present 0.94 (0.44–2.01) 0.86 Alcohol consumption, 1 SD increase 0.99 (0.78–1.27) 0.96 Smoking Past vs. never smoker 1.25 (0.70–2.22) 0.45 Current vs. never smoker 2.40 (1.30–4.40) 0.01 Intensive insulin treatment, current 1.18 (0.70–1.99) 0.53 Past severe hypoglycemia, present 2.00 (0.76–5.21) 0.15 Neuropathy, present 1.28 (0.79–2.08) 0.30 Nephropathy, present 1.20 (0.70–2.05) 0.49 Diabetic retinopathy Moderate to severe NPDR vs. none to mild 0.65 (0.26–1.60) 0.59 NPDR Proliferative vs. none to mild NPDR 0.68 (0.33–1.36) 0.63 NPDR, nonproliferative diabetic retinopathy.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1439 Hypoglycemia and smoking in type 1 diabetes
Table 3—ORs and 95% CI in multivariate analysis of factors related to severe hypoglycemia
OR (95% CI) Nephropathy Neuropathy Retinopathy Sex, male vs. female 1.64 (0.75–3.58) 1.74 (0.79–3.85) 1.47 (0.59–3.67) Age, 1 year increase 1.01 (0.97–1.04) 1.01 (0.97–1.04) 0.98 (0.95–1.03) A1C, 1 SD increase 0.86 (0.62–1.20) 0.85 (0.61–1.19) 0.93 (0.64–1.33) Waist-to-hip ratio, 1 SD increase 0.60 (0.40–0.90)* 0.59 (0.39–0.89)* 0.69 (0.44–1.10) Orthostatic hypotension, present 0.80 (0.32–1.99) 0.82 (0.33–2.05) 1.05 (0.39–2.83) Alcohol consumption, 1 SD increase 0.99 (0.71–1.41) 1.08 (0.76–1.53) 1.05 (0.72–1.53) Smoking Past vs. never smoker 1.02 (0.50–2.41) 0.98 (0.44–2.15) 0.93 (0.36–2.39) Current vs. never smoker 2.65 (1.20–5.82)* 2.68 (1.21–5.92)* 2.10 (0.90–5.01) Intensive insulin treatment, present 1.21 (0.60–2.43) 1.24 (0.62–2.48) 1.59 (0.72–3.54) Past severe hypoglycemia, present 2.76 (0.87–8.74) 2.59 (0.81–8.28) 2.60 (0.71–9.52) Nephropathy, present 1.86 (0.91–3.79) — — Neuropathy, present — 1.88 (0.98–3.60) — Retinopathy Moderate to severe NPDR vs. none to mild NPDR — — 0.70 (0.25–1.99) Proliferative vs. none to mild NPDR — — 0.99 (0.44–2.25) *P Ͻ 0.05. NPDR, nonproliferative diabetic retinopathy. likely to affect the association because pared with never smokers in this cohort 5. Donnelly LA, Morris AD, Frier BM, Ellis excessive insulin use has not been of type 1 diabetic individuals. JD, Donnan PT, Durrant R, Band MM, shown to be related to smoking. Fourth, Reekie G, Leese GP: Frequency and pre- although the WESDR is a prospective dictors of hypoglycaemia in type 1 and study, we performed a cross-sectional insulin-treated type 2 diabetes: a popula- analysis because new information re- Acknowledgments— This work was sup- tion-based study. Diabet Med 22:749– ported in part by Research Grant EY015117 755, 2005 garding insulin reactions and blood 6. Berry MG: Tobacco hypoglycemia. Ann pressure measurements in standing po- from the National Institutes of Health, Be- thesda, MD, and by the Mentor-Based Post- Intern Med 50:1149–1157, 1959 sitions were only obtained in this last 7. Bohan PT, Berry MG: Hypoglycemia and phase (2000–2001). As a consequence, doctoral Fellowship Award from the American Diabetes Association, Alexandria, VA (to the use of tobacco. GP 7: 63–64, 1953 this type of analysis limits us from de- R.K.). 8. Pedersen-Bjergaard U, Pramming S, termining antecedent-consequent rela- Parts of this study were presented in ab- Heller SR, Wallace TM, Rasmussen AK, tionships. Finally, the exclusion of stract form at the 66th Scientific Sessions of Jorgensen HV, Matthews DR, Hougaard some participants in the analysis re- the American Diabetes Association, Washing- P, Thorsteinsson B: Severe hypoglycaemia sulted in a population with different ton, DC, 9–13 June 2006. in 1076 adult patients with type 1 diabe- characteristics compared with the base- We are indebted to the WESDR cohort par- tes: influence of risk markers and selec- line cohort that might have compro- ticipants and physicians and their staff for tion. Diabetes Metab Res Rev 20:479–486, mised the generalizability of our their continued support and participation 2004 findings. In a long-term perspective, since 1980. 9. Klein R, Klein BE, Moss SE, DeMets DL, Kaufman I, Voss PS: Prevalence of diabe- death was the most common cause for tes mellitus in southern Wisconsin. Am J exclusion. If smokers had a higher risk References Epidemiol 119:54–61, 1984 of death, we might have underestimated 10. Klein BE, Klein R, McBride PE, Moss SE, the strength of the association reported. 1. Hypoglycemia in the Diabetes Control and Complications Trial: the Diabetes Prineas RJ, Reinke JO: Electrocardio- In addition, it is possible that individu- Control and Complications Trial Research graphic abnormalities in individuals with als with complications such as neurop- Group. Diabetes 46:271–286, 1997 long-duration type 1 diabetes. Diabetes athy and nephropathy who had a 2. ter Braak EW, Appelman AM, van de Care 28:145–147, 2005 history of severe hypoglycemia were LM, Stolk RP, van Haeften TW, Erkelens 11. Klein BE, Klein R, McBride PE, Cruicks- more likely to die and not participate DW: Clinical characteristics of type 1 hanks KJ, Palta M, Knudtson MD, Moss than those without a history of severe diabetic patients with and without se- SE, Reinke JO: Cardiovascular disease, hypoglycemia, leading to the lack of a verehypoglycemia.DiabetesCare23:1467– mortality, and retinal microvascular char- finding with these complications. How- 1471, 2000 acteristics in type 1 diabetes: Wisconsin Epidemiologic Study of Diabetic Retinop- ever, we believe the findings represent 3. Allen C, LeCaire T, Palta M, Daniels K, athy. Arch Intern Med 164:1917–1924, results from those with long-term type 1 Meredith M, D’Alessio DJ: Risk factors for frequent and severe hypoglycemia in type 2004 diabetes and are still generalizable to 1 diabetes. Diabetes Care 24:1878–1881, 12. Grading diabetic retinopathy from stereo- such a group. Despite these limitations, 2001 scopic color fundus photographs—an ex- our study showed that current smokers 4. Cryer PE, Davis SN, Shamoon H: Hypo- tension of the modified Airlie House presented significantly higher odds for glycemia in diabetes. Diabetes Care 26: classification: Early Treatment Diabetic severe hypoglycemia episodes com- 1902–1912, 2003 Retinopathy Study Research Group report
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1441 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Relationship of Physician Volume With Process Measures and Outcomes in Diabetes
1,2,3 ALEXANDER TURCHIN, MD, MS complex medical illness, such as diabetes, 4 MARIA SHUBINA, SCD in an outpatient setting. 1,3 MERRI L. PENDERGRASS, MD, PHD The number of patients with diabetes in the U.S. is increasing exponentially (13), while the number of endocrinolo- OBJECTIVE — The volume of patients cared for by an individual physician (physician vol- gists is not (14). Consequently, the major- ume) has been linked to improved outcomes for a number of conditions. It is not known whether ity of diabetes management will continue a similar association exists for treatment of diabetes. In this study we aimed to determine whether to be delivered by primary care physi- physician volume is associated with improved process measures and outcomes in diabetes care. cians. It has been suggested that patients may benefit from referral to high-volume RESEARCH DESIGN AND METHODS — This retrospective cohort study analyzed centers and physicians for treatment of electronic medical records data for 7,120 patients with diabetes treated by 368 primary care physicians at practices affiliated with two large academic hospitals. The associations between conditions where case volume is associ- physician volume of diabetic patients (diabetes volume) and annual A1C and LDL testing, as well ated with improved outcomes (8,15). If a as blood pressure, A1C, and LDL levels, were evaluated. causative association exists between phy- sician volume and outcomes in outpatient RESULTS — In multivariable analysis, absolute diabetes volume was linked to decreased odds treatment of a common disease with a of A1C testing (4% less for each additional patient seen; P ϭ 0.05), and relative diabetes volume high rate of complications, such as diabe- (fraction of the total patients seen who had diabetes) was associated with decreased odds of both tes, it could have extensive implications A1C (25% less for every 10% increase in the number of diabetic patients seen annually; P ϭ 0.03) for the health care system. In this paper, Ͻ and LDL testing (20% less for every 10% increase in the number of diabetic patients; P 0.001). we report the results of a study that as- Physician volume was not significantly associated with the odds of blood pressure, A1C, or LDL sessed whether the number of diabetic pa- control at the end of the study. tients cared for by an individual physician CONCLUSIONS — Higher physician volume in care of diabetic patients is associated with (diabetes volume) is an independent pre- decreased adherence to surveillance guidelines and no measurable difference in treatment dictor of quality of diabetes care. outcomes. RESEARCH DESIGN AND Diabetes Care 30:1442–1447, 2007 METHODS We conducted a retrospective cohort study of care of diabetic patients followed owering blood pressure, blood glu- ity of care of diabetic patients. Multiple by primary care physicians at Massachu- cose, and cholesterol levels decreases publications have shown that physicians setts General Hospital and Brigham and the rate of diabetes complications L with a higher number of patients with a Women’s Hospital between 1 January (1–3). Nevertheless, the majority of pa- particular condition or procedure have 2000 and 31 August 2005. Patients were tients with diabetes have blood pressure, better patient outcomes than low-volume included in our analysis if they were 18 A1C, and LDL cholesterol levels above physicians (8–11). Most of these reports years of age and older, had a documented those suggested by guidelines (4–7). analyze outcomes of surgical or other pro- diagnosis of diabetes, had at least two en- Diabetes care is complex and fre- cedures, and almost all focus on inpatient counters at least 1 year apart with a phy- quently involves coordinating multiple care (12). It is unknown whether these sician in a primary care specialty during medication, diet, and exercise regimens. findings can be generalized to the rela- the study period, and had at least one Individual physicians’ experience dealing tionship of outcomes with individual blood pressure, A1C, and LDL measure- with these complicated issues could be an physicians’ experience in treatment of a ment documented during the study pe- important factor contributing to the qual- riod. Documented diagnosis of diabetes ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● was ascertained using analysis of the text From the 1Division of Endocrinology, Brigham and Women’s Hospital, Boston, Massachusetts; 2Clinical of physician notes in the electronic med- Informatics Research and Development, Partners Healthcare System, Boston, Massachusetts; 3Harvard Med- ical record as previously described (16). 4 ical School, Boston, Massachusetts; and the Center for Clinical Investigation, Brigham and Women’s Hos- Patients treated by an endocrinologist pital, Boston, Massachusetts. Address correspondence and reprint requests to Alexander Turchin, MD, MS, Division of Endocrinology, were excluded. The institutional review Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115. E-mail: [email protected]. board at Partners HealthCare System ap- Received for publication 7 January 2007 and accepted 16 February 2007. proved the study. Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc07-0029. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Measures of physician experience A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion The primary measure of physician expe- factors for many substances. rience was the number of diabetic patients © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby treated annually by the physician (diabe- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tes volume). Secondary measures of phy-
1442 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Turchin, Shubina, and Pendergrass sician experience included the frequency spectively, in accordance with the guide- these outcomes were below goals at first of encounters with diabetic patients, the lines published before the beginning of measurement. All analyses were performed fraction of diabetic patients among all of the study period (18,19). with SAS statistical software, version 9.1. the physician’s patients, and the fraction RESULTS — We identified 21,912 pa- of encounters with diabetic patients Data sources Ն among all of the physician’s encounters. Demographic and health insurance infor- tients aged 18 years with a documented Diabetes volume was calculated as the mation, laboratory data, billing codes, diagnosis of diabetes who had at least one average number of patients with diabetes and the text of physician notes were ob- outpatient visit at either hospital during the physician had seen every year over the tained from the electronic medical record the study period and were not treated by course of the study. Frequency of encoun- system at Massachusetts General Hospital an endocrinologist. Among these, 7,120 ters with diabetic patients was calculated and Brigham and Women’s Hospital. patients had at least one note by a physi- as the average daily number of notes for Blood pressure values were extracted cian in a primary care specialty in the elec- patients with diabetes the physician au- from the text of physician notes in the tronic medical record, had at least two thored over the course of the study. Rela- electronic medical record as previously documented encounters at least 1 year tive diabetes volume was calculated as the described (20). Physician specialty and apart during the study period and at least ratio of the average annual number of pa- training status were obtained from the one documented blood pressure, A1C, tients with diabetes to the average annual Massachusetts Board of Registration in and LDL measurement, and were in- number of all patients seen by the physi- Medicine. cluded in the study. cian. Fraction of encounters with diabetic The mean age of the study patients patients was calculated as the ratio of the Statistical analysis was 63.7 years, 55.8% were women, and average daily number of notes for patients Summary statistics at both the patient and 58.5% were white (Table 1). The majority with diabetes to the average daily number the physician levels were constructed by (84.3%) of patients had either Medicare of all notes authored by the physician. using frequencies and proportions for cat- or a private health insurance. Median egorical data and by using means, SDs, length of primary care provider follow-up Outcome measures medians, and ranges for continuous vari- during the study period was 3.0 years, For each patient in the study, we com- ables. The univariate associations be- and 29% of patients had follow-up be- puted several process and intermediate tween physician diabetes volume and tween 1 and 2 years. outcome measures. Process measures process measures and outcomes of diabe- Diabetes care process measures and were based on the criteria used by the tes care were assessed by comparing these outcomes Health Employer Data and Information measures between physician volume On average A1C and LDL were measured Set (17) and included the fraction of cal- quartiles. Kruskal-Wallis was used for during 85 and 74% of patient-years, re- 2 endar years between the first and the last continuous variables and test for bi- spectively, while 63% of the patients had encounter with the patient’s primary care nary variables. A1C and 38% had LDL measured every physician when the patient had at least To account for clustering between pa- year. 31% of the study patients had both one A1C or LDL measurement. The pa- tients treated by the same physician and tests done at least once during every year tient’s primary care physician was identi- to adjust for other covariates, separate of the study. fied as the physician in a primary care multiple logistic regression models were The mean SBP and DBP levels of the specialty with whom the patient had the constructed for the probability of annual study patients were 130 and 75 mmHg, largest number of documented encoun- A1C and LDL measurements and the respectively. SBP was below the treatment ters over the study period. probability of the last blood pressure, goal for 38% of patients at their first study Intermediate outcomes included A1C, and LDL levels being below the visit and 51.5% at their last study visit, an A1C, LDL, systolic blood pressure (SBP), treatment goal. We fit the models using increase of 13.5%. Similarly, the fraction and diastolic blood pressure (DBP) levels. generalized estimating equations to cor- of patients with DBP below the treatment For every physician in the study, we de- rect for correlated observations (21). In goal increased from 76 to 87% between termined the change in the fraction of pa- addition to the measures of physician ex- their first and last study visits. tients for whom the corresponding perience, the covariates for the process The mean A1C of the study patients outcome was below the recommended measures models included patients’ age, was 7.6% and LDL 100 mg/dl. The frac- treatment goal over the course of the ethnicity, sex, primary language, and the tion of patients whose A1C and LDL were study. The change was calculated as the physician’s age and training level. Analy- below the treatment goals increased from difference between the fraction of patients sis was also adjusted for the documented 34 to 40% and from 35 to 56%, respec- whose last level of the corresponding out- diagnosis of coronary artery disease (as- tively, between their first and last study come variable measured on or before their certained using ICD-9 [International visits. At the last study visit, blood pres- last encounter with the physician was be- Classification of Diseases, Ninth Revision] sure, A1C, and LDL levels were all below low the recommended treatment goal and diagnostic codes in the billing data) (22) the treatment goals in 13% of the patients. the fraction of the same patients whose as a common comorbidity that signifi- first level of the outcome variable mea- cantly raises the risk of morbidity and Univariate analysis of physician sured on or after their first visit with the mortality in diabetic patients. The models experience and quality of diabetes physician was below the recommended for the proportions of patients with blood care treatment goal. This study used 129 and pressure, A1C, and LDL levels below the A total of 368 physicians who were iden- 84 mmHg, 7.0%, and 99 mg/dl as the rec- treatment goal at the last measurement also tified as primary care physicians of the ommended treatment goals of SBP and included testing frequency (A1C and LDL study patients were divided into quartiles DBP, A1C, and LDL cholesterol levels, re- only), length of follow-up, and whether based on the annual number of unique
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1443 Physician volume and diabetes care
Table 1—Patient characteristics diagnosis of coronary artery disease, physician training status, and age—the Variable Value association between patient volume and rates of annual testing remained signifi- n 7,120 cant for A1C but not LDL (Table 3). There Age (years)* 63.7 Ϯ 13.6 were no significant relationships between Women 3,971 (55.8) the annual number of diabetic patients Ethnicity seen by the physicians and the probability White 4,168 (58.5) that blood pressure, A1C, or LDL levels of Black 1,200 (16.9) their patients were below the recom- Hispanic 1,144 (16.1) mended level at the last study visit. Other (includes unknown) 608 (8.5) Other measures of physician experi- English is the primary language 5,862 (82.3) ence with care of diabetic patients showed CAD* 2,014 (28.3) similar results. For every extra daily en- Health insurance† counter with a diabetic patient, the odds Medicare 3,557 (50.0) that the physician’s patients would have Medicaid‡ 1,067 (15.0) A1C measured in a given year decreased Private 2,403 (34.3) by 25% (P ϭ 0.03) and the odds of an No insurance 93 (1.3) LDL cholesterol measurement decreased Ϯ Follow-up period (years) 3.1 1.4 by 20% (P Ͻ 0.001). The odds of the last Data are n (%) or means Ϯ SD unless otherwise indicated. *At least two billing codes representing coronary artery A1C measurement being less than 7.0% disease on record prior to the end of the study period. †At the end of the study period. ‡Includes FreeCare, a increased by 20% for every 1% rise in the program that provides fully or partially (depending on the income) subsidized health care in Massachusetts. fraction of the primary care physician’s encounters with diabetic patients among diabetic patients treated (Table 2). Physi- DBP was below goal. There was no signif- all of his/her patients (P ϭ 0.009). None cians in the higher volume quartiles had icant association of physician volume of the other associations between the slightly lower rates of annual A1C and quartile and the increase in the fraction of measures of relative experience with dia- LDL measurements and mean A1C levels. patients with A1C below goal. betic patients and outcomes of diabetes Physicians in the highest volume quartile care were statistically significant. had larger increases between the first and Multivariable analysis of physician Multivariable analysis of the probabil- last study encounters in the fraction of experience and quality of diabetes ity that the patient would have A1C mea- patients whose SBP and LDL levels were care sured in a given year (Fig. 1A) showed below the treatment goals but smaller in- In the analysis that adjusted for the pa- that the odds of testing rose by 10% (P Ͻ creases in the fraction of patients whose tients’ demographic characteristics— 0.001) for every decade increase in the
Table 2—Annual patient volume, process measures, and outcomes among physicians
Annual patient volume quartile Variable I II III IV P Physicians 96 89 90 93 Patients 223 475 1,486 4,936 Annual diabetes patients 3.67 (0.75–5.33) 7 (5.5–9.33) 16 (9.5–26.8) 43 (27.3–145.8) Residents 78 (81) 64 (72) 21 (23) 7 (8) Ͻ0.001 Annual process measures (%) A1C 87.6 87.8 87.3 83.2 Ͻ0.001 LDL 73.6 77.5 77.7 72.9 Ͻ0.001 Outcomes* SBP (mmHg) 128.0 Ϯ 13.7 130.7 Ϯ 14.0 130.0 Ϯ 12.9 130.3 Ϯ 12.2 0.014 DBP (mmHg) 73.8 Ϯ 7.5 74.1 Ϯ 8.6 73.9 Ϯ 7.8 75.3 Ϯ 7.5 Ͻ0.001 A1C (%) 7.8 Ϯ 1.6 7.8 Ϯ 1.5 7.6 Ϯ 1.4 7.6 Ϯ 1.4 Ͻ0.001 LDL (mg/dl) 94.7 Ϯ 29.2 96.0 Ϯ 29.6 98.1 Ϯ 29.7 101.0 Ϯ 28.8 Ͻ0.001 Increase in fraction of patients 8.1 3.0 10.9 15.8 0.001 with SBP under control (%) Increase in fraction of patients 15.9 8.4 7.1 10.8 0.025 with DBP under control (%) Increase in fraction of patients 5.7 3.7 5.4 5.6 0.38 with A1C under control (%) Increase in fraction of patients 11.5 17.8 14.8 20.6 Ͻ0.001 with LDL under control (%) Data are n, median (range), n (%), or mean Ϯ SD unless otherwise indicated. *Mean levels over the study period.
1444 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Turchin, Shubina, and Pendergrass
Table 3—Relationship of different measures of provider experience with process measures and outcomes
Diabetic patients* Encounters† Fraction of diabetic patients‡ Fraction of encounters§ OR P OR P OR P OR P Testing — — — — A1C 0.96 (0.93–1.0) 0.05 0.75 (0.58–0.97) 0.03 NS NS LDL NS 0.80 (0.70–0.91) Ͻ0.001 0.59 (0.39–0.88) 0.01 NS Control NS 0.87 (0.75–1.01) 0.06 NS NS SBP NS NS NS NS DBP NS NS NS NS A1C NS NS NS 1.19 (1.05–1.36) 0.009 LDL NS NS NS Data are ORs (95% CIs) unless otherwise indicated. * Per 10 patients with diabetes treated annually. †Per 1 daily encounter with a diabetic patient. ‡Per 1% of patients with diabetes among all patients seen annually. §Per 1% of encounters with diabetic patients among all patient encounters. NS, not significant. patient’s age. White patients had 22% age and training level, and frequency of residents, and it is possible that the resi- lower odds of annual A1C testing (P Ͻ A1C measurements did not reach statisti- dents’ patient populations are distinct 0.001), patients on Medicaid had 21% cal significance. from those of attending physicians. higher odds of testing than patients with Frequency of A1C measurements in- private health insurance (P ϭ 0.006), and CONCLUSIONS — In this large ob- creased significantly when patients were the diagnosis of coronary artery disease servational study, the analysis adjusted at higher risk of cardiovascular events: increased the odds of testing by 45% (P Ͻ for patient and physician characteristics older age, nonwhite race, and diagnosis of 0.001). did not demonstrate a consistent relation- coronary artery disease. It is therefore Multivariable analysis of the odds that ship with diabetes care outcomes for any possible that physicians take these risk the patient’s last A1C level during the of the measures of physician experience. factors into account when deciding on study period was below 7.0% (Fig. 1B) The most commonly used measure of how aggressively to treat their patients showed that patients whose first A1C physician experience, annual number of with diabetes. On the other hand, in- level was below 7.0% were 5.5 times as unique patients with diabetes, had a neg- creased intensity of monitoring did not likely to also have the last A1C level below ative association with process measures of appear to translate into improved out- 7.0% (P Ͻ 0.001). The odds of the last quality of diabetes care, such as annual comes: there was no association between A1C below 7.0% rose by 6.8% for every A1C and LDL measurements. the rate of A1C measurement and the decade of the patient’s age (P ϭ 0.008), by The discrepancies between the results odds of A1C levels reaching below the 6.6% for every year of follow-up (P ϭ of univariate and adjusted analyses could treatment goals. The main predictor of 0.01), and by 22% for patients whose pri- be explained by the differences both in whether a patient’s A1C level was below mary language was English (P ϭ 0.04). patient and physician populations (23). 7.0% at the end of the study was A1C level The relationships between the odds of the Average blood pressure and LDL levels in the beginning of the study. Clearly, de- last A1C measurement below 7.0% and were lower and A1C was higher in the spite a large number of new medications patient sex, ethnicity, insurance, diagno- lower quartiles. Most physicians in the and treatment regimens developed to sis of coronary artery disease, physician two lowest patient volume quartiles were treat diabetes over the last decade, the
Figure 1—Relationship of provider and patient factors and A1C measurements. Effect on frequency of A1C measurements (A) and effect on probability of last A1C measurement being Ͻ7.0% (B). F represent the estimates and whiskers the 95% CIs for odds ratios (ORs). A1C testing, ORs for the patient having A1C testing every single year vs. never; CAD, coronary artery disease; DM pts per year, effect of a 10-patient increase in the number of unique diabetic patients seen annually; Ethnicity, ORs for white vs. nonwhite; Insurance, estimate of the effect of Medicaid vs. private insurance; Language, ORs for English recorded as the primary language vs. any other primary language; Patient age and Provider age, ORs for every 10 years ’ increase in age; Physician training, estimate of the effect of the primary care physician being an attending vs. a resident.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1445 Physician volume and diabetes care natural history of diabetes remains diffi- In conclusion, the volume of diabetic W, Houck PM, Bratzler DW: Volume, cult to alter. patients cared for by individual physi- quality of care, and outcome in pneumo- This study provides evidence that the cians did not significantly affect A1C, nia. Ann Intern Med 144:262–269, 2006 effectiveness in diabetes care is not blood pressure, or LDL and was nega- 10. Kitahata MM, Koepsell TD, Deyo RA, achieved by the means of simple repeti- tively associated with the surveillance of Maxwell CL, Dodge WT, Wagner EH: Physicians’ experience with the acquired tion. Some of the other studies of the ef- these indicators. Other factors, such as immunodeficiency syndrome as a factor fect of physician volume on treatment of the severity of the preexisting disease, ap- in patients’ survival. N Engl J Med 334: common medical conditions and medical pear to be more powerful determinants of 701–706, 1996 treatment corroborate this finding (9), diabetes outcomes. 11. Ward MM: Association between physi- while many investigations of the effect of cian volume and in-hospital mortality in physician volume on less common dis- patients with systemic lupus erythemato- eases do not (10,11). One possible expla- Acknowledgments— This study was sup- sus. Arthritis Rheum 52:1646–1654, 2005 nation is that at some point the effect of ported in part by grants from the Diabetes 12. Halm EA, Lee C, Chassin MR: Is volume experience on outcomes reaches a pla- Trust Foundation and the Diabetes Action Re- related to outcome in health care? A sys- search and Education Foundation (to A.T.). teau: Studies where the lowest annual tematic review and methodologic critique of the literature. Ann Intern Med 137:511– number of patients was less than one 520, 2002 show correlation between physician vol- References 13. Boyle JP, Honeycutt AA, Narayan KM, ume and outcomes, while studies where 1. The effect of intensive treatment of diabe- Hoerger TJ, Geiss LS, Chen H, Thompson the lowest annual number of patients is tes on the development and progression TJ: Projection of diabetes burden through greater than three do not. It appears there- of long-term complications in insulin-de- 2050: impact of changing demography fore that physician volume is an imperfect pendent diabetes mellitus: the Diabetes and disease prevalence in the U.S. Diabe- predictor of outcomes and should be used Control and Complications Trial Research tes Care 24:1936–1940, 2001 with caution in referral policies (24). Group. N Engl J Med 329:977–986, 1993 14. Rizza RA, Vigersky RA, Rodbard HW, Our study has multiple strengths. 2. Tight blood pressure control and risk of Ladenson PW, Young WF Jr, Surks MI, First, it included several thousand ethni- macrovascular and microvascular com- Kahn R, Hogan PF: A model to determine cally diverse patients from two large hos- plications in type 2 diabetes: UKPDS 38: workforce needs for endocrinologists in the United States until 2020. Endocr Pract pitals that serve patients from all UK Prospective Diabetes Study Group. Bmj 317:703–713, 1998 9:210–219, 2003 socioeconomic strata. Second, the study 3. Colhoun HM, Betteridge DJ, Durrington 15. Kahn JM, Goss CH, Heagerty PJ, Kramer analyzed the association of physician vol- PN, Hitman GA, Neil HA, Livingstone SJ, AA, O’Brien CR, Rubenfeld GD: Hospital ume with both process measures and in- Thomason MJ, Mackness MI, Charlton- volume and the outcomes of mechani- termediate outcomes of diabetes care to Menys V, Fuller JH: Primary prevention of cal ventilation. N Engl J Med 355:41–50, investigate potential mechanisms mediat- cardiovascular disease with atorvastatin 2006 ing the effects of physician volume on in type 2 diabetes in the Collaborative 16. Turchin A, Kohane IS, Pendergrass ML: quality of care in diabetes. Third, while Atorvastatin Diabetes Study (CARDS): Identification of patients with diabetes the majority of the published investiga- multicentre randomised placebo- from the text of physician notes in the tions of the relationship between physi- controlled trial. Lancet 364:685–696, electronic medical record. Diabetes Care 28:1794–1795, 2005 cian volume and outcomes focus on 2004 4. Resnick HE, Foster GL, Bardsley J, Ratner 17. Espinet LM, Osmick MJ, Ahmed T, Villa- inpatient care, our study examined the RE: Achievement of American Diabetes gra VG: A cohort study of the impact of a quality of outpatient treatment of diabe- Association clinical practice recommen- national disease management program on tes, where most of the care for this disease dations among U.S. adults with diabetes, HEDIS diabetes outcomes. Dis Manag takes place. Finally, in our evaluation we 1999–2002: the National Health and Nu- 8:86–92, 2005 used several different measures of physi- trition Examination Survey. Diabetes Care 18. American Diabetes Association: Stan- cian experience with diabetes care, all of 29:531–537, 2006 dards of medical care for patients with which supported our conclusions. 5. Grant RW, Buse JB, Meigs JB: Quality of diabetes mellitus (Position Statement). The study has several limitations. It diabetes care in U.S. academic medical Diabetes Care 23 (Suppl. 1):S32–42, 2000 was restricted in scope to the patients of centers: low rates of medical regimen 19. The sixth report of the Joint National Committee on prevention, detection, physicians affiliated with academic hospi- change. Diabetes Care 28:337–442, 2005 6. Saydah SH, Geiss LS, Tierney E, Benjamin evaluation, and treatment of high blood tals practicing in eastern Massachusetts. SM, Engelgau M, Brancati F: Review of the pressure. Arch Intern Med 157:2413– This could limit its generalizability to performance of methods to identify dia- 2446, 1997 other patient and physician populations. betes cases among vital statistics, admin- 20. Turchin A, Kolatkar NS, Grant RW, Ma- Second, this was a retrospective study istrative, and survey data. Ann Epidemiol khni EC, Pendergrass ML, Einbinder JS: that relied on documentation of relevant 14:507–516, 2004 Using regular expressions to abstract findings in the electronic medical record. 7. Saaddine JB, Engelgau MM, Beckles GL, blood pressure and treatment intensifica- If the accuracy and availability of this doc- Gregg EW, Thompson TJ, Narayan KM: A tion information from the text of physi- umentation varied with physician experi- diabetes report card for the United States: cian notes. J Am Med Inform Assoc 13:691– ence, the study findings could be biased. quality of care in the 1990s. Ann Intern 695, 2006 Finally, the study could not account for Med 136:565–574, 2002 21. Zeger SL, Liang KY: Longitudinal data 8. Birkmeyer JD, Stukel TA, Siewers AE, analysis for discrete and continuous out- some factors with the potential to signifi- Goodney PP, Wennberg DE, Lucas FL: comes. 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quality improvement? The case of diabe- vided by different groups of physicians: 24. Epstein AJ, Rathore SS, Krumholz HM, tes, heart disease, and depression. Am J effects of patient case-mix (bias) and phy- Volpp KG: Volume-based referral for car- Med Qual 21:238–245, 2006 sician-level clustering on quality assess- diovascular procedures in the United 23. Greenfield S, Kaplan SH, Kahn R, Ni- ment results. Ann Intern Med 136:111– States: a cross-sectional regression analy- nomiya J, Griffith JL: Profiling care pro- 121, 2002 sis. BMC Health Serv Res 5:42, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1447 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
How Doctors Choose Medications to Treat Type 2 Diabetes A national survey of specialists and academic generalists
1,2 2 RICHARD W. GRANT, MD, MPH ENRICO CAGLIERO, MD cide which medicines to prescribe (8), 2 5 DEBORAH J. WEXLER, MD ERIC G. CAMPBELL, PHD and no studies, to our knowledge, have 3 2 ALICE J. WATSON, MD DAVID M. NATHAN, MD 4 focused on glycemia-lowering medicines. WILLIAM T. LESTER, MD In contrast to hyperlipidemia treat- ment (9) and, to a lesser extent, hyperten- sion management (10), until recently OBJECTIVE — Glycemic control remains suboptimal despite the wide range of available there have been no widely accepted treat- medications. More effective medication prescription might result in better control. However, the ment guidelines for hyperglycemia that process by which physicians choose glucose-lowering medicines is poorly understood. We sought to study the means by which physicians choose medications for type 2 diabetic patients. specifically recommend which medicines to prescribe and in what sequence. A re- RESEARCH DESIGN AND METHODS — We surveyed 886 physician members of cent American Diabetes Association either the Society of General Internal Medicine (academic generalists, response rate 30%) or the (ADA) and European Association for the American Diabetes Association (specialists, response rate 23%) currently managing patients with Study of Diabetes consensus statement type 2 diabetes. Respondents weighed the importance of 15 patient, physician, and nonclinical (11), developed in part to address subop- factors when deciding which medications to prescribe for type 2 diabetic subjects at each of three timal glycemic control, emphasizes three management stages (initiation, use of second-line oral agents, and insulin). common, inexpensive medications (met- RESULTS — Respondents reported using a median of five major considerations (interquartile formin, sulfonylureas, and insulin) and range 4–6) at each stage. Frequently cited major considerations included overall assessment of advocates a simple algorithm with the patient’s health/comorbidity, A1C level, and patient’s adherence behavior but not expert branch-point decisions based on A1C guidelines/hospital algorithms or patient age. For insulin initiation, academic generalists placed level, cost, and effectiveness of medica- greater emphasis on patient adherence (76 vs. 60% of specialists, P Ͻ 0.001). These generalists tions in lowering glycemia. Although data also identified patient fear of injections (68%) and patient desire to prolong noninsulin therapy are lacking to determine whether dissem- (68%) as major insulin barriers. Overall, qualitative factors (e.g., adherence, motivation, overall health assessment) were somewhat more highly considered than quantitative factors (e.g., A1C, ination of this new algorithm will change age, weight) with mean aggregate scores of 7.3 vs. 6.9 on a scale of 0–10, P Ͻ 0.001. practice patterns or improve glycemic control, prior research suggests that many CONCLUSIONS — The physicians in our survey considered a wide range of qualitative and physicians do not conform to standard quantitative factors when making medication choices for hyperglycemia management. The ap- practice or expert recommendations parent complexity of the medication choice process contrasts with current evidence-based treat- (12,13). ment guidelines. Population-based studies have re- Diabetes Care 30:1448–1453, 2007 peatedly demonstrated that current glyce- mic management continues to fall short of evidence-based A1C goals (14,15). To the here are over 30 unique medicines Given the wide array of options, it is not extent that variation from best practice re- from 9 different drug classes cur- surprising that physicians demonstrate sults in less effective glucose control, un- rently approved for the treatment of wide variation in the choice and sequence T derstanding practice variation in choice of hyperglycemia in type 2 diabetic patients, of medications prescribed for diabetes glycemic medicines may inform more ef- with dozens more medicines and several management (5–7). Few studies, how- new drug classes in development (1–4). ever, have evaluated how physicians de- fective interventions to improve type 2 di- abetes management. We hypothesized ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● that prescription choices may be driven From the 1General Medicine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Mas- by patient factors (e.g., weight, motiva- sachusetts; the 2Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massa- tion to improve), physician-specific vari- chusetts; the 3Partners Telemedicine Program, Massachusetts General Hospital, Harvard Medical School, 4 ables (e.g., usual practice patterns), Boston, Massachusetts; the Laboratory of Computer Science, Massachusetts General Hospital, Harvard and/or nonclinical issues (e.g., patient Medical School, Boston, Massachusetts; and the 5Institute for Health Policy, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. out-of-pocket expenses). To address Address correspondence and reprint requests to Richard W. Grant, MD, MPH, 50-9 Staniford St., Boston, these hypotheses, we conducted a survey MA 02114. E-mail: [email protected]. to elicit physicians’ considerations when Received for publication 8 December 2006 and accepted in revised form 20 February 2007. Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-2499. making prescription choices at various Abbreviations: ADA, American Diabetes Association; SGIM, Society of General Internal Medicine. stages of glycemic management. Because A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion evidence-based guidelines typically rely factors for many substances. on objectively measurable criteria such as © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby A1C level and weight, we also sought to marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. compare the relative importance respon-
1448 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Grant and Associates dents gave to qualitative versus quantita- zations were chosen as representative tors (e.g., subjective patient data and phy- tive criteria. professional societies for academic gener- sician factors). Scores were compared alists (SGIM) and for physicians with par- using Student’s t tests, stratified by spe- RESEARCH DESIGN AND ticular clinical interest in diabetes care cialty status. We repeated this analysis us- METHODS (ADA). Eligibility criteria for study partic- ing an alternative weighting approach ipation included status as a U.S. or Cana- (“major consideration” ϭϩ1, “minor Survey development dian physician, valid e-mail address consideration” and “not a consideration” We designed our survey to address three voluntarily listed in the published mem- ϭ 0) and obtained qualitatively similar key steps in the medication prescription bership directory, and that the physician results (data not shown). SAS (Version pathway for type 2 diabetic patients: 1) be currently managing patients with dia- 9.1; SAS Institute, Cary, NC) was used for choice of first agent; 2) use of thiazol- betes. Additional criteria for ADA mem- all analyses. This study was approved by idinediones (glitazones), which are often bers included a self-designated clinical the Massachusetts General Hospital Insti- considered second-line agents; and 3) ini- emphasis (vs. administration or re- tutional Review Board. tiation of insulin. search). The 12 eligible physicians with We convened four focus groups that membership in both societies were in- RESULTS included primary care physicians and dia- cluded with the ADA cohort under the betologists to generate a list of potential assumption that ADA membership con- Survey respondents factors considered by physicians when noted a special interest in diabetes care. Of the 886 eligible survey respondents, making glycemic medication choices. Endocrinologists comprised 54% of the 97% were staff physicians, and 3% were Based on feedback from these groups and ADA respondents. Compared with ADA fellows or residents. ADA respondents data available from the literature (16–18), physicians who were not endocrinolo- were in practice longer compared with we grouped our variables of interest into gists, a similar proportion of ADA endo- SGIM respondents (22 vs. 15 years since the following four mutually exclusive cat- crinologists worked in a community medical school graduation, respectively, egories: 1) objective patient clinical data, practice setting; the endocrinologists had P Ͻ 0.01) and were more likely to work in including patient’s age, weight, last- similar years of training and a higher ca- private practice (38 vs. 2%, P Ͻ 0.01) measured A1C, and for the questions seload of diabetic patients. than in an academic center (40 vs. 78%, about insulin, pattern of self-measured All physicians meeting eligibility cri- P Ͻ 0.01). Over two-thirds of ADA mem- glucose levels; 2) subjective patient fac- teria received an initial e-mail briefly de- bers (67%) reported treating Ͼ100 pa- tors, including adherence behavior, spe- scribing the study, enrollment in a $40.00 tients with type 2 diabetes in the prior cific medication requests, patient’s desire gift card lottery after survey completion, year compared with 41% of SGIM respon- to delay or avoid insulin injection, and for and a link to the web-based survey site. In dents (P Ͻ 0.01). Overall, 92% of physi- the questions about insulin, patient’s mo- the next 1–2 weeks, a reminder e-mail cians treated Ͼ20 patients with type 2 tivation to improve; 3) medication costs; was sent. Overall, 886 surveys were re- diabetes in the preceding year. and 4) physician factors, including physi- turned within 4 weeks of distribution, in- cian’s usual or prior practice, expert cluding 450 responses from SGIM Choice of first glycemic medicine guidelines or hospital algorithms, and members (30% response rate) and 436 Table 1 presents the list of variables con- physician’s assessment of patient’s health responses from ADA members (23% re- sidered when choosing which medicine status and comorbid conditions. For gli- sponse rate). to prescribe first for glycemic control in tazones, we asked about physicians’ de- type 2 diabetic patients, ranked by pro- sire to improve patient’s lipid profile Statistical analysis portion of respondents designating each and/or to reduce insulin resistance and For each stage of management, the pro- variable as a “major consideration”. Re- their desire to delay or avoid need for in- portion of respondents indicating that an spondents indicated a median of five ma- sulin. For insulin, we also asked about the item was a “major consideration” was tab- jor considerations (interquartile range influence of the doctor-patient therapeu- ulated and the proportions ranked. Gen- 4–6) when choosing which medicine to tic relationship. eralist and specialist responses were prescribe first. The three most frequently For each section of the survey, re- compared using 2 tests. In an explor- cited major considerations were: “assess- spondents were asked to indicate to what atory analysis, we also grouped the indi- ment of the patient’s health status and extent each factor was a “major consider- vidual survey items into two categories co-morbid conditions” (89% of respon- ation,” “minor consideration,” or “not a (quantitative vs. qualitative) and calcu- dents), “extent of HbA1c elevation” consideration” when making a medica- lated an aggregate score for each category (74%), and “patient’s weight” (66%). Al- tion prescription decision. Each question using the following method: For each though specialists and generalists differed also clearly asked respondents to exclude item, a response of “major consideration” significantly in the absolute percentage of any medical contraindications from con- was assigned ϩ2, “minor consideration” respondents ranking each factor as a ma- sideration. Respondents were given the was assigned ϩ1, and “not a consider- jor consideration, the rank order of fac- opportunity to list additional criteria not ation” was assigned 0. Scores were then tors was similar except for a greater included in the survey. summed, divided by the total number of relative emphasis by generalists on pa- items in the category, and converted to a tients’ adherence behavior, out-of-pocket Survey sample and administration 10-point scale. This average aggregate costs, and published guidelines. The Society of General Internal Medicine score was used to compare the relative In addition to the list of survey items, (SGIM) and ADA members were invited weight given to quantitative factors (e.g., 314 respondents (35%) wrote in addi- via e-mail in April 2006 to participate in clinically measured patient variables and tional considerations. These respondent the web-based survey. These two organi- medication costs) versus qualitative fac- comments could be grouped into the fol-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1449 Choosing medications to treat type 2 diabetes
Table 1—Major considerations when choosing initial hypoglycemic medical therapy We also asked survey respondents to indicate whether specific factors were a Specialist Academic generalist “major barrier,” “minor barrier,” or “not a Major considerations (n ϭ 379) (n ϭ 440) P barrier” to insulin initiation. The majority of generalists listed patients’ fear or resis- Assessment of patient’s health 93 (1) 85 (1) Ͻ0.001 tance to insulin injections (68%) and pa- and comorbid conditions tients’ preference to give lifestyle Extent of A1C elevation 86 (2) 64 (2) Ͻ0.001 modification and oral medicines more Patient’s weight 70 (3) 63 (3) 0.06 time to succeed (68%) as major barriers to Physician’s usual practice 68 (4) 54 (5) Ͻ0.001 insulin initiation. In contrast, few special- Patient’s adherence behavior 59 (5) 57 (4) 0.7 ists indicated any major barriers to insulin Patient’s out-of-pocket costs 49 (6) 52 (6) Ͻ0.001 initiation. The majority of respondents Expert guideline/hospital 37 (8) 47 (7) 0.01 also indicated that their own level of ex- algorithm perience prescribing insulin (86% spe- Patient’s age 38 (7) 22 (9) Ͻ0.001 cialists, 65% generalists) and concerns Patient’s request 16 (10) 26 (8) Ͻ0.001 about extra time required to address in- Patient’s tendency to complain 22 (9) 18 (10) 0.003 sulin dose adjustment (63% specialists, about side effects 53% generalists) were not barriers to in- Data are percentage (rank) of specialists vs. academic generalists listing each major consideration. Consid- sulin prescription. erations are listed in order of overall combined rank. Aggregate measures of quantitative versus qualitative factors lowing four broad categories: 1) unique Insulin use and barriers The aggregate mean scores of quantitative patient factors (e.g., alcoholism, history of Extent of A1C elevation, patient- items (extent of A1C elevation, age, injection drug use, long-distance truck measured blood glucose profiles, and weight, medication costs, pattern of mea- driving, dementia, eating habits, etc.), 2) concurrent health status/comorbid con- sured glucose levels) were compared with external forces (hospital formulary re- ditions were the three most frequently se- aggregate mean scores for qualitative strictions and availability of free samples), lected major considerations by both items (adherence, assessment of health 3) evidence-based approach (results from specialists and generalists when deciding status and comorbid conditions, usual clinical trials and efficacy of A1C lower- to initiate insulin therapy (Table 3). Over- practice, patient requests, tendency to ing), and 4) physiologic approach (esti- all, each respondent listed a median of complain about side effects, patient and mate of insulin resistance, drug five major considerations (4–7). As with physician attitudes toward insulin, pa- mechanisms, and pattern of recent glu- their prescribing attitudes regarding the tient motivation, and strength of thera- cose values). glitazones, specialists were less concerned peutic relationship). In this exploratory than generalists with existing guidelines, analysis, the qualitative criteria were with 26 vs. 15%, respectively, reporting given greater overall consideration than Use of glitazones that guidelines/algorithms were “not a the quantitative criteria (7.3 vs. 6.8, re- Ͻ Ͻ Specialists were more likely to prescribe consideration”, P 0.001 (Table 4). spectively, on a scale of 0–10, P 0.001). glitazones than were generalists (54 vs. 16%, respectively, prescribed glitazones frequently, P Ͻ 0.001). Among glitazone Table 2—Major considerations when choosing to prescribe a glitazone prescribers, respondents listed a median of five major considerations (4–6). Spe- Specialist Academic generalist cialists listed their assessment of the pa- Major considerations (n ϭ 369) (n ϭ 403) P tient’s health status and comorbid Assessment of patient’s health and 88 (1) 68 (2) Ͻ0.001 conditions, the extent of A1C elevation, comorbid conditions and motivation to improve lipid profiles/ Patient’s desire to avoid insulin 47 (7) 76 (1) Ͻ0.001 reduce insulin resistance as their three Extent of A1c elevation 65 (2) 60 (3) 0.26 leading considerations. In contrast, gen- Physician’s desire to improve lipid 63 (3) 39 (6) Ͻ0.001 eralists prescribed glitazones primarily to profile/reduce insulin resistance avoid insulin (Table 2). Generalists also Patient’s out-of-pocket costs 50 (6) 50 (5) 1.0 considered patient’s health status and co- Physician’s desire to avoid/delay 36 (8) 56 (4) Ͻ0.001 morbid conditions, the extent of A1C el- insulin evation, and out-of pocket expenses, but Physician’s usual practice 57 (4) 32 (8) Ͻ0.001 not lipid profile/insulin resistance, when Patient’s weight 53 (5) 25 (9) Ͻ0.001 considering this drug class. Twenty-five Expert guideline/hospital 24 (9) 36 (7) Ͻ0.001 percent of specialists reported that exist- algorithm ing guidelines or local hospital algorithms Patient request 13 (11) 15 (10) 0.03 were “not a consideration” when consid- Patient age 14 (10) 13 (11) 0.47 ering glitazones compared with 18% of Data are percentage (rank) of specialists vs. academic generalists listing each major consideration. Consid- generalists (P ϭ 0.01, Table 4). erations are listed in order of overall combined rank.
1450 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Grant and Associates
Table 3—Major considerations when choosing to initiate insulin therapy published algorithm that begins with metformin (when not contraindicated), Specialist Academic generalist followed by one of three choices (sulfo- Major considerations (n ϭ 370) (n ϭ 434) P nylureas, insulin, or glitazones) depend- ing on subsequent A1C levels, side effects, Extent of A1C elevation 93 (1) 92 (1) 0.82 and medication cost (11). Our findings Pattern of measured glucose levels 83 (2) 74 (4) 0.012 suggest that efforts to effectively imple- Assessment of patient’s health and 81 (3) 75 (3) 0.06 ment parsimonious guidelines may be comorbid conditions hindered by the current complexity of de- Patient’s motivation to improve 67 (4) 71 (5) 0.06 cision making reported by physicians. Patient’s adherence behavior 60 (5) 76 (2) Ͻ0.001 The relative importance of different Strength of therapeutic relationship 46 (6) 38 (6) Ͻ0.001 factors varied at each management stage. with patient When choosing to initiate drug therapy, Expert guideline/hospital algorithm 26 (7) 37 (7) Ͻ0.001 survey respondents often considered pa- Patient’s weight 20 (9) 24 (8) Ͻ0.001 tient weight and adherence behavior, two Patient age 20 (9) 20 (9) 0.92 factors particularly relevant to metformin Patient’s out-of-pocket costs 22 (8) 24 (8) 0.65 prescription. The prescription attitudes Data are percentage (rank) of specialists vs. academic generalists listing each major consideration. Consid- regarding glitazones differed markedly by erations are listed in order of overall combined rank. specialty status, both in frequency and ra- tionale. Specialists were much more likely Qualitative criteria were given an aggre- and the patient’s A1 level, adherence, and to consider prescribing these agents and, gate weight of 7.2 by academic generalists motivation to improve and/or avoid insu- in doing so, often considered intermedi- vs. 7.3 by specialists (P ϭ 0.09) and quan- lin. Many physicians also reported that ate physiologic end points (e.g., insulin titative criteria 6.6 vs. 7.1 by academic their choices were constrained by medi- sensitivity, lipid profile) not necessarily generalists and specialists, respectively, cation costs and/or formulary restrictions supported by large clinical trials of diabe- P Ͻ 0.001. but not by expert guidelines or hospital tes-related complications. In contrast, ac- algorithms. ademic generalists appeared to view CONCLUSIONS — This survey of What are the implications of our sur- glitazones as a means of delaying or avoid- over 850 practicing physicians examined vey for diabetes management? Although ing insulin. which factors were considered when there are many contributors to the ob- Although we did not specifically ask making medication choices at three dis- served difficulty in achieving national about frequency of insulin prescription, tinct stages of glycemic management. In goals of glycemic control, effective medi- other studies have consistently reported one of the largest and most detailed sur- cation prescription remains a central task greater insulin use by diabetes specialists, veys of physician decision making of its for physicians. Our survey respondents a reflection in part of their management of kind, we found that survey respondents considered a median of five qualitative patients with more severe disease (19,20). reported considering a range of issues and quantitative factors when choosing Prior studies have shown that patients when choosing drug treatment options, which medications to prescribe. The ap- cared for by specialists tend to have longer such as overall assessment of their pa- parent complexity of their medication de- duration of diabetes, more diabetes- tients’ health and comorbid conditions cision-making contrasts with a recently related comorbidity, more complex med- ical regimens, and higher levels of motivation (21–24). Regarding barriers to Table 4—Factors most frequently listed as “not a consideration” at each management stage insulin use, academic generalists high- lighted patient-derived barriers (patients’ Academic fears/resistance to insulin and patients’ Specialist generalist P preference to extend noninsulin therapy) while specialists indicated no major bar- When choosing initial hypoglycemic agent — riers to insulin treatment. This stark con- n 379 440 — trast in perceived patient preferences may Patient tendency to complain about side effects 16 25 0.001 reflect either very different patient popu- Patient’s specific medication request 15 16 0.59 lations treated or reluctance by generalists Expert guideline/hospital algorithm 17 14 0.23 to pursue aggressive insulin strategies in When choosing to prescribe a glitazone — patients with type 2 diabetes (25). Our n 369 403 — findings underscore the importance of Patient’s age 23 27 0.22 lowering barriers to starting insulin by de- Patient’s specific medication request 20 27 0.23 veloping means to support insulin initia- Expert guideline/hospital algorithm 25 18 0.01 tion and titration in the primary care When deciding to initiate insulin — setting. n 370 434 — Implementing guidelines, particu- Patient’s out-of-pocket expenses 25 26 0.81 larly static flow sheets, has had minimal Expert guideline/hospital algorithm 26 15 Ͻ0.001 impact for many clinical conditions (26– Patient’s age 18 17 0.7 28). In systems with electronic medical Data are percentages. records, sophisticated decision support
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1451 Choosing medications to treat type 2 diabetes driven by evidence-based treatment algo- versus patient physiology–based ap- population. Diabetes Care 24:1411–1415, rithms can be used to guide appropriate proaches to making management deci- 2001 prescription. In one recent example in- sions. Future studies investigating the 8. Segal R, Hepler CD: Drug choice as a volving hyperlipidemia management, process of medication initiation and ad- problem-solving process. Med Care 23: physicians choosing to initiate or increase justment should include this dichotomy. 967–976, 1985 9. National Cholesterol Education Program dose of statin therapy for their patients In summary, our results suggest that (NCEP) Expert Panel on Detection, Eval- with elevated LDL levels were presented in the face of limited evidence-based data uation, and Treatment of High Blood with a list of statins ranked by calculated to guide specific medication prescription Cholesterol in Adults (Adult Treatment LDL-lowering effect and relative out-of- choices (30), the physicians in our survey Panel III): Third report of the National pocket expense based on patient copays relied on a wide range of both clinically Cholesterol Education Program (NCEP) (29). This advanced decision support in- objective and patient-focused factors Expert Panel on Detection, Evaluation, tervention was effective in increasing sta- when managing hyperglycemia. Respon- and Treatment of High Blood Cholesterol tin prescription and LDL control in study dents reported integrating overall clinical in Adults (Adult Treatment Panel III) final patients. Many would argue that hyper- assessments with perceptions of patients’ report. Circulation 106:3143–3421, 2002 glycemia treatment is more complex than adherence, motivation, and concerns 10. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones statin adjustment. Given the emphasis about treatments—a more complicated DW, Materson BJ, Oparil S, Wright JT Jr, our respondents placed on difficult-to- view of medication prescribing than that Roccella EJ, the National Heart, Lung, and measure factors such as overall health, ad- recommended by recent guideline algo- Blood Institute Joint National Committee herence, and motivation, implementing rithms. Achieving more uniform and on Prevention, Detection, Evaluation, and advanced decision support for glycemia cost-effective hyperglycemic medication Treatment of High Blood Pressure; Na- management may present a difficult management may require both better ev- tional High Blood Pressure Education challenge. idence in favor of specific treatment strat- Program Coordinating Committee: The These data must be interpreted in the egies and further insight into why seventh report of the Joint National Com- context of the study design. Our relatively physicians make individual exceptions mittee on Prevention, Detection, Evalua- low response rate, while not unusual for from standard care. tion, and Treatment of High Blood e-mail–based surveys, falls short of ideal Pressure: the JNC 7 report. JAMA 289: 2560–2572, 2003 rates for survey research. More intensive 11. Nathan DM, Buse JB, Davidson MB, Heine subject recruitment may have led to Acknowledgments— This study was funded RJ, Holman RR, Sherwin R, Zinman B: higher response rates and possibly some in part by a Partners HealthCare System IS Management of hyperglycemia in type 2 qualitative differences in our results. Research Council award. R.W. Grant is sup- diabetes: a consensus algorithm for the Moreover, the academic generalists in our ported by a National Institute of Diabetes and initiation and adjustment of therapy: a survey are likely not representative of Digestive and Kidney Diseases Career Devel- consensus statement from the American opment Award (K23 DK067452), and D.M.N. Diabetes Association and the European community-based primary care physi- is supported by the Charlton Family Fund. cians who may have very different prac- Association for the Study of Diabetes. Di- tice styles and patient populations. Our abetes Care 29:1963–1972, 2006 findings may therefore not be generaliz- 12. El-Kebbi IM, Ziemer DC, Gallina DL, Dunbar V, Phillips LS: Diabetes in urban able to other health care systems or prac- References 1. Lebovitz HE: Therapeutic options in de- African-Americans. XV. Identification of tice environments. velopment for management of diabetes: barriers to provider adherence to manage- Given the paucity of evidence regard- pharmacologic agents and new technolo- ment protocols. Diabetes Care 22:1617– ing how glycemia-lowering medicines are gies. Endocr Pract 12:142–147, 2006 1620, 1999 prescribed in clinical practice, our survey 2. Bloomgarden ZT: Gut-derived incretin 13. Pugh MJ, Anderson J, Pogach LM, Ber- of a select subgroup of practicing U.S. and hormones and new therapeutic ap- lowitz DR: Differential adoption of phar- Canadian physicians serves to generate proaches. 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Grobbee DE: Initiation of glucose-lower- 23. Chin MH, Su AW, Jin L, Nerney MP: Vari- K: A systematic review of interventions to ing therapy in type 2 diabetes mellitus pa- ations in the care of elderly persons with improve diabetes care in socially disad- tients in general practice. Diabet Med 21: diabetes among endocrinologists, general vantaged populations. Diabetes Care 29: 896–900, 2004 internists, and geriatricians. J Gerontol A 1675–1688, 2006 19. Chin MH, Zhang JX, Merrell K: Specialty Biol Sci Med Sci 55:601–606, 2000 28. O’Connor PJ, Desai J, Solberg LI, Solberg differences in the care of older patients 24. Lawson VL, Lyne PA, Harvey JN, Bundy LI, Reger LA, Crain AL, Asche SE, Pearson with diabetes. Med Care 38:131–140, CE: Understanding why people with type TL, Clark CK, Rush WA, Cherney LM, 2000 1 diabetes do not attend for specialist ad- Sperl-Hillen JM, Bishop DB: Randomized 20. Huang ES, Gleason S, Gaudette R, Cagli- vice: a qualitative analysis of the views of trial of quality improvement intervention ero E, Murphy-Sheehy P, Nathan DM, people with insulin-dependent diabetes to improve diabetes care in primary care Singer DE, Meigs JB: Health care resource who do not attend diabetes clinic. J Health settings. Diabetes Care 28:1890–1897, utilization associated with a diabetes cen- Psychol 10:409–423, 2005 2005 ter and a general medicine clinic. J Gen 25. Peyrot M, Rubin RR, Lauritzen T, Skov- 29. Lester WT, Grant RW, Chueh H, Barnett Intern Med 19:28–35, 2004 lund SE, Snoek FJ, Matthews DR, Land- GO: Randomized controlled trial of an in- 21. Shah BR, Hux JE, Laupacis A, Zinman B, graf R, Kleinebreil L, the International van Walraven C: Clinical inertia in re- DAWN Advisory Panel: Resistance to in- formatics-based intervention to increase sponse to inadequate glycemic Control: sulin therapy among patients and provid- statin prescription for secondary preven- do specialists differ from primary care ers: results of the cross-national Diabetes tion of coronary disease. J Gen Intern Med physicians? Diabetes Care 28:600–606, Attitudes, Wishes, and Needs (DAWN) 21:22–29, 2006 2005 Study. Diabetes Care 28:2673–2679, 2005 30. Kahn SE, Haffner SM, Heise MA, Herman 22. Bell RA, Quandt SA, Arcury TA, Snively 26. Kirkman MS, Williams SR, Caffrey HH, WH, Holman RR, Jones NP, Kravitz BG, BM, Stafford JM, Smith SL, Skelly AH: Pri- Marrero DG: Impact of a program to im- Lachin JM, O’Neill MC, Zinman B, Viberti mary and specialty medical care among prove adherence to diabetes guidelines by G; ADOPT Study Group: Glycemic dura- ethnically diverse, older rural adults with primary care physicians. Diabetes Care 25: bility of rosiglitazone, metformin, or gly- type 2 diabetes: the ELDER Diabetes 1946–1951, 2002 buride monotherapy. N Engl J Med 355: Study. J Rural Health 21:198–205, 2005 27. Glazier RH, Bajcar J, Kennie NR, Willson 2427–2443, 2006
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1453 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Diabetes Care in Extended-Care Facilities Appropriate intensity of care?
1 RACHEL M. HOLT, OMSII end point related to diabetes (7,9). The 1,2 FRANK L. SCHWARTZ, MD American Diabetes Association (ADA) has 1,2 JAY H. SHUBROOK, DO published standards of care for physicians to follow for cardiovascular risk reduction in the ambulatory adult (11). Reducing OBJECTIVE — The American Diabetes Association (ADA) does not recognize different treat- cardiovascular risk in the older adult is of ment goals for the institutionalized adult compared with the outpatient adult with diabetes, nor paramount importance due to the in- has it outlined specific recommendations for this population. The purpose of this study was to creased risk for cardiovascular disease in examine physician management of patients with type 1 and type 2 diabetes residing in extended- this population (12). However, a recent care facilities and to compare this management with ADA standards of care for the outpatient adult. study (8) showed that the treatment and control of cardiovascular risk factors in RESEARCH DESIGN AND METHODS — This retrospective chart review included elderly outpatients with diabetes often do data from 108 residents with type 1 or type 2 diabetes at 11 extended health care facilities in the not meet these guidelines. Midwestern U.S. and included a review of the medical problem list, medication list, laboratory Very little has been published regard- reports, and all physician and consultation notes during the study period. ing glucose control for the institutional- ized person with diabetes (8,12–14). In RESULTS — Blood glucose was monitored in 98% of the subjects, and 38% met glucose goals. this population, the cardiovascular bene- A1C goal was achieved in 67% of patients. Blood pressure was monitored in 94% of patients, fit of tight glycemic control must be with 55% meeting goal. Thirty-one percent of patients had yearly lipids checked, 37% had annual electrocardiograms, 7% had urine analyzed for microalbuminuria, 42% were on aspirin, balanced with the increased risk of hypo- 87% received foot exams, 42% received dilated eye exams, 89% received influenza vaccinations, glycemic reactions and adverse side ef- and 46% received pneumoccocal vaccinations. fects from additional medication, such as high risk for serious hypoglycemia, bra- CONCLUSIONS — Care of the institutionalized elderly with diabetes fails to meet ADA dycardia, orthostatic hypotension, and standards of care for the outpatient adult. Separate practice guidelines are needed for people with myalgia, which could all lead to injurious diabetes who reside in extended care facilities in order to improve quality and consistency of falls or other adverse health effects (7,12). care. The American Geriatric Society (AGS) has Diabetes Care 30:1454–1458, 2007 published guidelines regarding glucose control for older ambulatory adults with diabetes (12). These guidelines acknowl- n estimated 21 million Americans the great majority of the mortality from edged the possible risks associated with have diabetes (1). Another 22 mil- the disease. Approximately 80% of people tight glycemic control and therefore sug- A lion have impaired glucose toler- with diabetes will die from cardiovascular gested a modified A1C goal of Ͻ8.0% ance, half of whom will go on to develop disease (6). Data suggest that people with (12). Although this is an important step, type 2 diabetes (2). The incidence of dia- diabetes, but no history of myocardial in- there is no specific recognition for the betes is expected to increase dramatically farction, have a similar risk for myocardial unique situation of the adult in the ex- over the next 50 years, with the largest infarction as those without diabetes who tended health care facility. increases occurring in the oldest age- have had a myocardial infarction (7). Because of the heterogeneity of the el- groups (3,4). The projected 336% in- Tight control of blood pressure, lipids, derly population, the treatment of diabe- crease in the incidence of diabetes by and blood glucose has been proven to de- tes and its comorbid diseases in this 2050 in the aged population (Ն75 years) crease morbidity and mortality outcomes will produce an enormous national eco- of aging people with diabetes (8–10). A population must take into account patient nomic burden (4,5). 1% reduction in A1C is associated with a age, duration since diagnosis, frailty sta- Diabetes is a known risk factor for 37% decline in microvascular complica- tus, and patient preferences (15–19). The cardiovascular disease, contributing to tions and a 21% reduction in risk of any earlier the age of onset of diabetes, the greater the burden from the disease and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● its complications. According to a recent From the 1Ohio University College of Osteopathic Medicine, Athens, Ohio; and the 2Appalachian Rural publication, knowledge of the duration of Health Institute Diabetes Center, Athens, Ohio. diabetes could indicate different treat- Address correspondence and reprint requests to Rachel M. Holt, OMSII, Cornwell Center, 65 Hospital ment goals and therefore should be pur- Dr., Athens, OH 45701. E-mail: [email protected]. sued (19). Frailty status has been shown Received for publication 10 November 2006 and accepted in revised form 20 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2311. to affect morbidity and is a stronger pre- Abbreviations: ADA, American Diabetes Association; AGS, American Geriatric Society. dictor for individual mortality than chro- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion nologic age (20,21). The benefit of factors for many substances. medical treatment in the frail elderly must © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby be weighed with the patient’s increased marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. risk for adverse effects from these medi-
1454 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Holt, Schwartz, and Shubrook cations (20–22). In addition, clinical Table 1—Clinical characteristics of nursing home residents goals to reduce morbidity and mortality must always be balanced with patient ADA/study Percent meeting preferences (18). goal goal (%) Long-term care facilities will likely bear much of the burden of caring for the Glucose goal Fasting (80–120 mg/dl) 38 increasing number of aging people in Postprandial (100–140 mg/dl) America. Due to the complexity of diabe- A1C Ͻ7% 67 tes, aging people with this disease are Blood pressure Ͻ140/90 mmHg 55 twice as likely to be admitted to a nursing ACE inhibitor/angiotensin receptor —52 home (23,24). People with diabetes also blocker require more skilled nursing care upon Lipids Yearly 31 admission than their nondiabetic coun- Electrocardiogram Yearly 37 terparts (23,24). People with diabetes, Microalbumin Yearly 7 therefore, present a unique challenge to Aspirin 75–325 mg 42 both physicians and nursing facility staff. Foot exam Monthly 87 Due to a lack of studies evaluating di- Podiatrist consult — 58 abetes control and treatment in the ex- Eye exam Yearly 42 tended care facility, little is known about Influenza vaccine Yearly 89 how diabetes is being managed in this set- Pneumoccocal vaccine One lifetime 46 ting. A 1999 article by Funnell (22) dis- cussed guidelines for care of the nursing home residents with diabetes. However, a documented history of type 1 or type 2 (79%), 23 men (21%), and 1 subject with diabetes care has changed dramatically in diabetes. Residents were excluded if they missing sex identification were included. the last 8 years due to recent research and had resided at the facility for Ͻ3ofthe Ninety-five percent of the study subjects the introduction of numerous new diabe- previous 12 months. Short-term rehabil- were Caucasian. The mean age of enrolled tes drug classes. The AGS produced rec- itation residents were also excluded from subjects was 82 Ϯ 9 years (range 41– ommendations for the older ambulatory the study. All chart reviews were com- 103). The overwhelming majority (95%) adult, but no specific guidelines were pleted by investigators and included re- had type 2 diabetes. Insulin was used by given for the older institutionalized adult view of the medical problem list, 60% of patients, and 50% of patients used (12). The ADA treatment guidelines rec- medication list, laboratory reports, and all oral glycemic controlling medication. ognize that softer treatment goals could physician and consultation notes during About half of the patients (49%) using in- be indicated for the older adult, but sep- the study period. No patient, physician, sulin were using sliding-scale coverage. arate treatment goals are not recom- or facility identifiers were included in the Primary care physicians managed the care mended for the institutionalized adult. chart review. The ADA standards of care of all study participants. Family practitio- Real-world experience demonstrates that for outpatient adults were used as a com- ners cared for the majority of patients providing intensive control for these pa- parison point for blood glucose (fasting (81%), with internists (11%) and geria- tients can be challenging at best and even 80–120 mg/dl, postprandial 100–140 tricians (8%) managing the remaining dangerous at times. To establish appro- mg/dl), A1C (Ͻ7.0%), blood pressure residents. priate guidelines, the strengths and weak- (Ͻ140/90 mmHg), and lipid levels (LDL nesses of current diabetes treatment in cholesterol Ͻ100 mg/dl, HDL cholesterol Glucose and A1C monitoring and extended care facilities must be identified. Ͼ45 mg/dl in men [Ͼ55 mg/dl in treatment The purpose of this study was to examine women], and triglycerides Ͻ150 mg/dl). Blood glucose was monitored in 98% of physician management of patients with All data were entered into an Excel data- the subjects (at least one finger stick glu- type 1 or type 2 diabetes residing in base by key and entry format. cose by the unit’s glucose meter per extended-care facilities. This study also month), but only 38% of subjects met looked at physician adherence to the ADA Statistical analysis glucose goals (fasting 80–120 mg/dl, standards of care for outpatients. Results were analyzed using SPSS version postprandial 100–140 mg/dl) (Table 1). 14.0 (SPSS, Chicago, IL). Percentages and At least one A1C per year was measured in RESEARCH DESIGN AND means Ϯ SD were used to describe the 84% of the patients, with 67% meeting METHODS — This retrospective data. The Pearson 2 test or Mann- goal (Ͻ7.0%). If the AGS goal of Ͻ8.0% chart review included data from 108 res- Whitney U test was used to determine dif- had been used for this study, 94% of pa- idents with physician-documented type 1 ferences between groups. Continuity tients would have met A1C goal. How- or type 2 diabetes at 11 extended health correction was used when necessary. Sta- ever, correlations using the AGS goal care facilities in the Midwestern U.S. Ap- tistical significance was determined at frequencies were not possible due the proval for the study was obtained from ␣ϭ0.05. small number of patients not meeting the Ohio University Institutional Review goal. A1C frequency was not significantly Board, and a letter of agreement was pro- RESULTS correlated with A1C goal being met (P ϭ vided by each of the participating facili- 0.20). Patients using insulin were less ties. A list of all current residents was Subject characteristics likely to meet glucose goals than their obtained from the director of nursing for All 108 subjects were identified as meet- non–insulin using counterparts (P ϭ each facility. Each chart was reviewed for ing inclusion criteria. A total of 84 women 0.0001). Insulin using patients were more
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1455 Diabetes guidelines in extended care facilities
formation due to the exclusion criteria may have affected study outcomes. Some patients residing at a facility for Ͻ1 year had limited data due to the timing of their annual screening tests and procedures that were absent from their chart. Because the study used a limited number of facil- ities located in only one region of the country, its generalizability for national trends could be limited. Also, because frailty status and age of onset of diabetes were not obtained in our chart review we were unable to stratify our data based on these two factors. However, our study Figure 1—Sliding scale and A1C. , no sliding scale; f, sliding scale. only included individuals who needed full-time institutionalized nursing care. One can infer that our patients are all con- sidered part of the frailest elderly group CONCLUSIONS likely to have three or four A1C measures — Although lim- and therefore cannot be stratified based per year, although results were not statis- ited, data regarding control and treatment ϭ on frailty status. tically significant (P 0.06). Patients us- of diabetes in the nursing home has Despite poor ADA guideline adher- ing insulin without a sliding scale shown that care of the older outpatient ence in a number of areas, this study correction were more likely to meet A1C person with diabetes often does not meet ϭ showed some positive data concerning goal (P 0.02) (Fig. 1). ADA standards of care (8,25). This study the care of diabetes in the extended care demonstrates that diabetes care in the ex- facility. Monthly foot exams were regu- Preventive medicine tended care facility is even further from larly performed in the nursing home Foot examinations were performed on meeting ADA guidelines for the outpa- (87%), and many residents received a po- 87% of patients in the study, with 58% of tient adult. diatrist consultation (58%). However, patients receiving podiatrist consulta- The limitations associated with this this reflects a difference from a 1999 Cen- tions. Less than half (42%) of the patients study should be considered before dis- ters for Disease Control and Prevention received dilated eye examinations. Influ- cussion of the results. Because there is no survey, which found that 89% of nursing enza vaccinations were given to 89% of gold standard for treatment of the institu- homes were offering podiatrist consulta- the subjects, but only 46% documented tionalized adult, the study treatment goals tions to residents (26). Reasons contrib- pneumoccocal vaccinations were given in used were not specific for this population. uting to this difference could be that fewer the past year. However, the ADA standards of care for nursing homes are offering podiatrist ser- the ambulatory adult were the most ap- vices to their residents than in 1999, that Depression propriate guidelines to use because sepa- our study facilities are not representative Depression was documented in 52% of rate guidelines have yet to be published. of a larger trend toward providing this patients. Fifty-eight percent of patients re- Although the AGS published guidelines service for residents, or that a lack of re- ceived documented pharmacological suggesting modified A1C goals in older imbursement for this service has de- treatment for depression, and 17% of pa- ambulatory adults with diabetes, there creased its use. tients had psychiatrist consultations. was no specific recognition of the institu- Influenza vaccinations were also reg- tionalized adult (12). Due to this fact and ularly given during the study period Monitoring and control of the fact that the AGS A1C goal recom- (89%), demonstrating another positive cardiovascular risk factors mendation (Ͻ8.0%) was based on level adherence to ADA guidelines. Pneumoc- Although 94% of patients had monthly IIIB evidence as referenced in the article cocal vaccinations were not routinely blood pressure checks, only 55% of pa- by Brown et al. (12) (level III, evidence documented (46%). However, because tients met the goal (Ͻ140/90 mmHg). from respected authorities based on clin- this study only looked at chart records Just over half (52%) of patients received ical experience, descriptive studies, or re- over 1 year’s time, this percentage does ACE inhibitor or angiotensin receptor ports of expert committees; level B, not necessarily represent the number of blocker therapy. However, blood pres- moderate evidence to support the use of a residents that were up to date with their sure goal was more likely to be met with- recommendation, which clinicians pneumoccocal vaccine because only one out the use of an ACE inhibitor or should do most of the time), AGS guide- to two lifetime immunizations are re- angiotensin receptor blocker (P ϭ 0.02). lines were not used as a comparison point quired before the age of 65 years. Yearly Lipids were checked yearly in only 31% in this study. If the AGS A1C guidelines dilated eye exams were documented in percent of patients, with 58% of those had been used, 94% of the study popula- less than half of the population (42%). checked meeting the LDL cholesterol goal tion would have met A1C goal compared Refraining from using this simple screen- (Ͻ100 mg/dl). Yearly electrocardiograms with the 67% who met the ADA goal. ing exam increases the occurrence of were reported in 37% of patients, 7% of Another limitation to the study was blindness, which in turn increases the patients had urine checked for mi- that chart review data were attained for likelihood for extended nursing home croalbuminuria, and 42% of patients only 1 year. Lack of chart documentation stays, contributes to falls, and decreases were on a daily aspirin regimen. or exclusion of pertinent health care in- quality of life (23). However, changes in
1456 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Holt, Schwartz, and Shubrook
ADA guidelines have occurred since the attention to both the screening and treat- treatment is needed before the patient re- start of this study. The 2006 ADA guide- ment of lipids (31). ceives mortality benefit (31). lines permit less frequent eye exams (ev- Only 7% of patients had urine Another reason for lack of adherence ery 2–3 years) after a normal initial exam checked for microalbumin. Microalbu- could be that competing medical ill- (27). min is an early screening tool for cardio- nesses, which are often present in patients When looking at the average A1C vascular disease and renal failure and has with diabetes, can make it difficult to (6.4%), it appears that glycemic control in been identified as an independent marker comprehensively treat all problems. Time the nursing home population is excellent. of cardiovascular mortality (12,32). Also, constraints that are placed on both physi- However, the low number of residents renal failure in the elderly has been shown cians and nursing home facility staff make (38%) meeting finger stick glucose goals to increase the risk of cardiovascular dis- the complex treatment of diabetes chal- indicates that there is a mismatch between ease (33). Electocardiograms were per- lenging. Lastly, limitations of treatment meeting glucose goal and meeting A1C formed in only 37% of patients. The may exist because diabetes is a very costly goal. Patients meeting A1C, but not glu- DIAD (Detection of Ischemia in Asymp- disease to treat. With extended care facil- cose, goals are likely having widely vari- tomatic Diabetics) study found that 22% ities already feeling financial constraints, able sugars. Increased glucose variability of low-risk asymptomatic adults with comprehensive care of the resident with may be dangerous for the elderly patient diabetes had silent coronary artery dis- diabetes presents an additional financial because they are likely to have hypogly- ease (34). These results indicate the even burden. cemic episodes that may not be identified. greater importance of early screening This study not only demonstrates that Also, recently research has demonstrated tools for the patient with diabetes. There- care of the institutionalized elderly is less a connection between glucose variability fore, greater efforts should be made to than optimal but also that practice guide- and oxidative stress on vascular tissue increase the prevalence of electrocardio- lines for this population are greatly (28). This has led to a proposal that min- gram and microalbumin checks in the in- needed. Specific guidelines concerning imal blood glucose variability should be a stitutionalized adult population. the care of diabetes in this population goal of diabetes treatment along with A1C Data have shown that low-dose aspi- would give physicians and nursing facility (28). rin (100 mg) reduces cardiovascular staff a solid framework for developing According to the Joint National Com- deaths in at-risk patients by 44% (35). treatment plans for this challenging pop- mittee on Prevention, Detection, Evalua- Aspirin, which is one of the most cost- ulation. Future studies are needed in or- tion, and Treatment of High Blood effective treatments for cardiovascular der to develop guidelines that will disease, was used by only 42% of patients improve the quality and consistency of Pressure, 20% of individuals aged 60–79 in this study. Lack of aspirin use could be care for extended care facility residents years are not treated for hypertension a result of physician apprehension to use with type 1 and type 2 diabetes. (29). Because only 55% of this study’s pa- the medication for fear of side effects such tients met blood pressure goal and only as bleeding. However, research has dem- 52% were on ACE inhibitors or angioten- onstrated that the risk of a major bleed in Acknowledgments— Special thanks to sin receptor blocker therapy, hyperten- elderly nursing home residents on aspirin Grace Brannan, PhD, and Michael Weiser, MS, sion treatment of the institutionalized therapy is very low (36). Because of the for their help with statistical analysis and ed- iting. Thanks also to Leonard Bertheau, DO; adult may be even less optimal than significant cardiovascular benefit, the low among the ambulatory elderly. Antihy- Cheri Cowan, CNP; and Theresa Phillips, cost, and the minimal risk of side effects, CNP, for their help with chart reviews. pertensive treatment has been shown to aspirin should be used more frequently in reduce coronary artery events (23%), this population. strokes (30%), cardiovascular deaths Failing to meet the challenge of the References (18%), and total deaths (13%) in the el- ADA standards of care in this study could 1. Centers for Disease Control and Preven- derly, with the greatest benefit seen in be a result of many factors. Control and tion: National diabetes fact sheet 2005: Ͼ those aged 70 years (30). Also, data treatment of diabetes in the institutional- national estimates on diabetes [article on- have shown that people with diabetes re- ized elderly is a complex and difficult task line], 2005. Available from http://www.c- ceive the greatest mortality benefit from due to the numerous comorbidities dc.gov/diabetes/pubs/factsheet05.htm. treating hypertension first, lipids second, present. In addition, physicians may feel Accessed 3 September 2006 2. Ramlo-Halsted BA, Edelman SV: The nat- and blood glucose third (31). The signif- that treating diabetes and its comorbidi- icant cardiovascular morbidity and mor- ural history of diabetes: implications for ties aggressively is less important in this clinical practice. Prim Car 26:771–790, tality benefit the elderly gain from population due to the shortened life ex- 1999 controlling hypertension indicates a need pectancy and possibility of adverse effects 3. King H, Aubert RE, Herman EH: Global for tighter blood pressure control than from treatment. However, this is contrary burden of diabetes, 1995–2025. Diabetes was found in this study. to data that has shown that only 2–4 years Care 21:1414–1431, 1998 Other cardiovascular screening and of treatment for hypertension or dyslipi- 4. Boyle JP, Honeycutt AA, Narayan KM, treatment parameters examined in this demia are needed before mortality benefit Hoerger TJ, Geiss LS, Chen H, Thompson study were also found to be less than op- is realized (31). Because the average TJ: Projection of diabetes burden through timal. Lipids were checked in only 31% of length of stay in a nursing facility is 2.5 2050. Diabetes Care 24:1936–1940, 2001 5. Harris MI: Diabetes in America: epidemi- patients, with 58% of those checked years, many residents would likely benefit ology and scope of the problem. Diabetes meeting goal. Because people with diabe- from treatment of hypertension or dyslip- Care 21 (Suppl. 3):C11–C14, 1998 tes receive the second greatest mortality idemia (26). Benefit from aggressive glu- 6. O’Keefe JH Jr, Miles JM, Harris WH, Moe benefit from control of this cardiovascular cose management may be less significant, RM, McCallister BD: Improving the ad- risk factor, there is a need for increased however, because an average of 8 years of verse cardiovascular prognosis of type 2
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diabetes. Mayo Clin Proc 74:171–180, older adults. JAMA 295:801–808, 2006 Complications 19:178–181, 2005 1999 16. Blaum CS, Ofstedal MB, Langa KM, Wray 28. Joint National Committee: The Seventh Re- 7. Shorr RI, Ray WA, Daugherty JR, Griffin LA: Functional status and health out- port of the Joint National Committee on Pre- MR: Incidence and risk factors for serious comes in older Americans with diabetes vention, Detection, Evaluation, and hypoglycemia in older persons using in- mellitus. J Am Geriatr Soc 51:745–753, Treatment of High Blood Pressure. Wash- sulin or sulfonylureas. Arch Intern Med 2003 ington, DC, National Institutes of Health, 157:1681–1686, 1997 17. Huang ES, Gorawara-Bhat R, Chin MH: 2004. (DHHS publ. no. 04-5230) 8. Smith NL, Savage PJ, Heckbert SR, Barz- Self-reported goals of older patients with 29. Staessen JA, Gasowski J, Wand JG, Thijs ilay JI, Bittner VA, Kuller LH, Psaty BM: type 2 diabetes mellitus. 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1458 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
Racial and Ethnic Variation in Access to Health Care, Provision of Health Care Services, and Ratings of Health Among Women With Histories of Gestational Diabetes Mellitus
1 CATHERINE KIM, MD, MPH tor assessment, i.e., cholesterol and blood 2 BRANDY SINCO, MS pressure measurement (6,7). However, 2 EDITH A. KIEFFER, MPH, PHD women with hGDM may have inadequate access to health care outside of preg- nancy; some insurers and Medicaid limit OBJECTIVE — The purpose of this study was to assess racial/ethnic variation in access to postdelivery coverage to one visit, at health care, use of particular health care services, presence of cardiovascular risk factors, and about 6 weeks postpartum, regardless of perceptions of health and impairment among women at risk for type 2 diabetes because of their health or disease status (8,9). Previous histories of gestational diabetes mellitus (hGDM). studies (10) suggested that this lack of ac- cess may be more marked in nonwhite RESEARCH DESIGN AND METHODS — We performed a cross-sectional study using racial/ethnic groups. In the third National the 2001–2003 Behavioral Risk Factor Surveillance System, a national population-based, ran- dom sample telephone survey. We assessed access to health care, use of family planning, mea- Health and Nutrition Examination Sur- surement and elevation of cholesterol, elevation of blood pressure, and respondents’ perceptions vey, Mexican Americans were signifi- of health and impairment among women aged 18–44 years with hGDM (n ϭ 4,718). Multivar- cantly less likely to have health insurance iate models adjusted for sociodemographic characteristics, BMI, presence of children in the than non-Hispanic whites (NHWs) or Af- household, and current smoking. rican Americans, and Mexican Americans and African Americans were less likely to RESULTS — Outcome measures were suboptimal across racial/ethnic groups. Approximately have private insurance. No studies have one-fifth of the overall population reported no health insurance, cost barriers to physician visits, investigated racial/ethnic variation in ac- and no primary care provider. One-quarter had no examination within the past year, and almost cess to health care nor its association with one-fifth reported no family planning and elevated cholesterol levels. Latinas were the most the provision of appropriate health care disadvantaged, with 40% reporting no health insurance and no primary care provider and one-fourth reporting suboptimal perceptions of health. Asian/Pacific Islanders were the most services to women with hGDM. advantaged in terms of health care access, cholesterol and blood pressure elevation, and impaired In our previous study using the Be- physical health. Racial/ethnic differences in health care use and presence of risk factors were not havioral Risk Factor Surveillance System entirely explained by health care access or other covariates. Survey (BRFSS), a national, population- based survey, we found that women with CONCLUSIONS — Significant racial/ethnic variation exists among women with hGDM for hGDM more often rated their health as access to and use of health care, presence of risk factors, and perceptions of health. fair or poor than did their unaffected counterparts (11). This perception of Diabetes Care 30:1459–1465, 2007 health may be more sensitive to distinc- tions between racial/ethnic groups than uccessful translation of diabetes pre- grams (4). For most women with histories traditional markers of morbidity and vention trials (1–3) into clinical of gestational diabetes mellitus (hGDM), mortality (12), particularly for women S practice requires that health care one of the recruitment criteria for the Di- with hGDM, who have a greater risk than providers monitor health status, provide abetes Prevention Program (5), appropri- unaffected women for developing future and reinforce prevention messages, and ate care also includes use of family chronic disease (13), but who may have refer patients to available prevention pro- planning (4) and cardiovascular risk fac- normal glucose after delivery. However, ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● to our knowledge, no studies have inves- tigated racial/ethnic variation in percep- From the 1Departments of Medicine and Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan; and 2School of Social Work, University of Michigan, Ann Arbor, Michigan. tions of health and impairment among Address correspondence and reprint requests to Catherine Kim, MD, MPH, 300 NIB, Room 7C13, Box women with hGDM. 0429, Ann Arbor, MI 48109. E-mail: [email protected]. In this article, we investigated racial/ Received for publication 13 December 2006 and accepted in revised form 4 March 2007. ethnic variation in access to health care, Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2523. Abbreviations: A/PI, Asian/Pacific Islander; BRFSS, Behavioral Risk Factor Surveillance System Survey; provision of health care regarding use of hGDM, history of gestational diabetes mellitus; NA/AN, Native American/Native Alaskan; NHW, non- family planning and cholesterol measure- Hispanic white. ment, presence of cardiovascular risk fac- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tors such as elevated cholesterol and factors for many substances. blood pressure, and perceptions of health © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby and impairment among women with marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. hGDM in the BRFSS. We hypothesized
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1459 Disparities among women with a history of GDM that minority women, particularly Lati- studies reported the validation of the ges- high school, and greater than high nas, would report decreased access, de- tational diabetes component. school), income level, current employ- creased family planning practices and ment, married or partnered status, pres- cholesterol screening, and poorer percep- Main outcome measures ence of children aged Ͻ18 years in the tions of health and degree of impairment Access to health care was measured by household, BMI (measured as weight in compared with NHW women. We also questions inquiring about lack of health kilograms divided by the square of height hypothesized that race/ethnicity would insurance, the presence of cost barriers to in meters), and current smoking. Reliabil- be independently associated with access physician visits in the past year, lack of a ity coefficients exceeded 0.75 for these measures, decreased use of family plan- primary care provider, location of pri- covariates and moderate to high validity ning, cholesterol screening, elevated cho- mary health care facility (no usual place of except where otherwise noted. Validity of lesterol and blood pressure, and care or primary source of care in emer- these measures is high (15); height is gen- perceptions of health and degree of im- gency room or urgent care facility versus erally overestimated by an average of 0.5 pairment after adjustment for other de- doctor’s office, outpatient department, inches, and in the BRFSS the correlation mographic characteristics. public health clinic, or community cen- between measured height and self- ter), and lack of a physical examination reported height was 0.92 in women. Sim- within the past year. Questions on cost ilarly, weight is generally underestimated, RESEARCH DESIGN AND barriers, location of primary care facility, and in the BRFSS the correlation between METHODS — We used data from the and physical examination were only asked measured weight and self-reported 2001–2003 waves of the BRFSS. This in 2003, 2002, and 2001, respectively. weight exceeded 0.90 (15). We collapsed cross-sectional telephone survey is con- Family planning questions included educational level into high school gradu- ducted by the Centers for Disease Control the question “Are you or your partner do- ate or not and income into Ͻ$25,000, and Prevention in conjunction with state ing anything now to keep from getting Ն$25,000, and unknown income as the health departments. The survey uses a pregnant?” and was asked only in 2002; patterns of effects between race/ethnic multistage cluster design based on ran- however, no questions inquired about the groups were similar in these categories. dom-digit dialing methods of sampling to desire for pregnancy. Women were clas- We classified women into obese (Ն30 kg/ select a representative sample from each sified as not using family planning if they m2), overweight (25–Ͻ30 kg/m2), nor- state’s noninstitutionalized civilian resi- did not use birth control. Women could mal or underweight (Ͻ25 kg/m2), and dents aged Ն18 years. Data collected also be classified as using birth control, unknown. from each state are pooled to produce na- being sterile, or lacking contact with men. We compared women with hGDM by tionally representative estimates. This Respondents were also asked, “Have you race/ethnicity in unadjusted analyses us- study used responses to a core set of ques- ever had your blood cholesterol ing Rao-Scott 2 tests for categorical vari- tions asked in all states. Median response checked?” If they answered “yes,” they ables (19) and Student’s t tests with rates varied from 77 to 80% over the were asked, “Have you ever been told by a survey-based standard errors for continu- study period (14). A detailed description doctor, nurse, or other health care profes- ous variables; the reference group was of the survey methods has been published sional that your blood cholesterol is NHWs. To examine the association be- previously (11,15). The sample included high?” These questions were asked only in tween the dependent variables of access to women aged 18–44 years who answered 2001 and 2003. health care measures and the primary in- the 2001–2003 survey question “Have Responses to perceptions of health dependent variable of race, we created a you ever been told by a doctor that you were excellent, very good, good, fair, and logistic regression model in which each have diabetes?” Responses included “yes,” poor (16). Impaired physical health was access to health care measure (lack of in- “yes but only during pregnancy,” “no,” defined as the presence of physical health surance, cost barriers to care, lack of pri- and “don’t know” or “not sure.” Partici- problems, including physical illness or in- mary care provider, and lack of pants who first answered “yes” were fur- jury, that prevented work or recreation on performance of physical examination ther asked “was this only when you were Ն15 days during the past 30 days (17). within the past year) was examined in a pregnant?” Women who responded “yes” Impaired mental health was defined as the separate model. Multivariate models ad- and “only during pregnancy” were classi- presence of mental health problems, in- justed for the covariates listed above. BMI fied as having hGDM, and women who cluding stress, depression, and problems was included as a covariate because responded “yes” were classified as having with emotions, that prevented work or greater BMI has been associated with current diabetes. Participants who re- recreation on Ն15 days during the past lower rates of insurance in other BRFSS sponded “no” were classified as not hav- 30 days (17). Impaired mental and phys- analyses, presumably because insurers ing hGDM, and women who responded ical health questions were asked in 2001 may be reluctant to insure those with this “don’t know” or “not sure” were classified and 2003 only. These measures have medical risk factor (20). as such. Thus, the categories of hGDM moderate to strong retest reliability (18). To examine the association between and diabetes were mutually exclusive. We the outcome measures of lack of use of excluded women who reported current Analysis family planning, lack of cholesterol diabetes from this analysis (n ϭ 4,412), The primary independent variable was screening, elevated cholesterol, and ele- and women who replied “don’t know, not self-reported race/ethnicity (NHW, non- vated blood pressure and the primary in- sure, or refused” (n ϭ 132), for a sample Hispanic African American, Hispanic or dependent variable of race/ethnicity, we size of 4,718. Five studies have reported Latina, Asian/Pacific Islander [A/PI], Na- created logistic regression models for high overall reliability of the BRFSS ques- tive American/Native Alaskan [NA/AN], each of these measures. That is, one tion about a diagnosis of diabetes ( or other). Covariates included age (years), model had lack of family planning as the 0.60–0.86) (15); to our knowledge, no education level (less than high school, dependent variable, another model had
1460 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kim, Sinco, and Kieffer aaaemaso ecnae 9%C) odfn niae infiatdfeecsfo Hs Dnmntricue 03rsodnsol.†Denomi only. respondents 2003 includes *Denominator NHWs. from differences significant only. indicates respondents font Bold 2000 CI). (95% percentages or means are Data 1— Table M (kg/m BMI aged Children hsclexamination Physical or care urgent is facility care health Primary are rprnrd()7. (74.7–79.0) 76.9 (%) partnered or Married opiaypoie % 47(281.)1. (9.0–27.3) 18.2 (12.8–16.7) 14.7 (%) provider primary No during cost of because doctor a see not Did urnl mlyd()6. 6.–77 06(51.2–70.0) 60.6 (62.7–67.7) 65.2 (%) employed Currently Income ohat nuac % 47(281.)1. (10.2–28.3) 19.2 (12.8–16.7) 14.7 (%) insurance health No hrceitcNWArcnAeia ipnco aiaN/NAP Total A/PI NA/AN Latina or Hispanic American African (33.1–33.8) 33.4 (88.7–95.5) 92.1 NHW (92.3–94.8) 93.5 (%) graduate school High (years) Age n Characteristic urn mkr()3. (27.8–32.7) 30.3 (%) smoker Current mrec aiiy(%)† facility emergency lack of cholesterol measurement as the (%)* year past dependent variable, a third model had el-
evated cholesterol as the dependent vari- Ͼ 2,0 % 13(69.0–73.7) 71.3 (%) $25,000 ndutdcaatrsiso oe ihahsoyo D yrace/ethnicity by GDM of history a with women of characteristics Unadjusted 2
able, and a fourth model had family )
planning as the dependent variable. We Ͻ hypothesized that these measures would (77.0–94.9) 85.9 (85.0–88.4) 86.7 (%) house in years 18 be influenced by access to health care, in Ͼ
that they required or could be (0.7–68.8) 34.7 enabled (22.4–44.4) 33.4 by (9.2–28.8) 19.0 (21.3–30.1) 25.7 (%)‡ ago year 1 physician examination (e.g., blood pres- sure elevation), laboratory test ordering (e.g., cholesterol checked), or prescrip- tion (e.g., family planning usage). There- fore, multivariate models examining family planning, cholesterol screening, and blood pressure elevation also in- cluded lack of insurance and lack of a pri- mary care provider as well as other 39(051.)3. 1.–69 05(142.)2. 083.)1. 03.)1. (13.4–20.9) 17.1 (0–31.6) 14.5 (0.8–39.1) 20.0 (11.4–29.6) 20.5 (14.2–46.9) 30.5 (10.5–17.3) 13.9 72(352.)2. 1.–39 73(603.)1. (4.4–32.9) 18.6 (16.0–38.7) 27.3 (12.9–33.9) 23.4 (13.5–20.8) 17.2 covariates (21). Multivariate models with (26.4–27.0) 26.7 elevated cholesterol as the dependent ,0 8 9 5 0 4,718 203 150 596 389 3,305 variable included only women who re- ported having a cholesterol level measured. To examine the association between the dependent variables of perceptions of health and impairment and the primary 45(35.8–53.3) 44.5 68(795.)3. (31.6–44.5) 38.1 (37.9–55.6) 46.8 13(30.0–32.6) 31.3 04(873.)2. 2.–94 91(872.)2. (24.4–26.1) 25.3 (28.7–29.4) 29.1 (27.6–29.4) 28.5 (28.7–32.1) 30.4 independent variable of race/ethnicity, (7.0–13.9) 10.5 (12.7–26.7) 19.7 we created logistic regression models sim- ilar to those already described for which the outcomes were fair or poor health (yes or no), impaired physical health (yes or no), and impaired mental health (yes or no). These models did not include access measures as covariates, as we did not hy- 63(94.5–98.1) 96.3 73(30.8–43.8) 37.3 90(42.5–55.6) 49.0 81(31.7–44.4) 38.1 75(50.9–64.2) 57.5 23(838.)6. 4.–81 70(987.)7. (72.2–76.2) 74.2 (59.8–74.1) 67.0 (48.1–78.1) 63.1 (78.3–86.3) 82.3 pothesize that self-rated health and im- (32.0–33.7) 32.9 pairment were dependent on health care (10). We evaluated the interactions be- tween age and race/ethnicity for all mod- els. These were not significant and therefore were not included in the final models. Tests for collinearity between 18(123.)3. (35.3–36.6) 35.9 (31.2–32.4) 31.8 58(939.)9. 8.–68 89(87.5–90.4) 88.9 (85.8–96.8) 91.3 (59.3–92.3) 75.8 24(10.1–34.6) 22.4 08(46.1–75.5) 60.8 41(10.5–37.7) 24.1 73(42.9–71.7) 57.3 89(469.)9. 9.–0.)8. (82.1–86.4) 84.2 (91.3–100.0) 96.0 (64.6–93.2) 78.9 these access measures did not show sig- (16.8–38.8) 27.8 nificant correlation. In all comparisons, the data were weighted to the age, sex,
and racial/ethnic distribution of the non- includes ‡Denominator only. respondents 2002 includes nator institutionalized population in the U.S. All analyses were performed using survey analysis procedures in SAS (version 9.1; SAS Institute, Cary, NC) to account for 44(26.7–42.2) 34.4 04(30.5–50.3) 40.4 60(47.0–65.0) 56.0 17(4.7–18.7) 11.7 . (0.0–7.9) 3.1 . (1.3–11.0) 6.1 the weighting and complex survey design. (0.0–12.9) 6.4
RESULTS — Of the 4,718 participants with hGDM, 58% were NHW, 9% were African American, 5% were A/PI, 2% were NA/AN, 25% were Latina, and 1% were other race/ethnicity. Unadjusted charac- teristics of women with hGDM by racial/ 65(22.3–30.7) 26.5 17(19.6–24.0) 21.7 93(56.9–61.7) 59.3 07(18.5–22.9) 20.7 96(15.8–23.4) 19.6 94(57.0–61.9) 59.4 33(21.4–25.2) 23.3 32(32.9–33.5) 33.2 ethnic category are reported in Table 1; (27.1–27.8) 27.4 point estimates and 95% CIs are pre- sented to facilitate comparisons. Com- pared with NHWs with hGDM, African Americans with hGDM were younger and more likely to have annual incomes
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1461 Disparities among women with a history of GDM
Table 2—Adjusted associations between racial/ethnic groups and access to health care measures
Characteristic African American Hispanic or Latina NA/AN A/PI n 389 596 150 203 Access measures* No health insurance 0.9 (0.5–1.5) 1.8 (1.3–2.5) 1.3 (0.7–2.6) 0.3 (0.1–0.7) Did not see a doctor because of cost during past year† 1.1 (0.4–2.6) 1.5 (0.8–3.0) 1.2 (0.5–3.0) 0.3 (0.1–1.1) No primary health care provider‡ 0.9 (0.5–1.5) 2.3 (1.6–3.3) 1.4 (0.6–3.4) 2.4 (1.6–3.6) Primary health care facility is emergency or urgent 2.4 (1.1–5.0) 1.1 (0.5–2.1) 1.5 (0.4–5.5) 1.3 (0.3–5.7) care facility§ʈ Physical examination Ͼ1 year ago¶ 0.6 (0.3–1.2) 1.3 (0.7–2.4) 1.4 (0.3–6.3) 0.1 (<0.1–0.6) Service measures* Not using family planning§# 0.8 (0.4–1.6) 0.6 (0.3–1.2) 3.5 (1.1–11.1) 1.3 (0.5–3.4) Cholesterol never checked** 0.7 (0.4–1.1) 1.3 (0.9–1.9) 0.7 (0.3–1.7) 0.7 (0.4–1.3) Cholesterol elevated** 1.1 (0.6–1.9) 1.2 (0.5–2.7) 0.9 (0.3–3.0) 0.3 (0.1–1.0) Blood pressure elevated**†† 1.4 (0.8–2.3) 1.0 (0.6–1.8) 1.8 (0.8–4.1) 0.1 (<0.1–0.4) Perceptions of health* Perception of health fair/poor 1.7 (1.0–3.0) 2.0 (1.3–3.0) 2.3 (0.9–6.1) 0.7 (0.3–1.5) Impaired physical health** 0.9 (0.4–2.0) 0.9 (0.5–1.8) 0.7 (0.3–1.7) <0.1 (<0.1–0.2) Impaired mental health** 1.1 (0.6–2.0) 1.3 (0.7–2.3) 1.7 (0.8–3.7) 1.2 (0.4–3.5) Data are odds ratios (95% CI). An elevated odds ratio indicates that race/ethnicity is associated with increased odds of the adverse outcome compared to NHWs. Bold text indicates significant differences from NHWs. *Models examining access measures and perceptions of health as dependent variables adjust for age, education, income, current employment, marital status, presence of children aged Ͻ18 years of age, smoking status, and BMI. Models examining service measures included these covariates, as well as lack of insurance and lack of a primary care provider. †Denominator includes only 2003 respondents. ‡No primary care provider includes only the “No” response; reference is Ն1 primary care provider. §Denominator includes only 2002 respondents. ʈReference ϭ doctor’s office, outpatient department at hospital, community center, or public health clinic. ¶Denominator includes only 2001 respondents. #Not using birth control or unknown, reference ϭ using birth control, sterile, not sexually active with men. **Denominator includes only 2001 and 2003 respondents. ††Reference category is “No” or “Only During Pregnancy.”
Ͻ$25,000 and greater than average BMI. port access measures, although as with After multivariable adjustment, Afri- They were less likely to be married or African Americans, CIs were wide. A/PIs can Americans were more likely than partnered and to smoke. They were sim- had more access to health care than NHWs to report that their primary loca- ilarly likely to be high school graduates, NHWs; they were less likely to report lack tion of health care consisted of an emer- employed, and to have children Ͻ18 of health insurance or recent examination gency room or urgent care facility and years of age in the household. Compared and cost barriers, although they were more poor perceptions of health (Table 2). After with NHWs with hGDM, Latinas with likely to lack a primary care provider. multivariable adjustment, Latinas were hGDM were more likely to be poor, to be Table 1 also shows unadjusted use of still more likely than NHWs to report lack heavier, and to have children Ͻ18 years services and presence of risk factors by of health insurance and a primary care of age in the household. They were less race/ethnicity with point estimates and provider and poor perceptions of health. likely to be high school graduates, to be 95% CIs to facilitate comparisons be- However, the associations between His- currently employed, and to smoke. Com- tween minority groups. Compared with panic ethnicity and lack of cholesterol pared with NHWs with hGDM, NA/ANs NHWs, African Americans reported sim- measurement and family planning no with hGDM were younger and were more ilar rates of family planning, cholesterol longer persisted. After multivariate ad- likely to be heavier. However, in contrast measurement and elevation, and blood justment, NA/ANs were more likely than with other racial/ethnic groups, A/PIs pressure elevation. Compared with NHWs to report lack of family planning. with hGDM were older and wealthier and NHWs, Latinas actually reported using In contrast, A/PIs were less likely than had a lower BMI than NHWs with hGDM. family planning more often and also re- NHWs to lack health insurance, a recent A/PIs were less likely to be employed and ported lack of cholesterol measurement physical examination, blood pressure el- were less often smokers than NHWs with more often. Compared with NHWs, NA/ evation, or impaired physical health and hGDM. ANs reported statistically similar use of almost less likely to have elevations in Table 1 also illustrates unadjusted ac- services and presence of risk factors, al- cholesterol. As in unadjusted analyses, cess to health care measures by race/ though CIs were wide. As with access A/PIs were still more likely to lack a pri- ethnicity with point estimates and 95% measures and other demographic charac- mary care provider. CIs to facilitate comparisons between teristics, A/PIs had a more favorable pro- Table 3 illustrates the associations be- NHW racial/ethnic groups. Compared file than NHWs, reporting cholesterol tween the dependent variables and co- with NHWs, African Americans were sim- elevation and blood pressure elevation variates other than race. Access measures ilarly likely to report access, although CIs less often. Latinas reported poor or fair were associated with greater income. A were wide. Compared with NHWs, Lati- perceptions of health more often than lack of health insurance and a lack of a nas were more likely to report lack of NHWs. A/PIs reported impaired physical recent physical examination were also as- health insurance and lack of a primary health less often than NHWs as well as sociated with a lack of high school educa- care provider. Compared with NHWs, most women from other racial/ethnic tion. Current smokers were more likely to NA/ANs were also similarly likely to re- groups (Table 1). report cost barriers to physician care.
1462 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kim, Sinco, and Kieffer mardmna elh10(.–.)10(.–.)12(.–.)07(.–.)07(.–.)07(.–.)08(0.5–1.1) 0.8 (0.5–1.0) 0.7 (0.4–1.3) 0.7 (0.5–1.1) 0.7 (0.8–1.9) 1.2 (0.6–1.9) 1.0 (1.0–1.0) 1.0 health mental Impaired lo rsueeeae . 1011 . 0416 . 0615 . 0513 . 0627 . 0818 . (0.7–1.8) 1.2 (0.8–1.8) 1.2 (0.6–2.7) 1.3 (0.5–1.3) 0.8 (0.6–1.5) 1.0 (0.4–1.6) 0.8 (1.0–1.1) 1.0 health physical Impaired fair/poor health of Perception elevated pressure Blood elevated Cholesterol o sn aiypann . 1010 . 0319 . 0615 . 0824 . 0936 . 0818 . (0.7–2.1) 1.2 (0.8–1.8) 1.2 (0.9–3.6) 1.8 (0.8–2.4) 1.3 (0.6–1.5) 1.0 (0.3–1.9) 0.8 (1.0–1.0) 1.0 checked never Cholesterol planning family using Not hsclexamination Physical ausaeod ais(5 I.Mliait oesaedsrbdi h eedt al .Bl etidctssgicn soitoswt depende with associations significant indicates text Bold 2. Table to legend the in described are models Multivariate CI). (95% †Income ratios odds are Values 3— Table rmr elhcr aiiyi mrec or emergency is facility care health Primary opiayhat aepoie . 1010 . 0820 . (0.6–1.2) 0.9 (0.8–2.0) 1.3 (1.0–1.0) 1.0 provider care health primary No i o e otrbcueo otduring cost of because doctor a see not Did Characteristic ohat nuac . (1.0–1.0) 1.0 insurance health No retcr facility care urgent Women who had children at home were year past less likely to use urgent care facilities for
their primary source of care. Women with Ͻ 2,0 sterfrnecategory. reference the is $25,000 children at home were more likely to re- race/ethnicity than other covariates between associations Adjusted port use of family planning. Younger women with lower education and in- comes were less likely to have their cho- Ն
lesterol measured. Of the women who (1.0–1.0) 1.0 ago year 1 had their cholesterol measured, older, overweight and obese, and uninsured women were more likely to report eleva- tions. Current smoking and obesity also predicted greater prevalence of hyperten- sion. Greater age, lower income, current smoking, and obesity were associated . (1.1–1.1) 1.1 (1.1–1.1) 1.1 (1.1–1.1) 1.1 . (0.9–0.9) 0.9 . 1010 . 0737 . (0.4–1.4) 0.7 (0.7–3.7) 1.6 (1.0–1.0) 1.0 with poorer perceptions of health and (0.4–1.3) 0.7 (0.4–1.9) 0.9 (1.0–1.0) 1.0 g (years Age
greater impairment. Ͼ 18) CONCLUSIONS — In a nationally representative population-based survey of women with hGDM, we found that sig- Ͻ . 1146 . (0.3–0.9) 0.6 (1.1–4.6) 2.2 . 1228 . 0408 . (0.2–0.4) 0.3 (0.4–0.8) 0.6 (1.2–2.8) 1.8 . 0732 . 0723 . 0615 . 0417 . 0919 . (0.8–1.9) 1.2 (0.9–1.9) 1.3 (0.4–1.7) 0.8 (0.6–1.5) (0.5–1.5) 0.9 0.9 (0.5–1.0) 0.7 (0.5–2.2) (0.7–2.3) 1.0 1.3 (0.9–2.4) 1.5 (0.7–3.2) 1.4 nificant lack of access, lack of recom- (0.9–2.7) 1.6 education* mended services, and poor perception of school High health exist across all racial/ethnic groups. In this population at high risk for future diabetes and pregnancies affected by glucose intolerance, approximately one-fifth reported a lack of insurance, cost Ͼ barriers to physician visits, and lack of a (0.4–0.9) 0.6 (0.5–0.9) 0.7 dcto*Income education* primary care provider. More than one- school High fourth reported lack of a physical exami- nation in the past year, which in turn is a missed opportunity for glucose screening and reinforcement of family planning, diet and exercise, and other preventive measures. Almost one-fifth of women at . 0205 . (0.3–0.8) 0.5 (0.3–0.9) 0.5 (0.2–0.5) 0.3 . (0.2–0.9) 0.5 . (0.3–0.6) 0.4 . (0.2–0.8) 0.4 risk for pregnancy did not use family (0.4–1.0) 0.6 (0.7–1.7) 1.1 (0.5–2.6) 1.1 (0.6–1.9) 1.1
planning. In this population at increased Ͼ risk for cardiovascular risk factors, ap- Married/partnered Employed unknown† Income $25,000† proximately one-fifth reported choles- terol elevation. Finally, in a relatively young population aged slightly Ͼ30 years, almost 15% reported poor percep- . 0422 . 0511 . (0.5–1.5) 0.8 (0.5–1.1) 0.7 (0.4–2.2) 1.0 . 0617 . 0611 . (0.9–1.7) 1.2 (0.6–1.1) 0.8 (0.6–1.7) 1.0 . 0417 . 0721 . (0.6–2.3) 1.2 (0.7–2.1) 1.2 (0.4–1.7) 0.8 . 0512 . 0610 . (0.6–1.1) 0.8 (0.6–1.0) 0.8 (0.5–1.2) 0.8 . 0211 . 0720 . (0.5–1.6) 0.9 (0.7–2.0) 1.2 (0.2–1.1) 0.5 . (0.5–1.1) 0.7 tion of health. category. reference the is education school *High variable. nt We also found that significant racial/ ethnic variation existed in measures of ac- cess to health care, use of services including family planning and cholesterol measurement, cholesterol and blood pressure elevation, and perception of . (0.5–0.9) 0.7 health and degree of impairment. Such (0.6–1.2) 0.8 (0.5–1.1) 0.8 variation persisted after multivariate ad- justment. With the exception of A/PIs, minority women reported less favorable profiles than NHW women. Hispanic women, the racial/ethnic group with the highest prevalence of hGDM, reported (0.7–1.4) 1.0 the greatest access barriers, more fre- quently reporting lack of health insurance and lack of a primary care provider. A/PIs reported a more favorable profile than women from other racial/ethnic groups,
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1463 Disparities among women with a history of GDM more frequently reporting health insur- has been reported previously (25). How- are suboptimal. Latinas, one of the racial/ ance and a recent physical examination ever, there were no associations between ethnic groups at highest risk for glucose and less frequently reporting cardiovas- access measures and actual cardiovascu- intolerance, have the greatest restrictions cular risk factor elevation and impaired lar risk factor levels. It is possible that the in access, care provided, and perception physical health. Associations between Af- number of women with cardiovascular of health and impairment. In addition, al- rican-American race/ethnicity and risk factor abnormalities was too small though access may be a necessary condi- NA/AN race/ethnicity with access, use of among women with hGDM or that access tion for care, it may not be adequate to services, presence of risk factors, and per- in and of itself does not guarantee a better improve care. These findings have impli- ception of health and impairment were risk factor profile (26). Conflicting rec- cations for the implementation of effec- less marked, but African-American ommendations (7,27) for cholesterol tive diabetes prevention strategies as well women still were more likely to report the screening in women aged Ͻ45 years may as other care. Future research should emergency room or urgent care facility as have affected associations between access characterize better the quality of care their primary health care facility. NA/AN and risk factor levels, although the direc- women with hGDM receive and the asso- women still reported lack of use of family tion of the bias is difficult to know; clini- ciation with outcomes. Given the rate of planning more frequently than NHWs, al- cal care guidelines recommend that adults obesity, blood pressure and cholesterol though this lack may have been due to with diabetes receive cholesterol screen- elevations, and future risk of diabetes in desire for pregnancy. Of note, the wide ing and do not distinguish between GDM this population, along with the increasing CIs for African Americans and NA/ANs and other types of diabetes. rates of these disorders in the general pop- suggest that significant variation exists Previous analyses have found that mi- ulation, improved provision of postpar- within these particular racial/ethnic nority women were less likely to engage in tum services could potentially reduce groups, indicating that finer characteriza- family planning than NHWs, although future cardiovascular morbidity. tions may be needed. use in NA/ANs was not commented upon The associations we observed be- (28). In our report, NA/AN women re- tween race/ethnicity and access measures ported lack of family planning more fre- Acknowledgments— This study was sup- and race/ethnicity and other covariates quently than NHW women after ported by National Institute of Diabetes and such as income have been observed in adjustment for access and other covari- Digestive and Kidney Diseases Grants K23DK071552 (to C.K.), R18DK062344–04 other populations besides women with ates, suggesting that some otherwise un- (to E.K.), and U50/CCU522189–02 (to B.S.). hGDM. Among individuals with diabetes defined characteristic associated with in the BRFSS, Gary et al. (22) found that NA/AN race/ethnicity placed women at minority populations were more likely to risk. Of note, before adjustment, Latinas References lack insurance and to report cost barriers actually reported greater use of birth con- 1. Knowler WC, Barrett-Connor E, Fowler to visiting a physician and having a recent trol in our report, although this finding SE, Hamman RF, Lachin JM, Walker EA, examination, even after adjustment for did not persist after adjustment for other Nathan DM: Reduction in the incidence of age, sex, income, and education. Of note, factors. The question about family plan- type 2 diabetes with lifestyle intervention the population with diabetes had better ning was available only in 2002, when or metformin. N Engl J Med 346:393–403, access to health care than women with interviews in Spanish were not an option. 2002 hGDM in our current report, with only So, the results for Latinas may be biased 2. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka about one-fifth of Hispanics with diabetes by misinterpretation of the question or by P, Keinanen-Kiukaanniemi S, Laakso M, reporting lack of insurance as opposed to omission of Spanish-speaking women. Louheranta A, Rastas M, Salminen V, the 38% of Latinas with hGDM in our We found that the association be- Uusitupa M: Prevention of type 2 diabetes report. Nelson et al. (23) also found that tween poorer self-rated health and Latina mellitus by changes in lifestyle among uninsured individuals with diabetes were ethnicity persisted after multivariate ad- subjects with impaired glucose tolerance. more likely to be African American or His- justment, as did the association between N Engl J Med 344:1343–1350, 2001 panic and to report low incomes and, A/PI ethnicity and better physical func- 3. Pan XR, Li GW, Hu YH, Wang JX, Yang consequently, to be less likely to have had tioning. Such associations have been doc- WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao diabetes-specific care measures. Of note, umented among women with (22) and HB, Liu PA, Jiang XG, Jiang YY, Wang JP, the more favorable profiles for A/PIs over- without diabetes (29,30), appear to be in- Zheng H, Zhang H, Bennett PH, Howard BV: Effects of diet and exercise in prevent- all have been noted, but significant varia- dependent of other risk factors for lower ing NIDDM in people with impaired glu- tion within this broad racial/ethnic self-rated health such as income and age, cose tolerance. Diabetes Care 20:537– category is seen; Southeast Asian groups and are potentially mediated by other 544, 1997 (24) and Pacific Islanders (25) tend to do markers of socioeconomic position and 4. American Diabetes Association: Gesta- worse than NHWs as well as A/PIs overall. social stressors (30–32). Again, signifi- tional diabetes mellitus. Diabetes Care 21: It is possible that such variations contrib- cant variations in health status exist S5–S19, 1998 ute to the higher odds of no primary care within the A/PI group, with subgroups, 5. Diabetes Prevention Program Research provider that we found among A/PIs. particularly Pacific Islanders and South- Group: Strategies to identify adults at After adjustment for lack of insurance east Asians, reporting poorer perception high-risk for type 2 diabetes: the Diabetes and lack of a primary provider, along with of health (24,25). Prevention Program. Diabetes Care 28: 138–144, 2005 other covariates, Latinas no longer re- We conclude that among women 6. Third Report of the Expert Panel on Detec- ported lower rates of cholesterol measure- with hGDM, a population at high-risk for tion, Evaluation, and Treatment of High ment than NHWs. A/PIs reported more glucose intolerance and for pregnancies at Blood Cholesterol in Adults (Adult Treatment favorable blood pressure and cholesterol high risk for glucose intolerance, access to Panel III): 10-Year Risk Calculator. Be- profiles than NHWs, an association that health care and provision of health care thesda, MD, National Heart, Lung, and
1464 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kim, Sinco, and Kieffer
Blood Institute, 2001 16. Ware JE Jr, Kosinski M, Keller SD: A 12- States,2001–2002. MMWR Morb Mortal 7. U.S. Preventive Services Task Force: item short-form health survey: construc- Wkly Rep 53:760–755, 2004 Screening adults for lipid disorders: rec- tion of scales and preliminary tests of 25. Sundaram AA, Ayala C, Greenlund KJ, ommendations and rationale. Am J Prev reliability and validity. Med Care 34:220– Keenan NL: Differences in the prevalence Med 20:73–76, 2001 233, 1996 of self-reported risk factors for coronary 8. Jones M, Cason C, Bond M: Access to pre- 17. Centers for Disease Control and Preven- heart disease among American women by ventive health care: is method of payment tion: The Behavioral Risk Factor Surveil- race/ethnicity and age: Behavioral Risk a barrier for immigrant Hispanic women? lance System: Measuring Healthy Days. Factor Surveillance System, 2001. Am J Womens Health Issues 12:129–137, 2002 Atlanta, GA, Centers for Disease Control Prev Med 29:25–30, 2005 9. Williams MA, Emanuel I, Kimpo C, and Prevention, 2003 26. Harris MI: Health care and health status Leisenring WM, Hale CB: A population- 18. Andresen EM, Catlin TK, Wyrwich KW, and outcomes for patients with type 2 di- based cohort study of the relation be- Jackson-Thompson J: Retest reliability of abetes. Diabetes Care 23:754–758, 2000 tween maternal birthweight and risk of surveillance questions on health-related 27. Third report of the National Cholesterol gestational diabetes mellitus in four racial/ quality of life. J Epidemiol Community Education Program (NCEP) Expert Panel ethnic groups. Paediatr Perinat Epidemiol Health 57:339–343, 2003 on Detection Evaluation, and Treatment 13:452–465, 1999 19. Rao JNK, Scott AJ: The analysis of categor- of High Blood Cholesterol in Adults 10. Harris MI: Racial and ethnic differences in ical data from complex surveys: chi- (Adult Treatment Panel III): final report. health care access and health outcomes squared tests for goodness of fit and Circulation 106:3143–3121, 2002 for adults with type 2 diabetes. Diabetes independence in two-way tables. JAm 28. Chuang CH, Chase GA, Bensyl DM, Weis- Care 24:454–459, 2001 Stat Assoc 76:221–230, 1981 man CS: Contraceptive use by diabetic 11. Kieffer EA, Sinco B, Kim C: Health behav- 20. Ayanian JZ, Weissman JS, Schneider EC, and obese women. Womens Health Issues iors in women with a history of gestational Ginsburg JA, Zaslavsky AM: Unmet 15:167–173, 2005 diabetes mellitus in the Behavioral Risk health needs of uninsured adults in the 29. Zahran HS, Kobau R, Moriarty DG, Zack Factor Surveillance System. Diabetes Care United States. JAMA 284:2061–2069, MM, Holt J, Donehoo R: Health-related 29:1788–1793, 2006 2000 quality of life surveillance–United States, 12. Otchet F, Carey MS, Adam L: General 21. Sambamoorthi U, McAlpine DD: Racial, 1993–2002. MMWR Surveill Summ 54:1– health and psychological symptom status ethnic, socioeconomic, and access dispar- 35, 2005 in pregnancy and the puerperium: what is ities in the use of preventive services 30. Avis NE, Ory M, Matthews KA, Schocken normal? Obstet Gynecol 94:935–941, among women. Prev Med 37:475–484, M, Bromberger J, Colvin A: Health-re- 1999 2003 lated quality of life in a multiethnic sam- 13. Kim C, Newton K, Knopp RH: Gestational 22. Gary TL, Narayan KM, Gregg EW, Beckles ple of middle-aged women: Study of diabetes and incidence of type 2 diabetes GL, Saadine JB: Racial/ethnic differences Women’s Health Across the Nation mellitus: a systematic review. Diabetes in the healthcare experience (coverage, (SWAN). Med Care 41:1262–1276, 2003 Care 25:1862–1868, 2002 utilization, and satisfaction) of US adults 31. Geronimus AT: Understanding and elim- 14. Centers for Disease Control and Preven- with diabetes. Ethn Dis 13:47–54, 2003 inating racial inequalities in women’s tion: Behavioral Risk Factor Surveillance 23. Nelson KM, Chapko MK, Reiber G, Boyko health in the United States: the role of the System, 2003 Summary Data Quality Re- EJ: The association between health insur- weathering conceptual framework. JAm port. Atlanta, GA, Centers for Disease ance coverage and diabetes care; data Med Womens Assoc 56:133–136, 2001 Control and Prevention, 2005 from the 2000 Behavioral Risk Factor Sur- 32. Krieger N, Smith K, Naishadham D, Hart- 15. Nelson DE, Holtzman D, Bolen J, Stanw- veillance System. Health Serv Res 40:361– man C, Barbaeu EM: Experiences of dis- yck CA, Mack KA: Reliability and validity 372, 2005 crimination: validity and reliability of a of measures from the Behavioral Risk Fac- 24. Centers for Disease Control and Preven- self-report measure for population health tor Surveillance System. Soz Praventivmed tion: Health status of Cambodians and research on racism and health. Soc Sci Med 46:S3–S42, 2001 Vietnamese-selected communities, United 61:1576–1596, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1465 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
The Underuse of Screening Services Among Elderly Women With Diabetes
A. MARSHALL MCBEAN, MD, MSC women with diabetes (adjusted OR 0.68 XINHUA YU, MB, PHD [95% CI 0.67–0.69]). This study examines the use of mam- mography in a larger U.S. population of OBJECTIVE — To determine whether the use of nondiabetes-related preventive services women with diabetes as well as two other (mammography, colorectal cancer screening, and bone density testing) among elderly diabetic preventive services: screening for colorec- women is different from the use among nondiabetic women. tal cancer and bone density testing.
RESEARCH DESIGN AND METHODS — Using a representative sample of the U.S. elderly female population and the linked Surveillance, Epidemiology, and End Results (SEER)- RESEARCH DESIGN AND Medicare files, we identified women with or without diabetes who were Ն67 years of age on 1 METHODS — The primary source of January 1999. All women with a prior history of cancer were excluded. Bivariate and multivariate data was the Sumdenom file from the analyses were used to compare the rates of preventive service use and to understand the factors merged Surveillance Epidemiology and influencing their use in the next 2–4 years. End Results (SEER)-Medicare data files created in 2003 (11). This file contains a RESULTS — Women with diabetes were less likely to have a mammogram (odds ratio [OR] random sample of 5% of women Ն65 0.83 [95% CI 0.78–0.88]), colorectal cancer screening (0.79 [0.70–0.88]), and bone density years of age living in SEER areas who had testing (0.63 [0.58–0.69]). Women with diabetes seen by endocrinologists had significantly no history of cancer from 1973 to 1999 higher rates of bone density testing than women seen by primary care physicians. Women seen ϭ by obstetrician/gynecologists had the highest rates of use of all three services. (n 109,138). Further, we used the Medicare claims files to exclude women CONCLUSIONS — Elderly women with diabetes are less likely to receive cancer and osteo- who developed cancer from 2000 to porosis screening than women without diabetes. Physicians treating these patients need to assure 2002, the end of our study period (n ϭ that they receive all recommended preventive services appropriate for their age. Additional 9,700). This resulted in 99,438 women national guidelines, practice-based improvements, and patient education targeting those at available to study. greatest risk of not receiving these services may be needed to achieve parity. Consistent with other studies using Medicare data, we excluded those benefi- Diabetes Care 30:1466–1472, 2007 ciaries who did not have both Medicare Part A and Part B (n ϭ 7,909), were en- ncreasing use of diabetes preventive of diabetic women in managed care rolled in managed care (n ϭ 31,781) or a services (A1C and serum lipid moni- plans in Michigan had mammograms hospice program (n ϭ 2,541), had end- I toring, proteinuria assessment, and and that 56% had Pap (Papanikolaou) stage renal disease (n ϭ 39), or did not dilated eye and foot examination) rec- smears in the prior 2 or 3 years, respec- reside in the SEER areas during the entire ommended by the American Diabetes tively. Increased use of diabetes process study period (n ϭ 2,626). This resulted in Association (ADA) and others are now and quality-of-care measures were asso- 54,542 eligible women. frequently reported by the National ciated with increased use of these two Medicare claims data from 1997 to Centers For Disease Control and Pre- screening services (9). Mammography 1998 were used to identify women with vention (CDC) and other researchers and Pap smear use in women without diabetes on 1 January 1999. We used our (1–8). Less frequently reported is the diabetes was not reported. Comparing validated algorithm that we recently re- use of other recommended preventive Ontario women between 50 and 67 ported (12) had a sensitivity of 90%, a services appropriate for the entire pop- years of age with diabetes to those with- specificity of 97%, and a positive predic- ulation, including those with diabetes, out diabetes, Lipscombe et al. (10) tive value of 93% for identifying Medicare such as cancer and osteoporosis screen- found a significantly lower rate of bien- beneficiaries with diabetes (13). A total of ing. Tabaei et al. (9) reported that 73% nial mammography use among the 8,232 women Ն67 years of age were ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● identified as having diabetes. Medicare national claims history and From the Division of Health Policy and Management, School of Public Health, University of Minnesota, outpatient files were used to determine Minneapolis, Minnesota. Address correspondence and reprint requests to A. Marshall McBean, MD, MSc, Division of Health Policy the study outcomes, 1999–2000 for and Management, University of Minnesota School of Public Health, MMC 97, 420 Delaware St., SE, Min- mammography and bone density testing neapolis, MN 55455. E-mail: [email protected]. and 1999–2002 for colorectal cancer Received for publication 31 October 2006 and accepted in revised form 23 February 2007. screening. These periods were based on Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2233. Abbreviations: ADA, American Diabetes Association; CDC, Centers for Disease Control and Prevention; Medicare reimbursement policy: 24 CMS, Centers for Medicare and Medicaid Services; HCPCS, Healthcare Common Procedure Coding System; months for bone density testing, 48 SEER, Surveillance, Epidemiology, and End Results. months for colorectal cancer screening, A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion and 24 months for mammography (the factors for many substances. commonly used period in literature). © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby The Healthcare Financing Adminis- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tration Common Procedure Coding Sys-
1466 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 McBean and Yu tem (HCPCS) codes 76090–76092, As a measure of diabetes preventive crude and age-adjusted rate ratios G0202 –G0207, and G0236 and the ICD- service use, we adopted the method of (women with diabetes/women without 9-CM code V76.12 were used to identify Tabaei et al. (9) and simply summed the diabetes) were 0.92 for mammography, mammograms. HCPCS codes G0104– diabetes preventive services received by 0.83 for colorectal cancer screening, and G0106 and G0120–G0122 or HCPCS diabetic women in 1997 and 1998 that we 0.70 for bone density testing (P Ͻ 0.0001 codes 44388, 44389, 44392, 44394, could measure using the Medicare admin- for each service). Multivariate analysis, 45378, 45380, 45383–45385, 45300, istrative data (A1C and LDL cholesterol which included all women in the study 45305, 45308, 45309, 45315, 45320, testing and eye examination). and was adjusted for all of the covariates 45330, 45331, 45333, 45338, 45339, We used the propensity score match- in Table 2, confirmed all three findings 74270, and 74280 accompanied by ICD- ing method to create an appropriate com- with significantly different adjusted ORs 9-CM codes V76.41 and V76.51 were parison population of women with no of 0.83 (95% CI 0.78–0.88) for mam- used to identify colorectal cancer screen- history of diabetes (15). These latter mography, 0.79 (0.70–0.88) for colorec- ing. Bone density testing was identified women were also identified in the SEER- tal screening, and 0.63 (0.58–0.69) for using HCPCS codes G0130–G0133, Medicare Sumdenom file. The propensity bone density testing. 76070, 76071, 76075, 76076, 76078, score for having diabetes or not having For the two cancer screening tests, the 76977, 78350, and 78351 and ICD- diabetes for each woman was obtained age-adjusted rates among diabetic women 9-CM procedure code 88.98 (8). from logistic regression in which all of the were significantly lower for almost all of In addition to age and race, two other covariables mentioned above were used the patient and health service characteris- covariates that could influence the use of as predictors. Each woman with diabetes tics compared with the rates among those these services were obtained from the was matched with an elderly woman without diabetes. The only exceptions Sumdenom file: Medicaid program par- without diabetes living in the same SEER were for those subgroups that tended to ticipation and rural residence. The 2000 area whose propensity score was nearest have the lowest rates: women Ն85 years U.S. Census Bureau ST3 file was used to to that of the person with diabetes but of age, those of black or “other” races/ determine the median household income within 0.5 of the SD of the score of the ethnicities, those in a state Medicaid- for each person’s zip code of residence. person with diabetes (one-to-one nearest operated programs, and those seen by The Medicare claims files from 1997 to neighbor method). The psmatch2 mod- “other” physicians (Table 2). For bone 1998 were used to determine whether a ule in Stata 9.1 was used for this matching density testing, the age-adjusted rates person had been hospitalized, and, if so, procedure (16). were significantly lower for all of the sub- whether in a teaching or a nonteaching Analyses were performed on the categories of patient and health service hospital; the specialties of physicians pro- matched cohorts (8,197 in each group). characteristics among women with diabe- viding care to the beneficiary; comorbidi- Univariate and bivariate analyses were tes compared with those without diabe- ties; and the average annual number of performed to describe and compare the tes. For those patient and health services physician visits. populations and their use of services. Dif- characteristics in which significant differ- Using the specialty identification ferences between cohorts were tested us- ences (P Ͻ 0.05) in the age-adjusted rates codes available in the Medicare data, ing the Z test. Multivariate logistic were found between those with diabetes physicians were grouped into primary regression analyses were carried out on and those without, the rates among those care (01 general practice, 08 family the cohort of women with diabetes for with diabetes were generally between 65 practice, 11 internal medicine, 38 geri- each preventive service to examine the and 77% of the rates among the women atric medicine, and 70 multispecialty impact of the covariates described above without diabetes. group practice), ob/gyn (16 ob/gyn), upon receipt of each service while simul- Among diabetic women, having vis- endocrinology (46 endocrinologist), taneously adjusting for the others. To ad- ited an endocrinologist and/or an ob/gyn and other (all other provider codes). If a just for possible geographical difference increased the use of each of the preventive woman was ever seen by an endocrinol- between SEER areas, we used the gener- services compared with visiting only pri- ogist or if ever seen by an ob/gyn, she alized estimate equation model with geo- mary care physicians. Among women was put in the appropriate group. If she graphic areas as the cluster variable. with diabetes, age-adjusted mammogra- was seen by both of these specialists, Differences were deemed statistically sig- phy rates were 14% greater among she was put in the endocrinologist plus nificant if the 95% CI did not include women who had seen an endocrinologist ob/gyn group. Among the remaining 1.00. All statistical analyses used SAS (40.7 of 100) than among women who women, those seen by a primary care (SAS GENMOD, version 9.1 for Win- had seen primary care physicians (35.9 of physician were put in that group. Those dows; SAS Institute, Cary, NC). 100; P ϭ 0.0418). Women with diabetes women not included in the prior groups who saw endocrinologists were 78% were put into the category “other,” RESULTS — The distributions of the more likely to have bone density testing which included women who had no demographic, clinical, and health service (19.7 of 100 vs. 11.1 of 100; P Ͻ 0.0001), physician visit in 1997 or 1998 (Ͻ1%). characteristics of those with diabetes and but no more likely to have colorectal can- Consistent with the recommendation the comparison population were similar, cer screening. However, those women of Klabunde et al. (14), we examined the except that even after the propensity score with diabetes who visited an ob/gyn had Medicare files to identify comorbidities matching, a slightly higher percentage of the highest rates of use for all three pre- and used the Charlson Index to categorize women without diabetes was seen by pri- ventive services. Compared with those and weigh them. Because all individuals mary care physicians (Table 1). who saw only primary care physicians, with diabetes would have a Charlson Women with diabetes were less likely the rates were 69% higher for mammog- score Ն1, diabetes was excluded when than those without diabetes to receive raphy, 59% higher for colorectal cancer calculating the Charlson scores. each of the three services (Table 2). The screening, and twice as great for bone
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1467 Diabetes and screening services
Table 1—Study subject characteristics
With diabetes Without diabetes P Total 8,197 (100.0) 8,197 (100.0) Age group (years) 67–74 3,549 (43.3) 3,509 (42.8) 0.0585 75–84 3,453 (42.1) 3,384 (41.3) 85ϩ 1,195 (14.6) 1,304 (15.9) Race White 5,968 (72.8) 6,010 (73.3) 0.7237 Black 1,041 (12.7) 1,011 (12.3) Other 1,188 (14.5) 1,176 (14.3) Rural residence No 7,238 (88.3) 7,239 (88.3) 0.9806 Yes 959 (11.7) 958 (11.7) State Medicaid program No 5,782 (70.5) 5,805 (70.8) 0.6932 Yes 2,415 (29.5) 2,392 (29.2) Median household income of zip code ($) Ͻ40,000 2,900 (35.4) 2,925 (35.7) 0.8792 40,000–51,999 2,844 (34.7) 2,846 (34.7) Ն52,000 2,453 (29.9) 2,426 (29.6) Hospitalization history Not hospitalized 4,744 (57.9) 4,723 (57.6) 0.3308 Hospitalized (nonteaching) 1,581 (19.3) 1,651 (20.1) Hospitalized (teaching) 1,872 (22.8) 1,823 (22.2) Charlson score 0 2,007 (24.5) 2,038 (24.9) 0.6763 1 1,473 (18.0) 1,498 (18.3) Ն2 4,717 (57.5) 4,661 (56.9) Medical specialty Primary care 6,201 (75.6) 6,444 (78.6) Ͻ0.0001 Endocrinologist 491 (6.0) 357 (4.4) Ob/gyn 998 (12.2) 950 (11.6) Endocrinologist plus ob/gyn 151 (1.8) 130 (1.6) Other 356 (4.3) 316 (3.9) Average number of physician visits per year 0–4 2,398 (29.3) 2,396 (29.2) 0.0976 5–9 2,955 (36.0) 3,017 (36.8) 10–14 1,606 (19.6) 1,583 (19.3) Ն15 1,238 (15.1) 1,201 (14.7) Number of different diabetes preventive services received 0 926 (11.3) 1 2,193 (26.8) 2 2,983 (36.4) 3 2,095 (25.6)
Data are n (%). density testing (P Ͻ 0.0001 for each com- The multivariate analysis performed significantly increased use of service over parison). They were 49, 50, and 12% only on those women with diabetes (Table visiting only primary care physicians. higher, respectively, among those who 3) confirmed the importance of visiting an The multivariate model showed the saw an ob/gyn compared with those who ob/gyn compared with only visiting a pri- following consistent results across all saw an endocrinologist (P Ͻ 0.0001, P ϭ mary care physician to achieve the highest three screening rates: rates decreased with 0.0001, and P ϭ 0.3058, respectively). rates of preventive service use. The adjusted age and were lower for those in state Med- The rates among those few women who relative odds of receiving a service among icaid administered programs, were hospi- visited both an endocrinologist and an ob/ those who visited an ob/gyn ranged from talized in the prior 2 years, had the gyn were not significantly different from 1.57 for colorectal screening to 2.80 for highest Charlson scores, and had less the rates among those who saw only an mammography. Only for bone density test- than five physician visits per year in the ob/gyn. ing did visiting an endocrinologist result in prior 2 years compared with those with
1468 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 McBean and Yu
Table 2—Crude, age-specific, and age-adjusted rates of preventive service use among elderly Medicare women
Mammogram Colorectal cancer screening Bone density testing With Without With Without With Without diabetes diabetes P* diabetes diabetes P* diabetes diabetes P* Crude rate 39.8 42.8 Ͻ0.0001 14.9 17.8 Ͻ0.0001 13.0 18.3 Ͻ0.0001 Age-specific rates (total) 67–74 (ref.) 52.0 55.5 0.0029 19.7 23.8 Ͻ0.0001 16.7 22.8 Ͻ0.0001 75–84 37.1 41.3 0.0004 13.4 16.5 0.0004 12.2 17.7 Ͻ0.0001 85ϩ 11.5 12.7 0.3319 4.9 4.8 0.9793 4.1 7.5 0.0002 Age-adjusted rates (total) 39.6 43.0 Ͻ0.0001 14.8 17.9 Ͻ0.0001 12.9 18.3 Ͻ0.0001 Race White 41.4 45.9 Ͻ0.0001 15.5 19.1 Ͻ0.0001 13.6 19.8 Ͻ0.0001 Black 36.8 37.3 0.8305 15.6 15.6 0.9733 6.6 9.1 0.0338 Other 33.5 33.8 0.8705 11.3 13.9 0.0549 14.8 19.0 0.0068 Rural residence No 39.9 43.0 0.0001 14.9 17.8 Ͻ0.0001 13.6 19.4 Ͻ0.0001 Yes 37.3 42.8 0.0132 14.2 18.0 0.0215 7.5 10.3 0.0296 State Medicaid program No 44.5 48.9 Ͻ0.0001 16.3 20.5 Ͻ0.0001 14.3 20.8 Ͻ0.0001 Yes 27.5 28.2 0.5825 11.2 11.1 0.9130 9.5 12.2 0.0023 Median household income of zip code ($) Ͻ40,000 36.3 39.3 0.0175 14.0 16.7 0.0040 10.2 15.1 Ͻ0.0001 40,000–51,999 40.7 43.1 0.0741 14.6 17.4 0.0039 14.4 18.7 Ͻ0.0001 Ն52,000 42.2 47.4 0.0003 16.1 19.7 0.0010 14.6 21.9 Ͻ0.0001 Hospitalization history Not hospitalized 44.7 46.8 0.0406 16.5 19.5 0.0001 13.9 20.2 Ͻ0.0001 Hospitalized (nonteaching) 30.3 36.7 0.0001 11.4 14.4 0.0109 11.6 15.3 0.0021 Hospitalized (teaching) 33.8 38.3 0.0042 13.0 16.1 0.0076 11.4 15.9 0.0001 Charlson score 0 45.8 50.1 0.0065 15.9 20.5 0.0001 12.9 19.3 Ͻ0.0001 1 42.4 46.9 0.0137 16.9 19.2 0.1074 14.4 20.9 Ͻ0.0001 Ն2 36.0 38.4 0.0155 13.7 16.0 0.0015 12.4 17.0 Ͻ0.0001 Medical specialty Primary care 35.9 39.5 Ͻ0.0001 13.7 16.1 0.0001 11.1 16.4 Ͻ0.0001 Endocrinologist 40.7 48.6 0.0219 14.5 19.5 0.0545 19.7 25.4 0.0496 Ob/gyn 60.7 66.1 0.0135 21.7 27.3 0.0041 21.9 29.7 0.0001 Endocrinologist plus ob/gyn 67.4 70.5 0.5779 22.3 29.4 0.1763 20.5 29.4 0.0829 Other 30.8 26.1 0.1783 10.8 14.3 0.1682 4.9 8.0 0.1048 Average number of physician visits per year 0–4 27.2 30.6 0.0101 9.9 12.2 0.0092 6.2 10.9 Ͻ0.0001 5–9 43.8 46.4 0.0415 15.5 18.9 0.0005 12.9 18.0 Ͻ0.0001 10–14 45.0 47.7 0.1220 17.6 20.5 0.0339 16.1 21.7 Ͻ0.0001 Ն15 45.1 51.9 0.0008 18.7 22.6 0.0166 21.0 29.3 Ͻ0.0001 Number of different diabetes preventive services received 0 19.7 NA 8.7 NA 6.2 NA 1 32.7 NA 12.0 NA 9.7 NA 2 41.4 NA 15.1 NA 14.0 NA 3 52.3 NA 19.7 NA 17.3 NA Data are percentages. *P values for the difference between women with and without diabetes. more visits, or did not have any diabetes ceiving an increasing number of diabetes out diabetes. The lower use of these three preventive service in the prior 2 years. In preventive services. preventive services are important findings addition, there were significant decreas- because women with diabetes are re- ing trends for all three services with in- CONCLUSIONS — The dominant ported to be at a higher risk for colorectal creasing Charlson scores. Increasing finding is that elderly women with diabe- cancer incidence and mortality (17,18) trends were associated with an increasing tes had significantly lower preventive and face the same risks for breast cancer number of physician visits and with re- health service use rates than women with- and osteoporosis. The most striking pos-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1469 Diabetes and screening services
Table 3—ORs and 95% CIs for patient and health service covariates among women with diabetes
Mammogram Colorectal cancer screening Bone density testing OR (95% CI) P* OR (95% CI) P OR (95% CI) P Age (per 10 years) 0.41 (0.38–0.43) 0.53 (0.50–0.57) 0.59 (0.52–0.66) Race White (ref.) Black 1.10 (0.94–1.29) 1.18 (0.94–1.48) 0.43 (0.36–0.50) Other 0.84 (0.75–0.93) 0.74 (0.59–0.91) 1.22 (1.05–1.41) Rural residence No Yes 1.00 (0.73–1.36) 1.04 (0.85–1.26) 0.71 (0.58–0.87) State Medicaid program No Yes 0.56 (0.50–0.61) 0.77 (0.72–0.83) 0.67 (0.54–0.82) Median household income of zip code ($) Ͻ40,000 (ref.) 0.6454 0.5214 0.7907 40,000–51,999 1.05 (0.93–1.19) 0.97 (0.82–1.15) 1.05 (0.90–1.23) Ն52,000 1.06 (0.83–1.34) 1.07 (0.88–1.29) 0.95 (0.64–1.41) Hospitalization history Not hospitalized (ref.) Hospitalized (nonteaching) 0.61 (0.52–0.72) 0.69 (0.59–0.80) 0.87 (0.76–0.98) Hospitalized (teaching) 0.62 (0.53–0.74) 0.74 (0.63–0.86) 0.71 (0.60–0.84) Charlson score 0 (ref.) Ͻ0.0001 0.0009 Ͻ0.0001 1 0.87 (0.76–0.99) 1.04 (0.90–1.20) 1.05 (0.87–1.27) Ն2 0.65 (0.58–0.72) 0.81 (0.71–0.92) 0.84 (0.78–0.92) Medical specialty Primary care (ref.) Endocrinologist 1.07 (0.85–1.34) 0.92 (0.71–1.20) 1.63 (1.35–1.96) Ob/gyn 2.80 (2.36–3.31) 1.57 (1.38–1.79) 1.73 (1.42–2.13) Endo plus ob/gyn 3.04 (2.33–3.96) 1.36 (0.76–2.42) 1.35 (1.09–1.66) Other 1.01 (0.84–1.22) 0.93 (0.61–1.43) 0.59 (0.31–1.13) Average number of physician visits per year 0–4 (ref.) Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 5–9 1.82 (1.61–2.05) 1.50 (1.30–1.72) 1.68 (1.51–1.86) 10–14 2.09 (1.87–2.32) 1.84 (1.53–2.22) 2.23 (2.00–2.50) Ն15 2.26 (1.89–2.69) 2.15 (1.61–2.88) 3.03 (2.51–3.66) Number of different diabetes preventive services received 0 (ref.) Ͻ0.0001 Ͻ0.0001 0.0125 1 1.76 (1.43–2.18) 1.26 (1.07–1.47) 1.40 (0.86–2.26) 2 2.29 (1.75–3.00) 1.50 (1.32–1.70) 1.84 (1.14–2.98) 3 3.42 (2.57–4.55) 1.95 (1.67–2.28) 2.20 (1.41–3.42) *P values are for a linear trend test of ORs. itive finding among those with diabetes cluded women with and without diabe- period. Thus, leaving screening or screen- was the association of receiving care from tes. The reasons for the strong positive ing motivation/scheduling to ob/gyns an ob/gyn with the highest rates of pre- associations are not clear (19,20). Wal- would be inadequate. Receipt of cancer ventive service use. Our findings are con- lace et al. (20) suggested that primary care screening care scheduling or motivation sistent with recent reports regarding physicians may defer to ob/gyns for fe- from endocrinologists would not solve mammography use among the managed- male-specific screening. While this might the problem either because too few care enrollees (Michigan) (9) and younger explain differences we found for mam- women with diabetes (6.0%) were seen by women (Ontario) (10) cited earlier. This mography and bone density testing, it endocrinologists. If we are to achieve the study extends those findings to elderly would not apply to our findings regarding “best practice” levels of care seen in Medicare beneficiaries living in the widely colorectal cancer screening. Also, defer- women treated by ob/gyns, then the use of located more-representative SEER areas. ring this care to ob/gyns would not be these services will have to be promoted Others have also reported higher good policy or practice for the elderly be- more effectively by primary care physi- rates of mammography among women cause we found that only 12% of elderly cians and others. While we found the who visited ob/gyns in studies that in- women visited an ob/gyn over a 2-year strongest associations with visiting an ob/
1470 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 McBean and Yu gyn, we are reluctant to attribute causality ple with diabetes in guidelines from fed- The major strengths of this study in- because it may be that the women who see eral or national organizations that clude the large size of the population or seek these physicians may be more pre- promote the use of prevention services studied, the use of SEER areas that are vention oriented. Nonetheless, our study but are not primarily or uniquely con- representative of the U.S. population, the met the criteria recently listed for address- cerned with diabetes such as the CDC, the accuracy of the SEER diagnoses, and the ing selection bias in studies such as ours National Cancer Institute, the American ability to exclude women with histories of (21). Cancer Society, and the CMS. An example breast and colorectal cancer from the Among women with diabetes, per- of such joint advocacy leading to success study. These latter women would likely haps the most disturbing finding was that in the promotion of preventive services have had mammograms or colorectal tests those who were in Medicaid-adminis- among people with diabetes was the effort that were part of follow-up for their can- tered programs were only about two-thirds to encourage influenza and pnuemococ- cer that would not be screening examina- as likely to receive any of the services (Table cal immunization. During the 1990s, the tions. Excluding these women increased 2). The relative odds in the multivariate CDC, the CMS, and the ADA all stressed the probability that the tests we counted analysis were similar: 0.56 for mammogra- that elderly individuals with diabetes were truly for screening. An additional phy, 0.77 for colorectal screening, and 0.67 should be vaccinated (26–28). As a re- strength of the study is that the propensity for bone density testing (Table 3). Women sult, in 2001, rates of influenza and pneu- score matching made the diabetes and in these programs are likely to be nursing mococcal vaccination were higher in nondiabetes study groups more compara- home residents with multiple chronic con- individuals with diabetes Ն65 years of ble in terms of the observable character- ditions with fewer visits to endocrinologists age compared with the total elderly pop- istics. Thus, the differences we found or ob/gyns, which might explain the lower ulation (influenza, 72.4 vs. 67.3%; pneu- between these two groups in the use of age-adjusted rates. However, this would not mococcal, 65.8 vs. 62.5%) (29). To our preventive services were more likely due explain why there was such a large differ- knowledge, there has been no particular to having diabetes and less likely due to ence after adjusting for all of the covariates. advocacy for cancer or osteoporosis potential confounders. Our study could It is not surprising that the use of the screening among women with diabetes be strengthened in several ways. Because screening services declined with age. This (2). Office-based interventions to identify of data limitations, we were obliged to use has been reported for mammography individuals with diabetes and their pre- zip code–level rather than individual- (22) and bone density testing (23), and it ventive service needs should be ex- level income information, which intro- likely reflects the strict adherence to panded. Examples of these interventions duces the possibility of ecologic bias. guidelines to mammography published include electronic reminder systems, spe- Also, we did not have information to mea- by organizations other than Centers for cific guidelines for disease management, sure practice characteristics such as size Medicare and Medicaid Services (CMS), and disease management programs in- and volume, use of information systems, as well as patient and physician prefer- volving different types of providers (3). or availability of diabetes care manage- ences. Bynum et al. (22) reported that Physician awareness of patients with low ment programs. health status, as measured by the propen- health literacy needs to increase. Inter- In conclusion, elderly women with sity to die, was independently associated ventions should be implemented to ad- diabetes are less likely than women with screening mammography use in the dress these needs in individuals with without diabetes to receive the three Medicare population. In our fully ad- diabetes who are at a higher risk of not recommended preventive services we justed analysis, we, too, found that those receiving preventive services. In our examined. If we are to achieve parity, with the highest Charlson scores were sig- study, individuals with low literacy were then it may be necessary to issue addi- nificantly less likely to receive any of the likely overrepresented in the group who tional guidelines emphasizing preven- three services (adjusted OR 0.65 for were state Medicaid program beneficia- tive care and initiate practice-based mammography, 0.81 for colorectal can- ries, a group that had among the lowest improvements targeting those at great- cer screening, and 0.84 for bone density rates of preventive service use. Over 33% est risk of not receiving these services. testing). of the elderly are reported to have mar- Among postmenopausal women, ginal or inadequate health literacy (30), bone mineral density is highest among and people with low health literacy are Acknowledgments— This study was sup- blacks, and osteoporotic fracture rates, less likely to achieve tight glycemic con- ported by grants from the National Institute of Aging (R01 AG 025079), the National Cancer including hip fracture, are highest among trol and more likely to have poor glycemic Institute (R01 CA 098974), and the National whites (23,24). In addition, postmeno- control (31). Elderly Medicare beneficia- Institute of Diabetes and Digestive and Kidney pausal black women do not perceive os- ries with inadequate health literacy are Diseases (R21 DK064833). teoporosis as a health risk (25). These less likely to receive preventive services factors may explain the large difference in (mammograms, Pap smears, and influ- the bone density measurement rates by enza and pneumococcal vaccination) References race. (32). Practicing physicians and residents 1. Centers for Disease Control and Preven- There are several ways in which parity routinely overestimate patients’ literacy tion: National Diabetes Surveillance Sys- might be achieved in the use of preventive levels (33–35). Fortunately, there have tem. Preventive Care Practice: Rates of services we examined (1). The ADA been reports of interventions successful at Preventive Care Practices [Internet], 2005. Available at http://www.cdc.gov/ should include specific recommendations improving diabetes care directed at peo- diabetes/statistics/preventive/mUSMenu. for cancer screening and bone density ple with diabetes with low health literacy htm. Accessed 30 June 2006 testing in the Standards of Medical Care in (36,37), as well as successful training pro- 2. Jencks SF, Huff ED, Cuerdon T: Change Diabetes (26). This should be combined grams to increase literacy knowledge in the quality of care delivered to Medi- with specific recommendations for peo- among family medicine residents (38). care beneficiaries, 1998–1999 to 2000–
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1472 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE
A Cohort Study of People With Diabetes and Their First Foot Ulcer The role of depression on mortality
1 1 KHALIDA ISMAIL, MRCPSYCH, PHD TRUDIE CHALDER, PHD The rate of recurrence of foot ulcers is 1 3 KIRSTY WINKLEY, PHD MICHAEL EDMONDS, MD estimated at 34, 61, and 70% in 1, 3, and 2 DANIEL STAHL, PHD 5 years, respectively (1). Around 15% de- velop osteomyelitis, and there is a twofold increase in mortality compared with peo- OBJECTIVE — The aim was to evaluate over 18 months whether depression was associated ple with diabetes without a foot ulcer (3, with mortality in people with their first foot ulcer. 10,11). Could psychological factors such as depressive disorders help to explain the RESEARCH DESIGN AND METHODS — A prospective cohort design was used. high rates of mortality and morbidity? Adults with their first diabetic foot ulcer were recruited from foot clinics in southeast London, The pooled prevalence of depressive U.K. At baseline, the Schedules for Clinical Assessment in Neuropsychiatry 2.1 was used to disorders in people with diabetes when define those who met DSM (Diagnostic and Statistical Manual of Mental Disorders)-IV criteria for minor and major depressive disorders. Potential covariates were age, sex, marital status, socio- diagnostic criteria are used is estimated at economic status, smoking, antidepressant use, A1C, macro- and microvascular complications, 11%, which is two times more common and University of Texas classification–based severity and size of ulcer. The main outcome was than the general population, and the esti- mortality 18 months later, and A1C was the secondary outcome. The proportion who had an mated pooled prevalence of depressive amputation, had recurrence, and whose ulcer had healed was recorded. symptoms using self-report measures is 31% (12). In cross-sectional studies RESULTS — A total of 253 people with their first diabetic foot ulcer were recruited. The (13,14), depressive disorders and symp- prevalence of minor and major depressive disorder was 8.1% (n ϭ 21) and 24.1% (n ϭ 61), toms are associated with poor glycemic respectively. There were 40 (15.8%) deaths, 36 (15.5%) amputations, and 99 (43.2%) recur- control and complications. Emerging ev- rences. In the adjusted Cox regression analysis, minor and major depressive disorders were idence from the U.S. shows that depres- associated with an approximately threefold hazard risk for mortality compared with no depres- sion (3.23 [95% CI 1.39–7.51] and 2.73 [1.38–5.40], respectively). There was no association sive symptoms are associated with between minor and major depression compared with no depression and A1C (P ϭ 0.86 and P ϭ increased mortality in diabetes, including 0.43, respectively). a dose-response–type association with se- verity of depression (15–20) based on CONCLUSIONS — One-third of people with their first diabetic foot ulcer suffer from clin- self-reported measures of depression ical depression, and this is associated with increased mortality. and/or diabetes. The received wisdom is that the mediating mechanism is via gly- Diabetes Care 30:1473–1479, 2007 cemic control, but prospective evidence for this association is still lacking (21). iabetic foot ulcers are one of the the onset and recurrence of foot ulcers People with early diabetic foot disease are most common, disabling, and (5–7). Primary and secondary prevention likely to fear the worst, such as gangrene D costly complications of diabetes (1– of diabetic foot ulcers can be achieved by or loss of a limb, but there is little epide- 3). The incidence and prevalence for foot daily foot examinations for painless ulcers miological evidence to support the role of ulcers is estimated at 2% and 5–7% per or injuries, regular podiatrist visits, use of psychological factors on adverse out- year, respectively (3,4). Duration of dia- appropriate foot wear, and maintenance comes (15,19). Depression, which can be betes, persistent hyperglycemia, and pe- of optimal diabetes self-care (8). Despite treated, often goes undetected in people ripheral neuropathy (associated with this, adverse outcomes following the on- with diabetes, and, even when detected, reduced pain sensation) are considered to set of foot ulcers are poor, and they are the treatment is not optimized (22). Our be well-known biological risk factors for most common reason for amputation (9). main hypothesis was that in people with ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● diabetes, depression was associated with increased risk of mortality following the From the 1Department of Psychological Medicine, Institute of Psychiatry, King’s College London, London, U.K.; the 2Department of Biostatistics, Institute of Psychiatry, King’s College London, London, U.K.; and the onset of their first foot ulcer compared 3Diabetic Foot Clinic, King’s College Hospital, London, U.K. with those who were not depressed. The Address correspondence and reprint requests to Khalida Ismail, Institute of Psychiatry, King’s College secondary hypothesis was that depression London, Weston Education Centre, 10 Cutcombe Rd., London, SE5 9RJ, U.K. E-mail: was prospectively associated with wors- [email protected]. Received for publication 10 November 2006 and accepted in revised form 7 March 2007. ening glycemic control. Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2313. Abbreviations: DSM, Diagnostic and Statistical Manual of Mental Disorders; SCAN 2.1, Schedules for Clinical Assessment in Neuropsychiatry 2.1. RESEARCH DESIGN AND A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion METHODS — The study protocol factors for many substances. was approved by the ethics committees © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby of the Institute of Psychiatry, King’s marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. College London, and the local partici-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1473 Diabetic foot ulcers and depression pating National Health Service trusts. Main explanatory variable Potential covariates All participants gave written informed Depression was measured using the Age, sex, self-reported ethnicity, socio- consent. Schedules for Clinical Assessment in Neu- economic status (36), smoking status A population-based cohort of adults, ropsychiatry 2.1 (SCAN 2.1) (30). Three (current, ex-, or nonsmoker), alcohol use aged Ն18 years with diabetes based on categories of depression were measured: (using the Alcohol Use Disorders Identi- World Health Organization criteria (23) those who met the Diagnostic and Statisti- fication Test: score Ն8 represented clini- and presenting with their first (baseline) cal Manual of Mental Disorders (DSM)-IV cally significant alcohol problems, and Ͻ foot ulcer was recruited between August criteria for major or minor depressive dis- 8 represented no problems) (37), and 2000 and October 2002 and prospec- orders and those who did not meet either antidepressant treatment were assessed at tively followed for 18 months. The setting (defined as no depression). The SCAN 2.1 baseline. Type and duration of diabetes and sampling frame constituted all the is a semistructured diagnostic interview (in years) and presence of complications community chiropody and hospital foot with good reliability and validity and was were recorded from medical notes. Mac- clinics within five National Health Service administered by a trained nurse (K.W.) rovascular complications were defined as health authorities in south London, U.K. (31). The SCAN 2.1 closely resembles the prior myocardial infarction, coronary and peripheral angioplasty, coronary artery (Lambeth, Southwark, Lewisham, North clinical psychiatric interview and allows bypass grafting, or cerebrovascular acci- Croydon, and Bexley and Greenwich), the interviewer to clarify the nature and dent. Microvascular complications were representing a population of 6 million, of severity of psychiatric symptoms and to exclude depressive symptoms judged sec- defined as retinopathy (background or which 80,000 are estimated to have dia- proliferative), measured using digital fun- betes (24,25). A similar model of multi- ondary to the direct physiological effects of their medical condition. Computerized dal examination; nephropathy (mac- disciplinary medical care of the diabetic roalbuminuria defined by a raised 24-h foot ulcer was used in each of these health algorithms generated the presence or ab- sence of a major depressive disorder protein or dialysis); and neuropathy (vi- authorities based on accepted local guide- bration perception threshold Ն25 volts). lines (26). (DSM-IV) (32). Current symptoms present in the preceding 4–6 weeks were We used the diet, exercise, and foot care We screened all people presenting subscales of the Summary of Diabetes with their first ulcer within the sampling assessed to reduce the bias of recalling symptoms of longer duration, as this pe- Self-Care Activities questionnaire, which frame. They were identified through a ro- is a brief and valid measure of adherence riod is considered the minimum neces- tating review of the preceding fortnight of to diabetes self-management (38). Partic- sary to capture depressive symptoms new and follow-up appointments at each ipants are asked to score, on a Likert scale present over 2 weeks, which is the mini- clinic. After an introduction by the podi- of 0–7, how often they have carried out mum duration criterion for DSM-IV. In- atrist, the researcher contacted the patient self-care activities over the last 7 days. ter-rater reliability for major depressive for an appointment to obtain informed disorders was assessed (K.W. and K.I.) in- consent and used a standardized checklist Statistical analysis dependently, conducting SCAN 2.1 inter- to assess for study eligibility. We invited STATA 9 (Stata, College Station, TX) was views of 10 people with diabetes not all of those eligible to participate. We de- used. Completers and dropouts at 18 involved in the study. A continuous mea- fined a clinically significant diabetic foot months were compared on baseline data sure of depressive symptoms was derived using the t test and 2 test for homogene- ulcer as follows: 1) the ulceration was in from the sum of the raw scores on all de- the anatomical foot, 2) there had to be a ity. The distribution of the main explana- pression items in the SCAN 2.1 using a tory variables and potential confounders full-thickness break in the epithelium separate algorithm (33). with a minimum width of 5 mm, and 3) at baseline and of the outcomes was com- Ն puted using percentage proportions or the arm-to-ankle ratio was 0.5 at either Ϯ the dorsalis pedis or anterior tibial sites means SD. We derived the mean A1C Main outcome measures from available measures at baseline and at using Doppler pressure readings (to ex- The date and cause of death was obtained clude severe ischemia) (27). When sub- 12 and 18 months to capture the assumed through the U.K.’s Central Register Office close temporal association between glyce- jects had more than one ulcer, the largest and coded according to ICD-10 codes. mic control and risk of ulceration. ulcer was defined as the baseline ulcer. A1C was measured at baseline and at 12 At baseline, univariate associations Exclusion criteria were 1) ulcer present and 18 months (34). First amputation, Ͼ between the association of baseline and for 1 year, 2) poor fluency in English, 3) first recurrence, and healing status were minor and major depressive disorders independent comorbid medical condi- measured during the 18 months using a compared with no depression and poten- tions associated with lower-extremity ul- standardized checklist completed by the tial explanatory variables were calculated. cers such as rheumatoid arthritis, and 4) clinic podiatrist, who was blind to the pa- Cox proportional hazards regression was severe mental illness such as schizophre- tient’s depression status at each patient used to study the relationship between nia or bipolar disorders, as they have clinic visit. Recurrence of foot ulcers was baseline DSM-IV minor and major de- mental health needs usually requiring defined as a recurrence of a full-thickness pressive disorders compared with no de- specialist services. Severity of the ulcer break in the epithelium with a minimum pression, with the binary outcome of was classified as superficial (grade 1) ver- width of 5 mm at the same or different site mortality adjusting for baseline potential sus deep (grade 2 or 3) based on the Uni- to the baseline ulcer. Healing was defined covariates that were either significantly versity of Texas classification (28), and as the complete closure of the ulcer with associated with depression or were clini- the surface area in centimeters squared skin intact (complete epithelialization) cally important, such as macrovascular (cm2) was measured using digital photog- and without drainage or sinus formation complications and type of diabetes, and raphy (29). (35). presented as hazard ratios and 95% CIs.
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The estimated survival curve was re- The baseline characteristics of the co- variable, and mortality (1.03 [1.01–1.06], ported such that the adjusted hazard ra- hort are reported in Table 1. Ten patients P ϭ 0.009; n ϭ 213). tios were standardized (in other words, all were prescribed an antidepressant (tricy- During the 18-month follow-up, the things being equal) by the average values clic [n ϭ 7] and selective serotonin re- proportion who underwent their first am- of those covariates that were included in uptake inhibitor [n ϭ 3]),6of10had putation was 15.5% (n ϭ 36) (all due to the final prediction model (except for se- major depressive disorder, and the re- diabetic foot disease) and those who had verity of ulcer in which case we standard- maining 4 had no depression. People with their first recurrence was 43.2% (n ϭ 99). ized as if the ulcer was severe [University major depressive disorder were more The coefficients of association, , of mor- of Texas grade 2 or 3]). The regression likely to be younger and have more severe tality with amputation, healing, and re- was repeated using depression as a con- and larger baseline ulcers (Table 1) than currence were of small effect sizes: Ϫ0.04 tinuous variable. In a secondary analysis, those who were not depressed. People (P ϭ 0.81), Ϫ0.24 (P Ͻ 0.001), and 0.25 missing observations of mean A1C were with minor depressive disorder were (P Ͻ 0.001), respectively. replaced with estimates using the expec- more likely to have a larger baseline ulcer At 18 months, mean A1C for no de- tation maximization imputation method. than those who were not depressed. pression (n ϭ 127), minor depressive dis- Quadratic effect of A1C was also assessed There were no differences in the diet, ex- order (n ϭ 11), and major depressive in the regression model to assess if this ercise, and foot care subscales of the Sum- disorder (n ϭ 42) was 8.2 Ϯ 1.8%, 8.2 Ϯ improved the fit. The overall fit of the mary of Diabetes Self-Care Activities 1.8%, and 8.6 Ϯ 1.9%, respectively. In model was assessed using Cox-Snell gen- scores between the three categories of de- ANCOVA, when adjusted for baseline eralized residual analysis (not presented), pression, except that people with major A1C and the covariates used in the sur- and robust standard errors were used to depressive disorder were less likely to ad- vival analysis, the association between mi- adjust for potential misspecification (39). here to their diet compared with those nor and major depressive disorders with To examine change in A1C over time in with no depression (P ϭ 0.002). A1C at 18 months was not significant minor and major depressive disorders During the 18 months of follow-up, when compared with no depression (ad- compared with those who were not there were 40 (15.8%) deaths. All deaths justed mean differences 0.1% [95% CI depressed, taking into account the base- were due to natural causes such as infec- Ϫ0.9 to 1.1] and 0.2% [Ϫ0.4 to 0.8], re- line A1C and other covariates, we did an tion (n ϭ 14), cardiovascular disease (n ϭ spectively). There was also no difference ANCOVA. The association between mor- 10), cerebrovascular accident (n ϭ 10), between major depressive and minor de- tality with amputation, recurrence, and cancer (n ϭ 4), renal failure (n ϭ 1), and pressive disorders at baseline and 18- healing status was assessed using the complications from liver disease (n ϭ 1). month A1C (0.2% [Ϫ1.0 to 1.3]). coefficient Of 10 people who had been prescribed an The calculation of the sample size was antidepressant, only 1 died. No patients CONCLUSIONS — We found that based on the pooled prevalence of major were receiving any psychological treat- one-third of people presenting with their depression of 14%, based on contempo- ments. In the Cox regression analysis (n ϭ first diabetic foot ulcer had clinically sig- raneous pooled data (40) that 30% of the 246), after adjusting for covariates (age, nificant depression (combining minor nondepressed subjects would have an ad- University of Texas severity, sex, smok- and major depressive disorders), and this verse outcome such as a recurrence of foot ing, mean A1C, marital status, and socio- was associated with an approximately ulcer 18 months later (1), a risk ratio of economic status) baseline minor and threefold increased risk of death 18 2.00 as the minimum clinically significant major depressive disorders were both sig- months later. There was no association effect of major depression, a two-tailed nificantly associated with an approxi- between depression at baseline and glyce- type 1 error of 0.05, and a power of 80%. mately threefold increase in the mic control 18 months later. We estimated that 162 nondepressed and likelihood of death (hazard ratio 3.23 The advantages of this study is that 27 depressed subjects were needed. An- [95% CI 1.39–7.51] and 2.73 [1.38– it was representative of hospital and ticipating a drop-out rate of 25%, our fi- 5.40], respectively) (Fig. 1) compared community settings practicing a similar nal estimated sample was 250 subjects. with those who had no depression. The model of medical care for foot ulcers in only other covariates that were signifi- a diverse socioeconomic and ethnic RESULTS — A total of 262 patients cantly associated with mortality were age population. We used a standardized presented with their first diabetic foot ul- (1.08 [1.05–1.11]) and, inversely, mean semistructured psychiatric interview to cer. Two hundred and sixty met the study A1C (0.74 [0.56–0.99]). The association generate the diagnosis of depression criteria, and of these 253 consented and between minor and major depressive dis- based on an internationally recognized constituted the cohort. Our follow-up order compared with no depression with psychiatric classification. We captured rates were 100% for mortality outcome; mortality did not significantly change if the dimensional nature of depression by 92.0, 93.7, and 90.5% for amputation the presence of macrovascular complica- including minor and major depressive (n ϭ 233), healing (n ϭ 237), and recur- tions (3.25 [1.39–7.62] and 2.74 [1.38– disorders and by deriving a continuous rence (n ϭ 229), respectively; and 72.3% 5.44], respectively) or type of diabetes measure of depressive symptoms from for A1C at 18 months (including those (3.25 [1.39–7.64] and 2.73 [1.38–5.40], the raw scores. The prospective design whose A1C was missing because they had respectively) were added to the model. as well as podiatrists remaining blind to died at 18 months). There were six (2.4%) Adding mean A1C as a quadratic term did depression status aimed to reduce bias patients for whom there was no A1C mea- not improve the fit. A missing value anal- in the assessment of outcomes. We surement at any time point. There was ysis replacing six missing values for mean achieved excellent follow-up rates for 90% agreement for major depressive dis- A1C did not alter the results. There was a mortality, but there were missing data order based on the 10 interviews con- significant association between depres- for the 18-month A1C, which was ducted by the two SCAN 2.1 raters. sion, when measured as a continuous partly attributable to the high rates of
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1475 Diabetic foot ulcers and depression
Table 1—Baseline characteristics of total study population and stratified by DSM-IV depressive disorder
Total Major depressive Minor depressive No depressive P population disorder disorder disorder value* n 253 61 21 171 Mean age (years) 62.0 Ϯ 13.9 57.4 Ϯ 14.5 65.2 Ϯ 13.6 63.3 Ϯ 13.4 0.01 Sex Female 92 (36.4) 26 (42.6) 7 (33.3) 59 (34.5) 0.50 Male 161 (63.6) 35 (57.4) 14 (66.7) 112 (65.5) Social class† I/II 85 (33.6) 16 (26.2) 9 (42.9) 60 (35.1) 0.40 III 94 (37.2) 22 (36.1) 8 (38.1) 64 (37.4) IV/V 74 (29.2) 23 (37.7) 4 (19) 47 (27.5) Marital status Married/cohabiting 125 (49.6) 28 (45.9) 11 (55) 86 (50.3) 0.74 Single/divorced/widowed 127 (50.4) 33 (54.1) 9 (45) 85 (49.7) Ethnicity White 182 (71.9) 43 (70.5) 15 (71.4) 124 (72.5) 0.95 Black/Asian/other 71 (28.1) 18 (29.5) 6 (28.6) 47 (27.5) Current smoking status Non- or ex-smoker 213 (84.2) 48 (78.7) 20 (95.2) 145 (84.8) 0.19 Smoker 40 (15.8) 13 (21.3) 1 (4.8) 26 (15.2) Alcohol problems AUDIT Ͻ8 214 (88.1) 52 (89.7) 18 (90) 144 (87.3) 0.86 AUDIT Ն8 29 (11.9) 6 (10.3) 2 (10) 21 (12.7) Type of diabetes Type 1 43 (17.0) 14 (23.0) 2 (9.5) 27 (15.8) 0.28 Type 2 210 (83) 47 (77.0) 19 (90.5) 144 (84.2) Microvascular complications None 32 (12.6) 6 (9.8) 1 (4.8) 25 (14.6) 0.33 One or more 221 (87.4) 55 (90.2) 20 (95.2) 146 (85.4) Macrovascular complications None 185 (73.1) 48 (78.7) 11 (52.4) 126 (73.7) 0.06 One or more 68 (26.9) 13 (21.3) 10 (47.6) 45 (26.3) Mean duration of diabetes (years) 14.7 Ϯ 13.2 13.0 Ϯ 10.4 19 Ϯ 18 14.7 Ϯ 13.4 0.2 Mean duration of ulcer (months) 3.1 Ϯ 3.6 3.1 Ϯ 3.4 2.6 Ϯ 3.5 3.2 Ϯ 3.7 0.77 Mean A1C (%) 8.2 Ϯ 1.7 8.5 Ϯ 1.8 7.5 Ϯ 1.7 8.2 Ϯ 1.7 0.12 University of Texas severity of ulcer Superficial (grade 1) 188 (74.3) 38 (62.3) 7 (33.3) 35 (20.5) 0.02 Deep ulcer (grade 2 or 3) 65 (25.7) 23 (37.7) 14 (66.7) 136 (79.5) Mean ulcer size (cm2) 3.2 Ϯ 6.7 4.7 Ϯ 10.5 5.5 Ϯ 8.5 2.3 Ϯ 4 0.01 Vibration perception threshold (volts) Ͻ25 47 (18.6) 11 (18.0) 1 (4.8) 35 (20.5) 0.22 Ն25 206 (81.4) 50 (82.0) 20 (95.2) 136 (79.5) Arm-to-ankle ratio Ն0.9 193 (76.3) 44 (72.1) 16 (76.2) 133 (77.8) 0.67 Ն0.5 to Ͻ0.9 60 (23.7) 17 (27.9) 5 (23.8) 38 (22.2) Data are means Ϯ SD or n (%). *2 Test for categorical variables or t test for continuous variables. †Social class occupations: I, professional; II, managerial; III, skilled; IV, semiskilled; and V, unskilled. AUDIT, Alcohol Use Disorders Identification Test. mortality. This may have led to biased sidual confounding from other diabetes and dysthymia, but this was unlikely to estimates of the association between de- complications and related conditions, but alter our findings as the prevalence of pression and glycemic control. this is unlikely as we explored this in the these disorders is approximately six times The limitations of our study are that modeling stage and we adjusted for the lower than major depressive disorders, we may have missed a small group of in- University of Texas classification and for and they have significant comorbidity stitutionalized or house-bound people, macrovascular complications. We did not with major depression (41,42). The high those whose ulcer was not accurately re- measure the presence of related depres- rates of depression are in keeping with the corded or diagnosed by the podiatrist, sive syndromes that do not meet the cri- literature that people with diabetes and and those who did not attend appoint- teria for minor or major depressive complications are about two to three ments. There is a small possibility of re- disorders, such as adjustment disorders times more likely to have depressive dis-
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tween minor and major depression in the risk of mortality, which is in contrast to findings in community samples (18). This was substantiated by the positive associa- tion between depressive symptoms and mortality. One possible explanation is that depression in people with diabetes complications may have a chronic and/or fluctuating course, as they have a greater burden of disease. The handful of studies on the course of depression suggest that it is chronic and disabling in diabetes (62,63). Our study demonstrates that a quar- ter of those presenting with their first di- abetic foot ulcer are suffering from a major depressive disorder, a further 8% have a minor depressive disorder, and both are associated with around a three- fold-increased mortality compared with those who are not depressed. Improve- ments in the screening, detection, and treatment of depression in this high-risk Figure 1—Predicted survival curve for subjects with and without DSM-IV depressive disorder. group could potentially lead to improved psychological and physical outcomes. orders, even when diagnostic criteria are did not observe any associations between used, and depressive symptoms than morbidity outcomes and mortality. those without complications (14). Although there is emerging evidence Acknowledgments— The funding body was Why do patients with depression and that depression increases mortality and not involved in the design and conduct of the diabetes have a significantly increased morbidity in people with diabetes, the study; the collection, management, analysis, risk of death compared with those who mediating mechanisms are less clear. and interpretation of the data; or the prepara- are not depressed? One possibility is that Some large-scale population-based pro- tion, review, or approval of the manuscript. We thank the Wellcome Trust for funding depression may lead to behavioral diffi- spective studies have reported that minor this project. We thank Maureen Bates and culties in adhering to the intensive medi- and major depression is associated with Melanie Doxford, Diabetic Foot Clinic, King’s cal regime, as reported in cross-sectional increased mortality in people with diabe- College Hospital, and Ian Aitkenhead for their community studies (43). There are sev- tes (17,18,20), but in randomized con- time and thoughts at the pilot stage. We also eral reasons why this mechanism is not trolled trials of interventions for thank all the participating patients and staff for the whole story. First, there was no asso- depression in diabetes, whereas depres- their time. We thank Professor Traolach ciation between depression at baseline sion scores tend to improve, glycemic Brugha and Dr. Trevor Hill, University of Le- and glycemic control 18 months later, control does not always improve (46–53). icester, U.K., for converting the SCAN 2.1 raw which is contrary to pooled data from Several alternative pathophysiologi- scores. Parts of this article were presented at cross-sectional studies (13). Second, be- cal processes that have been proposed to the 42nd European Association for the Study of Diabetes Annual Meeting, Copenhagen- havioral difficulties secondary to depres- explain the increased mortality in people Malmoe, Denmark-Sweden, 14–17 Septem- sion do not fully explain the increased with depressive disorders and cardiac ber 2006. mortality in people with other chronic mortality (44,54,55) may also apply to di- diseases. In a prospective study, un- abetes. Mechanisms proposed include de- healthy lifestyles and poor adherence creased heart rate variability secondary to References were not sufficient explanations for in- changes in autonomic tone (56), perhaps 1. Apelqvist J, Larsson J, Agardh C: Long- creased mortality in people with depres- secondary to diabetic autonomic neurop- term prognosis for diabetic patients with sive symptoms and cardiovascular disease athy; impairment of platelet function foot ulcers. J Intern Med 233:485–491, (44). In our study, we also did not find a (57); cytokine activation (58,59); and ac- 1993 consistent association between depres- tivation of the hypothalamic-pituitary- 2. Williams D: The size of the problem: ep- sion and diabetes self-care, but this may adrenal axis (60), which may increase the idemiological and economic aspects of have been partly due to the well- susceptibility to infection and cardiovas- foot problems in diabetes. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1479 Emerging Treatments and Technologies ORIGINAL ARTICLE
A Randomized, Double-Blind, Placebo- Controlled, Multicenter Study to Assess the Efficacy and Safety of Topiramate Controlled Release in the Treatment of Obese Type 2 Diabetic Patients
1 4 JULIO ROSENSTOCK, MD RICHARD STRAUSS, MD besity and weight gain are major 2 4 PRISCILLA HOLLANDER, MD ALBERT LEUNG, MD, PHD factors for type 2 diabetes (1,2), and 3 KISHORE M. GADDE, MD FOR THE OBD-202 STUDY GROUP 4 nearly 90% of the population with IANG UN PHD O X S , type 2 diabetes is considered overweight or obese (3). Weight reduction can signif- icantly improve multiple parameters of OBJECTIVE — This is a randomized, placebo-controlled study of the weight-loss efficacy metabolic control (4). and safety of a controlled-release (CR) formulation of topiramate in overweight and obese Topiramate has been approved in many patients with type 2 diabetes treated with diet and exercise alone or in combination with countries for the treatment of seizure disor- metformin. ders and the prophylaxis of migraine head- aches (5). Weight loss was incidentally but RESEARCH DESIGN AND METHODS — Patients with type 2 diabetes, BMI Ն27 consistently observed in most of the studies kg/m2, A1C Ͼ6.5 and Ͻ11.0%, treated with diet and exercise alone or in combination with in these neurologic indications, despite no metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR specific dietary interventions. Recently re- titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week ported placebo-controlled trials performed maintenance phase. in nondiabetic and diabetic populations have shown that treatment with topiramate RESULTS — A total of 111 subjects were randomized and analyzed. By the end of week (immediate release formulation dosed twice 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 daily) can induce significant weight loss (6– and 5.8%, respectively, of their baseline body weight (P Ͻ 0.001 vs. placebo). A1C im- 11). The controlled-release (CR) formula- proved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and tion of topiramate that utilizes an osmotic 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P Ͻ pump technology was developed to deliver 0.001 vs. placebo). Topiramate also significantly reduced blood pressure and urinary albu- once-daily dosing with improved tolerabil- min excretion. Adverse events were predominantly neuropsychiatric or central and periph- ity (12). eral nervous system related. This study aimed to evaluate the effi- cacy and safety of topiramate CR as a phar- CONCLUSIONS — Topiramate CR treatment produced significant weight loss and mean- macological adjunct in patients with type 2 ingful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated diabetes treated with diet and exercise alone with diet and exercise or in combination with metformin. However, the central nervous system or in combination with metformin. and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.
Diabetes Care 30:1480–1486, 2007 RESEARCH DESIGN AND METHODS — This study was spon- sored by Johnson & Johnson Pharmaceu- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tical Research & Development, LLC From the 1Dallas Diabetes and Endocrine Center, Dallas, Texas; 2Baylor Hospital, Dallas, Texas; 3Duke (Raritan, NJ), conducted in accordance University School of Medicine, Durham, North Carolina; and 4Johnson & Johnson Pharmaceutical Research with the Declaration of Helsinki and ICH & Development, Raritan, New Jersey. Good Clinical Practice, and approved by Address correspondence and reprint requests to Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center at Medical City, 7777 Forest Lane, C-685, Dallas, TX 75230. E-mail: [email protected]. ethics committees at all sites. All patients Received for publication 25 September 2007 and accepted in revised form 6 March 2007. provided full written informed consent Published online ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/ before enrollment. dc06-2001. Clinical trial reg. no. NCT00231647, clinicaltrials.gov. This study was performed at 22 outpa- Abbreviations: CNS, central nervous system; CR, controlled release; DIS, Diagnostic Interview Schedule; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test. tient clinical centers in the U.S. that enrolled This report describes an investigational use of topiramate. Topiramate is not approved in any country for obese patients with type 2 diabetes treated the treatment of obesity or diabetes. with diet and exercise alone or in combina- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tion with metformin. Eligible patients had factors for many substances. BMI between 27 and 50 kg/m2, A1C 6.5– © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 11.0%, and fasting plasma glucose 7.0– marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 13.3 mmol/l. Patients were excluded if they
1480 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Rosenstock and Associates had uncontrolled hypertension (systolic pletion or early withdrawal, the study Statistical analysis blood pressure Ն180 mmHg and diastolic drug was tapered over 2 weeks, and a final The sample size was selected to achieve at blood pressure Ն100 mmHg), diabetic mi- assessment was performed after a 2-week least 95% power to detect a 2.7% differ- crovascular complications, severe recurrent off-drug follow-up period. After the 1st ence between the mean percentage hypoglycemic episodes, any condition week of the study, a single reduction to weight loss in the placebo and the topira- likely to affect body weight, clinically signif- the next lower dose in a double-blind mate CR–treated arms. These calculations icant hepatic or renal disease, personal or manner was allowed if patients experi- used an SD of 3.8%, which was estimated family history of kidney stones, history of enced intolerable adverse events. Patients from the results of studies on immediate- neuropsychiatric disorder or central ner- on topiramate doses of 100 mg/day or release formation of topiramate (10,11). vous system (CNS) condition, including higher were down-titrated to 75 mg/day. The primacy efficacy analysis set was neuropsychiatric disorders diagnosed at Patients on topiramate doses of 75 and 50 predefined as a modified intention-to- screening using an abbreviated 11-item Di- mg/day were down-titrated to 50 and 25 treat analysis set, which consisted of all agnostic Interview Schedule (DIS) (13). In mg/day, respectively, and patients on randomized subjects who received at least addition, patients using medication ex- one dose of study drug and provided at topiramate 25 mg/day were withdrawn pected to influence weight or glycemic con- least one postbaseline efficacy evaluation. from the study. Placebo dose adjustments trol or using psychotropic medication were The primary end point was mean percent- were done similarly. also excluded. Patients receiving any an- age change in body weight from baseline tidiabetes medication, other than a stable to week 16 using the last observation car- dose of metformin, were excluded. Patients ried forward (LOCF) approach, which with changes in lipid or antihypertensive Assessments was analyzed by using ANCOVA with medications within 2 months of the study Weight was measured using calibrated treatment and diabetes treatment as fac- were also excluded. scales. Blood pressure was measured with tors and with baseline weight as covariate. This study was a randomized, dou- a wall-mounted sphygmomanometer and Response rates were analyzed using the ble-blind, placebo-controlled, multi- assessed as the mean of three sitting mea- Cochran-Mantel-Haenszel test stratified center, parallel-group study. There was surements taken after 5 min rest. Other by baseline diabetes treatment. Missing a 1-week screening phase, and eligible measurements included lipid profile, C- values were imputed on the basis of patients were randomized to placebo or reactive protein, and adiponectin. Oral LOCF. topiramate treatment and entered a glucose tolerance tests (OGTTs) (75 g) 7-week titration phase followed by a were administered at baseline and at the 9-week maintenance phase, a 2-week end of the maintenance phase (week 16) RESULTS taper, and a 2-week follow-up phase. with blood samples taken at 30 and 120 Randomization used an interactive min for the measurement of plasma glu- voice response system with a computer- Patient baseline characteristics and generated randomization schedule. Pa- cose, insulin, and C-peptide levels. A ho- disposition meostasis model assessment (HOMA) tients were stratified by concomitant  The study began recruitment on 4 Febru- metformin monotherapy and study cen- was used to derive estimates of -cell ary 2004, and the last patient completed ter. Treatment assignment was blinded function and insulin sensitivity (14). Uri- the study on 16 December 2004. The to the investigators, study site staff, and nary albumin-to-creatinine ratio was clinical centers screened 345 patients for patients. measured from a random single void participation in the study, of which 113 urine collection. Adverse events were re- were randomized and 111 included in the ported either spontaneously or in re- analysis. Two patients were excluded Nonpharmacologic treatment sponse to general, nondirect questions. from the analysis: one did not take any Patients were instructed to follow a non- Blood glucose monitors and diaries were study drug postrandomization, and the pharmacologic lifestyle intervention pro- distributed for recording of hypoglycemic other withdrew from the study (due to gram (Pathways to Change, Johnson & episodes. During the study, an abbrevi- possible anemia) after taking one dose of Johnson Healthcare Systems, Piscataway, ated six-item DIS was administered at ev- study drug but before any measurements NJ) for the duration of the study, includ- ery visit to screen for newly emergent had been made. Overall, 81% of placebo ing the follow-up period. The program depression and/or suicidal ideation. patients (n ϭ 46) and 72% of topiramate consisted of an individualized 600 kcal patients (n ϭ 39) completed the study. deficit diabetes diet, a behavioral modifi- Among patients treated with topiramate cation program, and a physical activity who completed the study, final dosing program. Patient withdrawal was 175 mg (n ϭ 34), 150 mg (n ϭ 1), 75 Patients were withdrawn from the study if mg (n ϭ 3), and 50 mg (n ϭ 1). they met predefined criteria for persistent Among the patients who withdrew Pharmacologic treatment hyperglycemia, unexplained severe hypo- from the study, the reasons for with- Eligible patients were randomized to pla- glycemia, frequent mild or moderate hy- drawal included adverse events (placebo cebo or topiramate CR 175 mg/day. Pa- poglycemia, or persistent asymptomatic 7%, topiramate 9%), patients’ choice (pla- tients randomized to topiramate had their hypoglycemia. Also, patients whose re- cebo 4%, topiramate 7%), loss to fol- dosage titrated upward by 25 mg/day sponses to the DIS suggested a diagnosis low-up (placebo 2%, topiramate 6%), each week over a 7-week period and then of depression or suicidal thoughts were and unknown (placebo 7%, topiramate continued on the 175 mg/day dose during withdrawn and referred for mental health 6%). Among patients treated with topira- the maintenance phase. On study com- consultation. mate who did not complete the study, fi-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1481 Topiramate in obese diabetic patients
Table 1—Patient characteristics at baseline (modified intent to treat)
Placebo Topiramate CR 175 mg/day Total n 57 54 111 Age (years) 53.5 Ϯ 11.1 51.8 Ϯ 11.5 52.7 Ϯ 11.3 Male (%) 42 22 32 White (%) 79 70 75 Body weight (kg) 110.2 Ϯ 19.4 106.0 Ϯ 17.2 108.1 Ϯ 18.4 BMI (kg/m2) 37.7 Ϯ 5.7 38.1 Ϯ 5.3 37.9 Ϯ 5.5 Fasting plasma glucose (mmol/l) 9.3 Ϯ 2.0 9.2 Ϯ 2.0 9.3 Ϯ 2.0 A1C (%) 7.5 Ϯ 0.82 7.6 Ϯ 0.93 7.5 Ϯ 0.87 Baseline diabetes treatment (%) Diet only 30 22 26 Diet and metformin 70 78 74 Data are means Ϯ SD unless otherwise indicated. nal dosing was 175 mg (n ϭ 7), 150 mg the placebo and topiramate groups, re- Other end points (n ϭ 1), 100 mg (n ϭ 2), 75 mg (n ϭ 2), spectively (P ϭ 0.078 vs. placebo). The A significant improvement was observed and 50 mg (n ϭ 4). hip circumference was reduced by 1.0 in systolic and diastolic blood pressure in Baseline characteristics and demo- and 3.2 cm in the placebo and topira- the topiramate compared with the pla- graphics of the patients are shown in Ta- mate groups, respectively (P ϭ 0.012 cebo group (Table 2). Topiramate treat- ble 1. The two treatment groups were vs. placebo). ment was also associated with a similar except that the placebo group had Glycemic control. Fasting plasma levels significant reduction in urinary albumin- a higher proportion of men. The propor- were reduced by 0.6 and 1.6 mmol/l from to-creatinine ratio (Table 2). tions of patients receiving concomitant a baseline of 9.3 and 9.2 mmol/l in the A comprehensive lipid profile per- antihypertensive or lipid-lowering agents placebo and topiramate groups, respec- formed at baseline and week 16 revealed were 59 and 29%, respectively. Over 95% tively (P ϭ 0.002 vs. placebo). A1C im- reductions in total, LDL, and HDL choles- of patients did not have any change in proved from a baseline of 7.4% in the terol and triglycerides with topiramate these concomitant medications or doses placebo and 7.6% in the topiramate treatment. These changes were not statis- over the study period. tically significant except for HDL choles- groups to 7.1 and 6.7%, respectively, rep- terol. However, there were no differences resenting a between-treatment group dif- in the total-to-HDL cholesterol ratio and Efficacy Ͻ ference of 0.5% (P 0.001) in the change LDL-to-HDL cholesterol ratio. There was Weight. Topiramate significantly re- from baseline. The treatment groups be- a nonsignificant reduction in C-reactive duced body weight during the 16 weeks gan to separate in A1C by week 4 of titra- protein and an increase in adiponectin of treatment (Table 2). By the end of tion (Fig. 1B). (P ϭ 0.058) with topiramate treatment. week 16, patients in the placebo and The proportion of patients having an topiramate groups lost 2.5 and 6.0 kg, absolute A1C reduction of at least 0.7% at which represented 2.3 and 5.8%, re- week 16 in the placebo and topiramate Safety spectively, of their baseline body weight groups was 25 and 48%, respectively Table 3 lists common adverse events that Ͻ (P 0.001 vs. placebo) or a placebo- (P ϭ 0.009 vs. placebo), and the propor- occurred in at least 5% of topiramate- subtracted weight loss of 3.5%. The tion of patients having an A1C reduction treated patients and at a greater incidence treatment groups began to diverge in of at least 1.0% was 21 and 35%, respec- versus placebo. These adverse events weight by week 2 of titration (Fig. 1A). tively (P ϭ 0.100 vs. placebo). The pro- were generally related to the CNS or pe- Similar differences in weight loss be- ripheral nervous system or were psychiat- portion of patients having achieved A1C tween topiramate and placebo were ob- ric in nature. The onset of CNS and Ͻ7.0% at week 16 in the placebo and served when completers were analyzed. psychiatric adverse events occurred pri- topiramate groups was 46 and 69%, re- The proportion of patients who lost ϭ marily during the 7-week titration phase Ն5% of baseline body weight at week spectively (P 0.014 vs. placebo). in the topiramate-treated subjects. Of the 16 in the placebo and topiramate Compared with placebo, patients on 23 topiramate-treated subjects with CNS groups was 19 and 50%, respectively topiramate also demonstrated a signifi- adverse events, 2 subjects had adverse (P Յ 0.001 vs. placebo), and the pro- cantly greater improvement in fasting events that persisted at the end of the portion of patients who lost Ն10% of plasma glucose and 2-h glucose following study. For the 18 topiramate-treated sub- baseline body weight was 2 and 20%, an OGTT. Consistent with these changes, jects with psychiatric adverse events, 4 respectively (P ϭ 0.002 vs. placebo). there were significant increases in 2-h insu- subjects had adverse events that per- Consistent with the effects of topira- lin and C-peptide values in the topiramate sisted. There was only one serious adverse mate on body weight, there were greater compared with the placebo group. Calcula- event in the topiramate group, a case of reductions in BMI and waist and hip tions based on HOMA revealed no signifi- renal calculus considered possibly drug- circumferences in the topiramate- cant differences between the two treatment related by the investigator. There were no treated patients. The waist circumfer- groups in basal pancreatic -cell function or deaths in the study. ence was reduced by 2.3 and 4.2 cm in insulin resistance. The overall incidence for withdrawal
1482 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Table 2—Mean changes from baseline (modified intent to treat, last observation carried forward) in primary and key secondary end points 1483
P for Placebo Topiramate CR 175 mg/day between- treatment Mean change Mean change group n Baseline Week 16 from baseline n Baseline Week 16 from baseline difference Ϯ Ϯ Ϫ Ϯ Ϯ Ϯ Ϫ Ϯ Ͻ
Rosenstock and Associates Body weight (kg) 55 109.7 19.6 107.3 19.7 2.5 3.1 54 106.0 17.2 100.0 18.1 6.0 5.2 0.001 % change from baseline Ϫ2.3 Ϯ 2.9 Ϫ5.8 Ϯ 4.8 Ͻ0.001 Anthropomorphic measurements BMI (kg/m2) 55 37.7 Ϯ 5.8 36.9 Ϯ 5.9 Ϫ0.8 Ϯ 1.1 54 38.1 Ϯ 5.3 36.0 Ϯ 5.9 Ϫ2.1 Ϯ 1.8 Ͻ0.001 Waist circumference (cm) 52 114.7 Ϯ 11.9 112.5 Ϯ 11.6 Ϫ2.3 Ϯ 4.7 47 115.4 Ϯ 11.4 111.2 Ϯ 12.7 Ϫ4.2 Ϯ 5.7 0.078 Hip circumference (cm) 52 123.0 Ϯ 13.1 122.0 Ϯ 13.1 Ϫ1.0 Ϯ 4.7 47 122.2 Ϯ 12.1 119.0 Ϯ 12.7 Ϫ3.2 Ϯ 4.5 0.012 Glycemic control parameters A1C (%) 55 7.4 Ϯ 0.83 7.1 Ϯ 0.89 Ϫ0.4 Ϯ 0.80 52 7.6 Ϯ 0.92 6.7 Ϯ 0.85 Ϫ0.9 Ϯ 0.77 Ͻ0.001 Fasting plasma glucose (mmol/l) 55 9.3 Ϯ 2.1 8.7 Ϯ 1.8 Ϫ0.6 Ϯ 1.8 52 9.2 Ϯ 2.1 7.6 Ϯ 2.2 Ϫ1.6 Ϯ 2.0 0.002 HOMA Pancreatic -cell function (%) 50 43.7 Ϯ 36.0 43.6 Ϯ 26.6 Ϫ0.1 Ϯ 27.9 45 54.7 Ϯ 69.4 54.8 Ϯ 75.7 0.0 Ϯ 71.5 0.665 Insulin resistance 50 4.8 Ϯ 4.6 4.0 Ϯ 2.3 Ϫ0.8 Ϯ 4.3 45 5.7 Ϯ 4.3 4.6 Ϯ 4.1 Ϫ1.1 Ϯ 3.6 0.583 OGTT Fasting plasma glucose (mmol/l) 44 9.2 Ϯ 1.9 8.6 Ϯ 1.8 Ϫ0.6 Ϯ 1.8 39 9.3 Ϯ 2.1 7.4 Ϯ 2.3 Ϫ1.9 Ϯ 1.8 0.001 2-h plasma glucose (mmol/l) 48 16.4 Ϯ 3.8 15.3 Ϯ 3.7 Ϫ1.1 Ϯ 2.9 42 15.7 Ϯ 3.2 13.1 Ϯ 4.1 Ϫ2.6 Ϯ 4.1 0.018 Baseline plasma insulin (IU/ml) 52 11.3 Ϯ 9.7 10.3 Ϯ 5.1 Ϫ1.1 Ϯ 8.4 45 13.6 Ϯ 10.1 12.7 Ϯ 10.1 Ϫ1.0 Ϯ 6.62 0.279 2-h plasma insulin (IU/ml) 47 34.6 Ϯ 27.4 34.1 Ϯ 23.3 Ϫ0.5 Ϯ 18.2 41 45.1 Ϯ 48.5 54.5 Ϯ 43.6 9.5 Ϯ 40.0 0.009 Mean blood pressure Systolic (mmHg) 55 127.9 Ϯ 15.16 123.7 Ϯ 14.3 Ϫ4.2 Ϯ 12.9 54 127.2 Ϯ 12.5 117.1 Ϯ 11.8 Ϫ10.2 Ϯ 12.8 0.004 Diastolic (mmHg) 55 78.4 Ϯ 8.9 76.8 Ϯ 10.6 Ϫ1.6 Ϯ 8.7 54 79.1 Ϯ 7.1 73.8 Ϯ 8.5 Ϫ5.3 Ϯ 8.5 0.032 Urinary albumin-to-creatinine 43 0.031 Ϯ 0.047 0.029 Ϯ 0.051 Ϫ0.002 Ϯ 0.038 39 0.046 Ϯ 0.086 0.018 Ϯ 0.025 Ϫ0.028 Ϯ 0.071 0.033 ratio (mg/mg creatinine) Lipid profile* Total cholesterol (mmol/l) 53 5.37 Ϯ 1.01 5.28 Ϯ 1.03 Ϫ1.4 Ϯ 11.6* 46 5.53 Ϯ 1.31 5.16 Ϯ 1.22 Ϫ5.9 Ϯ 12.2* 0.109
LDL cholesterol (mmol/l) 53 3.27 Ϯ 0.89 3.34 Ϯ 0.90 3.4 Ϯ 19.1* 46 3.40 Ϯ 1.04 3.29 Ϯ 0.98 Ϫ1.7 Ϯ 16.1* 0.250 2007 HDL cholesterol (mmol/l) 53 1.25 Ϯ 0.33 1.28 Ϯ 0.31 3.5 Ϯ 13.2* 46 1.18 Ϯ 0.31 1.15 Ϯ 0.28 Ϫ1.6 Ϯ 11.3* 0.016 UNE Triglycerides (mmol/l) 52 1.73 Ϯ 0.67 1.76 Ϯ 0.72 6.4 Ϯ 40.0* 46 2.02 Ϯ 1.22 1.72 Ϯ 1.09 Ϫ7.3 Ϯ 34.6* 0.246 Total-to-HDL cholesterol ratio 53 4.54 Ϯ 1.30 4.29 Ϯ 1.04 Ϫ0.25 Ϯ 0.68 46 4.93 Ϯ 1.63 4.66 Ϯ 1.34 Ϫ0.28 Ϯ 0.89 0.410 6, J LDL-to-HDL cholesterol ratio 53 2.79 Ϯ 1.03 2.73 Ϯ 0.84 Ϫ0.06 Ϯ 0.53 46 3.06 Ϯ 1.25 2.99 Ϯ 1.06 Ϫ0.06 Ϯ 0.68 0.413
Other end points NUMBER Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Adiponectin (ng/ml) 52 5,068 2,729 5,514 3,641 446 1,655 45 4,644 2,464 5,741 3,146 1,098 1,862 0.058 30, C-reactive protein (mg/l) 53 7.1 Ϯ 6.7 7.1 Ϯ 7.5 0.0 Ϯ 3.9 46 7.7 Ϯ 6.1 6.7 Ϯ 7.6 Ϫ1.1 Ϯ 6.3 0.522 Data are means Ϯ SD. *Changes in lipid parameters are listed as mean percentage change from baseline. VOLUME , ARE C IABETES D Topiramate in obese diabetic patients
bonate levels at the final visit. No other significant changes in laboratory ana- lytes were observed.
CONCLUSIONS — This randomized trial demonstrated the efficacy of topira- mate in a CR formulation as adjunctive therapy in obese individuals with type 2 diabetes treated with diet and exercise alone or in combination with metformin. Treatment with topiramate induced rapid and meaningful weight reduction and im- provement in glycemic control compared with placebo. These results are consistent with previously reported results in obese patients with type 2 diabetes treated with topiramate (10,11) or other weight-loss– inducing agents (15,16). The mechanism of action by which topiramate causes weight loss is not known. Animal studies suggest that cen- tral action may potentially reduce appe- tite and/or food intake (17,18). Studies in rodent models suggest that topiramate may also affect energy utilization, possi- bly due to stimulation of lipoprotein lipase in adipose tissue and skeletal mus- cle (19). It is not known whether topiramate’s effects on glycemic control parameters are independent of its weight loss effect. The HOMA analyses were inconclusive, but there was a significantly higher level of insulin secretion 2-h post-OGTT with im- proved glucose responses. Apart from effects on body weight and A1C, treatment with topiramate led to significant reductions in systolic and diastolic blood pressure compared with Figure 1—Mean percentage change in body weight (A) and A1C (B) from baseline over time. F, placebo. The degree of blood pressure re- topiramate treatment; E, placebo treatment. duction is similar to that observed in the trials of antihypertensive agents. A reduc- tion in urinary albumin excretion was also due to adverse events was 7% (four pa- the topiramate group had dose reduction observed, most likely related to improve- tients) in the placebo group and 9% (five or interruption of treatment due to intol- ments in blood pressure and glycemic patients) in the topiramate group. In the erable adverse events. control. The observed changes in these placebo group, two patients withdrew Three patients in each treatment surrogate markers suggest a potential for due to depression and two due to hyper- group reported hypoglycemic symptoms, improvement in the cardiovascular risk glycemia or worsening of diabetes con- but only one patient in the placebo group profile for this population of obese dia- trol. In the topiramate group, five patients had hypoglycemia confirmed by a low betic patients. However, the effect of topi- withdrew due to adverse events. Three of blood glucose value (40 mg/dl). The other ramate on lipids is neutral. There was a these patients had adverse events that patients reported hypoglycemic symp- small reduction in HDL cholesterol, with were considered drug related: one patient toms only. the ratios of total cholesterol and LDL had renal calculus, one had depression, Consistent with the carbonic anhy- cholesterol to HDL cholesterol not being and one patient had fatigue, dizziness, drase inhibitory effect of topiramate, different between the two treatment and confusion. The other two patients asymptomatic decrease in bicarbonate groups. The large variation in lipid mea- had non–drug-related adverse events of was observed. The changes from base- surements among subjects, as well as the anxiety and dizziness as judged by the in- line were 1.1 and 1.1 mmol/l for the small sample size, makes interpretation vestigator. One (2%) patient in the pla- placebo and topiramate groups, respec- difficult. Although C-reactive protein cebo group and seven (13%) patients in tively. All patients had normal bicar- level was reduced with topiramate treat-
1484 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Rosenstock and Associates
Table 3—Adverse events (safety population) tion: Prevalence of Overweight and Obe- sity Among Adults With Diagnosed Diabetes–United States, 1988–1994 and Topiramate 1999–2002. MMWR 53:1066–1068, CR 175 2004 Placebo mg/day 4. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, n 57 54 Ն Dahlgren S, Larsson B, Narbro K, Sjos- Patients with 1: trom CD, Sullivan M, Wedel H, Swedish Adverse event 42 (74) 49 (91) Obese Subjects Study Scientific Group: Serious adverse event 2 (4) 1 (2) Lifestyle, diabetes, and cardiovascular Adverse event resulting in discontinuation 4 (7) 5 (9) risk factors 10 years after bariatric sur- Common treatment-emergent adverse events* gery. N Engl J Med 351:2683–2693, Gastrointestinal system disorders 21 (37) 19 (35) 2004 Constipation 4 (7) 7 (13) 5. Topiramate (Topamax). In Physicians’ Dyspepsia 3 (5) 4 (7) Desk Reference. Montvale, NJ, Medical Gastroenteritis 2 (4) 3 (6) Economics Co, Inc, 2005, p. 2541–2549 6. Bray GA, Hollander P, Klein S, Kushner R, Body as a whole: general disorders 18 (32) 17 (31) Levy B, Fitchet M, Perry BH, for the U.S. Fatigue 2 (4) 6 (11) Topiramate Research Group: The effect of Pain 3 (5) 3 (6) topiramate on weight loss in obese sub- Central and peripheral nervous system disorders 12 (21) 23 (43) jects: a 6-month randomized placebo- Paresthesia 0 15 (28) controlled dose-ranging trial. Obes Res 11: Dizziness 2 (4) 8 (15) 722–733, 2003 Neuropathy 1 (2) 3 (6) 7. Wilding J, Van Gaal L, Rissanen A, Ver- Hypoesthesia 0 3 (6) cruysse F, Fitchet M, for the OBES-002 Respiratory system disorders 15 (26) 13 (24) Study Group: A randomized double- Upper respiratory tract infection 8 (14) 9 (17) blind placebo-controlled study of the long-term efficacy and safety of topira- Sinusitis 1 (2) 4 (7) mate in the treatment of obese subjects. Psychiatric disorders 6 (11) 18 (33) Int J Obes 28:1399–1410, 2004 Anxiety 2 (4) 4 (7) 8. Astrup A, Caterson I, Zelissen P, Guy- Difficulty with memory 0 4 (7) Grand B, Carruba M, Levy B, Sun X, Insomnia 1 (2) 3 (6) Fitchet M, for the OBES-004 Study Somnolence 0 4 (7) Group: Topiramate: long-term mainte- Appetite increased 0 3 (6) nance of weight loss induced by a low- Data are n (%). *Occurring in at least 5% of topiramate-treated patients and at a greater incidence than in calorie diet in obese subjects. Obes Res 12: placebo-treated patients, n (%). 1658–1669, 2004 9. Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Kumar A, Fitchet M: Efficacy and safety of topiramate in the treatment of ment, the difference from placebo was not verse event profile of topiramate CR obese subjects with essential hypertension. significant. makes it unsuitable for the treatment of Am J Card 96:243–251, 2005 The timing and frequency of CNS and obesity and diabetes. 10. Toplak H, A Hamann A, Moore R, Masson psychiatric adverse events reported were E, Gorska M, Vercruysse F, Sun X, Fitchet similar to those previously reported in M: Efficacy and safety of topiramate in obese nondiabetic and diabetic patients Acknowledgments— Principal investigators combination with metformin in the treat- (6–11) and also similar to those reported in the OBD-202 Study Group include: J. ment of obese subjects with type 2 diabe- on the topiramate label. There were sub- Anderson, L. Aronne, R. Atkinson, B. Feaver, tes: a randomized, double-blind, placebo- K. Gadde, H. Glatte, P. Hollander, L. Klaff, S. stantially more CNS and psychiatric ad- controlled study. Int J Obes (Lond) 31: Klein, D. Kreiger, T. Littlejohn, P. O’Neill, X. 138–146, 2007 verse events in patients treated with Pi-Sunyer, G. Raad, E. Riffer, J. Rosen, J. 11. Stenlof K, Rossner S, Vercruysse F, Kumar topiramate. These results, therefore, indi- Rosenstock, S. Schwartz, D. Smith, N. Soler, R. A, Fitchet M, Sjostrom L, for the OBDM- cate that a CR formulation does not pro- Vargas, and T. Wadden. 003 Study Group: Topiramate in the vide tolerability advantages over treatment of obese subjects with drug- immediate-release formulation. naı¨ve type 2 diabetes. Diabetes Obes Metab In summary, treatment with the CR References 9:360–368, 2007 formulation of topiramate was demon- 1. Chan JM, Rimm EB, Colditz GA, Stampfer 12. Wong PSL, Gupta SK, Stewart BD: Os- strated to effectively reduce body weight MJ, Willett WC: Obesity, fat distribution, motically controlled tablets. In Drugs and along with meaningful improvements in and weight gain as risk factors for clinical the Pharmaceutical Sciences: Modified- A1C levels and 2-h post-OGTT insulin se- diabetes in men. Diabetes Care 17:961– Release Drug Delivery Technology. Vol. cretion in addition to significantly lower- 969, 1994 126. Rathbone MJ et al., Eds. New York, 2. Hu FB, Manson JE, Stampfer MJ, Colditz Marcel Dekker, 2003 ing blood pressure and urinary albumin G, Liu S, Solomon CG, Willett WC: Diet, 13. Robins LN, Helzer JE, Croughan J, Ratcliff excretion in obese patients with type 2 lifestyle, and the risk of type 2 diabetes KS: National Institute of Mental Health diabetes treated with diet and exercise mellitus in women. N Engl J Med 345: Diagnostic Interview Schedule: its his- alone or with metformin monotherapy. 709–797, 2001 tory, characteristics, and validity. Arch However, the CNS and psychiatric ad- 3. Centers for Disease Control and Preven- Gen Psychiatry 38:381–389, 1981
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1485 Topiramate in obese diabetic patients
14. Wallace TM, Levy JC, Matthews DR: Use 949, 2005 tive line ‘depressed’ rats and upregulates and misuse of HOMA modeling. Diabetes 17. Gibbs JW 3rd, Sombati S, DeLorenzo NPY, galanin, and CRH-LI in the hypothal- Care 27:1487–1495, 2004 RJ, Coulter DA: Cellular actions of topi- amus: implications for mood-stabilizing 15. Curran MP, Scott LJ: Orlistat: A review of ramate: blockade of kainate-evoked in- and weight loss-inducing effects. Neuropsy- its use in the management of patients with ward currents in cultured hippocampal chopharmacology 28:1292– obesity. Drugs 64:2845–2864, 2004 neurons. Epilepsia 41 (Suppl. 1):S10– 1299, 2003 16. Vettor R, Serra R, Fabris R, Pagano C, Fed- S16, 2000 19. Richard D, Ferland J, Lalonde J, Samson erspil G: Effect of sibutramine on weight 18. Husum H, van Kammen D, Termeer E, P, Deshaies Y: Influence of topiramate in management and metabolic control in Bolwig TG, Mathe AA: Topiramate normal- the regulation of energy balance. Nutrition type 2 diabetes Diabetes Care 28:942– izes hippocampal NPY-LI in Flinders sensi- 16:961–966, 2000
1486 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Emerging Treatments and Technologies ORIGINAL ARTICLE
Effects of Once-Weekly Dosing of a Long- Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes
1 3 DENNIS KIM, MD MICHAEL TRAUTMANN, MD and insulin resistance (3,4). Furthermore, 1 1 LEIGH MACCONELL, PHD MARK FINEMAN, MS use of many antihyperglycemic medica- 1 1 DONGLIANG ZHUANG, PHD KRISTIN TAYLOR, PHD 2 tions is associated with weight gain (5). PRAJAKTI A. KOTHARE, PHD Incretin hormones, intestinally de- rived hormones that stimulate glucose- dependent insulin secretion in response OBJECTIVE — In patients with type 2 diabetes, exenatide reduces A1C, postprandial and to food intake, play an important role in fasting glucose, and weight. In this study we investigated the effects of continuous exenatide glucose homeostasis (6). Glucagon-like administration from a long-acting release (LAR) formulation. peptide-1 (GLP-1) is an incretin hormone RESEARCH DESIGN AND METHODS — In this randomized, placebo-controlled with multiple glucoregulatory actions, in- phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for cluding enhancement of glucose- 15 weeks to subjects with type 2 diabetes (n ϭ 45) suboptimally controlled with metformin dependent insulin secretion, suppression (60%) and/or diet and exercise (40%): 40% female, A1C (mean Ϯ SD) 8.5 Ϯ 1.2%, fasting of inappropriately elevated glucagon se- plasma glucose 9.9 Ϯ 2.3 mmol/l, weight 106 Ϯ 20 kg, and diabetes duration 5 Ϯ 4 years. cretion, slowing of gastric emptying, and reduction of food intake and body weight RESULTS — From baseline to week 15, exenatide LAR reduced mean Ϯ SE A1C by Ϫ1.4 Ϯ (6–9). Postprandial secretion of GLP-1 is 0.3% (0.8 mg) and Ϫ1.7 Ϯ 0.3% (2.0 mg), compared with ϩ0.4 Ϯ 0.3% with placebo LAR (P Ͻ Յ reduced in patients with type 2 diabetes 0.0001 for both). A1C of 7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg (10), suggesting that the GLP-1 signaling exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by Ϫ2.4 Ϯ 0.9 mmol/l (0.8 mg) and Ϫ2.2 Ϯ 0.5 mmol/l (2.0 mg) pathway is an attractive therapeutic tar- compared with ϩ1.0 Ϯ 0.7 mmol/l with placebo LAR (P Ͻ 0.001 for both). Exenatide LAR get. However, GLP-1 is rapidly degraded reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR by the enzyme dipeptidyl peptidase-IV had body weight reductions (Ϫ3.8 Ϯ 1.4 kg) (P Ͻ 0.05), whereas body weight was unchanged and has a relatively short half-life (ϳ2 with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event. min) (6). The therapeutic potential of the No subjects treated with exenatide LAR withdrew from the study. GLP-1 pathway has led to the develop- ment of a class of compounds called in- CONCLUSIONS — Exenatide LAR offers the potential of 24-h glycemic control and weight cretin mimetics that share several reduction with a novel once-weekly treatment for type 2 diabetes. glucoregulatory actions with GLP-1 but Diabetes Care 30:1487–1493, 2007 are resistant to dipeptidyl peptidase-IV degradation. Exenatide, with a half-life of 2.4 h and n the U.S., diabetes affects Ͼ21 million many medications available, the majority clinical effects lasting up to 8 h, is the first people, with combined direct and in- of people with type 2 diabetes are unable clinically available incretin mimetic (10– direct costs of $132 billion annually to maintain long-term glycemic control I 16). Compared with GLP-1 in preclinical (1). Treatment of this chronic, progres- (2). The high prevalence of obesity in this sive disease often requires daily blood population compounds this problem, as studies, exenatide has a 20- to 30-fold glucose monitoring and multiagent treat- obesity is a risk factor for developing type longer half-life and 5,500-fold greater po- ment regimens. However, despite the 2 diabetes and worsens hyperglycemia tency in lowering plasma glucose (7,17). In placebo-controlled clinical trials in pa- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tients not achieving adequate glycemic From the 1Amylin Pharmaceuticals, Inc., San Diego, California; 2Eli Lilly and Company, Indianapolis, control with metformin, a sulfonylurea, Indiana; and 3Eli Lilly and Company, Hamburg, Germany. or a combination of both, 30 weeks of 10 Address correspondence and reprint requests to Dennis Kim, MD, Amylin Pharmaceuticals, Inc., 9360 g subcutaneous exenatide twice daily Towne Centre Dr., Suite 110, San Diego, CA 92121. E-mail: [email protected]. Received for publication 20 November 2006 and accepted in revised form 28 February 2007. (BID) resulted in statistically significant Published ahead of print at http://care.diabetesjournals.org on 12 March 2007. DOI: 10.2337/dc06-2375. reductions in mean A1C, body weight, Clinical trial reg. no. NCT00103935, clinicaltrials.gov. fasting plasma glucose, and postprandial D.K., L.M., D.Z., M.F., and K.T. are employees and stockholders of Amylin Pharmaceuticals. P.K. and plasma glucose excursions (18–20). Pa- M.T. are employees and shareholders of Eli Lilly. Abbreviations: BID, twice daily; GLP-1, glucagon-like peptide-1; ITT, intention to treat; LAR, long-acting tients who continued in open-label exten- release. sion studies for a total of 1.5 years (82 A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion weeks) of BID exenatide treatment had factors for many substances. sustained A1C reductions and progres- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby sive body weight reductions (21). In marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. open-label comparator trials with insulin
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1487 Exenatide LAR in subjects with type 2 diabetes glargine or 70/30 insulin aspart, ex- ments through the 1996 South Africa End points enatide treatment resulted in A1C reduc- revision (24). Objectives of this study were to evaluate tions that were similar to those with In this multicenter subject- and in- the safety, tolerability, and pharmacoki- insulin but with better postprandial glu- vestigator-blinded phase 2 study, sub- netics of exenatide LAR. Additional objec- cose control and body weight reduction jects (n ϭ 45) were equally randomized tives were to evaluate pharmacodynamic instead of weight gain (22,23). Mild-to- to placebo LAR or 0.8 or 2.0 mg ex- (i.e., glucose), A1C, and weight effects of moderate nausea, which decreased over enatide LAR. Blinded, randomized exenatide LAR. Safety was assessed by ad- time, was the most common adverse study medication kits with unique verse events, clinical laboratory values, event associated with exenatide in all of package numbers were prepared sepa- physical examination, and electrocardio- these trials. rately and shipped to each clinical site. grams. Adverse events, as reported by the A long-acting release (LAR) ex- The study-site pharmacist contacted an subjects or noted by study-site staff inci- enatide formulation for subcutaneous interactive voice response system to dentally or as a result of nondirected injection in patients with type 2 diabe- randomly assign subjects to a treatment questioning, were categorized as mild if tes is under development to determine group and find out which medication transient, requiring no special treatment, whether superior glycemic control can and not interfering with daily activities kit to dispense to each subject. Doses be achieved when exenatide is continu- and as moderate if causing a low level of were targeted to result in concentra- ously present, compared with BID ex- inconvenience, possibly interfering with tions previously found to be therapeutic enatide, which may not provide daily activities, and ameliorated by simple with exenatide BID. Subjects under- complete coverage after midday meals therapeutic measures. An adverse event and overnight. In this report, we de- went a 3-day lead-in of 5 g exenatide was categorized as severe if it interrupted scribe the effects of once-weekly subcu- or placebo subcutaneous BID to deter- a subject’s usual daily activities and re- taneous administration of exenatide mine whether any subjects randomly quired systemic drug therapy or other LAR for 15 weeks on glycemic parame- assigned to exenatide LAR had an acute treatment. ters, weight, pharmacokinetics, safety, exenatide sensitivity. Then, once- and tolerability in patients with type 2 weekly subcutaneous injections of 0.8 Laboratory values diabetes. or 2.0 mg exenatide LAR or placebo LAR Blood to measure plasma exenatide was were administered at the study sites by drawn before study medication injec- RESEARCH DESIGN AND study personnel for 15 weeks, with no tion. Plasma exenatide concentrations METHODS — Subjects enrolled in changes in preexisting antidiabetes reg- were quantitated by a validated en- this study were 18–75 years of age, had imens. Subjects were monitored for ad- zyme-linked immunosorbent assay (25) type 2 diabetes treated for at least 3 verse events and pharmacokinetics at LINCO Diagnostic Services (St. months before screening with diet modi- during a subsequent 12-week follow-up Charles, MO). A1C was quantitated by fication with exercise (i.e., taking no an- period during which time no study Quintiles Laboratories (Smyrna, GA) tidiabetes agent) and/or metformin, A1C medications were administered. Gener- using high-performance liquid chroma- of 7.1–11.0%, fasting plasma glucose ally, visits were conducted at weekly in- tography (26,27). Anti-exenatide anti- 2 Ͻ14.4 mmol/l, and BMI 25–45 kg/m . tervals. Study recruitment began 16 bodies were measured in a fashion All of the subjects treated with metformin February 2005 and follow-up contin- similar to that described previously (25) (total daily dose ranging from 500 to ued through 17 October 2005. at LINCO Diagnostic Services. 2,550 mg) continued to receive the same For self-monitored blood glucose dose throughout the study, with the ex- profiles, subjects were given blood glu- Statistical analysis ception of a subject in the 2.0 mg ex- A sample size of 36 subjects was estimated cose meters and instructed to perform ϳ enatide LAR arm who discontinued measurements by fingerstick at the finger- to provide 95% CIs of 65–115 and metformin and added insulin lispro and tip. Preprandial glucose was measured 15 170–290 pg/ml for the mean exenatide insulin glargine to her regimen 6 weeks min before each meal, postprandial glu- concentrations at steady state for 0.8 and after the last dose of study medication. 2.0 mg exenatide LAR, respectively. The cose was measured 1.5–2 h after each Another change in antidiabetes treatment intent-to-treat (ITT) population com- meal, and an additional glucose measure- occurred when, after 9 weeks of placebo prised all randomized subjects who re- ment was taken at 0300 h. Measurements LAR, a subject initiated treatment with ceived at least one injection of lead-in glimepiride (this subject subsequently were recorded on 3 separate days for both medication (n ϭ 45), whereas the evalu- withdrew from the study because of loss baseline and week 15. able population consisted of subjects of glucose control). Subjects who had pre- Exenatide LAR consists of micro- from the ITT population who completed viously received exenatide treatment in a spheres composed of exenatide and a the study procedures through week 15 in clinical trial were excluded from the poly(lactide-coglycolide) polymeric ma- compliance with the protocol (n ϭ 43). study. Additionally, no subjects were trix. Poly(lactide-coglycolide) is a com- Descriptive statistics on demographics, treated with exenatide during the trial. A mon biodegradable medical polymer with safety, glycemic end points, and weight common clinical protocol was approved an extensive history of human use in ab- (i.e., mean values with either SE or SD, as for each site by an institutional review sorbable sutures and extended-release appropriate) were provided for the ITT board. All subjects provided written in- pharmaceuticals. After injection, ex- population. Descriptive statistics for self- formed consent before participation, and enatide is slowly released from the micro- monitored blood glucose measurements, the study was conducted in accordance spheres through diffusion and erosion. which contained week 15 measurements, with the principles described in the Dec- Placebo LAR contained 0.5% ammonium were performed for the evaluable popula- laration of Helsinki, including all amend- sulfate instead of exenatide. tion. The proportion of subjects achieving
1488 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kim and Associates
Figure 1— Study flowchart. Disposition of patients throughout the study, with baseline demographics. Demographic data are means Ϯ SD, except for sex, race, and diabetes treatment. Percentages may not add up to 100 because of rounding.
A1C Յ7.0% also depended on week 15 and 2.0-mg exenatide LAR groups to the line characteristics: A1C 8.5 Ϯ 1.2%, fast- measurements. The A1C target analysis was placebo LAR group with respect to the ing plasma glucose 9.9 Ϯ 2.3 mmol/l, performed on the subset of evaluable pa- change from baseline for A1C, fasting weight 106 Ϯ 20 kg, and diabetes dura- tients with baseline A1C Ͼ7% (n ϭ 41). plasma glucose, and body weight. Statis- tion 5 Ϯ 4 years. The different groups Plasma exenatide concentrations by tical significance was set at P Ͻ 0.05. (Fig. 1) varied in their sex, with more treatment and time were provided for women in the placebo LAR group and those subjects who received exenatide RESULTS more men in the exenatide LAR groups, LAR and completed the study. Exenatide and glycemia, with lower A1C and fasting pharmacokinetics were analyzed by stan- Subject demographics and plasma glucose in the 2.0-mg exenatide dard noncompartmental methods and disposition LAR group. Most subjects in this study summarized descriptively. Post hoc anal- Study subjects (n ϭ 45) were 40% female were receiving metformin (n ϭ 27), yses were performed to compare the 0.8- and had the following mean Ϯ SD base- whereas the remaining 18 subjects were
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1489 Exenatide LAR in subjects with type 2 diabetes
Figure 2— Plasma exenatide concentrations (means Ϯ SD) over time in subjects receiving exenatide LAR (n ϭ 31). Note that the last injection was administered at week 14. treated with diet modification and exer- from baseline to week 15 of Ϫ2.4 Ϯ 0.9 2.0 mg vs. placebo LAR), resulting in cise. Two subjects withdrew from the and Ϫ2.2 Ϯ 0.5 mmol/l for the 0.8- and mean A1C values of 7.2 and 6.6% in the study, both from the placebo LAR group. 2.0-mg exenatide LAR groups, respec- 0.8- and 2.0-mg exenatide LAR groups, One subject withdrew during the lead-in tively, compared with ϩ1.0 Ϯ 0.7 mmol/l respectively, compared with 9.0% for the period because of an adverse event, and for the placebo LAR group (P Ͻ 0.001 for placebo LAR group. Of evaluable subjects one subject withdrew during the treat- both 0.8 and 2.0 mg vs. placebo LAR) with baseline A1C Ͼ7% (n ϭ 41), 86% in ment period because of loss of glucose (Fig. 3A). the 2.0-mg group and 36% of subjects in control (Fig. 1). All three groups had similar self- the 0.8-mg group achieved an A1C of monitored blood glucose profiles and Յ7% at week 15, compared with 0% of Pharmacokinetics mean average daily blood glucose con- subjects in the placebo LAR group. With once-weekly exenatide LAR injec- centrations at baseline (placebo LAR 11.3 tions, mean plasma exenatide concentra- mmol/l, 0.8 mg exenatide LAR 11.4 Weight tions rose steadily. By week 2, treatment mmol/l, and 2.0 mg exenatide LAR 10.8 Body weight decreased progressively in with 2.0 mg exenatide LAR reached 50 mmol/l) (Fig. 3B). By week 15, the mean the 2.0-mg exenatide LAR group, with a pg/ml, a concentration previously shown average daily blood glucose concentration significant mean Ϯ SE change from base- to significantly reduce plasma glucose decreased for both LAR treatment groups line at week 15 of Ϫ3.8 Ϯ 1.4 kg (3.5% of (Fig. 2) (28). After ϳ6 weeks of treatment (week 15 values 9.2 mmol/l [0.8 mg] and total baseline body weight) (Fig. 3D)(P Ͻ with 2.0 mg exenatide LAR, plasma ex- 8.3 mmol/l [2.0 mg]) and rose for the pla- 0.05 for 2.0 mg exenatide LAR vs. placebo enatide concentrations were maintained cebo LAR group (12.2 mmol/l). Prepran- LAR). Body weight was unchanged for the at concentrations similar to the maximum dial and postprandial plasma glucose 0.8-mg exenatide LAR and placebo LAR concentration achieved with a single in- concentrations decreased for both ex- groups. jection of 10 g exenatide (steady-state enatide LAR groups, with the magnitude concentration of 232 pg/ml with 2.0 mg of postprandial excursions decreased by Safety and tolerability exenatide LAR compared with 211 pg/ml as much as fourfold with 2.0 mg ex- All adverse events were mild to moderate after a single injection of 10 g exenatide) enatide LAR compared with placebo LAR. in intensity, except for one severe adverse (16). The steady-state concentration with A1C was reduced at the first postex- event of urticaria and pruritus, which was 0.8 mg exenatide LAR was 111 pg/ml. Af- enatide LAR measurement (week 3) for considered to be related to shellfish inges- ter completion of the treatment phase at both exenatide LAR groups and progres- tion not to exenatide treatment. Nausea week 15, exenatide concentrations de- sively decreased throughout the treat- was the most frequently reported adverse creased steadily to below those consid- ment period (Fig. 3C). At week 15, event among exenatide LAR-treated sub- ered to have a therapeutic effect by week significant mean Ϯ SE A1C changes from jects (exenatide LAR 0.8 mg 19% and 2.0 21. baseline of Ϫ1.4 Ϯ 0.3 and Ϫ1.7 Ϯ 0.3% mg 27% vs. placebo LAR 15%), followed were observed for the 0.8- and 2.0-mg by gastroenteritis (exenatide LAR 0.8 mg Glycemic end points exenatide LAR groups, respectively, com- 19% and 2.0 mg 13% vs. placebo LAR Fasting plasma glucose was reduced rap- pared with ϩ0.4 Ϯ 0.3% for the placebo 0%), and hypoglycemia (exenatide LAR idly, with significant mean Ϯ SE changes LAR group (P Ͻ 0.0001 for both 0.8 and 0.8 mg 25% and 2.0 mg 0% vs. placebo
1490 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kim and Associates
Figure 3— Glycemic and weight parameters. Unless otherwise indicated: E, placebo LAR, n ϭ 14; f, 0.8 mg exenatide LAR, n ϭ 16; F, 2.0 mg exenatide LAR, n ϭ 15. *Statistically significant results: P Ͻ 0.05 compared with placebo LAR (A, C, and D). A: Fasting plasma glucose concentrations over time (ITT, n ϭ 45; mean Ϯ SE). B: Self-monitored blood glucose concentration profiles at baseline and week 15 (evaluable, n ϭ 43; mean Ϯ SE). E, placebo LAR, n ϭ 12; f, 0.8 mg exenatide LAR, n ϭ 16; F, 2.0 mg exenatide LAR, n ϭ 15. C: A1C (%) over time (ITT, n ϭ 45; mean Ϯ SE). D: Change in body weight from baseline over time (ITT, n ϭ 45; mean Ϯ SE).
LAR 0%). All episodes of nausea were occurred more frequently in exenatide or urinalysis values reported during the mild, with no reports of vomiting. Hy- LAR-treated patients (exenatide LAR 0.8 study. Further, there were no clinically poglycemic episodes, only one of which mg 13% and 2.0 mg 7% vs. placebo LAR significant abnormalities in vital signs and was confirmed with a blood glucose 0%). electrocardiogram interpretations. concentration (3.1 mmol/l), were mild There were no withdrawals because At week 15, 67% of subjects in the in intensity and were not related to the of adverse events during exenatide LAR exenatide LAR treatment groups were dose of exenatide LAR (as all occurred in treatment. There were no clinically signif- positive for anti-exenatide antibodies. In- the 0.8-mg group). Injection site bruising icant abnormal hematologic, chemistry, dividual subject profiles did not reveal a
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1491 Exenatide LAR in subjects with type 2 diabetes clear association between antibody re- LAR, as opposed to presumably only at ment of type 2 diabetes. The combined sponse and effects on safety or efficacy. breakfast and dinner with exenatide BID. potential benefits of improved glycemic Continuous GLP-1 infusion improves control and reduced weight in a novel glycemic control, weight, insulin sensitiv- once-weekly treatment regimen for pa- CONCLUSIONS — Development of ity, and -cell function (8,29). However, tients with type 2 diabetes merits longer- an exenatide formulation with once- whereas GLP-1, with a half-life of Ͻ2 min term large-scale studies to gain further weekly dosing that reduces A1C and (6), is administered as a continuous infu- insight into treatment with exenatide weight could provide patients and clini- sion, exenatide LAR, with a median half- LAR. cians with a novel tool with which to treat life of 2 weeks (data on file; Amylin type 2 diabetes. In this study, once- Pharmaceuticals, San Diego, CA), can be weekly exenatide LAR for 15 weeks had administered as a once-weekly subcuta- Acknowledgments— This work was sup- multiple metabolic effects, including sig- neous injection. Exenatide acts in a glu- ported by Amylin Pharmaceuticals, San Diego, nificant reductions of A1C, weight, and cose-dependent manner, affecting insulin CA, Eli Lilly and Company, Indianapolis, IN, fasting glucose and marked reduction of and glucagon secretion during hypergly- and Alkermes, Cambridge, MA. The authors thank the exenatide LAR clinical self-monitored postprandial glucose. cemia but not euglycemia or hypoglyce- team for their assistance in the conduct, report- Treatment with 2.0 mg exenatide LAR but mia. Therefore, continuous exenatide ing, and quality control of the study and devel- not with 0.8 mg reduced body weight, concentrations can potentially improve opment of the manuscript; the investigators indicating that higher exenatide concen- glycemic control and other metabolic Andrew Ahmann, Bruce Berwald, Eric Klein, trations are required for effects on weight. measures without increasing the risk of Sam D. Miller, John Pullman, and Richard Wein- This dose dependence in weight effects is clinically significant hypoglycemia. stein and the study site staffs for conducting the in keeping with the observed results of Exenatide LAR was well tolerated, study; the study subjects for their participation; 30-week placebo-controlled studies of with almost exclusively mild-to-moderate and Susanna Mac for writing of the manuscript. exenatide on a background of metformin adverse events. The relatively mild nausea We thank Alkermes for leading the development or sulfonylurea treatment (18,19). Like- profile with exenatide LAR compared of and for manufacturing the long-acting release formulation of exenatide. wise, the magnitude of postprandial glu- with that observed with exenatide BID cose excursions decreased as much as (18–20) may be due to the more gradual fourfold with 2.0 mg exenatide LAR increase in plasma exenatide concentra- References (compared with placebo LAR), which tions upon initiation of treatment. In sup- 1. National Diabetes Information Clear- may account for the greater magnitude of port of this hypothesis, stepwise inghouse. National diabetes statistics A1C reduction with the 2.0-mg dose. introduction of exenatide has been shown [article online], 2005. Available from A single dose of the BID formulation to reduce the incidence of nausea by ap- http://diabetes.niddk.nih.gov/dm/pubs/ of exenatide has a half-life of 2.4 h after proximately half (30). The formation of statistics/index.htm#7. Accessed 5 Sep- subcutaneous injection, predominantly anti-exenatide antibodies with exenatide tember 2006 because of renal clearance, and is admin- LAR treatment was not predictive of end 2. Koro CE, Bowlin SJ, Bourgeois N, Fedder istered before the two main meals of the point response or adverse safety outcome, DO: Glycemic control from 1988 to 2000 day, Ն6 hours apart (16). Improvements consistent with exenatide BID studies among U.S. adults diagnosed with type 2 in postprandial glycemia with exenatide (18–20). Longer-term studies are needed diabetes: a preliminary report. Diabetes Care 27:17–20, 2004 BID have been most pronounced at to examine the safety profile of exenatide 3. Mokdad AH, Ford ES, Bowman BA, Dietz breakfast and dinner, the meals before LAR. Thus far, exenatide BID has been on WH, Vinicor F, Bales VS, Marks JS: Prev- which exenatide is typically given, with the market for ϳ2 years and has been alence of obesity, diabetes, and obesity- some residual beneficial effects after studied in clinical trials of up to 3 years in related health risk factors, 2001. JAMA lunch and during fasting. In contrast, duration (31) without significant changes 289:76–79, 2003 treatment with exenatide LAR provides to its safety profile. 4. Maggio CA, Pi-Sunyer FX: The prevention 24-h exposure to therapeutic exenatide Although these findings are encour- and treatment of obesity: application to concentrations. This continuous expo- aging, the relatively modest size (45 sub- type 2 diabetes. Diabetes Care 20:1744– sure may account for the reduction in jects) and short duration (15 weeks) of 1766, 1997 fasting glucose observed with 15 weeks of the study and administration of exenatide 5. Purnell JQ, Weyer C: Weight effect of cur- rent and experimental drugs for diabetes exenatide LAR being fourfold greater than LAR by study staff must all be considered mellitus: from promotion to alleviation of that reported in 30-week studies with 10 when interpreting these findings. The re- obesity. Treat Endocrinol 2:33–47, 2003 g exenatide BID (18–20). In addition, ductions in A1C and weight did not ap- 6. Drucker DJ: Enhancing incretin action for exenatide LAR provides postprandial pear to plateau by week 15, so the full the treatment of type 2 diabetes. Diabetes glycemic control with all meals. This potential for and sustainability of glyce- Care 26:2929–2940, 2003 combination of daylong fasting and post- mic improvement and weight reduction 7. Parkes D, Jodka C, Smith P, Nayak S, prandial effects may explain why the A1C were not determined by this study. Addi- Rinehart L, Gingerich R, Chen K, Young reduction was approximately twice as tionally, the administration of injections A: Pharmacokinetic actions of exendin-4 large with 2.0 mg exenatide LAR com- by study staff at study sites ensured high in the rat: comparison with glucagon-like pared with exenatide BID and why the compliance and a uniform injection tech- peptide-1. Drug Dev Res 53:260–267, 2001 majority of subjects (86%) achieved target nique, which may not reflect real-world Յ 8. Zander M, Madsbad S, Madsen JL, Holst A1C values of 7%. Similarly, it is possi- clinical use. JJ: Effect of 6-week course of glucagon- ble that the twofold greater weight reduc- In this early study, the data suggest like peptide 1 on glycaemic control, insu- tion could reflect effects on food intake that a convenient, once-weekly exenatide lin sensitivity, and -cell function in type throughout the day with 2.0 mg exenatide formulation shows promise in the treat- 2 diabetes: a parallel-group study. 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359:824–830, 2002 cose-lowering and insulin-sensitizing ac- 24. World Medical Association Declaration of 9. Parkes DG, Pittner R, Jodka C, Smith P, tions of exendin-4: studies in obese Helsinski: Recommendations guiding Young A: Insulinotropic actions of ex- diabetic (ob/ob, db/db) mice, diabetic fatty medical physicians in biomedical re- endin-4 and glucagon-like peptide-1 in Zucker rats, and diabetic rhesus monkeys search involving human subjects. JAMA vivo and in vitro. Metabolism 50:583–589, (Macaca mulatta). Diabetes 48:1026– 277:925–926, 1997 2001 1034, 1999 25. Fineman MS, Bicsak TA, Shen LZ, Taylor 10. Toft-Nielsen MB, Damholt MB, Madsbad 18. DeFronzo RA, Ratner RE, Han J, Kim DD, K, Gaines E, Varns A, Kim D, Baron AD: S, Hilsted LM, Hughes TE, Michelsen BK, Fineman MS, Baron AD: Effects of ex- Effect on glycemic control of exenatide Holst JJ: Determinants of the impaired se- enatide (exendin-4) on glycemic control (synthetic exendin-4) additive to existing cretion of glucagon-like peptide-1 in type and weight over 30 weeks in metformin- metformin and/or sulfonylurea treatment 2 diabetic patients. J Clin Endocrinol Metab treated patients with type 2 diabetes. Di- in patients with type 2 diabetes. Diabetes 86:3717–3723, 2001 abetes Care 28:1092–1100, 2005 Care 26:2370–2377, 2003 11. Egan JM, Clocquet AR, Elahi D: The insu- 19. Buse JB, Henry RR, Han J, Kim DD, Fine- 26. Davis JE, McDonald JM, Jarett L: A high- linotropic effect of acute exendin-4 ad- man MS, Baron AD, Exenatide-113 Clin- performance liquid chromatography ministered to humans: comparison of ical Study Group: Effects of exenatide method for hemoglobin A1c. Diabetes 27: nondiabetic state to type 2 diabetes. J Clin (exendin-4) on glycemic control over 30 102–107, 1978 Endocrinol Metab 87:1282–1290, 2002 weeks in sulfonylurea-treated patients 27. Cole RA, Soeldner JS, Dunn PJ, Bunn HF: 12. Kolterman OG, Buse JB, Fineman MS, with type 2 diabetes. Diabetes Care 27: A rapid method for the determination of Gaines E, Heintz S, Bicsak TA, Taylor K, 2628–2635, 2004 glycosylated hemoglobins using high Kim D, Aisporna M, Wang Y, Baron AD: 20. Kendall DM, Riddle MC, Rosenstock J, pressure liquid chromatography. Metabo- Synthetic exendin-4 (exenatide) signifi- Zhuang D, Kim DD, Fineman MS, Baron lism 27:289–301, 1978 cantly reduces postprandial and fasting AD: Effects of exenatide (exendin-4) on 28. Taylor K, Kim D, Nielsen LL, Aisporna M, plasma glucose in subjects with type 2 di- glycemic control over 30 weeks in pa- Baron AD, Fineman MS: Day-long subcu- abetes. J Clin Endocrinol Metab 88:3082– tients with type 2 diabetes treated with taneous infusion of exenatide lowers gly- 3089, 2003 metformin and a sulfonylurea. Diabetes cemia in patients with type 2 diabetes. 13. Nielsen LL, Young AA, Parkes DG: Phar- Care 28:1083–1091, 2005 Horm Metab Res 37:627–632, 2005 macology of exenatide (synthetic ex- 21. Blonde L, Klein EJ, Han J, Zhang B, Mac 29. Larsen J, Hylleberg B, Ng K, Damsbo P: endin-4): a potential therapeutic for SM, Poon TH, Taylor KL, Trautmann ME, Glucagon-like peptide-1 infusion must be improved glycemic control of type 2 dia- Kim DD, Kendall DM: Interim analysis of maintained for 24 h/day to obtain accept- betes. Regul Pept 117:77–88, 2004 the effects of exenatide treatment on A1C, able glycemia in type 2 diabetic patients 14. Edwards CM, Stanley SA, Davis R, Brynes weight and cardiovascular risk factors who are poorly controlled on sulphony- AE, Frost GS, Seal LJ, Ghatei MA, Bloom over 82 weeks in 314 overweight patients lurea treatment. Diabetes Care 24:1416– SR: Exendin-4 reduces fasting and post- with type 2 diabetes. Diabetes Obes Metab 1421, 2001 prandial glucose and decreases energy in- 8:436–447, 2006 30. Fineman MS, Shen LZ, Taylor K, Kim DD, take in healthy volunteers. Am J Physiol 22. Heine RJ, Van Gaal LF, Johns D, Mihm Baron AD: Effectiveness of progressive Endocrinol Metab 281:E155–E161, 2001 MJ, Widel MH, Brodows RG, GWAA dose-escalation of exenatide (exendin-4) 15. Triplitt C, DeFronzo RA: Exenatide: first- Study Group: Exenatide versus insulin in reducing dose-limiting side-effects in in-class incretin mimetic for the treatment glargine in patients with suboptimally subjects with type 2 diabetes. Diabetes of type 2 diabetes mellitus. Expert Rev En- controlled type 2 diabetes. Ann Intern Med Metab Res Rev 20:411–417, 2004 docrinol Metab 1:329–341, 2006 143:559–569, 2005 31. Buse JB, MacConell L, Stonehouse AH, 16. BYETTA prescribing information [article 23. Nauck MA, Duran S, Kim D, Johns D, Guan X, Malone JK, Okerson TE, Maggs online], 2006. Available from http://pi. Festa A, Trautmann M: Effects of ex- DG, Dennis D, Kim DD: Exenatide main- lilly.com/us/byetta-pi.pdf. Accessed 5 enatide compared with twice-daily bipha- tained glycemic control with associated September 2006 sic insulin aspart in patients with type 2 weight reduction over three years in pa- 17. Young AA, Gedulin BR, Bhavsar S, Bodkin diabetes using sulphonylurea and met- tients with type 2 diabetes (Abstract). Di- N, Jodka C, Hansen B, Denaro M: Glu- formin (Abstract). Diabetologia 49:3, 2006 abetes 56 (Suppl. 1):60, 2007
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1493 Pathophysiology/Complications ORIGINAL ARTICLE
Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients An adaptive phenomenon?
1 5 MELANIA MANCO, MD, PHD VINCENZO TONDOLO phenomenon relating to environmental 2 3 JOSE´ M. FERNANDEZ´ -REAL MENOTTI CALVANI changes. This topic, not addressed before, 3 5 MARIA E. VALERA-MORA MARCO CASTAGNETO adds new insight into the complex mecha- 4 4 HENRI D´ECHAUD MICHEL PUGEAT nisms linking HPA activity to obesity. 5 3 GIUSEPPE NANNI GELTRUDE MINGRONE Diabetes Care 30:1494–1500, 2007
OBJECTIVE — Obesity, insulin resistance, and weight loss have been associated with utritional status and activity of the changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this hypothalamic-pituitary-adrenal association are available. In this study, we aim to investigate the effects of massive weight loss on (HPA) axis are strictly associated cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in for- N (1,2). However, little is known about the merly obese women. effect of starvation and intentional calorie RESEARCH DESIGN AND METHODS — Ten glucose-normotolerant, fertile, obese deprivation on the HPA axis (3,4). The women (BMI Ͼ40 kg/m2, aged 38.66 Ϯ 13.35 years) were studied before and 2 years after HPA axis controls the secretion of cortisol biliopancreatic diversion (BPD) when stable weight was achieved and were compared with with excessive secretion being inhibited age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous by negative feedback. Several studies sug- dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. gest that abnormalities in cortisol action Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secre- and HPA axis control may be a factor that tion was measured by a C-peptide deconvolution method. links disturbances of carbohydrate me- tabolism (which characterize insulin re- RESULTS — No difference was found in cortisol suppression after DEX-ST before or after sistance) and obesity (5–6). In obesity, weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P ϭ estimation of plasma cortisol does not re- 0.05) and postobese women (P Յ 0.01) as was the decrease in dehydroepiandrosterone (P Յ flect the function of the HPA axis (7), and 0.05 and P Յ 0.01, respectively). CBG decreased from 51.50 Ϯ 12.76 to 34.33 Ϯ 7.24 mg/l (P Յ levels of cortisol in obese patients have Ϯ Ϯ Յ 0.01) following BPD. FCI increased from 11.15 2.85 to 18.16 6.82 (P 0.05). Insulin been reported to be normal (8), low (9), secretion decreased (52.04 Ϯ 16.71 vs. 30.62 Ϯ 16.32 nmol/mϪ2; P Յ 0.05), and insulin Յ ϭ ϭ or increased (10). On the contrary, re- sensitivity increased by 163% (P 0.0001). Serum CBG was related to BMI (r0 0.708; P ϭ ϭ ϭ ϭ sponse to different stimuli (high secretion 0.0001), body weight (r0 0.643; P 0.0001), body fat percent (r0 0.462; P 0.001), ϭ ϭ ϭ ϭ of cortisol after laboratory stress tests or C-reactive protein (r0 0.619; P 0.004), and leptin (r0 0.579; P 0.007) and negatively to M value (r ϭϪ0.603; P ϭ 0.005). after different exogenous neuropeptides) 0 has been found to be altered (11). Com- CONCLUSIONS — After massive weight loss in morbidly obese subjects, an increase of free pared with these tests, the dexamethasone cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive suppression test (DEX-ST), mainly used in the diagnosis of Cushing’s disease, ap- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● pears to be inadequate. Nevertheless, it From the 1Liver Unit, “Bambino Gesu` ” Hospital and Research Institute, Rome, Italy; the 2Department of has been widely used to evaluate the HPA Diabetes, Endocrinology, and Nutrition, University Hospital of Girona, Girona, Spain; the 3Department of axis in obesity, and the outcomes are con- Internal Medicine, Catholic University, Rome, Italy; the 4Fe´de`ration d’Endocrinologie, Hospital Neuro- tradictory (12–14). The free cortisol in- 5 Cardiologique, Hospices Civils, Lyon, France; and the Department of Surgery, Catholic University; Rome, dex (FCI)— the total cortisol-to-cortisol– Italy. Address correspondence and reprint requests to Melania Manco, MD, PhD, via Pineta Sacchetti, 484, binding globulin ratio (CBG) — has also 00168, Rome, Italy. E-mail: [email protected]. been proposed to be able to evaluate HPA Received for publication 30 June 2006 and accepted in revised form 21 December 2006. axis activity (7,15) since it reflects the bi- M.C. is employed by Sigma-Tau (Italy). ologically active fraction of total cortisol Abbreviations: BPD, biliopancreatic diversion; CBG, cortisol-binding globulin; CRP, C-reactive protein; DEX, dexamethasone; DEX-ST, DEX suppression test; FCI, free cortisol index; FFM, fat-free mass; HPA, (7). Moreover, FCI is significantly associ- hypothalamic-pituitary-adrenal; OGTT, oral glucose tolerance test; RIA, radioimmunoassay. ated with several features of insulin resis- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tance syndrome (15). CBG levels are factors for many substances. generally decreased in obese and diabetic DOI: 10.2337/dc06-1353 subjects, although genetic factors are also © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby known to play a role in the interindividual marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. variation in CBG levels (16,17). Reduced
1494 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Manco and Associates levels of CBG favor locally increased cor- calciferol (400,000 UI intramuscular) oxidase method (Beckman, Fullerton, tisol disposal with no change in circulat- (Ostelin fl, Teofarma, Italy) every 2 CA), while FFAs were quantified by spec- ing cortisol; thus, fat accumulatates. weeks. Medical histories, physical ex- trophotometric measurements. Hor- Therefore, in obesity, tissues may be ex- aminations, electrocardiogram, and mones were assayed in duplicate. Plasma posed to a relative excess of cortisol with- blood screening showed that patients insulin was assayed by a microparticle en- out any increase in circulating cortisol. were in good health. None were taking zyme immunoassay (Abbott, Pasadena, Biliopancreatic diversion (BPD), a anticonvulsant medications or cortico- CA) (sensitivity 1 U/ml, intra-assay co- malabsorptive bariatric surgical tech- steroids. Depression was excluded by efficient of variation [CV] 6.6%). CBG nique, causes massive weight loss the Italian version of the Epidemiologi- was measured by radioimmunoassay (18,19), restoration of insulin sensitivity, cal Studies Depression Rating Scale (RIA) (Radim, KP31; Angleur, Liege, Bel- and amelioration of insulin secretion (21). gium). Intra- and interassay CVs were 3.6 (18). It restores the regular diurnal The ethical committee of Catholic Uni- and 7.5%, respectively; SHBG was quan- rhythm and pulsatility of insulin, leptin, versity approved the study, and subjects tified by an RIA method (CIS Bio Interna- and adiponectin but does not influence signed an informed consent document be- tional, Gif-sur-Yvette, France) (intra- and those of cortisol (19). fore participation. Body composition was interassay CVs 2.5 and 3.8%). Serum cor- Thus far, no data are reported in lit- estimated by the isotopic dilution method tisol was determined by RIA (cort-CTK erature concerning the effects of surgi- (22). Fat-free mass (FFM) was measured in cally induced massive and stable weight kilograms and obtained by dividing total 125; Dia Sorin, Saluggia, Italy) (sensitivity and fat mass loss on FCI and CBG con- body water by 0.73 (22). Subjects under- 2.7 nmol/l), interassay CVs at concentra- centrations and response to DEX-ST. The went BPD, which is a malabsorptive surgical tion levels of 16.6, 40.8, and 198.8 nmol/l present study aimed to investigate 10 glu- procedure (23). were 6.8, 14.6, and 4.3%, respectively, cose-normotolerant morbidly obese (BMI Insulin sensitivity was estimated by a and intra-assay CVs at concentrations of Ͼ40 kg/m2) women before and 2 years euglycemic-hyperinsulinemic clamp as 9.1, 45.9, and 135.3 nmol/l were 9.9, 5.7, after BPD for 1) changes of FCI and CBG previously described (24). Whole-body and 6.1%. ACTH was determined with an levels and 2) suppression of morning cor- glucose uptake, normalized by FFM (M immunoradiometric assay method (Ni- -1 Ϫ1 tisol, ACTH, and DHEA levels after intra- value in mmol kgFFM min ), was chols Institute Diagnostics, San Juan Cap- venous dexamethasone (DEX). determined during a primed constant in- istrano, CA) (sensitivity 0.22 pmol/l). fusion of insulin (at the rate of 6 pmol Interassay CV at concentrations of 1, 7.3, Ϫ Ϫ RESEARCH DESIGN AND min 1 kg 1). and 24.2 pmol/l were 2.4, 8.5, and 4.3%, METHODS — The study group in- -Cell function was estimated on 2-h and interassay CVs at concentrations of 1 cluded 10 normotensive obese women OGTT values of glucose, insulin, and C- and 24 pmol/l were 9.9 and 3.9%. Plasma (BMI Ͼ40 kg/m2) evaluated before and peptide. Samples were withdrawn every DHEA was assayed by RIA method 2 years after BPD. Postobese subjects 30 min. -Cell function was assessed us- (Radim, Pomezia, Italy) (sensitivity 15 pg/ were admitted monthly to our unit in ing a model describing the relationship ml; intra- and interassay CVs 3.1 and the first 3 months after surgery and were between insulin secretion and glucose 6.9%). Serum leptin was assayed using an controlled every 3 months thereafter. concentration, which has been previously ELISA kit (Linco Research, St. Charles, During the second year, they were ad- described in detail (18). The model ex- MO) (sensitivity 0.5 ng/ml). Intra- and in- mitted every 6 months. Patients were presses insulin secretion as a sum of two terassay CVs were 4.2 and 4.5%. C-reac-  required to record their weight components: -cell glucose sensitivity tive protein (CRP) was assessed by a monthly. A stable weight (fluctuation and the rate sensitivity. Basal and total in- Ͻ routine laboratory test (Beckman Coulter, 5%) is generally achieved by 12–15 sulin secretions during the OGTT were Fullerton, CA) months. Ten normal weight (BMI Յ24 calculated from the estimated model pa- kg/m2) volunteers recruited among rameters. Total insulin secretion was cal- nurses and students in the hospital staff culated as the integral over the first2hof Statistical methods served as healthy control subjects to the OGTT. Data are presented as means Ϯ SD unless evaluate suppressibility of the HPA axis Intravenous DEX-ST was performed otherwise stated. Before statistical analy- after DEX-ST. Subjects were nonsmok- as previously described (25). DEX phos- sis, normal distribution and homogeneity ers and were 20–35 years of age. Glu- phate (1 mg/h) (4 mg Soldesam; Lab Ital- of the variances were tested. All parame- cose tolerance was evaluated by a 75-g iani Farmaceutici, Milan, Italy) was ters fulfilled these conditions. Compari- oral glucose tolerance test (OGTT) (20). infused for 4 h beginning at 11.00 A.M. sons between groups were performed They were evaluated in the early follic- Blood samples were taken at 8:00 P.M. and ular phase by undergoing the OGTT 12:00, 8:00, and 11:00 A.M. before start- using paired t test while comparisons and the euglycemic-hyperinsulinemic ing the test and after at 3:00 and 8:00 P.M. among groups were performed using one- clamp study before the DEX-ST. None Samples were also taken at 12:00 and way ANOVA followed by Bonferroni’s of the study participants had endocrine 8:00 A.M. the following day to measure post-hoc test for multiple comparisons or nonendocrine diseases. They were cortisol, DHEA, and ACTH. whenever appropriate. Relationships be- not taking any medications except sub- tween variables were sought by linear cor- jects after BPD, who were prescribed Analytical assays relation analysis (Spearman’s r0). Levels oral supplementation of sulfate iron Samples were collected in tubes with of statistical significance were set at P (525 mg daily) calcium carbonate (1 g aproteinin (500 units/l) in an ice bath and Ͻ 0.05. Data analyses were performed daily), multivitamins (Supradyn Roche, frozen immediately at Ϫ80°C. Plasma with SPSS statistical software (SPSS Milan, Italy) (1 tablet a day), and ergo- glucose was measured by the glucose- V12.0; SPSS, Chicago, IL).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1495 Obesity, CBG, and FCI
Table 1—Anthropometrical characteristics and blood pressure of the studied subjects
Obese NGT women* Baseline After BPD† Control subjects* Age (years) 38.66 Ϯ 13.35 41.57 Ϯ 12.21 39.24 Ϯ 13.56 Body weight (kg) 114.56 Ϯ 13.88 85.60 Ϯ 14.25 60.23 Ϯ 10.21 BMI (kg/m2) 42.57 Ϯ 5.99 31.78 Ϯ 5.54 22.54 Ϯ 5.89‡ FFM (kg) 70.93 Ϯ 9.93 62.60 Ϯ 8.55 55.67 Ϯ 8.79‡ Fat mass (kg) 43.62 Ϯ 9.77 23 Ϯ 6.51 16.78 Ϯ 4.87‡ Waist-to-hip ratio 0.96 Ϯ 0.04 0.90 Ϯ 0.03 0.83 Ϯ 0.02‡ Systolic blood pressure (mmHg) 146.11 Ϯ 13.18 114.44 Ϯ 7.68 118.54 Ϯ 6.98 Diastolic blood pressure (mmHg) 88.88 Ϯ 1.76 80.0 Ϯ 8.08 81.2 Ϯ 7.10 Data are means Ϯ SD. *n ϭ 10. †P Յ 0.0001 (paired t test). ‡P Յ 0.001 (ANOVA). NGT, normal glucose tolerance.
RESULTS 56.49 to 41.16 Ϯ 24.01 pmol/l (P Յ Both fasting insulin secretion (55.54 Ϯ 0.05), respectively. Insulin sensitivity 23.45 pmol/min per m2, P Յ 0.001) and Body composition and analytic markedly increased by ϳ163% in the total insulin output (29.44 Ϯ 13.56 Ϫ parameters post-BPD group. The insulin-mediated nmol/m 2, P Յ 0.001) were significantly A stable weight was achieved after 13 Ϯ 2 glucose uptake (M value) improved from lower than in obese women. -Cell glu- Յ Ϯ Ϫ1 Ϫ1 months. Body weight (P 0.0001) and 14.92 1.23 mol kgFFM min to cose sensitivity was higher than in obese Յ Ϯ Ϫ1 Ϫ1 Ϯ 2 fat mass (P 0.0001) were significantly 39.13 0.98 mol kgFFM min women (96.78 3.28 pmol/min per m reduced 2 years after BPD (Table 1). FFM after BPD (P Յ 0.0001). per mmol/l , P Յ 0.05). and fat mass decreased by 25 and 45%, Both fasting insulin secretion (152.87 respectively, and lipid profile signifi- Ϯ 83.49 vs. 88.90 Ϯ 46.00 pmol/min per HPA axis suppressibility, CBG cantly ameliorated (Table 2). FFAs were m2, P Յ 0.05) and total insulin output levels, and FCI significantly lowered from 0.42 Ϯ 0.10 to (52.04 Ϯ 16.71 vs. 30.62 Ϯ 16.32 nmol/ No differences were found in fasting cor- Ϫ 0.20 Ϯ 0.07 mmol/l (P Յ 0.0001), and m 2, P Յ 0.05) decreased following BPD. tisol, DHEA, and ACTH among control, circulating sex hormone–binding globu- -Cell glucose sensitivity significantly in- obese, and post-BPD subjects. Effects of lin increased (Table 2) (P Յ 0.05). Levels creased (80.43 Ϯ 4.89 to 97.98 Ϯ 4.70 the DEX infusion on the three hormones of CRP significantly decreased from pmol/min per m2 per mmol/l, P Յ 0.05), are depicted in Fig. 1. Morning cortisol 1.03 Ϯ 0.24 to 0.22 Ϯ 0.08 mg/l (P Յ while the rate sensitivity (0.88 Ϯ 0.27 vs. (Fig. 1A) was significantly suppressed in 0.0001). 0.32 Ϯ 0.50 nmol/min per m2 per all subjects (89 Ϯ 3% in pre-BPD, 89 Ϯ mmol/l) and the potentiation factor 2% in post-BPD, and 89 Ϯ 5% in control Insulin sensitivity and secretion (0.87 Ϯ 0.10 vs. 0.83 Ϯ 0.3–fold) did not subjects) (P ϭ NS), decreasing from After BPD, fasting glucose and insulin de- change. In healthy subjects, mean glucose 555 Ϯ 115 nmol/l to 60 Ϯ 20 (P Յ Ϫ creased from 5.98 Ϯ 1.90 to 3.86 Ϯ 0.30 uptake was 42.34 Ϯ 1.02 mol kg 1 0.0001) in women before surgery, from Ϫ FFM mmol/l (P Յ 0.01) and from 93.60 Ϯ min 1 (P Յ 0.001 vs. obese women). 590 Ϯ 120to64Ϯ 22 nmol/l (P Յ
Table 2—Biochemical parameters in the studied groups
Obese NGT women* Baseline After BPD Control subjects* Fasting glucose (mmol/l) 5.98 Ϯ 1.90 3.86 Ϯ 0.30† 4.01 Ϯ 0.28ʈ Fasting insulin (pmol/l) 93.60 Ϯ 56.50 41.16 Ϯ 24.01‡ 40.78 Ϯ 20.76ʈ Total colesterol (mmol/l) 5.36 Ϯ 1.19 3.34 Ϯ 0.66§ 4.01 Ϯ 0.89 HDL cholesterol (mmol/l) 1.14 Ϯ 0.27 1.42 Ϯ 0.29‡ 1.49 Ϯ 0.31 Triglycerides (mmol/l) 1.45 Ϯ 0.60 1.0 Ϯ 0.45‡ 1.20 Ϯ 0.67 Albumin (g/dl) 4.06 Ϯ 0.27 3.94 Ϯ 0.37 4.01 Ϯ 0.41 Proteins (g/dl) 7.29 Ϯ 0.54 7.2 Ϯ 0.58 7.31 Ϯ 0.60 sGOT (UI/l) 20.1 Ϯ 6.08 27.71 Ϯ 6.60 25.89 Ϯ 8.90 sGPT (UI/l) 30.1 Ϯ 15.36 32.43 Ϯ 13.78 30.98 Ϯ 14.89 SBHG (nmol/l) 46.0 Ϯ 12.8 85.6 Ϯ 16.3‡ 80.9 Ϯ 21.7ʈ CBG (mg/l) 51.5 Ϯ 12.8 34.3 Ϯ 7.2† 44.1 Ϯ 6.0ʈ GH (ng/ml) 0.84 Ϯ 0.49 2.80 Ϯ 1.85† 1.89 Ϯ 1.42 Leptin (mg/ml) 63.3 Ϯ 2.9 21.8 Ϯ 4.3 19.9 Ϯ 7.7ʈ Data are means Ϯ SD. *n ϭ 10. †P Յ 0.01, ‡P Յ 0.05, and §P Յ 0.001 by paired t test. ʈP Յ 0.001 by ANOVA. ¶P Յ 0.0001. To convert glucose to mg/dl, divide by 0.05551. To convert insulin to UI/ml, multiply by 7.175. To convert triglycerides to mg/dl,divide by 0.01129. To convert cholesterol to mg/dl, divide by 0.0258. GH, growth hormone; SBHG, sex hormone–binding globulin; sGOT, serum gluamic oxaloacetic transaminase; sGPT, serum glutamic pyruvic transaminase.
1496 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Manco and Associates
Figure 1—Mean Ϯ SEM of cortisol (A), ACTH (B), and DHEA (C) before and after dexamethasone infusion. DEX-ST is represented by the square. Start of infusion is indicated by the black arrow. Level of significance at the ANOVA test followed by the Bonferroni’s post-hoc test was *P ϭ 0.05 between control subjects and obese women; §P Յ 0.01 between control subjects and women after BPD. Œ, control subjects; , obese women; ᭜, post-BPD women.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1497 Obesity, CBG, and FCI
0.0001) in the same subjects after sur- CONCLUSIONS — In the present less, changes in hepatic CBG expression at gery, and from 459 Ϯ 134 to 46 Ϯ 12 study, we observed a significant decrease the gene level might take place after sur- (P Յ 0.0001) in control subjects. in circulating CBG levels and a concomi- gery. Changes in CBG and FCI levels The lowest ACTH concentrations tant increase of the metabolically active might also be related to the improvement (Fig. 1B) were observed at midnight fol- free cortisol fraction in obese women after of the low-grade inflammatory status (28) lowing DEX-ST. The decrease in ACTH surgically induced weight loss (BPD). In- occurring in post BPD-patients (32), as levels was significantly greater in control terestingly, despite the complete suppres- suggested by the decrease of CRP. The subjects than in obese (P ϭ 0.05) and sion of cortisol secretion by DEX infusion observed dissociation between cortisol postobese (P Յ 0.01) women. At the mid- in all subjects independent of their body and DHEA response to the DEX-ST in night measurement, the ACTH concen- weight, the midnight fall in ACTH levels post-BPD women also supports this hy- tration decreased with respect to the value was significantly greater and the suppres- pothesis, with higher concentrations of measured the day before the test by sion of DHEA more enhanced in normal DHEA (the biologically active form of the 52.47 Ϯ 19.51% (57.68 Ϯ 18.85 to weight subjects compared with obese and hormone) in postobese women compared 32.11 Ϯ 11.27 pg/ml, P Յ 0.01) in obese post-BPD women (Fig. 1). A subtle pri- with obese and control subjects. mary dysfunction of the HPA axis might Finally, other pleiotropic effects of women, by 32.59 Ϯ 12.05% (50.24 Ϯ be envisaged in morbid obesity and after cortisol cannot be excluded. In fact, en- 6.92 to 39.40 Ϯ 19.62 pg/ml, P ϭ 0.01) BPD. In post-BPD women, the HPA axis terocytes experience an adaptational hy- after weight loss, and by 63.52 Ϯ 9.63% may adapt to a changing environment perplasia after jejunoileal bypass (33), (59.19 Ϯ 10.84 to 12.79 Ϯ 4.14 pg/ml, Յ leading to decreased CBG levels and an and glucocorticoids represent an impor- P 0.0001) in control subjects. Both be- overall increase in FCI. Several hypothe- tant factor in the modulation of intestinal fore and after surgery, obese women had ses can be formulated to explain the de- physiological functions, contributing to a higher values of ACTH than control sub- crease of CBG levels and the different more functional cell morphology and ϭ ϭ jects at midnight (P 0.02 and P response to the DEX-ST. production of a potent regulator of crypt 0.001, respectively) and in the early The decrease in CBG levels following cell proliferation (34). The increase in FCI morning following the DEX-ST (P ϭ BPD may alter the sensitivity of the pitu- might contribute to this long term- 0.001 and P Յ 0.0001). During the test, itary gland to cortisol. The recently re- adaptational hyperplasia. In contrast with mean concentrations of cortisol and ported (26) CBG-deficient mouse model previous reports (17), we did not find any ACTH were 196 Ϯ 60 nmol/l and is in agreement with the crucial role of the relation between fasting CBG and insulin 44.11 Ϯ 15.08 pg/ml in obese women, binding globulin in the ACTH feedback secretion, likely because of the small sam- 202 Ϯ 60 nmol/l and 48.25 Ϯ 13.34 regulation of glucocorticoids. Addition- ple size of patients or as a distinctive effect pg/ml in post-BPD women, and 211.72 Ϯ ally, a decrease in CBG levels would act to of the surgery. 45.25 nmo/l and 28.38 Ϯ 3.04 pg/ml in amplify the availability of metabolically Concerning the effect of the DEX-ST, control subjects. free cortisol at peripheral target organs. the dissociation between cortisol (which DHEA (Fig. 1C) decreased from Increased FCI might be a counteracting was fully suppressed in all subjects) and 39.79 Ϯ 5.02 to 14.14 Ϯ 3.71 nmol/l in mechanism to the risk of hypoglycemia DHEA in obese and postobese women obese women (P Յ 0.0001), 45.36 Ϯ (stressor). In fact, in healthy subjects, hy- compared with healthy control subjects, 8.80 to 22.63 Ϯ 5.73 nmol/l in post-BPD poglycemia is reversed by a small permis- as well as differences in ACTH levels, sug- women, and 43.54 Ϯ 6.67 to 6.16 Ϯ 1.05 sive amount of glucocorticoids (27). gest a different adrenal sensitivity and/or nmol/l in control subjects (P Յ 0.0001). Thus, postobese women may be able to pituitary response as seen in the presence DHEA concentration was significantly maintain an elevated level of free cortisol of a stress situation among the three lowered in control subjects compared available to all tissues without increasing groups. Previous studies, which have with obese women both before (P Յ 0.05) total cortisol as demonstrated in free- used an oral DEX-ST to indirectly test ac- and after (P Յ 0.01) weight loss. CBG living animals (28). Increased free cortisol tivity of the HPA axis in obesity, found no decreased significantly (Table 2) (P appears to promote food-seeking behav- impairment of cortisol suppression (12– ior in animals (28). 14). We used intravenous DEX infusion Յ0.01), and consequently, FCI signifi- CBG may also act as a proper hor- (25) to minimize the possible alteration in cantly increased (from 11.15 Ϯ 2.85 to mone (28,29), and its levels (4) or its oral DEX absorption and/or liver metab- 18.16 Ϯ 6.82, P Յ 0.05) after surgery. binding capacity (28,30) decrease in con- olism since postobese women had severe The FCI-to-ACTH ratio decreased from Ϯ Ϯ ϭ dition of restrain, stress, and reduced lipid malabsorption. Any attempt to ex- 8.36 3.22 to 10.08 2.77 (P NS). food intake. Nevertheless, in anorectic plain these results should take into ac- In obese women, serum CBG was re- ϭ ϭ women, we have previously found nor- count that in our series, data on cortisol lated to BMI (r0 0.708, P 0.0001), mal levels of CBG but rapid escape to the clearance and/or distribution volume, ϭ ϭ body weight (r0 0.643, P 0.0001), fat effect of DEX-ST (31). However, little is which can affect results, are lacking. ϭ ϭ mass percentage (r0 0.462, P 0.001), known about the transcriptional regula- Thus, we combined the DEX-ST with ϭ ϭ CRP (r0 0.619, P 0.004), and leptin tion of the CBG gene in response to FFA a single measurement of CBG and calcu- ϭ ϭ (r0 0.579, P 0.007) and negatively to or insulin sensitivity, and this may repre- lation of FCI. DEX-ST reliably explores ϭϪ ϭ M value (r0 0.603, P 0.005). sent a simplistic mechanism by which the negative feedback regulation of corti- Changes in sex hormone–binding glob- CBG levels are decreased. A reduced CBG sol on ACTH and relies on multiple time ulin negatively correlated with changes liver synthesis might also occur after bari- points. FCI is strongly associated with ϭϪ ϭ in fasting (r0 0.673, P 0.03) and atric surgery, but in our series, liver en- CBG-binding activity and with adrenal ϭϪ ϭ total (r0 0.634, P 0.048) insulin zymes and protein levels were unchanged cortisol production, but one morning secretion. after massive weight reduction. Neverthe- point alone for CBG and cortisol might
1498 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Manco and Associates not be representative of the whole-day man MF: Regulation of activity in the hy- 15. Hamrahian AH, Oseni TS, Arafah BM: FCI rhythm. Moreover, estimation of free pothalamo pituitary-adrenal axis is inte- Measurements of serum free cortisol in cortisol by equilibrium dialysis would be gral to a larger hypothalamic system that critically ill patients. N Engl J Med 350: more accurate than a derivative method to determines caloric flow. Endocrinology 1629–1638, 2004 assess the amount of free hormone. Addi- 135:1125–1134, 1994 16. Ousova O, Guyonnet-Duperat V, Ian- 3. Galvao-Teles A, Graves L, Burke CW, nuccelli N, Bidanel JP, Milan D, Genet tionally, we used an intravenous DEX-ST Fotherby K, Fraser R: Free cortisol in obe- C, Llamas B, Yerle M, Gellin J, Chardon (25) to minimize the possible variations sity: effect of fasting. Acta Endocrinol P, Emptoz-Bonneton A, Pugeat M, in DEX absorption in postobese women (Copenh) 81:321–329, 1976 Mormede P, Moisan MP: Corticosteroid who had severe lipid malabsorption. 4. Yanovski JA, Yanovski SZ, Gold PW, binding globulin: a new target for cortisol- The wide variability in the HPA axis Chrousos GP: Differences in cortico- driven obesity. Mol Endocrinol 18:1687–96, balance in weight loss subjects may be tropin-releasing hormone-stimulated 2004 related to the stress of starvation and/or to adrenocorticotropin and cortisol before 17. Fernandez-Real JM, Grasa M, Casamit- specific metabolic alterations rather than and after weight loss. J Clin Endocrinol jana R, Pugeat M, Barret C, Ricart W: to the weight loss per se. For instance, in Metab 82:1874–1878, 1997 Plasma total and glycosylated corticoste- starving subjects, Yanovski et al. (14) re- 5. Bjorntorp P, Rosmond R: Hypothalamic roid-binding globulin levels are associ- origin of the metabolic syndrome X. 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Calvani M, Scarfone A, Granato L, Mora They were not affected by hypertension, 8. Andrew R, Phillips DI, Walker BR: Obe- EV, Nanni G, Castagneto M, Greco AV, diabetes, or severe dyslipidemia. Thus, sity and gender influence cortisol secre- Manco M, Mingrone G: Restoration of tion and metabolism in man. J Clin adiponectin pulsatility in severely obese they may be the ones who have the fewest Endocrinol Metab 83:1806–1809, 1998 subjects after weight loss. Diabetes 53: abnormalities of their HPA axis. However, 9. Rask E, Olsson T, Soderberg S, Andrew R, 939–947, 2004 future studies addressing this issue will be Livingstone DE, Johnson O, Walker BR: 20. Report of the Expert Committee on the important to our understanding of dys- Tissue-specific dysregulation of cortisol Diagnosis and Classification of Diabetes regulation of the HPA axis. metabolism in human obesity. J Clin En- Mellitus. 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1500 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications ORIGINAL ARTICLE
Plasma Resistin, Associated With Single Nucleotide Polymorphism ؊420, Is Correlated With Insulin Resistance, Lower HDL Cholesterol, and High-Sensitivity C- Reactive Protein in the Japanese General Population
1 1 HARUHIKO OSAWA, MD, PHD WATARU NISHIDA, MD, PHD CONCLUSIONS — Plasma resistin was 2 5,6 YASUHARU TABARA, PHD KAZUYA YAMADA, PHD associated with SNP Ϫ420 and was correlated 3 7 RYUICHI KAWAMOTO, MD, PHD JUN NAKURA, MD, PHD with insulin resistance, low serum HDL cho- 4 JUN OHASHI, PHD KATSUHIKO KOHARA, MD, PHD7 lesterol, and high hs-CRP in the Japanese gen- 1 7 MASAAKI OCHI, BS TETSURO MIKI, MD, PHD eral population. 1 1 HIROSHI ONUMA, MD, PHD HIDEICHI MAKINO, MD, PHD Diabetes Care 30:1501–1506, 2007
OBJECTIVE — Resistin, secreted from adipocytes, causes insulin resistance in rodents. We esistin, secreted from adipocytes of previously reported that the G/G genotype of a resistin gene promoter single nucleotide poly- mice, antagonizes insulin action in morphism (SNP) at Ϫ420 increases type 2 diabetes susceptibility by enhancing promoter activ- ity. We report here on the relation between plasma resistin and either SNP Ϫ420 genotype or R vitro and in vivo (1,2). Serum resis- factors related to insulin resistance. tin is increased in obese diabetic mice and is reduced by insulin sensitizers, peroxi- RESEARCH DESIGN AND METHODS — We cross-sectionally analyzed 2,078 com- some proliferator–activated receptor ␥ li- munity-dwelling Japanese subjects attending a yearly medical checkup. The SNP Ϫ420 geno- gands (1,2). Overexpression of resistin type was determined by TaqMan analysis. Fasting plasma resistin was measured using an gene in the liver increases serum resistin enzyme-linked immunosorbent assay kit. and insulin resistance (3), whereas its dis- ruption reduces fasting plasma glucose RESULTS — Plasma resistin was associated with the SNP Ϫ420 genotype (P Ͻ 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly (FPG) (4). Therefore, an elevation in se- individuals, female subjects, nondrinkers, and subjects with high blood pressure (P Ͻ 0.001, rum resistin appears to cause insulin re- 0.003, Ͻ0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sistance in rodents, although some other sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pres- studies are not in agreement with this sure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively conclusion (5). correlated with plasma resistin (P Ͻ 0.001, 0.003, Ͻ0.001, 0.004, Ͻ0.001, and 0.003, respec- Type 2 diabetes is characterized by tively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin insulin resistance in insulin target tissues ϭ Ͻ was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P 0.001, 0.001, (6). Major genetic factors of type 2 diabe- and 0.006, respectively). tes, a probable polygenic disease, remain ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● to be identified, whereas it has been re- From the 1Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, ported that some single nucleotide poly- Ehime, Japan; the 2Department of Basic Medical Research and Education, Ehime University Graduate School morphisms (SNPs) are associated with of Medicine, Ehime, Japan; the 3Department of Internal Medicine, Seiyo-city Nomura Hospital, Ehime, type 2 diabetes (7). We recently reported Japan; the 4Department of Human Genetics, School of International Health, Graduate School of Medicine, that the G/G genotype of a human resistin the University of Tokyo, Tokyo, Japan; the 5Department of Biochemistry, Faculty of Medical Sciences, Ϫ 6 gene (RETN) SNP at 420 (rs1862513) University of Fukui, Fukui, Japan; CREST, Japan Science and Technology Agency, Fukui, Japan; and the 7Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan. was associated with type 2 diabetes sus- Address correspondence and reprint requests to H. Osawa, MD, PhD, Department of Molecular and ceptibility (8). Of the frequent SNPs in the Genetic Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, linkage disequilibrium area including Japan. E-mail: [email protected]. Or H. Makino, MD, PhD, Department of Molecular and Genetic SNP Ϫ420, only SNP Ϫ420 was signifi- Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. E-mail: [email protected]. cantly associated with type 2 diabetes. In Received for publication 20 September 2006 and accepted in revised form 10 March 2007. vitro, Sp1/3 transcription factors specifi- Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1936. cally recognized G at Ϫ420 and enhanced H.O. and Y.T. contributed equally to this work. resistin promoter activity. Subjects with Abbreviations: CRP, C-reactive protein; CVD, cardiovascular disease; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, high-sensitivity CRP; IRI, immu- G/G genotype had the highest serum re- noreactive insulin; SNP, single nucleotide polymorphism; SBP, systolic blood pressure. sistin, followed by C/G and C/C (8,9). A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Thus, the association between SNP Ϫ420 factors for many substances. and serum resistin in the general popula- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby tion merits further investigation. marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. It remains controversial whether cir-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1501 Plasma resistin in the Japanese population culating resistin levels are associated with Table 1—Characteristics of the population studied insulin resistance, type 2 diabetes, or ad- iposity in humans (9–17). It has been re- Characteristics ported that resistin is increased in type 2 diabetes (9,13) and in obesity (10,12). n (males/females) 2,078 (914/1,164) McTernan et al. (15) and Youn et al. (17) Age (years) 62 Ϯ 13 reported that resistin is increased in type BMI (kg/m2) 23.4 Ϯ 3.2 2 diabetes but not associated with BMI, SBP (mmHg) 139 Ϯ 22 although the role of obesity was not the DBP (mmHg) 82 Ϯ 12 primary focus of the former’s study. Silha Total cholesterol (mg/dl) 203 Ϯ 35 et al. (16), but not Lee et al. (14), found an HDL cholesterol (mg/dl) 62 Ϯ 16 association between resistin and insulin Triglycerides (mg/dl) 114 Ϯ 78 resistance. No association was detected FPG (mg/dl) 98 Ϯ 22 between resistin and either type 2 diabe- IRI (U/ml)* 6.7 Ϯ 5.0 tes or obesity (14). The discrepancy HOMA-IR† 1.6 Ϯ 1.4 among previous reports may be resolved Resistin (ng/ml) 11.5 Ϯ 6.6 by analyzing a larger number of samples. hs-CRP (mg/dl)‡ 0.075 Ϯ 0.086 Metabolic syndrome, a cluster of ab- Current smoking (%) 16.3 normalities including central obesity, Current drinking (%) 28.6 glucose intolerance or diabetes, hyperten- History of CVD (%)§ 7.3 sion, and dyslipidemia (high triglyceride Medication (%) levels and/or low HDL cholesterol), in- Hypertension 25.8 creases the risk of cardiovascular disease Diabetes 3.5 (CVD) (18). Because underlying insulin Hyperlipidemia 5.7 resistance could be fundamental for this SNP Ϫ420 genotype (CC/CG/GG) 938/902/238 syndrome, the relation between resistin Data are means Ϯ SD or n (%) unless otherwise noted. *n ϭ 2,017; †HOMA-IR calculated as fasting blood and metabolic syndrome factors should serum ϫ IRI/405; ‡n ϭ 1,875; §CVD includes stroke, myocardial infarction, and angina pectoris. DBP, be assessed. diastolic blood pressure. To determine the relation between plasma resistin and either SNP Ϫ420 or they were being treated with antihyper- CVD includes stroke, myocardial infarc- factors related to insulin resistance, we glycemic agents or had FPG levels of tion, and angina pectoris. Because Japa- cross-sectionally analyzed 2,078 subjects. Ն126 mg/dl. The association between nese individuals are generally leaner than Plasma resistin was associated with SNP SNP Ϫ420 and diabetes was not signifi- Caucasians, BMI Ն25 kg/m2 was used as Ϫ420 and was correlated with homeosta- cant, possibly because of the lack of the standard cutoff value for the diagnosis sis model assessment of insulin resistance power using the small numbers of dia- of obesity (19). Waist circumference data (HOMA-IR), lower HDL cholesterol, and betic subjects. The plasma samples were were not available in this study. Blood high-sensitivity C-reactive protein (hs- immediately separated, frozen, and pressure was measured using an auto- CRP). stored at Ϫ80°C. The baseline character- matic cuff-oscillometric device with an istics of the study subjects, such as alcohol appropriately sized cuff on the left arm RESEARCH DESIGN AND habituation, history or symptoms of CVD, (BP-103i; Colin, Aichi, Japan) after a rest- METHODS — All subjects were native and medication, were investigated in an ing period of at least 5 min in the sitting to Japan. We analyzed community- individual interview using a structured position. dwelling subjects attending a yearly med- questionnaire. The clinical characteristics ical checkup in a rural town located in of these subjects are summarized in Table SNP typing Ehime prefecture, Japan, in 2002. Of the 1. All subjects were informed of the pur- SNP Ϫ420 was typed by TaqMan analysis 2,889 subjects who agreed to participate, pose of the study and their consent was (Applied Biosystems). The probes used 2,078, for whom overnight fasting plasma obtained. The study was approved by the were VIC 5Ј-CATGAAGACGGAGGC samples (Ͼ11 h) were available, were an- ethics committee of the Ehime University C-3Ј for Ϫ420C and FAM 5Ј-ATGAAGA alyzed for plasma resistin levels. Because Graduate School of Medicine. Definitions GGGAGGCC-3Ј for Ϫ420G. Forward of the availability of plasma samples, im- used are as follows: obesity, BMI Ն25 kg/ and reverse primers were 5Ј-CCACCTCC munoreactive insulin (IRI) and hs-CRP m2; impaired glucose tolerance, FPG TGACCAGTCTCT-3Ј and 5Ј-AGCCTTC were measured in 2,017 and 1,875 sub- Ն110 mg/dl (6.1 mmol/l) and/or under CCACTTCCAACAG-3Ј, respectively. jects, respectively. Of the 2,078 subjects, medication of antihyperglycemic agents; When required, PCR direct sequencing 157 with A1C levels Ͻ5.6%, FPG levels high blood pressure, systolic blood pres- was performed as previously described Ͻ110 mg/dl, no history of diabetes, and sure (SBP) Ն140 mmHg and/or diastolic (8,20). no evidence of diabetes within first- pressure Ն90 mmHg and/or under med- degree relatives were used as nondiabetic ication with antihypertensive agents; hy- Measurement of plasma resistin and control subjects in a previous study (9). pertriglyceridemia, triglyceride levels hs-CRP levels There was no overlapping of samples be- Ն150 mg/dl (1.69 mmol/l) and/or under Plasma resistin was measured using a tween the present study and the other medication with antihyperlipidemic human resistin enzyme-linked immu- previous study (8). Of the 2,078 subjects, agents; and low HDL cholesterol, HDL nosorbent assay kit (LINCO Research) 151 were considered diabetic because cholesterol Ͻ40 mg/dl (1.04 mmol/l). following the manufacturer’s protocol as
1502 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Osawa and Associates
Figure 1—Fasting plasma resistin was highest in subjects with the G/G genotype of resistin SNP Ϫ420, followed by C/G and C/C in the Japanese general population (n ϭ 2,078). Fasting plasma samples from each subject were measured as described (see RESEARCH DESIGN AND METHODS). A: Fasting plasma resistin increased with an increased number of G allele. Data are means Ϯ SD for each of the SNP Ϫ420 genotypes. ANOVA was used for the statistical analyses (F ϭ 368.6, P Ͻ 0.0001). The calculated power based on the observed effect and the sample sizes with ␣ ϭ 0.05 was 0.999. Scheffe’s test was then used in post hoc analyses, and P Ͻ 0.0001 (*). B: The plasma resistin at the peak of the numbers of subjects with each genotype appears to be in the order G/G ϾC/G Ͼ C/C. Number of subjects are calculated for each 2.5 ng/ml range of plasma resistin in each of the SNP Ϫ420 genotypes. The range of plasma resistin in which the number of subjects was highest in each genotype was 15–17.5 (G/G), 7.5–10 (C/G), and 5–7.5 ng/ml (C/C). described (8). The linearity was main- plasma resistin, age, sex, and BMI were type, followed in order by those with C/G tained Ͻ0.16 ng/ml. Inter- and intra- involved as independent variables. CVD and those with C/C (F ϭ 368.6, P Ͻ assay coefficients of variation (CVs) were was involved as a dependent variable in 0.0001, power ϭ 0.999). This association 6.9 and 1.7% (low levels) and 7.2 and logistic regression analysis. ANOVA was was consistent when analyzed in either 8.1% (high levels), respectively. The kit used where indicated. All analyses were male (F ϭ 150.6, P Ͻ 0.0001) or female used had a good correlation with the performed with SPSS version 14.0J (SPSS, (F ϭ 221.3, P Ͻ 0.0001) subjects. When other kit (r ϭ 0.978; y ϭ 2.216x ϩ 8.0, Chicago, IL). Bonferroni’s correction was 50, 20, and 5% of the subjects were ran- where y is this kit and x is BioVender’s applied to the initial analyses of the rela- domly selected and compared using the kit). Plasma hs-CRP concentration was tion between plasma resistin and either SPSS program, these P values were con- measured using a previously validated as- categories (raw P value ϫ9 for ANOVA) sistently low (P Ͻ 0.0001). Therefore, say system (Dade Behring) (21). Inter- or continuous parameters (raw P value plasma resistin was associated with SNP and intra-assay CVs were 3.2 and 6.7%, ϫ10 for simple regression analysis) and Ϫ420 in this population. respectively. the subsequent multiple and logistic re- We then examined the number of gression analyses using factors selected subjects in each 2.5 ng/ml range of plasma Statistical analysis from these results (raw P value ϫ5). The resistin concentration based on the SNP To examine effects of SNP Ϫ420 on plasma proportion of variance of plasma resistin Ϫ420 genotype (Fig. 1B). The plasma re- resistin, a multiple regression analysis in- explained by SNP Ϫ420 was assessed sistin at the highest number of subjects volving SNP Ϫ420, age, sex, and BMI as based on results of a simple regression with each genotype appears to be in the independent variables and plasma resistin analysis. Power was calculated based on order of G/G Ͼ C/G Ͼ C/C. The range of as a dependent variable was used. In this the observed effect and sample sizes using plasma resistin was broadest in subjects analysis, the genotypes for SNP Ϫ420, general linear model for ANOVA (simple with G/G, followed in order by C/G and C/C, C/G, and G/G were denoted by two and multiple regression analyses with C/C (1.9–52.7, 2.2–46.2, and 2.2–35.2 dummy variables (c1 and c2 [0 and 0, 1 ␣ϭ0.05). Null hypotheses were rejected ng/ml, respectively), suggesting that fac- and 0, and 0 and 1, respectively]). To ex- at P Ͻ 0.05. tors other than SNP Ϫ420 genotype may amine the relation of plasma resistin with affect plasma resistin. age, sex, BMI, SBP, HDL cholesterol, tri- RESULTS To examine isolated effects of SNP glyceride levels, FPG, IRI, HOMA-IR, or Ϫ420 on plasma resistin, a multiple re- ,hs-CRP, simple regression analysis in- SNP ؊420 was associated with gression analysis involving SNP Ϫ420 volving plasma resistin as a dependent plasma resistin in the Japanese age, sex, and BMI as independent vari- variable was performed. A multiple re- general population ables was used. The SNP Ϫ420 genotype gression analysis was then performed us- We first assessed plasma resistin based on including G alleles (G/G vs. C/C, P Ͻ ing only the significant factors. HOMA- each genotype of SNP Ϫ420 in 2,078 sub- 0.001, power ϭ 0.999 and C/G vs. C/C, IR, HDL cholesterol, hs-CRP, or SBP was jects (Fig. 1A). Fasting plasma resistin was P Ͻ 0.001, power ϭ 0.999), higher age analyzed as a dependent variable, and highest in subjects with the G/G geno- (P Ͻ 0.001, power ϭ 0.999), and female
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1503 Plasma resistin in the Japanese population sex (P ϭ 0.001, power ϭ 0.894), but not Table 2—Age, female sex, SBP, low HDL cholesterol, HOMA-IR, and hs-CRP were correlated higher BMI (P ϭ 0.195, power ϭ 0.254), with plasma resistin was positively correlated with plasma re-  sistin. The standardized coefficient ( )of Unstandardized Standardized the G/G genotype compared with C/C was  ϭ Independent variable regression regression highest ( 0.480), followed by that of for simple regression coefficient coefficient P C/G compared with C/C ( ϭ 0.384) (age,  ϭ 0.100; female sex,  ϭ 0.060; Age (years) 0.055 0.104 Ͻ0.001* and BMI,  ϭ 0.024). Therefore, SNP Sex (male) Ϫ0.877 Ϫ0.066 0.003* Ϫ420 genotype was the strongest deter- BMI (kg/m2) 0.060 0.029 0.186 minant of plasma resistin among these SBP (mmHg) 0.019 0.063 0.004* factors. The contribution of this genotype HDL cholesterol (mg/dl) Ϫ0.033 Ϫ0.077 Ͻ0.001* to the observed total variance of resistin Triglyceride level (mg/dl) 0.001 0.014 0.533 (R2) was 26.1%. FPG (mg/dl) Ϫ0.003 Ϫ0.010 0.658 IRI (U/ml)† 0.120 0.090 Ͻ0.001* HOMA-IR‡ 0.401 0.082 Ͻ0.001* Plasma resistin was higher in elderly hs-CRP (mg/dl)§ 4.999 0.068 0.003* individuals, female subjects, Simple regression analysis was performed involving plasma resistin (ng/ml) as a dependent variable and each nondrinkers, and subjects with high factor as an independent variable. Sex: male ϭ 1; female ϭ 0. *P values remained significant after Bonfer- blood pressure roni’s correction (raw P value ϫ10); †IRI, n ϭ 2,017; ‡HOMA-IR, calculated as FPG ϫ IRI/405; §hs-CRP, We then examined mean plasma resistin n ϭ 1,875. Each calculated power based on the observed effect size and the sample size with ␣ϭ0.05 was in each category without considering the age (0.997), sex (0.852), BMI (0.262), SBP (0.822), HDL cholesterol (0.942), triglyceride level (0.096), FPG SNP Ϫ420 genotype. Plasma resistin was (0.073), IRI (0.982), HOMA-IR (0.959), and hs-CRP (0.839). higher in elderly individuals (aged Ն65 years) (mean Ϯ SD 12.2 Ϯ 7.1 vs. 10.9 Ϯ Plasma resistin was correlated with correlated with HOMA-IR, low HDL cho- 6.1; ANOVA P Ͻ 0.001, power ϭ 0.994), HOMA-IR, low HDL cholesterol, or lesterol, and hs-CRP, independent of age, female subjects (11.9 Ϯ 6.6 vs. 11.0 Ϯ hs-CRP, independent of age, sex, and sex, and BMI. 6.6; P ϭ 0.003, power ϭ 0.852), nonha- BMI bitual alcohol drinkers (12.0 Ϯ 6.7 vs. To examine isolated effects of plasma re- CONCLUSIONS — Our cross-sec- 10.4 Ϯ 6.3; P Ͻ 0.001, power ϭ 0.999), sistin on each factor, a multiple regression tional study that included 2,078 subjects subjects with high blood pressure analysis adjusted for age, sex, and BMI from the Japanese general population (11.9 Ϯ 6.9 vs. 11.0 Ϯ 6.2; P ϭ 0.001, was performed (Table 3). Factors signifi- shows that plasma resistin was associated power ϭ 0.905), those with low HDL cantly associated with plasma resistin in with SNP Ϫ420. Plasma resistin was cholesterol (13.0 Ϯ 8.3 vs. 11.4 Ϯ 6.5; Table 2, namely, HOMA-IR, HDL choles- higher in the elderly, female subjects, P ϭ 0.014, power ϭ 0.693), and those terol, hs-CRP, and SBP, were individually nondrinkers, and subjects with high with a history of CVD (12.5 Ϯ 6.7 vs. analyzed as a dependent variable. Among blood pressure. Multiple regression anal- 11.4 Ϯ 6.6; P ϭ 0.045, power ϭ 0.516). these factors, only HOMA-IR, low HDL ysis adjusted for age, sex, and BMI re- Age, sex, alcohol drinking, and high cholesterol, and hs-CRP were correlated vealed that plasma resistin was an blood pressure remained significant after with plasma resistin, with the caution that independent factor for HOMA-IR, low Bonferroni’s correction. Obesity (P ϭ plasma resistin has a relatively small effect HDL cholesterol, and hs-CRP. 0.613, power ϭ 0.080), IGT (P ϭ 0.733, on these parameters based on the regres- We found that SNP Ϫ420 was asso- power ϭ 0.063), or hypertriglyceridemia sion coefficients. Therefore, plasma resis- ciated with plasma resistin in the order (P ϭ 0.497, power ϭ 0.104) was not as- tin, associated with SNP Ϫ420, was G/G Ͼ C/G Ͼ C/C in a large number of sociated with plasma resistin.
Table 3—Plasma resistin was correlated with either HOMA-IR, low HDL cholesterol, or Age, female sex, SBP, low HDL hs-CRP, independent of age, sex, and BMI cholesterol, HOMA-IR, and hs-CRP were correlated with plasma resistin We then examined which factors are cor- Unstandardized Standardized related with plasma resistin (Table 2). Dependent variable regression coefficient regression coefficient Simple regression analysis revealed that (individually analyzed) of plasma resistin of plasma resistin P age, female sex, SBP, low HDL choles- HOMA-IR* 0.013 0.065 0.001† terol, IRI, HOMA-IR, and hs-CRP were HDL cholesterol (mg/dl) Ϫ0.190 Ϫ0.081 Ͻ0.001† correlated with plasma resistin. Each of hs-CRP (mg/dl) 0.001 0.061 0.006† these P values remains significant after SBP (mmHg) 0.062 0.018 0.346 Bonferroni’s correction. BMI, triglyceride All characteristics were adjusted for age, sex, and BMI. Multiple regression analysis involving age, sex levels, and FPG were not correlated with (male ϭ 1, female ϭ 0), BMI, and plasma resistin (ng/ml) as independent variables was performed, and plasma resistin. Therefore, with possible HOMA-IR, HDL, hs-CRP, and SBP were individually analyzed as a dependent variable. Each calculated effects of age and sex, high plasma resistin power based on the observed effect size and the sample size with ␣ϭ0.05 was HOMA-IR (0.908), HDL cholesterol (0.973), hs-CRP (0.780), or SBP (0.156). Logistic regression analysis involving CVD as a depen- was correlated with insulin resistance, dent variable and age, sex, BMI, and plasma resistin as independent variables showed that CVD was not low HDL cholesterol, high SBP, and high correlated with plasma resistin (unstandardized regression coefficient, 0.010; P ϭ 0.424). *HOMA-IR hs-CRP. calculated as FPG ϫ IRI/405; †P remained significant after Bonferroni’s correction (raw P value ϫ5).
1504 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Osawa and Associates samples. This finding provides strong ev- with C-reactive protein (CRP) in a cross- perresistinemia. Diabetes 53:1937–1941, idence for a tight correlation between a sectional analysis of 77 subjects having 2004 functional promoter SNP and its gene diabetes or its risk and 45 type 2 diabetic 4. Banerjee R, Rangwala S, Shapiro J, Rich A, product as the final output in humans. subjects, respectively. Al-Daghri et al. Rhoades B, Qi Y, Wang J, Rajala M, Pocai The association is also supported by stud- (30) showed that resistin is associated A, Scherer P, Steppan C, Ahima R, Obici S, Rossetti L, Lazar M: Regulation of fasted ies in which smaller numbers of samples with CRP in subjects with type 2 diabetes blood glucose by resistin. Science 303: were used, namely by Cho et al. (11) and or coronary artery disease in the Saudi 1195–1198, 2004 ourselves (8). Haplotypes including SNP Arabian population. Reilly et al. (31) re- 5. Way JM, Gorgun CZ, Tong Q, Uysal KT, Ϫ420 also show this similar tendency in ported that plasma resistin is correlated Brown KK, Harrington WW, Oliver WR Japanese subjects (22). A total of four in- with inflammatory markers and is predic- Jr, Willson TM, Kliewer SA, Hotamisligil dependent groups reported that the activ- tive of coronary atherosclerosis in hu- GS: Adipose tissue resistin expression is ity of the mutant RETN promoter mans, independent of CRP. In vitro, severely suppressed in obesity and stimu- including Ϫ420G is higher than that of resistin increases the expression of critical lated by peroxisome proliferator-acti- the wild type including Ϫ420C in vitro factors involved in atherosclerotic lesion, vated receptor gamma agonists. J Biol (8,11,22,23). Therefore, we propose that such as vascular cell adhesion mole- Chem 276:25651–25653, 2001 6. DeFronzo RA, Bonadonna RC, Ferrannini SNP Ϫ420 is a determinant of plasma re- cule-1, intracellular adhesion molecule-1, Ϫ E: Pathogenesis of NIDDM: a balanced sistin. Because only SNP 420 was typed and monocyte chemoattractant protein-1 overview. Diabetes Care 15:318–368, in this study, the other SNPs in RETN (32,33). Resistin also enhances human 1992 should be analyzed to further examine aortic smooth muscle cell proliferation 7. McCarthy MI: Progress in defining the this hypothesis. (34). Therefore, resistin could enhance molecular basis of type 2 diabetes mellitus Our findings have shown that plasma vascular inflammation resulting in ele- through susceptibility-gene identification. resistin was positively associated with vated serum hs-CRP, whereas an inflam- Hum Mol Genet 13 Spec No. 1:R33–R41, HOMA-IR, independent of age, sex, and matory cascade has been proposed to lead 2004 BMI. To our knowledge, the positive cor- to hyperresistinemia in humans (35). 8. Osawa H, Yamada K, Onuma H, Mu- relation between circulating resistin and In summary, SNP Ϫ420 was associ- rakami A, Ochi M, Kawata H, Nishimiya HOMA-IR in humans is supported in 2 of ated with plasma resistin in the Japanese T, Niiya T, Shimizu I, Nishida W, Hash- Ͼ iramoto M, Kanatsuka A, Fujii Y, Ohashi 10 previous studies, whereas the role of general population. Plasma resistin was J, Makino H: The G/G genotype of a resis- resistin as a factor inducing insulin resis- correlated with insulin resistance, lower tin single-nucleotide polymorphism at tance has been established in mice HDL cholesterol, and high hs-CRP. It is Ϫ420 increases type 2 diabetes mellitus (16,24). The lower power with small not clear what genetic or environmental susceptibility by inducing promoter activ- numbers of subjects may account for this factors other than SNP Ϫ420, age, and ity through specific binding of Sp1/3. Am J difference. The broader range of the assay sex affect plasma resistin and how resistin Hum Genet 75:678–686, 2004 used in this study could also be a contrib- induces insulin resistance in humans. 9. Osawa H, Onuma H, Ochi M, Murakami uting factor. It should be noted that serum Further studies will be required to clarify A, Yamauchi J, Takasuka T, Tanabe F, resistin probably exists as a hexamer (ma- these points. Shimizu I, Kato K, Nishida W, Yamada K, jor form) or trimer (a more biologically Tabara Y, Yasukawa M, Fujii Y, Ohashi J, Miki T, Makino H: Resistin SNP Ϫ420 active form) in mice, which may also af- determines its monocyte mRNA and se- fect the assay results (25). The existence Acknowledgments— This work was sup- rum levels inducing type 2 diabetes. Bio- of multimers in human serum has re- ported by grants for research of metabolic dis- chem Biophys Res Commun 335:596–602, cently been implicated (26). orders from Ehime University, Kurozumi 2005 We have shown that plasma resistin Medical Foundation, and Astellas Foundation 10. Azuma K, Katsukawa F, Oguchi S, Murata was inversely associated with serum HDL and for scientific research from the Ministry of M, Yamazaki H, Shimada A, Saruta T: Education, Culture, Sports, Science and Tech- Correlation between serum resistin level cholesterol, independent of age, sex, and nology of Japan; the Ministry of Health, La- and adiposity in obese individuals. Obes BMI. Resistin was reported to be associ- bour and Welfare of Japan; and the Japan Res 11:997–1001, 2003 ated with low HDL cholesterol in a Arteriosclerosis Prevention Fund. 11. Cho Y, Youn B, Chung S, Kim K, Lee H, smaller numbers of subjects (27,28). We thank M. Murase, T. Nishimiya, Dr. Yu K, Park H, Shin H, Park K: Common Hashiramoto, and Dr. Takata for suggestions. Overexpression of resistin in the liver us- genetic polymorphisms in the promoter We also thank C. Hiraoka, A. Murakami, and ing adenovirus in mice shows enhanced of resistin gene are major determinants of T. Takasuka for technical assistance. insulin resistance, low serum HDL cho- plasma resistin concentrations in hu- lesterol, and high triglyceride levels, mans. Diabetologia 47:559–565, 2004 which resembles the metabolic syndrome 12. Degawa-Yamauchi M, Bovenkerk JE, in humans (29). Insulin is known to up- References Juliar BE, Watson W, Kerr K, Jones R, Zhu regulate lipoprotein lipase, a critical factor 1. Steppan C, Lazar M: The current biology Q, Considine RV: Serum resistin (FIZZ3) producing HDL cholesterol through li- of resistin. J Intern Med 255:439–447, protein is increased in obese humans. poprotein metabolism. 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subjects and patients with type 2 diabetes. for single nucleotide polymorphisms in Mantzoros CS, Veves A: Circulating adi- Clin Chim Acta 339:57–63, 2004 the resistin gene: the absence of evidence ponectin and resistin levels in relation to 14. Lee J, Chan J, Yiannakouris N, Konto- for the association of three identified sin- metabolic factors, inflammatory markers, gianni M, Estrada E, Seip R, Orlova C, gle nucleotide polymorphisms with Japa- and vascular reactivity in diabetic patients Mantzoros C: Circulating resistin levels nese type 2 diabetes. Diabetes 51:863– and subjects at risk for diabetes. Diabetes are not associated with obesity or insulin 866, 2002 Care 27:2450–2457, 2004 resistance in humans and are not regu- 21. Ridker PM: High-sensitivity C-reactive 29. 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Patel S, Rajala M, Rossetti L, Scherer P, tions. Biochem Biophys Res Commun 314: by enzyme-linked immunosorbent assay Shapiro L: Disulfide-dependent multi- 415–419, 2004 using a newly developed monoclonal an- meric assembly of resistin family hor- 33. Verma S, Li SH, Wang CH, Fedak PW, Li tibody are elevated in individuals with mones. Science 304:1154–1158, 2004 RK, Weisel RD, Mickle DA: Resistin pro- type 2 diabetes mellitus. J Clin Endocrinol 26. Gerber M, Boettner A, Seidel B, Lammert motes endothelial cell activation: further Metab 89:150–156, 2004 A, Bar J, Schuster E, Thiery J, Kiess W, evidence of adipokine-endothelial inter- 18. Eckel RH, Grundy SM, Zimmet PZ: The Kratzsch J: Serum resistin levels of obese action. Circulation 108:736–740, 2003 metabolic syndrome. Lancet 365:1415– and lean children and adolescents: bio- 34. Calabro P, Samudio I, Willerson JT, Yeh 1428, 2005 chemical analysis and clinical relevance. ET: Resistin promotes smooth muscle cell 19. 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1506 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications ORIGINAL ARTICLE
Accelerated Loss of Skeletal Muscle Strength in Older Adults With Type 2 Diabetes The Health, Aging, and Body Composition Study
1,2 6 SEOK WON PARK, MD, DRPH TAMARA B. HARRIS, MD n industrialized countries, the major 3 7 BRET H. GOODPASTER, PHD ANN V. SCHWARTZ, PHD increase in the number of people 2 8 ELSA S. STROTMEYER, PHD FRANCES A. TYLAVSKY, PHD 2 1 with diabetes is attributed to the ag- EWIS ULLER MD, DRPH ONG WOOK HO MD I L H. K , Y - C , 2 2 ing of the population (1,2). In older ROBERT BROUDEAU, PHD ANNE B. NEWMAN, MD, MPH 4 adults, diabetes is associated with a CANDACE KAMMERER, PHD FOR THE HEALTH,AGING, AND BODY 5 two- to threefold increased risk of inju- NATHALIE DE REKENEIRE, MD COMPOSITION STUDY rious falls (3) and physical disability (4–8). Several factors have been identi- fied as contributors to diabetes-related OBJECTIVE — It has been shown that adults with either long-standing type 1 or type 2 disability including obesity (4,5), coro- diabetes had lower skeletal muscle strength than nondiabetic adults in cross-sectional studies. The aim of the study was to investigate longitudinal changes of muscle mass and strength in nary heart disease (4,5,7), stroke (4), community-dwelling older adults with and without type 2 diabetes. arthritis (4,5), depression (7), and vi- sual impairments (4,5), but still a large RESEARCH DESIGN AND METHODS — We examined leg and arm muscle mass and portion of the diabetes-disability rela- strength at baseline and 3 years later in 1,840 older adults aged 70–79 years in the Health, Aging, tionship is not explained by these fac- and Body Composition Study. Regional muscle mass was measured by dual energy X-ray ab- tors. Alterations in muscular function in sorptiometry, and muscle strength was measured using isokinetic and isometric dynamometers. diabetes, which can be a potential path- way, have not yet been explored. RESULTS — Older adults with type 2 diabetes (n ϭ 305) showed greater declines in the leg muscle mass (Ϫ0.29 Ϯ 0.03 vs. Ϫ0.23 Ϯ 0.01 kg, P Ͻ 0.05) and strength (Ϫ16.5 Ϯ 1.2 vs. Muscle weakness in diabetes has Ϫ12.4 Ϯ 0.5 Nm, P ϭ 0.001) compared with older adults without diabetes. Leg muscle quality, been considered a rare manifestation as- expressed as maximal strength per unit of muscle mass (Newton meters per kilogram), also sociated with severe diabetic neuropa- declined more rapidly in older adults with diabetes (Ϫ1.6 Ϯ 0.2 vs. Ϫ1.2 Ϯ 0.1 Nm/kg, P Ͻ thy (9). However, recent studies using 0.05). Changes in arm muscle strength and quality were not different between those with and quantitative assessments of muscular without diabetes. Rapid declines in leg muscle strength and quality were attenuated but re- function showed that skeletal muscle mained significant after controlling for demographics, body composition, physical activity, strength, especially in the lower extrem- ␣ combined chronic diseases, interleukin-6, and tumor necrosis factor- . ity, is generally lower in adults with di- abetes than in nondiabetic subjects CONCLUSIONS — In older adults, type 2 diabetes is associated with accelerated loss of leg muscle strength and quality. (10–12). The Health, Aging, and Body Composition Study (Health ABC) was Diabetes Care 30:1507–1512, 2007 designed to investigate the impact of changes in body composition and health conditions on age-related physi- ological and functional status among adults from 70 to 79 years of age. In this ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● cohort, we have reported that older From the 1Department of Internal Medicine, Pochon CHA University, Pochon, Korea; the 2Department of adults with type 2 diabetes had lower Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania; the 3Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; the 4Department of Human Genetics, University of Pittsburgh, skeletal muscle strength and quality Pittsburgh, Pennsylvania; the 5Division of Diabetes Translation, Centers for Disease Control and Prevention, (12). However, it is still unclear Atlanta, Georgia; the 6Laboratory for Epidemiology, Demography and Biometry, National Institute on Aging, whether lower muscle strength in dia- Bethesda, Maryland; the 7Department of Epidemiology and Biostatistics, University of California, San Fran- 8 betes is a consequence of diabetes or cisco, California; and the Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee. just a coincidence because previous Address correspondence and reprint requests to Seok Won Park, MD, DrPH, Department of Internal Medicine, Pochon CHA University, 351 Yatap-dong, Sungnam, 463-712, Korea. E-mail: [email protected]. studies were cross-sectional observa- Received for publication 15 December 2006 and accepted in revised form 5 March 2007. tions. To address this question, we re- Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2537. examined knee extensor and hand grip Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ strength and body composition 3 years dc06-2537. Abbreviations: Health ABC, Health, Aging, and Body Composition Study; IL-6, interleukin-6; TNF-␣, after the initial examination in the tumor necrosis factor-␣. Health ABC Study. We hypothesized A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion that older adults with type 2 diabetes factors for many substances. would show a greater decline in skeletal © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby muscle strength and quality than older marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. adults without diabetes.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1507 Muscle strength loss in type 2 diabetes
RESEARCH DESIGN AND allowed to produce three overlying Statistical analyses METHODS — The Health ABC Study curves, and the mean maximal torque was Baseline characteristics of the cohort are included well-functioning, community- recorded and used for the analysis. The presented separately for those with and dwelling older adults aged 70–79 years. right leg was used unless contraindicated without diabetes. 2 tests were calculated The Health ABC Study was described in by pain or history of joint replacement. for categorical variables, and a Student’s t detail elsewhere (12). Among 2,618 par- For validation of the knee strength assess- test was used for continuous variables to ticipants who had completed baseline as- ments, we performed a reliability study in test for any statistical differences between sessments for skeletal muscle mass and 63 participants. The interexaminer coef- the two groups. Longitudinal changes of strength, 1,840 (70.3%) were reexamined ficient of variation (CV) was 4.85% with muscle strength and quality were calcu- 3 years later. The reasons for not having lated in both absolute terms and relative ϭ no significant differences between exam- follow-up data were death (n 146), de- iners. The intraparticipant CV was terms (percent change from baseline). velopment of disability and/or institu- Differences between older adults with ϭ 10.68%, and the CV for combined effect tionalization (n 302), missed contact of examiner and participant was 11.73%. and without diabetes were assessed by (n ϭ 77), withdrawal of the participants general linear models controlling for sex, Isometric grip strength was assessed (n ϭ 11), inability to perform a knee race, age, and clinic site (model 1). Addi- for each hand. Participants with severe strength test (n ϭ 191), and missing data tional adjustments were made for BMI, hand pain or recent surgery were ex- on body composition (n ϭ 51). All par- baseline strength or quality, changes in ticipants provided informed consent be- cluded. The vast majority of participants muscle mass, and physical activity (model fore participating in the study. The (96%) who had leg strength testing also 2), plus combined chronic diseases and consent forms and study protocols were had grip strength testing. For these anal- diabetes-related complications (model 3) approved by the institutional review yses, we used the maximum of the force and inflammatory cytokines (log- boards at each field center. from two trials for the right upper extrem- transformed IL-6 and TNF-␣ in model 4). ity. A measure of muscle quality (leg- P Ͻ 0.05 was accepted as statistically sig- Diabetes assessment specific torque [Newton meters per nificant. All of the analyses were per- Participants were considered to have type kilogram] and arm-specific force [kilo- formed using SPSS software (version 2 diabetes if they had 1) a report of having grams per kilogram]) was created by tak- 12.0.0; SPSS, Chicago, IL). the diagnosis of diabetes with onset after ing the ratio of strength to the entire age 25 and/or 2) current use of oral hypo- corresponding leg or arm muscle mass in RESULTS — Among the 1,840 older glycemic medications or insulin, or 3)a kilograms measured by dual-energy X-ray adults with complete assessments of base- fasting plasma glucose concentration absorptiometry. line and follow-up skeletal muscle mass Ն7.0 mmol/l at baseline. Plasma glucose and strength tests, 305 (16.6%) had type was measured using an automated glu- 2 diabetes at baseline. Older adults with cose oxidase reaction (Vitros 950 ana- Other covariates type 2 diabetes were more likely to be lyzer; Johnson & Johnson, Rochester, Sociodemographic characteristics in- men and black and to have a lower level of NY), and A1C was measured by an enzy- cluded age, sex, race, and education. education (Table 1). Those with diabetes matic method (Bio-Rad, Hercules, CA). Combined chronic diseases such as coro- had greater body weight, BMI, and total nary heart disease, congestive heart fail- fat mass as well as higher total lean mass Body composition ure, stroke, peripheral artery disease, than their nondiabetic counterparts. As Lean masses of the upper and lower ex- knee osteoarthritis, depression, and can- expected, combined chronic conditions tremities and the total body were assessed cer were identified by self-report and con- such as coronary heart disease, peripheral using dual-energy X-ray absorptiometry firmed by treatment and medication use. artery disease, impaired vision, and renal (QDR 4500, software version 8.21; Ho- Self-reported poor eyesight was consid- insufficiency were more prevalent in logic, Bedford, MA). The validity and re- those with type 2 diabetes. IL-6 and ered as impaired vision. Renal insuffi- ␣ producibility of the body composition ciency was defined by serum creatinine TNF- levels were significantly higher in data in the Health ABC Study may be level Ͼ1.5 mg/dl in men and 1.2 mg/dl in older adults with diabetes (Table 1). found elsewhere (13,14). Quality assur- Both diabetic and nondiabetic older women (15). The ankle-arm index was ance measures included the use of a body adults lost significant amounts of initial calculated, and subclinical peripheral ar- composition phantom for calibration and muscle strength in 3 years. However, older tery disease was defined by ankle-arm in- annual assessment for potential site differ- Ͻ adults with type 2 diabetes lost their knee ences or drift over time. dex 0.9. Health-related behaviors extensor strength more rapidly than those including smoking, alcohol drinking, and without diabetes (P ϭ 0.001) (Table 2). Strength assessments level of physical activity (kilocalories per Older adults with type 2 diabetes also lost Strength was measured using an isoki- week) were determined by using a stan- greater amounts of leg lean mass than those netic dynamometer (125 AP; Kin-Com, dardized questionnaire (16). Interleu- without diabetes (P Ͻ 0.05). Furthermore, ␣ Chattanooga, TN) for knee extension and kin-6 (IL-6) and tumor necrosis factor- muscle quality (maximal strength per unit isometric dynamometer (Jaymar; JLW In- (TNF-␣) were measured in duplicate us- of muscle mass in Newton meters per kilo- struments, Chicago, IL) for hand grip ing an ultrasensitive enzyme-linked im- gram) declined more rapidly in older adults strength. For knee extension, maximal munosorbent assay (R&D Systems, with type 2 diabetes (P Ͻ 0.05). When ex- voluntary concentric isokinetic torque Minneapolis, MN). The lower limit of de- pressed in relative changes, older adults was assessed in Newton meters at an an- tection was Ͻ0.10 pg/ml for IL-6 and with type 2 diabetes showed ϳ50% more gular velocity of 60°/s. At least three, but 0.18 pg/ml for TNF-␣, with CVs of 6.3 rapid declines in knee extensor strength no more than six, maximal efforts were and 16.0%, respectively. (Ϫ9.0 vs. Ϫ13.5%, P ϭ 0.002) and muscle
1508 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Park and Associates
Table 1—Characteristics of participants by baseline diabetes status in the Health ABC Study strength and quality in older adults with type 2 diabetes remained significant Without diabetes With diabetes P value* throughout the adjustment models (Table 3). n 1,535 305 Sociodemographic CONCLUSIONS — In this study, Age (years) 73.4 Ϯ 2.8 73.5 Ϯ 2.7 0.772 older adults with type 2 diabetes lost Men (%) 47.7 59.1 Ͻ0.001 13.5% of their knee extensor strength, Blacks (%) 32.7 51.9 Ͻ0.001 whereas those without diabetes lost 9.0% Education Ͻ12 years (%) 19.8 30.9 Ͻ0.001 of initial strength in 3 years. An ϳ50% Anthropometric (body more rapid decline in the knee extensor composition) strength in older adults with diabetes was Height (cm) 166.6 Ϯ 9.2 167.0 Ϯ 9.3 0.312 not accounted for by a greater loss of leg Weight (kg) 75.2 Ϯ 14.4 81.0 Ϯ 14.1 Ͻ0.001 muscle mass. Muscle quality also declined BMI (kg/m2) 27.1 Ϯ 4.4 29.0 Ϯ 4.4 Ͻ0.001 more rapidly in older adults with type 2 Total body fat (%) 33.6 Ϯ 7.6 34.3 Ϯ 7.4 0.050 diabetes, suggesting that diabetes may re- Total fat mass (kg) 25.5 Ϯ 8.0 27.9 Ϯ 8.2 Ͻ0.001 sult in functional impairments in muscu- Total lean mass (kg) 47.5 Ϯ 10.1 50.7 Ϯ 9.9 Ͻ0.001 lar function of the lower extremities, not Chronic diseases (%) necessarily accompanied by loss of mus- Coronary heart disease 15.2 23.7 Ͻ0.001 cle mass. Congestive heart failure 1.5 2.9 0.094 Sarcopenia, a status of decreased skel- Stroke 1.8 1.9 0.860 etal muscle mass, is commonly observed PAD 3.0 5.8 0.014 in older adults as a result of age-related Knee osteoarthritis 8.4 6.8 0.347 loss of muscle mass (17–21). In general, it Depression 11.6 9.7 0.337 is frequently accompanied by lower skel- Cancer 21.0 16.6 0.079 etal muscle strength. However, determi- Impaired vision 16.7 25.7 Ͻ0.001 nants or risk factors for sarcopenia and Renal insufficiency 6.0 11.5 0.001 low muscle strength in older adults have Subclinical PAD† 9.5 19.1 Ͻ0.001 not been well identified (22). This is the Behavioral factors first epidemiological study showing that Current smoking (%) 8.5 6.5 0.243 type 2 diabetes is associated with rapid Alcohol drinking (%) 55.4 38.3 Ͻ0.001 loss of skeletal muscle mass and strength Physical activity 548 (119–1,446) 403 (57–1,235) 0.024 in older adults. It confirms the previous (kcal/week)‡ cross-sectional finding of lower muscle Biochemical strength in individuals with diabetes (10– Fasting glucose (mmol/l) 5.2 Ϯ 0.5 8.4 Ϯ 2.9 Ͻ0.001 12). It is also consistent with the finding A1C (%) 6.0 Ϯ 0.5 7.9 Ϯ 1.6 Ͻ0.001 of Andreassen et al. (23) who showed a IL-6 (pg/ml)‡ 1.63 (1.12–2.44) 2.16 (1.47–3.08) Ͻ0.001 rapid decline in ankle strength in patients TNF-␣ (pg/ml)† 3.03 (2.35–3.86) 3.41 (2.57–4.37) Ͻ0.001 with symptomatic diabetic neuropathy. Data are means Ϯ SD, proportions, or median (interquartile range). *P values are from age/sex/race-adjusted The findings of this longitudinal study logistic regression or linear models comparing participants with and without diabetes. †Subclinical periph- strongly suggest that low muscle strength Ͻ eral artery disease (PAD) was defined as ankle-arm index 0.9. ‡Wilcoxon rank-sum test for comparison of in adults with type 2 diabetes is a conse- medians. quence of rather than just a coincidence with type 2 diabetes. quality (Ϫ6.2 vs. Ϫ10.0%, P ϭ 0.01) in 3 changes in leg muscle mass, and physical We found discordance between the years than those without diabetes. How- activity (models 1 and 2). The association upper and lower extremities for diabetes ever, the changes in hand grip strength and of diabetes and loss of knee extensor and changes in muscle strength. A relative arm muscle quality were not different be- strength was slightly attenuated by addi- preservation of upper extremity strength tween those with and without diabetes al- tional adjustments for combined chronic has been observed in the process of aging though older adults with diabetes lost diseases and inflammatory cytokines (21,24). Our findings are, in fact, consis- greater amounts of arm muscle mass (Table (models 3 and 4). tent with previous cross-sectional studies 2). There was no indication of an interaction A greater decline of leg muscle quality showing decreased skeletal muscle effect (P Ͻ 0.10) of sex or race with diabetes in older adults with type 2 diabetes was strength at the ankle and knee but not at on the changes in muscle strength or muscle also evident, even after adjustments for the wrist and elbow in patients with type quality. demographics, BMI, baseline muscle 2 diabetes (10). Andersen et al. (11) re- Table 3 presents the changes in knee quality, changes in leg lean mass, and ported that upper extremity strength was extensor strength and muscle quality with physical activity (P ϭ 0.001, model 2). preserved even in long-standing type 1 controls for potential confounders. A Further adjustments for combined diabetic patients. They also found that greater decline of knee extensor strength chronic diseases and inflammatory cyto- muscle strength was related to the pres- in older adults with type 2 diabetes was kines attenuated the association of diabe- ence and severity of peripheral neuropa- not changed by adjustments for sex, race, tes and declines in muscle quality. thy in both type 1 and type 2 diabetic age, clinic site, BMI, baseline strength, However, the greater declines in muscle patients (10,11). It is well known that the
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1509 Muscle strength loss in type 2 diabetes
Table 2—Three-year changes in skeletal muscle strength, mass, and quality by baseline diabetes status in the Health ABC Study
Without diabetes With diabetes Baseline 36 months Change Baseline 36 months Change P value* n 1,535 305 Knee extensor Maximal torque (Nm) 109.1 Ϯ 0.7 96.8 Ϯ 0.7 Ϫ12.4 Ϯ 0.5† 111.3 Ϯ 1.5 94.8 Ϯ 1.5 Ϫ16.5 Ϯ 1.2‡ 0.001 Leg lean mass (kg) 7.52 Ϯ 0.03 7.29 Ϯ 0.03 Ϫ0.23 Ϯ 0.01‡ 7.96 Ϯ 0.07† 7.66 Ϯ 0.07† Ϫ0.29 Ϯ 0.03‡ 0.035 Specific torque (Nm/kg) 14.4 Ϯ 0.1 13.2 Ϯ 0.1 Ϫ1.2 Ϯ 0.1‡ 14.0 Ϯ 0.2† 12.4 Ϯ 0.2† Ϫ1.6 Ϯ 0.2‡ 0.034 Hand grip Maximal force (kg) 32.6 Ϯ 0.2 31.3 Ϯ 0.2 Ϫ1.3 Ϯ 0.1‡ 32.1 Ϯ 0.4 30.8 Ϯ 0.4 Ϫ1.3 Ϯ 0.3‡ 0.964 Arm lean mass (kg) 2.75 Ϯ 0.01 2.70 Ϯ 0.01 Ϫ0.06 Ϯ 0.01‡ 2.92 Ϯ 0.03† 2.83 Ϯ 0.03† Ϫ0.08 Ϯ 0.01‡ 0.025 Specific force (kg/kg) 12.0 Ϯ 0.1 11.8 Ϯ 0.1 Ϫ0.2 Ϯ 0.1‡ 11.2 Ϯ 0.1† 11.0 Ϯ 0.1† Ϫ0.2 Ϯ 0.1 0.757 Data are adjusted means Ϯ SE from linear models controlling for age, sex, race, and clinic site. *P values for comparison of 3-year changes between two groups. †P Ͻ 0.01 versus those without diabetes at the same time period. ‡P Ͻ 0.001 between baseline and 36 months within the same group. lower extremities are predominantly in- low-up examination. Among them, de- nitely a risk factor for physical disability, volved in diabetic neuropathy presum- clines in hand grip strength were greater independent of lower muscle mass itself ably because of a length-dependent in older adults with diabetes than in those (29). degeneration of nerve fibers (25,26). If without diabetes (Ϫ3.3 Ϯ 6.7 vs. Ϫ1.1 Ϯ Several studies suggested that the neuropathy is a factor, skeletal muscle 6.2 kg, P Ͻ 0.05), suggesting that strict combination of sarcopenia and obesity function is more likely to be affected in criteria for knee strength testing might se- (“sarcopenic obesity”) was more strongly the lower extremities than in the upper lect stronger individuals and actually ob- associated with disability than either body extremities. scure the true declines in muscle strength, composition type alone (30,31). It is pos- The exclusion of many participants particularly in those with diabetes (see sible that the rapid decline in muscle for follow-up knee extensor strength test Table 2 of the online appendix). strength in older adults with type 2 dia- may have potentially biased the results to Lower extremity strength is essential betes may be associated with sarcopenic the null because proportionally more for maintaining basic physical function, obesity. However, to our knowledge there subjects with diabetes were excluded be- especially mobility such as walking and is no study examining the changes in cause of high mortality and other reasons climbing stairs. It is well known that muscle strength in relation to sarcopenic (see Table 1 of the online appendix, avail- lower knee extensor strength is associated obesity. able at http://dx.doi.org/10.2337/dc06- with an increased risk of incident mobility The mechanisms for the rapid loss of 2537). We identified 47 participants with limitations (27–29). Although it is un- skeletal muscle strength, in older adults diabetes and 181 without diabetes who clear whether there is a certain threshold with diabetes are not known. Neuro- were excluded from the knee strength test level of leg strength to maintain physical pathic processes involving motor neurons but had the grip strength test at the fol- function, lower muscle strength is defi- could affect muscle strength, as evidenced by the close association of muscle Table 3—Adjusted 3-year changes in knee extensor strength and muscle quality by baseline strength and severity of diabetic neurop- diabetes status in the Health ABC Study athy in the previous cross-sectional obser- vations (10,11). Electrophysiological studies showed that muscle strength in Without diabetes With diabetes P value diabetic patients correlated with fiber n 1,535 305 density and amplitude of the macromotor Muscle strength (maximal unit potential, suggesting incomplete re- torque, Nm) innervation after axonal loss (32). Longi- Model 1 Ϫ12.4 Ϯ 0.5 Ϫ16.5 Ϯ 1.2 0.001 tudinal studies suggest an average loss of Model 2 Ϫ12.5 Ϯ 0.5 Ϫ16.2 Ϯ 1.1 0.001 compound muscle action potential am- Model 3 Ϫ12.5 Ϯ 0.5 Ϫ15.7 Ϯ 1.1 0.008 plitude at a rate of ϳ3%/year in patients Model 4 Ϫ12.7 Ϯ 0.5 Ϫ15.6 Ϯ 1.2 0.026 with type 2 diabetes over a 10-year period Muscle quality (specific (33). Further research should identify the torque, Nm/kg) role of the decrease in motor amplitudes Model 1 Ϫ1.22 Ϯ 0.07 Ϫ1.57 Ϯ 0.15 0.034 on skeletal muscle strength and quality in Model 2 Ϫ1.20 Ϯ 0.06 Ϫ1.69 Ϯ 0.14 0.001 subjects with diabetes. Model 3 Ϫ1.21 Ϯ 0.06 Ϫ1.64 Ϯ 0.14 0.006 In our study, adjustments for comor- Model 4 Ϫ1.24 Ϯ 0.06 Ϫ1.64 Ϯ 0.15 0.018 bid conditions such as cardiovascular dis- Data are adjusted means Ϯ SE. Model 1: adjusted for sex, race, age, and clinic site. Model 2: additionally ease, stroke, congestive heart failure, adjusted for BMI, baseline strength or quality, changes in leg lean mass, and physical activity. Model 3: peripheral arterial disease, depression, additionally adjusted for coronary heart disease, stroke, congestive heart failure, peripheral artery disease, knee osteoarthritis, cancer, depression, impaired vision, renal insufficiency, and subclinical peripheral artery impaired vision, and renal insufficiency disease (ankle arm index Ͻ0.9). Model 4: additionally adjusted for cytokines (log-transformed IL-6 and slightly attenuated the declines in muscle TNF-␣). strength. These results suggest that
1510 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Park and Associates chronic complications of diabetes have a abetes 55:1813–1818, 2006 References limited role in declines in skeletal muscle 13. Visser M, Fuerst T, Lang T, Salamone L, 1. Wild S, Roglic G, Green A, Sicree R, King Harris TB: Validity of fan beam dual-en- strength in older adults with diabetes. H: Global prevalence of diabetes: esti- However, we had no reliable assessment ergy x-ray absorptiometry for measuring mates for the year 2000 and projections fat-free and leg muscle mass. J Appl Physiol of nerve function in our study at baseline. for 2030. Diabetes Care 27:1047–1053, 87:1513–1520, 1999 It is possible that declines in muscle func- 2004 14. Tylavsky FA, Lohman TG, Dockrell M, tion may indeed be the result of diabetic 2. Boyle JP, Honeycutt AA, Narayan KM, Lang T, Schoeller DA, Wan JY, Fuerst T, neuropathy (23). Hoerger TJ, Geiss LS, Chen H, Thompson Cauley JA, Nevitt M, Harris TB: Compar- Another potential mechanism is in- TJ: Projection of diabetes burden through ison of the effectiveness of 2 dual-energy 2050: impact of changing demography x-ray absorptiometers with that of total creased levels of inflammatory cytokines and disease prevalence in the U.S. Diabe- in subjects with diabetes. It has been re- body water and computed tomography in tes Care 24:1936–1940, 2001 assessing changes in body composition ported that systemic inflammatory cyto- 3. Miller DK, Lui LY, Perry HM, Kaiser FE, ␣ during weight change. Am J Clin Nutr 77: kines such as TNF- and IL-6 have Morley JE: Reported and measured phys- 356–363, 2003 detrimental effects on muscle mass, ical functioning in older inner-city dia- 15. Couchoud C, Pozet N, Labeeuw M, Pou- strength, and physical performance in betic African Americans. J Gerontol A Biol teil-Noble C: Screening early renal failure: older adults (34,35). In our study, rapid Sci Med Sci 54:M230–M236, 1999 cut-off values for serum creatinine as an declines in muscle strength and quality in 4. Gregg EW, Beckles GL, Williamson DF, indicator of renal impairment. Kindey Int Leveille SG, Langlois JA, Engelgau MM, older adults with diabetes are attenuated, 55:1878–1884, 1999 Narayan KM: Diabetes and physical dis- 16. Brach JS, Simonsick EM, Kritchevsky S, albeit still significant, after adjusting for ability among U.S. adults. Diabetes Care IL-6 and TNF-␣. These findings may sug- Yaffe K, Newman AB: The association be- 23:1272–1277, 2000 tween physical function and lifestyle ac- gest a potential role of inflammatory cyto- 5. Gregg EW, Mangione CM, Cauley JA, tivity and exercise in the Health, Aging kines on the muscular function in Thompson TJ, Schwartz AV, Ensrud KE, and Body Composition Study. J Am Geri- diabetes. Nevitt MC: Diabetes and incidence of atr Soc 52:502–509, 2004 Our study has several limitations. The functional disability in older women. Di- 17. Evans WJ: What is sarcopenia? J Gerontol study participants were well-functioning, abetes Care 25:61–67, 2002 A Biol Sci Med Sci 50:5–8, 1995 community-dwelling older adults who 6. Ryerson B, Tierney EF, Thompson TJ, En- 18. Harris TB: Muscle mass and strength: re- gelgau MM, Wang J, Gregg EW, Geiss LS: were relatively healthier than other indi- lation to function in population studies. J Excess physical limitations among adults Nutr 127(5 Suppl.):1004–1006, 1997 viduals in the typical population of the with diabetes in the U.S. population, 19. Metter EJ. Lynch N. Conwit R. Lindle R: same age. There were many dropouts, and 1997–1999. Diabetes Care 26:206–210, ϳ Tobin J Hurley B: Muscle quality and age: only 70% of participants completed fol- 2003 cross-sectional and longitudinal compar- low-up assessments. However, we believe 7. De Rekeneire N, Resnick HE, Schwartz isons. J Gerontol 54:B207–218, 1999 that the loss to follow-up may produce an AV, Shorr RI, Kuller LH, Simonsick EM, 20. Roubenoff R, Hughes VA: Sarcopenia; underestimation of the true decline in Vellas B, Harris TB: Diabetes is associated current concepts. J Gerontol 55:M716– muscle function in those with diabetes with subclinical functional limitation in M722, 2000 nondisabled older individuals: The (see Tables 1 and 2 of the online appen- 21. Newman AB, Haggerty CL, Goodpaster B, Health, Aging, and Body Composition Harris TB, Kritchevsky SB, Nevitt M, dix). The questionnaire to assess physical study. Diabetes Care 26:3257–3263, 2003 Miles TP, Visser M: Strength and muscle activity in the Health ABC Study has not 8. Von Korff M, Katon W, Lin EH, Simon G, quality in a well-functioning cohort of been validated in older diabetic subjects. Ciechanowski P, Ludman E, Oliver M, older adults: the Health, Aging, and Body It may not be sensitive enough to detect Rutter C, Young B: Work disability among Composition Study. J Am Geriatr Soc 51: the influence of different physical activity individuals with diabetes. Diabetes Care 323–330, 2003 level on the changes in muscle strength 28:1326–1332, 2005 22. Goodpaster BH, Park SW, Harris TB, and quality in our study. We also lacked 9. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Kritchevsky SB, Nevitt M, Schwartz AV, Klein R, Pach JM, Wilson DM, O’Brien information about neuropathy at base- Simonsick EM, Tylavsky FA, Visser M, PC, Melton LJ, Service FJ: The prevalence Newman AB: The loss of skeletal muscle line, which would be related with muscu- by staged severity of various types of dia- strength, mass and quality in older adults: lar function in those with type 2 diabetes. betic neuropathy, retinopathy, and ne- the Health, Aging and Body Composition In summary, the present study dem- phropathy in a population-based cohort: Study. J Gerontol 61A:1059–1064, 2006 onstrates an accelerated loss of knee ex- the Rochester Diabetic Neuropathy 23. Andreassen CS, Jakobsen J, Andersen H: tensor strength and quality in older adults Study. Neurology 43:817–824, 1993 Muscle weakness: a progressive late com- with type 2 diabetes. 10. Andersen H, Nielsen S, Mogensen CE, Ja- plication in diabetic distal symmetric kobsen J: Muscle strength in type 2 dia- polyneuropathy. Diabetes 55:806–812, betes. Diabetes 53:1543–1548, 2004 2006 11. Andersen H, Poulsen PL, Mogensen CE, 24. Frontera WR, Hughes VA, Fielding RA, Acknowledgments— This study was sup- Jakobsen J: Isokinetic muscle strength in Fiatarone MA, Evans WJ, Roubenoff R: ported by National Institute on Aging Con- long-term IDDM patients in relation to di- Aging of skeletal muscle: a 12-yr longitu- tracts N01-AG-6-2101, N01-AG-6-2103, and abetic complications. Diabetes 45:440– dinal study. J Appl Physiol 88:1321–1326, N01-AG-6-2106 and in part by the Intramural 445, 1996 2000 Research program of the National Institutes of 12. Park SW, Goodpaster BH, Strotmeyer ES, 25. Said G, Goulon-Goeau C, Slama G, Tcho- Health, National Institute on Aging. Parts of De Rekeneire N, Harris TB, Schwartz AV, broutsky G: Severe early-onset polyneu- this study were presented orally at the 65th Tylavsky FA, Newman AB: Decreased ropathy in insulin-dependent diabetes annual meeting of the American Diabetes As- muscle strength and quality in older mellitus: a clinical and pathological study. sociation, San Diego, California, 10–14 June adults with type 2 diabetes: the Health, N Engl J Med 326:1257–1263, 1992 2005. Aging and Body Composition Study. Di- 26. Boulton AJM, Arezzo JC, Malik RA, So-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1511 Muscle strength loss in type 2 diabetes
senko JM: Diabetic somatic neuropathies. muscle fat infiltration as predictors of in- vaala E, Siitonen O, Uusitupa M: Natural Diabetes Care 27:1458–1486, 2004 cident mobility limitations in well-func- history of peripheral neuropathy in pa- 27. Visser M, Deeg DJH, Lips P, Harris T, tioning older adults. J Gerontol 60A:324– tients with non-insulin-dependent diabe- Bouter LM: Skeletal muscle mass and 333, 2005 tes mellitus. N Engl J Med 333:89–94, muscle strength in relation to lower-ex- 30. Baumgartner RN: Body composition in 1995 tremity performance in older men and healthy aging. Ann NY Acad Sci 904:437– 34. Visser M. Pahor M. Taaffe DR. Goodpaster women. J Am Geriatr Soc 48:381–386, 448, 2000 BH. Simonsick EM. Newman AB. Nevitt 2000 31. Baumgartner RN, Wayne SJ, Waters DL, M: Harris TB: Relationship of interleu- 28. Landers KA, Hunter GR, Wetzstein CJ, Janssen I, Gallagher D, Morley JE: Sar- kin-6 and tumor necrosis factor-␣ with Bamman MM, Weinsier RL: The interre- copenic obesity predicts instrumental ac- muscle mass and muscle strength in el- lationship among muscle mass, strength, tivities of daily living disability in the derly men and women: the Health ABC and the ability to perform physical tasks elderly. Obes Res 12:1995–2004, 2004 Study. J Gerontol 57:M326–M332, 2002 of daily living in younger and older 32. Andersen H, Stalberg E, Gjerstad MD, Ja- 35. Cesari M, Penninx BW, Pahor M, Lauret- women. J Gerontol 56:B443–B448, 2001 kobsen J: Association of muscle strength ani F, Corsi AM, Williams GR, Guralnik 29. Visser M, Goodpaster BH, Kritchevsky and electrophysiological measures of re- JM, Ferrucci L: Inflammatory markers SB, Newman AB, Nevitt MC, Rubin SM, innervation in diabetic neuropathy. Mus- and physical performance in older per- Simonsick EM, Harris TB, Health ABC cle Nerve 21:1647–1654, 1998 sons: the InCHIANTI Study. J Gerontol Study: Muscle mass, muscle strength, and 33. Partanen J, Niskanen L, Lehtinen J, Mer- 59:242–248, 2004
1512 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications ORIGINAL ARTICLE
The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes
1 1 SU CHI LIM, MBBS YEW SENG WU, DIP has been intensively investigated due to 2 1 NILS G. MORGENTHALER, MD, PHD SIEW KHENG GOH, BSC its vascular protective properties (e.g., va- 1 1 TAVINTHARAN SUBRAMANIAM, MBBS CHEE FANG SUM, MBBS sodilatory and antiproliferative) and promising potential as a therapeutic tar- get (4). However, understanding of the OBJECTIVE — Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive pathobiology of adrenomedullin in dia- factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel betic vasculopathy has only just begun. vascoactive factor, is deranged in subjects with type 2 diabetes. In healthy states, adrenomedullin cir- culates at low picomolar concentration, RESEARCH DESIGN AND METHODS — Using a new immunoluminometric method, which increases significantly in a number plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese of disease states including congestive subjects: healthy (n ϭ 100, fasting plasma glucose [FPG] Ͻ5.6 mmol/l), impaired fasting glucose (IFG) (n ϭ 60, FPG 5.6–6.9 mmol/l), and diabetic subjects with (n ϭ 100) and without (n ϭ heart failure, sepsis, essential hyperten- 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quanti- sion, and renal impairment (5). Although fied in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship a few studies have investigated the rela- between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function. tionship between adrenomedullin and type 1 diabetes (6), as far as we know, the RESULTS — We observed a stepwise increase in MR-proADM among the groups: healthy relationship between adrenomedullin group mean Ϯ SD 0.27 Ϯ 0.09, IFG group 0.29 Ϯ 0.13, diabetic group 0.42 Ϯ 0.13, and and type 2 diabetes has not been well elu- diabetic nephropathy group 0.81 Ϯ 0.54 nmol/l (diabetic vs. healthy and IFG groups, P ϭ 0.04; Ͻ cidated. Preliminary studies on small and diabetic nephropathy group vs. all, P 0.01). Statistical adjustment for sex, age, BMI, and numbers of type 2 diabetic subjects re- blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (ϭ0.11; P ϭ 0.01), insulin resistance index (ϭ0.20; P ϭ ported inconsistent results. Turk et al. (7) 0.001), LDL cholesterol (ϭ0.31; P Ͻ 0.001), and adiponectin (ϭ0.33; P Ͻ 0.001) were showed that type 2 diabetes was associ- significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. ated with significant elevation in plasma Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with adrenomedullin levels. However, this RCMP (r ϭ 0.43, P ϭ 0.002). finding was not replicated by another study, which demonstrated no difference CONCLUSIONS — Plasma MR-proADM concentration was elevated in subjects with type 2 in plasma adrenomedullin levels between diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to diabetic patients and control subjects (8). multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a Similarly, whether or not the presence of role in the pathogenesis of diabetic vasculopathy. diabetic microangiopathy resulted in ele- Diabetes Care 30:1513–1519, 2007 vation in adrenomedullin levels was also controversial. Nakamura et al. (9) sug- gested that increment in plasma ad- ndividuals with type 2 diabetes are at (2). By secreting a repertoire of finely reg- renomedullin was dependent on the risk for vascular injury. Although ma- ulated vasoactive factors with opposing severity of diabetic nephropathy, whereas I jor advances have been made in uncov- functions working in autocrine and para- other investigators reported otherwise ering the mechanism of diabetic crine fashion, the endothelium is pivotal (7). vasculopathy, the exact pathophysiology in maintaining vascular homeostasis (3). Metabolic factors that affect plasma remains incompletely understood (1). In Numerous vascoactive factors have been adrenomedullin concentrations were also recent years, the importance of endothe- described. Among these factors, ad- poorly understood. Animal model re- lial dysfunction has taken central stage renomedullin, a 52–amino acid peptide, ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● search revealed that hyperglycemia in- creased vascular adrenomedullin ex- 1 2 From the Department of Medicine, Alexandra Hospital, Singapore, Republic of Singapore; and the Re- pression (10). Other studies, however, search Department, B.R.A.H.M.S. AG Biotechnology Center, Hennigsdorf/Berlin, Germany. Address correspondence and reprint requests to Su Chi Lim, Department of Medicine, Alexandra Hos- cannot find any relationship between pital, 378 Alexandra Rd., Singapore 159964, Republic of Singapore. E-mail: [email protected]. plasma adrenomedullin concentrations Received for publication 12 September 2006 and accepted in revised form 6 March 2007. and the degree of metabolic control or Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1899. risk factors traditionally associated with Abbreviations: ACR, albumin-to-creatinine ratio; hsCRP, highly sensitive C-reactive protein; FPG, fast- ing plasma glucose; GLM, general linear model; HOMA-IR, homeostasis model assessment of insulin resis- endothelial injury (e.g., hypertension and tance; IFG, impaired fasting glucose; MR-proADM, midregional proadrenomedullin; RCMP, resting forearm dyslipidemia) (7,8). These studies were cutaneous microcirculatory perfusion. typically conducted among small num- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion bers of subjects in whom potential con- factors for many substances. founders (e.g., therapeutic agents) were © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby unaccounted. In addition, measurement marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. of plasma adrenomedullin was techni-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1513 Adrenomedulllin in diabetes
mg/g]) or persistently elevated serum creat- inine with a mean MDRD (Modified Diet in Renal Disease) formula–estimated glomer- ular filtration rate (16) of ϳ43 ml/min per 1.73 m2 (2). Individuals were excluded from the diabetic nephropathy group when renal diseases attributable to other causes were suspected. These exclusion criteria in- cluded the presence of hematuria, renal in- sufficiency of unexplained origin, urinary tract infection, and history of rapidly pro- gressive renal failure, glomerulonephritis, and polycystic kidney disease. Such strict criteria were employed so as to better un- derstand the effect of diabetic kidney dis- ease per se (and not other forms of renal impairment) on plasma adrenomedullin. To avoid misclassification, we decided to only include subjects with well-establish nephropathy in the diabetic nephropathy group because recent data suggested that early forms of diabetic nephropathy might Figure 1—Box plot of plasma MR-proADM concentrations among individuals with normal glu- remit spontaneously (17). As expected, cose tolerance (H), IFG, diabetes without nephropathy (DM) and diabetes with nephropathy more subjects from the diabetic nephropa- (DN). DM vs. H and IFG, P ϭ 0.04; DN vs. all, P Ͻ 0.01. thy group suffered from retinopathy (44% nonproliferative and 31% proliferative) compared with subjects from the diabetic cally demanding (11), subject to “noise” (FPG between 5.6 and 6.9 mmol/l), and group (20% nonproliferative and 12% pro- due to the very brief half life of mature 200 with type 2 diabetes (FPG Ն7.0 liferative) (P Ͻ 0.01), since diabetic ne- adrenomedullin (22 min) (12), and the mmol/l) (15), half of whom did not have phropathy is strongly associated with optimal assay format has not been well any evidence of nephropathy (diabetic retinopathy. standardized (13). Therefore, part of the group, n ϭ 100) whereas the remaining 100 We focused on the nondiabetic indi- inconsistent observations may be attrib- subjects had established diabetic nephrop- viduals (i.e., the healthy and IFG groups, utable to unstandardized assays. A new athy. Selection of these subjects was based n ϭ 160) to explore the relationship be- immunoluminometric assay targeted at on strict exclusion criteria. The healthy and tween major metabolic and inflammatory midregional proadrenomedullin ([MR- IFG groups were recruited among working biomarkers and MR-proADM. This was to proADM], conceptually equivalent to C- adults from the general population. Sub- avoid the influence of therapeutic agents peptide from the proinsulin molecule), jects from the healthy group were not taking such as glucose-, lipid-, and blood pres- was recently developed in one of the in- long-term medications or have any known sure–lowering agents, which were used vestigators’ (N.G.M.) laboratory (14). In history of chronic medical illness such as extensively among the diabetic and dia- this assay, plasma MR-proADM concen- diabetes or hypertension. The IFG subjects betic nephropathy groups. To explore tration was found to be stable at room did not have any known history of chronic the relationship between vascular func- temperature for up to 72 h, unchanged medical illness except that 12 self-reported tion and adrenomedullin, we randomly after four freeze-thaw cycles, and unaf- having hypertension, of whom 7 were tak- sampled 50 subjects from those individ- fected by sex, timing of sampling, or ing antihypertensive agents. These seven uals with type 2 diabetes to measure fasted versus fed state. Nonetheless, MR- subjects were not excluded, since the num- their resting forearm cutaneous micro- proADM measured by this new immuno- ber was small and the relationship between circulatory perfusion (RCMP) using luminometric method showed a robust commonly used anitihypertensive agents 2-dimensional laser Doppler flowmetry. difference between healthy and disease and plasma adrenomedullin is still unclear We made this decision based on two states (ischemic heart disease or sepsis) based on existing literature. The type 2 dia- considerations. First, we were inter- (14). Therefore, using this improved as- betic subjects were recruited from the am- ested in the relationship between say, we conducted a much larger study to bulatory care diabetes center of a secondary plasma MR-proADM and vascular func- examine the relationship between ad- hospital. Type 2 diabetic subjects with nor- tion in subjects with diabetes. Pooling renomedullin, metabolic factors, and vas- mal renal function (the diabetic group) were heterogeneous subjects from all four cular function in type 2 diabetes. strictly defined as early morning spot uri- study groups was therefore undesirable. nary albumin-to-creatinine ratio (ACR) Second, we observed from our initial RESEARCH DESIGN AND Յ3.3 mg per mmol/l (i.e., 30 mg/g) and results (Fig. 1) that subjects from the METHODS — We recruited four consistently normal serum creatinine. The healthy and IFG groups had little varia- groups of Chinese subjects: 100 healthy diabetic nephropathy group (n ϭ 100) was tion in plasma MR-proADM concentra- subjects with normal glucose tolerance defined according to the presence of pro- tions. Therefore, to explore the (fasting plasma glucose [FPG] Յ5.5 mmol/ teinuria Ն1.0 g/day (equivalent to spot uri- relationship between RCMP and MR- l), 60 with impaired fasting glucose (IFG) nary ACR Ն113 mg per mmol/l [i.e., 1,000 proADM in these nondiabetic individu-
1514 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Lim and Associates
Table 1—Clinical characteristics of healthy subjects (H), subjects with IFG, and type 2 diabetic subjects without nephropathy (DM) and with nephropathy (DN)
H IFG DM DN P for trend n 100 60 100 100 — Sex (% male) 50 32 58 55 0.007 Age (years) 40 Ϯ 14 44 Ϯ 11 58 Ϯ 10 61 Ϯ 10 Ͻ0.001 Duration of diabetes (years) — — 16 Ϯ 717Ϯ 9 0.55 BMI (kg/m2) 22.9 Ϯ 3.7 24.1 Ϯ 4.2 25.8 Ϯ 4.2 26.1 Ϯ 4.5 Ͻ0.001 Blood pressure (mmHg) — — — — — Systolic 121 Ϯ 14 126 Ϯ 22 136 Ϯ 17 147 Ϯ 21 Ͻ0.001 Diastolic 77 Ϯ 878Ϯ 12 81 Ϯ 881Ϯ 11 0.02 Fasting plasma glucose (mmol/l) 4.9 Ϯ 0.3 5.9 Ϯ 0.4 7.0 Ϯ 1.2 8.5 Ϯ 3.5 Ͻ0.001 A1C (%) — — 7.8 Ϯ 1.3) 8.1 Ϯ 1.6 0.07 MR-proADM (nmol/l) 0.27 Ϯ 0.09 0.29 Ϯ 0.13 0.42 Ϯ 0.13) 0.81 Ϯ 0.54 Ͻ0.001 Data are means Ϯ SD unless otherwise indicated. als would be statistically inefficient which were then read on a Vitros 700 perature, 14 days at 4°C, and 1 year at since the range of exposure (in this case, Chemistry Analyser. HDL cholesterol Ϫ20°C. MR-proADM) was limited. was measured after precipitation with dextran sulfate and magnesium chlo- Measurement of forearm cutaneous Major metabolic indicators ride. LDL cholesterol was calculated us- microcirculatory function Anthropometric data were measured for ing Friedewald’s formula. Detection of All vascular reactivity measurements were all individuals. Blood pressure was mea- MR-proADM was performed in dupli- performed on the same morning as the sured using a sphygmomanometer ac- cates in blinded samples using a novel clinical evaluation while the subjects were cording to standard procedures (18). sandwich immunoassay (B.R.A.H.M.S. still fasting. A single investigator, who Briefly, the subjects were rested for at least Sevadil LIA; B.R.A.H.M.S., AG, Hen- performed all the measurements (S.K.G.), 15 min. Blood pressure was measured nigsdorf/Berlin, Germany) as described was blinded to the medical history of the twice over the right arm 5 minutes apart in detail elsewhere (14). The assay has an subjects. in a sitting position. Should the two read- analytical detection limit of 0.08 nmol/l, Detailed methods for the measure- ings differ by Ͼ10 mmHg (either systolic and the interassay CV is Ͻ20% for values ment of cutaneous microcirculatory func- or diastolic), a third reading will be taken Ͼ0.12 nmol/l. The assay is linear on dilu- tion have been previously reported by our and the average of the closest two read- tion with undisturbed recovery of the collaborators (19). Briefly, the skin over ings will be recorded. Venous blood sam- analyte. EDTA, heparin, and citrate the extensor surface of the forearm was ples (taken after a 10-h fast) with EDTA as plasma samples are stable (Ͻ20% loss of tested by performing laser Doppler perfu- anticoagulant were kept in an icebox im- analyte) for at least 3 days at room tem- sion imaging measurements at baseline mediately after collection, and the plasma was separated from erythrocytes by cen- trifuging at 1,500g for 10 min at 4°C. The Table 2—Pearson coefficient of correlation between multiple metabolic factors and MR- plasma, if not analyzed, was frozen at proADM among nondiabetic individuals Ϫ80°C within 30 min of collection. To- gether with the fasting blood specimen, Pearson coefficient an early morning urine sample was col- Mean Ϯ SD Plasma of correlation with lected for the measurement of urinary al- concentration MR-proADM P bumin and creatinine using commercial Ϯ assay (Immulite; DPC UK) with a lower HOMA-IR 1.96 1.52 0.183 0.02 Ϯ detection limit of 6 mg/l. Plasma total adi- hsCRP (mg/l) 0.23 0.29 0.157 0.047 Ϯ ponectin concentration was measured us- Triglycerides (mM) 1.26 0.81 0.13 0.08 Ϯ Ϫ ing a commercial enzyme-linked LDL cholesterol (mmol/l) 3.35 0.88 0.13 0.08 Ϯ immunosorbent assay kit (R&D Systems, Waist circumference (cm) 76.0 14.2 0.14 0.08 Ϯ Minneapolis, MN) with a maximum intra- Total adiponectin ( g/ml) 7.65 4.88 0.13 0.10 2 Ϯ assay coefficient of variance (CV) of 7.4% BMI (kg/m ) 23.4 3.9 0.12 0.11 Ϯ and interassay CV of 8.4%. Glucose mea- Age (years) 40 11 0.09 0.22 Ϯ surements were carried out using the glu- HDL cholesterol (mmol/l) 1.67 0.45 0.08 0.27 Ϯ Ϫ cose oxidase method using the Vitros 700 Total cholesterol (mmol/l) 5.56 0.97 0.06 0.44 Ϯ Chemistry Analyser (Rochester, NY). Urinary ACR (mg/g) 13.4 26.2 0.03 0.68 Ϯ Ϫ Blood lipids (total cholesterol, triglycer- Systolic blood pressure 123 18 0.001 0.99 ides, and HDL cholesterol) were mea- (mmHg) Ϯ Ϫ sured by enzymatic methods using Diastolic blood pressure 77 10 0.003 0.97 Kodak Ektachem chemistry slides, (mmHg)
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1515 Adrenomedulllin in diabetes and after the iontophoresis of acetylcho- ides, LDL cholesterol, adiponectin), 0.001), 0.31 (P Ͻ 0.001) and 0.33 (P Ͻ line (endothelium-dependent vasodila- which showed a potentially important 0.001), respectively. Collectively, hsCRP, tion) and sodium nitroprusside ([NaNP] correlation (P Յ 0.1) with plasma MR- HOMA-IR, LDL cholesterol, and adi- endothelium-independent vasodilata- proADM (dependent variable), were in- ponectin predicted ϳ84% of changes in tion) using a laser Doppler perfusion im- corporated as independent variables in plasma MR-proADM concentration. ager (Lisca PIM 1.0; Lisca Development subsequent linear regression analysis. Detailed results of RCMP among a AB, Linkoping, Sweden). Baseline RCMP Waist circumference was not included in random sample of 50 subjects taken from (i.e., erythrocyte flux, in volts) was first the multivariate analysis due to strong co- individuals with diabetes (i.e., diabetic measured. Perfusion over the same area linearity with HOMA-IR (ϭ0.80). In [n ϭ 39] and diabetic nephropathy [n ϭ was again quantified after iontophoresis. fact, waist circumference is often used as a 11] groups) were as follows. The resting The percentage of increase (␦) in perfu- surrogate measurement of insulin resis- forearm skin temperature was 30.5 Ϯ sion over baseline as a reflection of mag- tance in epidemiological studies (22). 0.5°C. The RCMP, measured using 2-di- nitude of vasodilation (i.e., vascular Among the subpopulation of subjects mensional laser Doppler flowmetry, was reactivity) in response to acetylcholine with diabetes who had RCMP measured, 0.80 Ϯ 0.25 V. Pearson correlation be- and NaNP was then calculated. The re- Pearson correlation was employed to ex- tween RCMP and MR-proADM among producibility of the technique has been plore the relationship between plasma these 50 subjects with diabetes revealed previously reported (20). The CV of the MR-proADM concentrations, RCMP, and moderately strong correlation (r ϭ 0.43, baseline measurement was 14.1% and postchallenge change (␦) in microcircula- P ϭ 0.002) (Fig. 2). Linear regression (de- during maximal hyperemic response after tory perfusion. To further quantify the pendent variable, MR-proADM; indepen- the iontophoresis 13.7%. strength of association between MR- dent variable, RCMP) revealed a CV ()of The study was approved by the rele- proADM and RCMP, linear regression 0.80 (95% CI 0.30–1.30; P ϭ 0.002). In vant ethics committee and institution re- was performed using MR-proADM as the other words, a unit change in plasma MR- view board. Written informed consent independent variable and RCMP as the proADM concentration will, on average, was obtained from all the participants. dependent variable. The impact of ne- result in a 0.8 unit increase in cutaneous phropathy status (i.e., as defined in dia- blood flow. Statistical analysis betic and diabetic nephropathy groups) GLM analysis (to study the impact of SPSS for Windows (version 11.5; SPSS, on the relationship between MR-proADM nephropathy status on the relationship Chicago, IL) was used for statistical anal- and RCMP was also examined in multi- between MR-proADM and RCMP) re- yses. Comparison of proportions was car- variate analysis using a general linear vealed that nephropathy status had no ried out using 2 test for independence. model (GLM). In the GLM, MR-proADM significant influence on the observed re- BMI was calculated as weight in kilograms and nephropathy status (1 ϭ diabetic ne- lationship (ϭ0.004, 95% CI Ϫ0.16 to divided by the square of height in meters. phropathy group, 0 ϭ diabetic with nor- 0.15; F statistics ϭ 0.003, P ϭ 0.96). A formula was used to derive the ho- mal renal status group) were independent Therefore, analysis of RCMP was not meostasis model assessment of insulin re- variables, whereas RCMP was the depen- stratified by renal status. sistance (HOMA-IR): (fasting insulin ϫ dent variable. A P value of Ͻ0.05 was Correlations between MR-proADM glucose)/22.5 (21). considered statistically significant. and indexes of endothelial-dependent Analysis was not stratified by sex, as and -independent vascular reactivity (i.e., MR-proADM was unaffected by sex (14). RESULTS — The clinical characteris- percentage of increase [␦] in perfusion af- ANOVA with post hoc Tukey’s honestly tics and plasma MR-proADM concentra- ter iontophoretic transcutanoues delivery significant difference test was used for tions of the four groups of subjects of vasoactive substances acetylcholine comparison of MR-proADM between the studied are shown in Table 1. The differ- and NaNP) were unremarkable: acetyl- four groups. Subsequently, ANCOVA ence in unadjusted plasma MR-proADM choline challenge ␦ perfusion (r ϭ was employed to adjust for potential con- is also shown in Fig. 1. MR-proADM in- Ϫ0.19, P ϭ 0.17), NaNP challenge ␦ per- founders (sex, age, BMI, and blood pres- creased progressively from healthy indi- fusion (r ϭϪ0.20, P ϭ 0.16). sure) to determine whether MR-proADM viduals to type 2 diabetic patients with levels remained significantly different be- nephropathy (P Ͻ 0.001 for trend, Table CONCLUSIONS — There were three tween groups. Since the conclusions were 1). Post hoc pairwise comparisons re- main findings in our study. First, plasma unaffected by adjustment for potential vealed diabetic versus healthy and IFG, MR-proADM concentration was elevated confounders, the unadjusted MR- P ϭ 0.04; diabetic nephropathy versus in type 2 diabetic subjects with preserved proADM levels were reported. all, P Ͻ 0.01 (Fig. 1). renal function. This was further accentu- Among subjects without diabetes, Correlations between MR-proADM ated in the presence of established dia- Pearson correlation was employed to ex- and multiple metabolic factors ranked ac- betic nephropathy. Second, metabolic plore the relationship between plasma cording to P values are also shown in Ta- and inflammatory factors, namely insulin MR-proADM concentrations and multi- ble 2. Multiple linear regressions resistance, LDL cholesterol, adiponectin, ple metabolic factors (age, BMI, waist cir- (dependent variable: MR-proADM; inde- and hsCRP, appeared to be significant de- cumference, blood pressure, fasting pendent variables: hsCRP, HOMA-IR, terminants of plasma MR-proADM con- glucose, full lipids profile, HOMA-IR, triglycerides, LDL cholesterol, and adi- centrations. Third, MR-proADM was well early morning spot urinary ACR, highly ponecntin) revealed that hsCRP, HOMA- correlated with measurement of resting, sensitive C-reactive protein [hsCRP], and IR, LDL cholesterol, and adiponectin unprovoked microcirculatory blood flow, total adiponectin). Results were ranked were significant predictors of plasma MR- suggesting that it may be one of the deter- according to P values (Table 2). Metabolic proADM concentration with standard- minants of basal vascular perfusion in factors (i.e., HOMA-IR, hsCRP, triglycer- ized CVs () of 0.11 (P ϭ 0.01), 0.20 (P ϭ subjects with type 2 diabetes.
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abetic nephropathy (33,34). In addition, insulin resistance was found to be associ- ated with low-grade endothelial inflam- mation (manifesting as elevated hsCRP) (35), which has become increasingly rec- ognized as a determinant of vasculopathy (36). The relationship between LDL cho- lesterol and adrenomedullin is poorly un- derstood. Limited in vitro data from endothelial cells in rats suggested that ox- idized LDL might stimulate the secretion of adrenomedullin (37). Adiponectin has emerged as one of the most important adi- pocytokines at the crossroad of energy homeostasis, inflammation, and vascular injury (38). To our knowledge, the rela- tionship between adiponectin and ad- renomedullin has not been well studied. Nevertheless, very recent studies sug- gested that adiponectin might be associ- ated with reduced odds of renal Figure 2—RCMP vs. plasma MR-proADM concentrations among 50 subjects with type 2 dysfunction in subjects with type 2 diabe- diabetes. tes (39). Therefore, the observed relation- ship between adiponectin and MR- porADM in our study is potentially novel The first finding was interesting be- proADM clearance. It is known that and may require further investigations. cause it clarified the relationship between adrenomedullin could exert a wide range Taken together, our data suggested that plasma adrenomedullin concentrations of vascular actions (mostly protective). vasculopathic metabolic and inflamma- and type 2 diabetes. Our data suggested These include endothelium-dependent tory factors were associated with upregu- that MR-proADM was mildly elevated in and -independent vasodilation, antioxi- lation of MR-proADM, probably a subjects with uncomplicated type 2 dia- dative stress, stimulation of endothelial response to injury. To identify the inciting betes (Fig. 1). However, in the presence of nitric oxide production, antiproliferation factors is important as this could lead to diabetic nephropathy, plasma MR- of vascular smooth muscle cell, and ad- the discovery of novel therapeutic inter- proADM became markedly deranged ventitial fibroblast (26). Taken together, ventions. For instance, insulin sensitizer (consistent with Kinoshita et al. [13]). the elevation of plasma MR-proADM con- had been found to ameliorate renal dys- The strict criteria that we adopted for the centration in type 2 diabetes (especially in function in individuals with type 2 diabe- recruitment of subjects in the diabetic the presence of nephropathy) could be an tes (40). Lipid-lowering therapy may (normal renal function) and diabetic ne- appropriate physiological response to on- retard the progression of renal impair- phropathy (well established nephropa- going vascular injury (27). ment (41). Nevertheless, our study re- thy) groups was an advantage in helping Factors that upregulate adrenomedul- vealed that HOMA-IR, hsCRP, LDL to define the relationship between lin production are incompletely under- cholesterol, and adiponectin collectively diabetes and adrenomedullin; i.e., ad- stood. The role of hyperglycemia is accounted for ϳ84% of variation in renomedullin level increased with in- controversial. In vitro data suggested that plasma MR-proADM concentrations. creasing severity of diabetes. Based on hyperglycemia might increase vascular ad- Therefore, other determinants of plasma sequence homology, adrenomedullin was renomedullin expression (10). However, MR-proADM unidentified in our study thought to belong to the calcitonin gene– this notion could not be substantiated in should be investigated in future studies. related peptide superfamily (23). It was vivo (7,8). Other postulated mechanisms We observed that plasma MR- shown to be secreted from all three types included acute hyperinsulinemia (28), in- proADM concentration correlated mod- of cultured vascular cells: endothelium, creased oxidative stress (based on in vivo erately well with basal cutaneous vascular smooth muscle cell, and adven- studies) (29), and proatherogenic/ microcirculatory blood flow among sub- titial fibroblast. Previous elegant studies inflammatory factors such as angiotensin jects with type 2 diabetes. This suggested suggested kidney as an important source II, endothelin-1 (30), interleukin-1, and that adrenomedullin-mediated vasodila- of adrenomedullin (24), whereas pulmo- tumor necrosis factor-␣ (31) (based on tion could probably be one of the determi- nary vascular bed could be the main site cell culture studies). Our analysis re- nants of basal microcirculatory perfusion. A of receptor-dependent clearance of circu- vealed that among the multitude of met- growing body of animal and human pilot lating adrenomedullin (25). In contrast, abolic factors examined (Table 2), insulin studies corroborated our present observa- the exact site of clearance for MR- resistance, hsCRP, LDL cholesterol, and tion. These pilot studies showed that ad- proADM is not known at the moment. adiponecitn were significant determi- renomedullin induced vasodilation in Therefore, one possible explanation for nants of plasma MR-proADM concentra- isolated canine (42) and bovine (43) reti- the elevated plasma MR-proADM concen- tions. Our observation was noteworthy nal arteries (another microcirculatory tration among type 2 diabetes with ne- given that insulin resistance had been as- bed) in vitro. Similarly, adrenomedullin phropathy could be reduced MR- sociated with vascular injury (32) and di- also induced vasodilation of retinal arter-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1517 Adrenomedulllin in diabetes ies of diabetic male Wistar rats in vivo categorical diabetic and renal function moto S, Eto T: Plasma adrenomedullin (44). In a small number of healthy human status, we were unable to directly investi- levels in patients with diabetes. Diabetes subjects, Dorner et al. (45) reported that gate the relationship between plasma MR- Care 23:253–254, 2000 adrenomedullin dose dependently in- proADM and renal function (as estimated 9. Nakamura T, Honda K, Ishikawa S, Kita- creased choroidal blood flow and flow ve- by serum creatinine). This said, the limi- mura K, Eto T, Saito T: Plasma ad- renomedullin levels in patients with non- locity in the ophthalmic artery. Therefore, tation of serum creatinine as an estimate insulin dependent diabetes mellitus: close the novelty in our present observation of renal function (i.e., glomerular filtra- relationships with diabetic complications. was intriguing. One mechanism identi- tion rate) has been well recognized (16). Endocr J 45:241–246, 1998 fied in the pathogenesis of diabetic ne- In conclusion, our study revealed that 10. Hayashi M, Shimosawa T, Fujita T: Hy- phropathy was hemodynamic-mediated plasma MR-proADM concentration was el- perglycemia increases vascular adreno- vascular injury (46). Sustained increase in evated among subjects with type 2 diabetes, medullin expression. Biochem Biophys Res glomerular capillary pressure driven by which was further accentuated when ne- Commun 258:453–456, 1999 increase in plasma flow had been ob- phropathy set in. MR-proADM was related 11. Lewis LK, Smith MW, Yandle TG, Rich- served, especially in early stages of ne- to multiple metabolic factors and basal mi- ards AM, Nicholls MG: Adrenomedul- phropathy. The elevation in glomerular crocirculatory perfusion. Therefore, ad- lin(1–52) measured in human plasma by radioimmunoassay: plasma concentra- capillary pressure might be damaging to renomedullin might play a role in the tion, adsorption, and storage. Clin Chem glomerular endothelial, epithelial, and pathogenesis of diabetic vasculopathy. 44:571–577, 1998 mesangial cells, thereby initiating and 12. Meeran K, O’Shea D, Upton PD, Small CJ, contributing to the progression of ne- Ghatei MA, Byfield PH, Bloom SR: Circu- phropathy (47). Although numerous Acknowledgments— The study was funded lating adrenomedullin does not regulate mediators of diabetic hyperfiltration partially by the National Medical Research systemic blood pressure but increases had been proposed, the exact mecha- Council (NMRC/0518/2001) and National plasma prolactin after intravenous infu- nism remained unclear (48). It is there- Health Care Group (NHG-STP 04001; SIG sion in humans: a pharmacokinetic study. 06036), Ministry of Health of Singapore, Re- J Clin Endocrinol Metab 82:95–100, 1997 fore tempting to speculate that public of Singapore. endothelial-derived vasodilatory sub- 13. Kinoshita H, Fujimoto S, Tokura T, stances like adrenomedullin could be Hisanaga S, Kitamura K, Eto T: Plasma mature form of adrenomedullin in dia- involved, since MR-proADM was in- References betic nephropathy. Intern Med 40:841–2, creasingly elevated from healthy to re- 1. Brownlee M: Banting Lecture 2004: The 2001 nal-impaired subjects (Fig. 1) and well pathobiology of diabetic complications: a 14. Morgenthaler NG, Struck J, Alonso C, correlated to magnitude of microcircu- unifying mechanism. Diabetes 54:1615– Bergmann A: Measurement of midre- latory perfusion (Fig. 2). Should this be 1625, 2005 gional proadrenomedullin in plasma with the case, modulating adrenomedullin 2. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1519 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Abnormal Left Ventricular Energy Metabolism in Obese Men With Preserved Systolic and Diastolic Functions Is Associated With Insulin Resistance
1,2,3 4 GIANLUCA PERSEGHIN, MD TAMARA CANU ardiovascular disease is the leading 1 1 GEORGIA NTALI, MD FEDERICA COSTANTINO, PHD cause of death in patients with type 2,4 1 FRANCESCO DE COBELLI, MD FRANCESCA RAGOGNA, PHD 1 2,5 2 diabetes (1,2). The existence of a UIDO ATTUADA PHD AOLA CIFO PHD C G L , P S , 4 2,4,6 diabetic cardiomyopathy distinct from ANTONIO ESPOSITO, MD ALESSANDRO DEL MASCHIO, MD 4 1,2,3 ischemic injury was confirmed, but the ELENA BELLONI, MD LIVIO LUZI, MD challenge of recognizing its specific fea- tures remained unresolved because dia- betes could also provoke cardiac damage OBJECTIVE — Perturbations in cardiac energy metabolism might represent early alterations via coronary macrovascular disease, auto- in diabetes preceding functional and pathological changes. We evaluated left ventricular (LV) nomic dysfunction, and coronary micro- structure/geometry and function in relation to energy metabolism and cardiovascular risk factors vascular disease (3). It was proposed that in overweight/obese men using magnetic resonance techniques. altered metabolism and impaired insulin action in the heart might be cause and RESEARCH DESIGN AND METHODS — We studied 81 healthy men (aged 22–55 consequence of altered cardiac function years, with BMI between 19 and 35 kg/m2) by means of cardiac magnetic resonance imaging and (4) and that metabolic remodeling in dia- 31P-magnetic resonance spectroscopy in the resting and fasted conditions and stratified them in betes might precede, cause, and sustain quartiles of BMI (cut offs: 23.2, 25.5 and 29.0 kg/m2). the functional and structural/geometrical remodeling of the heart (5). In keeping RESULTS — LV mass increased across quartiles of BMI; meanwhile, the volumes did not with this hypothesis, cardiac energy me- differ. Parameters of LV systolic and diastolic function were not different among quartiles. The tabolism was found to be abnormal in pa- phosphocreatine-to-ATP ratio was reduced across increasing quartiles of mean Ϯ SD BMI tients with type 2 diabetes despite the lack (2.25 Ϯ 0.52, 1.89 Ϯ 0.26, 1.99 Ϯ 0.38, and 1.79 Ϯ 0.29; P Ͻ 0.006) in association with insulin of major cardiac dysfunctions (6) or the sensitivity (computer homeostasis model assessment 2 model); this relation was independent of presence of diastolic dysfunction (7). age, BMI, blood pressure, wall mass, HDL cholesterol, triglycerides, smoking habits, and meta- Those studies were performed in middle- bolic syndrome. age individuals (52–57 years old) in whom diabetes was diagnosed 1 (7) to 3 CONCLUSIONS — Abnormal LV energy metabolism was detectable in obese men in the (6) years earlier. Therefore, the question presence of normal function, supporting the hypothesis that metabolic remodeling in insulin whether the alterations of cardiac energy resistant states precedes functional and structural/geometrical remodeling of the heart regardless metabolism were due to the hyperglyce- of the onset of overt hyperglycemia. mic state itself or whether they were sec- ondary to the metabolic features Diabetes Care 30:1520–1526, 2007 characterizing the prediabetic state re- mained unanswered. This study was undertaken to assess ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● whether obesity was associated with im- From the 1Section of Nutrition/Metabolism, Department of Internal Medicine, Istituto Scientifico San Raf- paired cardiac structure/geometry, func- faele, Milano, Italy; the 2Unit of Clinical Spectroscopy, Istituto Scientifico San Raffaele, Milano, Italy; the tion, and energy metabolism and to 3Faculty of Exercise Sciences, Center of “Physical Exercise for Health and Wellness”; Universita` degli Studi di Milano; Milan, Italy; the 4Division of Diagnostic Radiology, Istituto Scientifico San Raffaele, Milano, Italy; establish whether these potential alterations the 5Division of Nuclear Medicine, Istituto Scientifico San Raffaele, Milano, Italy; and the 6Universita` Vita e were associated with the cardiovascular and Salute San Raffaele, Milan Italy. metabolic risk factors accompanying insu- Address correspondence and reprint requests to Gianluca Perseghin, MD, Faculty of Exercise Sciences, lin resistance conditions. Universita` degli Studi di Milano and Internal Medicine/Unit of Clinical Spectroscopy Istituto Scientifico San Raffaele, via Olgettina 60, 20132, Milano Italy. Email: [email protected]. Received for publication 28 November 2006 and accepted in revised form 1 March 2007. Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-2429. RESEARCH DESIGN AND G.N. is currently a clinical fellow in the Department of Endocrinology, Polikliniki Hospital, Athens, METHODS Greece. Abbreviations: FFA, free fatty acid; HOMA, homeostasis model assessment; HOMA-S%, HOMA of We selected 81 apparently healthy men insulin sensitivity; LV, left ventricular; MRI, magnetic resonance imaging; MRS, 31P-magnetic resonance with no previous history of diabetes, spectroscopy; PCr, phosphocreatine; TSH, thyroid-stimulating hormone. hypertension, dyslipidemias, coronary, A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion cerebral, or peripheral vascular events, factors for many substances. no history of dilated cardiomyopathy, © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby no previous knowledge of a pathologi- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cal ejection fraction or of resting elec-
1520 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Perseghin and Associates trocardiogram markers of cardiac using a 5-element cardiac phased array Statistical analysis ischemia, and no features compatible coil (SENSE-cardiac) and retrospective Data in text, tables, and figures are with the NYHA (New York Heart Asso- electrocardiogram triggering obtained means Ϯ SD. Analysis was performed us- ciation) classes for heart failure. They with Vectorcardiogram system (12) and ing SPSS software (version 10.0; SPSS, were not taking any medications, were standard MRI methodology as previ- Chicago, IL). When parameters showed a 18–55 years old, and had 18–35 kg/m2 ously described (11). skewed distribution (Kolmogorov- range of BMI; body weight was stable for Smirnov test of normality), they were log at least 6 months. We assessed the ha- transformed before the analysis (systolic bitual physical activity using a ques- and diastolic blood pressure, triglycer- Anaytical determinations tionnaire based on three components: ides, leptin, and TSH), and one-way We measured glucose concentration with physical activity at work, sport during ANOVA with Bonferroni post hoc analy- the glucose oxidase method (Beckman leisure time, and physical activity dur- sis or Kruskal-Wallis nonparametric test Coulter, Fullerton, CA). FFAs, triglycerides, ing leisure time excluding sports (8) as was used to compare variables between total cholesterol, and HDL cholesterol were previously reported (9,10). We assessed quartiles of BMI when appropriate. Two- measured as previously described (9,10). the metabolic syndrome using the Adult tailed Person’s correlation was performed Plasma insulin (intra- and interassay coeffi- Treatment Panel III definition with the to establish partial correlation coefficients cient of variation Ͻ3 and 6%, respectively; exception of the waist criteria; instead, a between variables. Nonparametric corre- cross-reactivity with C-peptide and proin- BMI Ͼ30 kg/m2 was used. All subjects lation coefficient was obtained using sulin Ͻ1%) and leptin was measured with gave informed consent after explanation Spearman’s rho when appropriate. We radioimmunoassay (Linco Research, St. of purposes, nature, and potential risks defined statistical significance as a P value Charles, MO). Serum resistin (BioVendor of the study. The protocol was approved Ͻ0.05. A prior power calculation analysis Laboratory Medicine, Brno, Czech Repub- by the Ethical Committee of the Istituto indicated that 17 subjects per group were lic) and adiponectin (B-Bridge Interna- Scientifico San Raffaele. required to provide a power of 90% to tional, Sunnyvale, CA) were measured by detect a 20% difference in PCr-to-ATP ra- ezyme-linked immunosorbent assay kits tio between groups. kits. Serum creatinine was measured using Experimental procedures an enzymatic method on a Hitachi 747 Subjects were instructed to consume an (11). TSH was measured by immunofluori- isocaloric diet and to abstain from exer- RESULTS metric method. We measured blood pres- cise activity for 3 days before the magnetic sure twice with volunteers in the lying resonance imaging (MRI) and 31P- Anthropometric and biochemical position. magnetic resonance spectroscopy (MRS) characteristics of study subjects studies. Volunteers underwent the proto- The anthropometric features of study col at 7:30–9:30 A.M. in the resting state subjects are summarized in Table 1. Age after a 10-h overnight fasting period and Calculations was not different among quartiles. Sys- after the collection of venous blood for the MRS analysis. 31P-MR spectra, trans- tolic blood pressure was higher in quartile assessment of plasma glucose, total cho- ferred to a remote SUN-SPARC worksta- IV than in quartiles I and II. HDL choles- lesterol, HDL cholesterol, triglycerides, tion, were quantified automatically in the terol was lower in quartile IV when com- free fatty acids (FFAs), insulin, leptin, adi- time domain, using Fitmasters. We cor- pared with quartiles I and II, and serum ponectin, resistin, thyroid-stimulating rected ATP for the contribution origi- triglycerides concentration was higher in hormone (TSH), and creatinine. nated from blood in the cardiac chambers quartile IV compared with quartile I. Fast- based on a previous study (13). We cor- ing FFA was not different among quar- rected PCr/ATP ratios for partial satura- tiles. Adiponectin and resistin were not Cardiac MRS tion effects using T1 values obtained from different among quartiles, while plasma We performed cardiac MRS using a inversion recovery experiments. Based on leptin concentration was higher propor- whole-body scanner (Gyroscan Intera the repetition time of 3.6 s, we applied a tionally to BMI. The habitual physical ac- Master 1.5 MR System; Philips Medical saturation correction factor of 1.35 tivity was lower in quartile IV than in Systems, Best, Netherlands). 31P spec- (14,15). An estimate of the signal-to- quartile I, due to the sport activity index tra were obtained by means of a 10-cm noise ratio of each spectra was obtained (3.39 Ϯ 1.04, 2.55 Ϯ 0.91, 2.29 Ϯ 0.71, diameter surface coil used for transmis- from the relative Cramer-Rao standard and 2.17 Ϯ 0.38 for quartiles I–IV, re- sion and detection of radio frequency deviation calculated for the PCr-to-ATP spectively; P Ͻ 0.001), which was higher signals at the resonance frequency of 31P ratio (15). in quartile I than in all the other quartiles (at 1.5 T, 25.85 MHz) as previously de- MRI analysis. Image analysis was per- (P Ͻ 0.03). scribed (11). In this setting, the volume of formed using an image-processing work- interest was 5 (caudocranial) ϫ 6 ϫ 6 cm. station (EasyVision; Philips Medical Cardiac MRI We performed MRI with Systems) by using the cardiac analysis Insulin sensitivity the above-described scanner using an software package as previously described Fasting plasma glucose was not different enhanced gradient system with a maxi- (11). among quartiles (P ϭ 0.14). In contrast, mum gradient strength of 30 mT/m and Insulin sensitivity. We estimated insu- plasma insulin was higher in quartiles III a maximum gradient slew rate of 150 lin sensitivity and secretion by the up- and IV than quartiles I and II (P Ͻ 0.05). Ϫ Ϫ mT m 1 s 1 and using the Cardiac dated computer model homeostasis Markers of insulin sensitivity (HOMA of Research software patch (operating sys- model assessment (HOMA)2 (16) avail- insulin sensitivity [HOMA-S%] and tem 9). The examination was performed able from www.ocdem.ox.ac.uk. HOMA2) were lower in quartiles III and
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1521 Cardiac energy metabolism in obesity
Table 1—Anthropometric, metabolic, and laboratory features and lifestyle habits of study subjects stratified for quartiles of BMI (kg/m2)
Quartile I Quartile II Quartile III Quartile IV 21.7 Ϯ 1.3 (18.5–23.2) 24.6 Ϯ 0.7 (23.3–25.5) 26.9 Ϯ 0.9 (25.5–29.0) 32.0 Ϯ 1.7 (30.0–35.3) Age (years) 31 Ϯ 735Ϯ 637Ϯ 937Ϯ 9 Height (cm) 177 Ϯ 6 177 Ϯ 6 177 Ϯ 7 175 Ϯ 8 Weight (kg)* 68 Ϯ 477Ϯ 584Ϯ 798Ϯ 9 Systolic BP (mmHg) 121 Ϯ 11 119 Ϯ 6 125 Ϯ 9 129 Ϯ 9† Diastolic BP (mmHg) 79 Ϯ 10 78 Ϯ 683Ϯ 883Ϯ 7 Creatinine (mol/l) 78 Ϯ 17 80 Ϯ 12 79 Ϯ 10 80 Ϯ 13 Glucose (mmol/l) 4.8 Ϯ 0.3 4.9 Ϯ 0.5 5.0 Ϯ 0.6 5.2 Ϯ 0.5 Insulin (pmol/l) 66 Ϯ 31 70 Ϯ 28 101 Ϯ 35† 105 Ϯ 38† Cholesterol (mmol/l) Total 4.22 Ϯ 0.68 4.81 Ϯ 0.61 5.08 Ϯ 1.30 4.84 Ϯ 1.29 HDL 1.49 Ϯ 0.34 1.47 Ϯ 0.37 1.32 Ϯ 0.29 1.12 Ϯ 0.29† Triglycerides 0.87 Ϯ 0.51 1.02 Ϯ 0.82 1.09 Ϯ 0.45 1.91 Ϯ 0.99‡ FFAs (mmol/l) 0.59 Ϯ 0.19 0.58 Ϯ 0.25 0.62 Ϯ 0.22 0.60 Ϯ 0.16 Leptin (ng/ml) 2.9 Ϯ 1.2 6.5 Ϯ 5.2 7.0 Ϯ 3.3‡ 13.5 Ϯ 6.0* Adiponectin (g/ml) 6.9 Ϯ 3.7 6.9 Ϯ 3.7 6.2 Ϯ 2.8 5.2 Ϯ 1.2 Resistin (ng/ml) 3.5 Ϯ 1.0 3.4 Ϯ 1.4 3.4 Ϯ 0.8 3.4 Ϯ 0.4 TSH (mU/l) 1.2 Ϯ 0.9 1.2 Ϯ 1.2 1.1 Ϯ 1.0 1.5 Ϯ 0.6 Smoking habits 3/20 6/21 8/20 5/20 PAI 9.1 Ϯ 1.6 8.1 Ϯ 1.2 8.0 Ϯ 1.3 7.7 Ϯ 0.9‡ HOMA2-S% 88 Ϯ 38 78 Ϯ 34 52 Ϯ 19† 49 Ϯ 20† HOMA2-B% 128 Ϯ 40 126 Ϯ 28 160 Ϯ 42† 156 Ϯ 41 HOMA2 1.39 Ϯ 0.65 1.52 Ϯ 0.58 2.15 Ϯ 0.76† 2.4 Ϯ 0.97† Data are means Ϯ SD (BMI range). *P Ͻ 0.001 vs. all other quartiles; †P Ͻ 0.05 vs. quartiles I and II; ‡P Ͻ 0.03 vs. quartile I; one-way ANOVA and Bonferroni post hoc analysis. BP, blood pressure; HOMA-B%, HOMA of -cell function; PAI, physical activity index.
IV than in quartiles I and II (P Ͻ 0.05). LV anatomical and functional wall mass was higher in quartile IV in HOMA2 of -cell function, as a marker of features comparison with quartiles I and II. End insulin secretion, was higher in quartile Morphological parameters of the LV are LV diastolic and systolic volumes were III in comparison with quartiles I and II. summarized in Table 2. The end diastolic not different among quartiles. The end di-
Table 2—Morphologic parameters and functional features of study subjects stratified for quartiles of BMI (kg/m2)
Quartile I Quartile II Quartile III Quartile IV 21.7 Ϯ 1.3 (18.5–23.2) 24.6 Ϯ 0.7 (23.3–25.5) 26.9 Ϯ 0.9 (25.5–29.0) 32.0 Ϯ 1.7 (30.0–35.3) Heart rate (beats/min) 63 Ϯ 13 63 Ϯ 963Ϯ 10 65 Ϯ 9 Morphologic features End diastolic volume (ml) 143 Ϯ 22 141 Ϯ 21 148 Ϯ 33 144 Ϯ 28 End systolic volume (ml) 56 Ϯ 14 55 Ϯ 13 56 Ϯ 16 51 Ϯ 14 End diastolic wall mass (g) 138 Ϯ 24 133 Ϯ 21 145 Ϯ 17 157 Ϯ 19* End diastolic wall mass/volume 0.97 Ϯ 0.16 0.94 Ϯ 0.10 1.02 Ϯ 0.18 1.12 Ϯ 0.19* ratio (g/ml) Systolic function Stroke volume (ml) 87 Ϯ 13 86 Ϯ 11 92 Ϯ 19 93 Ϯ 16 Cardiac output (l/min) 5.4 Ϯ 1.4 5.4 Ϯ 0.9 5.6 Ϯ 1.0 6.0 Ϯ 1.2 Ejection fraction (%) 61 Ϯ 562Ϯ 562Ϯ 465Ϯ 4 Diastolic function Early PFR (ml/s) 464 Ϯ 78 475 Ϯ 74 432 Ϯ 92 469 Ϯ 96 Atrial PFR (ml/s) 213 Ϯ 54 219 Ϯ 42 238 Ϯ 84 261 Ϯ 64 E/A peak flow 2.31 Ϯ 0.69 2.24 Ϯ 0.49 1.99 Ϯ 0.70 1.88 Ϯ 0.49 Deceleration time (ms) 176 Ϯ 26 183 Ϯ 34 197 Ϯ 39 183 Ϯ 35
Data are means Ϯ SD (BMI range) from two-tailed, independent-Samples t test. †P Ͻ 0.05 vs. quartiles I and II in one-way ANOVA and Bonferroni post hoc analysis. PFR: peak filling rate
1522 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Perseghin and Associates
CONCLUSIONS — The cardiac meta- bolic adaptation or maladaptation in re- sponse to diabetes could be considered at the basis of the functional and structural/ geometrical abnormalities affecting the dia- betic heart (4,5); two studies demonstrated an alteration of LV energy metabolism in type 2 diabetic patients without concomi- tant cardiac disease (6,7). These studies were performed in humans with established diabetes with high prevalence of comorbid conditions and use of multiple drugs; there- fore, the understanding of this alteration was extremely complex. It remained uncer- tain whether the abnormal cardiac energy metabolism was subsequent to the develop- ment of overt hyperglycemia or whether it was already present in the pre-diabetic state. The novel contribution of the present study was that the alteration of the LV energy me- tabolism affecting type 2 diabetic patients was manifested in young overweight/obese individuals in the absence of established co- Figure 1—Association between the PCr-to-ATP ratio and HOMA2-S in quartile I ( ), quartile II morbid conditions, drug administration, or ( ), quartile III (᭛), and quartile IV (‚)(r ϭ 0.43; P Ͻ 0.001). overt hyperglycemia. The abnormal cardiac energy homeostasis was not simply depen- dent on glucose toxicity, and other addi- tional factors might begin to influence astolic wall mass-to-volume ratio was under conditions where the chest and cardiac metabolism before the development consequently higher in quartile IV in heart were displaced using a 1.5-cm of overt hyperglycemia. comparison with quartiles I and II (P ϭ spacer so that the distance between the Taking into account that the over- 0.02). Parameters of systolic (stroke vol- coil and the heart was similar to the mean weight/obese individuals belonging to ume, cardiac output and ejection frac- distance measured in quartile IV, while quartiles II, III, and IV had lower PCr-to- tion) and diastolic (early and atrial peak the second acquisition was acquired with- ATP ratios in the absence of major LV dys- filling rates and deceleration time) func- out the spacer. PCr-to-ATP ratios ob- functions, the impact of functional tion were not different among quartiles. tained with the spacer (2.13 Ϯ 0.31) or abnormalities had to be excluded. Plausi- without it (1.85 Ϯ 0.27) were not differ- ble explanations for the finding were as LV PCr-to-ATP ratio ent (P ϭ 0.22). follows: 1) increased LV mass, 2) simulta- The PCr-to-ATP ratio was higher in quar- neous expression of metabolic and car- tile I (2.25 Ϯ 0.52) in comparison with diovascular risk factors (metabolic quartiles IV (1.79 Ϯ 0.29; P Ͻ 0.009), III syndrome), 3) insulin resistance, 4) in- (1.89 Ϯ 0.26; P Ͻ 0.02) and II (1.99 Ϯ Effects of hemodynamic and trinsic or acquired cardiac metabolic ab- 0.38; P Ͻ 0.05). The accuracy was excel- metabolic variables on the normalities. In support of the first lent (rCRSD 15 Ϯ 5%, 16 Ϯ 3%, 17 Ϯ 4% correlation between BMI and PCr/ potential explanation, the individuals be- and 18 Ϯ 3% in quartiles I, II, III and IV, ATP ratio longing to quartile IV were characterized ϭ respectively; P 0.11). The volume of Pearson correlation analysis showed that by slightly higher systolic blood pressure interest size was not different among the PCr/ATP ratio was associated with the in comparison with the individuals of quartiles (178 Ϯ 53, 157 Ϯ 61, 160 Ϯ 44, ϭϪ ϭ quartiles I and II (Table 1) and showed Ϯ 3 ϭ BMI (r 0.26; P 0.022), fasting and 178 49 cm , respectively; P plasma glucose (r ϭϪ0.32; P ϭ 0.01), higher end diastolic wall mass (Table 2). 0.62). Intra-assay variability was 7 Ϯ 4%. In patients with hypertension and LV hy- insulin (r ϭϪ0.32; P ϭ 0.012), leptin Interassay variability was 12 Ϯ 5%. The pertrophy, PCr-to-ATP ratio was reduced (r ϭϪ0.28; P ϭ 0.039), Adult Treatment distance between the center of the coil (17), and this reduction was associated Panel III–defined criteria of metabolic and the anterior margin of the LV wall was ϭϪ ϭ with the progression of heart failure in small but different, because of the thorax syndrome (r 0.29; P 0.012), patients with dilated and hypertrophic Ϯ HOMA2-S% (r ϭ 0.44; P ϭ 0.001; Fig. morphology, across quartiles (4.0 0.8, ϭ ϭ cardiomyopathy (18). The second plausi- 4.2 Ϯ 0.5, 4.5 Ϯ 0.7, and 5.3 Ϯ 0.7 cm; 1), HOMA2 (r 0.34; P 0.007), and ble explanation was supported by the fact ϭ ϭ P Ͻ 0.001). We assessed the effect of this physical activity index (r 0.27; P that the individuals of quartile IV were difference on the PCr-to-ATP ratio in a 0.035). When we performed multivariate characterized by reduced serum HDL subgroup of seven volunteers (aged 31 Ϯ regression analysis adjusting for the pa- cholesterol, increased serum triglycer- 3 years, BMI 23.3 Ϯ 1.2 kg/m2) in which rameters described above, HOMA2-S% ides, and a trend for higher plasma glu- two spectroscopic acquisitions were ob- was the only variable always associated cose. These parameters are included in tained. The first acquisition was acquired with the PCr/ATP (Table 3). the definition of the metabolic syndrome,
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1523 Cardiac energy metabolism in obesity
Table 3—Two-tailed Pearson’s correlation and adjusted partial correlation coefficients with PCr/ATP ratio
Variables Univariate Multivariate Model 1 Multivariate Model 2 Multivariate Model 3 Multivariate Model 4 Age———— R 0.19 ———— P 0.11 ———— BMI———— r Ϫ0.26 ———— P 0.022 ———— SBP———— r Ϫ0.11 Ϫ0.00 — — — P 0.33 0.98 — — — EDWM ———— r 0.0 0.13 — — — P 0.98 0.29 — — — HDL———— r 0.15 0.06 Ϫ0.07 — — P 0.23 0.62 0.61 — — Triglycerides ———— r Ϫ0.16 Ϫ0.06 Ϫ0.04 — — P 0.20 0.66 0.74 — — PAI———— r 0.273 0.23 0.21 0.21 — P Ͻ 0.035 0.08 0.12 0.13 — ATP III–defined MS ———— r Ϫ0.29 Ϫ0.13 Ϫ0.15 Ϫ0.14 Ϫ0.12 P Ͻ 0.012 0.25 0.23 0.29 0.41 HOMA2-S% ———— r 0.43 0.37 0.38 0.40 0.34 P Ͻ 0.001 0.007 0.005 0.003 0.017 Model 1 adjusted for age and BMI; Model 2 adjusted for age, BMI, PAS, and EDWM; Model 3 adjusted for age, BMI, SBP, EDWM, HDL cholesterol, and triglycerides; Model 4 adjusted for age, BMI, SBP, EDWM, HDL cholesterol, triglycerides, and physical activity index (PAI). EDWM, end diastolic wall mass; SBP, systolic blood pressure. which is considered a major risk factor for tients with essential hypertension (21), in ATP ratio (27), likely switching the en- cardiovascular disease. In the univariate association with higher BMI (22), in ergy substrate preference (28). Hence, we analysis, the metabolic syndrome was in- obese, diabetic patients with nonischemic may speculate that in patients with overt versely associated with the PCr-to-ATP heart failure (23) and in moderately obese type 2 diabetes, the increased FFAs avail- ratio (Table 3). It is not clear whether the subjects (24). We did not assess the intra- ability, pushing their own oxidative dis- metabolic syndrome has a single cause, cardiac fat content, and we did not find posal, induces a detrimental and but insulin resistance is considered its any correlation between PCr-to-ATP ratio proportional effect on the PCr-to-ATP ra- most important underlying risk factor and plasma FFA concentration as a tio (6). Peterson et al. (29), using positron (19). In this respect, HOMA2-S% was im- marker of lipotoxicity. This lack of asso- emission tomography in combination paired across quartiles of BMI and was ciation was in contrast with the finding with echocardiography, showed that in associated with the PCr-to-ATP ratio in reported in patients with overt type 2 di- young obese women cardiac efficiency univariate analysis (Fig. 1); multivariate abetes (6). This dichotomy may be due to was impaired in association with insulin analyses showed that the HOMA2-S% the different features of the study groups. resistance and myocardial fatty acids up- was the most relevant predictive factor of It is recognized as a dominance of fatty take, utilization, and oxidation regardless the PCr-to-ATP ratio, and only the degree acid metabolism by the heart in the fasted of FFA levels. of habitual physical activity attenuated, state; when the heart is acutely stressed, it The present work had some limita- but did not abolish, the association (Table switches from fat to carbohydrates as fuel tions. We estimated insulin sensitivity 3). Abnormal tissue energy metabolism, (25) because of a more convenient bal- and secretion using surrogate indexes. in association with whole-body insulin ance of oxygen consumption. In fact, ar- Even if they have the potential to provide resistance, was described also in the skel- tificial elevation of FFA in diabetic hearts meaningful insights into glucose metabo- etal muscle of type 2 diabetic patients (6) reduces cardiac efficiency via an oxygen lism (30), they are less sensitive and spe- and of their nondiabetic, first-degree rel- waste for noncontractile purposes (26). cific than the insulin clamp. We could not atives (20). This scenario was supported by our find- exclude that the association between in- How insulin resistance may influence ing in patients with heart failure in whom sulin sensitivity and the PCr-to-ATP ratio cardiac metabolism is a matter of intense treatment with Trimetazidine, a partial could be stronger if more specific mea- investigations. Excessive intramyocardio- fatty acids oxidation inhibitor, induced sures were employed. We must also state cellular fat content was described in pa- improvement of the LV function and PCr/ that a minimal concentric rearrangement
1524 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Perseghin and Associates of the LV geometry was detected in the 7. Diamant M, Lamb HJ, Groeneveld Y, A, Stoel BC, Doornbos J, van der Wall EE, individuals within quartile IV (Table 2); Endert EL, Smit JW, Bax JJ, Romijn JA, de de Roos A: Diastolic dysfunction in hyper- the ejection fraction may therefore be a Roos A, Radder JK: Diastolic dysfunction tensive heart disease is associated with al- crude estimate of the LV pump perfor- is associated with altered myocardial me- tered myocardial metabolism. Circulation mance. The use of a more direct measure tabolism in asymptomatic normotensive 99:2261–2267, 1999 patients with well-controlled type 2 dia- of load-independent wall mechanics (ob- 18. Nakae I, Mitsunami K, Omura T, Yabe T, betes mellitus. J Am Coll Cardiol 42:328– Tsutamoto T, Matsuo S, Takahashi M, tained by means of tagging MRI or tissue 335, 2003 Morikawa S, Inubushi T, Nakamura Y, Ki- Doppler echocardiography) (31), which 8. Baecke JAH, Burema J, Frijters JER: A noshita M, Horie M: Proton magnetic res- was not adopted in the present study, short questionnaire for the measurement onance spectroscopy can detect creatine could reveal the presence of a minimal of habitual physical activity in epidemio- depletion associated with the progression dysfunction in this subgroup. This limita- logical studies. Am J Clin Nutr 36:936– of heart failure in cardiomyopathy. JAm tion did not detract from the importance 942, 1982 Coll Cardiol 42:1587–1593, 2003 of the alteration of energy metabolism, 9. Perseghin G, Scifo P, De Cobelli F, Pa- 19. Grundy SM, Cleeman JI, Daniels SR, Do- which was also observed in the individu- gliato E, Battezzati A, Arcelloni C, Van- nato KA, Eckel RH, Franklin BA, Gordon als within quartiles II and III. zulli A, Testolin G, Pozza G, Del Maschio DJ, Krauss RM, Savage PJ, Smith SC Jr, A, Luzi L: Intramyocellular triglyceride In conclusion, abnormal LV energy Spertus JA, Costa F; American Heart Asso- content is a determinant of in vivo insulin ciation; National Heart, Lung, and Blood In- metabolism was detectable in obese but resistance in humans: a 1H–13C NMR otherwise healthy men, supporting the stitute: Diagnosis and management of the spectroscopy assessment in offspring of metabolic syndrome: an American Heart hypothesis that metabolic remodeling in type 2 diabetic parents. Diabetes 48: Association/National Heart, Lung, and insulin resistant states preceded the onset 1600–1606, 1999 Blood Institute Scientific Statement. Circu- of frank hyperglycemia and the develop- 10. Lattuada G, Costantino F, Caumo A, Ra- lation 112:2735–2752, 2005 ment of major functional and structural/ gogna F, Scifo P, De Cobelli F, Del Mas- 20. Petersen KF, Dufour S, Befroy D, Garcia geometrical remodeling of the heart. chio A, Luzi L, Perseghin G: Reduced R, Shulman GI: Impaired mitochondrial Based on this cross-sectional study, insu- whole body lipid oxidation is associated activity in the insulin-resistant offspring lin resistance may be a relevant factor to with insulin resistance but not with in- of patients with type 2 diabetes. N Engl the reduced LV PCr-to-ATP ratio; longi- tramyocellular lipid content in offspring J Med 350:664–671, 2004 of type 2 diabetic patients. Diabetologia 21. Szczepaniak LS, Dobbins RL, Metzger GJ, tudinal studies addressing the association 48:741–747, 2005 between these metabolic alterations and Sartoni-D’Ambrosia G, Arbique D, Vong- 11. Perseghin G, Fiorina P, De Cobelli F, Scifo patanasin W, Unger R, Victor RG: Myo- the future development of cardiac dys- P, Esposito A, Danna M, Canu T, Grem- cardial triglycerides and systolic function functions are warranted. izzi C, Secchi A, Luzi L, Del Maschio A: in humans: in vivo evaluation by localized Cross-sectional assessment of the effect of proton spectroscopy and cardiac imaging. kidney and kidney-pancreas transplanta- Magn Reson Med 49 :417–423, 2003 Acknowledgments— This study was sup- tion on resting left ventricular energy me- 22. Reingold JS, McGavock JM, Kaka S, ported by grants from the Italian Minister of tabolism in type 1 diabetic-uremic Tillery T, Victor RG, Szczepaniak LS: De- Health (RF 030.5/199). G.N. was the recipient patients: a 31P-MRS study. J Am Coll Car- termination of triglyceride in the human of the Marie Curie Host Fellowship of the Eu- diol 46:1085–1092, 2005 ropean Community (HPMT-CT-2001- 12. Chia JM, Fischer SE, Wickline SA, Lorenz myocardium by magnetic resonance 00329). CH: Performance of QRS detection for spectroscopy: reproducibility and sensi- cardiac magnetic resonance imaging with tivity of the method. Am J Physiol Endocri- a novel vectorcardiographic triggering nol Metab 289:E935–E939, 2005 References method. J Magn Reson Imaging 12:678– 23. Sharma S, Adrogue JV, Golfman L, Uray I, 1. Schernthaner G: Cardiovascular mortal- 688, 2000 Lemm J, Youker K, Noon GP, Frazier OH, ity and morbidity in type 2 diabetes 13. De Roos A, Doornbos J, Luyten PR, Oost- Taegtmeyer H: Intramyocardial lipid ac- mellitus. Diabetes Res Clin Pract 31:S3– erwaal LJMP, van der Wall EE, den Hol- cumulation in the failing human heart re- S13, 1996 lander JA: Cardiac metabolism in patients sembles the lipotoxic rat heart. FASEB J 2. Kannel WB, Hjortland M, Castelli WP: with dilated and hypertrophic cardiomy- 18:1692–1700, 2004 Role of diabetes in congestive heart fail- opathy: assessment with proton-de- 24. Kankaanpaa M, Lehto H-R, Parkka JP, ure: the Framingham study. Am J Cardiol coupled P-31 MR spectroscopy. J Magn Komu M, Viljanen A, Ferrannini E, Knu- 34:29–34, 1974 Reson Imaging 2:711–719, 1992 uti J, Nuutila P, Parkkola R, Iozzo P: Myo- 3. Picano E: Diabetic cardiomyopathy: the 14. Lamb HJ, Beyerbacht HP, Ouwerkerk R, cardial triglyceride content and epicardial importance of being earliest. J Am Coll Doornbos J, Pluim BM, van der Wall EE, fat mass in human obesity: relationship to Cardiol 42:454–457, 2003 van der Laarse A, de Roos A: Metabolic left ventricular function and serum free 4. Taegtmeyer H, McNulty P, Young ME: response of normal human myocardium fatty acid levels. J Clin Endocrinol Metab Adaptation and maladaptation of the to high dose atropine-dobutamine stress 91:4689–4695, 2006 heart in diabetes. I. General concepts. Cir- studied by 31P-MRS. Circulation 96: 25. Goodwin GW, Taylor CS, Taegtmayer H: culation 105:1727–33, 2002 2969–2977, 1997 Regulation of energy metabolism of the 5. Taegtmeyer H, Razeghi P: Heart disease in 15. Lamb HJ, Doornbos J, den Hollander JA, heart during acute increase in heart work. diabetes: resist the beginnings (Editorial). Luyten PR, Beyerbacht HP, van der Wall J Biol Chem 273:29530–29539, 1998 J Am Coll Cardiol 43: 315, 2004 EE, de Roos A: Reproducibility of human 26. How O-J, Aasum E, Severson DL, Chan 6. Scheuermann-Freestone M, Madsen PL, cardiac 31P-NMR spectroscopy. NMR WYA, Faadiel Essop M, Larsen TS: In- Manners D, Blamire AM, Buckingham RE, Biomed 9:217–227, 1996 creased myocardial oxygen consumption Styles P, Radda GK, Neubauer S, Clarke K: 16. Wallace TM, Levy JC, Matthews DR: Use reduces cardiac efficiency in diabetic Abnormal cardiac and skeletal muscle en- and abuse of HOMA modeling. Diabetes mice. Diabetes 55:466–473, 2006 ergy metabolism in patients with type 2 di- Care 27:1487–1495, 2004 27. Fragasso G, Perseghin G, De Cobelli F, abetes. Circulation 107:3040–3046, 2003 17. Lamb HJ, Beyerbacht HP, van der Laarse Esposito A, Palloshi A, Lattuada G, Scifo
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P, Calori G, Del Maschio A, Margonato A: 29. Peterson LR, Herrero P, Schechtman KB, ment of insulin sensitivity and -cell Effects of metabolic modulation by tri- Racette SB, Waggoner AD, Kisrieva-Ware function with the HOMA2 method. Dia- metazidine on left ventricular function Z, Dence C, Klein S, Marsala J, Meyer T, betes Care 29:2733–2734, 2006 and phosphocreatine/adenosine triphos- Gropler RJ: Effect of obesity and insulin 31. Palmon LC, Reichek N, Yeon SB, Clark phate ratio in patients with heart failure. resistance on myocardial substrate metab- NR, Brownson D, Hoffman E, Axel L: In- Eur Heart J 27:942–948, 2006 olism and efficiency in young women. tramural myocardial shortening in hyper- 28. Taegtmeyer H: Cardiac metabolism as a Circulation 109:2191–2196, 2004 tensive left ventricular hypertrophy with target for the treatment of heart failure. 30. Caumo A, Perseghin G, Brunani A, Luzi L: normal pump function. Circulation 89: Circulation 110:894–896, 2004 New insights on the simultaneous assess- 122–131, 1994
1526 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Association of A1C With Cardiovascular Disease and Metabolic Syndrome in Asian Indians With Normal Glucose Tolerance
1 1 JAMES DILLEY, MB, CHB GOPALAKRISHNAN SHARADA, MSC ity globally, particularly in type 2 diabetic 1 2 ANBAZHAGAN GANESAN, BSC O. DALE WILLIAMS, PHD subjects, as their CVD mortality risk is 1 1 RAJ DEEPA, MPHIL, PHD VISWANATHAN MOHAN, MD, PHD, DSC 1 equal to that of subjects without diabetes MOHAN DEEPA, MSC who had a previous episode of myocardial infarction (9). Recent prospective studies have shown that A1C is associated with OBJECTIVE — This study examines the association of A1C with cardiovascular disease CVD and mortality (10). This association (CVD) risk factors, coronary artery disease (CAD), and metabolic syndrome in Asian Indians has also recently been extended to nondi- with normal glucose tolerance (NGT). abetic subjects, as the relationship of CVD with glycemia is believed to be a contin- RESEARCH DESIGN AND METHODS — This cross-sectional study recruited subjects uum without a threshold effect (5–8). from phase III of the Chennai Urban Rural Epidemiology Study (CURES), an epidemiological study in a representative population of Chennai (formerly Madras) in South India, conducted However, there is uncertainty as to the between January 2003 and June 2004. Included were 1,644 subjects with NGT, i.e., fasting nature of the relationship, as some studies plasma glucose Ͻ100 mg/dl (5.6 mmol/l) and 2-h postload plasma glucose Ͻ140 mg/dl (7.8 report no statistically significant associa- mmol/l). A1C was measured using the Biorad Variant machine. Metabolic syndrome was defined tion (3) between A1C and CVD in nondi- based on modified Adult Treatment Panel III guidelines. abetic males while others do (4–8). Asian Indians are known to have very RESULTS — The mean Ϯ SD A1C value in the study cohort was 5.5 Ϯ 0.4%. A1C showed a high rates of premature coronary artery significant association with BMI (ϭ0.017, P Ͻ 0.001), systolic (ϭ0.002, P ϭ 0.028) and disease (CAD) and diabetes (11). This is diastolic (ϭ0.202, P ϭ 0.017) blood pressure, waist circumference (ϭ0.007, P Ͻ 0.001), ϭ Ͻ ϭ Ͻ attributed to the so-called Asian-Indian serum cholesterol ( 0.002, P 0.001), triglycerides ( 0.001, P 0.001), LDL cholesterol phenotype (12), characterized by rela- (ϭ0.002, P Ͻ 0.001), fasting insulin (ϭ0.009, P Ͻ 0.001), and homeostasis model assessment of insulin resistance (ϭ0.047, P Ͻ 0.001) after adjusting for age and sex. Regres- tively lower prevalence rates of obesity sion analysis showed that A1C had a strong association with metabolic syndrome that persisted but larger waist measurements indicating after adjusting for age and sex (odds ratio [OR] 2.9 [95% CI 2.08–4.00]; P Ͻ 0.001). A1C also abdominal obesity and increased insulin had a strong association with CAD (2.6 [1.23–5.63]; P ϭ 0.01), but the significance was lost resistance. In keeping with studies in the when adjusted for age and sex. West (13), we have shown that in Asian Indians also, the risk for CVD starts at the CONCLUSIONS — There is a strong association of A1C with prevalent CVD risk factors in stage of impaired glucose tolerance (IGT) Asian-Indian subjects with NGT. (14). However, to our knowledge, there are no data on the association of A1C with Diabetes Care 30:1527–1532, 2007 CVD risk in Asian Indians with normal glucose tolerance (NGT). It would be he DCCT (Diabetes Control and significant reductions in the risk of devel- worthwhile to look at the association of Complications Trial) and UKPDS oping microvascular complications for A1C with CVD risk factors in Asian Indi- T (UK Prospective Diabetes Study) every percentage of reduction in A1C lev- ans, as a recent analysis of global and re- demonstrated the importance of A1C in els (1,2). However, the association of A1C gional mortality indicated that South the development of long-term diabetes with cardiovascular disease (CVD) is less Asians had the highest mortality rates due microvascular complications (1,2). Fur- clear (3–8). to ischemic heart disease compared with ther, both studies elegantly demonstrated CVD is the principal cause of mortal- other countries and also had higher mean ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● plasma glucose levels (15). This study ex- From the 1Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, Chennai, amines the association of A1C with CVD India; and the 2Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Ala- risk factors, CAD, and metabolic syn- bama. drome in Asian Indians with NGT. Address correspondence and reprint requests to Dr. V. Mohan, MD, Chief of Diabetes Research, Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, 4, Conran Smith Road, Gopala- puram, Chennai 600 086, India. E-mail: [email protected]. RESEARCH DESIGN AND Received for publication 27 November 2006 and accepted in revised form 26 February 2007. METHODS — The Chennai Urban Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2414. Rural Epidemiology Study (CURES) is a Abbreviations: ATP, Adult Treatment Panel; CAD, coronary artery diasease; CURES, Chennai Urban Rural Epidemiology Study; CVD, cardiovascular disease; dBP, diastolic blood pressure; HOMA-IR, ho- large, cross-sectional study conducted in meostasis assessment of insulin resistance; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; a representative population of Chennai ROC, receiver-operator characteristic; sBP, systolic blood pressure. (formerly Madras), the largest city in A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Southern India, with a population of ap- factors for many substances. proximately 5 million people. The meth- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby odology of CURES has been reported marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. elsewhere (16). Briefly, the sampling for
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1527 A1C and CVD risk in Asian Indians
CURES was based on the model of sys- ing the Hitachi-912 Autoanalyser CAD. CAD was diagnosed based on a tematic random sampling, wherein, of the (Hitachi, Mannheim, Germany). The in- past history of documented myocardial 155 wards in Chennai, 46 were selected tra- and interassay coefficient of variation infarction and/or medical therapy (ni- to provide a total sample size of 26,001 (CV) for the biochemical assays ranged trates) or revascularization for CAD, elec- individuals Ն20 years of age. Phase I of between 3.1 and 7.6%. LDL cholesterol trocardiographic changes suggestive of CURES was conducted in the field and was calculated using the Friedewald for- Q-wave changes (Minnesota codes 1–1-1 involved a door-to-door survey in the se- mula (19) in subjects with triglycerides to 1–1-7), and/or ST segment depression lected wards. In Phase II, all the known Ͻ400 mg/dl (n ϭ 1,618). Serum insulin (Minnesota codes 4–1 to 4–2). diabetic subjects and age- and sex- concentration was estimated using Dako matched nondiabetic subjects were kits (Dako, Glostrup, Denmark); 1,515 Statistical analysis brought to our center for detailed anthro- individuals (92.8%) provided a sample Data management was done via Microsoft pometric measurements and biochemical for insulin assay. Insulin resistance was Access, and statistical analyses were done tests. estimated using the homeostasis assess- using the SPSS statistical package (Ver- This study recruited subjects from ment model of insulin resistance (HOMA- sion 10.0; Chicago, IL). Subjects with Phase III, in which every 10th subject re- IR): fasting insulin (U/ml) ϫ fasting A1C Ͻ4.0% were excluded, as this could cruited in Phase I were brought to the glucose (mmol/l)/22.5 (20). be due to presence of a variant A1C (n ϭ center for detailed studies, inclusive of 5). One-way ANOVA (Tukey’s honestly oral glucose tolerance in those without significant difference comparison) were Analysis of A1C self-reported diabetes. Phase III had a used as appropriate to compare means A1C was measured using a Variant ma- 90% response rate (2,350 of 2,600). Sub- among different groups. 2 test or Fisher’s chine (Biorad, Hercules, CA). Our center jects with diabetes, (IGT), and impaired exact test was used to compare propor- participates in the Unity program of Bio- fasting glucose (17,18) were excluded tions among groups. Study subjects were rad A1C standardization. The CV for A1C from the present study, which deals only categorized into quartiles of A1C; un- assay was 3.5%. The CV for inhouse qual- with subjects who had NGT (n ϭ 1,644), equal numbers were found in the quar- ity control was Ͻ2.5%. In the external defined as fasting plasma glucose Ͻ100 tiles because of decimals. Pearson’s quality assessment scheme, bias for A1C mg/dl (5.6 mmol/l) and 2-h postload correlation analysis was carried out to de- analysis was 1.75% and imprecision plasma glucose Ͻ140 mg/dl (7.8 mmol/ termine the correlation of A1C with car- 2.75%, indicating good reproducibility. l). Of the 1,644 NGT subjects identified in diovascular risk factors. Linear regression Phase III, A1C tests were conducted in analysis was done using A1C as the de- 1,632 (99.3%). Subjects with A1C Definitions and diagnostic criteria pendent variable and CVD risk factors as Ն7.0% were excluded (n ϭ 5). Metabolic abnormalities. Hypercholes- independent variables. In multiple linear terolemia (serum cholesterol Ն5.2 regression analysis (forward method), Anthropometric measurements mmol/l [Ն200 mg/dl] or subjects who HOMA-IR (correlation with fasting insu- Weight, height, and waist measurements self-reported hypercholesterolemia and lin CV 0.989), cholesterol (correlation were obtained using standardized tech- were on statins), hypertriglyceridemia with LDL cholesterol r ϭ 0.924), and niques as detailed elsewhere (16). Height (serum triglycerides Ն1.7 mmol/l [Ն150 CMI (correlation with waist circumfer- was measured with a tape to the nearest mg/dl] or subjects who self-reported hy- ence r ϭ 0.823) were not included to centimeter. Weight was measured with a pertriglyceridemia and were on drugs for avoid intercorrelation between indepen- traditional spring balance that was kept hypertriglyceridemia), and low HDL cho- dent variables. Logistic regression analy- on a firm horizontal surface. Waist size lesterol (male subjects: HDL cholesterol sis was done using CAD and metabolic was measured using a nonstretchable fi- Ͻ1.04 mmol/l [Ͻ 40 mg/dl] and female syndrome as dependent variables and ber measure tape. BMI was calculated as subjects: HDL cholesterol Ͻ1.3 mmol/l A1C as an independent variable. Receiv- the weight in kilograms divided by the [Ͻ 50 mg/dl]) were diagnosed based on er-operator characteristic (ROC) curves square of height in meters. Blood pres- Adult Treatment Panel (ATP) III guide- were constructed to identify the cut point sure was recorded in the sitting position lines (21). Metabolic syndrome was diag- of A1C with maximum accuracy for de- using the right arm to the nearest 2 nosed based on modified ATP III termining metabolic syndrome and CAD. mmHg with a mercury sphygmomanom- guidelines (21) if any three of the follow- Sensitivity, specificity, and accuracy for eter (Diamond Deluxe; Pune, India). Two ing abnormalities were present: abdomi- predicting metabolic syndrome were cal- readings were taken 5 min apart, and the nal obesity (defined as waist culated for different cut points of A1C. mean of the two was taken as the blood circumference Ն90 cm for male subjects pressure. and Ն80 cm for female subjects, accord- RESULTS — The study groups in- ing to modified Asia Pacific World Health cluded 1,620 subjects with NGT (734 Biochemical parameters Organization guidelines) (22), high blood men and 886 women). Men were older Fasting plasma glucose (glucose oxidase- pressure (systolic blood pressure [sBP] than women (38 Ϯ 13 vs. 36 Ϯ 11 years, peroxidase method), serum cholesterol Ն130 mmHg. diastolic blood pressure respectively, P ϭ 0.007), had lower BMIs (cholesterol oxidase-peroxidase-4– [dBP] Ն85 mmHg, or subjects who self- (22.3 Ϯ 4.0 vs. 22.8 Ϯ 4.1 kg/m2, P ϭ aminophenazone method) serum triglyc- reported hypertension and were on anti- 0.026), larger waist circumferences (83 Ϯ erides (glycerol phosphate oxidase- hypertensives), hypertriglyceridemia, or 12 vs. 80 Ϯ 11 cm, P Ͻ 0.001), and peroxidase-4–aminophenazone low HDL cholesterol. Obesity was defined higher sBP (117 Ϯ 16 vs. 114 Ϯ 16 method), and HDL cholesterol (direct as BMI Ն25 kg/m2 according to the mod- mmHg, P Ͻ 0.001), dBP (74 Ϯ 11 vs. method with polyethylene glycol– ified Asia Pacific World Health Organiza- 72 Ϯ 11 mmHg, P Ͻ 0.001), and serum pretreated enzymes) were measured us- tion guidelines (22). triglycerides (1.35 Ϯ 0.82 vs. 1.15 Ϯ 0.62
1528 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Dilley and Associates
Table 1—Clinical and biochemical characteristics of the study population according to quartiles of A1C
Quartiles of A1C Parameters 1st 2nd 3rd 4th P for trend n 316 426 426 452 — A1C (%) Ͻ5.1 5.1–5.4 5.5–5.7 Ͼ5.7 — Age (years) 33 Ϯ 11 34 Ϯ 10 38 Ϯ 11* 42 Ϯ 13† Ͻ 0.001 Sex (male) 147 (46.5) 185 (43.4) 189 (44.4) 213 (47.1) 0.694 BMI (kg/m2) 21.59 Ϯ 3.96 22.35 Ϯ 4.06 22.58 Ϯ 4.18‡ 23.52 Ϯ 3.91§ Ͻ 0.001 Waist circumference (cm) 78 Ϯ 12 80 Ϯ 11 81 Ϯ 12¶ 85 Ϯ 11ʈ Ͻ 0.001 sBP (mmHg) 112 Ϯ 15 114 Ϯ 14 116 Ϯ 17‡ 119 Ϯ 17** Ͻ 0.001 dBP (mmHg) 70 Ϯ 11 72 Ϯ 11 73 Ϯ 11‡ 74 Ϯ 10* Ͻ 0.001 Fasting plasma glucose (mmol/l) 4.51 Ϯ 0.40 4.57 Ϯ 0.36 4.66 Ϯ 0.40§ 4.73 Ϯ 0.38†† Ͻ 0.001 2-h plasma glucose (mmol/l) 5.43 Ϯ 1.04 5.45 Ϯ 1.08 5.43 Ϯ 1.09 5.79 Ϯ 1.06ʈ Ͻ 0.001 Total cholesterol (mmol/l) 4.17 Ϯ 0.97 4.38 Ϯ 0.80‡ 4.56 Ϯ 0.91* 4.81 Ϯ 1.01ʈ Ͻ 0.001 Serum triglycerides (mmol/l) 1.04 Ϯ 0.55 1.19 Ϯ 0.64‡ 1.26 Ϯ 0.68¶ 1.42 Ϯ 0.89** Ͻ 0.001 HDL cholesterol (mmol/l) 1.13 Ϯ 0.26 1.12 Ϯ 0.27 1.14 Ϯ 0.27 1.11 Ϯ 0.23 0.396 LDL cholesterol (mmol/l) 2.56 Ϯ 0.86 2.72 Ϯ 0.68‡‡ 2.84 Ϯ 0.78¶ 3.05 Ϯ 0.86** Ͻ 0.001 Fasting insulin (U/ml) 7.3 Ϯ 5.2 7.6 Ϯ 5.0 7.8 Ϯ 5.1 9.0 Ϯ 6.4† Ͻ 0.001 HOMA-IR 1.47 Ϯ 1.07 1.55 Ϯ 1.07 1.63 Ϯ 1.09 1.89 Ϯ 1.34** Ͻ 0.001 Hypertension 51 (16.1) 90 (21.1) 99 (23.2) 147 (32.5) Ͻ 0.001 Obesity 89 (28.2) 148 (34.7) 180 (42.3) 245 (54.2) Ͻ 0.001 High triglycerides 92 (29.2) 182 (42.8) 201 (47.2) 232 (51.4) Ͻ 0.001 Low HDL cholesterol 183 (58.1) 268 (63.1) 270 (63.5) 293 (65.0) 0.262 Metabolic syndrome 10 (3.2%) 26 (6.1%) 35 (8.2%) 45 (10.0%) Ͻ 0.001 CAD 5 (1.6%) 6 (1.5%) 10 (2.5%) 13 (3.1) 0.115 Data are means Ϯ SD or n (%) unless otherwise indicated. *P Ͻ 0.001 compared with 1st quartile and P Ͻ 0.05 compared with 2nd quartile; †P Ͻ 0.001 compared with first quartile and P Ͻ 0.01 compared with 2nd and 3rd quartiles; ‡P Ͻ 0.01 compared with 1st quartile; §P Ͻ 0.001 compared with 1st and 2nd quartiles; ¶P Ͻ 0.001 compared with 1st quartile; ʈP Ͻ 0.001 compared with 1st, 2nd, and 3rd quartiles; **P Ͻ 0.001 compared with 1st and 2nd quartile and P Ͻ 0.01 compared with 3rd quartile; ††P Ͻ 0.001 compared with 1st and 2nd quartile and P Ͻ 0.05 compared with 3rd quartile; and ‡‡P Ͻ 0.05 compared with 1st quartile. mmol/l, P Ͻ 0.001) but lower levels of quartile 1.04 Ϯ 0.24 mmol/l, 3rd quartile (ϭ0.017, P Ͻ 0.001), sBP (P ϭ 0.028), 2-h postload plasma glucose (5.38 Ϯ 1.15 1.05 Ϯ 0.25 mmol/l, and 4th quartile dBP (P ϭ 0.017), waist circumference vs. 5.66 Ϯ 1.0 mmol/l, P Ͻ 0.001) and 1.04 Ϯ 0.23 mmol/l; female subjects: 1st (P Ͻ 0.001), serum cholesterol (P Ͻ HDL cholesterol (1.05 Ϯ 0.25 vs. 1.19 Ϯ quartile 1.19 Ϯ 0.24 mmol/l, 2nd quartile 0.001), triglycerides (P Ͻ 0.001), LDL 0.25 mmol/l, P Ͻ 0.001). Mean A1C was 1.18 Ϯ 0.28 mmol/l, 3rd quartile 1.20 Ϯ cholesterol (P Ͻ 0.001), fasting insulin 5.5 Ϯ 0.4%, range 4.0–6.8%. 0.26 mmol/l, and 4th quartile 1.17 Ϯ (P Ͻ 0.001), and HOMA-IR (P Ͻ 0.001) The clinical and biochemical charac- 0.22 mmol/l). even after adjusting for age and sex, with teristics of the NGT group stratified ac- There was a linear increase in the the exception of HDL cholesterol, which cording to quartiles of A1C are shown in mean values of A1C with an increase in showed an association with A1C only af- Table 1. Age, BMI, waist circumference, number of components of metabolic syn- ter adding age and sex into the model sBP and dBP, serum cholesterol, triglyc- drome (one metabolic abnormality: 5.5 Ϯ (ϭϪ0.003, P ϭ 0.006). However, this erides, LDL cholesterol, fasting insulin, 0.4, two metabolic abnormalities: 5.6 Ϯ and HOMA-IR increased significantly 0.5, three or more metabolic abnormali- with increasing quartiles of A1C values (P ties: 5.7 Ϯ 0.5) compared with subjects Table 2—Pearson correlation coefficient of for trend Ͻ0.001). Prevalence of meta- with no metabolic abnormalities (5.4 Ϯ A1C with cardiovascular risk variables bolic abnormalities and the metabolic 0.4), P for trend Ͻ0.001). syndrome increase corresponded with in- Table 2 presents the results of the Correlation rP creases in quartiles of A1C (P for trend Pearson’s correlation analysis of A1C with Ͻ Ͻ0.001), with the exception of low HDL cardiovascular risk factors. A1C had a sig- Age 0.292 0.001 Ͻ cholesterol levels (P for trend ϭ 0.262). nificant correlation with age, BMI, waist BMI 0.159 0.001 Ͻ Though the prevalence of CAD increased circumference, sBP and dBP, serum cho- Waist circumference 0.216 0.001 Ͻ in the 3rd and 4th quartile compared with lesterol, triglycerides, LDL cholesterol, sBP 0.157 0.001 Ͻ the 1st quartile, the difference did not fasting insulin levels, and HOMA-IR (P Ͻ dBP 0.135 0.001 Ͻ reach statistical significance, probably be- 0.001). Total cholesterol 0.233 0.001 Ͻ cause of small numbers (n ϭ 34). HDL Table 3 presents the results of linear Serum triglycerides 0.180 0.001 Ϫ cholesterol failed to show any trend with regression analysis using A1C as a depen- HDL cholesterol 0.022 0.377 Ͻ increasing quartiles of A1C levels, even dent variable and CVD risk factors as in- LDL cholesterol 0.205 0.001 Ͻ when categorized sex wise (male subjects: dependent variables. A1C showed a Fasting insulin 0.117 0.001 Ͻ 1st quartile 1.06 Ϯ 0.27 mmol/l, 2nd significant association with BMI HOMA-IR 0.138 0.001
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1529 A1C and CVD risk in Asian Indians
Table 3—Association of A1C with metabolic 0.003), LDL cholesterol (P Ͻ 0.001), and however, the difference in prevalence be- abnormalities in nondiabetic subjects; depen- fasting insulin (P ϭ 0.026) had a signifi- tween quartiles did not reach statistical dent variable: A1C cant association with A1C. The model significance, probably because of small that used only age as the independent number of subjects with CAD (n ϭ 34). 2 ϭ Independent variables  P variable had r 8.6%, which increased to While regression analysis revealed that 13.8% when waist circumference, LDL A1C was significantly associated with Waist circumference cholesterol, triglycerides, and fasting in- CAD, this disappeared upon addition of Unadjusted 0.008 Ͻ0.001 sulin were incorporated into the model. age into the model. Adjusted for age 0.007 Ͻ0.001 Logistic regression using CAD as a de- Prospective studies have revealed and sex pendant variable showed that A1C had a A1C to be a predictor of total and all- sBP strong association with CAD (odds ratio cause mortality (5,6). Indeed, the Rancho Unadjusted 0.004 Ͻ0.001 [OR] 2.6 [95% CI 1.23–5.63], P ϭ 0.01). Bernardo Study (3) concluded that A1C is Adjusted for age 0.002 0.028 However, this association lost its signifi- a better predictor of CVD mortality than and sex cance when adjusted for age (1.5 [0.666– fasting and postload plasma glucose lev- dBP 3.20], P ϭ 0.34), probably because of els. A meta-analysis of several studies con- Unadjusted 0.005 Ͻ0.001 small numbers of subjects with CAD (n ϭ cluded that there is a linear relationship Adjusted for age 0.002 0.017 34). Regression analysis using metabolic between glucose levels and CVD (7). In and sex syndrome as a dependant variable our population, we reported that the Total cholesterol showed that A1C had a strong association prevalence of CAD is nearly 1.5 times Unadjusted 0.003 Ͻ0.001 with metabolic syndrome (3.5 [2.53– higher among subjects with IGT com- Adjusted for age 0.002 Ͻ0.001 4.75], P Ͻ 0.001), and this association pared with NGT (14). Further, preclinical and sex persisted even after adjusting for age (2.9 atherosclerotic markers like carotid in- Serum triglycerides [2.08–4.01], P Ͻ 0.001) and sex (2.9 tima media thickness also showed a linear Unadjusted 0.001 Ͻ0.001 [2.08–4.00], P ϭϽ0.001). increase with increasing severity of glu- Adjusted for age 0.001 Ͻ0.001 ROC analysis revealed that an A1C cose intolerance (27), indicating that the and sex cut point of Ն5.6% had maximum accu- atherosclerotic process starts to get accel- HDL cholesterol racy in determining metabolic syndrome erated even before clinical diabetes sets Unadjusted Ϫ0.001 0.377 (area under the curve 0.602, P Ͻ 0.001; in. Adjusted for age Ϫ0.003 0.006 accuracy 60%, sensitivity 57.5%, and Insulin resistance is considered to be and sex specificity 60.9%). A1C values of 5.0 and the link between glucose intolerance and LDL cholesterol 6.0% were also analyzed to determine CAD (28), and earlier population-based Unadjusted 0.003 Ͻ0.001 their efficiency; a value of 6.0% had a sen- studies demonstrated that plasma insulin Adjusted for age 0.002 Ͻ0.001 sitivity of 25.8% and specificity of 87.8%, levels had a strong association with CAD and sex while a value of 5.0% had a sensitivity of (29). In the present analysis, we observed Fasting insulin 96.3% and specificity of 9.8%. a strong association between A1C, fasting Unadjusted 0.009 Ͻ0.001 With regard to CAD, ROC curves had insulin, and insulin resistance, indepen- Adjusted for age 0.009 Ͻ0.001 an area under the curve of 0.605 (P ϭ dent of age and sex. One could speculate and sex 0.036), and A1C 5.6% had maximum ac- that this association could be through HOMA-IR curacy (56%), optimum sensitivity low-grade inflammation, which is Unadjusted 0.052 Ͻ0.001 (67.6%), and optimum specificity strongly associated with insulin resistance Adjusted for age 0.047 Ͻ0.001 (55.7%). A1C 6.0% had a sensitivity of (30). and sex 26.5% and specificity of 86.1%, while a Studies in different ethnic groups Multiple linear value of 5.0% had a sensitivity of 97.0% have assessed the relation between meta- conclusions and a specificity of 9.2%. bolic abnormalities in terms of CVD risk regression analysis factors and A1C. Similar to these popula- Age 0.008 Ͻ0.001 CONCLUSIONS — The main find- tion studies (31–33), we also found that Waist 0.004 Ͻ0.001 ings of the study are that in Asian Indians prevalence of all CVD risk factors in- circumference with NGT, A1C showed an association creased with increasing quartiles of A1C, Serum triglycerides 0.001 0.003 with most CVD risk factors, the metabolic and the difference reached statistical sig- LDL cholesterol 0.002 Ͻ0.001 syndrome, and CAD; the latter, however, nificance in the 3rd and 4th quartiles. Fasting insulin 0.004 0.026 was not significant when age was intro- Similar findings were reported in African duced into the model. Americans (33). However, unlike the A1C could be considered a good Chinese study in which age and sex al- association lost its significance when trig- marker for glycated proteins, which play a tered some of these associations (31), in lycerides were added into the model (ϭ contributory role in atherosclerosis the present analysis adjustments for age Ϫ0.002, P ϭ 0.160). Similar results were (23,24) not only in diabetic but also in and sex did not alter the association of obtained even when categorized based on nondiabetic subjects (25). This is sup- A1C with CVD risk factors. sex (men: ϭϪ0.001, P ϭ 0.574; wom- ported by the findings that even nondia- HDL cholesterol showed an associa- en: ϭϪ0.002, P ϭ 0.199). betic subjects with CAD have increased tion with A1C when age and sex were in- Multiple linear regression analysis re- levels of A1C (26). corporated into the model. However, this vealed that age (P Ͻ 0.001), waist circum- We observed a trend in prevalence of association disappeared when triglycer- ference (P Ͻ 0.001), triglycerides (P ϭ CAD with an increase in quartiles of A1C; ides were introduced into the model.
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These results are in accordance with those tion of A1C with CAD and its risk factors. with all-cause and cardiovascular mortal- reported in an earlier study by Bakker et The strengths of the study, however, are ity in the Hoorn population: the Hoorn al. (34), which suggested that within the that it is population based and performed Study. Diabetologia 42:926–931,1999 metabolic syndrome, disturbances of in a population at high risk of diabetes 7. Selvin E, Marinopoulos S, Berkenblit G, lipid and glucose coexit (34). and premature CAD. In summary, this Rami T, Brancati FL, Powe NR, Golden Multiple regression analysis using study reports that among Asian Indians SH: Meta-analysis: glycosylated hemoglo- bin and cardiovascular disease in diabetes various CVD risk factors revealed age, who are known to have high risk of pre- mellitus. Ann Intern Med 141:421–431, waist circumference, triglycerides, LDL mature CAD and diabetes, a linear rela- 2004 cholesterol, and fasting insulin to be as- tionship exists between A1C, CAD, and 8. Palumbo F, Bianchi C, Miccoli R, Del sociated with A1C. With age, glycation metabolic syndrome even among nondi- Prato S: Hyperglycaemia and cardiovas- of proteins increases; this supports the abetic subjects. cular risk. Acta Diabetol 40 (Suppl. 2): association of age with A1C observed in S362–S369, 2003 this study. The strong association of 9. Haffner SM, Lehto S, Ronnermaa T, waist circumference, fasting insulin, Acknowledgments— We thank the Chennai Pyorala K, Laakso M: Mortality from cor- and triglycerides with A1C and the fact Willingdon Corporate Foundation for their onary heart disease in subjects with type 2 that the prevalence of multiple sclerosis support for the CURES field studies. This is the diabetes and in nondiabetic subjects with 44th article from CURES. This study was also and without prior myocardial infarction. increases with increase in A1C quartiles supported in part by the Fogarty International suggest that A1C could be included as a N Engl J Med 339:229–234, 1998 Center (International Clinical, Operational, 10. O’Sullivan CJ, Hynes N, Mahendran B, diagnostic criteria for metabolic syn- and Health Services Research Training Award Andrews EJ, Avalos G, Tawfik S, Lowery drome instead of fasting plasma glu- Grant #D43-TW05816). J.D. is a medical stu- A, Sultan S: Haemoglobin A1c (HbA1C) cose, particularly in situations when a dent from Bristol University, Bristol, U.K., in non-diabetic and diabetic vascular pa- fasting sample is difficult to obtain. who worked on this during his elective posting tients: is HbA1C an independent risk fac- The NCEP (National Cholesterol Ed- at our centre. We thank Dr. Cora E. Lewis, tor and predictor of adverse outcome? Eur ucation Program) ATP III guidelines rec- Division of Preventive Medicine, University of J Vasc Endovasc Surg 32:188–197, 2006 ognized metabolic syndrome as a risk Alabama, Birmingham, Alabama, and Dr. My- 11. Deepa R, Gokulakrishnan K, Mohan V: factor for CAD, and this is confirmed by ron D. Gross, Department of Laboratory Med- Coronary artery disease among Indian di- icine/Pathology, University of Minnesota, several studies (21). In this study, A1C abetic subjects. In Type 2 Diabetes in South Minneapolis, MN for their critical suggestions Asians: Epidemiology, Risk Factors and Pre- levels increased with the number of com- in improving the manuscript. ponents of the metabolic syndrome, and vention. 1st ed. Mohan V, Rao GHR, Eds. NGT subjects with three or more meta- New Delhi, India, Jaypee Brothers Medi- bolic abnormalities had the highest A1C cal Publishers, 2006, p. 242–255 References 12. Deepa R, Sandeep S, Mohan V. Abdomi- (5.7%). Moreover, the prevalence of met- 1. Diabetes Control and Complications Trial nal obesity, visceral fat and type 2 diabe- abolic syndrome per se increases with Research Group: The absence of a glyce- tes: “Asian Indian Phenotype.” In Type 2 mic threshold for the development of quartiles of A1C. A study of African Amer- Diabetes in South Asians: Epidemiology, Risk long-term complications: the perspective icans suggested A1C to be a surrogate Factors and Prevention. 1st ed. Mohan V, of the Diabetes Control and Complica- marker for metabolic syndrome (33). In Rao GHR, Eds. New Delhi, India, Jaypee tions Trial. Diabetes 45:1289–1298, 1996 our study, an A1C cut point Ն5.6% was Brothers Medical Publishers, 2006, p. 2. UK Prospective Diabetes Study (UKPDS) 138–152 found to have the highest accuracy of pre- Group: Intensive blood-glucose control 13. Rennert NJ, Charney P: Preventing car- dicting both metabolic syndrome and with sulphonylureas or insulin compared CAD. with conventional treatment and risk of diovascular disease in diabetes and The present study supports the EPIC complications in patients with type 2 di- glucose intolerance: evidence and im- (European Investigation of Cancer and abetes (UKPDS 33). Lancet 352:837–853, plications for care. Prim Care 30:569– Nutrition)-Norfolk study, which reported 1998 592, 2003 3. Park S, Barrett-Connor E, Wingard DL, 14. Mohan V, Deepa R, Rani SS, Premalatha an association of A1C with CVD risk even G: Chennai Urban Population Study in the nondiabetic range. In that study, Shan J, Edelstein S: GHb is a better pre- dictor of cardiovascular disease than fast- (CUPS No. 5): prevalence of coronary ar- 0.1–0.2% reduction in A1C was shown to tery disease and its relationship to lipids reduce risk of total mortality by 5.1% (4). ing or postchallenge plasma glucose in women without diabetes: the Rancho Ber- in a selected population in South India: Hence, estimation of A1C appears to be a nardo Study. Diabetes Care 19:450–456, the Chennai Urban Population Study useful measure even among the nondia- 1996 (CUPS No. 5). J Am Coll Cardiol 38:682– betic population in assessing an individ- 4. Khaw KT, Wareham N, Luben R, Bing- 687, 2001 ual’s cardiovascular risk. The advantages ham S, Oakes S, Welch A, Day N: 15. Danaei G, Lawes CM, Vander Hoorn S, of this test are that it can be measured at Glycated haemoglobin, diabetes, and Murray CJ, Ezzati M: Global and regional any time of the day with a very small mortality in men in Norfolk cohort of Eu- mortality from ischaemic heart disease blood sample (5 l). The disadvantages ropean Prospective Investigation of Can- and stroke attributable to higher-than- are that A1C cannot be measured in the cer and Nutrition (EPIC-Norfolk). Br optimum blood glucose concentration: comparative risk assessment. Lancet 368: presence of hemoglobin variants by sev- Med J 322:15–18, 2001 1651–1659, 2006 eral methods, costs, and the difficulty in 5. Sigal RJ: Haemoglobin A1c concentra- tions were associated with increased car- 16. Deepa M, Pradeepa R, Rema M, Mohan A, standardization (35). diovascular disease and all cause Deepa R, Shanthirani S, Mohan V.: The One of the major limitations of this mortality. Evid Based Med 10:57–57, 2005 Chennai Urban Rural Epidemiology study is that, as a cross-sectional study, it 6. de Vegt F, Dekker JM, Ruhe HG, Ste- Study (CURES): study design and meth- cannot provide evidence for a cause-and- whouwer CDA, Nijpels G, Bouter LM, odology (urban component) (CURES-I). J effect relationship between the associa- Heine RJ: Hyperglycaemia is associated Assoc Physicians India 51:863–870, 2003
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17. American Diabetes Association: Diagnosis Stern D: Advanced glycation endproducts 30. Deepa R, Velmurugan K, Arvind K, Si- and classification of diabetes mellitus interacting with their endothelial receptor varam P, Sientay C, Uday S, Mohan V: (Position Statement). Diabetes Care 27 induce expression of vascular cell adhe- Serum levels of interleukin 6, C-reactive (Suppl. 1): S5–S10, 2004 sion molecule-1 (VCAM-1) in cultured protein, vascular cell adhesion molecule 18. Alberti KG, Zimmet PZ: Definition, diag- human endothelial cells and in mice. 1, and monocyte chemotactic protein 1 in nosis and classification of diabetes melli- J Clin Invest 96:1395–1403, 1995 relation to insulin resistance and glucose tus and its complications: part 1: 24. Bucala R, Tracey KJ, Cerami A: Advanced intolerance: the Chennai Urban Rural Ep- diagnosis and classification of diabetes glycosylation products quench nitric ox- idemiology Study (CURES). Metabolism mellitus, provisional report of a WHO ide and mediate defective endothelium- 55:1232–1238, 2006 consultation. Diabet Med 15:539–553, dependent vasodilatation in experimental 31. Ko GT, Chan JC, Woo J, Lau E, Yeung VT, 1998 diabetes. J Clin Invest 87:432–438, 1991 Chow CC, Li JK, So WY, Chan WB, Cock- 19. Friedewald WT, Levy RI, Fredrickson DS: 25. Nakamura Y, Horii Y, Nishino T, Shiiki H, ram CS: Glycated haemoglobin and car- Estimation of the concentration of low- Sakaguchi Y, Kagoshima T, Dohi K, Ma- diovascular risk factors in Chinese density lipoprotein cholesterol in plasma kita Z, Vlassara H, Bucala R: Immunohis- subjects with normal glucose tolerance. without use of the preparative ultracentri- tochemical localization of advanced Diabet Med 15:573–578, 1988 fuge. Clin Chem 18:499–502, 1972 glycosylation endproducts in coronary 32. Barrett-Connor E, Criqui MH, Witztum 20. Matthews DR, Hosker JP, Rudenski AS, atheroma and cardiac tissue in diabetes JL, Philippi T, Zettner A: Population- Naylor BA, Treacher DF, Turner RC: Ho- mellitus. Am J Pathol 143:1649–1656, based study of glycosylated hemoglobin, meostasis model assessment: insulin re- 1993 lipids, and lipoproteins in nondiabetic sistance and b cell function from fasting 26. Kanauchi M, Hashimoto T, Tsujimoto N: adults. Arteriosclerosis 7:66–70, 1987 plasma glucose and insulin concentra- Advanced glycation end products in non- 33. Osei K, Rhinesmith S, Gaillard T, Schus- tions in man. Diabetologia 28:412–419, diabetic patients with coronary artery dis- 1985 ease. Diabetes Care 24:1620–1623, 2001 ter D: Is glycosylated hemoglobin A1c a 21. Executive Summary of the Third Report 27. Mohan V, Gokulakrishnan K, Sandeep S, surrogate for metabolic syndrome in non- of the National Cholesterol Education Srivastava BK, Ravikumar R, Deepa R: In- diabetic, first-degree relatives of African- Program (NCEP): Expert Panel on Detec- timal media thickness, glucose intoler- American patients with type 2 diabetes? tion, Evaluation, and Treatment of High ance and metabolic syndrome in Asian J Clin Endocrinol Metab 88:4596–4601, Blood Cholesterol in Adults (Adult Treat- Indians the Chennai Urban Rural Epide- 2003 ment Panel III) JAMA 285:2486–2497, miology Study (CURES-22). Diabet Med 34. Bakker SJ, Dekker JM, Heine RJ: Associa- 2001 23:845–850, 2006 tion between A1C and HDL-cholesterol 22. World Health Organization, International 28. Reaven GM: Banting lecture 1988: role of independent of fasting triglycerides in a Association for the Study of Obesity and insulin resistance in human disease. Dia- Caucasian population: evidence for en- International Obesity Task Force: The betes 37:1595–1607, 1988 hanced cholesterol ester transfer induced Asia Pacific Perspective: Redefining Obe- 29. Lehto S, Ronnemaa T, Pyorala K, Laakso by in vivo glycation. Diabetologia 41: sity and its Treatment. Health Communi- M: Cardiovascular risk factors clustering 1249–1250, 1998 cations Australia Pty Limited, Sydney, with endogenous hyperinsulinemia pre- 35. Higgins TN, Blakney GB, Dayton J: Ana- 2000, p. 17–21 dict death from coronary heart disease in lytical evaluation of the Bio-Rad variant II 23. Schmidt AM, Hori O, Chen JX, Li JF, patients with type II diabetes. Diabetologia automated HbA(1C) analyzer. Clin Bio- Crandall J, Zhang J, Cao R, Yan SD, Brett J, 43:148–155, 2000 chem 34:361–365, 2001
1532 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Relationship Between Metabolic Risk Factor Clustering and Cardiovascular Mortality Stratified by High Blood Glucose and Obesity NIPPON DATA90, 1990–2000
1,2 1 AYA KADOTA, MD YOSHIKUNI KITA, PHD he World Health Organization 1 4 ATSUSHI HOZAWA, MD AKIRA OKAYAMA, MD (WHO) states that individual risk 1 5 TOMONORI OKAMURA, MD YASUYUKI NAKAMURA, MD 1 2 factors for cardiovascular disease AKASHI ADOWAK MD TSUNORI ASHIWAGI MD T T K , A K , 1 1 (CVD) convey greater CVD risk. Fur- KOSHI NAKMAURA, MD HIROTSUGU UESHIMA, MD 1 thermore, even though each one of YOSHITAKA MURAKAMI, PHD FOR THE NIPPON DATA RESEARCH 3 these risk factors alone is not serious, TAKEHITO HAYAKAWA, PHD GROUP the risk becomes more “powerful” when they are combined (1). Metabolic syn- drome is the concept of clustering risk OBJECTIVE — Metabolic syndrome is diagnosed according to several criteria. Of these, some factors comprising insulin resistance, require glucose intolerance and others require obesity for the diagnosis. We investigated the abdominal fat distribution, dyslipide- relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality mia, and hypertension (2–5). stratified by high blood glucose or obesity. Several institutions have established their own diagnostic criteria for metabolic RESEARCH DESIGN AND METHODS — We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood syndrome. The National Cholesterol Ed- glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multi- ucation Program (NCEP) considers that variate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering each metabolic factor has the same impor- metabolic factors was calculated using the Cox proportional hazards model. tance (6), whereas the WHO requires im- paired glucose tolerance among its RESULTS — During follow-up, 173 participants died of CVD. The numbers of metabolic risk criteria to diagnose metabolic syndrome ϭ factors and CVD mortality were positively correlated (Ptrend 0.07). The HR was obviously (7). Finally, the International Diabetes higher among participants with than among those without high blood glucose and clustering of Federation (IDF) and the Japanese guide- Ն2 other metabolic risk factors (HR 3.67 [95% CI 1.49–9.03]). However, the risk increase was lines require central obesity defined by only modest in participants without high blood glucose even if they had Ն2 other metabolic risk waist circumference to diagnose meta- factors (1.99 [0.93–4.28]). Conversely, metabolic risk factor clustering was related to CVD bolic syndrome (8,9). Thus, whether a re- mortality irrespective of obesity. lationship between metabolic risk factor clustering and CVD mortality differs ac- CONCLUSIONS — Our findings suggest that glucose tolerance plays an important role in cording to obesity or impaired glucose CVD mortality. Because the prevalence of nonobese participants with several metabolic risk tolerance, which are both required for a factors was quite high and their CVD risk was high, excluding them from the diagnosis of diagnosis of metabolic syndrome, should metabolic syndrome because of the absence of obesity might overlook their risk. be determined. Thus, in the present study, we investigated the association be- Diabetes Care 30:1533–1538, 2007 tween metabolic factor clustering and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● CVD mortality stratified according to obe-
1 2 sity or impaired glucose tolerance in a From the Department of Health Science, Shiga University of Medical Science, Otsu, Japan; Department of population-based cohort study in the Jap- Internal Medicine, Shiga University of Medical Science, Otsu, Japan; 3Department of Public Health Science, Shimane University, Izumo, Japan; 4Department of Preventive Cardiology, National Cardiovascular Center, anese general population. Suita, Japan; and 5Cardiovascular Epidemiology, Kyoto Women’s University, Kyoto, Japan. Address correspondence and reprint requests to Aya Kadota, MD, Department of Health Science, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan. E-mail: [email protected]. RESEARCH DESIGN AND ac.jp. METHODS — Cohort studies of the Received for publication 19 October 2006 and accepted in revised form 6 March 2007. National Survey on Circulatory Disor- Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2074. ders, Japan, are referred to as NIPPON Members of the NIPPON DATA Research Group can be found in an online appendix at http://dx.doi.org/ 10.2337/dc06-2074. DATA (National Integrated Project for Abbreviations: CVD, cardiovascular disease; IDF, International Diabetes Federation; NCEP, National Prospective Observation of Noncom- Cholesterol Education Program; WHO, World Health Organization. municable Disease and Its Trends in the A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Aged). NIPPON DATA includes two co- factors for many substances. hort studies. Baseline data were sur- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby veyed in 1980 and in 1990 (NIPPON marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DATA80 and NIPPON DATA90), and
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1533 Metabolic factor clustering and CVD mortality
Table 1—Means and prevalence of baseline characteristics of 2,999 men and 4,220 women aged >30 years (NIPPON DATA90, 1990)
Number of metabolic factors Baseline risk characteristics 012 3 4 5 n 1,604 2,657 1,643 942 336 37 Women (%) 67.3 54.3 59.4 55.4 56.9 56.0 Age (years) 44.1 Ϯ 11.0 52.7 Ϯ 13.6 56.0 Ϯ 13.4 56.1 Ϯ 12.5 58.0 Ϯ 13.2 58.6 Ϯ 11.2 BMI (kg/m2) 20.9 Ϯ 2.0 21.9 Ϯ 2.4 24.1 Ϯ 3.2 25.5 Ϯ 3.1 26.7 Ϯ 2.4 27.8 Ϯ 2.0 Systolic blood pressure (mmHg) 114.9 Ϯ 8.8 137.2 Ϯ 19.7 141.8 Ϯ 19.0 145.8 Ϯ 17.4 149.2 Ϯ 16.4 154.3 Ϯ 18.4 Diastolic blood pressure (mmHg) 71.7 Ϯ 7.5 82.1 Ϯ 11.4 84.3 Ϯ 11.4 86.7 Ϯ 10.8 88.1 Ϯ 11.5 89.7 Ϯ 12.0 Total cholesterol (mg/dl) 194.2 Ϯ 32.0 198.6 Ϯ 36.2 206.0 Ϯ 37.9 217.3 Ϯ 40.8 224.6 Ϯ 42.7 237.8 Ϯ 43.7 Triglycerides (mg/dl) 78 (57–106) 95 (70–127) 127 (91–176) 192 (131–252) 255 (205–346) 269 (214–363) HDL cholesterol (mg/dl) 63.5 Ϯ 12.8 58.2 Ϯ 14.6 49.5 Ϯ 13.2 42.4 Ϯ 10.9 37.5 Ϯ 7.8 36.2 Ϯ 6.8 Blood glucose (mg/dl) 92.6 Ϯ 13.5 98.4 Ϯ 22.5 105.5 Ϯ 33.0 114.4 Ϯ 45.9 126.5 Ϯ 51.3 196.7 Ϯ 69.7 High blood pressure (%) 0.0 72.1 82.8 93.7 99.4 100 High triglycerides (%) 0.0 2.8 20.0 55.1 89.3 100 Low HDL cholesterol (%) 0.0 16.1 46.0 73.5 93.2 100 High blood glucose (%) 0.0 2.1 11.7 19.2 33.3 100 Drinking Never drinker (%) 73.8 64.0 70.9 66.8 73.8 73.0 Ex-drinker (%) 2.3 2.7 3.4 3.8 3.3 10.8 Current drinker (%) 23.9 33.3 25.7 29.4 22.9 16.2 Smoking Never smoker (%) 65.8 58.2 61.6 58.1 54.2 56.8 Ex-smoker (%) 8.6 11.2 11.8 12.3 13.7 10.8 Current smoker (%) 25.6 30.6 26.6 29.6 32.1 32.4 Physical activity Yes (%) 18.9 20.3 20.6 21.2 19.3 24.3 No for physical problems (%) 3.4 5.3 6.8 7.1 9.0 10.8 No for other reasons (%) 77.7 74.4 72.6 71.8 71.7 64.9 Data are %, mean Ϯ SD, or median (interquartile range). Metabolic factors were defined as follows: obesity as BMI Ն25 kg/m2, high blood pressure as systolic blood pressure Ն130 mmHg and/or diastolic blood pressure Ն85 mmHg and/or medication, high blood glucose as nonfasting blood glucose Ն140 mg/dl and/or medication, high triglycerides as nonfasting triglycerides Ն200 mg/dl and/or medication, low HDL cholesterol as HDL cholesterol Յ40 md/dl for men or Յ50 mg/dl for women. the details of these cohorts have been were followed until 15 November 2000. ipants (2,999 men and 4,220 women) reported (10–15). Here, we analyzed The participation rate in this survey was were included in the analysis. data from NIPPON DATA90 because 76.5%. Of the 8,384 participants, 1,165 the baseline survey of NIPPON DATA80 were excluded because of a history of Follow-up survey does not include some important meta- coronary heart disease or stroke (n ϭ The underlying causes of death in the Na- bolic factors such as HDL cholesterol. 371), information missing at the base- tional Vital Statistics were coded accord- A total of 8,384 residents (3,504 line survey (n ϭ 636), and failure to ing to the ICD-9 until the end of 1994 and men and 4,880 women, aged Ն30 access because of incomplete residential according to the ICD-10 from the start of years) from 300 randomly selected dis- access information at the first survey 1995 until the end of 2000. Details of tricts participated in the survey and (n ϭ 158). The remaining 7,219 partic- these classifications are described else- where (10–15). The Institutional Review Board of Shiga University of Medical Sci- Table 2—Multiple adjusted HRs and 95% CIs according to the individual components of ence (No. 12–18, 2000) approved this metabolic risk factor in 2,999 men and 4,220 women aged >30 years (NIPPON DATA90, study. 1990–2000) Baseline examination Component of metabolic factor n HR (95% CI) Nonfasting blood samples were obtained Obesity 1,706 0.87 (0.60–1.27) at the baseline survey. The serum was sep- High blood glucose 579 1.45 (0.99–2.14) arated and centrifuged soon after blood High blood pressure 4,530 2.07 (1.21–3.52) coagulation. Plasma samples were col- High triglycerides 1,259 1.42 (0.95–2.11) lected in siliconized tubes containing so- Low HDL cholesterol 2,224 0.79 (0.56–1.12) dium fluoride and shipped to one HRs were estimated by a Cox proportional hazards model adjusted for sex, age, total cholesterol, smoking laboratory (SRL, Tokyo, Japan) for blood habits, drinking habits, physical activity, and other components of metabolic factors. Metabolic factors were measurements. Plasma glucose was mea- defined as in the footnote to Table 1. n is the number of participants who had the conditions. sured enzymatically. Serum triglycerides
1534 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kadota and Associates
Table 3—Multiple adjusted HRs and 95% CIs according to number of metabolic factors in higher in the group with more metabolic 2,999 men and 4,220 women >30 years (NIPPON DATA90, 1990–2000) factors, but the trend was not statistically ϭ significant (Ptrend 0.074). The relation- Number of Cardiovascular ship between numbers of risk factors and CVD mortality did not differ according to metabolic factors n Person-years deaths HR (95% CI) ϭ sex (Pinteraction 0.70). We therefore 0 1,604 15,740 8 1.00 (—) combined men and women in the follow- 1 2,657 25,398 67 1.93 (0.92–4.05) ing analyses. The tendency for HR to be 2 1,643 15,526 52 1.94 (0.91–4.13) higher in those with more metabolic fac- 3 942 8,999 29 2.12 (0.96–4.70) tors was similar for heart disease (three 4 336 3,167 15 2.44 (1.02–5.84) risk factors: HR 2.08 [95%CI 0.67–6.48]; 5 37 361 2 3.27 (0.69–15.50) four risk factors: 3.97[1.24–12.72]; five Ptrend 0.074 risk factors: not applicable) and stroke HRs were estimated by a Cox proportional hazards model adjusted for sex, age, total cholesterol, smoking (three risk factors: 2.07 [0.67–6.37]; four habits, drinking habits, and physical activity. Metabolic factors were defined as in the footnote to Table 1. risk factors: 1.23 [0.30–5.05]; five risk factors: 6.26 [CI, 1.13–34.60]) mortality. and total cholesterol were also measured compare the dichotomized variables to The HR tendency for all-cause mortality enzymatically, and HDL cholesterol was examine differences in baseline character- was similar, but the number of clustering measured after heparin-calcium precipi- istics of participants according to the metabolic factors was not significantly re- tation (16). numbers of clustering metabolic factors. lated to all-cause mortality (three risk fac- BMI was calculated as weight in kilo- The multivariate adjusted hazard ra- tors: 1.16 [0.81–1.65]; four risk factors: grams divided by the square of height in tio (HR) of all CVD mortality for each 1.18 [0.77–1.80]; five risk factors: 1.44 meters. Baseline blood pressure was mea- group was calculated using the Cox pro- [0.57–3.63]). sured by trained observers using a stan- portional hazards model adjusted for age, Table 4 shows multiple adjusted dard mercury sphygmomanometer on the sex, total cholesterol, smoking, drinking, HRs (95% CI) due to the number of right arm of seated participants. Public and physical activity category. When we metabolic factors except high blood glu- health nurses obtained information on calculated HR for an individual compo- cose stratified by high blood glucose. smoking, alcohol consumption, physical nent of a metabolic factor, we further ad- The HRs trended to increase in both activity, and medical history. We divided justed for other components of the groups (with and without high blood participants into four categories of smok- metabolic factor. We used nonobese par- glucose). The HR for CVD in partici- ers (never-smoked, ex-smoker, and cur- ticipants without any metabolic factor or pants with Ն3 metabolic factors but rent smoker Ͻ20 or Ն20 cigarettes/day) participants with neither a metabolic fac- high blood glucose was modest and not and six categories of drinking (never- tor nor high blood glucose as references in statistically significant. Conversely, HRs drinker; ex-drinker; and current drinker analyses stratified by obesity or high were obviously higher for participants of 1, 2, 3, and 4 gou of sake/day; 1 gou blood glucose (required component by with high blood glucose and Ն2 other [180 ml] is equivalent to 23 g of alcohol) the IDF and WHO, respectively). Because metabolic factors than those for partic- (11). We divided participants into three leaner participants also have a higher ipants with neither metabolic factors categories of physical activity (yes or no CVD mortality risk in Japan, we further nor high blood glucose. The risk in- for physical problems, and no for any analyzed a data subset excluding leaner creases were statistically significant. other reason). participants (BMI Ͻ18.5 kg/m2) (18,19). Table 4 also shows multiple adjusted We defined metabolic factors as fol- All CIs were estimated at the 95% HRs (95% CI) for CVD mortality accord- lows: obesity, BMI Ն25 kg/m2; high level. P Ͻ 0.05 was considered signifi- ing to the number of metabolic factors blood pressure, systolic blood pressure cant. The Statistical Package for the So- other than obesity stratified by obesity. Ն130 mmHg, diastolic blood pressure cial Sciences (version 11.0J; SPSS Japan, The relationship between HRs and the Ն85 mmHg, administration of antihyper- Tokyo, Japan) was used to perform all numbers of metabolic factors was positive tensive agents, or any combination of analyses. in both obese and nonobese groups. This these; and high blood glucose, serum glu- relationship was unchanged when partic- cose Ն140 mg/dl, medication for diabe- RESULTS — Table 1 shows the base- ipants with lower BMI (Ն18.5 kg/m2) tes, or both. Because our samples were line characteristics of the study partici- were excluded. nonfasting, the postload blood glucose pants according to the numbers of level for diagnosis of impaired glucose tol- metabolic factors. Total person-years CONCLUSIONS — We found that erance was Ն140 mg/dl (17). We defined were 69,170, and the mean follow-up pe- metabolic factor clustering was positively high triglycerides as nonfasting serum tri- riod was 9.6 years. During follow-up, 625 associated with CVD mortality in the gen- glyceride Ն200 mg/dl and also as taking participants died of all causes and 173 eral Japanese population. The risk in- medication for dyslipidemia. Low HDL died of CVD. Table 2 shows the multiple crease in participants with both high cholesterol was defined as serum HDL adjusted HRs and 95% CIs according to blood glucose and Ն2 metabolic factors cholesterol Յ40 mg/dl for men and Յ50 individual components of metabolic risk was significantly higher than in those with mg/dl for women. factors. neither high blood glucose nor metabolic Table 3 shows the number of deaths, risk factors. The risk in nonobese partici- Statistical analysis multiple adjusted HRs, and 95% CIs ac- pants with more metabolic factors was Continuous variables were compared us- cording to various numbers of metabolic also increased. ing ANOVA, and the 2 test was used to factors. The HRs for CVD mortality were Although investigating the relation-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1535 Metabolic factor clustering and CVD mortality
Table 4—Blood glucose category–specific multiple-adjusted HRs and 95% CIs according to number of metabolic factors other than high blood glucose and BMI category–specific multiple-adjusted HRs and 95% CIs according to the number of metabolic factors other than obesity in 2,999 men and 4,220 women aged >30 years (NIPPON DATA90, 1990–1999)
Number of Cardiovascular metabolic factors n Person-years deaths HR (95% CI) HR (95% CI) High blood glucose Without 0 1,604 15,740 8 1.00 (—) 1 2,600 24,867 65 1.91 (0.91–4.02) 2 1,451 13,796 45 1.99 (0.93–4.28) Ն3 985 9,522 22 1.61 (0.71–3.67) With 0 and 1 249 2,241 9 1.78 (0.68–4.67) 2 181 1,638 12 3.67 (1.49–9.03) Ն3 149 1,267 12 3.25 (1.31–8.06) BMI Ͻ25 kg/m2 0 1,604 15,740 8 1.00 (—) 1.00 (—) 1 2,474 23,576 67 1.98 (0.94–4.17) 2.14 (0.85–5.43) 2 993 9,282 37 1.95 (0.90–4.25) 2.24 (0.86–5.82) Ն3 442 4,108 24 2.83 (1.25–6.39) 3.35 (1.25–8.95) Ն25 kg/m2 0 and 1 833 8,045 15 1.75 (0.73–4.16) 2.12 (0.76–5.89) 2 551 5,339 10 1.47 (0.57–3.75) 1.78 (0.59–5.19) Ն3 322 3,080 12 2.37 (0.96–5.89) 2.84 (0.99–8.17) HRs were estimated by a Cox proportional hazards model adjusted for sex, age, total cholesterol, smoking habits, drinking habits, and physical activity. High blood glucose was defined as nonfasting blood glucose Ն140 mg/dl and/or medication. Metabolic factors were defined as follows: obesity as BMI Ն25 kg/m2, high blood pressure as systolic blood pressure Ն130 mmHg and/or diastolic blood pressure Ն85 mmHg and/or medication, high triglycerides as nonfasting triglycerides Ն200 mg/dl and/or medication, low HDL cholesterol as HDL cholesterol Յ40 mg/dl for men or Յ50 mg/dl for women. In the group with high blood glucose, 0 and 1 metabolic factors were combined because we found only two cardiovascular deaths in the group whose number of metabolic factors was 0. *HRs (95% CI) were analyzed for participants with BMI Ͼ18.5 kg/m2. Metabolic factors were defined as follows: high blood pressure as systolic blood pressure Ն130 mmHg and/or diastolic blood pressure Ն85 mmHg and/or medication, high blood glucose as nonfasting blood glucose Ն140 mg/dl and/or medication, high triglycerides as nonfasting triglycerides Ն200 mg/dl and/or medication, low HDL cholesterol as HDL cholesterol Յ40 mg/dl for men or Յ50 mg/dl for women. In the group with BMI Ն25 kg/m2, 0 and 1 metabolic factors were combined because we found no cardiovascular death in the group whose number of metabolic factors was 0. ship between metabolic factor clustering other metabolic syndrome components indicates visceral fat more accurately than and CVD mortality is important, prospec- (8). The IDF guidelines do not essentially BMI in terms of predicting diabetes (30). tive studies on the topic are still scarce. require insulin resistance because it is dif- However, we did not have any informa- On the basis of the NCEP and WHO def- ficult to measure in day-to-day clinical tion about waist circumference and used initions of metabolic syndrome, several practice (7,8). However, although in- BMI as it closely correlates with waist cir- investigators have reported that partici- creased waist circumference is an impor- cumference. Furthermore, BMI has been pants with metabolic syndrome or meta- tant component of metabolic syndrome, used to diagnose obesity in many epide- bolic factor clustering have a high HR of some individuals with multiple risk fac- miological studies of metabolic syndrome CVD mortality (20–25). Ford (26) sum- tors and an increased risk of CVD mortal- (22,23), indicating that BMI was accept- marized prospective cohort studies and ity have normal waist circumference able for our purposes. However, because reported that the HRs of CVD mortality (28,29). For example, Katzmarzyk et al. of the use of BMI, we might have under- were 1.65 [5% CI 1.38–1.99] according (28) reported that waist circumference is estimated the impact of obesity on CVD to the NCEP definition and 1.93 [1.39– a valuable component of metabolic syn- mortality. A similar study using waist cir- 2.67] according to the WHO definition, drome, but they also raised the concern cumference should clarify the relation. respectively. This result is consistent with that the IDF requirement of an increased The WHO guidelines indicate that our findings that participants with more waist circumference warranted caution the presence of diabetes, impaired glu- metabolic factors have a higher risk of because a large proportion of individuals cose tolerance, or insulin resistance is CVD mortality. Our results were also with normal waist circumference also necessary for a diagnosis of metabolic comparable with those of a prospective have multiple risk factors and an in- syndrome because this condition is con- study in Japan showing that the relative creased risk of mortality. sidered a special classification for those risk of cardiac diseases was 2.23 [1.14– We found here that nonobese partic- with the potential for diabetes (mani- 4.34] in participants with Ն3 metabolic ipants with three or more metabolic fac- fested as impaired glucose tolerance, im- factors compared with that in participants tors had significantly higher HRs for CVD paired fasting glucose, or insulin with Ͻ3 metabolic factors (27). death and that their risk was similar to resistance determined using the hyperin- The IDF definition requires obesity that of obese participants with the corre- sulinemic-euglycemic clamp) (1,7). Here, for diagnosis of metabolic syndrome. sponding number of metabolic factors. we also stratified participants according These guidelines explain that central (ab- Thus, a proportion of high-risk partici- to blood glucose level and found that the dominal) obesity is a prerequisite for this pants might be overlooked if obesity is a HR was higher among those with than diagnosis because it is easy to assess and diagnostic requirement for metabolic syn- among those without high blood glucose. independently associated with each of the drome. Waist circumference supposedly These findings suggest that glucose toler-
1536 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kadota and Associates ance plays an important role in CVD mor- body obesity, glucose intolerance, hyper- Hayakawa T, Kita Y, Kadowaki T, Oka- tality. Some reports have shown higher triglyceridemia, and hypertension. Arch mura T, Minowa M, Iimura O, NIPPON HRs with use of the WHO rather than the Intern Med 149:1514–1520, 1989 DATA80 Research Group: Cigarette NCEP definition of metabolic syndrome. 4. DeFronzo RA, Ferrannini E: Insulin resis- smoking as a risk factor for stroke death in This result means that the participants tance: a multifaceted syndrome responsi- Japan. Stroke 35:1836–1841, 2004 ble for NIDDM, obesity, hypertension, 15. Nakamura Y, Yamamoto T, Okamura T, with impaired glucose tolerance have dyslipidemia, and atherosclerotic cardio- Kadowaki T, Hayakawa T, Kita Y, Saitoh higher HRs, a finding that the present re- vascular disease. Diabetes Care 14:173– S, Okayama A, Ueshima H, NIPPON sults support (26). However, several par- 194, 1991 DATA80 Research Group: Combined car- ticipants with clustering of metabolic 5. Fujioka S, Matsuzawa Y, Tokunaga K, Ta- diovascular risk factors and outcome: factors other than impaired glucose toler- rui S: Contribution of intra-abdominal NIPPON DATA80, 1980–1994. Circ J 70: ance also had an increased risk of CVD visceral fat accumulation to the impair- 960–964, 2006 mortality. ment of glucose and lipid metabolism in 16. Nakamura M, Sato S, Shimamoto T: Im- Some limitations other than using human obesity. Metabolism 36:54–59, provement in Japanese clinical laboratory BMI should be noted about the present 1987 measurements of total cholesterol and study. First, we used nonfasting blood 6. Executive summary of the Third Report of HDL-cholesterol by the US Cholesterol the National Cholesterol Education Pro- Reference Method Laboratory Network. J samples and thus we might have misclas- gram (NCEP) Expert Panel on Detection, Atheroscler Thromb 10:145–153, 2003 sified participants with high blood glu- Evaluation, and Treatment of High Blood 17. American Diabetes Association: Diagnosis cose or hypertriglyceridemia. Second, we Cholesterol in Adults (Adult Treatment and classification of diabetes mellitus. Di- did not adjust for socioeconomic status Panel III). JAMA 285:2486–2497, 2001 abetes Care 28 (Suppl. 1):S37–S42, 2005 because relevant information was not 7. Alberti KG, Zimmet P: Definition, diagno- 18. Cui R, Iso H, Toyoshima H, Date C, available. However, all Japanese are cov- sis and classification of diabetes mellitus Yamamoto A, Kikuchi S, Kondo T, ered by the national health insurance pro- and its complications. Part 1: diagnosis Watanabe Y, Koizumi A, Wada Y, Inaba Y, gram and socioeconomic status does not and classification of diabetes mellitus pro- Tamakoshi A, JACC Study Group: Body affect access to treatment. Therefore, the visional report of a WHO consultation. mass index and mortality from cardiovas- impact of socioeconomic status on our Diabet Med 15:539–553, 1998 cular disease among Japanese men and findings should be minimal. 8. Alberti KGMM, Zimmet P, Shaw J: Meta- women: the JACC Study. Stroke 36:1377– bolic syndrome—a new world-wide defi- 1382, 2005 In summary, the CVD risk was obvi- nition: a consensus statement from the 19. Oki I, Nakamura Y, Okamura T, ously higher among individuals with than International Diabetes Federation. Diabet Okayama A, Hayakawa T, Kita Y, among those without high blood glucose Med 23:469–480, 2006 Ueshima H: Body mass index and risk of and multiple metabolic risk factors, sug- 9. The Examination Committee of Criteria stroke mortality among a random sample gesting that high blood glucose plays an for ‘Obesity Disease’ in Japan, Japan Soci- of Japanese adults: 19-year follow-up of important role in CVD mortality. Con- ety for the Study of Obesity: New criteria NIPPON DATA80. Cerebrovasc Dis 22: versely, the prevalence of nonobese par- for ‘obesity disease’ in Japan. Circ J 66: 404–415, 2006 ticipants with several metabolic factors 987–992, 2002 20. Isomaa B, Almgren P, Tuomi T, Forsen B, was quite high and their CVD risk was 10. Okamura T, Hayakawa T, Kadowaki T, Lahti K, Nissen M, Taskinen MR, Groop high. Thus, metabolic factors should be Kita Y, Okayama A, Ueshima H, NIPPON L: Cardiovascular morbidity and mortal- DATA90 Research Group: The inverse re- ity associated with the metabolic syn- carefully considered and appropriately lationship between serum high-density drome. Diabetes Care 25:683–689, 2001 managed even among individuals with a Ͻ lipoprotein cholesterol and all-cause mor- 21. Wilson PWF, Kannel WB, Silbershatz H, BMI 25. tality in a 9.6-year follow up study in the D’Agostino RB: Clustering of metabolic Japanese general population. Atheroscle- factors and coronary heart disease. Arch rosis 184:143–150, 2006 Intern Med 159:1104–1109, 1999 Acknowledgments— This study was sup- 11. Hozawa A, Okamura T, Kadowaki T, Mu- 22. Hu G, Qing Q, Tuomilehto J, Balkau B, ported by a grant-in-aid from the Ministry of rakami Y, Nakamura K, Hayakawa T, Kita Borch-Johnsen K, Pyorala K, DECODE Health and Welfare under the auspices of the Y, Nakamura Y, Okayama A, Ueshima H, Study Group: Prevalence of the metabolic Japanese Association for Cerebro-cardiovas- NIPPON DATA90 Research Group: syndrome and its relation to all-cause and cular Disease Control, a Research Grant for ␥-Glutamyltransferase predicts cardio- cardiovascular mortality in nondiabetic Cardiovascular Diseases (7A-2) from the Min- vascular death among Japanese women. European men and women. Arch Intern istry of Health, Labor and Welfare, and a Atherosclerosis. In press Med 164:1066–1076, 2004 Health and Labor Sciences Research Grant, Ja- 12. Nakamura K, Okamura T, Hayakawa T, 23. 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Geneva, Switzerland, World NIPPON DATA90 Research Group: onary heart disease, stroke, and type 2 Health Organization, 1999 Chronic kidney disease is a risk factor for diabetes mellitus. Arch Intern Med 165: 2. Reaven GM: Banting Lecture: Role of in- cardiovascular death in a community- 2644–2650, 2005 sulin resistance in human disease. Diabe- based population in Japan: NIPPON 25. McNeil AM, Rosamond WD, Girman C, tes 37:1595–1607, 1988 DATA90. Circ J 70:954–959, 2006 Golden SH, Schmidt MI, East HE, Ballan- 3. Kaplan NM: The deadly quartet: upper- 14. Ueshima H, Choudhury SR, Okayama A, tyne CM, Hess G: The metabolic syn-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1537 Metabolic factor clustering and CVD mortality
drome and 11-year risk of incident of metabolic syndrome defined by the Na- drome by the International Diabetes Fed- cardiovascular disease in the atheroscle- tional Cholesterol Education Program- eration is less likely to identify rosis risk in communities study. Diabetes Adult Treatment Panel III to Japanese metabolically abnormal but non-obese in- Care 28: 385–390, 2005 men—the Tannno and Sobetsu Study. dividuals than the definition by the re- 26. Ford ES: Risks for all-cause mortality, car- Hypertens Res 28:203–208, 2005 vised National Cholesterol Education diovascular disease, and diabetes associ- 28. Katzmarzyk PT, Janssen I, Ross R, Church Program: the Korea NHANES Study. Int J ated with the metabolic syndrome: a TS, Blair SN: The importance of waist cir- Obes (Lond) 31:528–534, 2007 summary of the evidence. Diabetes Care cumference in the definition of metabolic 30. Ohnishi H, Saitoh S, Takagi S, Katoh N, 28:1769–1778, 2005 syndrome: prospective analyses of mor- Chiba Y, Akasaka H, Nakamura Y, Shi- 27. Takeuchi H, Saitoh S, Takagi S, Ohnishi tality in men. Diabetes Care 29:404–409, mamoto K: Incidence of type 2 diabetes in H, Ohhata J, Isobe T, Shimamoto K: Met- 2006 individuals with central obesity in a rural abolic syndrome and cardiac disease in 29. Yoon YS, Lee ES, Park C, Lee S, Oh SW: Japanese population. Diabetes Care Japanese men: applicability of the concept The new definition of metabolic syn- 29:1128–1129, 2006
1538 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Exercise Capacity and Body Mass as Predictors of Mortality Among Male Veterans With Type 2 Diabetes
PAUL A. MCAULEY, PHD SWEE Y. TAN, MD runs contrary to current clinical beliefs, JONATHAN N. MYERS, PHD VICTOR F. FROELICHER, MD we decided to explore this further using a JOSHUA P. ABELLA, MD subpopulation of male veterans with doc- umented type 2 diabetes from our exer- cise testing database. OBJECTIVE — To demonstrate the relation of exercise capacity and BMI to mortality in a The primary aims of this study of population of male veterans with type 2 diabetes. male veterans with type 2 diabetes were to examine 1) the independent risks of mor- RESEARCH DESIGN AND METHODS — After excluding two underweight patients tality associated with low fitness and (BMI Ͻ18.5 kg/m2), the study population comprised 831 consecutive patients with type 2 Ϯ adult-onset obesity and 2) the associa- diabetes (mean age 61 9 years) referred for exercise testing for clinical reasons between 1995 tions among fitness, BMI, and mortality. and 2006. Exercise capacity was determined from a maximal exercise test and measured in metabolic equivalents (METs). Patients were classified both according to BMI category (18.5– 24.9, 25.0–29.9, and Ն30 kg/m2) and by exercise capacity (Ͻ5.0 or Ն5.0 maximal METs). The association among exercise capacity, BMI, other clinical variables, and all-cause mortality was RESEARCH DESIGN AND assessed by Cox proportional hazards. Study participants were followed for mortality up to 30 METHODS — The Veterans Exercise June 2006. Testing Study (VETS) is a prospective ep- idemiologic investigation of Ͼ7,000 vet- RESULTS — During a mean follow-up of 4.8 Ϯ 3.0 years, 112 patients died, for an average eran patients referred to two university- annual mortality rate of 2.2%. Each 1-MET increase in exercise capacity conferred a 10% survival ϭ affiliated Veterans Affairs medical centers benefit (hazard ratio 0.90 [95% CI 0.82–0.98]; P 0.01), but BMI was not significantly (Long Beach VA, from 1987 to 1991; Palo associated with mortality. After adjustment for age, ethnicity, examination year, BMI, presence of cardiovascular disease (CVD), and CVD risk factors, diabetic patients achieving Ͻ5 maximal Alto VA, from 1992 to 2006). From this METs were 70% more likely to die (1.70 [1.13–2.54]) than those achieving Ն5 maximal METs. database, a total of 869 men were recog- nized as having type 2 diabetes. (Cases of CONCLUSIONS — There was a strong inverse association between exercise capacity and type 2 diabetes could only be docu- mortality in this cohort of men with documented diabetes, and this relationship was independent mented from 1995 onwards; hence, all of BMI. participants in the current study were evaluated at the Palo Alto VA.) Of these, Diabetes Care 30:1539–1543, 2007 36 subjects were excluded because of missing data on height, weight, or exer- ndividuals volunteering and qualifying risk of mortality associated with low fit- cise capacity. In addition, two patients for military service differ from the gen- ness and obesity developing in later life. were excluded because they were under- I eral population in several respects; While obesity is a well-recognized risk weight (BMI Ͻ18.5 kg/m2). Therefore, most notably, they had to have met fitness factor for the development of type 2 dia- participants for the present analysis were and weight criteria at the time of their en- betes (2), it is uncertain whether obesity is 831 men with type 2 diabetes who com- listment and must have maintained these an independent mortality predictor in pleted a baseline medical examination levels for the duration of their service. For people already having the disease. More- and maximal exercise test at least once at example, the maximum allowable over, the association of fitness with mor- the Palo Alto VA Health Care System be- weights for the various branches of ser- tality in patients with diabetes remains tween 1995 and 2006. Type 2 diabetes vice translate into a BMI of 25.9–29.9 largely unexplored. was defined as a physician-diagnosed his- kg/m2 (1). Therefore, obesity, when Recent reports have suggested that tory of type 2 diabetes, treatment with an present in a veteran patient population, mortality risk in men with type 2 diabetes oral hypoglycemic agent, or a fasting must have developed after discharge, thus is independent of BMI after adjustment plasma glucose level Ն7.0 mmol/l (Ն126 providing an opportunity to evaluate the for fitness (3,4). Because this observation mg/dl) at baseline (5). Only two patients ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● were identified as receiving insulin treat- From the Cardiology Division, VA Palo Alto Health Care System/Stanford University, Palo Alto, California. ment at baseline. The study population Address correspondence and reprint requests to Paul McAuley, PHD, VA Palo Alto Health Care System, consisted of 62% non-Hispanic whites, Cardiology 111C, 3801 Miranda Ave., Palo Alto, CA 94304. E-mail: [email protected]. 15% Hispanics, and 14% African Ameri- Received for publication 22 November 2006 and accepted in revised form 23 February 2007. cans who ranged in age from 23 to 88 Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2397. Ϯ Abbreviations: ACLS, Aerobics Center Longitudinal Study; CVD, cardiovascular disease; MET, metabolic years (average 61.3 9.3). All subjects equivalent; VETS, Veterans Exercise Testing Study. gave informed consent for participation A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion in the study. Additional information on factors for many substances. study methods and subject characteristics © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby of this cohort have been published else- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. where (6,7).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1539 Mortality predictors among veterans with diabetes
Mortality surveillance Security (12) and as we have previously ing for age, ethnicity, and examination Study participants were followed from reported (6,13). year (Table 2), each 1-MET increase in their baseline examination until their exercise capacity was associated with a death or until 30 June 2006. The Califor- Statistical analysis 10% reduction in mortality (hazard ratio nia Health Department Service and Social The statistical software NCSS (Kaysville, [HR] 0.90 [95% CI 0.82–0.98]). The HR Security Death Indexes were used to as- UT) was used for all statistical analyses. for mortality associated with a low exer- certain the vital status of each subject. Ac- The mean and SD of each variable was cise capacity (Ͻ5 METs) was 1.80 (1.21– curacy of deaths was reviewed by two calculated with participants categorized 2.69), and after further adjustment for clinicians blinded to exercise test results as survivors or decedents. Cox propor- BMI, CVD, and CVD risk factors, the HR and confirmed using the Veterans Affairs tional hazards analyses were used to as- was 1.70 (1.13–2.54). The only other computerized medical records. Thus, to sess the independent and joint effects of predictors of mortality were current our knowledge, no patients were lost to fitness, BMI, and prevalent cardiovascular smoking (1.93 [1.22–3.05]) and CVD follow-up. disease (CVD) and CVD risk factors at (1.72 [1.17–2.52]). Conversely, BMI was baseline with the risk of all-cause mortality. not a significant predictor of mortality Clinical evaluation and exercise To evaluate the relation of exercise ca- (0.98 [0.95–1.02] per BMI unit). testing pacity to mortality, Ͻ5 maximal METs To address the effects of current Maximal exercise testing was performed was used as the cut point for low fitness smoking and preexisting CVD as con- using an individualized ramp protocol (8) and patients classified accordingly. Sur- founding variables, we performed three on either a treadmill (n ϭ 780) or an elec- vival analysis was performed using separate analyses on the variables from tromagnetically braked cycle ergometer Kaplan-Meier curves to compare mortal- Table 2 by 1) adding current smoking to (n ϭ 51). Before ramp testing, patients ity rates by Ͻ5 and Ն5 maximal METs the adjusted HRs; 2) calculating age-, eth- completed a Veterans Specific Activity and within each BMI category. Separate nicity-, and examination year–adjusted Questionnaire (VSAQ) to estimate their survival analyses were performed to com- HRs in the nonsmoking subgroup (n ϭ exercise capacity, which allowed most pa- pare mortality rates by BMI category for 698); and 3) calculating age-, ethnicity-, tients to reach maximal exercise within each fitness classification. The Cox- and examination year–adjusted HRs in the recommended range of 8–12 min (9). Mantel probability test was used to test for the subgroup not having preexisting CVD A microcomputer automatically in- significant differences between groups, (n ϭ 606). Further adjustment for current creased workload after an individualized and P Ͻ 0.05 was accepted as statistically smoking strengthened the CVD-mortality walking speed (treadmill) or watts (cycle) significant. association (HR 1.85 [95% CI 1.25– was established and predicted values for 2.72]), and compared with the main co- maximal exercise capacity were entered. RESULTS — During a mean follow-up hort, low fitness was a stronger mortality Immediately before the exercise test, of 4.8 Ϯ 3.0 years, 112 deaths were re- predictor in the subgroup not having pre- height and weight were measured using corded. The general characteristics of the existing CVD (1.97 [1.12–3.46]). Other- standard procedures and BMI calculated study population, grouped by survival wise, the results were not appreciably as weight in kilograms divided by the status, are presented in Table 1. Approx- affected. square of height in meters. Subjects were imately one-half of these diabetic patients To further assess associations among assigned to categories of normal weight were obese (BMI Ն30.0 kg/m2), 74% had fitness, BMI, and mortality, we classified (BMI 18.5–24.9 kg/m2), overweight hypertension (diastolic blood pressure patients according to Ͻ5 and Ն5 maxi- (25.0–29.9 kg/m2), and obese (Ն30.0 Ն90 mmHg and/or systolic blood pres- mal METs. We identified 167 patients kg/m2). sure Ն140 mmHg), 49% had hypercho- achieving Ͻ5 maximal METs, which rep- Blood pressure was recorded on alter- lesterolemia (Ն5.6 mmol/l), and 27% had resented the least fit 20% of all partici- nate minutes throughout the test, and a CVD (history of myocardial infarction, pants. Kaplan-Meier survival analyses 12-lead electrocardiogram was recorded congestive heart failure, stroke, and/or were performed to compare mortality each minute. The patient’s subjective coronary bypass surgery). In general, sur- rates by fitness classification for each BMI level of exertion was assessed by the Borg viving patients were younger and fitter, category (Fig. 1). Next, we generated 6-20 scale (10). Standard clinical criteria had a significantly higher BMI, included a Kaplan-Meier survival plots by BMI cate- for terminating the tests (e.g., fall in sys- lower percentage of current smokers, and gories for each fitness classification (Fig. tolic blood pressure, ST-segment depres- had a lower prevalence of CVD and a 2). Survival rates were higher among sub- sion Ͼ2 mm, dangerous arrhythmias) higher prevalence of hypercholesterol- jects with higher levels of fitness for each were followed (11), but no heart rate or emia than decedents. Low fitness (Ͻ5 weight classification, but weight classifi- time limit was imposed, and a maximal METs) was less than half as prevalent cation did not significantly affect mortal- effort was encouraged. Patients were dis- among surviving patients compared with ity risk among patients with Ն5 maximal couraged from holding onto the handrails those who had died (17 vs. 39%, respec- METs. However, among patients with low for support. Standardized equations were tively; P Ͻ 0.001). Age-predicted mean exercise capacity, overweight and obesity used to determine the calculated peak maximum heart rates were 86 and 82% were protective. metabolic equivalents (METs) on the ba- for survivors and decedents, respectively. sis of treadmill speed and grade or cycle The mean peak rating of perceived exer- CONCLUSIONS — Our main find- ergometer watts (11). Exercise capacity tion (Borg 6-20 scale) was 17, which did ing was that fitness is a powerful and in- was expressed as the maximal MET value not differ significantly between survival dependent predictor of mortality in men attained during the exercise test. Low fit- status categories, suggesting that the ex- with diabetes, and this association is in- ness was defined as Ͻ5 METs according ercise test was maximal for most patients. dependent of BMI. We recently reported to the disability evaluation under Social In a multivariate model after adjust- an obesity paradox (i.e., higher BMI is as-
1540 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 McAuley and Associates
Table 1—Baseline characteristics of 831 men with type 2 diabetes grouped by survival status, VETS 1995–2006 participants
Total Survived Died P n (%) 831 719 (86.5) 112 (13.5) Age (years) 61.3 Ϯ 9.3 60.5 Ϯ 9.0 66.3 Ϯ 10.0 Ͻ0.001 Age Ն65 years (%) 34.8 31.2 58.0 Ͻ0.001 Non-Hispanic white ethnicity (%) 61.7 61.4 63.4 0.69 BMI (kg/m2) 31.1 Ϯ 5.9 31.4 Ϯ 6.0 29.2 Ϯ 4.7 Ͻ0.001 BMI Ն35 kg/m2 (%) 20.6 21.4 15.2 0.1 Resting heart rate (beats/min) 79.1 Ϯ 26.7 79.6 Ϯ 28.5 76.6 Ϯ 12.3 0.28 Resting systolic BP (mmHg) 133.2 Ϯ 18.8 132.7 Ϯ 18.5 136.4 Ϯ 20.6 0.08 Resting diastolic BP (mmHg) 79.1 Ϯ 10.8 79.4 Ϯ 10.7 77.1 Ϯ 11.0 0.03 Cigarette smoking (%) Never 30.1 31.3 22.3 0.05 Past 53.9 53.7 55.4 0.74 Current 16.0 15.0 22.3 0.05 Hypertension (%) 73.8 74.2 71.4 0.53 Hypercholesterolemia (%) 49.0 50.5 39.3 0.03 Prevalent CVD (%)* 27.3 24.4 45.5 Ͻ0.001 Exercise capacity (METs)† 7.3 Ϯ 2.8 7.5 Ϯ 2.7 6.1 Ϯ 2.9 Ͻ0.001 Ͻ5 METs (%) 20.3 17.3 39.3 Ͻ0.001 Peak systolic BP (mmHg) 176.3 Ϯ 26.7 177.1 Ϯ 26.4 170.4 Ϯ 28.7 0.02 Peak heart rate (beats/min) 135.5 Ϯ 21.9 137.0 Ϯ 21.9 125.7 Ϯ 19.2 Ͻ0.001 Perceived exertion (Borg scale) 16.7 Ϯ 2.1 16.7 Ϯ 2.1 16.9 Ϯ 2.1 0.36 Data are means Ϯ SD unless otherwise indicated. *CVD includes history of myocardial infarction, congestive heart failure, stroke, and/or coronary bypass surgery. †1 MET ϭ 3.5 ml kgϪ1 minϪ1 oxygen uptake; exercise capacity is the maximal METs achieved during the exercise test and is calculated from treadmill speed and grade or cycle ergometer watts using standard equations. BP, blood pressure. sociated with lower mortality) among a powerful predictor of mortality, as we current study. Veterans differ from other 6,876 patients from VETS and found that reported here. In contrast, however, we populations of patients in several re- each 1-unit increment in BMI conferred a found an insignificant association be- spects. One of the most prominent differ- 3% survival benefit (14). However, BMI tween age-, ethnicity-, and examination ences is the meeting of selection criteria at (as a continuous variable) was neither year–adjusted BMI and mortality. This the time of enlistment. These criteria in- protective nor predictive in the current disparate finding is perhaps due to popu- clude, among other things, minimum study of 831 male veterans with type 2 lation differences, namely, that all our height requirements, maximum weight diabetes. subjects were clinically referred, older requirements, and exclusion of recruits Among patients with type 2 diabetes, (mean age 61.3 Ϯ 9.3 vs. 49.3 Ϯ 9.5 years having certain preexisting health prob- CVD accounts for Ͼ75% of total mortal- in the ACLS), more ethnically diverse, lems. Consequently, individuals having ity (15), and hypertension, dyslipidemia, and veterans. This latter factor—the “vet- obesity in early life are excluded from our and smoking are each independent pre- eran effect”—may explain the different ef- population. It is noteworthy in this con- dictors of CVD mortality (16,17). How- fects of BMI in the ACLS versus the text that pediatric obesity has been shown ever, the relation of obesity to CVD mortality remains controversial. For ex- Table 2—Age-, ethnicity-, and examination year–adjusted HRs of all-cause mortality accord- ample, the UK Prospective Diabetes Study ing to exercise capacity, BMI, and other clinical variables for 831 men with diabetes, VETS (UKPDS) reported that high BMI was not 1995–2006 a major risk factor for coronary artery dis- ease among patients with diabetes (18). We were not able to ascertain cause- Variable HR (95% CI) P specific mortality in the current study. Maximal METs (per 1-MET increment)* 0.90 (0.82–0.98) 0.014 Nevertheless, in our cohort of men with BMI (per 1-unit increment) 0.98 (0.94–1.02) 0.27 type 2 diabetes, those who were over- Hypertension 1.03 (0.69–1.57) 0.86 weight or obese were not at greater risk of Hypercholesterolemia 1.07 (0.73–1.57) 0.74 mortality than patients of normal weight, Smoking and this relationship was independent of Current 1.93 (1.22–3.05) 0.005 fitness. Past 0.79 (0.55–1.16) 0.24 The Aerobics Center Longitudinal CVD† 1.72 (1.17–2.52) 0.006 Study (ACLS) of men with diabetes found Low fitness (Ͻ5 maximal METs) 1.80 (1.21–2.69) 0.004 a positive association between BMI and *1 MET ϭ 3.5 ml kgϪ1 minϪ1 oxygen uptake; exercise capacity is maximal METs achieved during the all-cause mortality, but this association exercise test and is calculated from treadmill speed and grade or cycle ergometer watts using standard was not significant when adjusted for fit- equations. †CVD includes history of myocardial infarction, congestive heart failure, stroke, and/or coronary ness (3). They also found that fitness was bypass surgery.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1541 Mortality predictors among veterans with diabetes
pared with obese (Ն30.0 kg/m2) patients (P Ͻ 0.01). However, we insert a note of caution here, as the normal-weight group comprised only 9% of the study popula- tion. Regardless, among the subgroup with low fitness (representing 20% of the cohort), those classified as overweight (25.0–29.9 kg/m2) or obese (Ն30.0 kg/ m2) had improved survival compared with those of normal weight (18.5–24.9 kg/m2). An obesity paradox was therefore evident among diabetic veterans with low fitness but not among those with higher levels of fitness. Our study has several strengths, in- cluding 1) all subjects underwent an ex- tensive physical examination, which provides thorough information on the presence or absence of baseline disease; 2) cardiorespiratory fitness was determined by maximal exercise testing; and 3) our sample size consisted of Ͼ800 men with documented type 2 diabetes with an av- Figure 1— A: Survival curves illustrating the probability of surviving with different levels of erage follow-up of nearly 5 years. How- exercise capacity from 831 men with type 2 diabetes (Ͻ5 METs vs. Ն5 METs, P Ͻ 0.001). B: ever, a lack of information on oral Survival curves in 78 normal-weight (BMI 18.5–24.9 kg/m2) men with type 2 diabetes (Ͻ5 METs Ն Ͻ 2 hypoglycemic medication use (e.g., met- vs. 5 METs, P 0.001). C: Survival curves in 330 overweight (BMI 25.0–29.9 kg/m ) men with formin) limits this investigation. Another type 2 diabetes (Ͻ5 METs vs. Ն5 METs, P Ͻ 0.01). D: Survival curves in 423 obese (BMI Ն30.0 kg/m2) men with type 2 diabetes (Ͻ5 METs vs. Ն5 METs, P Ͻ 0.05). The area under the survival limitation of our study is that it included curves is the total life expectancy for populations with an exercise capacity of Ͻ5 METs or an only men who had prior military service exercise capacity of Ն5 METs (VETS 1995–2006). to have a greater impact on disease out- comes than obesity that develops in later life. For example, Barker et al. (19) re- cently examined the effects of birth weight and childhood growth rates on subsequent disease risk in Finnish men and women. They reported that the rate of childhood gain in BMI between 2 and 11 years of age was strongly related to the risk of coronary events and insulin resis- tance in later life. Such individuals would be excluded from the veteran population by reason of weight. Finally, the influence of self-selection in our population must be considered. Individuals volunteering and qualifying for military service may be more likely to be predisposed toward physical fitness or have other health at- tributes than those avoiding military service. We found that the inability to achieve 5 maximal METs was as powerful a mor- tality predictor as CVD and smoking and Figure 2— A: Survival curves illustrating the probability of surviving with different weight was a stronger predictor of mortality than ϭ more traditional risk factors, such as hy- categories from 831 men with type 2 diabetes (overweight vs. normal weight, P 0.18; obese vs. normal weight, P Ͻ 0.01). B: Survival curves in 664 men with type 2 diabetes with an exercise percholesterolemia and hypertension. capacity of Ն5 METs (overweight vs. normal weight, P ϭ 0.9; obese vs. normal weight, P ϭ 0.56). When considering BMI as a categorical C: Survival curves in 167 men with type 2 diabetes with an exercise capacity of Ͻ5 METs variable, the probability of surviving was (overweight vs. normal weight, P Ͻ 0.05; obese vs. normal weight, P Ͻ 0.01). The area under the significantly lower among patients of nor- survival curves is the total life expectancy for normal weight (BMI 18.5–24.9 kg/m2), overweight mal weight (BMI 18.5–24.9 kg/m2) com- (25.0–29.9 kg/m2), or obese (Ն30.0 kg/m2) populations (VETS 1995–2006).
1542 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 McAuley and Associates and were referred for exercise testing for Med 113:486–490, 2002 Williams & Wilkins, 2005 clinical reasons. Thus, we evaluated sur- 2. Eckel RH, Kahn R, Robertson RM, Rizza 12. Social Security Administration: Disability vival in the context of a clinical popula- RA: Preventing cardiovascular disease and Evaluation Under Social Security. Balti- tion, many of whom were limited by diabetes: a call to action from the Ameri- more, MD, Social Security Administra- symptoms, medications, and other factors can Diabetes Association and the Ameri- tion, 2003 (SSA Publ. no. 64-039, ICN can Heart Association. Diabetes Care 29: related to CVD. Any effort to predict mor- 468600) 1697–1699, 2006 13. McAuley P, Myers J, Abella J, Froelicher tality by using fitness, BMI, or clinical or 3. Church TS, Cheng YJ, Earnest CP, Barlow V: Evaluation of a specific activity ques- demographic data should be considered CE, Gibbons LW, Priest EL, Blair SN: Ex- tionnaire to predict mortality in men re- population specific. Therefore, our re- ercise capacity and body composition as ferred for exercise testing. Am Heart J 151: sults may not apply to more general or predictors of mortality among men with 890.e1–e7, 2006 healthier populations, and while these re- diabetes. Diabetes Care 27:83–88, 2004 14. McAuley P, Myers J, Abella J, Froelicher sults may urge exercise and increased fit- 4. Church TS, LaMonte MJ, Barlow CE, Blair V: Body mass, fitness and survival in vet- ness as accepted clinical treatment for SN: Cardiorespiratory fitness and body eran patients: another obesity paradox? type 2 diabetes, long-term effects of exer- mass index as predictors of cardiovascular Am J Med. In press cise and fitness are virtually unknown. In mortality among men with diabetes. Arch 15. 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BMJ 316:823– cused on increasing physical activity and elicher VF: Comparison of the ramp ver- 828, 1998 fitness in overweight/obese patients with sus standard exercise protocols. J Am Coll 19. Barker DJP, Osmond C, Forsen TJ, Kajan- tie E, Eriksson JG: Trajectories of growth type 2 diabetes. Accordingly, the benefits Cardiol 17:1334–1342, 1991 9. Myers J, Do D, Herbert W, Ribisl P, Fro- among children who have coronary associated with increased fitness— events as adults. N Engl J Med 353:1802– regardless of whether weight loss is elicher VF: A nomogram to predict exer- cise capacity from a specific activity 1809, 2005 achieved—should be stressed. questionnaire and clinical data. Am J Car- 20. Romero-Corral A, Montori VM, Somers diol 73:591–596, 1994 VK, Korinek J, Thomas RJ, Allison TG, 10. Borg GAV: Psychophysical bases of per- Mookadam R, Lopez-Jimenez F: Associa- References ceived exertion. Med Sci Sports Exerc 14: tion of bodyweight with total mortality 1. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1543 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
What Is the Best Predictor of Future Type 2 Diabetes?
MUHAMMAD A. ABDUL-GHANI, MD, PHD RALPH A. DEFRONZO, MD shown to reduce conversion rate from KEN WILLIAMS, MS MICHAEL STERN, MD IGT to diabetes by 31% (3), 75% (6), and 25% (7), respectively. The results of these long-term, prospective studies emphasize OBJECTIVE — We sought to assess insulin secretion/insulin resistance index in predicting the importance of identifying subjects at the risk for future type 2 diabetes high risk for type 2 diabetes in order to offer them an intervention program that RESEARCH DESIGN AND METHODS — A total of 1,551 nondiabetic subjects from will prevent/halt their progression to the San Antonio Heart Study received an oral glucose tolerance test (OGTT) with measurement overt diabetes. Demonstration of IGT of plasma glucose and insulin concentrations at 0, 30, 60, and 120 min at baseline and after 7–8 most commonly has been used to identify years of follow-up. Insulin secretion/insulin resistance index was calculated as the product of ⌬ ⌬ ⌬ ⌬ subjects at high risk for the development Matsuda index and I0–30/ G0–30 or I0–120/ G0–120. The discriminatory power of various prediction models for development of type 2 diabetes was tested with the area under the of type 2 diabetes. Indeed, all published receiver-operating characteristic (ROC) curve. studies that have evaluated intervention strategies for preventing type 2 diabetes RESULTS — Insulin secretion/insulin resistance index (0- to 30- and 0- to 120-min time have recruited subjects with IGT (4–7). periods) had the greatest areas under the ROC curve (0.85 and 0.86, respectively), which were However, in prospective epidemiological significantly greater than the 2-h plasma glucose concentration during the OGTT or the San studies, only 30–40% of subjects with Ͻ Ͻ Antonio Diabetes Prediction Model (SADPM) (P 0.001 and P 0.0001, respectively). A model IGT ultimately develop type 2 diabetes based on the combination of the SADPM and a modified version of the insulin secretion/insulin (8–10). Furthermore, ϳ40% of subjects resistance index or 1-h plasma glucose concentration had equal power to predict the risk for who develop type 2 diabetes have normal future type 2 diabetes compared with the insulin secretion/insulin resistance index. glucose tolerance (NGT) at baseline (8). CONCLUSIONS — The insulin secretion/insulin resistance index is useful as a predictor of This limits the use of IGT as the sole future development of type 2 diabetes. A model based on the combination of the SADPM and means to identify subjects at high risk for either a modified version of the insulin secretion/insulin resistance index or 1-h plasma glucose type 2 diabetes. Such observations have concentration can equally predict future type 2 diabetes. prompted the search for alternative mod- els that more accurately identify subjects Diabetes Care 30:1544–1548, 2007 at high risk for future type 2 diabetes. A number of models for identifying high- he worldwide prevalence of type 2 declined by 14%, while it increased by risk subjects have been proposed (11– diabetes is increasing at epidemic 54% in individuals with type 2 diabetes 13). These models are based on risk T proportions. In the year 2000, there over the same period (2). factors for type 2 diabetes, including age, were 150 million individuals with type 2 Recent clinical trials have demon- ethnicity, obesity, lipid profile, blood diabetes worldwide, and this number is strated that, in subjects at high risk for pressure, and fasting plasma glucose con- expected to double in the next 25 years type 2 diabetes, both lifestyle changes and centration. Although all of these models (1). This increase in type 2 diabetes prev- pharmacological intervention can reduce have value for identifying subjects at risk alence is also associated with increases in the incidence of type 2 diabetes. A mod- for future development of type 2 diabetes, both morbidity and mortality (2), despite erate increase in physical activity, accom- their predictive power is similar to or only the decrease in cardiovascular morbidity panied with modest (5–7%) reduction in slightly greater than the 2-h plasma glu- and mortality in nondiabetic individuals body weight, reduced the conversion rate cose concentration (11–13). over the same time period (3). For exam- of impaired glucose tolerance (IGT) to Type 2 diabetes is characterized by ple, in the year 2000 (when compared type 2 diabetes by 58% (4,5). Pharmaco- defects in both insulin secretion and in- with 1990), the rate of cardiac events in logical intervention with metformin, tro- sulin action (14). Both -cell dysfunction nondiabetic subjects in New York City glitazone, and acarbose also have been and insulin resistance can be demon- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● strated long before overt diabetes is diag- nosed, e.g., in subjects with IGT or in From the Divisions of Diabetes and Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. NGT subjects with positive family history Address correspondence and reprint requests to Muhammad A. Abdul-Ghani, MD, PhD, Diabetes Divi- of type 2 diabetes (14,15). Insulin secre- sion, University of Texas Health Science Center, 7703 Floyd Curl Dr., MS 7886, San Antonio, TX 78229. tion and insulin resistance can be quanti- E-mail: [email protected]. fied with the hyperglycemic and Received for publication 26 June 2006 and accepted in revised form 9 March 2007. Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1331. euglycemic insulin clamp techniques, re- Abbreviations: IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose spectively (16). However, these tech- tolerance test; ROC, receiver-operating characteristic; SADPM, San Antonio Diabetes Prediction Model. niques are labor intensive and are difficult A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion to apply in clinical practice or in large ep- factors for many substances. idemiological studies. Surrogate mea- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby sures of insulin secretion and insulin marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. sensitivity have been developed from oral
1544 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Abdul-Ghani and Associates glucose tolerance tests (OGTTs) (17–20). high degree of cross-reactivity with pro- RESULTS — The study included These indexes correlate reasonably well insulin (ϳ70%). The diagnosis of diabe- 1,551 subjects: at baseline, 1,257 had with insulin secretion and insulin sensi- tes was based upon World Health normal NGT, 88 had isolated impaired tivity measured with the hyperglycemic Organization criteria (26): 2-h plasma fasting glucose, 154 had isolated IGT, and and insulin clamp techniques. Previous glucose Ն200 mg/dl or fasting plasma 52 had both impaired fasting glucose and epidemiological studies have demon- glucose Ն126 mg/dl. Subjects on insulin IGT. A total of 179 subjects progressed to strated that OGTT-derived measures of or oral antihyperglycemic medications type 2 diabetes after 7–8 years of follow- insulin resistance and impaired insulin also were considered to have diabetes. up; the remaining 1,372 subjects re- secretion can predict future development mained free of diabetes at follow-up. of type 2 diabetes (21,22). However, no Table 1 presents the anthropometric and previous study has examined the ability of Calculations metabolic characteristics of the two study an insulin secretion/insulin resistance in- Areas under the glucose and insulin groups: progressors and nonprogressors. dex to predict future type 2 diabetes and curves were calculated by the trapezoid Subjects who progressed to type 2 diabe- compared this index with other predictive rule. Matsuda index of insulin sensitivity tes were older and had higher BMI, fasting models of type 2 diabetes. (17) was calculated as previously re- plasma glucose, insulin and triglyceride ported. A variation of Matsuda index was concentrations, and 2-h plasma glucose RESEARCH DESIGN AND calculated by using plasma glucose and and insulin concentrations during OGTT. METHODS — All subjects were par- insulin concentrations at 30 min during Indexes of insulin secretion and insulin ticipants of the San Antonio Heart Study the OGTT in place of mean plasma glu- sensitivity also were lower in subjects (23–25), which is a population-based, ep- cose and insulin concentrations. We refer who progressed to type 2 diabetes com- idemiological study of type 2 diabetes and to this index as the modified Matsuda in- pared with subjects who remained free of cardiovascular disease. A total of 2,941 dex. The insulinogenic index was calcu- diabetes at follow-up. Mexican Americans and non-Hispanic lated by dividing the increment in serum The area under the ROC curve is pre- whites, aged 25–68 years, were enrolled insulin at 30 min by the increment in sented in Table 2. Similar to previous in phase 2 of the San Antonio Heart plasma glucose at 30 min of OGTT. The studies (11), the 2-h plasma glucose con- Study. We excluded phase 2 participants insulin secretion/insulin resistance (dis- centration had an area under the ROC with overt diabetes at baseline based on position) index was calculated as the curve of 0.79 and was comparable to the World Health Organization criteria (26). product of insulin secretion measured area under the ROC curve of the SADPM ⌬ ⌬ ⌬ ⌬ We also excluded all phase 1 participants, with ( I0–30/ G0–30 or I0–120/ G0–120) (0.80). Both the SADPM and 2-h plasma since in these participants plasma glucose and insulin sensitivity index (Matsuda or glucose concentration had significantly levels were not measured at 30 and 60 modified Matsuda indexes). A previously greater area under the ROC curve (0.80 min. A total of 2,616 eligible participants, described, multivariate model for predict- and 0.79, respectively) compared with who were free of type 2 diabetes at base- ing future type 2 diabetes, called the San fasting plasma glucose concentration line, completed a 7- to 8-year follow-up Antonio Diabetes Prediction Model (ROC ϭ 0.75, P Ͻ 0.05). examination. Of these 2,616 participants, (SADPM) (11) (which includes age, sex, The insulin secretion/insulin resis- ⌬ 1,551 had plasma glucose and insulin ethnicity, BMI, blood pressure, fasting tance index, calculated either with I0–30/ ⌬ ⌬ ⌬ measurements at 0, 30, 60, and 120 min plasma glucose, triglycerides, and HDL), G0–30 or I0–120/ G0–120 (as a measure during the baseline OGTT and constitute was also examined, as was the predictive of insulin secretion) and with the Matsuda the study population. The study was ap- value of the 1-h plasma glucose concen- index (as a measure of insulin sensitivity), proved by the institutional review board tration during the OGTT. had the greatest areas under the ROC of University of Texas Health Science curve (0.85 and 0.86, respectively), and Center at San Antonio. All subjects gave both were significantly greater than that written informed consent. Statistical methods of 2-h plasma glucose concentration and Variables are presented as means Ϯ SD. the SADPM (P Ͻ 0.0001). Combining the Definition of variables and outcomes The significance of the mean differences SADPM with the insulin secretion/insulin All studies were performed in a mobile was tested with Student’s t test. Statistical resistance index did not further improve clinic following a 12-h overnight fast. A significance was considered at the level of its predictability (Table 2). The area un- fasting blood specimen was obtained for P Ͻ 0.05. Assessment of the predictive der the ROC curve for the modified insu- determination of plasma glucose and se- discrimination of the various models was lin secretion/insulin resistance index rum insulin and lipid concentrations. Fol- made using the receiver-operating char- measured with the modified (30-min) lowing collection of baseline blood acteristic (ROC) curve by plotting the sen- Matsuda index was 0.83, which is only sample, subjects ingested 75 g glucose sitivity against the corresponding false- slightly less than that of the unmodified (Orangedex; Custom Laboratories, Balti- positive rate. The area under the ROC index. However, the combination of the more, MD) and blood obtained at 30, 60, curve was used as a measure of how well a modified insulin secretion/insulin resis- and 120 min for determination of plasma continuous variable predicts the develop- tance index with the SADPM had compa- glucose and serum insulin concentra- ment of type 2 diabetes. To examine rable area under the ROC curve (0.86) to tions. Plasma glucose and serum lipids whether differences between two areas the unmodified insulin secretion/insulin were measured with an Abbott Bichro- under ROC curves were statistically dif- resistance index. matic Analyzer (South Pasadena, CA). Se- ferent, the algorithm developed by De- Plasma glucose concentration at 1 h rum insulin was measured by Long et al. (27) was used. Statistical during the OGTT had a stronger correla- radioimmunoassay (Diagnostic Products, analyses were performed with the SAS tion with insulin secretion, insulin resis- Los Angeles, CA), which has a relatively statistical software system (Cary, NC). tance, and insulin secretion/insulin
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1545 Prediction of future type 2 diabetes
Table 1—Clinical, anthropometric, and metabolic characteristics of the study groups quired (2-h) to complete the OGTT has limited its widespread use in clinical prac- Nonprogressors Progressors P tice. Moreover, although the present re- sults demonstrate that the OGTT n 1,372 179 NS diagnosis of IGT has high specificity Age (years) 43 Ϯ 11 48 Ϯ 10 NS (92%) in predicting which subjects are at Sex (% male) 44 39 NS high risk for developing type 2 diabetes, it 2 BMI (kg/m ) 27.1 Ϯ 5.0 31.3 Ϯ 5.2 Ͻ0.0001 has much lower sensitivity (51%). Thus, Positive family history (%) 29 48 NS if one relies exclusively on the OGTT di- LDL cholesterol (mg/dl) 123 Ϯ 35 124 Ϯ 35 NS agnosis of IGT for identifying high-risk Triglycerides (mg/dl) 134 Ϯ 90 192 Ϯ 121 Ͻ0.0001 individuals, about half of those who ulti- HDL cholesterol (mg/dl) 47 Ϯ 13 42 Ϯ 11 Ͻ0.0001 mately convert to type 2 diabetes would Ϯ Ϯ Total cholesterol (mg/dl) 196 39 200 38 NS not have been identified. Ϯ Ϯ Ͻ Fasting glucose (mg/dl) 85 10 95 12 0.0001 Our results demonstrate that the in- Ϯ Ϯ Ͻ 2-h plasma glucose (mg/dl) 100 29 140 36 0.0001 sulin secretion/insulin resistance index is Ϯ Ϯ Ͻ Fasting insulin ( U/ml) 12 13 22 18 0.0001 the best predictor of future type 2 diabetes Ϯ Ϯ Ͻ 2-h serum insulin ( U/ml) 84 88 156 125 0.0001 (Table 2). When it is calculated with ei- ⌬ Ϫ1 Ϫ1 Ϯ Ϯ Ͻ G(AUC)0–120 (mg dl h ) 65 43 123 44 0.0001 ther ⌬I /⌬G or ⌬I /⌬G ⌬ ⌬ Ϯ Ϯ Ͻ 0–30 0–30 0–120 0–120 I0–120/ G0–120 2.9 2.6 2.1 2.2 0.0001 (as the measure of insulin secretion) and ⌬ ⌬ Ϯ Ϯ Ͻ I0–30/ G0–30 2.4 1.6 1.3 0.9 0.0001 the Matsuda index (as the measure of in- Matsuda index 5.1 Ϯ 5.4 2.3 Ϯ 2.0 Ͻ0.0001 Ϯ Ϯ Ͻ sulin resistance), it has the greatest area Modified Matsuda index 4.8 5.7 2.6 2.1 0.0001 under the ROC curve (0.85 and 0.86, re- ⌬I /⌬G ϫ Matsuda index 20 Ϯ 14 3.6 Ϯ 3.6 Ͻ0.0001 0–120 0–120 spectively). Combining the SADPM pre- ⌬I /⌬G ϫ Matsuda index 10.1 Ϯ 12.1 2.5 Ϯ 2.7 Ͻ0.0001 0–30 0–30 dictive model (11) with the insulin ⌬I /⌬G ϫ modified Matsuda index 9.1 Ϯ 10.7 2.8 Ϯ 2.3 Ͻ0.0001 0–30 0–30 secretion/insulin resistance index does Data are means Ϯ SD unless otherwise indicated. AUC, area under the curve; NS, not significant. not further enhance its predictability. Of note, in previous studies indexes of insu- resistance index compared with the 2-h the greatest specificity (92%) but the sen- lin secretion and insulin resistance were plasma glucose concentration (Table 3). sitivity was only 51%. The use of plasma found to be significant independent pre- Therefore, we examined the ability of the glucose concentration ϭ 155 mg/dl at 60 dictors for future type 2 diabetes (21,22). 1-h plasma glucose concentration to pre- min during the OGTT as a cut point had Although they were not compared with dict future type 2 diabetes. The area under 75% sensitivity and 79% specificity. Both the 2-h plasma glucose concentration, all the ROC curve for 1-h plasma glucose the 0- to 30-min and 0- to 120-min insu- of the indexes that were tested had an area (0.84) (Table 2) was significantly greater lin secretion/insulin resistance indexes under the ROC curve Ͻ0.8 (21). No pre- than the area under the ROC curve for the had greater sensitivity compared with vious study has assessed the ability of any 2-h plasma glucose concentration and the IGT, although the specificity declined insulin secretion/insulin resistance index SADPM (both P ϭ 0.01). Addition of the slightly (Table 2). to predict future type 2 diabetes. One lim- 1-h plasma glucose concentration to the itation in using the insulin secretion/ SADPM significantly improved its pre- CONCLUSIONS — Clinical trails insulin resistance index for predicting dictability at a level similar to that of in- consistently have demonstrated that life- future type 2 diabetes is the need to mea- sulin secretion/insulin resistance index. style intervention in subjects with IGT sure the plasma glucose and insulin con- When a cut point for continuous vari- markedly reduces the risk for conversion centrations every 30 min during the ables was used as a threshold for predict- to type 2 diabetes. However, the identifi- OGTT. This limitation can be overcome ing future type 2 diabetes, IGT (2-h cation of subjects with IGT requires that by using the modified insulin secretion/ plasma glucose ϭ 140–199 mg/dl) had an OGTT be performed, and the time re- insulin resistance index. Although the
Table 2—Area under the ROC curve for various predictive models for future development of type 2 diabetes
Parameter ROC P vs. G120 ROC combined model* Cutoff Sensitivity Specificity Fasting plasma glucose 0.75 0.05 Plasma glucose at 30 min 0.77 0.24 Plasma glucose at 60 min 0.84 0.01 0.86† 155 0.75 0.79 Plasma glucose at 120 min 0.79 140 0.51 0.92 SADPM 0.80 Glucose (AUC) 0–120 min 0.83 0.06 0.87† 0.83 0.71 ⌬ ⌬ ϫ Ͻ I0–120/ G0–120 Matsuda index 0.86 0.0001 0.86† 4.5 0.82 0.76 ⌬ ⌬ ϫ I0–30/ G0–30 Matsuda index 0.85 0.005 0.87† 3.1 0.83 0.77 ⌬ ⌬ ϫ I0–30/ G0–30 modified 0.83 0.1 0.86† 3.5 0.82 0.71 Matsuda index *The combined model is comprised of the combination of each parameter with SADPM. †P Ͻ 0.0001 vs. SADPM; P ϭ NS vs. ROC. AUC, area under the curve.
1546 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Abdul-Ghani and Associates
Table 3—Pearson’s correlation coefficients between plasma glucose concentration at 60 and tions. Diabetes Care 21:1414–1431, 1998 120 min during the OGTT versus indexes of insulin secretion and insulin resistance 2. Fang J, Alderman MH: Impact of the in- creasing burden of diabetes on acute myo- cardial infarction in New York City: Glucose at Glucose at 1990–2000. Diabetes 55:768–773, 2006 Parameter 60 min P 120 min P 3. Gillum RF: Trends in acute myocardial infarction and coronary heart disease in Fasting plasma glucose 0.5 Ͻ0.0001 0.35 Ͻ0.0001 Ͻ the United States. J Am Coll Cardiol 23: Plasma glucose at 120 min 0.6 0.0001 — — 1273–1277, 1994 Ϫ Ͻ Ϫ Ͻ Matsuda index 0.44 0.0001 0.39 0.0001 4. The Diabetes Prevention Program Group: ⌬ ⌬ Ϫ Ͻ Ϫ I0–30/ G0–30 0.36 0.0001 0.14 0.07 Reduction in the incidence of type 2 dia- ⌬Glucose (AUC) 0–120 min 0.91 Ͻ0.0001 0.73 Ͻ0.0001 betes with lyfe style intervention or met- ⌬ ⌬ ϫ Ϫ Ͻ Ϫ Ͻ I0–120/ G0–120 Matsuda index 0.44 0.0001 0.34 0.0001 formin. N Engl J Med 346:393–403, 2002 ⌬ ⌬ ϫ Ϫ Ͻ Ϫ Ͻ I0–30/ G0–30 Matsuda index 0.53 0.0001 0.36 0.0001 5. Tuomilehto J, Lindstrom J, Eriksson JG, AUC, area under the curve. Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, the Finnish Diabetes Preven- area under the ROC curve (0.83) for the two purposes: 1) identification of high- tion Study Group: Prevention of type 2 modified insulin secretion/insulin resis- risk target populations for clinical and diabetes mellitus by changes in lifestyle ⌬ tance index calculated with I0–30/ public health intervention and 2) eluci- among subjects with impaired glucose ⌬ G0–30 and a modified version of the dating the pathogenesis of the disease. tolerance. N Engl J Med 344:1343–1350, Matsuda index (calculated with plasma The models presented in this study reflect 2001 glucose and insulin concentrations at fast- primarily the second goal. They demon- 6. Knowler WC, Hamman RF, Edelstein SL, ing and 30 min) is slightly lower than that strate that a prediction model based on Barrett-Connor E, Ehrmann DA, Walker of the unmodified index, combination of the pathophysiology of the disease per- EA, Fowler SE, Nathan DM, Kahn SE, the the modified insulin secretion/insulin re- forms superiorly to other clinical models Diabetes Prevention Program Research sistance index and SADPM has an area in predicting the risk of future type 2 di- Group: Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention under its ROC curve that is comparable to abetes. With respect to the first goal, one Program. Diabetes 54:1150–1156, 2005 that of the unmodified index in predicting must weigh the greater accuracy of the 7. Chiasson JL, Josse RG, Gomis R, Hanefeld future diabetes. Use of this model in clin- presented models against the added cost, M, Karasik A, Laakso M, the STOP- ical practice is more convenient than the both in terms of dollars and inconve- NIDDM Trail Research Group: Acarbose OGTT diagnosis of IGT because it re- nience associated with performing the for prevention of type 2 diabetes mellitus: quires the measurement of plasma glu- OGTT, which the SADPM does not re- the STOP-NIDDM randomised trial. Lan- cose and insulin concentrations only at quire. Depending on the circumstances, cet 359:2072–2077, 2002 baseline (fasting) and 30 min following one or another approach may be 8. Unwin N, Shaw J, Zimmet P, Alberti the glucose load. preferred. KGMM: Impaired glucose tolerance and Simply measuring the plasma glucose In summary, the present results dem- impaired fasting glycemia: the current sta- tus on definition and intervention. Diabet concentration at 1 h during the OGTT onstrate that the insulin secretion/insulin Med 19:708–723, 2002 also is a good predictor for future type 2 resistance index derived from the OGTT 9. Ramachandran A, Snehalatha C, Naik RA, diabetes. It has a greater area under the provides a superior method for predicting Mohan V, Shobana R, Viswanathan M: ROC curve compared with the 2-h plasma future development of type 2 diabetes Significance of impaired glucose tolerance glucose concentration, and, when com- compared with the diagnosis of IGT based in an Asian Indian population: a follow- bined with the SADPM, its area under the on the 2-h plasma glucose concentration. up study. Diabetes Res Clin Pract 3:173– ROC curve is comparable with the insulin The combination of the SADPM with the 178, 1986 secretion/insulin resistance index. Fur- 1-h plasma glucose concentration and a 10. Edelstein SL, Knowler WC, Bain RP, An- thermore, if one uses a cut point of 155 modified version of the insulin sensitivity/ dres R, Barrett-Connor EL, Dowse GK, mg/dl for the 1-h plasma glucose concen- insulin resistance index provides alterna- Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF: Predictors tration, this has 50% greater sensitivity in tive predictive models with similar of progression from impaired glucose predicting future type 2 diabetes com- precision and does not require the mea- tolerance to NIDDM: an analysis of six pared with the OGTT diagnosis of IGT surement of plasma glucose concentra- prospective studies. Diabetes 46:701–710, with only a modest (ϳ15%) decline in tion 2 h after ingestion of the glucose load. 1997 specificity. Because the glucose assay is 11. Stern MP, Williams K, Haffner SM: Iden- universally standardized, the combina- tification of persons at high risk for type 2 tion of 1-h plasma glucose concentration Acknowledgments— This work was sup- diabetes mellitus: do we need the oral glu- and the SADPM provides an additional ported by a General Clinical Research Center cose tolerance test? Ann Intern Med 136: method for predicting future type 2 dia- Grant RR01346 fund from the VA Research 575–581, 2002 Service, National Institutes of Health Grant 12. Schmidt MI, Duncan BB, Bang H, Pankow betes. This combination is more accurate DK-24092, and a VA Merit Award (to R.A.D.). than 2-h plasma glucose concentration JS, Ballantyne CM, Golden SH, Folsom AR, Chambless LE, the Atherosclerosis during the OGTT and more convenient Risk in Communities Investigators: than the diagnosis of IGT because the References Identifying individuals at high risk for plasma glucose concentration is mea- 1. King H, Aubert RE, Herman WH: Global diabetes: the Atherosclerosis Risk in sured at 1 h instead of after 2 h. burden of diabetes, 1995–2025: preva- Communities study. Diabetes Care 28: Prediction models can serve one of lence, numerical estimates, and projec- 2013–2018, 2005
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1548 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Vitamin D, Parathyroid Hormone Levels, and the Prevalence of Metabolic Syndrome in Community-Dwelling Older Adults
1,2 1 JARED P. REIS, PHD DEBORAH L. WINGARD, PHD studies have been inconsistent (17). In 1 1 DENISE VON M¨UHLEN, MD, PHD ELIZABETH BARRETT-CONNOR, MD addition, evidence from a small clinical 1 DONNA KRITZ-SILVERSTEIN, PHD sample (1) and a national population- based cohort participating in the Third National Health and Nutrition Examina- OBJECTIVE — Accumulating research suggests low-circulating vitamin D concentrations, tion Survey (18) has implicated low i.e., 25-hydroxyvitamin-D [25(OH)D], may be associated with an increased prevalence of met- 25(OH)D with an increased prevalence of abolic syndrome; however, previous studies have not accounted for parathyroid hormone (PTH) metabolic syndrome. levels. We examined the association of 25(OH)D and PTH with the prevalence of metabolic Vitamin D and PTH are both respon- syndrome in a community-based cohort of older adults. sible for maintaining extracellular cal- cium homeostasis (19). Vitamin D RESEARCH DESIGN AND METHODS — Participants included 410 men and 660 women, 44–96 years old, who completed a follow-up clinic visit in 1997–1999 as part of the increases the efficiency of intestinal cal- Rancho Bernardo Study. Sex-specific logistic regression models were fit to estimate the odds of cium absorption, and PTH is secreted in ATP III (Adult Treatment Panel III)-defined metabolic syndrome across quintiles of 25(OH)D response to low-circulating calcium con- and PTH, adjusting for age, season, and major lifestyle factors. centrations. Elevated PTH secondary to low vitamin D increases calcium resorp- RESULTS — In men, there was a significant trend (P ϭ 0.03) of increasing adjusted odds for tion from the skeleton at the expense of an metabolic syndrome with increasing PTH concentrations, primarily due to an odds ratio of 2.02 increased risk of fracture (20). Secondary (95% CI 0.96–4.24) in men in the top quintile (Ն63 ng/l) of PTH concentration. This associ- hyperparathyroidism may also increase ation remained unchanged after taking into account 25(OH)D levels and excluding men with the risk of developing components of diabetes or impaired renal function; it was attenuated after adjustment for the homeostasis model metabolic syndrome, including hyperten- assessment of insulin resistance. Neither PTH in women nor 25(OH)D levels in either sex was related to the metabolic syndrome. sion (21–26), obesity (6,9,10,27–29), and diabetes (30–32). However, we are CONCLUSIONS — These findings suggest an increased risk of metabolic syndrome with unaware of previous research investigat- elevated PTH levels in older men and no effect of 25(OH)D concentrations in either sex. The ing whether PTH levels are also associated reason for the sex difference in the PTH–metabolic syndrome association is unknown. Prospec- with the metabolic syndrome. tive studies are necessary to better determine the roles of 25(OH)D and PTH in the etiology of Previous studies linking low metabolic syndrome. 25(OH)D with an increased prevalence of metabolic syndrome (1,18) were limited Diabetes Care 30:1549–1555, 2007 by their inability to simultaneously ac- count for PTH, since both vitamin D and ecreased vitamin D and elevated pected to be involved in the regulation of PTH operate within a tightly controlled parathyroid hormone (PTH) levels blood pressure, based on blood pressure feedback system to maintain extracellular D may play a role in the etiology of reduction with vitamin D3 supplementa- calcium concentrations (19). The pur- metabolic syndrome, either through an tion in patients with essential hyperten- pose of the present study was to examine association with individual components sion (11,12). Other evidence suggests a the cross-sectional association of both of metabolic syndrome or via insulin re- role for vitamin D in maintaining normal 25(OH)D and PTH concentrations with sistance (1,2). Vitamin D levels have been insulin synthesis and secretion (13,14). the prevalence of metabolic syndrome in a shown to be inversely related both with Deficient 25-hydroxyvitamin D community-based cohort of older adults. fasting glucose concentrations (3–5) and [25(OH)D] may also be a risk factor for adiposity (6–10) and have been sus- diabetes (5,15,16), although previous RESEARCH DESIGN AND ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● METHODS Study participants were members of the From the 1Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California; and the 2Graduate School of Public Health, San Diego State University, San Diego, California. Rancho Bernardo Study cohort, else- Address correspondence and reprint requests to Elizabeth Barrett-Connor, MD, Department of Family where described in detail (33). Briefly, be- and Preventive Medicine, University of California, San Diego, 9500 Gilman Dr., 0607, La Jolla, CA 92093- tween 1972 and 1974, 82% of all adults 0607. E-mail: [email protected]. living in the southern California commu- Received for publication 29 November 2006 and accepted in revised form 19 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2438. nity of Rancho Bernardo were enrolled in Abbreviations: 25(OH)D, 25-hydroxyvitamin-D; CBP, competitive binding protein; HOMA-IR, ho- a study of heart disease risk factors as part meostasis model assessment of insulin resistance; PTH, parathyroid hormone. of the Lipid Research Clinics Prevalence A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Study. Nearly all subjects were Caucasian factors for many substances. and of middle to upper-middle class, as © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby assessed by the Hollingshead’s index (34). marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Between 1997 and 1999, 89% (420 men
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1549 Vitamin D, PTH, and metabolic syndrome and 676 women) of the local surviving was separated and stored at Ϫ70°C in women; 4) systolic blood pressure community-dwelling members aged within 30 min of collection. Serum Ն130 mmHg, diastolic blood pressure ϩ Ն 44–96 years attended a follow-up visit, at 25(OH)D [25(OH)D2 25(OH)D3] was 85 mmHg, or use of antihypertensive which a medical evaluation was per- measured in the research laboratory of M. medication; or 5) fasting glucose Ն6.1 formed and a blood sample obtained. Af- Holick, using vitamin D competitive mmol/l (110 mg/dl). BMI was calculated ter excluding participants who did not binding protein (CBP) recognition and as weight in kilograms divided by the have adequate blood samples for mea- chemiluminescence detection (Nichols square of height in meters. Diabetes was surement of 25(OH)D and PTH levels Institute Diagnostics, San Clemente, CA) defined by history (type 1 or type 2 dia- (n ϭ 18) and those who were missing val- as described by Chen et al. (36). The rat betes), use of diabetes medications, or a ues for one or more of the components of serum vitamin D binding protein has high fasting plasma glucose level Ն7.0 mmol/l metabolic syndrome (n ϭ 8), there re- affinity for 25(OH)D. The intra- and in- (126 mg/dl). Impaired renal function was mained 410 men and 660 women for terassay coefficients of variation (CVs) defined as a creatinine clearance Ͻ30.0 these analyses. The University of Califor- were 8 and 10%, respectively. The limit of ml/min based on the Cockcroft-Gault for- nia, San Diego Human Subjects Protec- detection was 12.5 nmol/l, and the refer- mula (39). tions Program approved this study, and ence range was 25–130 nmol/l. The PTH Because the prevalence of metabolic all participants provided written in- assay was performed in the same labora- syndrome and some of its components formed consent before participation. tory using a chemiluminescence assay differed significantly between men and (Nichols Institute Diagnostics) for the women, sex-specific analyses were per- Clinical evaluation measurement of intact PTH; intra- and in- formed. Age-adjusted rates were calcu- During the clinic visit, standardized ques- terassay CVs were both 6% with a refer- lated by the direct method using the total tionnaires were used to obtain medical ence range of 10–65 ng/l. population as the standard; differences by history and lifestyle behavior informa- Plasma triglycerides and HDL were sex and presence of metabolic syndrome tion. Data on the frequency of alcoholic measured in a Centers for Disease Control were tested with the stratified Mantel- beverage consumption (daily or almost and Prevention–certified lipid research Haenszel test. Age-adjusted means of con- daily, three or four times per week, once clinic laboratory. Triglycerides were mea- tinuous characteristics were compared by or twice per week, once or twice per sured by enzymatic techniques using an sex and metabolic syndrome status using month, or less often then once per ABA-200 biochromatic analyzer (Abbott ANOVA. PTH was positively skewed and month), cigarette smoking (current, Laboratories, Irving, TX). HDL was mea- was therefore log transformed or catego- former, or never), and participation in sured after precipitation of the other li- rized depending on the type of analysis strenuous exercise 3 or more days per poproteins with heparin and manganese conducted; untransformed means are re- week (yes/no) were obtained. Women chloride according to standardized proce- ported for ease of interpretation. Sex- were also asked about their current or dures of the Lipid Research Clinics man- specific logistic regression models were fit former use of hormone replacement ther- ual (37). Fasting plasma glucose was to estimate the odds of metabolic syn- apy. Current use of estrogen with or with- measured by the glucose oxidase method. drome and its components across quin- out progestin, diabetes and blood Fasting insulin was determined by a dou- tiles of 25(OH)D and PTH after adjusting pressure medications, and vitamin D and ble antibody in a research laboratory (38). for age (years), current smoking, alcohol calcium supplement use were validated Serum creatinine levels were measured by use (Ն3 times per week), exercise, season by the examination of pills and prescrip- SmithKline Beecham clinical laboratories. of study participation, and, for women, tions brought to the clinic for that pur- Creatinine clearance, calculated with the hormone therapy. Models of metabolic pose. Cockcroft-Gault formula, {[140 Ϫ age syndrome components were additionally Blood pressure was measured twice in (years)] ϫ weight (kg)}/[72 ϫ creatinine adjusted for the other components. Men seated subjects after a 5-min rest using a (mg/dl)] (multiplied by 0.85 for women), and women in the lowest quintile of either mercury sphygmomanometer according was used as a measure of renal function 25(OH)D or PTH served as the referent to the Hypertension Detection and Fol- (39). Insulin resistance was estimated by groups unless otherwise noted. Tests for a low-up Program protocol (35). The aver- the homeostasis model assessment of in- linear trend were conducted by entering age of the two measurements was used in sulin resistance (HOMA-IR) index, calcu- the categorical 25(OH)D and PTH vari- analyses. Body weight and height were lated as [fasting glucose (mmol/l) ϫ ables into the regression models as an or- measured with a standard physician’s fasting insulin (U/ml)]/22.5, as de- dinal term. Because diabetes is frequently scale and stadiometer while participants scribed by Levy et al. (40) associated with vitamin D insufficiency were wearing light clothing and no shoes. and mild renal impairment may affect Waist circumference was measured at the Statistical analysis 25(OH)D-PTH homeostasis, analyses bending point (the natural indentation The metabolic syndrome was defined ac- were repeated after exclusion of those when bending sideward) and at the nar- cording to the NCEP/ATP III (National with diabetes or impaired renal function. rowest circumference. The correlation be- Cholesterol Education Program/Adult Effect modification by current hormone tween these two measures was 98%, and Treatment Panel III) (41). Participants use in women was investigated in strati- the measure at the bending point was were classified as having prevalent meta- fied models. SAS (version 9.1; SAS Insti- used in these analyses. bolic syndrome if they had three or more tute, Cary, NC) was used to perform all of the following five components: 1) waist analyses, with statistical significance at Laboratory methods circumference Ͼ102 cm in men, Ͼ 88 cm P Ͻ 0.05 using two-sided tests. Blood was obtained by venipuncture after in women; 2) triglycerides Ն1.69 mmol/l an overnight fast and placed into tubes (150 mg/dl); 3) HDL Ͻ1.04 mmol/l (40 RESULTS — Men and women were of that were protected from sunlight. Serum mg/dl) in men, Ͻ 1.3 mmol/l (50 mg/dl) similar age (men 74.5 Ϯ 9.5 years;
1550 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Reis and Associates
ϭ Table 1—Age-adjusted characteristics of the study sample: Rancho Bernardo, CA, 1997–1999 est; Ptrend 0.04) nor after excluding men with diabetes or impaired renal func- Variables Men Women P tion (2.17 [0.80–5.89] comparing the highest PTH quintile with the lowest; ϭ n 410 660 Ptrend 0.08). Adjustment for HOMA-IR, Clinical however, appeared to at least partly ex- Age (years)* 74.5 Ϯ 9.5 74.6 Ϯ 10.7 0.1 plain the elevated risk of increased PTH BMI (kg/m2) 26.5 Ϯ 0.2 24.9 Ϯ 0.2 Ͻ0.0001 on the metabolic syndrome (1.68 [0.64– Waist (cm) 95.0 Ϯ 0.5 79.9 Ϯ 0.4 Ͻ0.0001 4.40], comparing the highest PTH quin- Ϯ Ϯ ϭ SBP (mmHg) 135.4 1.0 136.7 0.8 0.3 tile with the lowest; Ptrend 0.2). Partial DBP (mmHg) 75.2 Ϯ 0.5 72.9 Ϯ 0.4 Ͻ0.0001 correlations comparing 25(OH)D and Diabetes (%) 13.2 7.1 0.001 PTH with HOMA-IR were r ϭϪ0.13 and Biochemical measures† 0.12 (P Ͻ 0.05 for both), respectively, in Triglycerides (mmol/l) 1.4 Ϯ 0.04 1.4 Ϯ 0.03 0.7 men and r ϭϪ0.07 and 0.01 (P Ͼ 0.05 Glucose (mmol/l) 5.9 Ϯ 0.02 5.4 Ϯ 0.02 Ͻ0.0001 for both), respectively, in women. When HDL (mmol/l) 1.3 Ϯ 0.05 1.7 Ϯ 0.04 Ͻ0.0001 adjusted for BMI, the OR for the meta- ATP III–defined MetSyn (%) 23.5 18.0 0.03 bolic syndrome comparing men in the MetSyn criteria (%)‡ highest quintile of PTH with men in the Abdominal obesity 20.3 22.0 0.5 lowest did not change (2.03 [0.84–4.89], ϭ High blood pressure 72.5 68.2 0.1 Ptrend 0.04). No significant associations High triglycerides 23.2 26.9 0.2 of 25(OH)D or PTH with the metabolic Hyperglycemia 30.8 12.0 Ͻ0.0001 syndrome in women nor 25(OH)D with Low HDL 20.9 17.2 0.1 the metabolic syndrome in men were Number of MetSyn criteria (%)‡ 0.004 found (Table 3). Further evaluation of the 0 13.5 19.3 25(OH)D–PTH–metabolic syndrome as- 1 40.0 41.3 sociations among women who were cur- 2 22.9 21.3 rent users of hormone therapy versus 3 14.3 11.2 never/former users revealed similar non- 4 7.0 5.3 significant findings (data not shown). 5 2.2 1.5 To more fully examine the potential Serum 25(OH)D (nmol/l) 108.9 Ϯ 0.3 101.6 Ϯ 0.2 0.002 effect of 25(OH)D on the increased odds PTH (ng/l)§ 51.3 Ϯ 1.2 50.1 Ϯ 1.0 0.3 of metabolic syndrome observed in men Data are means Ϯ SE or percentages unless otherwise indicated. *Unadjusted means Ϯ SD. †To convert to in the top quintile of PTH, we jointly clas- conventional units (mg/dl), multiply triglycerides by 89, glucose by 39, and HDL by 18. ‡Criteria as defined sified men into groups defined by quintile Ϯ by the NCEP/ATP III (41). §Untransformed means SE; P based on log-transformed data. DBP, diastolic of PTH and median 25(OH)D levels blood pressure; MetSyn, metabolic syndrome; SBP, systolic blood pressure. (105.0 nmol/l) [i.e., high vs. low 25(OH)D]. Results of this analysis re- women 74.6 Ϯ 10.7 years). The age of cantly higher among men with the meta- vealed similar increases but nonsignifi- Ͼ92% (n ϭ 379) of men and Ͼ89% (n ϭ bolic syndrome compared with men cant adjusted odds of metabolic 587) of women was Ն60 years. The age- without the metabolic syndrome (P ϭ syndrome among men in the highest adjusted prevalence of metabolic syn- 0.004) but were similar by metabolic syn- quintile of PTH with high and low drome was higher in men than women drome status in women (P ϭ 0.9). Neither 25(OH)D (OR 1.89 [95% CI 0.73–4.91] (23.5 vs. 18.0%, respectively, P ϭ 0.03) diastolic blood pressure nor mean and 2.11 [0.74–6.02], respectively) com- (Table 1). The prevalence of metabolic 25(OH)D concentrations varied by pres- pared with men in the lowest quintile of syndrome components defined according ence of metabolic syndrome in either sex. PTH and high 25(OH)D. to the sex-specific cut-points of NCEP/ The sex-specific associations of Among the components, a significant ATP III did not vary significantly by sex, 25(OH)D and PTH with the metabolic inverse multivariate association of except for fasting hyperglycemia, which syndrome and its components are dis- 25(OH)D with fasting hyperglycemia in was more common in men than women played in Table 3. In men, a significant men and a positive association with high (30.8 vs. 12.0%, respectively, P Ͻ positive trend (P ϭ 0.03) in the adjusted triglycerides in women were present ϭ 0.0001). Women had significantly lower odds of metabolic syndrome across in- (Ptrend 0.01 for both) (Table 3). The mean 25(OH)D concentrations (P ϭ creasing quintiles of PTH was found; this adjusted odds of high blood pressure, hy- 0.002) than men, but PTH levels did not association was largely explained by odds perglycemia, and low HDL were signifi- vary by sex (P ϭ 0.30). ratio (OR) 2.02 (95% CI 0.96–4.24) cantly elevated among men in the highest Hormone therapy and alcohol con- among men in the top quintile of PTH quintile of PTH compared with men in sumption were significantly lower among (Ն63 ng/l). A modest J- or U-shaped as- the lowest quintile. A positive association women with the metabolic syndrome sociation was found (P value for quadratic of PTH with abdominal obesity in women ϭ ϭ compared with women without the met- PTH 0.08). Results were not materially was noted (Ptrend 0.03). abolic syndrome (Table 2). Both men and changed after including 25(OH)D levels women with the metabolic syndrome re- as a covariate in the multivariate model CONCLUSIONS — In the current ported lower rates of exercise than those (OR 1.90 [95% CI 0.90–4.02], compar- study, we found no evidence of an asso- without. Mean PTH levels were signifi- ing the highest PTH quintile with the low- ciation of 25(OH)D with the metabolic
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1551 Vitamin D, PTH, and metabolic syndrome
Table 2—Age-adjusted metabolic syndrome* components, health-related behaviors, 25(OH)D, and PTH levels in men and women with and without metabolic syndrome: Rancho Bernardo, CA, 1997–1999
Men Women MetSyn MetSyn MetSyn MetSyn present absent P present absent P n 97 313 120 540 Age (years)† 72.9 Ϯ 8.9 75.0 Ϯ 9.7 0.07 75.8 Ϯ 9.7 74.3 Ϯ 11.0 0.2 MetSyn components Waist circumference (cm) 103.6 Ϯ 0.9 92.2 Ϯ 0.5 Ͻ0.0001 92.0 Ϯ 0.9 77.2 Ϯ 0.4 Ͻ0.0001 SBP (mmHg) 140.5 Ϯ 2.0 133.7 Ϯ 1.1 0.003 141.4 Ϯ 1.8 135.7 Ϯ 0.9 0.005 DBP (mmHg) 75.0 Ϯ 0.9 75.2 Ϯ 0.5 0.8 73.5 Ϯ 0.9 72.7 Ϯ 0.4 0.5 Triglycerides (mmol/l)‡§ 2.3 Ϯ 0.1 1.1 Ϯ 0.1 Ͻ0.0001 2.1 Ϯ 0.1 1.3 Ϯ 0.03 Ͻ0.0001 Fasting glucose (mmol/l)‡ 6.9 Ϯ 0.1 5.6 Ϯ 0.05 Ͻ0.0001 6.4 Ϯ 0.1 5.3 Ϯ 0.04 Ͻ0.0001 HDL (mmol/l)‡ 1.1 Ϯ 0.03 1.4 Ϯ 0.02 Ͻ0.0001 1.3 Ϯ 0.04 1.8 Ϯ 0.02 Ͻ0.0001 Health-related behaviors (%) Vitamin D supplement use 10.2 9.3 0.7 26.8 28.9 0.7 Calcium supplement use 14.9 23.8 0.08 55.6 58.3 0.6 Thyroid hormone use 6.7 8.9 0.4 22.8 20.7 0.8 Current hormone therapy — — — 36.9 50.6 0.005 Current smoker 2.5 4.8 0.4 3.4 5.0 0.5 Alcohol use (Ն3 times per week) 57.8 57.7 0.9 28.4 45.0 0.001 Exercise (Ն3 times per week) 68.6 80.4 0.01 51.7 73.1 Ͻ0.0001 Serum 25(OH)D (nmol/l) 104.0 Ϯ 3.4 110.4 Ϯ 1.9 0.1 97.9 Ϯ 3.2 102.5 Ϯ 1.5 0.2 PTH‡ (ng/l) 57.3 Ϯ 2.7 49.4 Ϯ 1.5 0.004 51.2 Ϯ 2.2 49.8 Ϯ 1.1 0.9 Data are means Ϯ SE or percentages unless otherwise indicated. *Criteria as defined by the NCEP/ATP III (41), see text for full description. †Unadjusted means Ϯ SD. ‡To convert to conventional units (mg/dl), multiply triglycerides by 89, fasting glucose by 39, and HDL by 18. §Untransformed means Ϯ SE; P based on log-transformed data. DBP, diastolic blood pressure; MetSyn, metabolic syndrome; SBP, systolic blood pressure. syndrome in either sex, but there was a ing a significant association of higher PTH has been associated with impaired significant trend for increasing odds of dietary calcium and dairy intake with a glucose tolerance (45) and decreased in- metabolic syndrome with increasing PTH reduced risk of metabolic syndrome in sulin sensitivity in normotensive, glu- levels in older men. This association was young and middle-aged adults (42,43). cose-tolerant adults (2). Insulin resistance independent of the potential confounding Thus, a dietary pattern characterized by a is widely proposed as the mechanism un- effects of age, season, major lifestyle fac- high intake of calcium may downregulate derlying the metabolic syndrome (46). tors, diabetes, renal function, and PTH release, resulting in a reduced risk of Alternatively, the association of increased 25(OH)D levels and was not observed in metabolic syndrome. In the present PTH with the metabolic syndrome may be women with or without current hormone study, the use of calcium supplements explained through relations with individ- use. To our knowledge, this is the first was not significantly associated with the ual components, especially high blood population-based study to investigate the metabolic syndrome (see Table 2). Fur- pressure, hyperglycemia, and low HDL, association of both 25(OH)D and PTH ther studies are needed to confirm the ob- which were all significantly elevated in with the metabolic syndrome. served association of PTH with the men with the highest PTH levels (see Ta- Vitamin D and PTH are together re- metabolic syndrome and to uncover the ble 3). sponsible for maintaining extracellular potential role of PTH in studies of calcium The results of this study suggest that calcium homeostasis. Vitamin D facili- intake in association with the metabolic the association of increased PTH with the tates intestinal calcium absorption, while syndrome. metabolic syndrome may be limited to low serum calcium concentrations stimu- In the present study, HOMA-IR partly men, especially those with the highest late the secretion of PTH to increase cal- explained the association of elevated PTH PTH levels. We are unsure as to why this cium resorption from the skeleton and with the metabolic syndrome in men, association was not observed in women, increase the renal reabsorption of cal- suggesting that insulin resistance may at although these findings may be at least cium. This resultant secondary hyper- least partly mediate the association of partly attributable to sex differences in the parathyroidism has been shown to high PTH levels with increased odds of prevalence of metabolic syndrome or cal- increase the risk of fracture (20), hyper- metabolic syndrome. Primary and sec- cium absorption. It has been previously tension (21,22,24–26), obesity ondary hyperparathyroidism have been demonstrated that increases in estrogen (6,9,10,27–29), and diabetes (30–32). previously suspected to be involved in levels result in concomitant increases in Results of the present study suggest that glucose metabolism and diabetes (44). the intestinal absorption of calcium (47). hyperparathyroidism may contribute to Clinical investigations consistently show In addition, in the current study, 57.8% the development of metabolic syndrome, a two- to fourfold elevated risk of diabetes of women reported the use of calcium an association that is biologically plausi- among individuals with hyperparathy- supplements, compared with 21.8% of ble based on epidemiologic studies show- roidism (30–32). In addition, elevated men. Thus, the greater bioavailability of
1552 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1553
Table 3—Age-adjusted prevalence, adjusted ORs, and 95% CIs of metabolic syndrome and its components by quintiles of 25(OH)D and PTH among men and women: Rancho Bernardo, CA, Reis and Associates 1997–1999
Metabolic syndrome* Abdominal obesity High blood pressure High triglycerides Hyperglycemia Low HDL OR OR OR OR OR OR Quintiles Prevalence† (95% CI)‡ Prevalence† (95% CI)§ Prevalence† (95% CI)§ Prevalence† (95% CI)§ Prevalence† (95% CI)§ Prevalence† (95% CI)§ 25 (OH)D (nmol/l) Men I(Ͻ087.5) 29.6 1.0 (ref.) 29.8 1.0 (ref.) 75.8 1.0 (ref.) 32.0 1.0 (ref.) 42.9 1.0 (ref.) 23.2 1.0 (ref.) II (8.75–97.4) 26.7 0.83 (0.39–1.73) 17.3 0.51 (0.22–1.20) 72.4 0.92 (0.41–2.07) 19.3 0.52 (0.22–1.19) 37.5 0.93 (0.45–1.93) 21.7 1.03 (0.44–2.42) III (97.5–110.0) 22.7 0.68 (0.32–1.43) 22.3 0.82 (0.38–1.79) 73.1 0.90 (0.41–1.96) 23.4 0.69 (0.32–1.50) 25.7 0.46 (0.22–0.96) 21.7 1.39 (0.61–3.18) IV (110.1–126.2) 21.4 0.65 (0.32–1.34) 18.0 0.61 (0.28–1.32) 69.7 0.88 (0.42–1.84) 23.2 0.78 (0.37–1.63) 28.1 0.53 (0.26–1.08) 19.5 1.11 (0.49–2.52) V(Ն126.3) 21.8 0.57 (0.26–1.25) 17.9 0.47 (0.20–1.13) 72.2 1.28 (0.58–2.81) 21.9 0.62 (0.28–1.41) 24.7 0.43 (0.20–0.95) 23.0 1.51 (0.63–3.62) Ptrend 0.08 0.1 0.04 0.2 0.6 0.6 0.1 0.5 0.004 0.001 0.6 0.4 Women I(Ͻ77.5) 24.4 1.0 (ref.) 32.9 1.0 (ref.) 74.7 1.0 (ref.) 27.1 1.0 (ref.) 18.8 1.0 (ref.) 24.0 1.0 (ref.) II (77.5–92.4) 15.5 0.96 (0.48–1.90) 22.2 0.84 (0.44–1.61) 65.2 0.77 (0.40–1.46) 21.1 0.85 (0.44–1.62) 9.1 0.60 (0.26–1.39) 18.5 1.30 (0.64–2.65) III (92.5–103.7) 17.2 0.96 (0.51–1.79) 21.7 0.82 (0.45–1.50) 66.3 0.80 (0.44–1.47) 22.5 0.93 (0.51–1.69) 12.1 0.84 (0.40–1.76) 17.8 1.15 (0.58–2.26) IV (103.8–119.9) 20.9 1.33 (0.69–2.57) 22.5 0.82 (0.43–1.56) 66.5 0.81 (0.43–1.53) 33.5 1.68 (0.92–3.08) 13.2 0.94 (0.44–2.04) 14.1 0.78 (0.37–1.63) V(Ն120.0) 12.6 0.88 (0.43–1.80) 15.0 0.51 (0.26–1.02) 71.5 1.01 (0.53–1.93) 29.6 1.68 (0.91–3.10) 8.2 0.62 (0.26–1.46) 11.0 0.77 (0.35–1.69) Ptrend 0.1 0.9 0.01 0.09 0.8 0.8 0.2 0.01 0.1 0.6 0.02 0.3 PTH (ng/l) Men I(Ͻ35.0) 19.7 1.0 (ref.) 19.5 1.0 (ref.) 63.8 1.0 (ref.) 26.6 1.0 (ref.) 22.3 1.0 (ref.) 17.0 1.0 (ref.) II (35.0–42.9) 16.6 0.62 (0.27–1.44) 17.3 0.74 (0.31–1.78) 73.6 2.15 (1.03–4.47) 16.9 0.53 (0.23–1.23) 23.5 0.94 (0.42–2.10) 19.1 1.37 (0.56–3.35) III (43.0–49.9) 23.0 0.93 (0.42–2.05) 22.6 1.17 (0.51–2.70) 70.2 1.43 (0.70–2.92) 22.6 0.89 (0.40–1.97) 24.9 0.76 (0.34–1.70) 17.0 1.03 (0.42–2.56) IV (50.0–62.9) 21.9 0.88 (0.40–1.94) 18.7 0.76 (0.33–1.78) 75.9 1.80 (0.87–3.74) 20.8 0.73 (0.33–1.63) 33.4 1.41 (0.66–3.03) 18.7 1.23 (0.51–2.98) V(Ն63.0) 36.0 2.02 (0.96–4.24) 21.8 0.65 (0.28–1.53) 80.1 2.41 (1.10–5.26) 30.9 0.96 (0.44–2.12) 46.4 2.16 (1.01–4.59) 33.6 2.33 (1.02–5.35) Ͻ Ptrend 0.009 0.03 0.6 0.4 0.4 0.08 0.2 0.8 0.001 0.02 0.02 0.07
Women 2007 I(Ͻ33.0) 16.6 1.0 (ref.) 16.0 1.0 (ref.) 61.4 1.0 (ref.) 32.4 1.0 (ref.) 10.3 1.0 (ref.) 16.0 1.0 (ref.) II (33.0–40.9) 19.9 1.38 (0.70–2.71) 20.7 1.31 (0.65–2.63) 67.7 1.25 (0.70–2.22) 24.1 0.62 (0.34–1.11) 13.2 1.12 (0.50–2.51) 21.0 1.52 (0.74–3.14) UNE
III (41.0–48.9) 15.7 0.85 (0.41–1.75) 18.7 1.22 (0.60–2.51) 70.0 1.51 (0.84–2.72) 26.0 0.79 (0.44–1.41) 7.9 0.60 (0.24–1.50) 14.5 0.84 (0.39–1.84) 6, J IV (49.9–63.9) 18.5 1.02 (0.51–2.06) 30.6 2.53 (1.28–5.00) 72.0 1.50 (0.81–2.78) 26.8 0.70 (0.38–1.27) 11.9 0.77 (0.33–1.81) 18.6 0.82 (0.38–1.75) V(Ն64.0) 21.2 1.13 (0.57–2.26) 26.0 1.70 (0.85–3.40) 68.1 1.27 (0.70–2.31) 28.4 0.86 (0.48–1.54) 17.6 1.31 (0.59–2.92) 16.4 0.69 (0.31–1.50) NUMBER Ptrend 0.6 0.9 0.02 0.03 0.3 0.3 0.9 0.8 0.3 0.7 0.9 0.1
*Criteria as defined by the NCEP/ATP III (41). †Adjusted for age (years). ‡Adjusted for age (years), current smoking, alcohol use (Ն3 times per week), exercise (Ն3 times per week), season of study participation, 30, and, in women, hormone therapy. §Adjusted for variables listed above in addition to other components of metabolic syndrome. VOLUME , ARE C IABETES D Vitamin D, PTH, and metabolic syndrome calcium and the increased use of dietary levels. At the time the blood samples were 1995 supplements may result in significant measured, a radioimmunoassay was not 4. Ortlepp JR, Metrikat J, Albrecht M, von metabolic differences regarding circulat- available, and high-performance liquid Korff A, Hanrath P, Hoffmann R: The vi- ing calcium homeostasis. In fact, in the chromatography was more costly and la- tamin D receptor gene variant and physi- present study, mean 25(OH)D concentra- bor intensive. Recently, laboratory com- cal activity predicts fasting glucose levels in healthy young men. Diabet Med tions were significantly lower in women parisons have shown that CBP assays may 20:451–454, 2003 compared with men. To compensate for produce higher 25(OH)D levels com- 5. Scragg R, Sowers M, Bell C: Serum 25- low bioavailable vitamin D, it would be pared with radioimmunoassay or high- hydroxyvitamin D, diabetes, and ethnic- expected that PTH levels would be higher performance liquid chromatography ity in the Third National Health and in women. However, no significant sex methods (49,50). Nevertheless, routine Nutrition Examination Survey. Diabetes differences in mean PTH concentrations assays accurately rank individuals across Care 27:2813–2818, 2004 were observed. Future studies are re- the range of 25(OH)D levels (50), and 6. Bell NH, Epstein S, Greene A, Shary J, quired to confirm these sex-specific therefore the use of the CBP assay should Oexmann MJ, Shaw S: Evidence for alter- findings. not have affected the associations or lack ation of the vitamin D-endocrine system Results of this study differ from two of associations between 25(OH)D and the in obese subjects. J Clin Invest 76:370– 373, 1985 recent reports showing a significant in- metabolic syndrome reported here. We 7. Buffington C, Walker B, Cowan GS Jr, verse association between 25(OH)D lev- acknowledge that the external validity of Scruggs D: Vitamin D deficiency in the els and the prevalence of metabolic our findings may be limited to middle- to morbidly obese. Obes Surg 3:421–424, syndrome (1,18). Using cross-sectional upper-middle class Caucasians and may 1993 data from the Third National Health and not be generalizable to other groups or to 8. Liel Y, Ulmer E, Shary J, Hollis BW, Bell Nutrition Examination Survey, Ford et al. individuals residing outside a climate NH: Low circulating vitamin D in obesity. (18) showed that the odds of metabolic similar to that of southern California. Calcif Tissue Int 43:199–201, 1988 syndrome were 54% lower (OR 0.46 In conclusion, we found that elevated 9. Parikh SJ, Edelman M, Uwaifo GI, Freed- [95% CI 0.32–0.67]) among U.S. adults PTH levels were associated with an in- man RJ, Semega-Janneh M, Reynolds J, in the highest quintile of 25(OH)D com- creased prevalence of metabolic syn- Yanovski JA: The relationship between pared with those in the lowest quintile, drome in men, but not women, and this obesity and serum 1,25-dihydroxy vita- min D concentrations in healthy adults. with a significant trend of decreasing ORs association was not explained by age, sea- Ͻ J Clin Endocrinol Metab 89:1196–1199, across increasing quintiles (Ptrend son, major lifestyle factors, diabetes, renal 2004 0.001). These results were independent function, or 25(OH)D concentrations. 10. Snijder MB, van Dam RM, Visser M, Deeg of numerous confounding factors. In an- We also found evidence that this associa- DJ, Dekker JM, Bouter LM, Seidell JC, other study of 126 healthy, glucose- tion may be at least partly mediated Lips P: Adiposity in relation to vitamin D tolerant adults, the crude prevalence of through insulin resistance. The reason for status and parathyroid hormone levels: a metabolic syndrome was nearly three the sex difference in the PTH–metabolic population-based study in older men and times higher among those with vitamin D syndrome association is unknown. No as- women. J Clin Endocrinol Metab 90:4119– insufficiency [25(OH)D Ͻ50 nmol/l] sociation of 25(OH)D with the metabolic 4123, 2005 compared with those with higher syndrome was found in either sex. Pro- 11. Lind L, Wengle B, Wide L, Ljunghall S: ϭ Reduction of blood pressure during long- 25(OH)D levels (30 versus 11%, P spective studies are needed to further in- term treatment with active vitamin D (al- 0.0076) (1). The nonsignificant findings vestigate the putative etiologic roles for phacalcidol) is dependent on plasma in the present cohort may reflect their res- 25(OH)D and PTH in the development of renin activity and calcium status: a dou- idence in a southern California commu- metabolic syndrome in older adults. ble-blind, placebo-controlled study. Am J nity, which has a sunny and temperate Hypertens 2:20–25, 1989 year-round climate, reducing the variabil- 12. Pfeifer M, Begerow B, Minne HW, Nachti- ity observed in 25(OH)D. Skin exposure Acknowledgments— The Rancho Bernardo gall D, Hansen C: Effects of a short-term to sunlight (UVB radiation) is the pre- Study was funded by National Institute of Di- vitamin D(3) and calcium supplementa- dominant source of vitamin D, and UVB abetes and Digestive and Kidney Diseases tion on blood pressure and parathyroid Grant DK31801 and by National Institute on exposure varies greatly by latitude of res- hormone levels in elderly women. J Clin Aging Grant AG07181. Endocrinol Metab 86:1633–1637, 2001 idence (48). Thus, an effect of vitamin D 13. Lee S, Clark SA, Gill RK, Christakos S: in the pathogenesis of the metabolic ab- 1,25-Dihydroxyvitamin D3 and pancre- normalities underlying the metabolic syn- References atic beta-cell function: vitamin D recep- drome should not be completely ruled 1. Chiu KC, Chu A, Go VL, Saad MF: Hypo- tors, gene expression, and insulin out. vitaminosis D is associated with insulin secretion. Endocrinology 134:1602–1610, This study is limited by the cross- resistance and beta cell dysfunction. Am J 1994 sectional nature of these data, which im- Clin Nutr 79:820–825, 2004 14. Norman AW, Frankel JB, Heldt AM, pedes the ability to infer causality due to 2. Chiu KC, Chuang LM, Lee NP, Ryu JM, Grodsky GM: Vitamin D deficiency inhib- the absence of a temporal relation, and by McGullam JL, Tsai GP, Saad MF: Insulin its pancreatic secretion of insulin. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1555 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Is There a Single Underlying Factor for the Metabolic Syndrome in Adolescents? A confirmatory factor analysis
CHAOYANG LI, MD, PHD risk factors considering the potential phe- EARL S. FORD, MD, MPH notypic traits or components of the met- abolic syndrome in children and adolescents (5–15). The number of com- OBJECTIVE — The lack of a universally applicable model for the metabolic syndrome in the ponents ranged from 5 to 26, and the pediatric population makes it difficult to define this syndrome and compare its prevalence across number of factors identified ranged from studies and diverse populations. We sought to assess whether a single underlying factor could 1 to 7. The most frequently examined represent the metabolic syndrome in adolescents. measurements included one or more an- thropometric measures, blood pressure, RESEARCH DESIGN AND METHODS — Using data from the National Health and and concentrations of triglycerides, HDL Nutrition Examination Survey (1999–2002), we conducted a confirmatory factor analysis to assess the validity of waist circumference, triglycerides, fasting insulin, and systolic blood pres- cholesterol, and fasting insulin. No con- sure (SBP) as potential phenotypic traits for the metabolic syndrome in adolescents aged 12–17 sensus on the type and number of com- years (n ϭ 1,262). A multiple-group approach was used to test the invariance in factor loadings ponents for the metabolic syndrome has across sex and race/ethnicity. been reached thus far. Confirmatory factor analysis (CFA) RESULTS — The estimates of factor loadings for the total sample were 0.76, 0.46, 0.81, and has been used to evaluate the models with 0.42 for waist circumference, triglycerides, fasting insulin, and SBP, respectively. The goodness- four factors (16–18), a second-order fac- of-fit indexes were adequate for the total sample (comparative fit index, 0.99; standardized root tor (16), and one factor (19) in adults. mean square residual, 0.02), Caucasian boys (1.0; 0.01), African-American boys (0.99; 0.03), Using waist circumference or waist-to-hip Mexican-American boys (1.0; 0.01), Mexican-American girls (1.0; 0.01), and Caucasian girls (0.95; 0.04) and acceptable for African-American girls (0.94; 0.05). There were no significant ratio, BMI, fasting insulin or insulin sen- differences in factor loadings of the four measured variables between boys and girls and among sitivity, fasting glucose, triglycerides, the three racial or ethnic subgroups. HDL cholesterol, systolic blood pressure (SBP), and diastolic blood pressure CONCLUSIONS — The metabolic syndrome as a single underlying factor for the four simple (DBP), the four-factor model appeared to phenotypic traits may be plausible in adolescents. The proposed model appears to be general- be supported among Europeans, African izable across sex and race/ethnicity. Americans, and Hispanics (16–18) and provided insights in understanding the Diabetes Care 30:1556–1561, 2007 interrelationships among the measured variables. However, it did not directly ad- etabolic syndrome is a clustering Blood Cholesterol in Adults (Adult Treat- dress the nature of the metabolic syn- of metabolic risk factors including ment Panel III) (2), the prevalence of the drome as a single underlying factor. Using M abdominal obesity, dyslipidemia, metabolic syndrome was 4% during waist circumference, triglycerides–to–HDL glucose intolerance, and elevated blood 1988–1994 and increased to 6.4% dur- cholesterol ratio, homeostasis model as- pressure, and it has become a health chal- ing 1999–2000 (3) among adolescents in sessment of insulin resistance (HOMA-IR), ϳ lenge in children and adolescents (1). Us- the U.S. The prevalence was 30% and mean arterial pressure (MAP), a sin- ing a modification of the definition among U.S. overweight adolescents (4). gle-factor model of the metabolic syn- proposed by the National Cholesterol Ed- About a dozen studies have used ex- drome was identified in adults (19). This ucation Program Expert Panel on Detec- ploratory factor analysis to examine the model greatly simplified the modeling tion, Evaluation, and Treatment of High relationships of traditional and emerging process, yet calculating the three secondary ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● variables still required six direct measures. From the Division of Adult and Community Health, National Center for Chronic Disease Prevention and Lack of a universally acceptable and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia. applicable model for the metabolic syn- Address correspondence and reprint requests to Chaoyang Li, MD, PhD, Centers for Disease Control and Prevention, 4770 Buford Highway, MS K66, Atlanta, GA 30341. E-mail: [email protected]. drome in the pediatric population makes Received for publication 6 December 2006 and accepted in revised form 4 March 2007. it difficult to define this syndrome and Published ahead or print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06- compare its prevalence across studies and 2481. diverse populations. Using clinically The findings and conclusions in this article are those of the authors and do not necessarily represent the available measures and a conceptually views of the Centers for Disease Control and Prevention. Abbreviations: CFA, confirmatory factor analysis; CFI, comparative-fit index; DBP, diastolic blood simple model may be a practical way to pressure; HOMA-IR, homeostasis model assessment of insulin resistance; MAP, mean arterial pressure; SBP, define the metabolic syndrome and may systolic blood pressure. spur physicians to diagnose the syndrome A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion among their patients. Fasting insulin was factors for many substances. Ͼ © 2007 by the American Diabetes Association. highly correlated with HOMA-IR (r The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 0.95) (20), and adding fasting glucose to marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1556 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Li and Ford fasting insulin appeared to provide little level was calculated using triglyceride used to determine whether the factor improvement in relation to insulin resis- concentration divided by HDL choles- loadings between the two groups were tance in both adults (21) and children terol concentration. statistically significant. The Bonferroni (22). Elevated triglycerides have been Waist circumference was measured adjustments of the P values were applied considered a key marker for atherogenic by two trained health technicians using a for the comparisons of overall factor load- dyslipidemia (23). In addition, SBP was steel measuring tape to the nearest 0.1 cm ings among the three racial or ethnic sub- related to fasting insulin and body com- at the high point of the iliac crest at min- groups (0.05/3 ϭ 0.017), the four position measures, whereas DBP was not imal respiration when the participant was individual factor loadings (0.05/4 ϭ or was weakly related to these measures in in a standing position (29). Up to four SBP 0.013) by sex, and the six pairs of factor children and adolescents (24). and DBP readings were obtained from loadings (0.05/6 ϭ 0.008) of the final Thus, we proposed a new model us- participants. The average of the last two model for the total sample. ing four simple and directly measured measurements of SBP and DBP for the variables—waist circumference, triglyc- participants who had three or four mea- RESULTS — In the final analytic sam- erides, fasting insulin, and SBP—as the surements, the last measurement for the ple, 51.2% were boys, 29.4% Caucasians, potential phenotypic traits of the meta- participants with only two measure- 30.7% African Americans, and 39.9% bolic syndrome in adolescents. The goals ments, and the only measurement for the Mexican Americans. The means Ϯ SD and of this study were to examine the con- participants who had one measurement correlation coefficients of waist circum- struct validity and goodness of fit of the were used to establish high blood pres- ference, triglycerides, fasting insulin, and one-factor model proposed in adolescents sure status. MAP was calculated as DBP ϩ SBP are shown in Table 1. and to test the invariance in factor load- 1/3(SBP Ϫ DBP). The four-factor model proposed by ings across sex and race/ethnicity. Shen et al. (16) was carefully specified, yet Statistical analysis resulted in no convergence. The correla- RESEARCH DESIGN AND Fasting insulin, HOMA-IR, triglycerides, tion coefficients of DBP (ranged from 0.02 METHODS — The 1999–2002 Na- and triglycerides–to–HDL cholesterol to 0.10) or fasting glucose (0.04 to 0.22) tional Health and Nutrition Examination were log transformed to approximate a with other components were low. The es- Survey used a multistage, stratified sam- normal distribution. All variables were timates of goodness of fit for the one- pling design to represent the noninstitu- standardized (mean ϭ 0 and SD ϭ 1) for factor CFA model proposed in adults by tionalized civilian U.S. population age and sex. The four-factor model and Pladevall et al. (19) were adequate (Fig. (25,26). Participants were interviewed at the one-factor CFA model in adults were 1A). However, the factor loading for MAP home and were invited to attend a mobile specified according to Shen et al. (16) and was low (ϭ0.12), indicating a poor examination center where they provided Pladevall et al. (19). The one-factor model validity of this measure. a blood sample and were examined. We proposed in adolescents was specified as The estimates of goodness of fit for limited the analyses to boys and girls aged follows: waist circumference, triglycer- the one-factor CFA model proposed in 12–17 years who attended the morning ides, fating insulin, and SBP may be influ- the present study were adequate (Fig. 1B). medical examination, had fasted Ն8h, enced by an underlying factor, the The overall estimates of factor loadings for and had complete data on all variables “metabolic syndrome,” and a measure- the total sample were 0.76, 0.46, 0.81, (n ϭ 1,262). Only non-Hispanic Cauca- ment error. No correlated measurement and 0.42 for waist circumference, triglyc- sians, non-Hispanic African Americans, errors between any two measures were as- erides, fasting insulin, and SBP, respec- and Mexican Americans were included in sumed. The factor loading () of each tively. All estimates of factor loadings the final analyses. measured variable indicates the strength were Ͼ0.3, indicating an acceptable validity Serum specimens were frozen at of its association with the underlying fac- of the four directly measured variables. ϽϪ70°C, shipped on dry ice, and stored tor. We used a cutoff value of Ϯ0.3 as the The forthcoming analyses were based at ϽϪ70°C until analysis. Plasma insulin minimal level of a practically significant on the one-factor model in adolescents concentration was measured via a Phar- factor loading (30) and ␣ϭ0.05 as the sig- proposed in the present study. The esti- macia insulin radioimmunoassay kit nificance level for two-tailed statistical tests. mates of goodness-of-fit indexes were ex- (Pharmacia Diagnostics, Uppsala, Swe- The estimates of the parameters were cellent for Caucasian (Fig. 2A), African- den). Plasma glucose concentration was obtained using the maximum likelihood American (Fig. 2C), and Mexican- measured by using an enzymatic reaction method of the Mplus software (31). The American (Fig. 2E) boys and Mexican- (Cobas Mira Chemistry System; Roche 2 test, comparative fit index (CFI), and American girls (Fig. 2F); good for Diagnostic Systems, Montclair, NJ). De- standardized root mean square residual Caucasian girls (Fig. 2B); and acceptable tails on insulin assays can be found else- were used to assess the goodness of fit of for African-American girls (Fig. 2D). where (25–27). The HOMA-IR was the hypothesized model to the data Among the four measures, fasting insulin calculated as [glucose (mmol/l) ϫ insulin (30,31). A cutoff value between 0.90 and had the largest factor loading for the met- (U/ml)]/22.5 (28). Triglyceride concen- 0.95 for CFI is recommended as an ac- abolic syndrome in all sex- and race/ tration level was measured enzymatically ceptable fit (32), and a cutoff value of ethnicity-specific subgroups, except in in serum after being hydrolyzed to glyc- Ն0.95 for CFI or Յ0.08 for standardized African-American girls. erol using a series of coupled reactions. root mean square residual is recom- The estimates of factor loadings of the HDL cholesterol level was directly mea- mended for a good fit (32). four measures for the metabolic syn- sured on a Hitachi 704 Analyzer after the A multiple-group analysis was con- drome were similar between boys and precipitation of other lipoproteins with a ducted to test the invariance of factor girls (2 ϭ 4.88 [3 d.f.], P ϭ 0.18). There heparin-manganese chloride mixture. loadings in the CFA model across sex and was no statistical significance in the esti- The triglycerides–to–HDL cholesterol race/ethnicity. The 2 difference test was mates of factor loadings between boys and
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1557 The metabolic syndrome in adolescents
Table 1—Components of the four measured variables for the one-factor model by sex and race HDL cholesterol and triglycerides–to– among U.S. adolescents aged 12–17 years using the 1999–2002 National Health and Nutrition HDL cholesterol (r ϭϪ0.69). The factor Examination Survey loading of triglycerides (ϭ0.46) was similar to triglycerides–to–HDL choles- ϭ Correlation coefficient (r)* terol ratio ( 0.50), but slightly larger than that of HDL cholesterol (ϭ Waist Fasting Ϫ0.38). Multiple group analyses indi- Means Ϯ SD circumference Triglycerides insulin SBP cated that the factor structure of the Total (n ϭ 1,262) model using HDL cholesterol differed be- Waist circumference 79.75 Ϯ 14.18 1.00 tween African Americans and Mexican 2 ϭ ϭ Triglycerides 0.97 Ϯ 0.58 0.34 1.00 Americans ( 10.82 [3 d.f.], P Ϯ 0.0127). In addition, the factor loading of Fasting insulin 81.96 54.24 0.59 0.39 1.00 ϭ SBP 109.16 Ϯ 10.40 0.38 0.13 0.29 1.00 fasting insulin ( 0.81) was similar to ϭ that of HOMA-IR (ϭ0.78) but larger Caucasian boys (n 182) ϭ Waist circumference 79.60 Ϯ 14.77 1.00 than that of fasting glucose ( 0.17). Triglycerides 1.09 Ϯ 0.68 0.45 1.00 Fasting insulin 70.56 Ϯ 47.84 0.64 0.46 1.00 CONCLUSIONS — Based on the ad- SBP 110.27 Ϯ 11.58 0.50 0.33 0.45 1.00 equate fit and valid factor structures of the AA boys (n ϭ 213) one-factor model proposed in the present Waist circumference 78.28 Ϯ15.54 1.00 study, waist circumference, triglycerides, Triglycerides 0.79 Ϯ 0.37 0.33 1.00 fasting insulin, and SBP may be poten- Fasting insulin 76.87 Ϯ 44.02 0.63 0.40 1.00 tially useful as the four phenotypic traits SBP 113.68 Ϯ 10.93 0.42 0.13† 0.31 1.00 of an underlying factor that defines the MA boys (n ϭ 251) metabolic syndrome in adolescents. Of Waist circumference 82.74 Ϯ 14.77 1.00 the four simple and clinically available Triglycerides 1.06 Ϯ 0.66 0.47 1.00 Fasting insulin 86.35 Ϯ 64.05 0.68 0.54 1.00 SBP 111.47 Ϯ 9.87 0.34 0.20‡ 0.32 1.00 Caucasian girls (n ϭ 189) Waist circumference 76.70 Ϯ 10.89 1.00 Triglycerides 0.99 Ϯ 0.44 0.11 1.00 Fasting insulin 72.43 Ϯ 39.91 0.46 0.28 1.00 SBP 105.30 Ϯ 9.32 0.32 0.02§ 0.27 1.00 AA girls (n ϭ 175) Waist circumference 80.27 Ϯ 15.25 1.00 Triglycerides 0.78 Ϯ 0.41 0.22 1.00 Fasting insulin 98.45 Ϯ 67.05 0.52 0.34 1.00 SBP 107.97 Ϯ 9.21 0.38 0.05ʈ 0.20 1.00 MA girls (n ϭ 252) Waist circumference 80.06 Ϯ 2.82 1.00 Triglycerides 1.04 Ϯ 0.69 0.38 1.00 Fasting insulin 85.83 Ϯ 51.88 0.58 0.47 1.00 SBP 105.96 Ϯ 8.89 0.35 0.22 0.36 1.00 For waist circumference, triglycerides, fasting insulin, and blood pressure, the units are cm, mmol/l, pmol/l, and mmHg, respectively. *Statistically significant at ␣ϭ0.001 unless otherwise noted. †P ϭ 0.05; ‡P ϭ 0.002; §P ϭ 0.82; ʈP ϭ 0.48. AA, African American; MA, Mexican American.
2 ϭ 2 ϭϪ ϭ Figure 1—Construct validity and goodness- girls among Caucasians ( 6.26 [3 fasting insulin ( 0.06 [1 d.f.], P of-fit indexes of the one-factor CFA models of d.f.], P ϭ 0.10), African Americans (2 ϭ 0.81) and between triglycerides and SBP 2 the metabolic syndrome among U.S. adoles- 0.73 [3 d.f.], P ϭ 0.87), and Mexican ( ϭ 0.77 [1 d.f.], P ϭ 0.38). The factor cents aged 12–17 years, National Health and 2 Americans ( ϭ 3.21 [3 d.f.], P ϭ 0.36), loading of waist circumference was greater Nutrition Examination Survey (1999–2002). suggesting similarity in the construct va- than that of triglycerides (2 ϭ 59.78 [1 Measurement errors were not specified to be lidity of the measured variables for the d.f.], P Ͻ 0.01) and SBP (2 ϭ 77.43 [1 correlated in the CFA model. For clarity of metabolic syndrome across sex. No statis- d.f.], P Ͻ 0.01). The factor loading of fast- demonstration, the error terms of the CFA tically significant differences in the overall ing insulin was greater than that of trig- model were not shown. A: One-factor model in 2 ϭ Ͻ adults proposed by Pladevall et al. (19). n ϭ factor loadings among the three racial/ lycerides ( 79.14 [1 d.f.], P 0.01) 2 ϭ ϭ ϭ ϭ ethic subgroups were detected using Bon- and SBP (2 ϭ 89.37 [1 d.f.], P Ͻ 0.01). 1,262; 0.81; df 2; P 0.66; CFI 1.0; standardized root mean square residual ϭ ferroni adjustments for P values at the HDL cholesterol was inversely corre- ϭϪ 0.01. B: One-factor model in adolescents using 0.017 level (Table 2). lated with triglycerides (r 0.42). The direct measures. n ϭ 1,262; 2 ϭ 10.70; df ϭ There were no statistically significant correlation between triglycerides and 2; P ϭ 0.005; CFI ϭ 0.99; standardized root differences in the estimates of factor load- triglycerides–to–HDL cholesterol ratio mean square residual ϭ 0.02. Waist, waist cir- ings between waist circumference and (r ϭ 0.93) was stronger than that between cumference.
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fasting insulin as a potential component for the metabolic syndrome. At the sim- plest level, it is as good a surrogate esti- mate of insulin resistance (20–22) as various combinations of fasting insulin and glucose concentration such as HOMA-IR (28). Of greater clinical rele- vance may be the pathophysiological role that hyperinsulinemia plays in the devel- opment of the clinical abnormalities that occur more frequently in individuals who are insulin resistant. Finally, the construct validity of fasting insulin was similar to that of HOMA-IR, yet much greater than that of fasting glucose in the definition of the metabolic syndrome. The use of triglycerides in lieu of a triglycerides–to–HDL ratio or HDL cho- lesterol as a possible component of the metabolic syndrome in adolescents may have the following advantages: 1) triglyc- erides correlated more closely to triglyc- erides–to–HDL cholesterol ratio than HDL cholesterol; 2) the model using trig- lycerides was less variant in factor struc- tures than that using HDL cholesterol across sex and race/ethnicity; 3) elevated triglyceride concentrations have been considered a key marker for atherogenic dyslipidemia or the lipid triad, i.e., raised triglyceride levels, small LDL particles, and low HDL cholesterol (23); and 4) low HDL cholesterol was a component of the metabolic syndrome only in the presence of hypertriglyceridemia in patients with Figure 2—Factor loadings and goodness-of-fit indexes of one-factor CFA model for metabolic type 2 diabetes (33). Therefore, triglycer- syndrome by sex and race/ethnicity among U.S. adolescents aged 12–17 years, National Health ides appeared to be a preferable measure and Nutrition Examination Survey (1999–2002). Measurement errors were not specified to be of dyslipidemia in the definition of the correlated in the CFA model. For clarity of demonstration, the error terms of the CFA model were not shown. A: Caucasian boys: n ϭ 182; 2 ϭ 0.25; df ϭ 2; P ϭ 0.89; CFI ϭ 1.0; standardized root metabolic syndrome in adolescents. mean square residual ϭ 0.01. B: Caucasian girls: n ϭ 189; 2 ϭ 6.29; df ϭ 2; P ϭ0.04; CFI ϭ Insulin resistance and abdominal 0.95; standardized root mean square residual ϭ 0.04. C: African-American boys: n ϭ 213; 2 ϭ obesity have been proposed as major un- 3.55; df ϭ 2; P ϭ 0.17; CFI ϭ 0.99; standardized root mean square residual ϭ 0.03. D: African- derlying causes for the metabolic syn- American girls: n ϭ 175; 2 ϭ 8.2; df ϭ 2; P ϭ 0.02; CFI ϭ 0.94; standardized root mean square drome (34,35). Direct comparison of the residual ϭ 0.05. E: Mexican-American boys: n ϭ 251; 2 ϭ 0.37; df ϭ 2; P ϭ 0.83; CFI ϭ 1.0; relative importance of insulin resistance standardized root mean square residual ϭ 0.01. F: Mexican-American girls: n ϭ 252; 2 ϭ 0.39; and abdominal obesity in the metabolic ϭ ϭ ϭ ϭ df 2; P 0.82; CFI 1.0; standardized root mean square residual 0.01. Waist, waist syndrome is difficult and scarce in litera- circumference. ture. A previous study (15) showed that obesity might be a stronger component of measures, waist circumference and fast- construct validity (ϭ0.12). In fact, the metabolic syndrome in adolescents ing insulin appeared to be the major com- MAP, as a measure of average pressure than hyperinsulinemia. Our results, how- ponents in the syndrome. In particular, throughout the cardiac cycle, has been ever, that fasting insulin and waist cir- the one-factor model seemed to be gener- studied less in relation to insulin resis- cumference were approximately equally alizable in various subpopulations be- tance or obesity among both children and associated with the metabolic syndrome, cause no significant differences in the adults. In contrast, SBP was positively as- suggest that both insulin resistance and factor structures of the model across sex sociated with insulin resistance, whereas abdominal obesity may be the key fea- and race/ethnicity were detected in our DBP was not or was weakly associated tures of the syndrome. study. with insulin resistance (24). Thus, the use Our results provide a conceptual Despite an overall adequate fit for the of SBP as a potential component for the framework of the metabolic syndrome in model proposed by Pladevall et al. (19) in metabolic syndrome seemed to be more adolescents. To be useful in clinical prac- adults, MAP as a potential component for tenable than either MAP or a combination tice, research, and surveillance, findings the metabolic syndrome in adolescents of SBP and DBP in adolescents. from factor analyses have to be translated may be questionable because of its poor There are several advantages of using into a practical definition of the metabolic
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1559 The metabolic syndrome in adolescents
Table 2—Tests of equality for the factor loading of each measured variable between racial/ syndrome. One approach would be to ethnical groups by sex among U.S. adolescents aged 12–17 years using the 1999–2002 Na- emulate the definitions of the metabolic tional Health and Nutrition Examination Survey syndrome among adults, such as the ones developed by the National Cholesterol With equality With free 2 difference Education Program and the World Health constrains parameters test* Organization, and use threshold values for the components specific to children 2 2 2 Comparing group df df ⌬ df P and adolescents, as recommended in Total guidelines for waist circumference AA vs. Caucasian (4,36,37) and SBP (38). Adult thresholds Overall 19.83 9 14.10 6 5.73 3 0.13 for triglycerides would need to be adapted Waist circumference 19.31 7 15.38 6 3.93 1 0.05 to children and adolescents (2). The Triglycerides 19.31 7 18.43 6 0.88 1 0.35 threshold value of Ͼ20 mU/l for fasting Fasting insulin 19.31 7 19.28 6 0.02 1 0.88 plasma insulin concentration proposed SBP 19.31 7 15.56 6 3.75 1 0.05 by the American Heart Association may MA vs. Caucasian be potentially useful for the clinical as- Overall 21.00 9 14.10 6 6.89 3 0.08 Waist circumference 9.82 7 9.80 6 0.02 1 0.89 sessment of insulin resistance in pediatric Triglycerides 9.82 7 7.34 6 2.49 1 0.11 population (39). Another approach Fasting insulin 9.82 7 9.76 6 0.06 1 0.80 would be to develop a risk score for the SBP 9.82 7 4.99 6 4.84 1 0.03 metabolic syndrome based on multivari- AA vs. MA ate modeling or on summing z-scores for Overall 23.82 9 14.10 6 9.72 3 0.02 the components. Because such a risk Waist circumference 21.42 7 16.73 6 4.69 1 0.03 score is a continuous measure, one or Triglycerides 21.42 7 13.38 6 8.04 1 Ͻ0.01 more cut points could be established, Fasting insulin 21.42 7 21.35 6 0.07 1 0.79 leading to a classification such as having SBP 21.42 7 21.42 6 0.00 1 1.00 or not having the metabolic syndrome or Boys AA vs. Caucasian such as low, medium, or high risk for the Overall 8.87 9 4.16 6 4.71 3 0.19 metabolic syndrome. Waist circumference 8.51 7 7.59 6 0.92 1 0.34 In conclusion, our findings have im- Triglycerides 8.51 7 5.85 6 2.66 1 0.10 plications in clinical practice, epidemio- Fasting insulin 8.51 7 7.19 6 1.32 1 0.25 logic research, and public health SBP 8.51 7 6.90 6 1.60 1 0.21 surveillance. The one-factor model uses MA vs. Caucasian valid, simple, and easily available mea- Overall 13.82 9 4.16 6 9.66 3 0.02 sures to define the metabolic syndrome; Waist circumference 10.27 7 9.65 6 0.62 1 0.43 thus, it may facilitate the diagnosis of the Triglycerides 10.27 7 10.25 6 0.02 1 0.88 syndrome in clinical settings and the de- Fasting insulin 10.27 7 5.64 6 4.63 1 0.03 SBP 10.27 7 3.31 6 6.96 1 Ͻ0.01 velopment of a case definition for use in AA vs. MA surveillance. In addition, the model ap- Overall 10.03 9 4.16 6 5.87 3 0.12 peared to be consistent across sex and ra- Waist circumference 9.79 7 7.48 6 2.31 1 0.13 cial/ethnic subgroups and therefore could Triglycerides 9.79 7 6.17 6 3.61 1 0.06 be generalized to diverse populations. It Fasting insulin 9.79 7 9.59 6 0.20 1 0.66 might be of particular interest to use valid SBP 9.79 7 8.91 6 0.88 1 0.35 and universally applicable measures to Girls define the metabolic syndrome in the pe- AA vs. Caucasian diatric population, given the lack of a Overall 19.00 9 14.89 6 4.11 3 0.25 standard pediatric definition of the syn- Waist circumference 18.60 7 15.28 6 3.33 1 0.07 Triglycerides 18.60 7 18.12 6 0.49 1 0.49 drome to date. Fasting insulin 18.60 7 17.31 6 1.29 1 0.26 SBP 18.60 7 16.55 6 2.05 1 0.15 References MA vs. Caucasian 1. Goran MI, Ball GD, Cruz ML: Obesity and Overall 21.15 9 14.89 6 6.27 3 0.10 risk of type 2 diabetes and cardiovascular Waist circumference 12.95 7 12.85 6 0.10 1 0.75 disease in children and adolescents. J Clin Triglycerides 12.95 7 7.56 6 5.39 1 0.02 Endocrinol Metab 88:1417–1427, 2003 Fasting insulin 12.95 7 9.69 6 3.26 1 0.07 2. Executive summary of the Third Report of SBP 12.95 7 12.42 6 0.53 1 0.47 the National Cholesterol Education Pro- AA vs. MA gram (NCEP) Expert Panel on Detection, Overall 20.14 9 14.89 6 5.25 3 0.15 Evaluation, and Treatment of High Blood Waist circumference 13.85 7 10.86 6 2.99 1 0.08 Cholesterol in Adults (Adult Treatment Triglycerides 13.85 7 10.48 6 3.37 1 0.07 Panel III). JAMA 285:2486–2497, 2001 Fasting insulin 13.85 7 13.49 6 0.36 1 0.55 3. Duncan GE, Li SM, Zhou XH: Prevalence SBP 13.85 7 13.10 6 0.75 1 0.39 and trends of a metabolic syndrome phe- *⌬2 difference is the 2 value in the model with equality constrains subtracts 2 value in the model with free notype among U.S. Adolescents, 1999– parameters. AA, African American; MA, Mexican American. 2000. Diabetes Care 27:2438–2443, 2004
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1561 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Effect of BMI on Lifetime Risk for Diabetes in the U.S.
K.M.V. NARAYAN, MD EDWARD W. GREGG, PHD RESEARCH DESIGN AND JAMES P. BOYLE, PHD DAVID F. WILLIAMSON, PHD METHODS — We calculated preva- THEODORE J. THOMPSON, MS lence and incidence rates for 2004 from the nationally representative U.S. Na- tional Health Interview Survey (NHIS) OBJECTIVE — At birth, the lifetime risk of developing diabetes is one in three, but lifetime data (8–11). Multiyear data (1997– risks across BMI categories are unknown. We estimated BMI-specific lifetime diabetes risk in the 2004) were modeled to improve preci- U.S. for age-, sex-, and ethnicity-specific subgroups. sion of estimates for 2004. The NHIS is ϭ an ongoing, continuous, nationwide, RESEARCH DESIGN AND METHODS — National Health Interview Survey data (n cross-sectional survey of the U.S. nonin- 780,694, 1997–2004) were used to estimate age-, race-, sex-, and BMI-specific prevalence and incidence of diabetes in 2004. U.S. Census Bureau age-, race-, and sex-specific population and stitutionalized population. The NHIS mortality rate estimates for 2004 were combined with two previous studies of mortality to uses a multistage probability sampling estimate diabetes- and BMI-specific mortality rates. These estimates were used in a Markov strategy to select households and individ- model to project lifetime risk of diagnosed diabetes by baseline age, race, sex, and BMI. uals each year. Between 1997 and 2004, 301,840 households and 780,694 indi- RESULTS — Lifetime diabetes risk at 18 years of age increased from 7.6 to 70.3% between viduals participated, and in 2004 alone, underweight and very obese men and from 12.2 to 74.4% for women. The lifetime risk difference 36,579 households and 94,460 individu- was lower at older ages. At 65 years of age, compared with normal-weight male subjects, lifetime als participated. The overall response rate risk differences (percent) increased from 3.7 to 23.9 percentage points between overweight and varies annually but is ϳ90%. very obese men and from 8.7 to 26.7 percentage points for women. The impact of BMI on Prevalence was assessed from the an- diabetes duration also decreased with age. swer to the question, “Have you ever been CONCLUSIONS — Overweight and especially obesity, particularly at younger ages, sub- told by a doctor or health professional stantially increases lifetime risk of diagnosed diabetes, while their impact on diabetes risk, life (other than during pregnancy, if female) expectancy, and diabetes duration diminishes with age. that you have diabetes or sugar diabetes?” Incidence was assessed from age at the Diabetes Care 30:1562–1566, 2007 time of survey and the answer to the ques- tion, “How old were you when a doctor he prevalence of diagnosed diabetes (6,7), they have been used in public edu- first told you that you had diabetes or among U.S. adults has risen twofold cation campaigns for disease prevention sugar diabetes?” We calculated the num- T in the past 40 years and 75% during (10–14). Lifetime risk estimates for di- ber of years each person had been diag- the past 25 years (1,2). The lifetime risk of abetes according to BMI would be valu- nosed with diabetes by subtracting the diabetes in the U.S. in 2000 was 33% for able for 1) communicating an indi- age at which they were diagnosed from male subjects and 39% for female subjects vidual’s risk of diabetes given his/her their current age. Adults who had a value and was even higher among U.S. minority BMI and 2) identifying groups of indi- of 0 were identified as having been diag- groups (3). BMI is a powerful and modi- viduals who would benefit most from nosed with diabetes within the last year; fiable risk factor for diabetes (4,5). How- primary prevention. one-half of the adults who had a value of 1 ever, the impact of BMI on the lifetime In this study, we estimate the lifetime were classified as having been diagnosed risk of diabetes has not been evaluated, risk of diabetes (risk from age 18 years with diabetes within the last year. Self- and no data are available on the compar- until death or age 85 years) by baseline reported weight and height were used to ative lifetime risks of diabetes across cat- age, race, sex, and BMI for the U.S. pop- calculate BMI. egories of BMI. Because lifetime risk ulation and present the results in a form There were 15,843 prevalent cases of estimates are easily understood measures suitable for communication with individ- diagnosed diabetes among the 242,957 of the impact of disease in individuals uals at risk and with policy makers. respondents, and 1,514 incident cases ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● among the 228,628 nondiabetic respon- dents, aged 18–84 years, in the NHIS for From the Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia. 1997–2004. We used Bayesian hierarchi- Address correspondence and reprint requests to K.M. Venkat Narayan, Hubert Professor of Global Health cal logistic regression (12) with random & Epidemiology, Emory University, Atlanta, GA 30322. E-mail: [email protected]. intercepts by calendar year to estimate di- Received for publication 19 December 2006 and accepted in revised form 8 March 2007. abetes prevalence and incidence as a func- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2544. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ tion of age (18–84 years in 1-year dc06-2544. intervals), race/ethnicity (non-Hispanic Abbreviations: NHIS, National Health Interview Survey. white, non-Hispanic black, Hispanic, or A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion other), sex, and BMI (underweight, factors for many substances. Ͻ18.5 kg/m2; normal weight, 18.5 to © 2007 by the American Diabetes Association. Ͻ 2 Ͻ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 25 kg/m ; overweight, 25 to 30 kg/ 2 2 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. m ; obese, 30 to Ͻ35 kg/m ; and very
1562 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Narayan and Associates
Table 1—Remaining lifetime risk of developing diabetes by baseline BMI and age
Remaining lifetime risk Non-Hispanic White Black Hispanic Total Baseline age BMI group (years) (kg/m2) Male Female Male Female Male Female Male Female 18 Ͻ18.5 6.2 9.8 9.0 14.9 9.7 15.5 7.6 (0.2–25.9) 12.2 (4.0–24.4) 18.5 to Ͻ25 16.9 14.5 21.4 18.4 25.0 21.5 19.8 (16.1–23.8) 17.1 (14.2–20.4) 25 to Ͻ30 25.5 30.7 33.1 39.3 36.9 43.4 29.7 (25.9–33.7) 35.4 (31.3–20.4) 30 to Ͻ35 51.8 48.8 61.3 60.1 68.1 66.0 57.0 (51.4–62.6) 54.6 (49.2–60.3) 35ϩ 66.1 69.3 72.9 79.8 81.1 86.0 70.3 (63.9–76.5) 74.4 (69.1–79.3) 45 Ͻ18.5 6.0 9.1 9.2 14.1 9.3 14.0 6.9 (0.1–23.8) 10.6 (3.1–22.2) 18.5 to Ͻ25 15.9 13.2 20.7 16.7 23.3 18.9 17.7 (14.2–21.5) 14.7 (12.1–17.7) 25 to Ͻ30 23.7 27.5 31.7 35.6 33.8 38.0 26.2 (22.7–30.0) 30.4 (26.5–34.7) 30 to Ͻ35 47.5 42.2 59.2 53.4 62.9 56.4 50.9 (45.1–56.9) 45.8 (40.3–51.7) 35ϩ 59.4 58.4 71.0 71.2 75.6 74.5 62.7 (55.2–69.8) 62.2 (55.9–68.4) 65 Ͻ18.5 2.1 3.5 2.5 4.2 3.0 4.9 2.2 (0.0–8.7) 3.7 (0.7–9.4) 18.5 to Ͻ25 10.2 9.0 10.3 8.7 14.0 11.9 10.8 (8.2–13.7) 9.3 (7.4–11.7) 25 to Ͻ30 13.8 17.3 14.4 17.5 18.6 22.5 14.5 (11.7–17.6) 18.0 (14.9–21.6) 30 to Ͻ35 28.3 26.3 29.8 26.9 37.2 33.8 29.6 (23.8–36.1) 27.3 (22.0–33.1) 35ϩ 33.2 34.9 35.2 35.7 43.6 44.3 34.7 (25.8–44.5) 36.0 (27.8–45.0) Data are percent or percent (95% Bayesian CI). obese, Ͼ35 kg/m2). To derive 2004 age-, death without diabetes. We estimated two diabetic individuals in the 2004 U.S. race/ethnicity-, sex-, BMI category–, and probabilities for individuals who have de- population. diabetes-specific mortality rates, we used veloped diabetes: 1) the probability of re- the following additional sources: 1) U.S. maining diabetic (for this analysis we RESULTS Census Bureau 2004 population and assumed that once diagnosed, diabetes mortality rates by age, race/ethnicity, and was not reversible) and 2) the probability Lifetime risk by BMI sex (13); 2) NHIS estimates of BMI prev- of dying with diabetes. Lifetime diabetes risk increases with base- alence by age-group, race/ethnicity, and Using these probabilities in a Markov line BMI in both sexes and at every base- sex; 3) age-group– and sex-specific rela- chain model (16), we estimated the fol- line age (Fig. 1). At 18 years of age, for tive risk estimates of death attributable to lowing for each race/ethnicity, sex, and male subjects, the remaining lifetime dia- diabetes (14); and 4) age-group– and BMI category: 1) the remaining lifetime betes risk ranged from 7.6% for those BMI-specific relative risk estimates of with BMI Ͻ18.5 kg/m2 to 70.3% for those risk for diabetes among indviduals who Ͼ 2 death (15). are not diabetic at a specific “baseline” BMI 35 kg/m . For female subjects, the age, 2) the average remaining lifetime, remaining lifetime risk ranged from 12.2 Markov chain model to 74.4% for baseline BMIs of Ͻ18.5 and and 3) the average duration of diabetes. Markov chain models simulate the pro- Ͼ35 kg/m2, respectively. The increase in The Markov chain model presented here gression of individuals through mutually remaining lifetime diabetes risk by BMI, can be considered an extension of the life exclusive disease states. Transitions be- however, is less steep at older baseline tween states take place at discrete inter- table technique. It begins with age- ages. At 65 years of age, the remaining vals, and the number of individuals who specific transition rates for a given time lifetime risk ranged from 2.2 to 34.7% for move from one state to another during period, and then it assumes that this male subjects with BMIs of Ͻ18.5 and each cycle is determined by transition schedule of rates is in operation for the Ͼ35 kg/m2, respectively, and from 3.7 to probabilities (detailed in “A Markov lifetime of a hypothetical birth cohort. 36.0% for female subjects with BMIs of Chain Model for Lifetime of Risk by BMI” This cohort is “aged” year by year to pro- Ͻ18.5 and Ͼ35 kg/m2, respectively. found in an online appendix at http:// duce remaining lifetime risks for diabetes At 18 years of age, compared with dx.doi.org/10.2337/dc06-2544). For at each age, assuming that the age-specific normal weight, the absolute increase in each race/ethnicity-sex-BMI combina- transition rates do not change. We esti- lifetime risk for male subjects was 9.9, tion, we estimated three age-specific mated 40 sets of parameters and the asso- 37.2, and 50.5 percentage points for over- 1-year transition probabilities for nondi- ciated Markov chains corresponding to weight, obese, and very obese, respec- abetic individuals up through age 84 the race/ethnicity-sex-BMI combinations. tively; for female subjects, the absolute years: 1) the probability of remaining We calculated all race/ethnicity estimates increase in lifetime risk was 18.3, 37.5, nondiabetic, 2) the probability of becom- (Table 1) by weighing the race/ethnicity- and 57.3 percentage points, respectively. ing diabetic, and 3) the probability of specific values by the proportions of non- By comparison, at 65 years of age, com-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1563 BMI and diabetes risk in the U.S.
and obese individuals than between nor- mal weight and overweight individuals. These results are consistent with the find- ings that individuals with BMI Ն30 kg/m2 have a clear elevated risk of death (15,17). Furthermore, recent analyses of national diabetes trends also indicate that the sub- stantial majority of the secular increase in diabetes has occurred in individuals with BMI Ն30 kg/m2 (18). These estimates of lifetime risk for di- abetes must be carefully interpreted. The lifetime risk estimates are for an “average person” in the U.S. population in 2004. The level of diabetes risk factors, espe- cially obesity, genetic background, diet, physical activity, and socioeconomic fac- tors, may raise or lower the lifetime risks away from the average for an individual. Our data on diagnosed diabetes and BMI were based on self-report. The accu- racy of self-reporting for diabetes is rea- sonably high in population surveys; self- reported diabetes has high specificity and a positive predictive value but low sensi- tivity (19,20). When comparing self- reported to measured weight and height, heavier individuals tend to underreport their weight more than leaner individuals, and shorter individuals tend to overreport their height (21). The magnitude of re- Figure 1— Remaining average lifetime risk of diabetes by age and BMI among women (A) and porting error depends on the mode of as- men (B). sessment, however. For example, when prevalence estimates for obesity were compared, it was found that bias in self- pared with normal weight, lifetime risk kg/m2, respectively, and 57.9 and 53.5 reported weight was larger in telephone increased for male subjects by only 3.7, years, respectively, for female subjects. interviews than in-person interviews 18.8, and 23.9 percentage points for over- The impact of BMI on life expectancy and (22). In the setting of rigorous in-person weight, obese, and very obese, respec- years spent with diabetes decreases with interviews, as in the NHIS, it has been tively, and for female subjects by only 8.7, age. Because of the earlier onset of disease, shown that relationships with serum glu- 18.0, and 26.7 percentage points. The re- the number of expected years with diabe- cose and other physiologic measures are maining lifetime risk for diabetes was gen- tes is longer with increasing BMI at all equally strong for self-reported and mea- erally higher among minority groups in baseline ages and in both sexes. The im- sured weight and height (23). both sexes and at all ages and baseline pact of BMI on expected years with diabe- We assumed that diabetes incidence BMI strata (Table 1). tes, however, decreases with increasing rates would be constant over the remain- age. ing lifetime of the cohort, even though Expected years with and without obesity is rapidly increasing in the U.S. diabetes CONCLUSIONS — Taken as a whole, (24). The incidence of diabetes may also The average number of years of life re- our data suggest that adult lifetime risk of consequently increase in the future maining with and without diabetes by diabetes is most strongly affected by BMI (25,26). An additional factor that may sex, baseline age, and BMI are shown in Ն30 kg/m2 and that the impact of BMI, ex- limit the accuracy of our projections is the Fig. 2. Women, on average, have both pressed in terms of absolute risk of diabetes, projected increase in life expectancy, par- longer life expectancies and spend more diminishes with increasing age at risk. Our ticularly for U.S. ethnic minority groups years with diabetes. There is a U-shaped data also underscore the strong impact of (27), which will also increase the average association between BMI and life expect- obesity on diabetes-associated morbidity lifetime risk for diabetes in the total U.S. ancy in men and women at all baseline and mortality, but the impact of BMI on population. Our estimates, however, are ages, with the lowest life expectancy expected years with diabetes and life ex- based on age-, sex-, race/ethnicity-, and among individuals with BMI Ͻ18.5 pectancy also decreases with age. BMI-specific diabetes incidence and mor- kg/m2 and those with BMI Ն35 kg/m2. Although the lifetime risk of diabetes tality rates. Another limitation is that we For example, remaining life expectancy at is directly related to BMI in both sexes, the did not have BMI-specific data on life ex- 18 years of age is 53.5 and 47.9 years for incremental increase in absolute risk pectancy for individuals with diabetes, male subjects with BMI Ͻ18 and Ն35 among men is larger between overweight and we had to use the relative risks of BMI
1564 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Narayan and Associates
than the values we used, then the dura- tion with diabetes will be less; however, the precise impact on lifetime risk of dia- betes is not clear. Unlike estimates of lifetime risks re- ported for other diseases and condi- tions—based on local or regional epidemiological cohort studies of disease incidence—our estimates are based on nationally representative data. Cohort studies are subject to several biases, in- cluding volunteer bias for healthy partic- ipants, and temporal trends within a cohort may also confound the estimation of lifetime risks. Our method of estima- tion of lifetime risk allows for more accu- rate inference to the general population than methods based on the experience of subjects followed in cohort studies. Major clinical trials have shown that diabetes can be delayed or prevented among high-risk individuals (5). Our findings on the lifetime risk by BMI point to individuals with BMI Ն30 kg/m2 as an important subgroup for targeted diabetes prevention efforts. This is particularly true among individuals Ն65 years of age, who are at increased risk of diabetes pri- marily because of age. Our analyses also confirm the large marginal increase in expected years with diabetes and in life- years lost from diabetes among individu- als with BMI Ն30 kg/m2 and the rather smaller impact among individuals with BMI 25–30 kg/m2, compared with nor- mal-weight individuals. Although obesity appears to have a much more pronounced Figure 2—Average number of years of life remaining with (f) and without ( ) diabetes, ac- cording to baseline age and BMI among women (A) and men (B). impact on risk of diagnosed diabetes than overweight, there is concern about young individuals who begin adulthood in the on mortality for the general population in The data used for our estimates did overweight category. This is because our estimations. Finally, we have com- not differentiate between type 1 and type young adults who are already overweight puted remaining lifetime risks based on 2 diabetes. However, type 2 diabetes ac- are substantially more likely to become the BMI at one point in time. BMI, how- counts for up to 95% of cases (29). obese earlier in adulthood than their nor- ever, generally increases with age until the Among children, however, type 1 diabe- mal-weight peers. fifth and sixth decades of life and de- tes poses a greater risk, but we have de- Individuals with BMI Ն30 kg/m2 are creases thereafter (28). Although it is dif- fined lifetime risk as the risk of diabetes at substantially heightened lifetime risk of ficult to predict the magnitude and from age 18 years to death or age 85 years. diabetes, excess years with diabetes, and direction of bias attributable to use of a Although the accuracy of our estimates excess life-years lost to diabetes. If this single BMI value, we may have underesti- depends on the accuracy of the relative heightened risk can be communicated in mated risk attributable to BMI in our risks for death from diabetes and of BMI a way individuals can readily understand, study. In younger adults, a single BMI that we used, we believe that the age- they may become motivated. Estimates of value may lead to an underestimation of specific relative risk estimates used lifetime risks may help this process. their risk of future diabetes because they closely reflect those of individuals with will likely continue to gain weight for sev- diabetes in the U.S., and the age- and sex- eral decades. For older adults, a single specific estimates of relative risk that we References BMI value may also lead to an underesti- used are consistent with recent estimates 1. Gregg EW, Cadwell BL, Cheng YJ, Cowie CC, Williams DE, Geiss L et al: Trends in mation of their remaining lifetime risk be- from a National Health and Nutrition Ex- the prevalence and ratio of diagnosed to cause it will not reflect the preceding amination Survey (NHANES II) mortality undiagnosed diabetes according to obe- decades of exposure to BMI levels that study and with those from previous stud- sity levels in the U.S. Diabetes Care 27: were likely elevated before experiencing ies (30,31). If the true age-specific relative 2806–2812, 2004 age-related weight loss. risks of death from diabetes are higher 2. Centers for Disease Control and Preven-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1565 BMI and diabetes risk in the U.S.
tion: National Diabetes Surveilliance Sys- sumptions of the resident population by correction for self-report bias: analysis of tem: data and trends, [Internet], 2006. age, sex, race/ethnicity, and Hispanic ori- health surveys. J R Soc Med 99:250–257, Available from http://www.cdc.gov/diabetes/ gin: lowest, middle, and highest series, 2006 statistics/index.htm. Accessed 13 April 2007 1999 to 2100. Washington DC: U.S. Cen- 23. McAdams MA, Van Dam RM, and Hu FB: 3. Narayan KM, Boyle JP, Thompson TJ, So- sus Bureau; 2000 Comparison of self-reported and mea- rensen SE, Williamson DF: Lifetime risk 14. Tierney EF, Geiss LS, Engelgau MM, sured BMI as correlates of disease markers of diabetes mellitus in the United States. Thompson TJ, Schaubert D, Shirley LA, in U.S. adults. Obesity. 15:188–196, 2007 JAMA 290:1884–1890, 2003 Vukelic PJ, McDonough SL: Population- 24. Flegal KM, Carroll MD, Ogden CL, John- 4. Ford ES, Williamson DF, Liu S: Weight based estimates of mortality associated son CL: Prevalence and trends in obesity change and diabetes incidence: findings with diabetes: use of a death certificate among US adults, 1999–2000. JAMA from a national cohort of US adults. Am J check box in North Dakota. Am J Public 288:1723–1727, 2002 Epidemiol 146:214–222, 1997 Health 91:84–92, 2001 25. Leibson CL, O’Brien PC, Atkinsin E, 5. Diabetes Prevention Program Research 15. Flegal KM, Graubard BI, Williamson DF, Palumbo PJ, Melton III LJ: Relative con- Group. Reduction in the incidence of type Gail MH: Excess deaths associated with tributions of incidence and survival to 2 diabetes with lifestyle intervention or underweight, overweight, and obesity. increasing prevalence of adult-onset dia- metformin. N Engl J Med 2002;346:393– JAMA 293:1861–1867, 2005 betes mellitus: a population-based study. 403 16. Hoel PG, Port SC, Stone CJ: Markov Am J Epidemiol 146:12–22, 1997 6. Phillips K, Glendon G, Knight JA: Putting Chain. In Introduction to Stochastic Processes. 26. Burke JP, Williams K, Gaskill SP, Hazuda the risk of breast cancer in perspective. Boston, MA, Houghten Mifflin Company, HP, Haffner SM, Stern MP: Rapid rise in N Engl J Med 340:141–144, 1999 1972, p. 1–39 the incidence of type 2 diabetes from 7. Sasieni PD, Adams J: Standardized life- 17. Gu D, He J, Duan X, Reynolds K, Wu X, 1987 to 1997: results from the San Anto- time risk. Am J Epidemiol 149:869–875, Chen J, Huang G, Chen C, Whelton PK: nio Heart Study. Arch Intern Med 159: 1999 Body weight and mortality among men 1450–1456, 1999 8. National Center for Health Statistics: and women in China. JAMA 295: 27. National Center for Health Statistics: 1990 National Health Interview Survey 776–783, 2006 Health, United States, 2002 [Internet], [database on CDROM]. CD-ROM Series 18. Gregg EW, Cheng YJ, Thompson TJ, 10, No. 4. SETS Version 1.21. Washing- Narayan KM, Williamson DF The contri- 2007. Available at www.cdc.gov/nchs/ ton, DC, U.S. Government Printing Of- butions of changes in prevalence of over- hus.htm. Accessed 13 April 2007 fice, 1993 weight, obesity, and severe obesity to the 28. Williamson DF, Kahn HS, Remington PL, 9. Design and estimation for the National increase in diabetes prevalence in the Anda RF: The 10-year incidence of over- Health Interview Survey, 1995–2004. Vi- U.S.: 1976–2004 (Abstract). Diabetes.In weight and major weight gain in United tal Health Stat 2 130:1–31, 2000 press States adults. Arch Int Med 150:665–672, 10. Department of Health and Human Ser- 19. O’Connor PJ, Rush WA, Pronk NP, Cher- 1990 vices: Summary Health Statistics for U.S. ney LM. Am J Man Care 4:335–342, 1998 29. Harris MI: Summary. In Diabetes in Amer- Children: National Health Interview Sur- 20. Saydah SH, Geiss, Tierney E, Benjamin ica. 2nd ed. Washington, DC, Govt. Print- vey, 1998. Atlanta: Centers for Disease SM, Engelgau M, Brancati F: Review of the ing Office, 1995, p. 1–14 (NIH Pub- Control and Prevention; 2002. Available at performance of methods to identify dia- lication No. 95-1468) www.cdc.gov/nchs/data/series/sr10/sr10 betes cases among vital statistics, admin- 30. Gu K, Cowie CC, Harris MI: Mortality in 208.pdf. Accessed 13 April 2007 istrative, and survey data. Ann Epidemiol adults with and without diabetes in a na-
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1566 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk ORIGINAL ARTICLE
Strong Association Between Time Watching Television and Blood Glucose Control in Children and Adolescents With Type 1 Diabetes
1,2,3 1,2,3 HANNA D. MARGEIRSDOTTIR, MD KNUT DAHL-JØRGENSEN, MD least one television set in almost every 1,2,3 JAKOB R. LARSEN, MD FOR THE NORWEGIAN STUDY GROUP FOR home in the country and 34% of all chil- 4 CATHRINE BRUNBORG, MSC CHILDHOOD DIABETES 4 dren having a television in their bedroom LEIV SANDVIK, PHD (18). Patients with type 1 diabetes are at higher risk of developing CVD than the gen- OBJECTIVE — To examine the relationship between blood glucose control and the time eral population (19), and long-term blood spent watching television in Norwegian children and adolescents with type 1 diabetes in a glucose control is a strong predictor for population-based study. CVD in type 1 diabetes (20–22). The devel- opment of atherosclerosis starts early in life RESEARCH DESIGN AND METHODS — A total of 538 children and adolescents from (19). To our knowledge, no studies have 9 hospitals in the eastern part of Norway participated in the study; 70% of eligible subjects participated. The time spent watching television and time using a computer was recorded reported the influence of television watch- separately by interview together with clinical data. Mean (ϮSD) age was 13.1 Ϯ 3.7 years, mean ing on blood glucose control or CVD risk diabetes duration was 5.4 Ϯ 3.4 years, and mean A1C was 8.6 Ϯ 1.3% (reference range 4.1–6.4). factors in children and adolescents with type 1 diabetes. RESULTS — Sixty-two patients (11%) watched television Ͻ1 h daily (mean A1C 8.2 Ϯ 0.9%), 189 patients (35%) watched television between 1 and 2 h daily (8.4 Ϯ 1.2%), 166 RESEARCH DESIGN AND patients (31%) watched television 2–3 h daily (8.7 Ϯ 1.4%), 75 patients (14%) watched televi- METHODS — The study was ap- sion 3–4 h daily (8.8 Ϯ 1.2%), and 46 patients (9%) watched television Ն4 h daily (9.5 Ϯ 1.6%). Ͻ proved by the Governmental Regional This trend was highly significant (P 0.001). The association between television viewing and Committee for Ethics in Medical Research A1C remained significant, even after adjusting for age and BMI and insulin dose. No correlation and the Norwegian Data Inspection between A1C and the use of a personal computer was observed. Board. The subjects gave written in- CONCLUSIONS — Extensive television watching is associated with poor blood glucose formed consent. control in children and adolescents with type 1 diabetes. The study was performed in 2001 in eight pediatric departments in Norway. Diabetes Care 30:1567–1570, 2007 The clinics are located in the middle and east part of Norway, covering one large edentary behavior is associated with activity (1,3,7,14). These studies emphasize city (Oslo), smaller cities and towns, and increased risk of obesity and cardio- the relevance of studying sedentary behav- countryside areas. All diabetic children in S vascular disease (CVD) risk factors ior as a distinct entity. Norway are treated at the pediatric clinics (1–3), and physical inactivity and lack of Children and adolescents in the U.S. of the public hospitals. A total of 70% of physical fitness are directly associated with spend more time watching television than eligible subjects participated (hospital increased mortality from CVD (4,5). One of any other activity except sleep, and the range 46–100%), with all but one clinic Ͼ the most common leisure time sedentary time spent watching television may even reporting 60% of their patients. behaviors, television viewing, has been exceed time spent in school (6,9,13,15). Data were collected from a case studied extensively in nondiabetic subjects The vast majority of children in the U.S. record form based on the World Health (6–13). Findings suggest that this behavior are growing up in homes where television Organization Basic Information Sheet for has an effect on obesity and CVD risk factors is a near-constant presence (16,17). The children and adolescents. The case record that is independent of leisure time physical situation is similar in Norway, with at form includes detailed information about ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● the insulin regimen, acute and chronic complications, age, height, weight, pu- From the 1Faculty of Medicine, University of Oslo, Oslo, Norway; the 2Department of Pediatrics, Ullevaal University Hospital, University of Oslo, Oslo, Norway; the 3Diabetes Research Centre, Aker and Ullevaal berty stages, blood pressure, and tobacco University Hospitals, Oslo, Norway; and the 4Center for Medical Statistics, Ullevaal University Hospital, smoking. It also includes in-depth family University of Oslo, Oslo, Norway. history of diabetes and CVD. Daily time Address correspondence and reprint requests to Hanna Dis Margeirsdottir, Department of Pediatrics, spent watching television or using a com- Ullevaal University Hospital, 0407 Oslo, Norway. E-mail: [email protected]. Received for publication 12 October 2006 and accepted in revised form 9 March 2007. puter (including time spent playing com- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2112. puter games) was recorded separately by Abbreviations: CVD, cardiovascular disease. interview of the patient and, in the A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion younger children, by interview of one or factors for many substances. both of the parents. Subjects were asked © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby for the number of hours spent watching marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. television and video/DVDs for both week-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1567 Television viewing and blood glucose control
Table 1—Patient characteristics A statistically significant positive as- sociation between television viewing and Male subjects Female subjects Total age and insulin dose (IE/kg) was demon- strated but not with BMI z score (see Ta- n 265 273 538 ble 2). Multiple regression analysis Age (years) 13.1 Ϯ 3.5 13.0 Ϯ 3.9 13.1 Ϯ 3.7 showed a strong association between tele- Duration of disease (years) 5.4 Ϯ 3.1 5.7 Ϯ 3.5 5.6 Ϯ 3.4 vision viewing and A1C even after adjust- A1C (%) 8.6 Ϯ 1.3 8.7 Ϯ 1.3 8.6 Ϯ 1.3 ing for age and BMI and insulin dose BMI (kg/m²) 19.3 Ϯ 3.1 20.3 Ϯ 3.1 19.8 Ϯ 3.1 (Table 3). Data are means Ϯ SD. CONCLUSIONS — In the present days and weekend days. The average association between television viewing population-based study of 538 children number of hours watching television per and A1C remained significant after ad- and adolescents with type 1 diabetes, we day was used for data analysis. All patients justing for other independent variables. A show for the first time a continuous in- were interviewed and examined at the significance level of 5% was used. crease in A1C with every hour of watch- outpatient clinic they attended. The re- ing television. This association was sponsible physician performed an ex- RESULTS — The number of patients independent of age, duration of disease, tended and standardized examination of included in the study was 538. The mean and BMI. The American Academy of Pe- all patients. A1C was measured in the age of the patients was 13.1 Ϯ 3.7 years, diatrics recommends that children’s tele- same central laboratory for all patients by diabetes duration was 5.4 years, and the vision viewing should be limited to no high-performance liquid chromatogra- mean A1C was 8.6 Ϯ 1.3% (Table 1). more than 2 h per day (15). Fifty-five per- phy (Variant; Bio-Rad, Richmond, CA), They watched television for 1.9 h per day cent of the patients in our study exceeded Diabetes Control and Complications Trial (range 0–8) (114 min per day) on aver- this limit. standardized. The intra-assay coefficient age. There were no differences between Several modes of behavior might ex- of variation was Ͻ3%. Reference values male and female subjects with regard to plain the positive association between were 4.1–6.4%. age, diabetes duration, A1C, and hours of television viewing and A1C. Television Statistical analysis. All statistical analy- watching television. The distribution of viewing might displace physical activity ses were done using the SPSS software the number of hours of television viewing and encourage poor dietary habits. How- package for Windows, version 14.0 per day is shown in Table 2. A total of 62 ever, physical activity and television view- (SPSS, Chicago, IL). Data are presented by patients (11%) watched television Ͻ1h ing are poorly related in other studies in means Ϯ SD or proportions. The BMI val- daily (mean A1C 8.2 Ϯ 0.9%). A total of the general population (11,12,24). Fur- ues were standardized by conversion to z 189 patients (35%) watched television thermore, physical activity is not neces- score in groups defined by age and sex, between 1 and 2 h daily (mean A1C 8.4 Ϯ sarily associated with good metabolic using the Centers for Disease Control and 1.2%). A total of 166 patients (31%) control in type 1 diabetic patients (25– Prevention growth charts 2000 (23). This watched television 2–3 h daily (mean 27). Therefore, our results can probably calculation was done using EpiInfo 2005 A1C 8.7 Ϯ 1.5%). A total of 75 patients not be explained as a result of little phys- version 3.3.2 (Centers for Disease Con- (14%) watched television 3–4 h daily ical activity alone. However, even though trol, Atlanta, GA). Spearman’s correlation (mean A1C 8.8 Ϯ 1.2%). A total of 46 physical activity does not seem to influ- coefficient was used to analyze the asso- patients (9%) watched television Ն4h ence A1C in other studies, sedentary be- ciation between two continuous vari- daily (mean A1C 9.5 Ϯ 1.6%). Figure 1 havior like television watching might do ables. Differences in continuous variables shows the relationship between viewing so. Energy expenditure during television between male and female subjects were hour and A1C. There was a continuous viewing seems to be lower than during tested with a Mann-Whitney test. Unad- increase in A1C with every hour of watch- any other sedentary activities (28) and justed linear regression was used to ana- ing television, and the test for trend was even below resting level (29). Television lyze the association between television highly significant (P Ͻ 0.001) (Table 2). viewing also has been found to be associ- viewing and independent variables of in- No association between A1C and the use ated with snacking behavior, and partici- terest. Further multiple regression analy- of a personal computer was found (data pants who spend more time watching sis was used to determine whether the not shown). television tend to follow an unhealthy eat-
Table 2—A1C, age, and BMI and insulin dose related to hours of watching television
BMI z Insulin dose Television viewing n (%) A1C (%) Age (years) BMI (kg/m²) score (units kgϪ1 dayϪ1) Ͻ1 h 62 (11.5) 8.19 Ϯ 0.9 12.76 Ϯ 4.1 19.28 Ϯ 3.4 0.14 Ϯ 0.9 0.90 Ϯ 0.3 1–2 h 189 (35.1) 8.39 Ϯ 1.2 12.20 Ϯ 3.9 19.32 Ϯ 3.2 0.28 Ϯ 0.9 0.91 Ϯ 0.3 2–3 h 166 (30.9) 8.67 Ϯ 1.5 13.40 Ϯ 3.4 20.05 Ϯ 3.6 0.22 Ϯ 1.0 0.99 Ϯ 0.4 3–4 h 75 (13.9) 8.80 Ϯ 1.2 13.68 Ϯ 2.9 20.34 Ϯ 3.5 0.23 Ϯ 1.0 1.12 Ϯ 0.4 Ն4 h 46 (8.6) 9.48 Ϯ 1.6 14.61 Ϯ 3.4 21.84 Ϯ 3.0 0.29 Ϯ 0.8 0.98 Ϯ 0.4 Trend analysis (P values) Ͻ0.001 Ͻ0.001 Ͻ0.002 0.88 0.001 Data are means Ϯ SD unless otherwise indicated.
1568 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Margeirsdottir and Associates
Table 3—TV viewing according to A1C, age, BMI z score and insulin dose
Crude estimate Variable (95% CI) P value Adjusted (95% CI)* P value A1C (%) 0.22 (0.15–0.30) Ͻ0.001 0.19 (0.10–0.27) Ͻ0.001 Age (years) 0.06 (0.03–0.09) Ͻ0.001 0.05 (0.01–0.08) 0.01 BMI z score 0.01 (Ϫ0.10 to 0.12) 0.88 Ϫ0.006 (Ϫ0.12 to 0.11) 0.91 Insulin dose 0.47 (0.18–0.76) 0.001 0.13 (Ϫ0.19 to 0.44) 0.42 (units kgϪ1 dayϪ1) *Adjusted for all other variables in the table with multiple regression analysis. ing pattern (30,31). The combination of indicator of this. These individuals might be sclerosis (20) and CVD events (21). Our those factors, less physical activity, in- inclined to watch more television. Environ- findings lend support to the American creased sedentary behavior, less energy mental factors, particularly parental behav- Academy of Pediatrics’ recommendation expenditure, and increased food and en- iors, have been considered to be important and suggest that encouraging children ergy intake could, at least in part, explain influences on adolescent television habits, with type 1 diabetes to watch less televi- our finding. as adolescents of heavy television–viewing sion may be important for improved A significant association between ex- parents report spending more time watch- blood glucose control and better health cessive television viewing and obesity has ing television (32,33). Lower socioeco- outcomes. been found (6,8,10,11). In addition, sev- nomic status and parental education and eral studies have reported that this asso- living in a single-parent home also has been ciation is independent of physical activity reported to be associated with higher televi- Acknowledgments— The authors thank the and fitness level (7,9,11,24) and highly sion viewing time (34–36). Furthermore, following members of the Norwegian Study specific for television viewing. Other sed- elevated depressive symptoms is associated Group of Childhood Diabetes who partici- entary leisure activities did not show any with a higher level of television viewing in pated in data collection in this study: Halvor Bævre, Ola Talleraas, Sigurd Børsting, Helge significant association with obesity adolescents as well as adults (2,36,37). Vogt, Hans Jakob Bangstad, Hilde Bjørn- (24,29). However, we found no associa- A limitation of this study is that we dalen, Kjell Stensvold, Bjørn Halvorsen, and tion between television viewing and BMI z did not register physical activity, eating Kristin Hodnekvamm. Knut Lande and Kari score in our study, and the regression habits, or other leisure activities apart Oppsiøn were responsible for centralized analysis showed that the association be- from television viewing, nor do we have A1C analysis. Siv Janne Kummrnes and Beth tween television viewing and A1C was in- any information about the socioeconomic Tyrdal were responsible for study coordinat- dependent of BMI. or psychological status of our patients. ing functioning. Several other factors might influence Additional work is required to elucidate the observed relationship between televi- the potential behavioral and psychologi- sion viewing and A1C. Such factors include cal mechanisms for the observed associa- References socioeconomic status and psychosocial fac- tions. However, a potential implication of 1. Kronenberg F, Pereira MA, Schmitz MK, tors, such as family structure and function, this study is to ask about the time spent Arnett DK, Evenson KR, Crapo RO, parenting style, and depressive symptoms. watching television and other leisure ac- Jensen RL, Burke GL, Sholinsky P, Ellison RC, Hunt SC: Influence of leisure time Individuals who generally cannot cope very tivities, especially if the metabolic control physical activity and television watching well with life and those living in poorly of the children is poor. on atherosclerosis risk factors in the functioning families might have problems Improvement in long-term blood glu- NHLBI Family Heart Study. Atherosclero- with meeting the challenges of type 1 dia- cose control is important because it is a sis 153:433–443, 2000 betes, and the high level of A1C is simply an strong predictor of early coronary athero- 2. Sidney S, Sternfeld B, Haskell WL, Jacobs DR Jr, Chesney MA, Hulley SB: Television viewing and cardiovascular risk factors in young adults: the CARDIA study. Ann Epi- demiol 6:154–159, 1996 3. Jakes RW, Day NE, Khaw KT, Luben R, Oakes S, Welch A, Bingham S, Wareham NJ: Television viewing and low participa- tion in vigorous recreation are indepen- dently associated with obesity and markers of cardiovascular disease risk: EPIC-Nor- folk population-based study. Eur J Clin Nutr 57:1089–1096, 2003 4. National Institutes of Health Consensus Development Panel on Physical Activity and Cardiovascular Health: Physical ac- tivity and cardiovascular health. JAMA 276:241–246, 1996 5. Paffenbarger RS Jr, Hyde RT, Wing AL, Figure 1—Relationship between hours of watching television and A1C. Lee IM, Jung DL, Kampert JB: The associ-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1569 Television viewing and blood glucose control
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Endestad T, Brandtzæg PB, Heim J, Torg- barger RS Jr: Compendium of physical Kraemer HC, Wilson DM, Hayward C, ersen L, Kaare BH: A Digital Childhood. activities: classification of energy costs of Taylor CB: Does television viewing in- Oslo, NOVA-Norwegian Social Research, human physical activities. Med Sci Sports crease obesity and reduce physical activ- 2005 Exerc 25:71–80, 1993 ity? Cross-sectional and longitudinal 19. Dahl-Jorgensen K, Larsen JR, Hanssen KF: 29. Klesges RC, Shelton ML, Klesges LM: Ef- analyses among adolescent girls. Pediat- Atherosclerosis in childhood and adoles- fects of television on metabolic rate: po- rics 91:273–280, 1993 cent type 1 diabetes: early disease, early tential implications for childhood obesity. 8. Robinson TN: Reducing children’s televi- treatment? Diabetologia 48:1445–1453, Pediatrics 91:281–286, 1993 sion viewing to prevent obesity: a ran- 2005 domizedcontrolledtrial.JAMA282:1561– 20. Larsen J, Brekke M, Sandvik L, Arnesen 30. 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1570 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition BRIEF REPORT
Adolescents at Risk for MODY3 Diabetes Prefer Genetic Testing Before Adulthood
1,2,3 4 BRITA LILJESTROM¨ , MD LEENA SARELIN, RN and early detection of MODY. The bene- 1,2 5 TIINAMAIJA TUOMI, MD, PHD KATJA AKTAN-COLLAN, MD, PHD fits and disadvantages of the gene test 1,4 6,7 BO ISOMAA, MD, PHD HELENA K¨AARI¨ AINEN¨ , MD, PHD were discussed. The subjects and their guardians gave informed consent to the study. Analyses were performed using utations in the hepatocyte nuclear for MODY, and a normal result cannot Fisher’s exact test, 2 test with Yates cor- factor (HNF)-1␣ gene cause an exclude future risk. A genetic test seems rection, or Mann-Whitney U test. M autosomally, dominantly inher- to be warranted before adulthood, either ited form of diabetes, maturity-onset dia- to confirm carrier status in these pre- betes of the young (MODY) type 3, which screened subjects or in all at-risk subjects. RESULTS — Of the 39 invited adoles- is characterized by poor insulin secretion A predictive test, whether a clinical or cents, 29 (11 male and 18 female) from 17 in response to glucose together with good specific gene test, may have some negative sibships participated in the study and sensitivity to insulin and sulfonylurea impact on the adolescents’ self-esteem took the gene test. Of these, 4 of 5 diabetic medication and low renal threshold for and their future plans, as they may feel and 5 of 24 nondiabetic subjects were glucose (1). The lifetime risk of diabetes predestined to become diabetic. In the found to be carriers. Those declining had may be as high as 95% for individuals case of minors, predictive testing involves parents who had previously declined par- carrying the most common Pro291fsinsC ethical questions regarding decision- ticipation (10). Twenty-five parents, at mutation. Glucose tolerance deteriorates making and the benefit of testing as op- least one per adolescent (8 males and 17 in most cases during the pubertal years posed to possible negative effects (8,9). female, 14 MODY3 carriers), and 105 (2–5). However, because of fasting nor- We studied the attitudes to genetic testing other adults (34 male and 17 female, 14 moglycemia, clinical diagnosis is often in adolescents, their parents, and other carriers) also participated. Most partici- delayed despite high postprandial glucose adults in MODY3 families. pants (78%) irrespective of age consid- concentrations and an increased A1C ered that genetic testing should be value. Diabetes complications are com- performed before adulthood (Fig. 1). Pre- mon, and proliferative retinopathy has RESEARCH DESIGN AND viously, the decision about genetic testing been detected already at diagnosis of dia- METHODS — Adolescents (aged of minors has been made by the parents betes in a 19-year-old carrier (6). On the 12–18 years), their parents, and other ␣ (12,13). Since 1992 in Finland, the child other hand, while the incidence of diabe- adults from families with HNF-1 muta- has a right to participate in the decision- tes among mutation carriers steeply in- tions from the Botnia Study (10,11) were making at as early an age as possible, and creases in puberty, at least 20% remain offered genetic counseling and a gene test the opinion of children aged Ն12 years nondiabetic until their 30s (2,4,5). Ab- for MODY3 irrespective of their previous must be heard (14). Although the major- normal glucose tolerance in subjects at diabetes status. Data on glucose tolerance ity of parents (89%) preferred joint deci- risk for MODY3 can be diagnosed with an were obtained either earlier or at the time sion-making, many (60%) also favored oral glucose tolerance test. Urine glucose of the gene test. Data on attitudes to ge- testing before the age of 12 years, when analysis after a large oral glucose load has netic testing and counseling were col- the decision would be made solely by the also been advocated as a noninvasive lected by questionnaires before and 1 year parents. This differed from the adoles- screening tool in young children (7). Al- after the counseling and possible gene cents’ preference (Ͻ12 years: 28%, P ϭ though an aberrant result from these tests test. The counseling included informa- 0.005). Two parents favored prenatal has diagnostic value for diabetes and a tion about MODY, its inheritance, and the testing. Before counseling, the adults were certain predictive value in identification nature of the gene defect, risk of MODY, also specifically asked about their atti- of probable carriers, they are not specific and the methods available for follow-up tudes toward prenatal diagnosis of ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● MODY3: 38% considered the possibility From the 1Research Program for Molecular Medicine, Folkha¨lsan Research Center, Helsinki University and to be good, 23% bad, and 40% were Genetic Institute, Helsinki, Finland; the 2Department of Medicine, Helsinki University Hospital, Helsinki, 3 4 hesitant. Most of them were critical to- Finland; the Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland; the Malmska ward the suggestion, as a prenatal diag- Municipal Health Center and Hospital, Jakobstad, Finland; the 5Department of Social Psychology, University of Helsinki, Helsinki, Finland; the 6Department of Medical Genetics, University of Turku, Turku, Finland; nosis of MODY3 was either regarded as and the 7Department of Paediatrics, Turku University Hospital, Turku, Finland. unethical or as having no implications Address correspondence and reprint requests to Brita Liljestro¨m, Botnia Study, B330b, Biomedicum for the pregnancy. Helsinki, P.O. Box 700, 00029 Helsinki, Finland. E-mail: brita.liljestrom@kuh.fi. While the majority of adolescents Received for publication 17 August 2006 and accepted in revised form 22 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-1744. (72%) also preferred joint decision- T.T. is currently a research fellow at the Academy of Finland. making about taking the test, almost one- Abbreviations: MODY, maturity-onset diabetes of the young. third (28%) wanted to make the decision A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion alone, and as many as 55% actually chose factors for many substances. to receive their test results alone. By con- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby trast, before the counseling, the majority marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. of their parents considered that they
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1571 Genetic testing of adolescents for MODY3
References 1. Hattersley AT, Pearson ER: Minireview: pharmacogenetics and beyond: the inter- action of therapeutic response, beta-cell physiology, and genetics in diabetes. En- docrinology 147:2657–2763, 2006 2. Klupa T, Warram JH, Antonellis A, Pez- zolesi M, Nam M, Malecki MT, Doria A, Rich SS, Krolewski AS: Determinants of the development of diabetes (maturity- onset diabetes of the young-3) in carriers of HNF-1␣ mutations: evidence for par- ent-of-origin effect. Diabetes Care 25: 2292–2301, 2002 3. Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njølstad PR, Hansen T, Costa A, Con- get I, Pedersen O, Søvik O, Lorini R, Groop L, Froguel P, Hattersley AT: The genetic abnormality in the beta-cell deter- mines the response to an oral glucose load. Diabetologia 45:427–435 2002 4. Frayling T, Evans JC, Bulman MP, Pear- Figure 1—Opinions before genetic counseling of the three groups of subjects (parents, n ϭ 25; son E, Allen L, Owen K, Bingham C, Han- other adults, n ϭ 105; and adolescents, n ϭ 29) from MODY3 families on the age at which gene nemann M, Shepherd M, Ellard S, testing should be performed (%). None of the subjects opted for “never”, which was an alternative. Hattersley AT: -cell genes and diabetes: P ϭ 0.005 for the difference between parents and adolescents with respect to testing in childhood. molecular and clinical characterization of mutations in transcription factors. Diabe- tes 50:94–100, 2001 should be present at their children’s test been tested or at the test result. All nega- 5. Honkanen EH, Isomaa B, Sarelin L, Lehto disclosure (80%, P ϭ 0.039 vs. adoles- tive response came from newly identified M, Groop LC, Tuomi T: Onset of glucose cents). After the counseling, the adults MODY families, in whom the incident intolerance in MODY3 Pro291fsInsC mu- changed their opinion toward allowing case had been diagnosed only 1–2 years tation carriers coincides with pubertal the adolescents to receive the results earlier. years: a prospective follow-up study (Ab- alone, if they wished (16 vs. 27% before stract). Diabetologia 45: A129, 2002 vs. after counseling, respectively; P ϭ 6. Isomaa B, Henricsson M, Lehto M, Fors- 0.0355). blom C, Karanko S, Sarelin L, Haggblom CONCLUSIONS — Genetic testing M, Groop L: Chronic diabetic complica- One year after the disclosure of test for MODY3 can be considered beneficial tions in patients with MODY3 diabetes. results, 21 adolescents returned the fol- for early detection of MODY. Most ado- Diabetologia 41:467–473, 1998 low-up questionnaire. All 12 noncarriers lescents at risk for MODY3 accepted and 7. Stride A, Ellard S, Clarck P, Shakespear L, and 8 of the 9 mutation carriers correctly understood the gene test. However, at Salzmann M, Shepherd M, Hattersley AT: reported their test result and its interpre-  least 25% were dissatisfied with having -cell dysfunction, insulin sensitivity, tation, but 1 carrier could not say what and glycosuria precede diabetes in taken the test although they had received the result meant. Most (17 of 21, 76%) hepatocyte nuclear factor-1␣ mutation were satisfied with their decision about proper counseling. Both adolescents and carriers. Diabetes care 28:1751–1756, taking the test and would have made the adults considered that such testing 2005 same choice again. They would also have should already be offered before adult- 8. Shepherd M, Hattersley AT, Sparkes AC: recommended it to a friend who was in hood, but their views differed on whether Predictive genetic testing in diabetes: a case study of multiple perspectives. Qual the same situation. However, four sub- to wait until the child is old enough to participate in the decision-making. In any Health Res 10:242–259, 2000 jects (three carriers and one noncarrier) 9. Shepherd M, Ellis I, Ahmad A, Todd P, were dissatisfied with having taken the case, educational counseling needs to be Bowen-Jones D, Mannion G, Ellard S, test. One had not really reacted to learn- provided. Sparkes AC, Hattersley A: Predictive test- ing that he/she was a carrier but was angry ing in maturity-onset-diabetes of the at having been tested when diagnosed young (MODY). Diabet Med 18:417–421, 2001 with diabetes 1 year later at a clinical fol- Acknowledgments— The study was sup- 10. Lehto M, Wipemo C, Ivarsson SA, low-up. This shows that the adolescents ported by grants from the Academy of Finland, may be more disposed to “natural opti- Lindgren C, Lipsanen-Nyman M, Weng the Finnish Diabetes Research Foundation, J, Wibell L, Widen E, Tuomi T, Group L: mism,” in that they understand but do not the Sigrid Juselius Foundation, the Folkhalsan necessarily internalize the risk of diabetes. High frequency of mutations in MODY Research Foundation, the Finska La¨karesa¨ll- and mitochondrial genes in Scandina- Also, at least one of the eight nonre- skapet, Novo Nordisk, the Jalmari and Rauha vian patients with familial early-onset sponders (four carriers and four noncar- Ahokas Foundation, and the Helsinki Univer- diabetes. Diabetologia. 42:1131–1137, riers) aggressively reacted immediately sity Central Hospital. 1999 after hearing that he/she was a carrier. Not The Botnia Research Group is acknowl- 11. Liljestrom B, Aktan-Collan K, Isomaa B, returning the posttest questionnaire pre- edged for recruiting and clinically studying the Sarelin L, Uutela A, Groop L, Kaariainen sumably reflects dissatisfaction at having subjects. H, Tuomi T: Genetic testing for maturity
1572 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Liljestro¨m and Associates
onset diabetes of the young: uptake, atti- attitudes about autonomy and confidenti- Parental attitudes regarding carrier testing tudes and comparison with hereditary ality in genetic testing for breast-ovarian in children at risk for fragile X syndrome. non-polyposis colorectal cancer. Diabeto- cancer susceptibility. Am J Med Genet 73: Am J Med Genet 82:206–211, 1999 logia 48:242–250, 2005 296–303, 1997 14. Meincke: Geenit kertovat: geenitestit 12. Benkendorf JL RJ, Hughes CA, Eads N, 13. McConkie-Rosell ASG, Rounds K, Dawson la¨a¨kinta¨- ja bio-oikeuden na¨ko¨kulmasta. Willison J, Powers M, Lerman C: Patients’ DV, Sullivan JA, Burgess D, Lachiewicz AM: Lakimies 8:1202–1221, 1999 [in Finnish]
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1573 Clinical Care/Education/Nutrition BRIEF REPORT
Thiazolidinedione Treatment Decreases Bone Mineral Density in Type 2 Diabetic Men
1,2 SUBHASHINI YATURU, MD waist measurements and ratio, and blood 1 BARBARA BRYANT, BS pressure. The dose of rosiglitazone was 4 3 SUSHIL K. JAIN, PHD mg twice a day. We excluded the data of the subjects with chronic renal insuffi- ciency, hyperparathyroidism, and Cush- ase-control studies of patients with in troglitazone-treated mice (17). There is ing’s syndrome and of those who were on fractures have found that subjects limited information on the effect of thia- glucocorticoids and gonadotropin- C with diabetes have at least a twofold zolidinediones on BMD in humans. A re- releasing hormone analogs. higher risk of fracture than subjects with- cent study has suggested that BMD measurements were performed out diabetes (1), with an increased risk of thiazolidinedione use may cause bone using dual-energy X-ray absorptiometry hip, humerus, and foot fractures in el- loss in older women with type 2 diabetes (DEXA) (Lunar Prodigy) at the lumbar derly diabetic subjects (2–4). Risk factors (18). In the present study on 160 men spine: anteroposterior (AP) and lateral that contribute to increased fracture in di- with type 2 diabetes, we examined BMD (L1–4) and the proximal femur (total hip, abetic subjects include number of falls in patients on rosiglitazone treatment femoral neck, and trochanter) and 33% (5,6), insulin use (7,8), functional disabil- compared with matched men with type 2 radius. The precision of DEXA scans is ity (9–11), diabetes duration (7,12), and diabetes not on rosiglitazone treatment 1–1.8%. Annualized absolute change in poor vision (7). Recent studies report that and found that rosiglitazone treatment BMD was calculated as the difference be- older women and African Americans have increases bone loss in men with type 2 tween the results of the baseline and fol- higher incidence of osteoporotic fractures diabetes. low-up hip scans divided by the time (13). In addition, lower bone strength between scans in years. Annualized per- (bone mineral density [BMD]) might be RESEARCH DESIGN AND centage of change in BMD was calculated expected to increase risk for the develop- METHODS — After institutional re- by dividing the annualized absolute ment of osteoporosis and fracture. view board approval, we retrieved the change by the baseline BMD. We com- Type 2 diabetic patients are widely clinical data for the previous 4 years of pared the BMD data of subjects with dia- prescribed drugs called thiazolidinedi- 354 subjects with diabetes and compared betes and on rosiglitazone with those of ones, which increase insulin sensitivity with BMD data of age- and BMI-matched subjects with diabetes and not on rosigli- via activation of peroxisome proliferator– nondiabetic subjects. Among 354 sub- tazone using unpaired t test. A P value activated receptor (PPAR)-␥ receptors. jects with diabetes, we had follow-up Ͻ0.05 on two-tailed testing was consid- However, it is not known whether thiazo- BMD data for 32 men with type 2 diabetes ered significant. lidinedione use has any effect on bone receiving rosiglitazone (considered the mass and thereby increases risk of frac- study group) and 128 men with type 2 RESULTS AND DISCUSSION — ture in type 2 diabetic patients. In animal diabetes not receiving any thiazolidinedi- The BMD data at both AP spine and hip in studies, thiazolidinedione treatment was one (considered the control group). Clin- subjects with diabetes were similar to associated with bone loss in a mouse ical data included are history of smoking, those of subjects with no diabetes when model (14,15), which was explained by alcohol consumption, hypertension, cor- matched for age and BMI (data not given possible imbalance in bone from in- onary artery disease, stroke, current med- here). Among men with type 2 diabetes, creased apoptotic death of osteogenic ications, and duration of diabetes and 160 subjects had a follow-up DEXA with cells and diminished bone formation family history of diabetes and osteoporo- a mean interval of 16 months, including (15), and also in ovariectomized rats (16). sis. Other details collected include height, 128 subjects with diabetes and not receiv- Other investigators did not find bone loss weight, BMI, abdominal girth, hip-to- ing rosiglitazone (control group) and 32 ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● subjects with diabetes and receiving ros- From the 1Department of Endocrinology, Overton Brooks VA Medical Center, Shreveport, Louisiana; the 2 iglitazone (study group). The BMD and Department of Endocrinology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; clinical characteristics of subjects with and the 3Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana. Address correspondence and reprint requests to Subhashini Yaturu, MD, Department of Endocrinology, type 2 diabetes are shown in Table 1. Overton Brooks VA Medical Center/LSUHSC, Shreveport, LA 71101-4295. E-mail: subhashini.yaturu@ There was no significant difference in the med.va.gov or [email protected]. baseline BMD data at both AP spine and Received for publication 26 December 2006 and accepted in revised form 5 March 2007. hip in subjects with type 2 diabetes with Published ahead of print at http//:care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2606. Abbreviations: AP, anteroposterior; BMD, bone mineral density; DEXA, dual-energy X-ray absorptiom- or without rosiglitazone. Since all of the etry; PPAR, peroxisome proliferator–activated receptor. follow-up DEXA data were not collected See accompanying Editorial on p. 1670. at exact similar intervals, annualized per- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion centage changes were calculated. Annual- factors for many substances. ized absolute percentage changes in both © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby groups were compared, and the results marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. are shown in Table 1.
1574 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Yaturu, Bryant, and Jain
Table 1—Annualized percentage change in BMD and clinical characteristics of diabetic sub- 2. Forsen L, Meyer HE, Midthjell K, Edna jects on rosiglitazone compared with diabetic subjects not on rosiglitazone with follow-up TH: Diabetes mellitus and the incidence BMD of hip fracture: results from the Nord- Trondelag Health Survey. Diabetologia 42: 920–925, 1999 Diabetic subjects not Diabetic subjects 3. Michaelsson K, Holmberg L, Mallmin H, on rosiglitazone on rosiglitazone P Sorensen S, Wolk A, Bergstrom R, Ljun- ghall S: Diet and hip fracture risk: a case- n 128 32 control study: study group of the Multiple Total AP spine BMD Risk Survey on Swedish Women for Eat- Ϯ Ϯ Baseline 1.133 0.19 1.160 0.17 NS ing Assessment. Int J Epidemiol 24:771– Ϯ Ϯ Annualized % change 2.3 2.9 0.69 2.4 0.03* 782, 1995 Total hip BMD 4. Cummings SR, Nevitt MC, Browner WS, Baseline 0.934 Ϯ 0.14 0.915 Ϯ 0.18 NS Stone K, Fox KM, Ensrud KE, Cauley J, Annualized % change Ϫ0.137 Ϯ 1.9 Ϫ1.19 Ϯ 1.8 0.006* Black D, Vogt TM: Risk factors for hip Femoral neck BMD fracture in white women: study of Osteo- Baseline 0.828 Ϯ 0.13 0.839 Ϯ 0.14 NS porotic Fractures Research Group. N Engl Annualized % change Ϫ0.20 Ϯ 1.25 Ϫ1.22 Ϯ 1.3 0.0001* J Med 332:767–773, 1995 Age (years) 68 Ϯ 10 70 Ϯ 9NS5. Schwartz AV, Hillier TA, Sellmeyer DE, Basal metabolic index 30 Ϯ 5.5 32 Ϯ 4.8 NS Resnick HE, Gregg E, Ensrud KE, Schrei- ner PJ, Margolis KL, Cauley JA, Nevitt A1C 8.1 Ϯ 1.4 7.5 Ϯ 2.1 NS MC, Black DM, Cummings SR: Older Fasting glucose (mmol/l) 158 Ϯ 52 160 Ϯ 48 NS Ϯ Ϯ women with diabetes have a higher risk of Serum creatinine (mg/dl) 1.2 0.6 1.1 0.8 NS falls: a prospective study. Diabetes Care Ϯ Ϯ Total cholesterol (mg/dl) 203 60 199 48 NS 25:1749–1754, 2002 HDL cholesterol (mg/dl) 34 Ϯ 18 38 Ϯ 22 NS 6. Wallace C, Reiber GE, LeMaster J, Smith LDL cholesterol (mg/dl) 122 Ϯ 46 120 Ϯ 41 NS DG, Sullivan K, Hayes S, Vath C: Inci- Hypertension (%) 92 82 NS dence of falls, risk factors for falls, and Coronary artery disease (%) 62 56 NS fall-related fractures in individuals with Family history of diabetes (%) 62 70 NS diabetes and a prior foot ulcer. Diabetes Current smokers (%) 20 18 NS Care 25:1983–1986, 2002 7. Ivers RQ, Cumming RG, Mitchell P, Data are means Ϯ SD. *P Ͻ 0.05 is considered significant. Baseline BMD indicates BMD at the initiation of rosiglitazone. Peduto AJ: Diabetes and risk of fracture: the Blue Mountains Eye Study. Diabetes Care 24:1198–1203, 2001 BMD in subjects with type 2 diabetes This study is retrospective. Limita- 8. Schwartz AV, Sellmeyer DE, Ensrud KE, was similar to that in nondiabetic sub- tions include that there were no bone Cauley JA, Tabor HK, Schreiner PJ, Jamal jects. This finding is consistent with that turnover markers for comparison and SA, Black DM, Cummings SR: Older of a previous study (19). A novel finding that the data groups are not large enough women with diabetes have an increased in our report is the adverse effect of ros- to perform regression analyses for con- risk of fracture: a prospective study. J Clin iglitazone, a thiazolidinedione, on skele- founding factors such as age, duration of Endocrinol Metab 86:32–38, 2001 tal health in humans. There was a diabetes, use of insulin, association of hy- 9. Gregg EW, Mangione CM, Cauley JA, significant difference in the BMD, with pertension, and other factors such as Thompson TJ, Schwartz AV, Ensrud KE, loss of bone at both the spine and hip in smoking and alcoholism. Nevertheless, Nevitt MC: Diabetes and incidence of type 2 diabetic subjects on rosiglitazone this study shows a significant increase in functional disability in older women. Di- (Table 1). This study confirms the results bone loss both at total hip and femoral abetes Care 25:61–67, 2002 10. Ryerson B, Tierney EF, Thompson TJ, En- of previous animal studies and shows the neck areas in type 2 diabetic men on ros- gelgau MM, Wang J, Gregg EW, Geiss LS: possible adverse effect of rosiglitazone on iglitazone treatment. This suggests that Excess physical limitations among adults skeletal health in men. thiazolidinedione treatment is a risk fac- with diabetes in the U.S. population, Osteoblasts and adipocytes are de- tor and can contribute to excess incidence 1997–1999. Diabetes Care 26:206–210, rived from a common multipotential mes- of fractures in diabetes. 2003 enchymal stem cell progenitor (18–20). 11. Gregg EW, Beckles GL, Williamson DF, PPAR-␥ is essential for normal adipocyte Leveille SG, Langlois JA, Engelgau MM, differentiation and proliferation as well as Acknowledgments— S.Y. is supported by a Narayan KM: Diabetes and physical dis- fatty acid uptake and storage. The thia- research grant in aid from Proctor and Gamble ability among older U.S. adults. Diabetes zolidinediones rosiglitazone and pioglita- and by the Veterans Health Administration. Care 23:1272–1277, 2000 zone are commonly used to increase S.K.J. is supported by the National Institute of 12. Nicodemus KK, Folsom AR: Type 1 and Diabetes and Digestive and Kidney Diseases and insulin sensitivity for the treatment of type 2 diabetes and incident hip fractures the Office of Dietary Supplements. in postmenopausal women. Diabetes Care type 2 diabetes (21). It has been shown ␥ 24:1192–1197, 2001 that activation of PPAR- 2 with rosiglita- 13. Strotmeyer ES, Cauley JA, Schwartz AV, zone stimulates adipogenesis and inhibits References de Rekeneire N, Resnick HE, Zmuda JM, osteoblastogenesis (22). This may be a 1. Meyer HE, Tverdal A, Falch JA: Risk fac- Shorr RI, Tylavsky FA, Vinik AI, Harris potential mechanism for the loss of BMD tors for hip fracture in middle-aged Nor- TB, Newman AB: Reduced peripheral observed in hips of rosiglitazone-treated wegian women and men. Am J Epidemiol nerve function is related to lower hip diabetic men. 137:1203–1211, 1993 BMD and calcaneal QUS in older white
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1575 Thiazolidinediones and BMD
and black adults: the Health, Aging, and with the PPARgamma agonist BRL49653 19. Beresford JN: Osteogenic stem cells and Body Composition Study. J Bone Miner Res (rosiglitazone). Calcif Tissue Int 75:329– the stromal system of bone and marrow. 21:1803–1810, 2006 337, 2004 Clin Orthop Relat Res 270–280, 1989 14. Rzonca SO, Suva LJ, Gaddy D, Montague 17. Tornvig L, Mosekilde LI, Justesen J, Falk 20. Bennett JH, Joyner CJ, Triffitt JT, Owen DC, Lecka-Czernik B: Bone is a target for E, Kassem M: Troglitazone treatment in- ME: Adipocytic cells cultured from mar- the antidiabetic compound rosiglitazone. creases bone marrow adipose tissue vol- row have osteogenic potential. J Cell Sci Endocrinology 145:401–406, 2004 ume but does not affect trabecular bone 99:131–139, 1991 15. Soroceanu MA, Miao D, Bai XY, Su H, volume in mice. Calcif Tissue Int 69:46– 21. Yki-Jarvinen H: Thiazolidinediones. N Engl Goltzman D, Karaplis AC: Rosiglitazone 50, 2001 J Med 351:1106–1118, 2004 impacts negatively on bone by promoting 18. Pittenger MF, Mackay AM, Beck SC, 22. Lecka-Czernik B, Gubrij I, Moerman EJ, osteoblast/osteocyte apoptosis. J Endocri- Jaiswal RK, Douglas R, Mosca JD, Moor- Kajkenova O, Lipschitz DA, Manolagas nol 183:203–216, 2004 man MA, Simonetti DW, Craig S, Mar- SC, Jilka RL: Inhibition of Osf2/Cbfa1 ex- 16. Sottile V, Seuwen K, Kneissel M: En- shak DR: Multilineage potential of adult pression and terminal osteoblast differen- hanced marrow adipogenesis and bone re- human mesenchymal stem cells. Science tiation by PPARgamma2. J Cell Biochem sorption in estrogen-deprived rats treated 284:143–147, 1999 74:357–371, 1999
1576 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition BRIEF REPORT
Prevention of Transition From Incipient to Overt Nephropathy With Telmisartan in Patients With Type 2 Diabetes
1 6 HIROFUMI MAKINO, MD YASUHIKO IWAMOTO, MD ing Cox’s proportional hazard model. The 2 7 MASAKAZU HANEDA, MD RYUZO KAWAMORI, MD protocol conformed to the principles of 3 8 TETSUYA BABAZONO, MD MASAHIRO TAKEUCHI, SCD, MPH 4 9 the Declaration of Helsinki and was ap- TATSUMI MORIYA, MD SHIGEHIRO KATAYAMA, MD 5 proved by the institutional review boards SADAYOSHI ITO, MD FOR THE INNOVATION STUDY GROUP at the 142 study centers (7). Patients pro- vided written informed consent before enrollment. o date, evidence for long-term reno- creatinine Ͻ1.5 mg/dl (men) and Ͻ1.3 protection with angiotensin recep- mg/dl (women). Exclusion criteria in- RESULTS — Of the 527 randomized T tor blockers (ARBs) has come almost cluded type 1 diabetes, age of diabetes patients (mean age 61.7 years), 13 were exclusively from Caucasian patients (1– onset Ͻ30 years, seated systolic blood excluded from primary analysis because 3), despite Japanese people being at high pressure (SBP)/diastolic blood pressure of suspected type 1 diabetes or UACR risk of diabetic nephropathy and very sus- (DBP) Ն180/100 mmHg, and definable measurements being missing during ceptible to end-stage renal disease (4–6). chronic kidney disease other than dia- treatment. Mean duration of follow-up We conducted the INNOVATION Study betic nephropathy. A total of 527 patients was 1.3 Ϯ 0.5 years (maximum 2.3 (Incipient to Overt: Angiotensin II out of 1,855 screened were randomized years). Transition rates to overt nephrop- Blocker, Telmisartan, Investigation on to 80 or 40 mg telmisartan or placebo; the athy were 80 mg telmisartan (n ϭ 168) Type 2 Diabetic Nephropathy) to evaluate starting dose was 20 mg, titrated to 40 mg 16.7%, 40 mg telmisartan (n ϭ 172) the efficacy of an ARB in preventing tran- after 2 weeks or to 80 mg after a further 2 22.6%, and placebo (n ϭ 174) 49.9% sition from microalbuminuria to overt ne- weeks. Minimum treatment period was 1 (both telmisartan doses vs. placebo, P Ͻ phropathy in Japanese patients (7). This year for each patient. Primary efficacy end 0.0001) (Fig. 1A). In addition, 163 nor- study is the first large-scale clinical study point was the transition rate from incipi- motensive patients were included in the to investigate prevention of overt diabetic ent to overt nephropathy (UACR Ͼ300 study. Transition rates in normotensive nephropathy using an ARB in normoten- mg/g and increase Ն30% from baseline at patients were 80 mg telmisartan (n ϭ 51) sive and hypertensive Japanese patients two consecutive 4-week visits). Second- 11.0%, 40 mg telmisartan (n ϭ 58) with type 2 diabetes. ary end point was microalbuminuria re- 21.0%, and placebo (n ϭ 54) 44.2% mission (UACR Ͻ30 mg/g). Frequency (both telmisartan doses vs. placebo, P Ͻ RESEARCH DESIGN AND and severity of adverse events were also 0.01) (Fig. 1B). After adjustment for METHODS — The randomized, mul- assessed. The Kaplan-Meier method was changes in SBP, telmisartan still decreased ticenter, double-blind, placebo- used to determine transition rates to overt the transition rate to overt nephropathy. controlled trial was performed in patients nephropathy; log-rank test was used for Telmisartan (80 and 40 mg) reduced aged from 30 to 74 years with type 2 dia- pairwise comparison between treatment mean UACR at final observation by 58.8 betes and urinary albumin-to-creatinine groups. Effect of blood pressure reduc- and 37.9 mg/g, respectively, and placebo ratio (UACR) 100–300 mg/g and serum tion on transition rate was estimated us- increased UACR by 40.9 mg/g (both tel- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● misartan doses vs. placebo, P Ͻ 0.0001). From the 1Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Microalbuminuria remission at final ob- Dentistry, and Pharmaceutical Sciences, Okayama, Japan; the 2Department of Medicine, Division of Metab- servation occurred in 21.2% with 80 mg olism and Biosystemic Science, Asahikawa Medical College, Hokkaido, Japan; the 3Division of Nephrology telmisartan, 12.8% with 40 mg telmisar- and Hypertension, Diabetes Center, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan; 4 tan, and 1.2% with placebo (both telmis- the Department of Endocrinology, Diabetes, and Metabolism, Kitasato University School of Medicine, Ͻ Kanagawa, Japan; the 5Division of Nephrology, Tohoku University Graduate Medical School, Miyagi, Japan; artan doses vs. placebo, P 0.001). One the 6Department of Medicine, Diabetes Center, Tokyo Women’s Medical University School of Medicine, or more adverse event was recorded in Tokyo, Japan; the 7Department of Medicine, Medical School, Juntendo University, Tokyo, Japan; the 8Di- Ͼ90% of patients in each treatment 9 vision of Biostatistics, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan; and the Divi- group; most events were mild or moder- sion of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School, Saitama, Japan. Address correspondence and reprint requests to Professor Hirofumi Makino, Department of Medicine and ate in intensity. Regarding the decrease of Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, blood pressure, SBP/DBP fell from 138/78 2-5-1 Shikata-cho, Okayama, Japan. E-mail: [email protected]. mmHg to 128/72 mmHg with 80 mg Received for publication 21 November 2006 and accepted in revised form 5 March 2007. telmisartan, from 137/78 mmHg to Published ahead of print at http://care.diabetesjournals.org on 26 March 2007. DOI: 10.2337/dc06-1998. 128/72 mmHg with 40 mg telmisartan, Clinical trial reg. no. NCT00153088, clinicaltrials.gov. Abbreviations: ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; SBP, systolic blood and from 137/77 mmHg to 132/74 pressure; UACR, urinary albumin-to-creatinine ratio. mmHg with placebo (each blood pressure A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion change at 1 year from baseline P Ͻ 0.01). factors for many substances. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby CONCLUSIONS — Patients with type marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 diabetes and microalbuminuria receiving
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1577 INNOVATION Study on telmisartan
References 1. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Re- muzzi G, Snapinn SM, Zhang Z, Shahinfar S, for the RENAAL Study Investigators: Effects of losartan on renal and cardiovas- cular outcomes in patients with type 2 di- abetes and nephropathy. N Engl J Med 345: 861–869, 2001 2. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, for the Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesar- tan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851– 860, 2001 3. Parving HH, Lehnert H, Bro¨chner- Mortensen J, Gomis R, Andersen S, Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the de- velopment of diabetic nephropathy in pa- tients with type 2 diabetes. N Engl J Med 345:870–878, 2001 4. Hollenberg NK: Higher incidence of dia- betic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Curr Hypertens Rep 3:177, 2001 5. US Renal Data System: USRDS 2005 An- nual Data Report: Atlas of End-Stage Renal Disease in the United States. Available from http://www.usrds.org/adr_2005.htm 6. Nakai S, Shinzato T, Nagura Y, Masakane I, Kitaoka T, Shinoda T, Yamazaki C, Sa- kai R, Ohmori H, Morita O, Iseki K, Kiku- chi K, Kubo K, Suzuki K, Tabei K, Fushimi K, Miwa N, Wada A, Yanai M, Akiba T: Patient Registration Committee, Japanese Society for Dialysis Therapy, To- kyo: an overview of regular dialysis treat- ment in Japan (as of December 31, 2001). Ther Apher Dial 8:3–32, 2004 7. Makino H, Haneda M, Babazono T, Figure 1—Kaplan-Meier curves for transition from incipient to overt nephropathy in patients Moriya T, Ito S, Iwamoto Y, Kawamori R, treated once daily with 80 mg telmisartan (T80), 40 mg telmisartan (T40), and placebo. Takeuchi M, Katayama S, for the Incipient to Overt; Angiotensin II–Blocker, Telmis- 80 or 40 mg telmisartan achieved superior overt nephropathy in normotensive pa- artan, Investigation on Type 2 Diabetic renoprotection, demonstrated by lower tients, suggesting telmisartan had a Nephropathy Study Group: The telmisar- transition rates to overt nephropathy, com- blood pressure–independent effect. tan renoprotective study from incipient pared with placebo. Achievement of mi- Further evidence for this is that differ- nephropathy to overt nephropathy: ratio- croalbuminuria remission was superior ences in transition rates with respective nale, study design, treatment plan and baseline characteristics of the incipient to with 80 or 40 mg telmisartan than with pla- treatments were maintained when ad- overt: angiotensin II receptor blocker, cebo. Remission is a key goal for renopro- justment was made for SBP reduction. telmisartan, investigation on type 2 dia- tection, as well as cardiovascular protection The beneficial effects of telmisartan betic nephropathy (INNOVATION) (8). Remission rates compare very favorably were dose dependent. study. J Int Med Res 33:677–686, 2005 with those reported in Caucasian hyperten- Overall, telmisartan reduced transi- 8. Ruggenenti P, Schieppati A, Remuzzi G: sive patients with type 2 diabetes and mi- tion from incipient to overt nephropathy Progression, remission, regression of croalbuminuria treated with irbesartan (3). and induced remission of albuminuria in chronic renal diseases. Lancet 357:1601– Telmisartan also reduced transition to Japanese type 2 diabetic patients. 1608, 2001
1578 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition BRIEF REPORT
Non–Glycemic-Dependent Reduction of Late Pregnancy A1C Levels in Women With Type 1 Diabetes
1 2 LUCRECIA HERRANZ, MD CRISTINA GRANDE, SCD (nearest to conception) and the measure- 1 1 LOURDES SAEZ-DE-IBARRA, BSC LUIS F. PALLARDO, MD ment nearest to 36 weeks’ gestation. Statistical analyses were conducted using SPSS version 8.0 statistical software reduction of A1C levels during tal’s ethical committee, and all women (SPSS, Chicago, IL). To compare mean pregnancy in women without dia- gave their informed consent. values among quantitative variables, the A betes has been reported (1–6), sug- From our Diabetes and Pregnancy paired-samples Student’s t test was used. gesting that the goal for A1C during Unit, we selected 68 women with type 1 Pearson correlation coefficient was used pregnancy complicated with diabetes diabetes, aged 32.0 Ϯ 3.0 years, with di- to measure the linear relation between should be lowered. The decrease in fast- abetes duration 14.6 Ϯ 7.5 years and A1C and mean glucose. Multivariate lin- ing blood glucose levels during the first prepregnancy BMI 24.6 Ϯ 3.4 kg/m2, ear regression analysis was performed to trimester of normal pregnancy (7,8) may who performed home blood glucose estimate the effect of pregnancy on the explain the lower A1C levels found in monitoring using the same type of glucose relation between A1C and mean glucose. early pregnancy (1,2,3,5). A further de- meter (OneTouch profile; LifeScan, Mil- In this model, the dependent variable was crease of A1C in late pregnancy in women pitas, CA) from at least 3 months before A1C and the independent variables were without diabetes has been reported by conception and throughout pregnancy. mean glucose and pregnancy status. Preg- Nielsen et al. (3), which may be related to nancy status was coded as a categorical All women were on flexible basal bolus ϭ decreased erythrocyte life span (9,10). insulin regimens and were trained to ad- variable (preconception 0; third tri- mester ϭ 1). Glucose and A1C are re- In women with type 1 diabetes, just their insulin dose. ported as means Ϯ SD. A P value Ͻ0.05 strict glycemic control during preg- Glucose readings stored in the meter was considered significant. nancy leads to a reduction in A1C lev- were downloaded to a computer (diabetes els, which may be insufficient to management software In Touch; Life- RESULTS — Preconception mean glu- prevent the complications of pregnancy Scan) at each visit. Mean glucose levels cose was 138.9 Ϯ 17.9 mg/dl (range 88; in type 1 diabetes (11,12). Since the de- were obtained from the glucose readings median 140.5), and preconception A1C crease in A1C during normal pregnancy for the 12 weeks before conception (pre- was 6.6 Ϯ 0.6% (range 2.9; median 6.6), is related to lower blood glucose and to conception) and for the third trimester with a significant correlation between decreased erythrocyte lifespan (6–10), (from 25 gestational weeks to 36 com- them (r ϭ 0.648; P Ͻ 0.001). Third tri- some of the reduction of A1C observed plete gestational weeks). The mean num- mester mean glucose was 129.0 Ϯ 13.1 in pregnant women with type 1 diabetes ber of glucose readings per day was 4.3 for mg/dl (range 48; median 129), and third will not be related to improved glycemic preconception and 5.6 for third trimester. trimester A1C was 6.0 Ϯ 0.5% (range 2.2; control. Therefore, A1C levels in preg- A1C was measured in EDTA-anticoagu- median 6.1), with a significant correlation nancies complicated by diabetes can be lated fresh blood samples, using a high- between them (r ϭ 0.580; P Ͻ 0.001). misleading when evaluating the degree performance liquid chromatography There was a significant decrease both in of glycemic control. The aim of this mean glucose and in A1C (P Ͻ 0.005) study was to quantify the decrease in DCCT (Diabetes Control and Complica- tions Trial)-aligned method (Variant II from preconception to third trimester. A1C levels during late pregnancy in The regression equation to predict A1C women with type 1 diabetes who were HPLC analyzer; BioRad, Richmond, VA). The A1C reference intervals are 4–6%, from mean glucose and pregnancy status not dependent on glycemic control. ϭ ϩ ϫ and the interassay precision coefficient of was: A1C 3.66 (0.02 mean glu- ϩ Ϫ ϫ RESEARCH DESIGN AND variation for control materials with a cose) ( 0.38 pregnancy status). The 2 Ͻ METHODS — This study was per- DCCT-assigned A1C content of 5.3 and R of the model was 0.531 (P 0.001). 9.6% is 2.1 and 2%, respectively. The The SE for the constant was 0.33, and the formed at the Hospital Universitario La  Paz, Madrid, Spain. Ethical approval for A1C levels included in this study were the SEs for the -coefficients for mean glu- this research was provided by the hospi- last measurement during preconception cose and pregnancy status were 0.02 and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● 0.08, respectively. Figure 1 shows the re- gression lines for the relation between From the 1Department of Endocrinology, Hospital La Paz, Madrid, Spain; and the 2Department of Biochem- istry, Hospital La Paz, Madrid, Spain. A1C and mean glucose before pregnancy Address correspondence and reprint requests to Lucrecia Herranz, Unidad de Diabetes, Hospital Univer- (pregnancy status ϭ 0) and in late preg- sitario La Paz, Paseo de la Catellana 261, 28046 Madrid, Spain. E-mail: [email protected]. nancy (pregnancy status ϭ 1). Received for publication 19 December 2006 and accepted in revised form 4 March 2007. Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2568. CONCLUSIONS — From our data, A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion the regression line to predict third trimes- factors for many substances. ter A1C (pregnancy status ϭ 1) would be: © 2007 by the American Diabetes Association. ϭ ϩ ϫ Ϫ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby A1C 3.66 (0.02 mean glucose) marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 0.38, while the regression line to predict
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1579 Late pregnancy A1C levels in type 1 diabetes
tiglioni MT, Songini M, Tocco G, Masin M, Plebani M, Lapolla A: Reference inter- vals for hemoglobin A1c in pregnant women: data from an Italian multicenter study. Clin Chem 52:1138–1143, 2006 2. Radder JK, van Roosmalen J: HbA1c in healthy pregnant women. Neth J Med 63: 256–259, 2005 3. Nielsen LR, Ekbom P, Damm P, Glu¨ mer C, Frandsen MM, Jensen DM, Mathiesen
ER: HbA1c levels are significantly lower in early and late prenancy. Diabetes Care 27: 1200–1201, 2004 4. O’Kane MJ, Lynch PLM, Moles KW, Ma- gee SE: Determination of a diabetes con- trol and complications trial-aligned HbA(1c) reference range in pregnancy. Clin Chim Acta 311:157–159, 2001 5. Hartland AJ, Smith JM, Clark PM, Web- ber J, Chowdhury T, Dunne F: Establish- ing trimester-and ethnic group-related reference ranges for fructosamine and HbA1c in non-diabetic pregnant women. Ann Clin Biochem 36:235–237, 1999 6. Pettit DJ, Venkat Narayan KM: Glycosy- lated hemoglobin in pregnancy (Letter). Diabetes Care 19:1455, 1996 7. Mills JL, Jovanovic Y, Knopp R, Aarons J, Conley M, Park E, Lee YJ, Holmes L, Simpson JL, Metzger B: Physiological re- duction in fasting plasma glucose concen- tration in the first trimester of pregnancy: the Diabetes in Early Pregnancy Study. Metabolism 47:1140–1144, 1998 8. Cousins L, Rigg L, Hollingsworth D, Brink G, Aurand J, Yenn SSC: the 24-hour excur- sion and diurnal rhythm of glucose, insulin Figure 1—Regression lines for the relation between A1C and mean glucose before pregnancy and and C-peptide in normal pregnancy. Am J in late pregnancy. Obstet Gynecol 136:483–488, 1980 9. Lurie S, Danon D: Life span of erythro- preconception A1C (pregnancy status ϭ 0) A1C is insufficient for preventing diabe- cytes in late pregnancy. Obstet Gynecol 80: would be: A1C ϭ 3.66 ϩ (0.02 ϫ mean tes-related complications of pregnancy 123–126, 1992 glucose). This means that in women with (13,14), since the A1C value will be lower 10. Lurie S: Age distribution of erythrocyte type 1 diabetes, a reduction of ϳ0.4% in the independently of glycemic control. While population in late pregnancy. Gynecol Ob- A1C value can be expected in late preg- it seems difficult to achieve the glucose stet Invest 30:147–149, 1990 nancy, which is not dependent on mean levels reported in healthy pregnant 11. Kilpatrick ES: HbA1c measurement. J Clin glucose levels. Figure 1 shows that for any women (15), it is of clinical importance to Pathol 57:344–345, 2004 mean glucose value, the A1C predicted will note that when evaluating third trimester 12. Kilpatrick ES, Maylor PW, Keevil BG: Bi- ological variation of glycated hemoglobin. be lower in late pregnancy than before preg- A1C levels in women with type 1 diabetes ϳ Diabetes Care 21:261–264, 1998 nancy (e.g., for a mean glucose of 140 mg/ the value will be 0.4% lower, without 13. Evers IM, de Valk HW, Visser GHA: Risk dl, the A1C would be 6.5% before any improvement in glycemic control. of complications of pregnancy in women pregnancy and 6.1% in late pregnancy). Several studies suggest that the nor- with type 1 diabetes: nationwide prospec- Biological variation in A1C, which is mal upper reference range of A1C in preg- tive study in the Netherlands. BMJ 328: distinct from that attributable to mean nant women should be lower (1–3). Since 915–918, 2004 glucose, cannot account for the change in women with type 1 diabetes a decrease 14. Evers IM, de Valk HW, Mol BWJ, ter observed. Variation of A1C between indi- in third trimester A1C value will occur Braak EWMT, Visser GHA: Macrosomia viduals, which represents the main source regardless of glycemic control, we con- despite good glycaemic control in type 1 of A1C variation (11), does not influence clude that the A1C goal in late pregnancy diabetic pregnancy; results of a nation- our results, since the same women were should be lowered 0.4% for pregnancies wide study in the Netherlands. Diabetolo- gia 45:1484–1489, 2002 studied before pregnancy and during complicated with diabetes. 15. Parretti E, Mecacci F, Papini M, Cioni R, pregnancy. Within-individual changes in Carignani L, Mignosa M, La Torre P, A1C are too small (12) to explain a reduc- References Mello M: Third-trimester maternal glu- tion of 0.4% in A1C. 1. Mosca A, Paleari R, Dalfra` MG, Di Cian- cose levels from diurnal profiles in non Our results provide an additional ex- niG, Cuccuru I, Pellegrini G, Mallogi L, diabetic pregnancies. Diabetes Care 24: planation to the fact that near-normal Bonomo M, Granata S, Ceriotti F, Cas- 1319–1323, 2001
1580 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition BRIEF REPORT
Reduction of Microalbuminuria in Patients With Type 2 Diabetes The Shiga Microalbuminuria Reduction Trial (SMART)
THE SHIGA MICROALBUMINURIA REDUCTION two-way, repeated-measures ANOVA TRIAL (SMART) GROUP* model.
ϭ lthough the reduction of blood disease other than diabetic nephropathy, RESULTS — Patients (n 341) were pressure to Ͻ130/80 mmHg using cardiovascular accidents within the pre- enrolled for screening, and 153 patients A rennin-angiotensin system (RAS)- ceding 6 months, severe peripheral vas- were randomly assigned to the valsartan blocking drugs has been recommended cular disease, congestive heart failure, group or the amlodipine group. Three pa- for diabetic patients with hypertension pregnancy, and childbearing potential. At tients were excluded from efficacy analy- ses due to loss of follow-up. In summary, (1,2), there have been no controlled stud- the beginning of the screening period, cal- we analyzed a total of 150 patients (mean ies comparing the therapeutic effects of cium channel blockers or ARBs were age 62 years, male/female 51/99). The the RAS blocker with another antihyper- withdrawn from patients if they had al- tensive agent targeting the target blood baseline characteristics (age, sex, history ready been administered to the patient. of cardiovascular diseases, total choles- pressure level. Therefore, the objective of Other antihypertensive medications were this study was to assess the effect of an terol, HDL, A1C, and smoking) of the two maintained at the same dosage through- groups were similar. At baseline, 72 pa- angiotensin receptor blocker (ARB), val- out the study. The patients were ran- sartan, on microalbuminuria in compari- tients (34 of 73 in the valsartan group and domly assigned to receive either 80 mg 38 of 77 in the amlodipine group) were son with that of a calcium channel valsartan once daily or 5 mg amlodipine blocker, amlodipine, in patients with the treated with ACE inhibitors for at least 3 Ͻ once daily. The target blood pressure was months. The frequency of antihyperten- targeting blood pressure level 130/80 Ͻ130/80 mmHg. If adequate blood pres- mmHg. sive drug usage was not different between sure control was not achieved with the the two groups. The A1C levels at the end initial dose of the study drug by week 4 of RESEARCH DESIGN AND of the follow-up period of the two treat- Ϯ METHODS the intervention period, the valsartan or ment groups were similar (7.2 1.1% vs. — From December 2003 Ϯ through March 2006, we recruited Japa- amlodipine dose was doubled. If neces- 7.5 1.3%, respectively). Over the study nese type 2 diabetic patients who had at sary, additional antihypertensive drugs period, the reductions in blood pressure least a 5-year history of diabetes and per- (except ACE inhibitors) could be added were also similar between the two treat- sistent microalbuminuria (urinary albu- after week 8 of the intervention period. ment groups (Fig. 1A). The percentage of min creatinine ratio [ACR] 30–299 ACR was measured at the central labora- the patients who achieved the target sys- g/mg creatinine on the average of first- tory (Medic Lab) using the first morning tolic blood pressure (SBP) was 50.7% in voided urine samples for 3 consecutive urine samples. The study was approved the valsartan group and 48.1% in the am- days) (3,4). The other inclusion criterion by the ethics committee of Shiga Univer- lodipine group. was a baseline blood pressure Ն140/90 sity of Medical Science and was under- At the end of study, the changes in the and Յ180/110 mmHg in the patients taken in accordance with the Declaration ACR from baseline was 68% in the valsar- of Helsinki. Written informed consent tan group and 118% in the amlodipine who were not taking antihypertensive Ͻ agents and Ն130/80 and Յ180/110 was obtained from all patients. group (P 0.001) (Fig. 1B). The fre- mmHg in the patients taking antihyper- Analyses were performed with the last quency of patients who achieved remis- tensive agents. The exclusion criteria were observation carried forward method. Dif- sion (shift of the ACR from micro- type 1 diabetes, a baseline serum creati- ferences between the study groups in albuminuria to normoalbuminuria) or nine Ͼ133 mmol/l, a baseline serum po- blood pressure and the percentage change regression (50% reduction in the ACR tassium Ͼ5.6 mmol/l, kidney or renal in the ACR were analyzed by applying the from baseline) of microalbuminuria (5–7) was significantly higher in the valsartan ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● group than in the amlodipine group (re- ϭ Address correspondence and reprint requests to Atsunori Kashiwagi, MD, PhD, Department of Medicine, mission 23 vs. 11%, P 0.011; regres- Shiga University of Medical Science, Seta, Otsu 520-2192, Japan. sion 34 vs. 16%, P ϭ 0.008). In patients Received for publication 8 December 2006 and accepted in revised form 2 March 2007. who were also treated with ACE inhibi- Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc06-2493. tors, the ACR in the valsartan group was Clinical trial reg. no. NCT00202618, clinicaltrials.gov. significantly reduced than that in the am- *Members of the SMART group can be found in the APPENDIX. Ϫ Abbreviations: ACR, albumin creatinine ratio; ARB, angiotensin receptor blocker; RAS, rennin- lodipine group (valsartan group 26%, angiotensin system; SBP, systolic blood pressure. amlodipine group ϩ8%, P ϭ 0.04). Fig- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ure 1C shows the changes of in the ACR in factors for many substances. relation to the SBP (controlled group © 2007 by the American Diabetes Association. Ͻ Ն The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 130 mmHg; uncontrolled group 130 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mmHg) and the treatments. In the valsar-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1581 Reduction microalbuminuria in type 2 diabetes
group, the changes in the ACR were dif- ferent between the two subgroups (con- trolled group Ϫ11%; uncontrolled group ϩ40%, P Ͻ 0.001). The changes in the ACR were also different between the paired valsartan and amlodipine subgroups.
Safety In the amlodipine group, one experi- enced a cerebral hemorrhage, one re- ported angina pectoris, and one had leg edema. No correlation between these events and the test drug was proven by the safety board. There were no deaths related to the study medication. No sig- nificant changes were observed in the se- rum creatinine and potassium levels in either group.
CONCLUSIONS — A recent meta- analysis showed that the benefit of RAS inhibitors on renal outcome most likely resulted from a blood pressure effect (8). They emphasized that the lack of advan- tage of RAS inhibitors over other antihy- pertensive drugs beyond lowering blood pressure in preventing diabetic nephrop- athy. In this open-label, randomized study, the reductions in blood pressure were similar between the valsartan group and the amlodipine group. However, val- sartan was more effective than amlodipine for reducing microalbuminuria. In addi- tion, the reduction of the ACR was signif- icantly greater in the valsartan group with uncontrolled SBP than that in the amlo- dipine group with controlled SBP. These findings showed that the antiprotenuric effect of valsartan may be independent of its effect on blood pressure. We conclude that ARBs can therefore be a first-line drug for the patients with type 2 diabetes and microalbuminuria.
APPENDIX
Writing committee Takashi Uzu, Makoto Sawaguchi, Hiroshi Maegawa, and Atsunori Kashiwagi. Ϯ Ϯ Figure 1—Time-course changes in blood pressure (A; means SD) and ACR (B; means 95% SMART Group CI) in patients administrated with valsartan ( ) or amlodipine (f). C: Time-course changes in ACR in a subset of patients with controlled blood pressure (end point SBP Ͻ130 mmHg) treated Safety board: Koubin Tomita (Tomita with valsartan ( ) or amlodipine (f) and a subset of patients with uncontrolled blood pressure clinic), Naoki Horide (Horide clinic), and (end point SBP Ն130 mmHg) treated with valsartan ( ) or amlodipine ( ). *P Ͻ 0.005 and Toshihiro Kawabata (Kawabata clinic). **P Ͻ 0.001 between the groups. SMART Investigators Daisuke Koya (Kanazawa Medical Univer- tan group, there was a progressive reduc- nificant difference was found regarding sity), Takashi Uzu, Hiroshi Maegawa, tion in the ACR (controlled group Ϫ40%; the change in the ACR between the two (Shiga University of Medical Science), Ma- uncontrolled group Ϫ23%), and no sig- subgroups. However, in the amlodipine sataka Nishimura (Nagahama City Hospi-
1582 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 The SMART Group tal), Shyu Yamada (Kohka Public Hospital), Roccella EJ, National Heart, Lung, and Med J 11:130–134, 1987 Yasuo Kida, Tetsuya Hashimoto (Second Blood Institute Joint National Committee 5. Perkins BA, Ficociello LH, Silva KH, Okamoto General Hospital), Noriko Taka- on Prevention, Detection, Evaluation, and Finkelstein DM, Warram JH, Krolewski hara (Ako City Hospital), Katuya Egawa Treatment of High Blood Pressure; Na- AS: Regression of microalbuminuria in (Nagahama Red Cross Hospital), Masanori tional High Blood Pressure Education type 1 diabetes. N Engl J Med 348:2285– Program Coordinating Committee: The Iwanishi, Ntsuki Harada (Kusatsu General 2293, 2003 Seventh Report of the Joint National 6. Viberti G, Wheeldon NM, MicroAlbumin- Hospital), Tetsuro Arimura (Social Insur- Committee on Prevention, Detection, ance Shiga Hospital), Aya Kadota (Seta uria Reduction With VALsartan (MARVAL) Evaluation, and Treatment of High Blood Study Investigators: Microalbuminuria re- Clinic), Toshiki Fujita (Biwako Ohashi Pressure: the JNC 7 report. JAMA 289: duction with valsartan in patients with type Hospital), Motoyoshi Ikebuchi (Ikebuchi 2560–2572, 2003 2 diabetes mellitus: a blood pressure-inde- Clinic), Katsuhiko Sakamoto (Sakamoto 2. Cifkova R, Erdine S, Fagard R, Farsang C, pendent effect. Circulation 106:672–678, Heagerty AM, Kiowski W, Kjeldsen S, Clinic), Yoshihiko Nishio, Satoshi Ugi, Os- 2002 Luscher T, Mallion JM, Mancia G, Poulter amu Sekine, Toshiro Sugimoto, Shin-ichi 7. Araki S, Haneda M, Sugimoto T, Isono N, Rahn KH, Rodicio JL, Ruilope LM, van Araki, Keiji Isshiki, Makoto Sawaguchi M, Isshiki K, Kashiwagi A, Koya D: Fac- (Shiga University of Medical Science), Zwieten P, Waeber B, Williams B, Zanchetti A, ESH/ESC Hypertension Guidelines tors associated with frequent remission Nobuo Shirahashi (Osaka City University), Committee: Practice guidelines for primary of microalbuminuria in patients with Masakazu Haneda (Asahikawa Medical care physicians: 2003 ESH/ESC hyperten- type 2 diabetes. Diabetes 54:2983– College), and Atsunori Kashiwagi (Shiga sion guidelines. J Hypertens 21:1779–1786, 2987, 2005 University of Medical Science). 2003 8. Casas JP, Chua W, Loukogeorgakis S, Val- 3. American Diabetes Association: Ne- lance P, Smeeth L, Hingorani AD, Mac- phropathy in diabetes. Diabetes Care 27 Allister RJ: Effect of inhibitors of the References (Suppl. 1):S79–S83, 2004 renin-angiotensin system and other anti- 1. Chobanian AV, Bakris GL, Black HR, 4. Woolerton J, Jury DR, Dunn PJ, Speed JF: hypertensive drugs on renal outcomes: Cushman WC, Green LA, Izzo JL Jr, Jones Urine albumin creatinine ratio and clini- systematic review and meta-analysis. Lan- DW, Materson BJ, Oparil S, Wright JT Jr, cal correlates in a diabetic population. NZ cet 366:2026–2033, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1583 Clinical Care/Education/Nutrition BRIEF REPORT
Evaluation of a Teaching and Treatment Program in Over 4,000 Type 2 Diabetic Patients After Introduction of Reimbursement Policy for Physicians
1 3 STEFAN KORSATKO, MD ROBERT GFRERER, PHD abetes Indicator Project (EUDIP) (11). 2 4 WOLFGANG HABACHER, MSC PETER MRAK, MD This form must be completed for each 2 4 IVO RAKOVAC, MSC BERND BAUER, MD patient at baseline and at follow-up. Ev- 1 5 JOHANNES PLANK, MD MANFRED GROßSCHADL¨ , MD ery 3 months, a benchmarking report is 2 1,2 SABINE SEEREINER, MSC HOMAS IEBER MD 1 T R. P , compiled and sent to each participating PETER BECK, MSC physician. An annual report analyzes the effects of the program that suggests adaptations to the steering committee, atient education in diabetes has be- RESEARCH DESIGN AND which reviews current data biannually. come an integral part of diabetes METHODS — The Styrian Diabetes A postgraduate meeting is offered twice P management (1–3). Systematic re- Type 2 Education Project is a combined a year. views report the best results in terms of intervention consisting of a structured improved metabolic control, weight loss, DTTP and a special training for the edu- RESULTS — During 4 project years, and diabetes-related knowledge in cases cating staff. The DTTP is a 16-h course, 120 physicians and 52 diabetes educators where mainly nurses provide patient ed- conducted at the primary health care taught the DTTP course to 4,396 patients ucation combined with structured and level. It is well evaluated and transferable with type 2 diabetes (55% female, aged regular patient review. Therefore, patient (6–10). The program covers nine educa- 63.8 Ϯ 10.7 years, diabetes duration 5.0 Ϯ education is recommended as a necessary tion areas: basic diabetes information, 6.2 years, BMI 29.7 Ϯ 5.1 kg/m2, baseline component in promoting good diabetes self-monitoring, medication and hypo- A1C 7.6 Ϯ 1.6%; all mean Ϯ SD). A total of control (4,5). glycemia, diet, foot care, physical activity, 2,122 (48%) individuals attended the fol- In 2000, the Styrian Diabetes Type 2 sick day rules, and late complications. low-up assessment. All target parameters Ͻ Education Project was implemented Training of the educators (physicians and significantly (P 0.001) improved after 1 Ϫ Ϯ Ϫ Ϯ across the Austrian province of Styria. diabetes educators) focuses on the discus- year (A1C 0.4 1.3%, BMI 0.4 2.4 2 Ϫ Ϯ Until then, no formal implementation or sion of evidence-based therapy and ther- kg/m , body weight 1.1 6.2 kg, systolic blood pressure Ϫ1.8 Ϯ 19.3 mmHg, dia- reimbursement of educational efforts had apy goals. Role-playing techniques are Ϫ Ϯ been provided in the Austrian health care used to improve patient education skills. stolic blood pressure 1.1 10.8 mmHg, cholesterol Ϫ0.1 Ϯ 1.1 mmol/l, LDL cho- system. The primary objective of the One year after the initial teaching pro- lesterol Ϫ0.2 Ϯ 0.9 mmol/l, and triglycer- project was to provide free access to a gram, a 2-h refresher course including a ides Ϫ0.1 Ϯ 1.8 mmol/l). Changes in structured diabetes teaching and treat- follow-up assessment is held. The remu- glucose-lowering treatments are illustrated ment program (DTTP) at the primary neration for one training course (6–12 in Fig. 1. Although insulin therapy was not health care level throughout the province participants) is $870 and $183 for the an inclusion criterion, 1.1% of the patients to patients with type 2 diabetes who are follow-up. were already on insulin at baseline and 6% not using insulin for glycemic control. The project is supported by a qual- at follow-up. Sixty-six percent of the pa- Here, we report its overall acceptance and ity management concept using a docu- tients had eye examinations within 1 year effectiveness 4 years after its systematic mentation form that includes most of before the course and 69% (P ϭ 0.04.) at implementation. the data proposed by the European Di- follow-up. The rate of foot examinations did not change significantly (86–85% at fol- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● low-up, P ϭ 0.28). From the 1Department of Internal Medicine, Medical University, Graz, Austria; 2Joanneum Research, Graz, 3 4 More information on the project, the Austria; Human Technology, Styria, Austria.; the General Hospital Ho¨rgas Enzenbach, Enzenbach, Aus- documentation form, statistical analysis, tria; and a 5private practice, Seiersberg, Austria. Address correspondence and reprint requests to Stefan Korsatko, MD, Department of Internal Medicine, baseline characteristics, change in A1C, Division of Diabetes and Metabolism, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. and treatment for arterial hypertension E-mail: [email protected]. and blood lipids are available in an on- Received for publication 11 October 2006 and accepted in revised form 12 March 2007. line-only appendix (available at http:// Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2095. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ dx.doi.org/10.2337/dc06-2095). dc06-2095. Abbreviations: DTTP, diabetes teaching and treatment program. CONCLUSIONS — Our evaluation A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion demonstrates that a teaching and treat- factors for many substances. ment program for patients with type 2 di- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby abetes can successfully be implemented marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. throughout the area at the primary health
1584 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Korsatko and Associates
onstrates, by means of improved interme- diate outcome parameters, that a teaching and treatment program for patients with type 2 diabetes who are not using insulin for glycemic control was successfully im- plemented province wide at the primary health care level.
Acknowledgments— The authors thank all members of Forum for Quality Systems in Di- abetes Care, the Styrian Medical Association, the regional health insurance fund (Gebiets- krankenkasse), the Styrian government, and all participating physicians and diabetes educators.
References 1. Deakin T, McShane CE, Cade JE, Wil- liams RDRR: Group based training for self-management strategies in people with type 2 diabetes mellitus. The Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD003417.pub2. DOI:10.1002/ 14651858. CD003417.pub2, 2005 Figure 1— Change in hypoglycemic treatment before training and at follow-up. Insulin denotes 2. Renders CM, Valk GD, Griffin SJ, Wagner insulin use, either as single therapy or in combination with other oral antidiabetes agents (OAD). EH, Eijk Van JT, Assendelft WJ: Interven- Among combinations of OAD, the combination of metformin and sulfonylureas was the most tions to improve the management of dia- frequent and was prescribed in 55 and 58% of patients receiving Ͼ1 OAD at baseline and follow- f betes in primary care, outpatient and up, respectively. , before education; , follow-up. community settings: a systematic review (Review). Diabetes Care 24:1821–1833, 2001 care level. Our large-scale cohort showed penses for documentation are too high 3. Norris SL, Lau J, Smith SJ, Schmid CH, an improvement of all target parameters and that remuneration for the follow-up Engelgau MM: Self-management educa- with an A1C reduction comparable to examination is not attractive. Otherwise, tion for adults with type 2 diabetes: a previous randomized studies (12,13). based on physicians’ opinions, patients meta-analysis of the effect on glycemic The relative increase of patients treated do not show up at follow-up because of control. Diabetes Care 25:1159–1171, with biguanides at follow-up may ac- loss of motivation, a guilty conscience be- 2002 4. Burgers JS, Bailey JV, Klazinga NS, Van count partly for the decrease of A1C and cause they did not modify their behavior Der Bij AK, Grol R, Feder G, AGREE Col- for the observed weight reduction. Apart after the training course, or they do not laboration: Comparative analysis of rec- from the effects of the training program, see the sense of a follow-up, having al- ommendations and evidence in diabetes including improved drug intake compli- ready heard everything in the initial guidelines from 13 countries. Diabetes ance, increase of physical activity pat- course. It is possible that the patients lost Care 25:1933–1939, 2002 terns, and changes in nutritional habits to follow-up were less successful in reach- 5. International Diabetes Federation: Global (9,10), the metabolic improvement could ing their treatment targets than the others. Guideline for Type 2 Diabetes [Internet], be further explained either by an increase One can speculate whether a personal re- 2005. Available from http://www.idf.org/ in medication dosage or by initiation of minder for patients, as installed for phy- webdata/docs/idf_GGT2D.pdf. Accessed insulin therapy. sicians, would have further increased the 20 April 2006 6. Pieber TR, Holler A, Siebenhofer A, Brun- The low follow-up rate is a limitation follow-up rate. ner GA, Semlitsch B, Schattenberg S, of the project. Randomized controlled tri- The introduction of a structured Zapotoczky H, Rainer W, Krejs GJ: Eval- als on similar topics obtain follow-up documentation led to a more accurate uation of a structured teaching and treat- rates of at least ϳ80% (2), while in inter- and comprehensive monitoring of the ment programme for type 2 diabetes in rupted time series and before-and-after patient. Eye examination rate (69%) general practice in a rural area of Austria. studies, which are more comparable to was clearly higher compared with a sur- Diabet Med 12:349–354, 1995 our study, these rates are seldom vey (57.6%) by Saaddine et al. (14). The 7. Gagliardino JJ, Etchegoyen G, PENDID- achieved. However, sustained implemen- early educational intervention and in- LA Research Group: A model educational tation of education programs within the tensified screening and treatment for program for people with type 2 diabetes: a health system has rarely been subject to secondary complications in our pro- cooperative Latin American implementa- tion study (PEDNID-LA). Diabetes Care evaluation in the literature. Through a gram will likely postpone the outbreak 24:1001–1007, 2001 standardized questionnaire sent to partic- of diabetes-related comorbidity as pre- 8. Mu¨ hlhauser I, Berger M: Patient educa- ipating physicians, reasons for the low fol- viously shown in disease management tion: evaluation of a complex interven- low-up rate were determined. The most programs (15,16). tion. Diabetologia 45:1723–1733, 2002 common response was that operating ex- In conclusion, our investigation dem- 9. Kronsbein P, Jo¨rgens V, Mu¨ hlhauser I,
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1585 Teaching and treatment program for diabetes
Scholz V, Venhaus A, Berger M: Evalua- Schober E, Boran G, Tolis G: European quality of care in the 1990’s. Ann Intern tion of a structured treatment and teach- Union diabetes indicators: fact or fiction? Med 136:565–574, 2002 ing programme on non-insulin-dependent Eur J of Public Health 13 (Suppl.):51–54, 15. Trento M, Passera P, Bajardi M, Toma- diabetes. Lancet 2:1407–1411, 1998 2003 lino M, Grassi G, Borgo E, Donnola C, 10. Gru¨ sser M, Bott U, Ellermann P, Krons- 12. Lozano ML, Armale MJ, Tena DI, Sanchez Cavallo F, Bondonio P, Porta M: Life- bein P, Jo¨rgens V: Evaluation of a struc- NC: The education of type-2 diabetics. style intervention by group care pre- tured treatment and teaching program for Aten Primaria 23:485–492, 1999 vents deterioration of type II diabetes: a non–insulin-treated type 2 diabetic out- 13. Brown SA, Garcia AA, Kouzekanani K, 4-year randomized controlled clinical patients in Germany after the nationwide Hanis CL: Culturally competent diabetes trial. Diabetologia 45:1231–1239, 2002 introduction of reimbursement policy for self-management education for Mexican 16. Lavery LA, Wunderlich RP, Tredwell JL: physicians. Diabetes Care 16:1268–1275, Americans. Diabetes Care 25:159–168, Disease management for the diabetic foot: 1993 2002 effectiveness of a diabetic foot prevention 11. Beaufort CE, Reunanen A, Raleigh V, 14. Saaddine JB, Engelgau MM, Beckles GL, program to reduce amputations and hos- Storms F, Kleinbreil L, Gallego R, Giorda Gregg EW, Thompson TJ, Narayan KM: A pitalizations. Diabetes Res Clin Pract 70: C, Midthjell K, Jecht M, de Leeuw I, diabetes report card for the United States: 31–37, 2005
1586 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Clinical Care/Education/Nutrition BRIEF REPORT
Gain in Patients’ Knowledge of Diabetes Management Targets Is Associated With Better Glycemic Control
1 3 PADMALATHA BERIKAI, MD, MS BARBARA SAVOY, MS, RD, CDE group” if their pretest score was Ͼ40%. 2 3 PETER M. MEYER, PHD KELLY KOZIK, RD, CDE We defined knowledge gainers as achiev- 1,3 1,3 RASA KAZLAUSKAITE, MD, MS LEON FOGELFELD, MD ers of a posttest score of Ն80 and 100% for the low and high baseline knowledge groups, respectively. Patients with lower ptimal glycemic, lipid, and blood Ն7% measured within 1 month of receiv- than these posttest scores were classified pressure control has been shown to ing DSME and with an ϳ6-month fol- as nongainers. The posttest score cutoff, O decrease the microvascular and ma- low-up A1C measurement (ranging 3–12 Ն80%, was chosen for the first group to crovascular complications of diabetes (1– months and at least 3 months from the assess the effect of considerable knowl- 10). However, the status of control of baseline A1C) were selected for this edge gain (Ն ϫ2) on study outcome, and these cardiovascular risk factors in indi- study. A1C was measured by the high- the posttest score of 100% was chosen for viduals with diabetes is far from optimal performance liquid chromatography the next group to allow maximal possible (11,12). Lack of patients’ knowledge of method throughout the study period. Af- gain in the score. Patients with a pretest the targets of diabetes care might be one of ter the educational sessions, patients re- score of 100% were classified as nongain- the reasons for the low level of control of ceived follow-up medical care by ers if their posttest score was lower. risk factors. Some studies showed that endocrinologists in conjunction with Knowledge gain as a predictor of tar- only 23–25% of individuals with diabetes their primary care providers. get A1C achievement was tested by logis- know what the target A1C level is (Ͻ7%), A simple five-item questionnaire tic regression using SPSS version 12.0 and about the same percent of patients (found in an online appendix, “ABC test,” (Chicago, IL). The tests were two-sided know how to interpret A1C values in re- at http://dx.doi.org.10.2337/dc06-2026) with a 5% significance level. lation to their own glycemic control on glycemic control, blood pressure, and (13,14). Improving patients’ knowledge LDL cholesterol targets, as recommended RESULTS — A total of 155 subjects might help attain the goals of diabetes by American Diabetes Association (19), met the eligibility criteria, 94% had the management, but the supporting studies was administered to English-speaking pa- baseline A1C performed on or within 1 are limited (14–18). tients before (pretest) and after (posttest) month before the day of receiving DSME, We investigated whether the gain in DSME. The correct answer for each ques- and 97% had type 2 diabetes. A total of 93 the knowledge of the targets of diabetes tion carried a score of 20%. The test was subjects (60%) were classified as knowl- care after receiving diabetes self- validated by a method similar to the one edge gainers, and 62 subjects (40%) were management education (DSME) predicts developed by Paddock et al. (20). classified as nongainers. Patient charac- the achievement of target A1C levels The opportunity to show improve- teristics including demographic variables, (Ͻ7%) at 6 months. ment from pretest to posttest was not the duration of diabetes, BMI, baseline A1C, same for all individuals. It was higher for number of follow-up visits to the diabetes RESEARCH DESIGN AND patients with lower pretest scores and vice center, and the duration of follow-up METHODS — This is a retrospective versa, as was also noted in other training were similar between knowledge gainers study of adult diabetic subjects who re- programs (21). Based on this consider- and nongainers as shown in Table 1. ceived DSME in the American Diabetes ation, the knowledge gain was measured Overall, 5.2% of the patients were Association–certified Diabetes Center of in relation to the baseline score. Subjects new to diabetes therapy during the study, John H. Stroger, Jr. Hospital of Cook were classified into “low baseline knowl- and there was a slightly higher use of County between 2001 and 2004. edge group” if their pretest score was combination therapy with oral agents Patients with baseline A1C levels Յ40% and “high baseline knowledge plus insulin (13.5 vs. 16.8%) at follow- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● up. Though the hypoglycemic therapy
1 2 deemed appropriate by the treating phy- From the Division of Endocrinology, Rush University Medical Center, Chicago, Illinois; the Department of sicians somewhat changed over time, Preventative Medicine, Rush University Medical Center, Chicago, Illinois; and the 3Division of Endocrinol- ogy, John H. Stroger, Jr. Hospital, Chicago, Illinois. there were no significant differences in Address correspondence and reprint requests to Leon Fogelfeld, MD, 1900 W. Polk St., Room 812, the type of therapy between study groups Chicago, IL 60612. E-mail: [email protected]. at baseline (P ϭ 0.47) or at follow-up Received for publication 3 October 2006 and accepted in revised form 12 March 2007. (P ϭ 0.74), as shown in Table 1. Further- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2026. Additional information for this article can be found in an online appendix at http://dx.doi.org.10.2337/ more, there was no difference in the num- dc06-2026. ber of oral agents between gainers and Abbreviations: DSME, diabetes self-management education. nongainers at follow-up (monotherapy, A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 87.5 vs. 86.4%; dual therapy 12.5 vs. factors for many substances. 11,4%; and triple therapy, 0 vs. 2.3%, © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby respectively). marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Overall, A1C decreased from 10.1 Ϯ
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1587 Patients’ diabetes knowledge and glycemic control
Table 1—Comparison of baseline and follow-up characteristics in knowledge gainers and an odds ratio of 2.3 (95% CI of 1.1–5.0%, nongainers P ϭ 0.028) after adjusting for baseline A1C, duration of diabetes, sex, ethnicity, Characteristic Knowledge gainers Nongainers P BMI, and the number of visits to the dia- betes center. n (%) 93 (60) 62 (40) In particular, subgroup analysis At baseline showed the gainers in the low baseline Sex* 0.19 knowledge group attained more than Male 52.7 41.9 twofold higher target A1C rate (45.5%) Female 47.3 58.1 than nongainers (20%, P ϭ 0.021). In the Ethnicity* 0.16 high baseline knowledge group, target African American 51.6 66.1 A1C rates were higher in the gainers Caucasian 12.9 9.7 (46.9%) than nongainers (37.5%), but Asian 18.3 16.1 the difference was not statistically signifi- Hispanic 11.8 1.6 cant (P ϭ 0.2). Other 5.4 6.5 Education* 0.48 CONCLUSIONS — Our results showed Less than high school 20.4 24.2 that the gain in the knowledge of the tar- High school 7.5 4.8 gets of diabetes care after receiving DSME Some college/trade school 52.7 59.7 independently predicted the achievement College graduation 19.4 11.3 of target A1C levels. The difference in the Employment* 0.24 target A1C achievement rate between Unemployed 74.2 85.5 knowledge gainers and nongainers was Part time 17.2 9.7 significant in the low baseline knowledge Full time/data not available 8.6 4.8 group but not in the high baseline knowl- Age in years (mean Ϯ SD)† 53.2 Ϯ 10.9 56.0 Ϯ 11.4 0.12 edge group. Duration of diabetes in years 1.5 (0.5, 11.5) 1.5 (0.5, 9.5) 0.61 Rothman et al. (22) reported similar (median 25th, 75th results with their multidisciplinary diabe- percentiles)‡ tes management program, where the in- BMI (kg/m2)† 32.7 Ϯ 8.0 31.4 Ϯ 10.1 0.38 tervention patients achieved significantly A1C % (median)‡ 10.2 Ϯ 2.1 (9.7) 9.9 Ϯ 2.5 (9.1) 0.13 higher target A1C rates than control sub- Type of diabetes therapy* 0.47 jects in the low literacy group but not in Oral agents 62.4 72.6 the high literacy group. Insulin 16.1 8.1 Knowledge gain, measured in relation Insulin ϩ oral agents 14.0 12.9 to the baseline knowledge, was found to No therapy or data not available 7.5 6.5 be a good indicator of the impact of dia- Pretest score (%)† 52.0 Ϯ 26.2 47.4 Ϯ 25.2 0.34 betes education on glycemic control in Mean improvement in score (%)§ this study. The DSME might have im- Entire group 44.3 Ϯ 23.6 17.1 Ϯ 19.5 Ͻ0.001 proved patients’ understanding of the im- Low baseline knowledge groupʈ 63.2 Ϯ 15.5 27.4 Ϯ 15.1 Ͻ0.001 portance of reaching the targets and High baseline knowledge group¶ 28.7 Ϯ 16.3 6.3 Ϯ 15.6 Ͻ0.001 motivated them to adopt better self- At follow-up management practices leading to better Follow-up in months† 6.5 Ϯ 2.3 6.4 Ϯ 2.0 0.79 glycemic control in gainers, though our Diabetes center visits† 3.7 Ϯ 1.6 3.6 Ϯ 1.5 0.59 study is limited in that we did not evaluate A1C % (median)‡ 7.6 Ϯ 1.9 (7.1) 7.9 Ϯ 1.9 (7.5) 0.18 the self-management behaviors. Type of diabetes therapy* 0.74 The significant drop in A1C at fol- Oral agents 68.8 71 low-up for the entire group might be the Insulin 12.9 9.7 result of a combination of factors—the ef- Insulin ϩ oral agents 17.2 16.1 fect of the multidisciplinary intervention, No therapy or data not available 1.1 3.2 especially for some of the patients who Subjects attaining target A1C** might have previously lacked regular di- Entire group 46 29 0.03 abetes care. In addition, about one-half of Low baseline knowledge groupʈ 45.5 20 0.02 the subjects had diabetes of relatively High baseline knowledge group¶ 46.9 37.5 0.20 short duration (Ͻ1.5 years), which is Data are % or means Ϯ SD. *Pearson’s 2 (categorical variables). †Two-sample t test (normally distributed). more responsive to therapy. ‡Mann-Whitney analysis (nonparametric). §Paired Wilcoxon analysis. ʈSubjects with a pretest score of This study suggests that patients with Յ Ͼ 40%. ¶Subjects with a pretest score of 40%. **Logistic regression. low baseline knowledge should receive spe- cial attention in DSME programs, as knowl- 2.3% at baseline to 7.7 Ϯ 1.9% at 6.4 Ϯ higher in knowledge gainers versus non- edge gain in this group can significantly 2.1 months follow-up (P Ͻ 0.001) with gainers (46 vs. 29%, P ϭ 0.032). Knowl- improve glycemic control. Special educa- 39.4% achieving the target A1C levels of edge gain remained an independent tional interventions need to be considered Ͻ7%. The target A1C achievement was predictor of target A1C achievement with for individuals who do not gain adequate
1588 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Berikai and Associates knowledge after standard DSME. Evalua- 6. UK Prospective Diabetes Study Group: Quesenberry K, Priest L, Butcher MK, tion by simple pre- and posttests may help Tight blood pressure control and risk of Flook BN, Helgerson SD, Gohdes D: Do to identify such subjects. macrovascular and microvascular com- persons with diabetes know their (A1C) plications in type 2 diabetes: UKPDS 38. number? Diabetes Educ 28:99–105, 2002 BMJ 317:703–713, 1998 14. Agrawal V, Korb P, Cole R, Barnes CS, Rhee 7. Collins R, Armitage J, Parish S, Sleigh P, Acknowledgments— The members of the MK, Ziemer DC, Caudle JM, Khedkar S, Peto R, Heart Protection Study Collabora- Diabetes Center of John H. Stroger, Jr. Hospi- Phillips LS: Patients who know the A1C tive Group: MRC/BHF Heart Protection tal, and the faculty of the Masters of Science in goal have better glycemic control. (Abstract) Study of cholesterol-lowering with simva- Clinical Research Program at Rush University Diabetes 54 (Suppl. 1):298-OR, 2004 statin in 5,963 people with diabetes: a are gratefully acknowledged for their contri- 15. Norris SL, Engelgau MM, Narayan KM: randomised placebo-controlled trial. Lan- bution and suggestions. We thank Lucia Free- Effectiveness of self-management training cet 361:2005–2016, 2003 man for technical assistance. in type 2 diabetes: a systematic review of 8. Colhoun HM, Betteridge DJ, Durrington randomized controlled trials. Diabetes PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton- Care 24:561–587, 2001 References Menys V, Fuller JH;, CARDS Inves- 16. Norris SL, Lau J, Smith SJ, Schmid CH, 1. Stratton IM, Adler AI, Neil HA, Matthews tigators: Primary prevention of cardio- Engelgau MM: Self-management educa- DR, Manley SE, Cull CA, Hadden D, vascular disease with atorvastatin in type 2 tion for adults with type 2 diabetes: a Turner RC, Holman RR: Association of diabetes in the Collaborative Atorvastatin meta-analysis of the effect on glycemic glycaemia with macrovascular and micro- Diabetes Study (CARDS): multicentre ran- control. Diabetes Care 25:1159–1171, vascular complications of type 2 diabetes domised placebo-controlled trial. Lancet 2002 (UKPDS 35): prospective observational 364:685–696, 2004 17. Norris SL: Self-management education in study. BMJ 321:405–412, 2000 9. Pyorala K, Pedersen TR, Kjekshus J, type 2 diabetes: what works? Practical 2. The effect of intensive treatment of diabe- Faergeman O, Olsson AG, Thorgeirsson Diabetology 22:7–13, 2003 tes on the development and progression G: Cholesterol lowering with simvastatin 18. Levetan CS, Dawn KR, Robbins DC, Rat- of long-term complications in insulin-de- improves prognosis of diabetic patients ner RE: Impact of computer-generated
pendent diabetes mellitus: the Diabetes with coronary heart disease: a subgroup personalized goals on HbA1c. Diabetes Control and Complications Trial Re- analysis of the Scandinavian Simvastatin Care 25:2–8, 2002 search Group. N Engl J Med 329: 977– Survival Study (4S). Diabetes Care 20: 19. American Diabetes Association: Stan- 986, 1993 614–620, 1997 dards of medical care in diabetes—2006 3. Nathan DM, Cleary PA, Backlund JY, Ge- 10. Goldberg RB, Mellies MJ, Sacks FM, Moye (Position Statement). Diabetes Care 29 nuth SM, Lachin JM, Orchard TJ, Raskin LA, Howard BV, Howard WJ, Davis BR, (Suppl. 1):S4–S42, 2006 P, Zinman B, Diabetes Control and Com- Cole TG, Pfeffer MA, Braunwald E, CARE 20. Paddock LE, Veloski J, Chatterton ML, plications Trial/Epidemiology of Diabetes Investigators: Cardiovascular events and Gevirtz FO, Nash DB: Development and Interventions and Complications (DCCT/ their reduction with pravastatin in dia- validation of a questionnaire to evaluate EDIC) Study Research Group: Intensive betic and glucose-intolerant myocardial patient satisfaction with diabetes disease diabetes treatment and cardiovascular infarction survivors with average choles- management. Diabetes Care 23:951–956, disease in patients with type 1 diabetes. terol levels: subgroup analyses in the cho- 2000 N Engl J Med 353: 2643–53, 2005 lesterol and recurrent events (CARE) trial. 4. Selvin E, Marinopoulos S, Berkenblit G, Circulation 98:2513–2519, 1998 21. Hovland CI, Lumsdaine AA, Sheffield FD: Rami T, Brancati FL, Powe NR, Golden 11. Saydah SH, Fradkin J, Cowie CC: Poor The baseline for measurement of percent- SH: Meta-analysis: glycosylated hemoglo- control of risk factors for vascular disease age change. In Experiments on Mass Com- bin and cardiovascular disease in diabetes among adults with previously diagnosed munication. Princeton, NJ, Princeton mellitus. Ann Intern Med 141:421–431, diabetes. JAMA 291:335–342, 2004 University Press, 1949, p. 284–289 2004 12. Chuang LM, Tsai ST, Huang BY, Tai TY: 22. Rothman RL, DeWalt DA, Malone R, Bry- 5. Gaede P, Vedel P, Larsen N, Jensen GV, The status of diabetes control in Asia: a ant B, Shintani A, Crigler B, Weinberger Parving HH, Pedersen O: Multifactorial cross-sectional survey of 24 317 patients M, Pignone M: Influence of patient liter- intervention and cardiovascular disease in with diabetes mellitus in 1998. Diabet acy on the effectiveness of a primary patients with type 2 diabetes. N Engl J Med Med 19:978–985, 2002 care-based diabetes disease management 348:383–393, 2003 13. Harwell TS, Dettori N, McDowall JM, program. JAMA 292:1711–1716, 2004
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1589 Clinical Care/Education/Nutrition BRIEF REPORT
Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism
1 7 VASSILI VALAYANNOPOULOS, MD FRANCIS BRUNELLE, MD, PHD high-glucose dietary treatment failed to 2 2,8 MARTINE VAXILLAIRE, PHD PHILIPPE FROGUEL, MD, PHD control hypoglycemia. A transhepatic 3 9 YVES AIGRAIN, MD, PHD JEAN-JACQUES ROBERT, MD, PHD 4 9 pancreatic catheterization with venous FRANCIS JAUBERT, MD, PHD MICHEL POLAK, MD, PHD 5 3 sampling of glucose, insulin, and C- CHRISTINE BELLANNE´-CHANTELOT, MD CLAIRE NIHOUL-F´EKET´ E´, MD, PHD 6 1 peptide, as previously described (17), re- MARIA-JOAO RIBEIRO, MD, PHD PASCALE DE LONLAY, MD, PHD vealed hypersecretion of insulin in the lower part of the pancreatic body. Via pancreatic surgery with a preoperative eonatal hyperinsulinism is the most (5,15–16). Conversely, focal hyperinsu- histological analysis, a focal lesion of 15 important cause of hypoglycemia in linism can be cured by limited pancre- mm of diameter on the lower part of the N infancy (1,2). The inappropriate atectomy (6,17). Genetic counseling is pancreatic body was identified. oversecretion of insulin is responsible for dramatically different, as focal hyperinsu- The second child, a girl, also suffered profound hypoglycemia, requiring ag- linism is considered a sporadic molecular from neonatal hypoglycemic seizures. gressive treatment to prevent brain dam- event with a very low recurrence risk Treatment by diazoxide, nifedipin, and age (1–3). Neonatal hyperinsulinism is (10,18), while diffuse hyperinsulinism is injection of somatostatin was not success- often resistant to medical therapy (1–4), inherited in a recessive pattern for neona- ful, and the child was infused with high Ϫ Ϫ and pancreatectomy is required for many tal onset forms (12–14,19) and in domi- doses of glucose (15 mg kg 1 mn 1) sufferers (1,5–6). The histopathological nant or sporadic transmission for late- and continuous infusion of glucagon (2 18 lesions associated with neonatal hyperin- onset hyperinsulinism (19). We present mg/day). An F-fluoro-L-DOPA positron sulinism may be described as diffuse or here the first case of coexistence of both emission tomography study was per- focal (7–8). Focal adenomatous islet cell focal and diffuse neonatal hyperinsulin- formed, showing a diffuse uptake of the hyperplasia is sporadic and has been ism in the same consanguineous family radiotracer in the pancreatic area, com- demonstrated to arise in individuals who with a dramatically different treatment patible with a diffuse form of hyperinsu- have a germline mutation in the paternal and outcome. linism. allele of the sulfonylurea receptor 1 ABCC8 gene (9,10) or the inward- RESEARCH DESIGN AND rectifying potassium channel Kir6.2 METHODS — The first child, a boy, of RESULTS — A limited pancreatec- (KCNJ11) (10) in addition to a somatic a consanguineous couple (first cousins) of tomy fully cured the first child, who, now loss of the maternally derived chromo- Portuguese ancestry (Fig. 1) presented at 6 years old, is healthy with no relapse of some region 11p15 in adenomatous birth with an increased weight and body  hypoglycemia. Loss of 11p15 heterozy- pancreatic -cells (9–11). Diffuse hyper- length. He presented with hypoglycemic gosy of maternal origin was found in the insulinism may be familial and arises from seizures during the first day of life. Re- lesion with positive proinsulin staining in the autosomal recessive inheritance of peated hypoglycemias (ranging from 1.7  Ͼ -cells (Fig. 1A) and absence of expres- mutations in both ABCC8 (12) and to 2.3 mmol/l, reference range 2.7) sion of the p57 protein (Fig. 1B). A pater- KCNJ11 (13–14) genes. The therapeutic were found during the 1st month, associ- nally inherited heterozygous mutation of outcome for the patients is heavily depen- ated with high insulin levels (ranging the ABCC8 gene (G228D) was also iden- dent on distinguishing between the two from 5.5 to 18 mU/l, reference range tified. The maternal genotype was not histopathological lesions. Diffuse hyper- Ͻ0.4 in hypoglycemia) consistent with tested. As focal hyperinsulinism is spo- insulinisms, which are unresponsive to the diagnosis of persistent neonatal hy- radic, reassuring genetic counseling was medical treatment, require extensive pan- perinsulinism. Medical treatment with given in another center. createctomy, with a high risk of diabetes diazoxide and somatostatin along with On the second child, a near-total pan- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● createctomy was performed after a perop- From the 1Department of Metabolic Disorders, Hoˆpital Necker-Enfants Malades, Paris, France; the 2Lille erative histological confirmation of the Institute of Biology, Lille, France; the 3Department of Pediatric Surgery, Hoˆpital Necker-Enfants Malades, diffuse form (Fig. 1C), and the child de- 4 5 Paris, France; the Department of Pathology, Hoˆpital Necker-Enfants Malades, Paris, France; the Depart- veloped signs of diabetes requiring insu- ment of Biology, Hoˆpital Saint-Antoine, Paris, France; the 6Service Hospitalier Fre´de´ric Joliot, Orsay, France; the 7Department of Radiology, Hoˆpital Necker-Enfants Malades, Paris, France; the 8Department of Genomic lin injections a few weeks after surgery. Medicine8, Hammersmith Hospital, Imperial College, London, U.K.; and the 9Department of Endocrinology, Moreover, the child acquired neurologi- Hoˆpital Necker-Enfants Malades, Paris, France. cal impairment with psychomotor retar- Address correspondence and reprint requests to Vassili Valayannopoulos, Department of Metabolic dation due to repeated hypoglycemic Disorders, Hoˆpital Necker-Enfants Malades, 149, Rue des Se`vres, 75015 Paris, France. E-mail: vassili. [email protected]. seizures, with brain atrophy on the mag- Received for publication 25 November 2006 and accepted in revised form 13 March 2007. netic resonance imaging scan. Molecular Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-2327. analysis of the ABCC8 gene displayed a A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion homozygous mutation identical to the factors for many substances. one found in the first child at the het- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby erozygous form. Both parents were found marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. heterozygous for this mutation (Fig. 1).
1590 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Valayannopoulos and Associates
Figure 1—Pedigree of a consanguineous couple with two children presenting with hyperinsulinism. Both parents are heterozygous for the G228D mutation (half-black symbol) on the ABCC8 gene. The first child is heterozygous like his parents but developed a focal form of hyperinsulinism. The focal lesion has been confirmed by histology, showing positive proinsulin staining (A). P57, a maternal-origin protein, is not expressed on the focal lesion (B). The second child is homozygous for the G228D mutation (full black symbol) and has diffuse hyperinsulinism, confirmed by histological examination, showing positive proinsulin staining in all surgical samples taken from different parts of the pancreas (C).
CONCLUSIONS — We present here focal or diffuse, was finally equal to the risk 637–643, 1993 the first report on both focal (sporadic) of relapse of a diffuse form. 7. Goossens A, Gepts W, Saudubray JM, and diffuse (familial) forms of hyperinsu- In conclusion, this familial presenta- Bonnefont JP, Nihoul-Fekete C, Heitz PU, linism occurring in the same family and tion confirms the possibility of the occur- Kloppel G: Diffuse and focal nesidioblas- showing well-characterized genetic pat- rence of focal hyperinsulinism in con- tosis: a clinocopathological study of 24 patients with persistent neonatal hyperin- terns. In the first child, a paternally inher- sanguineous families. Genetic counseling sulinemic hypoglycemia. Am J Surg Pathol ited ABCC8 mutation associated with a should be prudent in consanguineous 3:766–775, 1989 loss of the maternal wild-type chromo- families and should include molecular 8. Rahier J, Fa¨ltK,Mu¨ ntefering H, Becker K, some in the pancreatic lesion was respon- screening for both parents, regardless of Gepts W, Falkmer S: The basic structural sible for the focal lesion. Paternal and the histological form of hyperinsulinism. lesion of persistent neonatal hypoglycae- maternal mutations in the ABCC8 gene mia with hyperinsulinism: deficiency of due to consanguinity were responsible for pancreatic D cells or hyperactivity of B the recurrence of hyperinsulinism in the References cells? Diabetologia 26:282–289, 1984 second child, with a diffuse pattern. Re- 1. Stanley CA: Hyperinsulinism in infants 9. Verkarre V, Fournet JC, de Lonlay P, cent estimations from France, Japan, and and children. Ped Clin North Am 44:363– Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, the U.S. suggested that 40–65% of all hy- 374, 1997 2. Bruining GJ: Recent advances in hyperin- Saudubray JM, Junien C: Maternal allele perinsulinism patients have a focal form loss with somatic reduction to homozy- (20,21). Usually, genetic counseling in sulinism and the pathogenesis of diabetes mellitus. Current Opinion in Pediatrics gosity of the paternally inherited muta- cases of focal hyperinsulinism is reassur- 2:758–765, 1990 tion of the SUR1 gene leads to congenital ing, as the paternally inherited ABCC8 3. Thomas CG Jr, Underwood LE, Carney hyperinsulinism in focal islet cell adeno- mutation and the loss of the maternal CN, Dolcourt JL, Whitt JJ: Neonatal and matous hyperplasia of the pancreas. J Clin 11p15 allele in the pancreatic cells are infantile hypoglycemia due to insulin ex- Invest 102:1286–1291, 1988 two independent genetic events. Indeed, cess: new aspects of diagnosis and surgical 10. Fournet JC, Mayaud C, de Lonlay P, loss of 11p15 heterozygosy may be re- management. Ann Surg 185:505–517, Gross-Morand MS, Verkarre V, Castanet garded as the “second hit” according to 1977 M, Devillers M, Rahier J, Brunelle F, Rob- Knudson’s model, based on the paradigm 4. Touati G, Poggi-Travert F, Ogier de ert JJ, Nihoul-Fekete C, Saudubray JM, Junien C: Unbalanced expression of of retinoblastoma (22), whereas the germ- Baulny H, Rahier J, Brunelle F, Nihoul- Fekete C, Czernichow P, Saudubray JM: 11p15 imprinted genes in focal forms of line, inherited mutation may be regarded Long-term treatment of persistent hyper- congenital hyperinsulinism: association as the “first hit”. However, unlike muta- insulinaemic hypoglycaemia of infancy with a reduction to homozygosity of a tions of genes involved in-cell growth or with diazoxide : a retrospective review of mutation in ABCC8 or KCNJ11. Am J DNA repair, the germline ABCC8 muta- 77 cases and analysis of efficacy-predict- Pathol 158:2177–2184, 2001 tion is not expected to trigger the “second ing criteria. Eur J Pediatr 157:628–633, 11. de Lonlay P, Fournet JC, Rahier J, Gross- hit,” unless by chance. Thus, the rate of so- 1998 Morand MS, Poggi-Travert F, Foussier V, matic mutation (loss of 11p15 maternal al- 5. Shilyanski J, Fisher S, Cutz E, Perlman K, Bonnefont JP, Brusset MC, Brunelle F, lele) and, consequently, the risk of having Filler RM: Is 95% pancreatectomy the Robert JJ, Nihoul-Fekete C, Saudubray another child with a focal form remains low. procedure of choice for treatment of per- JM, Junien C: Somatic deletion of the im- printed 11p15 region in sporadic persis- By contrast, in this consanguineous family, sistent hyperinsulinemic hypoglycemia of the neonate? J Pediatr Surg 32:342–346, tent hyperinsulinemic hypoglycemia of the risk of occurrence of a diffuse form of 1997 infancy is specific of focal adenomatous hyperinsulinism was 25%, as the risk for the 6. Thornton PS, Alter CA, Levitt Katz LE, hyperplasia and endorses partial pancre- offspring to be the carrier of a heterozygous Baker L, Stanley CA: Short- and long-term atectomy. J Clin Invest 100:802–807, mutation was 50%. The global risk for re- use of octreotide in the treatment of con- 1997 currence of hyperinsulinism in this family, genital hyperinsulinism. J Pediatr 123: 12. Nestorowicz A, Wilson BA, Schoor KP,
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1591 Two forms of hyperinsulinism in a family
Inoue H, Glaser B, Landau H, Stanley CA, ameh M, Cerasi E, Landau H. Hyperinsu- 19. Fournet JC, Junien C: Genetics of congen- Thornton PS, Clement JP 4th, Bryan J, linemic hypoglycemia of infancy nesi- ital hyperinsulinism. Endocr Pathol 15: Aguilar-Bryan L, Permutt MA: Mutations dioblastosis) in clinical remission : high in- 233–240, 2004 in the sulfonylurea receptor gene are as- cidence of diabetes mellitus and persistent 20. Tanizawa Y, Matsuda K, Matsuo M, Ohta sociated with familial hyperinsulinism in b-cell dysfunction at long-term follow-up: Y, Ochi N, Adachi M, Koga M, Mizuno S, Ashkenazi Jews. Hum Mol Genet 5:1813– J Clin Endocrinol Metab 80:386–392, 1995 Kajita M, Tanaka Y, Tachibana K, Inoue 1822, 1996 16. Labrune P, Lechevallier S, Rault M, H, Furukawa S, Amachi T, Ueda K, Oka Y: 13. Thomas P, Ye Y, Lightner E: Mutation of Odie`vre M: Diabetes mellitus 14 years af- Genetic analysis of Japanese patients with the pancreatic islet inward rectifier Kir6.2 ter subtotal pancreatectomy for neonatal persistent hyperinsulinemic hypoglyce- also leads to familial persistent hyperinsu- hyperinsulinism. J Pediatr Surg 25:1246– mia of infancy: nucleotide-binding fold-2 linemic hypoglycemia of infancy. Hum 1247, 1990 mutation impairs cooperative binding of Mol Gen 5:1809–1812, 1996 17. Lyonnet S, Bonnefont JP, Saudubray JM, adenine nucleotides to sulfonylurea re- 14. Nestorowicz A, Inagaki N, Gonoi T, Nihoule-Fekete C, Brunelle F: Localisation ceptor 1. Diabetes 49:114–120, 2000 Schoor KP, Wilson BA, Glaser B, Landau of focal lesion permitting partial pancre- 21. Stanley CA: Advances in diagnosis and H, Stanley CA, Thornton PS, Seino S, Per- atectomy in infants (Letter). Lancet 2:671, treatment of hyperinsulinism in infants mutt MA: A nonsense mutation in the in- 1989 and children (Letter). J Clin Endocrinol ward rectifier potassium channel gene, 18. Sempoux C, Guiot Y, Rahier J: The focal Metab 87:4857–4859, 2002 Kir6.2, is associated with familial hyperin- form of persistent hyperinsulinemic 22. Knudson AG Jr: Mutation and cancer: sta- sulinism. Diabetes 46:1743–1748, 1997 hypoglycemia of infancy. Diabetes 50 tistical study of retinoblastoma. Proc Natl 15. Leibowitz G, Glaser B, Higazi AA, Sal- (Suppl.1):S182–S183, 2001 Acad SciUSA68:820–823, 1971
1592 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research BRIEF REPORT
Relationship Between BMI and Age at Diagnosis of Type 1 Diabetes in a Mediterranean Area in the Period of 1990–2004
1 3 MARGA GIMENEZ´ , MD NURIA DE LARA, BN RESULTS — From 1990 to 2004, 222 2 1 EVA AGUILERA, MD, PHD JOANA NICOLAU, MD subjects (6.9%) were diagnosed between 3 1 CONXA CASTELL, MD, PHD IGNACIO CONGET, MD, PHD 2 and 4.9 years of age, 638 (19.9%) be- tween 5 and 9.9 years of age, 877 (27.4%) between 10 and 14.9 years of age, 713 n 2001, Wilkin (1) postulated that type nean subjects in whom diabetes became (22.3%) between 15 and 19.9 years of 1 and type 2 diabetes are mostly the manifest between 1990 and 2004. age, and 753 patients (23.5%) between I same disorder, only distinguished by 20 and 25 years of age. The proportion of the rate of -cell loss with three different subjects in each group by age at diagnosis accelerators participating in the process RESEARCH DESIGN AND during the period 1998–2000 (n ϭ 579) (2,3). METHODS — We analyzed data on did not differ greatly from the whole co- Since 2002, many articles have sup- 3,203 subjects (1,836 male, 2–24 years of hort: 5.9, 19.2, 28.1, 21.4, and 25.4% in ported the “accelerator hypothesis,” age at diagnosis) with newly diagnosed each different age-group, respectively. In showing that BMI and changes in weight type 1 diabetes included in the Catalan terms of BMI at diagnosis and age at diag- are inversely related to age at diagnosis of Registry database for new cases of type 1 nosis, there were no differences between type 1 diabetes (4–6). Recently, Knerr et diabetes between 1990 and 2004 (10). the two cohorts. al. (7), in a large cohort of children with Data on BMI corresponded to information The patients diagnosed with type 1 type 1 diabetes, concluded that a higher obtained during the 1st week after the di- diabetes had a lower BMI than the refer- BMI was associated with a younger age at agnosis. The patients were classified into ence population in all groups of age at diagnosis of type 1 diabetes and that an five groups according to age at diagnosis diagnosis. These results remained un- increased weight gain could be consid- (2–4.9, 5–9.9, 10–14.9, 15–19.9, and changed when data were analyzed by sex ered a risk factor for early manifestation of 20–25 years). BMI was compared with or in the 1998–2000 cohort. the disease. Dabelea et al. (8) concluded standards from a cross-sectional epidemi- For the period of 1990–2004, we did that increasing BMI is associated with ological study of a representative sample not observe any significant change in the younger age at diagnosis only in subjects of Spanish population (n ϭ 3,534, 1998–  BMI SD score of either sex regardless of with a reduced -cell function and hy- 2000, 2–24 years of age) (11). Sex- and the age at diagnosis. In the cohort 1990– pothesized that obesity is accelerating the age-adjusted BMI SD scores were calcu- 2004, there was a significant positive cor- onset of type 1 diabetes at a higher stage in lated. A subgroup of 579 patients diag- relation between patient BMI SD score the natural history of the disease, after nosed during the period 1998–2000 was and the age at diagnosis of type 1 diabetes substantial autoimmune destruction of also selected from the total cohort exactly (Fig. 1.). Actually, each year increase in the -cell has occurred. However, as ex- matching the study period of the refer- age at diagnosis increased BMI SD score pected, other studies did not agree with ence population. by 2%. In regard to the relationship be- the postulate (9). Comparisons between groups of age tween these two variables in each Until now, the data testing the accel- at diagnosis and reference values were age-group, a negative nonsignificant cor- erator hypothesis comes almost exclu- performed using the Wilcoxon test. Sim- relation was only observed in the young- sively from Anglo-Saxon and central ple correlations (Spearman’s) were calcu- ϭϪ European populations. The aim of our lated between age at diagnosis and BMI est group (r 0.101). In the remaining study was to investigate the relationship SD score, as well as a linear regression groups, the correlation between patient Ͻ BMI SD score and age at diagnosis was between BMI and the age at onset of type analysis. A P value 0.05 was considered ϭ ϭ 1 diabetes in a large cohort of Mediterra- statistically significant. also positive (r 0.251, r 0.228, and r ϭ 0.141, respectively, P Ͻ 0.001; and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● r ϭ 0.048, P ϭ 0.219) in each different From the 1Institut d’Investigacions Biome`diques August Pi i Sunyer, Hospital Clı´nic I, Universitari, Barce- age-group at diagnosis. The relationship lona, Spain; the 2Endocrinology Unit, Hospital Germans Trias I Pujol, Badalona, Spain; 3Consell Assessor per between BMI SD score and the age at di- a la Diabetis a Catalunya, Barcelona, Spain. agnosis did not differ when the analysis Address correspondence and reprint requests to Dr I. Conget, Endocrinology and Diabetes Unit, Villarroel was performed by sex. 170, 08036 Barcelona, Spain. E-mail: [email protected]. Received for publication 20 December 2006 and accepted in revised form 23 February 2007. When the subgroup of subjects diag- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2578. nosed between 1998 and 2000 were con- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion sidered as a whole, a positive correlation factors for many substances. was again found between BMI SD score © 2007 by the American Diabetes Association. ϭ Ͻ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby and age at diagnosis (r 0.147, P marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 0.001). A negative nonsignificant correla-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1593 BMI and age at diagnosis of type 1 diabetes
Figure 1— Relationship between BMI SD score and age at diagnosis of type 1 diabetes (1990–2004). A: Total cohort. B: Male. C: Female. SDS, SD score. tion was only observed in the youngest sible that the additional metabolic esis, longitudinal studies in risk groups group (r ϭϪ0.174). In this cohort, when demands associated with higher BMI can- (i.e., first-degree relatives of type 1 dia- weight loss before diagnosis (reported for not be compensated only in subjects with betic subjects) well before clinical onset each individual subject) was considered a highly diminished -cell function. Un- would be needed. in the analysis, we did not observe any fortunately, data concerning -cell func- In summary, in our large cohort of change in the results. tion was not available in our study. Mediterranean subjects with recently di- Excluding recent data by Knerr et al., agnosed type 1 diabetes, increasing BMI is CONCLUSIONS — Our data, col- previous studies carried out in the U.K. not uniformly associated with younger lected from a National registry of newly showing the relationship between age at diagnosis. Although our data did diagnosed type 1 diabetes from a Mediter- younger age at diagnosis and higher BMI not agree with the accelerator hypothesis, ranean area over a period of 15 years involved a small number of subjects the postulate is worthy of interest, mainly (1990–2004) indicates that BMI at diag- (4,5,8). To our knowledge, this is the first in childhood-onset type 1 diabetes in nosis of the disease has not substantially study in a large cohort of a Mediterranean Western societies in which obesity has increased. In addition, we found a posi- National Registry for new cases of type 1 risen to epidemic proportions in this age- tive association between BMI SD score diabetes in which the accelerator hypoth- group. and the age at diagnosis of type 1 diabetes. esis is tested. Our results did not fit with Compared with other geographical the hypothesis and point to the heteroge- areas, Spain has an intermediate preva- neity of the disease in different popula- Acknowledgments— We are indebted to all lence of overweight and obesity in chil- tions (14,15). Accordingly, in a recent of those involved in reporting the data of newly diagnosed type 1 diabetic subjects to dren and young adults (11). However, study including children who were either the National Catalan Registry. The National over the past decades an increased trend from the U.K. or originally from the south Catalan Registry for type 1 diabetes partici- toward higher rates has been observed of Asia, Porter et al. did not confirm the pates in the EURODIAB study group. (12,13). We did not observe an increase accelerator hypothesis (9). It is plausible in BMI or BMI SD score at diagnosis in any that this hypothesis does or does not be- of the age-groups evaluated. In the come manifest depending on the genetic References present study, a higher BMI SD score at background and environmental factors, 1. Wilkin TJ: The accelerator hypothesis: diagnosis was not associated with a including the prevalence of overweight weight gain as the missing link between younger age at onset of type 1 diabetes. To and obesity. type I and type II diabetes. Diabetologia the contrary, in the whole cohort we Our study has several limitations. 44:914–922, 2001 2. Daneman D: Is the ‘Accelerator Hypothe- found a positive correlation between First, it is cross-sectional in nature, it has sis’ worthy of our attention? Diabet Med higher BMI SD score and older age at di- a long recruitment period, and influence 22:115–117, 2005 agnosis. However, it should be pointed by secular trends in BMI cannot be ruled 3. Boitard C, Efendic S, Ferrannini E, Hen- out that in both cohorts (1990–2004 and out. Second, we lack of biological evi- quin JC, Steiner DF, Cerasi E: A tale of two 1998–2000) in the 2–4.9 years of age dence to support diabetes classification in cousins: type 1 and type 2 diabetes (Edi- group there was a nonsignificant trend to- terms of pancreatic autoantibodies avail- torial). Diabetes 54 (Suppl. 2):S1–S3, ward an association between a higher BMI ability. However, recently, as a part of the 2005 SD score and a younger age at diagnosis. It European multicenter study Insulin De- 4. Kibirige M, Metcalf B, Renuka R, Wilkin is well recognized that in type 1 diabetes pendent Diabetes in Young Adults in TJ: Testing the accelerator hypothesis: the the younger the age at diagnosis the lower Europe (IDA), we investigated the consis- relationship between body mass and age  at diagnosis of type 1 diabetes. Diabetes the -cell function. In the study by Dabe- tency in clinical diagnosis of type 1 diabe- Care 26:2865–2870, 2003 lea et al. (8), 70% of the participants had tes. The percentage agreement between 5. Betts P, Mulligan J, Ward P, Smith B, fasting C-peptide Ͻ0.5 ng/ml with BMI original classification and reclassification Wilkin T: Increasing body weight predicts and a younger age at diagnosis being as- was 92%. Finally, we are aware that in the earlier onset of insulin-dependant di- sociated only in these subjects. It is pos- order to truly test the accelerator hypoth- abetes in childhood: testing the ‘accelera-
1594 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Gime´nez and Associates
tor hypothesis’ (2). Diabet Med 22:144– size, -cell function, and age at onset of 2000 study]. MedClin (Barc) 120:608– 151, 2005 type 1 (autoimmune) diabetes. Diabetes 612, 2003 [In Spanish] 6. Pundziute-Lycka A, Persson LA, Ceder- Care 29:290–294, 2006 13. Aranceta-Bartrina J, Serra-Majem L, Foz- mark G, Jansson-Roth A, Nilsson U, Wes- 9. Porter JR, Barrett TG: Braking the acceler- Sala M, Moreno-Esteban B: [Prevalence of tin V, Dahlquist G: Diet, growth, and the ator hypothesis? Diabetologia 47:352– obesity in Spain]. MedClin (Barc) 125:460– risk for type 1 diabetes in childhood: a 353, 2004 466, 2005 [In Spanish] matched case-referent study. Diabetes 10. Goday A, Castell C, Tresserras R, Canela J, 14. Aguilera E, Casamitjana R, Ercilla G, Care 27:2784–2789, 2004 Taberner JL, Lloveras G: Incidence of type Oriola J, Gomis R, Conget I: Adult-onset 7. Knerr I, Wolf J, Reinehr T, Stachow R, 1 (insulin-dependent) diabetes mellitus atypical (type 1) diabetes: additional in- in Catalonia, Spain: the Catalan Epidemi- Grabert M, Schober E, Rascher W, Holl sights and differences with type 1A diabe- RW: The ‘accelerator hypothesis’: rela- ology Diabetes Study Group. Diabetologia tes in a European Mediterranean pop- tionship between weight, height, body 35:267–271, 1992 mass index and age at diagnosis in a large 11. Serra ML, Ribas BL, Aranceta BJ, Perez ulation. Diabetes Care 27:1108–1114, cohort of 9,248 German and Austrian RC, Saavedra SP, Pena QL: [Childhood 2004 children with type 1 diabetes mellitus. and adolescent obesity in Spain: results of 15. Conget I, Aguilera E, Pellitero S, Naf S, Diabetologia 48:2501–2504, 2005 the enKid study (1998–2000)]. MedClin Bendtzen K, Casamitjana R, Gomis R, 8. Dabelea D, D’Agostino RB Jr, Mayer-Davis (Barc) 121:725–732, 2003 [In Spanish] Nicoletti F: Lack of effect of intermittently EJ, Pettitt DJ, Imperatore G, Dolan LM, 12. Aranceta J, Perez RC, Serra ML, Ribas BL, administered sodium fusidate in patients Pihoker C, Hillier TA, Marcovina SM, Quiles IJ, Vioque J, Tur MJ, Mataix VJ, with newly diagnosed type 1 diabetes Linder B, Ruggiero AM, Hamman RF: Llopis GJ, Tojo R, Foz SM: [Prevalence of mellitus: the FUSIDM trial. Diabetologia Testing the accelerator hypothesis: body obesity in Spain: results of the SEEDO 48:1464–1468, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1595 Epidemiology/Health Services/Psychosocial Research BRIEF REPORT
Extended Analyses of the Association Between Serum Concentrations of Persistent Organic Pollutants and Diabetes
1 3 DUK-HEE LEE, MD, PHD MICHAEL STEFFES, MD, PHD Diabetes (n ϭ 179) was defined as 2 4,5 IN-KYU LEE, MD, PHD DAVID R. JACOBS,JR., PHD follows: 1) fasting plasma glucose Ն126 mg/dl or nonfasting plasma glucose Ն200 mg/dl or 2) reported history of e recently reported on serum especially important from the view- physician-diagnosed diabetes. Exclu- concentrations of six persistent points of both toxicology and regula- sion of nonfasting subjects did not W organic pollutants (POPs) and tion. Therefore, in this article we report greatly change the findings, but we re- prevalence of diabetes in a random U.S. on the diabetes associations of 19 POPs tained the criteria in our previous article sample (1). Most previous epidemiologi- within five POP subclasses, each de- for consistency. Logistic regression was cal studies were restricted from studying tected among at least 60% of study sub- used to calculate multivariable-adjusted several POPs given cost and serum jects, i.e., in a manner identical to our odd ratios (ORs), with adjusting vari- amounts needed. Focus on selected POPs most recent analysis of POPs and insu- ables (Table 1). All statistical analyses may be appropriate in occupational or ac- lin resistance in the NHANES dataset were performed with SAS (version 9.0; cidental high exposure, but, in the general (2). SAS Institute, Cary, NC) population with only background POP exposure, there is a need to study the con- RESULTS — In separate models of centrations of many interrelated POPs. RESEARCH DESIGN AND each POP individually, most POPs be- Our initial approach to risk charac- METHODS — We used the NHANES longing to all five subclasses of POPs terization was to calculate a summary to 1999–2002 public use dataset. Serum were positively associated with the accumulate risk of exposure across six concentrations of POPs were measured by prevalence of diabetes but differed sub- POPs (1). Even though the summary of high-resolution gas chromatography/ stantially across POP subclasses. Spe- six POPs was strongly associated with high-resolution mass spectrometry. cific PCDDs or PCDFs were weakly diabetes, individual POPs had substan- There were 1,721 persons aged Ն20 years associated with diabetes, while POPs tial differences in strength of association with all information on the selected 19 belonging to PCBs or OC pesticides (1). Thus, it is also of interest to esti- POPs (Table 1). were strongly associated. mate risk within subclasses of POPs that For each POP, subjects with serum After adjusting for age, there were have similar physical and chemical concentrations under the limit of detec- positive pairwise correlations (r ϭ 0.23– properties. All POPs measured in the tion were the reference, and remaining 0.73) among serum concentrations of the National Health and Nutrition Exami- subjects with detectable values (mini- five POP subclasses. Thus, although etio- nation Survey (NHANES) can be di- mally 60% of those assayed for each POP) logical relationships with diabetes could vided into five subclasses: were put in quartiles. To yield a cumula- be restricted to several specific POPs, the polychlorinated dibenzo-p-dioxins tive measure of three PCDDs, we summed correlation between POPs could lead to (PCDDs), polychlorinated dibenzo- the ranks of the three PCDDs, then di- positive epidemiologic associations with furans (PCDFs), dioxin-like polychlori- vided into quartiles. We assigned and cu- diabetes for most POPs. When the five nated biphenyls (PCBs), nondioxin-like mulated POP subclasses similarly for the POP subclasses were modeled simulta- PCBs, and organochlorine (OC) pesti- three PCDFs, the four dioxin-like PCBs, neously, only dioxin-like PCBs and OC cides. Such specificity about diabetoge- the five nondioxin-like PCBs, and the four pesticides were statistically significantly nicity of POP subclasses would be OC pesticides. associated with diabetes; PCDDs and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● nondioxin-like PCBs were not associated From the 1Preventive Medicine and Health Promotion Research Center, Kyungpook National University, with diabetes. PCDFs were weakly asso- 2 Daegu, Korea; the Department of Endocrinology, School of Medicine, Kyungpook National University, ciated with diabetes. Further adjustment Daegu, Korea; the 3Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; the 4Department of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minne- for dietary fiber intake, total sugar intake, sota; and the 5Department of Nutrition, University of Oslo, Oslo, Norway. saturated fat intake, exercise, or place of Address correspondence and reprint requests to Duk-Hee Lee, MD, PhD, Preventive Medicine, School of residence did not materially change the Medicine, Kyungpook University, 101 Dongin-dong, Jung-gu, Daegu, Korea 700–422. E-mail: results. In addition, inclusion of both BMI [email protected]. Received for publication 12 January 2007 and accepted in revised form 2 March 2007. and waist circumference may overadjust, Published ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/dc07-0072. but elimination of either variable from the Abbreviations: NHANES, National Health and Nutrition Examination Survey; OC, organochlorine; PCB, model did not change the results. polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxins; PCDF, polychlorinated dibenzo- furans; POP, persistent organic pollutants. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion CONCLUSIONS — Among ϳ50 factors for many substances. POPs measured in NHANES datasets, © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby we previously examined only the 6 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. POPs detected among at least 80% of
1596 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Lee and Associates by categories of POPs (1,721/179 ؍ Table 1—Adjusted OR* (95% CI) of prevalence of diabetes (n/n
Detectable Detectable Ͻ Ͻ Ͻ Ն Analytes (%) Nondetectable 25th 25th to 50th 50th to 75th 75th Ptrend Separate models† D03 76 Referent 0.5 (0.2–1.0) 1.0 (0.6–1.8) 1.1 (0.7–1.9) 1.5 (0.9–2.5) 0.09 D05§ 88 Referent 0.9 (0.4–2.2) 1.8 (0.8–3.8) 1.8 (0.8–3.8) 2.1 (1.0–4.6) Ͻ0.01 D07§ 80 Referent 1.8 (0.9–3.9) 2.3 (1.1–4.7) 1.9 (0.9–3.9) 2.5 (1.2–5.3) 0.04 All PCDDs summed‡ — Referent 0.9 (0.5–1.7) 1.5 (0.8–2.6) 1.8 (1.0–3.3) Ͻ0.01 F03 61 Referent 2.6 (1.5–4.5) 1.6 (0.9–2.9) 2.4 (1.4–4.1) 2.7 (1.5–4.7) Ͻ0.01 F04 70 Referent 2.3 (1.3–4.2) 1.4 (0.7–2.6) 2.8 (1.6–4.9) 2.4 (1.4–4.3) Ͻ0.01 F08 77 Referent 1.4 (0.8–2.5) 1.9 (1.1–3.2) 1.5 (0.8–2.6) 2.4 (1.4–4.0) Ͻ0.01 All PCDFs summed‡ — Referent 2.3 (1.2–4.3) 2.6 (1.4–4.9) 3.7 (2.0–7.1) Ͻ0.01 074 62 Referent 3.5 (1.8–6.5) 3.4 (1.8–6.4) 4.1 (2.1–7.9) 4.2 (2.0–8.6) Ͻ0.01 118 66 Referent 5.1 (2.3–11.0) 6.9 (3.2–14.9) 7.5 (3.5–16.2) 12.6 (5.6–28.3) Ͻ0.01 126 79 Referent 0.9 (0.4–1.9) 1.4 (0.7–2.7) 2.0 (1.0–3.7) 4.2 (2.3–7.8) Ͻ0.01 156 79 Referent 1.1 (0.6–2.2) 1.9 (1.0–3.5) 2.0 (1.0–3.9) 2.2 (1.1–4.4) Ͻ0.01 All DPCBs summed‡ — Referent 9.0 (2.7–30.3) 18.6 (5.5–62.7) 24.3 (7.0–84.5) Ͻ0.01 138 76 Referent 2.2 (1.0–4.8) 4.0 (2.0–8.0) 5.6 (2.7–11.5) 6.5 (3.1–13.6) Ͻ0.01 153§ 80 Referent 2.8 (1.2–6.6) 4.5 (2.0–10.3) 6.2 (2.7–14.3) 6.8 (2.8–16.1) Ͻ0.01 170 68 Referent 2.2 (1.2–4.2) 2.3 (1.2–4.6) 3.4 (1.7–6.8) 4.4 (2.1–9.2) Ͻ0.01 180 78 Referent 3.0 (1.3–6.7) 5.2 (2.3–11.8) 5.3 (2.2–12.4) 8.2 (3.4–20.2) Ͻ0.01 187 63 Referent 2.2 (1.2–4.0) 2.2 (1.1–4.2) 4.4 (2.3–8.5) 4.3 (2.1–8.5) Ͻ0.01 All NPCBs summed‡ — Referent 3.0 (1.5–6.1) 4.2 (2.0–8.8) 6.2 (2.8–13.6) Ͻ0.01 PDE§ 100 — Referent 1.3 (0.7–2.6) 1.6 (0.6–3.2) 2.9 (1.5–5.6) Ͻ0.01 OXY§ 82 Referent 0.8 (0.3–1.8) 1.5 (0.7–3.4) 3.0 (1.4–6.6) 4.6 (2.0–10.4) Ͻ0.01 TNA§ 89 Referent 1.1 (0.3–3.7) 2.3 (0.8–7.1) 4.5 (1.5–13.6) 8.0 (2.6–24.8) Ͻ0.01 BHC 77 Referent 2.5 (1.0–6.6) 3.0 (1.2–7.9) 5.7 (2.2–14.7) 7.0 (2.7–18.1) Ͻ0.01 All OC pesticides summed‡ — Referent 3.8 (1.4–10.5) 6.4 (2.3–17.4) 13.9 (5.0–38.7) Ͻ0.01 Simultaneous models† PCDDs — — Referent 0.4 (0.2–0.8) 0.5 (0.3–1.0) 0.5 (0.2–0.9) 0.25 PCDFs — — Referent 1.8 (0.9–3.6) 1.7 (0.–3.5) 2.2 (1.1–4.7) 0.08 DPCBs — — Referent 8.6 (2.3–31.8) 16.0 (2.3–31.8) 15.7 (3.4–71.2) Ͻ0.01 NPCBs — — Referent 0.7 (0.3–1.7) 0.6 (0.2–1.5) 0.6 (0.2–1.7) 0.45 OC pesticides — — Referent 2.4 (0.8–7.0) 3.4 (1.1–10.0) 6.8 (2.2–21.3) Ͻ0.01 *Adjusted for age, sex, race, poverty income ratio, BMI, and waist circumference. †Separate model: each POP or summary of subclasses of POPs was modeled one by one; simultaneous model: five subclasses of POPs were included in one model. ‡Detectable values of each POP were individually ranked, and the rank orders of the individual POPs in each subclass were summed to arrive at the subclass value. All undetectable values were ranked as 0. The summary values were categorized by cutoff points of 25th, 50th, 75th, and 90th values of the sum of ranks. §Detectable in Ͼ80% of participants and previously reported (ref. 1). 074: 2,4,4Ј,5- tetrachlorobiphenyl; 118: 2,3Ј,4,4Ј,5-pentachlorobiphenyl; 126: 3,3Ј,4,4Ј,5-pentachlorobiphenyl; 156: 2,3,3Ј,4,4Ј,5-hexachlorobiphenyl; 138: 2,2Ј,3,4,4Ј,5-hexa- chlorobiphenyl; 153: 2,2Ј,4,4Ј,5,5Ј-hexachlorobiphenyl; 170: 2,2Ј,3,3Ј,4,4Ј,5-heptachlorobiphenyl; 180: 2,2Ј,3,4,4Ј,5,5Ј-heptachlorobiphenyl; 187: 2,2Ј,3,4Ј,5,5Ј, 6-heptachlorobiphenyl; BHC: Beta-hexachlorocyclohexane; DPCB: dioxin-like PCBs; D03: 1,2,3,6,7,8,-hexachlorodibenzo-p-dioxin; D05: 1,2,3,4,6,7,8- heptachlorodibenzo-p-dioxin; D07: 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; F03: 2,3,4,7,8-pentachlorodibenzofuran; F04: 1,2,3,4,7,8-hexachlorodibenzofuran; F08: 1,2,3,4,6,7,8-heptachlorodibenzofuran; NPCB: nondioxin-like PCBs; PDE: p,pЈ-Dichlorodiphenyltrichloroethane; OXY: oxychlordane; TNA: trans-nonachlor. study subjects (1). This analytic strategy the six POPs detectable among at least tion to diabetes, relaxing the criterion for was carefully chosen to assure that the 80% of study subjects may avoid this bias, the reference category to include more reference group reliably had low levels it limited inference about other POPs that POPs in comprehensive and systemic of POPs, to yield a valid reference group may be also important. Among the six analyses that reflect all five subclasses is risk estimate and at the same time a POPs we investigated (1), two are PCDDs, needed. valid relative estimate for those with de- one is a nondioxin-like PCB, and three are The extended analyses presented here tectable POPs compared with this refer- OC pesticides; none were PCDFs or diox- found that the dioxin-like PCB and OC- ence group (3). Given sufficient serum, in-like PCBs. One recent study (4) using pesticide subclasses were the most POPs would be detectable in almost all the same NHANES dataset (1) examined strongly associated with diabetes. The in- humans. The problem of a valid refer- associations of diabetes with three other terpretation of current findings as causal ence arises because POP serum concen- POPs that were not included in our anal- is limited because of the cross-sectional trations are generally low, but yses (D03 [1,2,3,6,7,8,-hexachlorod- design. The apparent contradiction of a nondetectable concentrations are not ibenzo-p-dioxin], PCB126, and p,pЈ- dramatic increase in type 2 diabetes inci- necessarily 0, given limited amounts of DDT), detectable in 76, 79, and 41% of dences coupled with a decreasing pattern serum for analysis. the sample aged Ն20 years. Considering of the serum concentrations of POPs in Although our previous restriction to the probable importance of POPs in rela- the general population over several de-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1597 Persistent organic pollutants and diabetes cades may be explained by persistence betic adults: results from the National Acknowledgments— This study was partly Health and Nutrition Examination Sur- and increased toxicity of POPs in obesity supported by the Brain Korea 21 project in vey 1999–2002. Diabetes Care 30:622– (1,3). 2007. Sorting out exactly which POPs are 628, 2007 causal is challenging. Consistency 3. Lee DH, Jacobs DR, Porta M: Could low level background exposure to persistent across studies and across conceptually References organic pollutants contribute to the so- related approaches to the question of 1. Lee DH, Lee IK, Song KE, Steffes M, To- POPs and diabetes can be helpful. As an scano W, Baker BA, Jacobs DR Jr: A cial burden of type 2 diabetes? J Epide- strong dose-response relation between miol Community Health 60:1006–1008, example of consistency, we reported 2006 that some PCBs and OC-pesticides were serum concentrations of persistent or- ganic pollutants and diabetes: results 4. Everett CJ, Frithsen IL, Diaz VA, Koop- also positively associated with ho- man RJ, Simpson WM Jr, Mainous AG meostasis model assessment of insulin from the National Health and Examina- tion Survey. Diabetes Care 29:1638– 3rd: Association of a polychlorinated resistance among participants without 1644, 2006 dibenzo-p-dioxin, a polychlorinated bi- diabetes (2). Both PCBs and OC- 2. Lee DH, Lee IK, Jin SH, Steffes M, Jacobs phenyl, and DDT with diabetes in the pesticides may be primary targets of fur- DR: Association between serum concen- 1999–2002 National Health and Nutri- ther toxicological and epidemiological trations of persistent organic pollutants tion Examination Survey. Environ Res studies. and insulin resistance among nondia- 103:413–418
1598 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Epidemiology/Health Services/Psychosocial Research BRIEF REPORT
Maintenance of Glucose Control in Patients With Type 1 Diabetes During Acute Mental Stress by Riding High-Speed Rollercoasters
1,2 4 PETER WIESLI, MD BURKHARDT SEIFERT, PHD of 158 Ϯ 16 bpm (P Ͻ 0.001). Blood 3 1 PIERRE-ALEXANDRE KRAYENBUHL¨ , MD CHRISTOPH SCHMID, MD pressure increased from 124/79 Ϯ 12/9 to 1 ORANNA KERWER 160/96 Ϯ 17/14 mmHg between the two rides (P Ͻ 0.001). Salivary cortisol in- creased from 6.3 nmol/l (range 2.8–11.4) atients with diabetes and health an ambulatory blood pressure monitoring to a maximum of 19.3 nmol/l (5.6–49.3) care providers are often con- device), heart rate (by 24-h electrocardio- 60 min following the ride (P ϭ 0.008). P fronted with questions concerning gram), and salivary cortisol were moni- Glucose concentrations of 10 patients in- psychological stress as a possible reason tored during a preceding control day vestigated in the fasting state remained for glucose excursions; chronic psycho- without stress application and on the fairly stable, both during the control and social stress has been associated with stress testing day. Glucose concentrations stress testing day (Figure 1A). At the time higher levels of A1C and poor adher- were monitored in 5-min intervals by the of stress application, glucose concentra- ence to treatment (1,2). Few studies Medtronic MiniMed continuous glucose tions were 6.2 Ϯ 1.6 mmol/l on control have addressed the effect of acute psy- monitoring system (CGMS). Capillary and 6.7 Ϯ 2.3 mmol/l on stress testing chological stress on glucose concentra- blood glucose concentrations were deter- day (P ϭ NS). A two-factor repeated- tions in patients with type 1 diabetes, mined in 15- to 30-min intervals by re- measures ANOVA showed no significant showing no or only minor effects, such flectance meter (results not shown, differences in glucose concentrations be- as an increase in insulin resistance and consistent with CGMS data). A total of 10 tween the control and stress days. Ten slightly delayed decreases in glucose patients performed the rides in the fasting patients were investigated in the post- concentrations following moderate state. Patients were allowed to drink water prandial state (Fig. 1B). Baseline glucose stress in the postprandial period (3–5). and injected their basal insulin as usual. concentrations before the intake of the Since many patients and caregivers have An additional 10 patients were riding the meal on control and intervention days challenged this view, we asked patients rollercoasters 75 min after intake of a were 7.2 Ϯ 2.2 and 6.6 Ϯ 2.4 mmol/l with type 1 diabetes to monitor glucose standard meal containing 50 g carbohy- (P ϭ NS), respectively. Glucose concen- concentrations during a strongly stress- drates (with the same prandial insulin trations increased comparably in re- ing experiment. dose on both days). The rides were per- sponse to the meal, by 3.7 Ϯ 2.6 mmol/l formed between 1:00 and 3:00 P.M. The on the control day and by 3.3 Ϯ 2.0 RESEARCH DESIGN AND protocol was approved by the ethics com- mmol/l on the stress testing day, and re- METHODS — A total of 20 patients mittee of the University Hospital of Zu- turned to baseline within 3 h after the with type 1 diabetes (all on intensified in- rich; all patients gave written informed meal on both days. There appeared to be sulin treatment) were recruited from a re- consent. an attenuated increase in postprandial cent study investigating the effect of acute glucose concentrations during the 30 min moderate psychosocial stress on glucose RESULTS — Mean Ϯ SD age of 20 pa- before the ride. However, a two-factor re- concentrations (5). Patients were exposed tients (8 female) with type 1 diabetes was peated-measures ANOVA revealed no to acute mental stress by riding on two 37 Ϯ 11 years, diabetes duration 14 Ϯ 10 significant difference of glucose concen- different rollercoasters within 15 min. years, BMI 24.7 Ϯ 4.5 kg/m2, and A1C trations between the control and stress The first rollercoaster was a steel coaster 7.6 Ϯ 0.9%. Blood pressure, heart rate, days. starting from a height of 240 feet and and salivary cortisol remained stable for reaching a speed of 79 mph with four pos- the observed period during the control CONCLUSIONS — We found that se- itive Gs and the second an indoor coaster day. During the rides, heart rate rose from vere short-lived mental stress, as docu- in absolute darkness. Blood pressure (by 82 Ϯ 7 bpm at baseline up to a maximum mented by markedly increased heart rate ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● and blood pressure (reflecting sympathetic activation) and salivary cortisol, barely af- From the 1Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital of Zurich, Zurich, Switzerland; 2Medizinische Klinik, Endokrinologie und Diabetologie Kantonsspilal Frauen- fected glucose control in patients with type feld, Frauenfeld, Switzerland; the 3Department of Internal Medicine, Medical Policlinic, University Hospital 1 diabetes, consistent with previous reports of Zurich, Zurich, Switzerland; and 4Department of Biostatistics, University of Zurich, Zurich, Switzerland. investigating the effect of moderate mental Address correspondence and reprint requests to Peter Wiesli, MD, Kantonsspital Frauenfeld, Mediz- stress on glucose control (3–5). The main- inische Klinik, Endokrinologie und Diabetologie, Frauenfeld, Switzerland. E-mail: [email protected]. Received for publication 11 October 2006 and accepted in revised form 21 February 2007. tenance of glucose control (as shown in Fig. Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-2102. 1 only by interstitial but confirmed by less Abbreviations: CGMS, continuous glucose monitoring system. frequent capillary readings) is all the more A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion remarkable since patients with type 1 dia- factors for many substances. betes are unable to adapt insulin secretion. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby Our patients (type 1 diabetes duration 14 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. years, mean age at diagnosis of diabetes 21
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1599 Acute mental stress in type 1 diabetes
glucose fluxes (appearance and disappear- ance) so that glucose homeostasis during acute mental stress can be maintained. However, our study was carried out with patients in reasonable metabolic control and cannot necessarily be extrapolated to the many patients who face mental stress with poor glycemic control or have chronic mental stress. In the fasting state, glucose concen- trations tended to decrease during the control day and remained stable during and following the rides. Thus, a minor effect of mental stress on glucose control cannot be excluded definitively, but it ap- pears that acute short-term mental stress in the fasting state is hardly responsible for clinically relevant glucose excursions. Following the intake of a meal, the in- crease of glucose concentrations on stress testing day was slightly attenuated, and glucose concentrations tended to remain lower throughout the experiment. The at- tenuation of the rise in postprandial glu- cose concentrations failed to reach significance and was noticed 30 min be- fore the rides (i.e., when patients were an- ticipating the rides) and is possibly explained by increased utilization of glu- cose by the brain, heart, or respiratory muscles (i.e., by tissues in which the ac- tivity is markedly increased in response to stress). Following the ride, the difference in glucose concentrations between the stress and control days became smaller, and almost identical glucose values were observed 3 h after the meal. In conclusion, most patients with type 1 diabetes exposed to strong short- lived mental stress (i.e., riding on roller- coasters) can keep good glycemic control without adjusting the insulin dose.
Acknowledgments— The study was finan- cially supported by an unrestricted grant of Roche-Disetronic Switzerland. We thank Dagmar Holm and Monika Voggenreiter for analyzing the blood pres- Figure 1—Glucose concentrations measured by CGMS on the control day without stress (circles) sure data, Clemens Kirschbaum for cortisol and on the stress testing day (squares) in 20 patients with type 1 diabetes. In total, 10 patients were analysis, and Frank Enselait for analyzing riding the rollercoasters in the fasting state (A) and 10 patients after intake of a standard meal at the electrocardiograms. Ϫ75 min (B). The ride on the first rollercoaster started at time 0 and the ride on the second rollercoaster at time 10 min. Glucose concentrations are shown as change from baseline values (difference from the glucose value at time Ϫ45 min in fasting patients and from the glucose value References at time Ϫ105 min in patients taking a standard meal at Ϫ75 min). A two-factor repeated- 1. Lloyd CE, Dyer PH, Lancashire RJ, Har- measures ANOVA revealed no significant difference of glucose concentrations between control and ris T, Daniels JE, Barnett AH: Associa- stress testing days, neither in the fasting nor postprandial state. tion between stress and glycemic control in adults with type 1 (insulin- dependent) diabetes. Diabetes Care 22: 1278–1283, 1999 years) were unlikely to have relevant resid- resulting in an upregulation of insulin- 2. Hains AA, Berlin KS, Davies WH, Parton ual insulin secretion and were on a fixed counterregulatory hormones. The latter EA, Alemzadeh R: Attributions of ado- insulin dose when they faced a challenge, may contribute to an excellent matching of lescents with type 1 diabetes in social
1600 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Wiesli and Associates
situations: relationship with expected bolic control in patients with type I dia- 5. Wiesli P, Schmid C, Kerwer O, Nigg-Koch adherence, diabetes stress, and meta- betes mellitus. N Engl J Med 314:1078– C, Klaghofer R, Seifert B, Spinas GA, bolic control. Diabetes Care 29:818– 1084, 1986 Schwegler K: Acute psychological stress 822, 2006 4. Moberg E, Kollind M, Lins PE, Adamson affects glucose concentrations in patients 3. Kemmer FW, Bisping R, Steingruber HJ, U: Acute mental stress impairs insulin with type 1 diabetes following food intake Baar H, Hardtmann F, Schlaghecke R, sensitivity in IDDM patients. Diabetologia but not in the fasting state. Diabetes Care Berger M: Psychological stress and meta- 37:247–251, 1994 28:1910–1915, 2005
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1601 Epidemiology/Health Services/Psychosocial Research BRIEF REPORT
Depression Among Type 2 Diabetes Rural Appalachian Clinic Attendees
1 2 MARY DE GROOT, PHD BRENDA PINKERMAN, PHD Analyses were conducted using SAS 1 3 TODD DOYLE, BS JAY SHUBROOK, DO version 8.0e (16). Logistic regression 1 3 ERIN HOCKMAN, MS ROBERT GOTFRIED, DO 1 4 analyses were conducted to assess predic- CHARLES WHEELER, BA, BS FRANK SCHWARTZ, MD tors of depression status, coded dichoto- mously as “depressed” (BDI-II score Ն20) or “nondepressed” (Յ19). Overall model he prevalence and impact of type 2 RESEARCH DESIGN AND fit was evaluated using Hosmer- diabetes in Appalachia is understud- METHODS — Participants, recruited Lemeshow goodness-of-fit statistic (17). T ied despite the presence of high-risk from family medicine and endocrinology Test of discrimination of depression sta- socioeconomic conditions (e.g., low practices, were diagnosed with type 2 di- tus was evaluated by examining the area levels of education and income). Appala- abetes for Ն1 year and aged Ն18 years, under the receiver-operating characteris- chian counties experience greater bur- with the ability to provide informed con- tic curve (ROC) (17). Multiple regression dens of poverty, income inequality, sent. Patients (n ϭ 628) were identified analysis was used to assess correlates of unemployment (1), and diabetes com- from billing and registry databases. Of depression severity, using BDI-II score as pared with non-Appalachian counties (2– these, 288 patients responded to letters of a continuous outcome measure. 5). Rates of comorbid depression have not invitation for study participation from been documented in this region. their medical provider. Thirty-two partic- RESULTS — The sample was predom- Patients with type 2 diabetes are two ipants did not meet inclusion criteria, and inantly female (60%, n ϭ 121), white times more likely to experience depres- 55 declined participation (9.8% refusal (94%, n ϭ 188), married (71%, n ϭ 141), sive symptoms than their peers without rate). A total of 201 (36% response and completed high school or less (53%, n ϭ diabetes (6). Depression prevalence in 78.5% cooperation rates) completed 106), and had a mean age of 57 Ϯ 12 studies using self-report depression in- questionnaires and consented to release years. Forty-five percent (n ϭ 87) re- ventories was found to be 32.9%, with medical record data. ported a total annual income of $20,000 lower rates (28.5%) observed in studies Participants completed the Beck De- or less, with 43% (n ϭ 87) working out- using diagnostic interview schedules pression Inventory (BDI)-II (14), which side the home. Eighty percent (n ϭ 161) (6,7). Depressive symptoms are associ- assesses depressive symptom severity for reported owning their own home. ated with worsened blood glucose levels 2 weeks prior to administration. Demo- The mean duration of type 2 diabetes (8), diabetes complications (9), increased graphic questionnaire variables included was 9.7 Ϯ 8.2 years, with the majority of functional disability (10), worsened ad- age, ethnicity, Appalachian heritage, patients receiving oral agents (49%, n ϭ herence to diabetes regimen (11), higher marital status, income, and educational 98) or combination treatment (27%, n ϭ ambulatory care costs (12), and increased status. Economic resource variables in- 54). Mean A1C value was 7.5 Ϯ 1.6%. mortality (13). cluded employment status, total annual Mean number of diabetes complications The current study was conducted to income, home ownership, appraisal of fi- was 1.1 Ϯ 1.2, with cardiovascular dis- identify rates of self-reported depression nancial status and optimism, and pres- ease (22.1%, n ϭ 44), neuropathy and to identify the socioeconomic and ence of health insurance (15). (16.6%, n ϭ 33), and coronary heart dis- medical correlates of depression among Medical records were reviewed for ease (13.6%, n ϭ 27) noted most fre- type 2 diabetic patients attending family the year before study participation. Vari- quently. The mean number of prescribed medicine and endocrinology appoint- ables included physician diagnosis of type medications was 7.7 Ϯ 3.9. ments from rural Appalachian counties of 2 diabetes, A1C (normal reference range Ϯ ϩ The mean BDI-II score was 14.5 southeastern Ohio and West Virginia. It 4.3–5.7% [DCA2000 Analyzer; Bayer 12.0. Of participants, ϳ58% (n ϭ 116) was hypothesized that poverty would in- Diagnostics]), total cholesterol, BMI, dia- reported few depressive symptoms (score crease the risk of comorbid depression in betes complications and risk factors, and 0–13), 12% (n ϭ 23) with mild symp- this region. prescribed medications. toms (14–20), 16% (n ϭ 31) with mod- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● erate symptoms (21–28), and 16% (n ϭ 30) with severe symptoms (Ն29). When From the 1Department of Psychology, Ohio University, Athens, Ohio; the 2James A. Haley Veterans Hospital, Tampa, FL; the 3Department of Family Medicine, Ohio University College of Osteopathic Medicine, Athens, the moderate and severe categories were Ohio; and the 4Department of Specialty Medicine, Ohio University College of Osteopathic Medicine, Athens, combined, 31% (n ϭ 61) of participants Ohio. reported clinically significant levels of de- Address correspondence and reprint requests to Mary de Groot, PhD, Assistant Professor, Department of pressive symptoms. Psychology, 239 Porter Hall, Athens, OH 45701. E-mail: [email protected]. Received for publication 28 July 2006 and accepted in revised form 24 February 2007. Results of the logistic and multiple re- Published ahead of print at http://care.diabetesjournals.org on 12 March 2007. DOI: 10.2337/dc06-1599. gression analyses are shown in Table 1. Abbreviations: BDI, Beck Depression Inventory. Younger age, unemployment, lack of A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion home ownership, greater number of med- factors for many substances. ications, and higher BMI significantly pre- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby dicted depression status. Depression marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. severity was associated with younger age,
1602 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 de Groot and Associates
Table 1—Regression models to assess socioeconomic and medical correlates of depression
Logistic regression model predicting depression status Predictors B SE Wald OR (95% CI) Younger age Ϫ0.04 0.02 5.39* 0.96 (0.93–0.99) Unemployment 1.07 0.45 5.75* 2.92 (1.22–6.99) Lack of home ownership 1.34 0.49 7.31* 3.81 (1.45–10.03) No. of medications 0.12 0.06 4.56* 1.13 (1.01–1.26) Duration of diabetes Ϫ0.03 0.02 1.15 0.98 (0.93–1.02) BMI 0.05 0.03 4.43* 1.10 (1.00–1.11) Hosmer-Lemeshow goodness-of-fit test 2(8, n ϭ 152) ϭ 4.22; P ϭ 0.84 ROC ϭ 0.80 R2 ϭ 0.23
Multiple regression model to assess correlates of depression severity Predictors B  SE — Younger age Ϫ0.27 Ϫ0.27† 0.09 — Unemployment 4.30 0.18* 2.01 — Income Ϫ0.64 Ϫ0.09 0.67 — Lack of home ownership 2.07 0.07 2.34 — Ability to make ends meet Ϫ1.79 Ϫ0.18 0.99 — Exercise Ϫ0.83 Ϫ0.13 0.49 — BMI 0.11 0.08 0.11 — No. of complications Ϫ1.07 Ϫ0.13 0.73 — Duration of diabetes Ϫ0.05 Ϫ0.03 0.13 — No. of medications 0.45 0.16* 0.23 — Overall model test F ϭ 8.33† R2 ϭ 0.43 Adjusted R2 ϭ 0.43 — *P Ͻ 0.05, †P Ͻ 0.0001. unemployment, and greater number of rate, and the use of self-report question- 2. Mokdad AH, Bowman BA, Ford ES, Vini- prescribed medications. naires. Response rates were comparable cor F, Marks JS, Koplan JP: The continu- with those observed in studies of other ing epidemics of obesity and diabetes in CONCLUSIONS — In this study, low-income populations (20–22) and the United States. JAMA 286:1195–1200, 31% of Appalachian participants reported may reflect barriers endemic to the rural 2001 3. Centers for Disease Control: BFRSS 2005 comorbid diabetes and depression, a rate research (23). Although rates of depres- Data, State of Ohio [article online], 2005. comparable with average prevalence esti- sion are higher in self-report question- Available from http://apps.nccd.cdc.gov/ mates in studies using self-report ques- naires than psychiatric interviews (6), brfss/display.asp?catϭDB&yrϭ2002& tionnaire assessment methods (5,7). observed rates were not inflated com- qkeyϭ1364&stateϭUS. Accessed 28 July Models predicting depression status pared with other national samples. 2006 and severity found younger, unemployed Findings from this study document a 4. Voinovich Center for Leadership and participants and those who did not own substantial burden of clinically significant Public Affairs: Appalachian Rural Health their own homes at increased risk of de- depressive symptoms (one in three partic- Institute Health Needs Assessment Survey pression. These findings are consistent ipants) in this Appalachian region. Pov- Report of Findings. Athens, OH, Ohio Uni- with those observed in urban ethnic mi- erty increases the risk of depression in versity Voinovich Center for Leadership nority samples (18,19), suggesting that diabetes. Further investigation into treat- and Public Affairs, 2006 5. Dabney B Gosschalk A: Diabetes in Rural poverty may represent a common risk fac- ment availability and effectiveness is America. In Rural Healthy People 2010. tor across ethnic groups for comorbid de- needed in light of the economic vulnera- College Station, TX, Texas A&M Univer- pression in diabetic individuals. The bility of this region. sity Health Science Center, School of Ru- cross-sectional study design does not per- ral Public Health, 2006 mit determination of the casual direction 6. Anderson RJ, Freedland KE, Clouse RE, of this relationship. Acknowledgments— Partial support for this Lustman PJ: The prevalence of comorbid Contrary to previously published study was received from the National Insti- depression in adults with diabetes: a studies (8), we did not observe significant tutes of Health (DK071545). meta-analysis. Diabetes Care 24:1069– differences in average A1C by depression 1078, 2001 status. This may be due to the limited 7. Anderson D, Horton C, O’Toole M, Brownson C, Fazzone P, Fisher E: Inte- variability in A1C observed in the sample References 1. Black DA, Sanders SG: Labor market grating depression care with diabetes care as a whole. performance, poverty, and income in- in real-world settings: lessons from the Limitations to the current study in- equality in Appalachia [article online], Robert Wood Johnson Foundation Diabe- clude the cross-sectional nature of the 2004. Available from http://www.arc.gov/ tes Initiative. Diabetes Spectrum 20: 10– study design, the use of a clinic patient images/reports/labormkt/labormkt.pdf. 16, 2007 population, limited recruitment response Accessed 18 July 2006 8. Lustman PJ, Anderson RJ, de Groot M,
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1603 Depression in Appalachia
Carney RM, Clouse RE: Depression and toms and mortality among persons with Sherraden M, Haire-Joshu D: Depression poor glycemic control: a meta-analytic re- and without diabetes. Am J Epidemiol 161: and poverty among African-American view of the literature. Diabetes Care 23: 652–660, 2005 women at risk for type 2 diabetes. Ann 934–942, 2000 14. Beck AT, Steer RA, Brown GK: BDI-II Beck Behav Med 25:172–181, 2003 9. de Groot M, Anderson RJ, Freedland KE, Depression Inventory Manual. 2nd ed. San 20. Blumenthal DS, Sung J, Coates R, Wil- Clouse RE, Lustman PJ: Association of de- Antonio, TX, Harcourt, Brace & Com- liams J, Liff J: Recruitment and retention pression and diabetes complications: a pany, 1996 of subjects for a longitudinal cancer pre- meta-analysis. Psychosom Med 63:619– 15. Auslander WF, Haire-Joshu D, Houston vention study in an inner-city black com- 630, 2001 C, Williams JH, Krebill H, Assessing eco- munity. Health Serv Res 30:197–205, 1995 10. Egede LE: Diabetes, major depression and nomic assets: relationship to health be- 21. Moorman PG, Newman B, Millikan RC, functional disability among U.S. adults. haviors and readiness to prevent NIDDM Tse C, Sandler DP: Participation rates in a Diabetes Care 27:421–428, 2004 in black women (Abstract). Diabetes 46 case-control study: the impact of age, 11. Ciechanowski PS, Katon WJ, Russo JE: (Suppl. 1):135A race, and race of interviewer. Ann Epide- Depression and diabetes: impact of de- 16. SAS Institute: Version 8.03e [computer miol 9:188–195, 1999 pressive symptoms on adherence, func- software]. Cary, NC, 2001 22. Gilliss CL, Lee KA, Gutierrez Y, Taylor D, tion, and costs. Arch Intern Med 160: 17. Tabachnick PFL: Using Multivariate Statis- Beyene Y, Neuhaus J, Murrell N: Recruit- 3278–3285, 2000 tics. 4th ed. New York, Allyn & Bacon, 2001 ment and retention of healthy minority 12. Egede LE, Zheng D, Simpson K: Comor- 18. Jackson-Triche ME, Greer Sullivan J, women into community-based longitudi- bid depression is associated with in- Wells KB, Rogers W, Camp P, Mazel R: nal research. J Womens Health Gend Med creased health care use and expenditures Depression and health-related quality of 10:77–85, 2001 in individuals with diabetes. Diabetes Care life in ethnic minorities seeking care in 23. DiBartolo MC, McCrone S: Recruitment 25:464–470, 2002 general medical settings. J Affect Disord of rural community-dwelling older 13. Zhang X, Norris SL, Gregg EW, Cheng YJ, 58:89–97, 2000 adults: barriers, challenges, and strate- Beckles G, Kahn HS: Depressive symp- 19. de Groot M, Auslander W, Williams JH, gies. Aging Ment Health 7:75–82, 2003
1604 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Emerging Treatments and Technologies BRIEF REPORT
Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients With Hypertension
1 2 KWANG KON KOH, MD JEONG-A KIM, PHD underwent a 3-week washout period. At 2 1 MICHAEL J. QUON, MD, PHD WOOK-JIN CHUNG, MD the end of the washout period, partici- 1 4 SANG JIN LEE, MD YONGHEE LEE, PHD pants were randomly assigned to either 1 1 SEUNG HWAN HAN, MD EAK KYUN SHIN, MD 3 40–80 mg efonidipine or placebo daily JEONG YEAL AHN, MD during 8 weeks. Patients were then crossed over to the second treatment arm on completion of the first treatment arm ypertension is characterized by en- sure (9). Therefore, we hypothesized (without washout phase). The Green dothelial dysfunction and fre- that efonidipine therapy may simulta- Cross Pharmaceutical company (Yongin, H quently clusters with metabolic neously improve endothelial dysfunc- Korea) provided the identical placebo disorders that are characterized by insulin tion, adipocytokine profiles, and other (purchased by investigators). One patient resistance (1,2). These comorbidities may metabolic parameters in nondiabetic suffered from facial flushing and was be explained, in part, by reciprocal rela- patients with hypertension. withdrawn. Thus, data from 38 patients tionships between endothelial dysfunc- were analyzed. This study was approved tion and insulin resistance (1). By contrast RESEARCH DESIGN AND by the Gil Hospital Institute Review with calcium channel blockers (CCBs), METHODS — We evaluated effects of Board. treatment of hypertension with -block- efonidipine in a randomized, double- Blood samples were obtained at ers and diuretics is associated with a blind, placebo-controlled, crossover 8:00 A.M. following an overnight fast be- higher risk of type 2 diabetes (3). This study. Thirty-nine hypertensive patients fore and after each treatment period. advantage of CCBs may relate to specific (systolic blood pressure [SBP] Ͻ180 Assays for plasma insulin, malondialde- mechanisms that target the vicious syn- mmHg and diastolic blood pressure hyde, adiponectin, leptin, and resistin ergy between endothelial dysfunction and [DBP] Ͻ110 mmHg) were considered el- were performed in duplicate by immu- insulin resistance. CCBs activate nitric ox- igible for this study. We excluded patients noradiometric assay or by enzyme- ide (NO) synthase in vitro and enhance with severe hypertension, unstable an- linked immunosorbent assay as NO production in vivo (4). This may im- gina, acute myocardial infarction, or renal previously described (11–13). Quanti- pact on the roles of adiponectin, leptin, insufficiency. None of our subjects were tative insulin sensitivity check index and resistin to influence metabolic sig- diabetic (based on history or criteria ac- (QUICKI) was calculated as described nals, inflammation, and atherosclerosis cording to the Report of the Expert Com- (14). Imaging studies of the right bra- (5–7). mittee on the Diagnosis and Classification chial artery were performed by ultra- Efonidipine hydrochloride is a 1,4- of Diabetes Mellitus [10]) or smokers. To sound as described (11–13). dihydropyridine–type CCB with long- minimize acute side effects, during an ini- Data are expressed as means Ϯ SEM lasting vasodilator actions and little tial run-in period, study medication was or median (range 25–75%). We used reflex tachycardia (8). Efonidipine im- titrated from 40 to 80 mg efonidipine up- paired Student’s t test or Wilcoxon’s proves endothelial function in patients wards over a 2-week period if no hypo- signed-rank test to compare relative with hypertension when compared with tension (SBP Ͻ100 mmHg) or changes in response to treatment. Pear- doses of nifedipine that result in com- hypertension (SBP Ͼ140 mmHg) was son’s or Spearman’s correlation coeffi- parable decreases in mean blood pres- noted. After the run-in period, all patients cient analysis was used to assess ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● associations between parameters. We cal- From the 1Department of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea; the culated that 30 subjects would provide 2Diabetes Unit, Laboratory of Clinical Investigation, National Center for Complementary and Alternative 80% power for detecting an absolute in- Medicine, National Institutes of Health, Bethesda, Maryland; the 3Department of Cardiology, Laboratory crease of Ն1.5% in flow-mediated dila- 4 Medicine, Gachon Medical School, Incheon, Korea; and the Department of Statistics, Ewha Womans tion of the brachial artery between University, Seoul, Korea. ␣ϭ Address correspondence and reprint requests to Kwang Kon Koh, MD, Professor of Medicine, Department placebo and efonidipine, with 0.05 of Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea (15). A value of P Ͻ 0.05 was considered 405-760. E-mail: [email protected]. to represent statistical significance. Received for publication 5 November 2006 and accepted in revised form 18 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2267. Abbreviations: CCB, calcium channel blocker; DBP, diastolic blood pressure; SBP, systolic blood pres- RESULTS — The mean age of our sub- sure; QUICKI, quantitative insulin sensitivity check index. jects was 46 Ϯ 2 years, and the male: A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion female proportion was 21:17. Baseline factors for many substances. characteristics are reported in Table 1. No © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby carryover effects were found (data are not marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. shown).
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1605 Vascular and metabolic effects of efonidipine
Table 1—Effects of efonidipine in 38 patients with hypertension
Percentage Variables Baseline Placebo Efonidipine changes BMI (kg/m2) 24.7 Ϯ 0.5 24.7 Ϯ 0.5 24.6 Ϯ 0.5 0.4 Ϯ 0.3 (2.0) Heart rate (bpm) 86 Ϯ 282Ϯ 2 (12) 84 Ϯ 2 (13) 4 Ϯ 3 (16) SBP (mmHg) 155 Ϯ 2 148 Ϯ 2 (15) 134 Ϯ 2 (14)* Ϫ9 Ϯ 1 (8) DBP (mmHg) 95 Ϯ 191Ϯ 1 (9) 83 Ϯ 2 (9)* Ϫ9 Ϯ 1 (8) Lipids (mg/dl) Total cholesterol 186 Ϯ 4 183 Ϯ 5 (31) 187 Ϯ 5 (29) 3 Ϯ 2 (12) Triglycerides 162 Ϯ 19 157 Ϯ 18 (112) 155 Ϯ 16 (101) 15 Ϯ 9 (54) LDL cholesterol 105 Ϯ 4 102 Ϯ 4 (22) 106 Ϯ 4 (25) 5 Ϯ 3 (16) HDL cholesterol 49 Ϯ 353Ϯ 3 (20) 50 Ϯ 2 (14) Ϫ3 Ϯ 3 (21) Vasomotor function Flow-mediated dilation (%) 4.28 Ϯ 0.22 5.42 Ϯ 0.26 (1.58) 6.20 Ϯ 0.25 (1.52)* 21 Ϯ 7 (41) Nitroglycerin dilation (%) 13.87 Ϯ 0.70 14.62 Ϯ 0.68 (4.21) 14.84 Ϯ 0.80 (4.90) 2 Ϯ 4 (23) Malondialdehyde (mol/l) 1.20 Ϯ 0.04 1.22 Ϯ 0.04 (0.25) 1.12 Ϯ 0.05 (0.31)† Ϫ8 Ϯ 3 (18) C-reactive protein (mg/l) 0.80 (0.50–1.40) 0.85 (0.40–1.40) 0.65 (0.50–1.30) 25 Ϯ 18 (109) Insulin resistance Adiponectin (g/ml) 4.3 Ϯ 0.6 4.2 Ϯ 0.6 (3.7) 4.6 Ϯ 0.6 (3.9)† 15 Ϯ 4 (23) Insulin (U/ml) 7.33 (4.89–12.05) 7.63 (4.91–11.25) 6.78 (4.50–9.20) 3 Ϯ 8 (52) Glucose (mg/dl) 103 Ϯ 2 102 Ϯ 2 (12) 100 Ϯ 2 (15) Ϫ2 Ϯ 2 (10) QUICKI 0.360 Ϯ 0.010 0.351 Ϯ 0.006 (0.039) 0.359 Ϯ 0.007 (0.040) 3 Ϯ 2 (13) Leptin (ng/ml) 5.2 Ϯ 0.6 5.2 Ϯ 0.6 (3.6) 4.7 Ϯ 0.5 (3.3)† Ϫ12 Ϯ 4 (26) Resistin (ng/ml) 7.66 (5.81–10.34) 7.76 (5.83–10.41) 8.12 (5.31–9.99)* Ϫ1 Ϯ 6 (39) Data are expressed as means Ϯ SEM (SD) or median (25–75th percentile). *P Ͻ 0.001 vs. placebo. †P Ͻ 0.05 vs. placebo. QUICKI ϭ 1/͓log (insulin) ϩ log (glucose)͔ (ref. 14).
When compared with placebo, efo- adiponectin and HDL cholesterol levels function in patients with hypertension (9) nidipine therapy reduced SBP and DBP by (r ϭ 0.434, P ϭ 0.006) and QUICKI (r ϭ when compared with nifedipine. Finally, 9 Ϯ 1% (P Ͻ 0.001) and 9 Ϯ 1% (P Ͻ 0.379, P ϭ 0.019) following efonidipine urinary excretion of 8-hydroxy-2Ј- 0.001), respectively. When compared therapy. In a multiple regression model, deoxyguanosine and serum malondialde- with placebo, efonidipine improved flow- percentage changes in adiponectin levels hyde–modified LDL are both decreased mediated dilator response to hyperemia following efonidipine therapy persisted as by efonidipine, but not nifedipine, ther- by 21 Ϯ 7% (P Ͻ 0.001) and reduced an independent predictor of percentage apy. Although we did not directly com- plasma malondialdehyde levels by 8 Ϯ changes in HDL cholesterol levels (ϭ pare efonidipine with other CCBs in the 3% (P ϭ 0.011). 0.459, P ϭ 0.006) and QUICKI (ϭ current study, it will be of interest to do so There were positive correlations be- 0.467, P ϭ 0.067). in future studies. tween baseline adiponectin and HDL cho- Following efonidipine therapy, im- Potential mechanisms for CCBs to in- lesterol levels (r ϭ 0.533, P Ͻ 0.001), as provement in flow-mediated dilation was fluence insulin sensitivity may relate to well as between baseline BMI and baseline correlated with percentage changes in their ability to target the vicious synergy adiponectin (r ϭϪ0.507, P ϭ 0.001) or plasma levels of malondialdehyde (r ϭ between endothelial dysfunction and in- leptin (r ϭ 0.508, P ϭ 0.001) levels. Ϫ0.479, P ϭ 0.002), leptin (r ϭϪ0.424, sulin resistance. Therefore, we assessed When compared with placebo, efonidi- P ϭ 0.008), insulin (r ϭϪ0.354, P ϭ metabolic parameters including plasma pine therapy increased plasma adiponec- 0.029), and QUICKI (r ϭ 0.471, P ϭ levels of lipids, adiponectin, leptin, resis- tin levels by 15 Ϯ 4% (P ϭ 0.013) and 0.003). Improvement in flow-mediated tin, and QUICKI. Efonidipine had a neu- decreased plasma leptin and resistin lev- dilation persisted as an independent pre- tral metabolic effect with respect to the els by 12 Ϯ 4% (P ϭ 0.030) and 1 Ϯ 6% dictor of percentage changes in malondi- lipid profile and QUICKI. However, im- (P ϭ 0.001), respectively. Insulin sensi- aldehyde (ϭϪ0.822, P ϭ 0.017) and provement in flow-mediated dilation per- tivity assessed by QUICKI did not signif- QUICKI (ϭ1.032, P ϭ 0.034). Follow- sisted as an independent predictor of icantly change (increase of 3 Ϯ 2%, P ϭ ing efonidipine therapy, there were signif- changes in QUICKI. 0.239). Plasma resistin levels were not icant correlations between percentage Amlodipine has no significant effect correlated with either insulin sensitivity changes in plasma levels of malondialde- on adiponectin levels in patients with hy- or BMI. There were no significant corre- hyde and leptin (r ϭ 0.364, P ϭ 0.025). pertension (17). In our study, efonidipine lations between percentage changes in increased adiponectin levels without a adiponectin and percentage changes in CONCLUSIONS — Efonidipine has corresponding change in BMI. Increasing leptin or resistin levels following efo- distinct properties when compared with adiponectin levels is predicted to improve nidipine therapy (Ϫ0.054 Յ r Յ other CCBs. Efonidipine has higher affin- both insulin sensitivity and endothelial ϩ Ϫ0.030). However, we did observe cor- ity for T-type Ca2 channels (16) and a function by multiple mechanisms (18). relations between percentage changes in larger effect in improving endothelial Regulation of metabolic homeostasis and
1606 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Koh and Associates hemodynamic homeostasis may be cou- Shintani Y, Minamino T, Kitamura S, Lee Y, Shin EK: Anti-inflammatory and pled by vascular actions of insulin to stim- Tomoike H, Hori M, Kitakaze M: A cal- metabolic effects of candesartan in hyper- cium channel blocker activates both tensive patients. Int J Cardiol 108:96–100, ulate production of NO (19). In the Ј current study, changes in adiponectin lev- ecto-5( )-nucleotidase and NO synthase 2006 els persisted as an independent predictor in HUVEC. Biochem Biophys Res Com- 13. Koh KK, Quon MJ, Han SH, Chung W-J, mun 311:625–628, 2003 Ahn JY, Kim J, Kang WC, Lee Y, Shin EK: of changes in HDL cholesterol levels and 5. Han SH, Quon MJ, Kim JA, Koh KK: Adi- Additive beneficial effects of fenofibrate QUICKI. Effects of efonidipine to reduce ponectin and cardiovascular disease: re- combined with candesartan in the treat- plasma leptin and malondialdehyde lev- sponse to therapeutic interventions. JAm ment of hypertriglyceridemic, hyperten- els and improve endothelium-dependent Coll Cardiol 49:531–538, 2007 sive patients. Diabetes Care 29:195–201, dilation are significantly correlated. In 6. Correia ML, Haynes WG: Leptin, obesity 2006 summary, efonidipine therapy simulta- and cardiovascular disease. Curr Opin 14. Katz A, Nambi SS, Mather K, Baron AD, neously improves blood pressure, endo- Nephrol Hypertens 13:215–223, 2004 Follmann DA, Sullivan G, Quon MJ: thelial function, and metabolic 7. Verma S, Li SH, Wang CH, Fedak PW, Li Quantitative insulin sensitivity check in- parameters without substantially altering RK, Weisel RD, Mickle DA: Resistin pro- dex: a simple, accurate method for assess- insulin sensitivity in nondiabetic patients motes endothelial cell activation: further ing insulin sensitivity in humans. J Clin evidence of adipokine-endothelial inter- Endocrinol Metab 85:2402–2410, 2000 with hypertension. action. Circulation 108:736–740, 2003 15. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, 8. Honda M, Hayashi K, Matsuda H, Kubota Kim HS, Shin MS, Ahn TH, Choi IS, Shin E, Tokuyama H, Okubo K, Takamatsu I, EK: Pleiotropic effects of angiotensin II Acknowledgments— This study was sup- Ozawa Y, Saruta T: Divergent renal vaso- receptor blocker in hypertensive patients. ported by grants from an established inves- dilator action of L- and T-type calcium J Am Coll Cardiol 42:905–910, 2003 tigator award (2005-1) from the Gil Medical antagonists in vivo. J Hypertens 19:2031– 16. Lee TS, Kaku T, Takebayashi S, Uchino T, Center, Gachon Medical School, Incheon, 2037, 2001 Miyamoto S, Hadama T, Perez-Reyes E, Korea. 9. Oshima T, Ozono R, Yano Y, Higashi Y, Ono K: Actions of mibefradil, efonidipine Teragawa H, Miho N, Ishida T, Ishida M, and nifedipine block of recombinant T- Yoshizumi M, Kambe M: Beneficial effect and L-type Ca channels with distinct in- References of T-type calcium channel blockers on en- hibitory mechanisms. Pharmacology 78: 1. Kim J, Montagnani M, Koh KK, Quon MJ: dothelial function in patients with essen- 11–20, 2006 Reciprocal relationships between insulin tial hypertension. Hypertens Res 28:889– 17. Watanabe S, Okura T, Kurata M, Irita J, resistance and endothelial dysfunction: 894, 2005 Manabe S, Miyoshi K, Fukuoka T, Mu- molecular and pathophysiological mech- 10. The Expert Committee on the Diagnosis rakami K, Higaki J: The effect of losartan anisms. Circulation 113:1888–1904, and Classification of Diabetes Mellitus: and amlodipine on serum adiponectin in 2006 Report of the Expert Committee on the Japanese adults with essential hyperten- 2. Garcia-Puig J, Ruilope LM, Luque M, Fer- Diagnosis and Classification of Diabetes sion. Clin Ther 28:1677–1685, 2006 nandez J, Ortega R, Dal-Re R, AVANT Mellitus. Diabetes Care 21 (Suppl. 1):S5– 18. Koh KK, Han SH, Quon MJ: Inflammatory Study Group Investigators: Glucose me- S22, 1998 markers and the metabolic syndrome: in- tabolism in patients with essential hyper- 11. Koh KK, Quon MJ, Han SH, Ahn JY, Jin sights from therapeutic interventions. JAm tension. Am J Med 119:318–326, 2006 DK, Kim HS, Kim DS, Shin EK: Vascular Coll Cardiol 46:1978–1985, 2005 3. Taylor EN, Hu FB, Curhan GC: Antihy- and metabolic effects of combined ther- 19. Chen H, Montagnani M, Funahashi T, pertensive medications and the risk of in- apy with ramipril and simvastatin in pa- Shimomura I, Quon MJ: Adiponectin cident type 2 diabetes. Diabetes Care 29: tients with type 2 diabetes. Hypertension stimulates production of nitric oxide in 1065–1070, 2006 45:1088–1093, 2005 vascular endothelial cells. J Biol Chem 278: 4. Asano Y, Kim J, Ogai A, Takashima S, 12. Koh KK, Quon MJ, Han SH, Chung W-J, 45021–45026, 2003
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1607 Emerging Treatments and Technologies BRIEF REPORT
Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes
1 4 TINA VILSBØLL, MD, DMSC JEAN-PIERRE COURREGES` , MD After 14 weeks of treatment, esti- 2 5 MILAN ZDRAVKOVIC, MD, PHD ROBERT VERHOEVEN, MD mated change in A1C for placebo, 1.90, 2 6 TU LE-THI, MSC INGRID BUGANOV´ A´, MD 1.25, or 0.65 mg was ϩ0.29, Ϫ1.45, 1 7 THURE KRARUP, MD, DMSC STEN MADSBAD, MD, DMSC Ϫ Ϫ 3 1.40, and 0.98%, respectively OLE SCHMITZ, MD, DMSC (change for 1.90 mg vs. placebo: Ϫ1.74% [95% CI Ϫ2.18 to Ϫ1.29], P Ͻ 0.0001; 1.25 mg vs. placebo: Ϫ1.69% [Ϫ2.13 to iraglutide is a long-acting human were assessed: A1C, insulin, proinsulin, Ϫ1.24], P Ͻ 0.0001; and 0.65 mg vs. pla- glucagon-like peptide-1 (GLP-1) an- glucagon, fructosamine, lipids, home- cebo: Ϫ1.27% [Ϫ1.72 to Ϫ0.82], P Ͻ L alog (1–4), and the current study measured seven-point plasma glucose 0.0001). The proportion of patients was undertaken to evaluate efficacy and profiles, and body weight. Safety param- reaching A1C Ͻ7% was 46% (1.90 mg), safety after 14 weeks’ treatment with lira- eters (adverse events, hypoglycemic epi- 48% (1.25 mg), 38% (0.65 mg), and 5% glutide in patients with type 2 diabetes. sodes, clinical laboratory parameters, (placebo) in the four groups, respectively. antibodies against liraglutide, vital signs, FPG was significantly reduced (1.90 mg RESEARCH DESIGN AND electrocardiogram, and thyroid (includ- vs. placebo: Ϫ3.4 mmol/l [Ϫ4.4 to METHODS — Main inclusion criteria ing ultrasonography) and parathyroid pa- Ϫ2.4], P Ͻ 0.0001; 1.25 mg vs. placebo: Ն were patients aged 18 years with type 2 rameters were assessed. Liraglutide or Ϫ3.4 mmol/l [Ϫ4.4 to Ϫ2.4], P Ͻ Ն Յ diabetes and A1C 7.5 and 10.0% placebo was administered in the evening 0.0001; and 0.65 mg vs. placebo: Ϫ2.7 Ն Յ (diet) or 7.0 and 9.5% (mono–oral (as in the most recently completed phase mmol/l [Ϫ3.7 to Ϫ1.7], P Ͻ 0.0001). For antidiabetes drug); previous therapy was 2 study) (6) as once-daily subcutaneous the 1.90 mg group, the fractions of pa- discontinued. Fasting plasma glucose injections in the abdomen or thigh. tients reaching 90 min postmeal glucose (FPG) at randomization was 7–13 Ͼ values below the American Diabetes As- mmol/l. If FPG was 15 mmol/l during RESULTS — Baseline characteristics sociation treatment goal of Ͻ10 mmol/l the study, the patient was withdrawn. The are given in Table 1. The placebo group was 46, 51, and 56% of patients after study was conducted in accordance with accounted for almost one-half of the pa- breakfast, lunch, and dinner, respec- the Declaration of Helsinki (5). The study tient withdrawals, primarily due to inef- tively. Corresponding values were 15, 23, was double-blind, randomized (1:1:1:1), fective therapy. Withdrawals due to and 23%, respectively, in the placebo- and placebo-controlled using three doses adverse events were infrequent and oc- treated group. For both the 1.90 and 1.25 of liraglutide (0.65, 1.25, or 1.90 mg). curred at a comparable level in all groups mg groups, the fraction of patients with The following main efficacy parameters (Table 1). Ͻ ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● FPG 10 mmol/l was significantly differ- ent from that of patients given placebo 1 2 From the Department of Internal Medicine, Gentofte Hospital, Hellerup, Denmark; Novo Nordisk, Bags- (P Ͻ 0.05) at each meal, respectively. værd, Denmark; 3Århus Hospital, Århus, Denmark; 4Centre Hospitalier de Narbonne, Narbonne, France; 5Gelre Ziekenhuis, Apeldoorn, the Netherlands; 6Dibetologicka´ Ambulancia, Zilina, Slovakia; and Analysis of homeostasis model assess- 7Hvidovre Hospital, Copenhagen, Denmark. ment showed a significant increase (1.90 Address correspondence and reprint requests to Tina Vilsbøll, MD, DMSC, Internal Medicine F, Gentofte mg vs. placebo: 86% [48–134], P Ͻ Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: [email protected]. 0.0001; 1.25 mg vs.placebo: 134% [86– Received for publication 22 December 2006 and accepted in revised form 9 March 2007. 93], P Ͻ 0.0001; and 0.65 mg vs. pla- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2593. Ͻ Clinical trial reg. no. NCT00154401, clinicaltrials.gov. cebo: 75% [40–120%], P 0.0001). A T.V. is an external consultant to Novo Nordisk and a member of the advisory panels of Merck Sharp & dose-dependent decrease in insulin resis- Dohme (MSD), the Scandinavian Expert Group of Incretins, and Novartis. T.L.-T. is an employee and tance (homeostasis model assessment) stockholder of Novo Nordisk. T.K. is a member of the advisory board of MSD. O.S. is a member of the was observed (not significant [NS]). The advisory panels of Amylin and Eli Lilly. S.M. has served as a consultant or advisor to Novartis, Novo Nordisk, MSD, Phizer, Abbott Laboratories, Sanofi-Aventis, Astra-Zeneca, and Johnson & Johnson. median change from baseline in proinsu- Abbreviations: FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1. lin-to-insulin ratio was significant for all A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion three liraglutide groups versus placebo factors for many substances. (1.90 mg: Ϫ0.19, P ϭ 0.0111; 1.25 mg: © 2007 by the American Diabetes Association. Ϫ ϭ Ϫ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 0.28, P 0.0062; and 0.65 mg: 0.15, marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. P ϭ 0.0218).
1608 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Vilsbøll and Associates
Table 1—Patient disposition and characteristics
Liraglutide All 1.90 mg 1.25 mg 0.65 mg Placebo Patient disposition — ———— Screened 377 ———— Randomized 165 ———— Exposed 163 41 42 40 40 Withdrawn 25 6 3 5 11 Adverse event 7 2113 Noncompliance 2 1001 Ineffective therapy 14 2237 Other 2 1010 Completed 140 37 39 35 29 Included in ITT population 163 41 42 40 40 Baseline characteristics — ———— Age (years) — 55.4 Ϯ 11.4 53.8 Ϯ 10.7 56.5 Ϯ 9.3 57.7 Ϯ 8.2 Sex (male/female) (n) — 30/11 23/19 27/13 19/21 BMI (kg/m2) — 29.9 Ϯ 4.2 31.2 Ϯ 4.7 28.9 Ϯ 3.9 30.4 Ϯ 4.0 A1C (%) — 8.5 Ϯ 0.9 8.3 Ϯ 0.8 8.1 Ϯ 0.6 8.2 Ϯ 0.7 Duration of diabetes (years) — 4.0 (1–29) 7.0 (0–21) 6.0 (1–25) 5.0 (1–23) Previous diabetes treatment — ———— Diet — 7897 OAD (metformin) — 14 19 15 17 OAD (SU) — 19 14 16 15 OAD (repaglinide) — 1101 FPG (mmol/l) — 12.3 Ϯ 3.1 11.9 Ϯ 2.4 11.3 Ϯ 2.7 11.3 Ϯ 2.2 Insulin (pmol/l) — 63 Ϯ 35 60 Ϯ 37 59 Ϯ 45 70 Ϯ 51 Proinsulin (pmol/l) — 45 Ϯ 28 38 Ϯ 19 34 Ϯ 24 35 Ϯ 20 Proinsulin-to-insulin ratio — 0.74 Ϯ 0.26 0.70 Ϯ 0.30 0.88 Ϯ 0.52 0.59 Ϯ 0.33 Glucagon (pmol/l) — 23 Ϯ 721Ϯ 723Ϯ 919Ϯ 6 C-peptide (pmol/l) — 1138 Ϯ 455 1076 Ϯ 405 1176 Ϯ 640 1260 Ϯ 515 Fructosamine (mol/l) — 360 Ϯ 75 341 Ϯ 74 358 Ϯ 75 330 Ϯ 59 Data are means Ϯ SD or median (range) unless otherwise indicated. Data for age, sex, duration of diabetes, and previous treatment were recorded at screening and diabetes characteristics at baseline. Two patients withdrew from the study before receiving study medication; one because of withdrawal of consent and one because of noncompliance. The adverse event withdrawals were as follows: placebo: blood glucose increased (2 patients), hyperglycemia/nausea; 0.65 mg: diarrhea; 1.25 mg: injection site rash; and 1.90 mg: tachypnoea/gastrooesophageal reflux disease, constipation. ITT, intent to treat.
Body weight decreased in all treat- electrocardiogram. Lipid parameters (to- across the liraglutide treatment groups, ment groups, with a maximum estimated tal, LDL, VLDL, and HDL cholesterol; free although nausea seemed somewhat loss of 2.99 kg in the 1.90 mg liraglutide fatty acids, and apolipoprotein B) showed higher in the 1.90 and 0.65 mg groups group. The difference compared with pla- no consistent changes among treatment. (10% of subjects vs. 2–3% in the 1.25 mg cebo was significant for the 1.90 mg Triglyceride levels decreased compared and placebo groups, respectively). Diar- group (Ϫ1.21 kg [95% CI Ϫ2.36 to with placebo (1.90 mg vs. placebo: Ϫ22% rhea was reported by 26 of 123 and 5 of Ϫ0.06], P ϭ 0.0390). There was a signif- [Ϫ35 to Ϫ6%], P ϭ 0.0110; 1.25 mg vs. 40, nausea by 9 of 123 and 1 of 40, and icant lowering in fasting glucagon con- placebo: Ϫ15% [Ϫ30 to 2%], P ϭ vomiting by 4 of 123 and 0 of 40 subjects centrations in the 1.90 mg liraglutide 0.0854; and 0.65 mg vs. placebo: Ϫ19% treated with liraglutide and placebo, re- group compared with placebo (Ϫ3.26 [Ϫ33 to Ϫ2%], P ϭ 0.0304). spectively. Only 4 of 123 liraglutide- pmol/l [Ϫ6.52 to 0.00], P ϭ 0.0497). Sys- The overall fractions of patients with treated patients withdrew from the study tolic blood pressure decreased signifi- adverse events were comparable across because of gastrointestinal adverse cantly (1.90 mg vs. placebo: Ϫ7.9 mmHg the four groups, ranging from 43 to 51% events. The incidence of gastrointestinal [Ϫ12.9 to Ϫ2.9], P ϭ 0.0023; 1.25 mg of patients. The fractions of patients re- adverse events decreased over time. The vs. placebo: Ϫ5.2 mmHg [Ϫ10.2 to porting a gastrointestinal adverse event effect on body weight did not change Ϫ0.2], P ϭ 0.0417; 0.65 mg vs. placebo: were 37, 29, 38, and 23% of patients for when excluding patients with duration of Ϫ7.4 mmHg [Ϫ12.4 to Ϫ2.4], P ϭ 1.90 mg, 1.25 mg, 0.65 mg, and placebo, gastrointestinal events Ͼ7 days. Three se- 0.0041). Diastolic blood pressure respectively (NS), with a higher event rate rious adverse events were reported by two dropped 2–3 mmHg using all doses of reported at the highest dose group in patients (one in the placebo group and liraglutide when compared with placebo comparison with placebo (P Ͻ 0.05). The one in the 1.90 mg group [influenza]). No (NS). There was no significant effect on individual gastrointestinal adverse events major or minor hypoglycemic episodes pulse or clinically relevant changes in were reported at similar frequencies were reported. There was no treatment-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1609 Liraglutide, glycemic control, and weight related effect on induction of antibodies gets well-described abnormalities in the treatment with the long-acting gluca- and no clinically relevant changes in type 2 diabetes phenotype. gon-like peptide 1 analog liraglutide safety laboratory parameters, including (NN2211): a 12-week, double-blind, ran- thyroid ultrasonography, were observed domized, controlled trial. Diabetes Care after treatment with liraglutide. Acknowledgments— We are indebted to the 27:1335–1342, 2004 principal investigators who participated and 5. World Medical Association: Declaration their staff, as follows. Denmark: K. Kølendorf, of Helsinki: recommendations guiding CONCLUSIONS — The present H. Perrild, and H.H. Lervang. France: E. physicians in biomedical research involv- study demonstrated sustained effect of Aboud, C. Le Devehat, M. Vimeaux, D. Gouet, ing human subjects. JAMA 277:925–926, T. Godeau, M. Bernardin, M. Issa-Sayegh, Y. the long-acting GLP-1 analog liraglutide 1997 Hadjali, A. Blaimont, R. Mira, F. Galtier, A. 6. Nauck MA, Hompesch M, Filipczak R, Le on glycemic control in patients with type Farret, J.P. Gagnol, Y. Lorcy, M. Rodier, A. TD, Zdravkovic M, Gumprecht J: Five 2 diabetes without any major or minor Maubon, S. Schuldiner, B. Vialettes, C. Mattei, weeks of treatment with the GLP-1 ana- hypoglycemic episodes. At the highest B. Catargi, B. Gatta, P. Duvezin-Caubat, and P. logue liraglutide improves glycaemic con- dose, liraglutide monotherapy reduced Serusiat. Slovakia: Z. Nemethyova, T. Kup- trol and lowers body weight in subjects the estimated average A1C levels by cova, M. Macko, I. Tkac, K. Suschozova, L. with type 2 diabetes. Exp Clin Endocrinol 1.74% from an average A1C of 8.5%, Fabryova, V. Uliciansky, K. Raslova, P. Farkas, Diabetes 114:417–423, 2006 when compared with placebo. When J. Okapcova, and J. Fabry. Netherlands: J.B.L. 7. Standards of medical care in diabetes– given one of the two highest doses of lira- Hoekstra, P.H.L.M. Geelhoed-Duvestijn, P.A. 2006 (Position Statement). Diabetes Care glutide, almost one-half of the patients Van Meurs, H. Seinen, and F.H. Kauw. 29 (Suppl. 1):S4–S42, 2006 managed to reach the American Diabetes 8. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control Association target for postprandial con- References with sulphonylureas or insulin compared trol (7), confirming a full 24-h coverage of 1. Agerso H, Vicini P: Pharmacodynamics of with conventional treatment and risk of liraglutide on glycemic control (2). Fur- NN2211, a novel long acting GLP-1 de- complications in patients with type 2 di- thermore, in spite of improved glycemic rivative. Eur J Pharmacol Sci 19:141–150, 2003 abetes (UKPDS 33). Lancet 352:837–853, control, which is often associated with an 1998 increase in body weight (8), a dose- 2. Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, 9. Piper K, Dijkstra I, Dunleavey L, Hanley dependent decrease in body weight was NA: The long-acting GLP-1 analog, lira- seen. Adverse events related to the gastro- Landau BR, Schmitz O: One week’s treat- ment with the long-acting glucagon-like glutide, increases beta cell numbers dur- intestinal system and headaches were the peptide 1 derivative liraglutide (NN2211) ing early human development (Abstract). most frequently reported adverse events. markedly improves 24-h glycemia and ␣- Diabetologia A394, 2005 In addition to a beneficial effect of lira- and -cell function and reduces endoge- 10. Rolin B, Larsen MO, Gotfredsen CF, Dea- glutide on -cell function, in current nous glucose release in patients with type con CF, Carr RD, Wilken M, Knudsen and in previous studies (9–11), a poten- 2 diabetes. Diabetes 53:1187–1194, 2004 LB: The long-acting GLP-1 derivative tial effect on lowering of blood pressure 3. Knudsen LB, Nielsen PF, Huusfeldt PO, NN2211 ameliorates glycemia and in- was observed in the current study. The Johansen NL, Madsen K, Pedersen FZ, creases beta-cell mass in diabetic mice. mechanism behind the effect on blood Thogersen H, Wilken M, Agerso H: Potent Am J Physiol Endocrinol Metab 283:E745– derivatives of glucagon-like peptide-1 E752, 2002 pressure remains unknown. However, 11. Sturis J, Gotfredsen CF, Romer J, Rolin B, since the effect on blood pressure oc- with pharmacokinetic properties suitable for once daily administration. J Med Chem Ribel U, Brand CL, Wilken M, Wasser- curred earlier than the effect on body 43:1664–1669, 2000 mann K, Deacon CF, Carr RD, Knudsen weight, it suggests that the effect cannot 4. Madsbad S, Schmitz O, Ranstam J, Jakob- LB: GLP-1 derivative liraglutide in rats only be ascribed to the lowering in body sen G, Matthews DR: Improved glycemic with beta-cell deficiencies: influence of weight. In conclusion, the long-acting, control with no weight increase in pa- metabolic state on beta-cell mass dynam- once-daily GLP-1 analog, liraglutide, tar- tients with type 2 diabetes after once-daily ics. Br J Pharmacol 140:123–132, 2003
1610 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications BRIEF REPORT
Thyroid Autoimmunity at Onset of Type 1 Diabetes as a Predictor of Thyroid Dysfunction
1 2 GEMMA C. GONZALEZ´ , MD DIDAC MAURICIO, MD 1 diabetes diagnosis developed hypothy- 2 2 ISMAEL CAPEL, MD ALBERTO DE LEIVA, MD roidism; he was a 14-year-old subject at 3 2 JOSE´ RODR´IGUEZ-ESPINOSA, MD ANTONIO P´EREZ, MD type 1 diabetes onset who later turned TPO-Ab positive and developed hypothy- roidism 15 years after diabetes diagnosis. ype 1 diabetes and autoimmune thyroid autoimmunity at diagnosis was Tg-Abs were less sensitive than TPO-Abs, thyroid diseases (AITDs) often coex- not determined in 17 patients. The re- being negative in 8 of 18 patients who T ist in the same individual and in the maining 176 patients were included in developed hypothyroidism. The mean same family. In the general population, the study. The mean age at diabetes diag- time to thyroid dysfunction development AITD is more frequent in female subjects nosis was 24.4 Ϯ 9.4 years, 65% were from type 1 diabetes onset was 8.1 Ϯ 4.2 and prevalence increases with age. In di- male subjects, and the percentage of islet years. Interestingly, the seven TPO-Ab– abetic patients, age and sex distributions cell antibody positivity was 76%. The positive patients who maintained normal are similar, but the prevalence is higher mean follow-up was 9.6 Ϯ 4.3 years. Thy- thyroid function after 8.0 Ϯ 5.0 years of and increases with duration of the disease roid autoimmunity was determined at on- follow-up were younger at type 1 diabetes (1–4). Thyroid dysfunction can affect set by hemagglutination, measuring onset than the patients who developed metabolic control in type 1 diabetes, and thyroperoxidase autoantibodies (TPO- thyroid dysfunction (20.1 Ϯ 6.2 vs. some studies (3) have shown a higher se- Abs) and tyroglobulin autoantibodies 29.5 Ϯ 11.8 years; P Ͻ 0.05). Further- verity of diabetes when it is associated (Tg-Abs), and were considered positive at more, patients who developed thyroid with AITD, although other studies (4) did a dilution of Ն1/100. All patients under- dysfunction were older at type 1 diabetes not find these differences. Nevertheless, went clinical follow-up, and thyrotropin diagnosis than those who did not (28.7 Ϯ there is general agreement (5,6) on the (TSH) was monitored every 1–2 years us- 12 vs. 23.9 Ϯ 8.9 years; P Ͻ 0.05). As utility of systematic screening of AITD in ing a commercial noncompetitive immu- expected, there were also sex differences, the type 1 diabetes population given its noassay. Thyroid dysfunction was with thyroid dysfunction more frequent high prevalence, but procedure and fre- diagnosed in the presence of a serum TSH in female subjects than in male subjects quency remain controversial. The aim of alteration (normal range 0.3–5 mUI/l) (11 of 61 [18.3%] and 8 of 114 [7.0], the present study was to determine the with or without symptoms. Statistical respectively; P Ͻ 0.05) presence of thyroid autoantibodies at type analysis was performed with SPSS version Table 1 shows the prevalence of thy- 1 diabetes onset and its predictive capac- 14.0 for Windows using 2 and Student’s roid dysfunction according to the pres- ity for the future development of thyroid t tests. Data are expressed as means Ϯ SE. ence of TPO-Abs at type 1 diabetes onset. dysfunction. Statistical significance was established at Further data analysis showed that the P Ͻ 0.05. presence of TPO-Abs at type 1 diabetes RESEARCH DESIGN AND onset can predict the development of thy- METHODS — Between September RESULTS — Twenty-five of 176 pa- roid dysfunction with 95% sensitivity (18 1987 and January 1994, 204 patients tients (14.2%) were TPO-Ab positive at of 19 cases of future thyroid dysfunction were consecutively diagnosed with type 1 type 1 diabetes diagnosis. Eighteen of were detected), 96% specificity (150 of diabetes at our institution. One patient these 25 patients developed thyroid dys- 157 patients were correctly classified as had developed primary hypothyroidism 3 function at follow-up (primary hypothy- normal), a 99% negative predictive value years before the development of type 1 roidism, defined as TSH Ͼ5 mUI/l in 17 (only 1 of 151 patients classified as nor- diabetes, 10 patients were not followed cases and hyperthyroidism in 1 case). mal later developed thyroid dysfunction), up after a few months from diagnosis, and Only 1 of the 151 negative subjects at type and 72% positive predictive value (7 of 25 patients remained normal in the follow- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● up). From the 1Pediatric Department, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; the 2Endocrinology Department, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; and the 3Biochemical Department, Hospital Santa Creu i Sant Pau, Auton- CONCLUSIONS — The present omous University of Barcelona, Barcelona, Spain. study confirmed the high prevalence of Address correspondence and reprint requests to Gemma Carreras Gonza´lez, Hospital Sant Pau, Pediatric thyroid autoimmunity and thyroid dys- Department, Sant Antoni M Claret 167, 08025 Barcelona, Spain. E-mail: [email protected]. function in young adults with type 1 dia- Received for publication 22 December 2006 and accepted in revised form 12 March 2007. Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2595. betes. In addition, the determination of Abbreviations: AITD, autoimmune thyroid disease; TG-Ab, tyroglobulin autoantibody; TPO-Ab, thy- TPO-Abs at type 1 diabetes onset was roperoxidase autoantibody; TSH, thyrotropin. highly sensitive in the prediction of the A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion development of thyroid dysfunction. factors for many substances. Although there is general agreement © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby that the high prevalence of thyroid dys- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. function in type 1 diabetes subjects justi-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1611 Autoimmune thyroid disease in type 1 diabetes
Table 1—Prevalence of thyroid dysfunction according to the presence of TPO-Abs at type 1 Jime´nez L, Go´mez JM, Soler J: Clinical diabetes onset presentation and early course of type 1 diabetes in patients with and without thy- roid autoimmunity. Diabetes Care 22: Thyroid dysfunction No thyroid dysfunction Total 377–381, 1999 Positive TPO-Ab presence at 18 (10.2) 7 (42) 25 (14.2) 5. Jaeger C, Hatziagelaki E, Petzoldt R, Bret- diabetes onset zel RG: Comparative analysis of organ- specific autoantibodies and celiac disease- Negative TPO-Ab presence 1 (0.6) 150 (85.2) 151 (85.8) associated antibodies in type 1 diabetic at diabetes onset patients, their first-degree relatives, and Total 19 (10.8) 157 (89.2) 176 (100) healthy control subjects. Diabetes Care 24: Data are n (%). 27–32, 2001 6. Glastras SJ, Craig ME, Verge CF, Chan AK, Cusumano JM, Donaghue KC: The fies screening in all patients (5,6), it is not diagnosis. In agreement with previous role of autoimmunity at diagnosis of type clear which is the best procedure and how studies (8,13), Tg-Abs were less sensitive 1 diabetes in the development of thyroid often to perform it. The American Diabe- and did not increase TPO-Ab–positive and celiac disease and microvascular tes Association (7) and several authors predictive value. Thereafter, an annual complications. Diabetes Care 28:2170– (8,9) recommend annual screening for TSH determination would be performed 2175, 2005 thyroid disease in all type 1 diabetes sub- only in subjects with positive autoanti- 7. Silverstein J, Klingensmith G, Copeland jects with TSH measurement; this proce- bodies. Using this procedure, only one K, Plotnick L, Kaufman F, Laffel L, Deeb dure is considered the most sensitive way case of hypothyroidism was missed, ap- L, Grey M, Anderson B, Holzneister LA, to identify patients with thyroid dysfunc- pearing 15 years after the onset of diabe- and Clark N: ADA statement. Care of chil- tion, as autoantibodies may persist for tes in a patient who was a 14-year-old at dren and adolescents with type 1 diabe- many years without thyroid dysfunction. diabetes onset and who was later TPO-Ab tes. Diabetes Care 28 :186–212, 2005 However, the American Diabetes Associ- positive. 8. Hansen D, Bennedbaek FN, Hoier-Mad- sen M, Hegedu¨ s L, Jacobsen BB: A pro- ation recommendations note that the Considering that the prevalence of spective study of thyroid dysfunction, presence of thyroid autoantibodies in- TPO-Ab positivity may increase with time morphology and autoimmunity in young crease the risk for thyroid disease, and (1,3,8), further studies are required to in- patients with type 1 diabetes. Eur J Endo- Hansen et al. (8) did not find any initial vestigate if additional determination of crinol 148:245–251, 2003 TPO-Ab–negative patients who devel- TPO-Abs after diagnosis may be useful, 9. Hoffman RP: Thyroid stimulating hor- oped thyroid disease after 3 years of specially in younger patients. mone screening is more sensitive for de- follow-up. Other authors (10,11) recom- tecting thyroid abnormalities in children mend screening using TSH and TPO-Abs. and adolescents with type 1 diabetes (Let- In a cohort of 58 type 1 diabetic patients Acknowledgments— This study was funded ter). Diabetes Care 26:255, 2003 enrolled in the Diabetes Control and by Grants ISCIII-RETIC RD06, PI052099 and 10. Umpierrez GE, Latif KA, Murphy MB, Complications Trial and followed for 18 PI051540 from the Fondo de Investigacio´n Lambeth HC, Stentz F, Bush A, Kitabchi years, Umpierrez et al. (10) observed that Sanitaria, Carlos III Health Institute, Spain. A: Thyroid dysfunction in patients with type 1 diabetes. Diabetes Care 26:1181– TPO-Ab–positive subjects were 17.9 1185, 2003 times more likely to develop thyroid dys- References 11. Baker JM: Clinical review: type 1 diabetes- function. These authors recommended associated autoimmunity: natural history, annual screening using TSH determina- 1. Kordonouri O, Klinghammer A, Lang EB, Gru¨ ters-Kieslich A, Grabert M, Holl RW: genetic associations and screening. J Clin tion, particularly in patients with positive Thyroid autoimmunity in children and Endocrinol Metab 91:1210–1217, 2006 TPO-Abs. Barker (11) screened type 1 di- adolescent with type 1 diabetes. Diabetes 12. Maugendre D, Guilhem I, Karacatsanis C, abetic patients with TPO-Abs and thyroid Care 25:1346–1350, 2002 Poirier JY, Leguerrier AM, Lorcy Y, Der- function at onset and every 1–2 years 2. Kordonouri O, Hartmann R, Deiss D, rien C, Sonnet E, Massart C: Anti-TPO thereafter and patients with positive TPO- Wilms M, Gru¨ ters-Kieslich A: Natural antibodies and screening of thyroid dys- Abs every 6–12 months. Finally, a third course of autoimmune thyroiditis in type function in type 1 diabetic patients. Ann group of authors (1,12) recommends 1 diabetes: association with gender, age, Endocrinol (Paris) 61:524–530, 2000 [Ar- TSH determination only in TPO-Ab– diabetes duration and puberty. Arch Dis ticle in French] positive patients. In our study, the high Child 90:411–414, 2005 13. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer sensitivity and especially the high nega- 3. Franzese A, Buono P, Mascolo M, Leo AL, Valerio G: Thyroid autoimmunity starting CA, Braverman LE: Serum TSH, T4, and tive predictive value of TPO-Abs for the during the course of type 1 diabetes de- thyroid antibodies in the United States development of thyroid dysfunction over notes a subgroup of children with more population (1988 to 1994): National a mean follow-up of 9.6 years support a severe diabetes. Diabetes Care 23:1201– Health and Nutrition Examination Survey screening strategy with determination of 1202, 2000 (NHANES III). J Clin Endocrinol Metab 87: TPO-Abs in all type 1 diabetic subjects at 4. Ferna´ndez-Casta´ner M, Molina A, Lo´pez- 489–499, 2002
1612 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications BRIEF REPORT
Digenic Inheritance of Hepatocyte Nuclear Factor-1␣ and -1 With Maturity-Onset Diabetes of the Young, Polycystic Thyroid, and Urogenital Malformations
1 2 BEATE KARGES, MD KLAUS ZERRES, MD sulin 223.8, 124.1, and 145.6 pmol/l, re- 2 1 CARSTEN BERGMANN, MD KLAUS-MICHAEL DEBATIN, MD spectively). In contrast, there was a 1 1 KATRINA SCHOLL, MD MARTIN WABITSCH, MD sustained insulin release after arginine in- 1 4 EBERHARD HEINZE, MD WOLFRAM KARGES, MD 3 fusion (maximum serum insulin 543.1, FRANZ MAXIMILIAN RASCHE, MD 363.0, and 655.0 pmol/l, respectively). Abdominal ultrasound in the index patient showed agenesis of the right kid- eterozygous mutations of the POU ternal grandmother had diabetes treated ney and a didelphic uterus with hypoplas- A/homeodomain transcription fac- with glibenclamide until she died 20 tic right uterine horn and hemiatresia of H tors hepatocyte nuclear factor years ago, aged 62 years. Two asymptom- the cervix, which was confirmed by hys- (HNF)-1␣ and -1 cause maturity-onset atic sisters of the index patient were diag- teroscopy. In both of her sisters, no ab- diabetes of the young (MODY) in humans nosed with diabetes at the age of 14 years normalities of the urogenital system were (1). HNF-1␣ and -1 act in a complex and 19 years. Their fasting serum glucose identified by ultrasound. In the index pa- network of transcription factors regulat- was 7.3 and 6.8 mmol/l, respectively, and tient and the younger sister, polycystic ing tissue-specific gene expression in the A1C was 6.0 and 6.1%. Two hours after a changes in both thyroid lobes with Ͼ50 pancreas and other epithelial organs. 75-g oral glucose challenge, their glucose cysts up to 4 mm in size were detected by Patients with mutations of HNF-1 levels were 10.1 and 13.1 mmol/l, respec- high-resolution (12 MHz) ultrasound, (MODY5) are characterized by urogenital tively. and single thyroid cysts were identified in malformations, while extrapancreatic Fasting C-peptide was 299.7 pmol/l the father and the older sister. No cystic or manifestations in patients with diabetes in the index patient, and 599.4 and 566.1 other lesions in the liver were identified in and HNF-1␣ mutations (MODY3) are not pmol/l in her sisters; all had normal insu- any individual. well known (2). lin sensitivity (homeostasis model assess- HNF-1 sequence analysis in the in- ment 2.0, 1.7, and 1.8, respectively) and dex patient revealed a heterozygous 2 HISTORY AND normal BMI (Ͻ25 kg/m ). Liver, kidney, genomic missense variant (c.1006CϾG) EXAMINATION — After an occa- and thyroid function tests including se- in exon 4, resulting in the substitution of sional blood glucose reading of 13.4 rum thyrotropin, free T4 and T3, creati- a highly conserved residue (p.His336Asp) mmo/l, the diagnosis of diabetes was es- nine, and other standard laboratory in the protein’s transactivation domain. tablished in a 13-year-old girl. She was parameters were normal in all sisters, and This novel variant was detected in 1 of asymptomatic except for mild chronic serum islet cell autoantibodies and 400 chromosomes in healthy individuals lower abdominal discomfort. Her fasting GAD65 antibodies were negative. by denaturing high-performance liquid glucose was 9.3 mmol/l, A1C was 8.5% chromatography. Sequencing identified  (normal 4.2–6.1), and urine ketones INVESTIGATION — -Cell func- HNF-1 c.1006CϾG in the younger sis- were negative. After brief insulin treat- tion was assessed after intravenous chal- ter and the father but not in the older di- ment, she received 0.5 mg/day lenge with glucose (0.5 g/kg bolus) and abetic sister. Thus, this mutation could glimepiride, with a current A1C of 5.6%. L-arginine (0.7g/min for 30 min). In the not exclusively account for the diabetes Her father (Fig. 1), diagnosed with di- index patient and her sisters, insulin se- phenotype in this family. abetes at the age of 27 years, has received cretion was significantly impaired after We next analyzed HNF-1␣ and iden- insulin since the age of 38 years. The pa- intravenous glucose (maximum serum in- tified a heterozygous genomic mutation ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● (c.526 ϩ 1delGTAA) in the canonic splice From the 1Department of Pediatric Endocrinology and Diabetes, University Children’s Hospital, University site of intron 2 in all diabetic individuals 2 of Ulm, Ulm, Germany; the Institute for Human Genetics, Rheinisch-Westfa¨lische Technische Hochschule but not in unaffected family members (RWTH) Aachen University, Aachen, Germany; the 3Department of Nephrology, University of Ulm, Ulm, Germany; and the 4Department of Endocrinology and Diabetes, RWTH Aachen University, Aachen, Ger- (Fig. 1). This novel mutation is predicted many. to result in aberrant HNF-1␣ splicing (3), Address correspondence and reprint requests to Beate Karges, MD, Department of Pediatric Endocrinol- with the introduction of a premature ter- ogy and Diabetes, University Children’s Hospital, University of Ulm, Eythstrasse 24, D-89075 Ulm, Ger- mination codon at amino acid position many. E-mail: [email protected]. Received for publication 28 December 2006 and accepted in revised form 19 February 2007. 194 and deletion of the POU A and trans- Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-2618. activation domains. Abbreviations: HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young. To rule out further modifying gene A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion effects, additional candidate genes puta- factors for many substances. tively involved in the HNF transcriptional © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby network were sequenced. In the promoter marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. of HNF-6, a sequential heterozygous sin-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1613 HNF-1␣, HNF-1, and digenic MODY
HNF-1 transcription factors in thyroid disease involving differential transacti- vation of HNF-3 or other target genes, however, must await experimental confirmation.
References 1. Fajans SS, Bell GI, Polonsky KS: Molecu- lar mechanisms and clinical pathophysi- ology of maturity-onset diabetes of the young. N Engl J Med 345:971–980, 2001 2. Bellanne-Chantelot C, Chauveau D, Gau- tier JF, Dubois LaForgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel Figure 1—Pedigree of family with MODY, polycystic thyroid, and urogenital malformations. The LH, Velho G, Timsit J: Clinical spectrum ␣  clinical phenotype (filled symbols) is shown in relation to the HNF-1 (upper row) and HNF-1 associated with hepatocyte nuclear factor- allelic status (lower row) of each individual. n.a., not available. 1beta mutations. Ann Intern Med 140: 510–517, 2004 3. Wang M, Marin A: Characterization and gle nucleotide polymorphism (c.1- In several, but not all, diabetic pa- prediction of alternative splice sites. Gene 400AϾC, c.1-390CϾA, and c.1- tients in these kindred, a second mutation 366:219–227, 2006 385GϾA) was identified in all diabetic was identified in HNF-1, leading to a 4. Pearson ER, Badmand MK, Lockwood patients but also in the unaffected nonconservative amino acid substitution CR, Clark PM, Ellard S, Bingham C, Hat- mother. No sequence variation was de- in the highly conserved region of the tersley AT: Contrasting diabetes pheno- tected in the index patient’s genomic transactivation domain. This molecular types associated with hepatocyte nuclear ␣  DNA in the coding regions of HNF-4␣, feature and the low allelic frequency factor -1 and -1 mutations. Diabetes insulin promoter factor 1/pancreatic duo- suggest that c.1006CϾG is indeed a Care 27:1102–1107, 2004 denal homeobox-1, NeuroD (causing pathogenic HNF-1 variant. Strikingly, 5. Malecki MT, Skupien J, Gorczynska-Ko- siorz S, Klupa T, Nazim J, Moczulski DK, MODY 1, 4, and 6, respectively), nor in urogenital and polycystic thyroid changes  Sieradzki J: Renal malformations may be HNF-6, HNF-3 , and chicken ovalbumin but not metabolic characteristics were linked to mutations in the hepatocyte nu- upstream promoter transcription factors I associated with the mutant HNF-1 al- clear factor-1 alpha (MODY3) gene. Dia- and II. lele, while MODY segregated with the betes Care 28:2774–2776, 2005 HNF-1␣ variant. 6. Ryffel GU: Mutations of the human genes CONCLUSIONS — We have identi- In polarized epithelial cells, HNF-1␣ encoding the transcription factors of the fied a novel heterozygous HNF-1␣ splice and -1 cooperate in a network of tran- hepatocyte nuclear factor (HNF)1 and site mutation that segregates with diabe- scriptional regulators including HNF-4␣ HNF4 families: functional and pathologi- tes and impaired glucose-dependent in- and -3, and both HNF-1␣ and - homo- cal consequences. J Mol Endo 27:11–29, sulin secretion, typical of MODY3 (4). In and heterodimerize for DNA binding via 2001 7. Hiesberger T, Bai Y, Shao X, McNally BT, addition, polycystic thyroid, renal, and their NH2-terminal dimerization domains Sinclair AM, Tian X, Somlo S, Igarashi P: genital abnormalities were found to ex- (6). It is conceivable that the extended Mutation of hepatocyte nuclear factor- tend the clinical phenotype of MODY in MODY phenotype observed in these kin- 1beta inhibits Pkhd1 gene expression and this kindred. In a recent report, renal dred may result from the digenic inacti- produces renal cysts in mice. J Clin Invest agenesis has been described in two fami- vation of HNF-1␣ and -1. In the kidney, 113:814–825, 2004 lies with HNF-1␣ mutations, including a inactivation of HNF-1 inhibits the ex- 8. Bohn S, Thomas HE, Turan G, Ellard S, patient with a different HNF-1␣ splice pression of the polycystic kidney disease Bingham C, Hattersley AT, Ryffel GU: site variant and a bicornute uterus (5). gene Pkhd1 (7), and distinct functional Distinct molecular and morphogenetic The association of HNF-1␣ mutants with characteristics of HNF-1 mutants lead to properties of mutations in the human a polycystic thyroid phenotype, however, a spectrum of kidney malformations in- HNF1beta gene that lead to defective kid- ney development. J Am Soc Nephrol 14: has not been observed thus far. Consider- cluding polycystic phenotypes (8). ␣ ␣   2033–2041, 2003 ing that HNF-1 mutations are the most HNF-1 and -1 interact with HNF-3 ,a 9. de Felice M, di Lauro R: Thyroid develop- common cause of MODY, extrapancreatic forkhead transcription factor expressed in ment and its disorders: genetics and mo- manifestations seem overall rare in early thyroid organogenesis and in the lecular mechanisms. Endocrine Reviews HNF-1␣ mutation carriers. adult thyroid (9). The putative role of 25:722–746, 2004
1614 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Pathophysiology/Complications BRIEF REPORT
Insulin-Like Growth Factor Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes
1 4 ABEL L´OPEZ-BERMEJO, MD KATHERINE L. PRATT, MS able serum samples were used for mea- 2 5 JAVAD KHOSRAVI, PHD ROSER CASAMITJANA, PHD suring IGFBP-rP1 in 10 patients in the 1 4,6 WIFREDO RICART, MD RON G. ROSENFELD, MD intervention group and 14 patients in the 3 1 ANTONI CASTRO, MD, PHD JOSE´ MANUEL FERNANDEZ´ -REAL, MD, PHD 4 observation group (online appendix Ta- VIVIAN HWA, PHD ble 1 [available at http://dx.doi.org/ 10.2337/dc06-1905]). The clinical and biochemical characteristics of these sub- ype 2 diabetes is characterized by vasomotor responses that follow iron de- jects were comparable with those of the variable degrees of vascular dys- pletion in high-ferritin type 2 diabetes. initial cohort (3). T function (1,2). We have recently re- Subjects were studied in the postab- ported improved vasomotor responses in RESEARCH DESIGN AND sorptive state. Anthropometry, blood pressure, and insulin sensitivity (K , high-ferritin type 2 diabetic patients fol- METHODS — The study subjects ITT from insulin tolerance tests) were as- lowing bloodletting (3), an intervention (n ϭ 24 male patients, mean Ϯ SD age 2 sessed as previously reported (15). Bra- that is believed to reduce the deleterious 55.5 Ϯ 8.1 years, BMI 29.1 Ϯ 3.6 kg/m , effects of circulating iron on vascular and A1C 6.2 Ϯ 0.9%), are part of a well- chial artery vascular reactivity was function (4,5). characterized sample of high-ferritin type assessed by a high-resolution external ul- Insulin-like growth factor binding 2 diabetic patients subjected to bloodlet- trasound (Toshiba SSH-140A) in re- protein–related protein 1 (IGFBP-rP1) is ting as previously reported by us (3,15). sponse both to reactive hyperemia (flow- a 30 kDa modular glycoprotein known to mediated endothelium-dependent In the original cohort, 28 diabetic patients be secreted by vascular and nonvascular with elevated serum ferritin concentra- vasodilation [EDV]) and to 400 g sub- cells (6–8). Besides its involvement in de- tions were randomized to either iron de- lingual glyceryl trinitrate, a direct smooth velopmental processes and tumor growth pletion (intervention group; n ϭ 13) or to muscle dilator (endothelial-independent (9,10), IGFBP-rP1 may play a role in the observation (n ϭ 15) according to a ran- vasodilation [EIV]), as previously de- vasculature, given its abundance as an en- domization table that included age, BMI, scribed (3,16). dothelial marker (11–13), its stimulatory and A1C. The two groups were also Serum glucose, insulin, C-peptide, actions on prostacyclin synthesis (7), and matched for pharmacological treatment transferrin, transferrin saturation index, its vasodilatory effects on the retina of di- and chronic diabetes complications. The ferritin, and A1C were measured as pre- abetic rats (14). iron depletion intervention consisted of viously reported (3,15). Whole-blood he- To our knowledge, no clinical studies three blood extractions (each 500 ml) at moglobin and hematocrit were have examined the role of serum IGFBP- 2-week intervals. The patients were stud- determined by routine laboratory tests rP1 as a vascular factor. We hypothesized ied at baseline and 3 months after the last (Coulter Electronics, Hialeah, FL). Serum IGFBP-rP1 was measured by an enzyme- that circulating IGFBP-rP1 is linked to the phlebotomy. In the present study, avail- linked immunosorbent assay with a coef- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ficient of variation Ͻ7% (13). Statistical analyses were performed From the 1Department of Endocrinology, Dr. Josep Trueta Hospital, Girona, Spain; the 2Diagnostic System Laboratories, Toronto, Ontario, Canada; the 3Department of Internal Medicine, Dr. Josep Trueta Hospital, using SPSS 12.0 software. The study was Girona, Spain; the 4Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon; the powered to detect significant changes in 5Endocrine Laboratory, University Clinical Hospital, Barcelona, Spain; and the 6Lucile Packard Foundation serum IGFBP-rP1 of at least 1 SD (paired- for Children’s Health, Palo Alto, California. samples t test) following phlebotomy. Address correspondence and reprint requests to Abel Lo´pez-Bermejo, Dr. Josep Trueta Hospital, Av. Francia s/n, 17007 Girona, Spain. E-mail: [email protected]. The experimental protocol was ap- Received for publication 12 September 2006 and accepted in revised form 15 February 2007. proved by the ethics committee of the Hos- Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-1905. pital of Girona. Informed written consent Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ was obtained from the study subjects. dc06-1905. R.G.R. has received honoraria from Genentech, Lilly, Tercica, Novo, and Pfizer. Abbreviations: EDV, endothelium-dependent vasodilation; EIV, endothelial-independent vasodilation; RESULTS — At baseline, circulating IGFBP-rP1, insulin-like growth factor binding protein–related protein 1. IGFBP-rP1 was directly correlated with A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion EDV (r ϭ 0.48, P ϭ 0.018) but not with factors for many substances. EIV (r ϭϪ0.08, P ϭ NS) in high-ferritin © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby type 2 diabetic subjects studied as a single marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. group. IGFBP-rP1 was also correlated
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1615 IGFBP-rP1 and vascular reactivity with BMI (r ϭ 0.57, P ϭ 0.003) and met- artery diameter, smoking, BMI, C- hemoglobin on the vasculature and that abolic parameters (C-peptide [r ϭ 0.58, peptide, insulin sensitivity, A1C, hemo- increased IGFBP-rP1, in turn, may con- ϭ ϭϪ ϭ P 0.004] and KITT [r 0.46, P globin, or ferritin). Multivariate analyses tribute to improve EDV after bloodletting. 0.034] but not A1C [r ϭ 0.03, P ϭ NS]) in documented also independent associa- Further research will determine whether these subjects. tions between the changes in IGFBP-rP1 there is a role for IGFBP-rP1 in the vascu- As expected, bloodletting caused sig- and those in hemoglobin and EDV on fol- lar dysfunction of type 2 diabetes. nificant reductions in hemoglobin, fer- low-up (data not shown). ritin, and transferrin saturation index in the intervention group (P Ͻ 0.05 to P Ͻ CONCLUSIONS — Our results sug- Acknowledgments— This study was sup- 0.001). In parallel, both serum IGFBP- gest for the first time that circulating IG- ported by grants PI041407 (to A.L.-B.) and rP1 and EIV significantly increased in the FBP-rP1 is related to vascular function in BFU2004-03654/BFI and CB06/03/0010 (to intervention group but not in the obser- high-ferritin type 2 diabetic patients. J.M.F.-R.). A.L.-B. is a research investigator of Ͻ Ͻ the Fund for Scientific Research “Ramon y Ca- vation group (P 0.05 and P 0.01, Bloodletting is associated with improved jal,” Spain. respectively; online appendix Table 2). vasomotor responses (3) and with posi- Figure 1 depicts significant differences in tive changes in circulating IGFBP-rP1. the absolute changes at 4 months for he- Our data concur with previous re- moglobin, IGFBP-rP1, and both EDV and ports showing stimulatory effects of IG- References 1. Feener EP, King GL: Vascular dysfunction EIV between the two randomization FBP-rP1 on prostacyclin synthesis (7) and Ͻ ϭ in diabetes mellitus. Lancet 350 (Suppl. groups (P 0.05 to P 0.001). Of note, on blood flow in the rat retina (14) and 1):SI9–SI13, 1997 the changes in IGFBP-rP1 correlated with suggest that factors associated with endo- 2. Schalkwijk CG, Stehouwer CD: Vascular those of hemoglobin (r ϭϪ0.59, P ϭ thelial stress, namely obesity and blood complications in diabetes mellitus: the 0.009) and of EDV (r ϭ 0.58, P ϭ 0.005) hemoglobin, are possible regulators of the role of endothelial dysfunction. Clin Sci at follow-up. serum levels of IGFBP-rP1 in high-ferritin (Lond) 109:143–159, 2005 The novel association between hemo- type 2 diabetic subjects (2,18). While it is 3. Fernandez-Real JM, Penarroja G, Castro globin and IGFBP-rP1 was also docu- well known that cell-free hemoglobin acts A, Garcia-Bragado F, Lopez-Bermejo A, mented for baseline values in these as a nitric oxide scavenger (19,20), the Ricart W: Blood letting in high-ferritin subjects (r ϭ 0.61, P ϭ 0.002), as well as role of cell-associated hemoglobin (i.e., type 2 diabetes: effects on vascular reac- tivity. Diabetes Care 25:2249–2255, 2002 in a cross-sectional analysis of a sample of that carried by erythrocytes) is more com- 4. Pieper GM, Siebeneich W: Diabetes-in- nondiabetic men previously reported by plex, as it may act as a nitric oxide gener- duced endothelial dysfunction is pre- us (n ϭ 113; r ϭ 0.28, P ϭ 0.003 [17]). ator by virtue of its nitrite reductase vented by long-term treatment with the On multiple regression analyses, both activity (21). The current clinical evi- modified iron chelator, hydroxyethyl BMI (ϭ0.47, P ϭ 0.01) and hemoglo- dence, however, is supportive of a delete- starch conjugated-deferoxamine. J Car- bin (ϭ0.40, P ϭ 0.03), but not other rious effect on vascular function also for diovasc Pharmacol 30:734–738, 1997 metabolic parameters or ferritin, were in- cell-associated hemoglobin (22,23). 5. Nitenberg A, Paycha F, Ledoux S, Sachs R, dependently associated with baseline se- Given the cross-sectional nature of Attali JR, Valensi P: Coronary artery re- rum IGFBP-rP1, explaining 34 and 12% our study, we cannot establish a cause- sponses to physiological stimuli are im- of its variance, respectively. Only age effect relationship in the sequence of proved by deferoxamine but not by L-arginine in non-insulin-dependent dia- (ϭϪ0.51, P ϭ 0.004) and IGFBP-rP1 events that follow bloodletting in high- ϭ ϭ betic patients with angiographically nor- ( 0.51, P 0.004) were significantly ferritin type 2 diabetic patients, but it is mal coronary arteries and no other risk associated with baseline EDV, explaining herein suggested that phlebotomy causes factors. Circulation 97:736–743, 1998 24 and 20% of its variance, respectively, increases in circulating IGFBP-rP1 by al- 6. Ono Y, Hashimoto T, Umeda F, Masakado after adjusting for effect modifiers (basal leviating the deleterious effects of blood M, Yamauchi T, Mizushima S, Isaji M, Na- wata H: Expression of prostacyclin-stim- ulating factor, a novel protein, in tissues of Wistar rats and in cultured cells. Biochem Biophys Res Commun 202:1490–1496, 1994 7. Yamauchi T, Umeda F, Masakado M, Isaji M, Mizushima S, Nawata H: Purification and molecular cloning of prostacyclin- stimulating factor from serum-free condi- tioned medium of human diploid fibroblast cells. Biochem J 303:591–598, 1994 8. Swisshelm K, Ryan K, Tsuchiya K, Sager R: Enhanced expression of an insulin growth factor-like binding protein (mac25) in senescent human mammary epithelial Figure 1— Changes in hemoglobin (Hb), IGFBP-rP1, EDV, and EIV from baseline following 4 cells and induced expression with retinoic months of bloodletting (f; intervention, n ϭ 10) or no treatment ( ; observation, n ϭ 12). (In the acid. Proc Natl Acad SciUSA92:4472– observation group, two outlier subjects with significant decreases in hemoglobin values were not 4476, 1995 included in the analysis; thus, the resulting n for this group was 12.) Changes are expressed as SD 9. Sprenger CC, Damon SE, Hwa V, Rosen- scores (SDS), calculated by dividing the absolute changes during the 4 months by the correspond- feld RG, Plymate SR: Insulin-like growth ing baseline SD in the study subjects. Plots represent means Ϯ 95% CI. *P Ͻ 0.05, **P Ͻ 0.01, factor binding protein-related protein 1 ***P Ͻ 0.001. (IGFBP-rP1) is a potential tumor suppres-
1616 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Lo´pez-Bermejo and Associates
sor protein for prostate cancer. Cancer Res 3408, 2003 gel DJ, Stamler JS: The oxyhemoglobin re- 59:2370–2375, 1999 14. Hata Y, Clermont A, Yamauchi T, Pierce action of nitric oxide. Proc Natl Acad Sci U 10. Burger AM, Leyland-Jones B, Banerjee K, EA, Suzuma I, Kagokawa H, Yoshikawa SA96:9027–9032, 1999 Spyropoulos DD, Seth AK: Essential roles H, Robinson GS, Ishibashi T, Hashimoto 19. Rother RP, Bell L, Hillmen P, Gladwin of IGFBP-3 and IGFBP-rP1 in breast can- T, Umeda F, Bursell SE, Aiello LP: Retinal MT: The clinical sequelae of intravascular cer. Eur J Cancer 41:1515–1527, 2005 expression, regulation, and functional hemolysis and extracellular plasma he- 11. St Croix B, Rago C, Velculescu V, Tra- bioactivity of prostacyclin-stimulating moglobin: a novel mechanism of human verso G, Romans KE, Montgomery E, Lal factor. J Clin Invest 106:541–550, 2000 disease. JAMA 293:1653–1662, 2005 A, Riggins GJ, Lengauer C, Vogelstein B, 15. Fernandez-Real JM, Penarroja G, Castro 20. Faivre-Fiorina B, Caron A, Fassot C, Fries Kinzler KW: Genes expressed in human A, Garcia-Bragado F, Hernandez-Aguado I, Menu P, Labrude P, Vigneron C: Pres- tumor endothelium. Science 289:1197– I, Ricart W: Blood letting in high-ferritin ence of hemoglobin inside aortic endo- 1202, 2000 type 2 diabetes: effects on insulin sensitiv- thelial cells after cell-free hemoglobin 12. Akaogi K, Okabe Y, Sato J, Nagashima Y, ity and beta-cell function. Diabetes 51: administration in guinea pigs. Am J Physiol Yasumitsu H, Sugahara K, Miyazaki K: 1000–1004, 2002 276:H766–H770, 1999 Specific accumulation of tumor-derived 16. Celermajer DS, Sorensen KE, Gooch VM, 21. Kim-Shapiro DB, Schechter AN, Gladwin adhesion factor in tumor blood vessels Spiegelhalter DJ, Miller OI, Sullivan ID, MT: Unraveling the reactions of nitric ox- and in capillary tube-like structures of Lloyd JK, Deanfield JE: Non-invasive de- ide, nitrite, and hemoglobin in physiology cultured vascular endothelial cells. Proc tection of endothelial dysfunction in chil- and therapeutics. Arterioscler Thromb Vasc Natl Acad Sci U S A 93:8384–8389, 1996 dren and adults at risk of atherosclerosis. Biol 26:697–705, 2006 13. Lopez-Bermejo A, Khosravi J, Corless Lancet 340:1111–1115, 1992 22. Natali A, Toschi E, Baldeweg S, Casolaro CL, Krishna RG, Diamandi A, Bodani U, 17. Lopez-Bermejo A, Khosravi J, Fernandez- A, Baldi S, Sironi AM, Yudkin JS, Ferran- Kofoed EM, Graham DL, Hwa V, Rosen- Real JM, Hwa V, Pratt KL, Casamitjana R, nini E: Haematocrit, type 2 diabetes, and feld RG: Generation of anti-insulin-like Garcia-Gil MM, Rosenfeld RG, Ricart W: endothelium-dependent vasodilatation of growth factor-binding protein-related Insulin resistance is associated with in- resistance vessels. Eur Heart J 26:464– protein 1 (IGFBP-rP1/MAC25) monoclo- creased serum concentration of IGF- 471, 2005 nal antibodies and immunoassay: quanti- binding protein-related protein 1 (IGFBP- 23. Madsen PL, Scheuermann Freestone M, fication of IGFBP-rP1 in human serum rP1/MAC25). Diabetes 55:2333–2339, Neubauer S, Channon K, Clarke K: Hae- and distribution in human fluids and tis- 2006 moglobin and flow-mediated vasodila- sues. J Clin Endocrinol Metab 88:3401– 18. Gow AJ, Luchsinger BP, Pawloski JR, Sin- tion. Clin Sci (Lond) 110:467–473, 2006
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1617 Cardiovascular and Metabolic Risk BRIEF REPORT
Leisure-Time Physical Activity Is Associated With the Metabolic Syndrome in Type 1 Diabetes Effect of the PPAR␥ Pro12Ala polymorphism: the FinnDiane Study
1,2 1,2,5 JOHAN WADEN´ , MD MAIJA WESSMAN, PHD was studied from 840 of the 1,028 pa- 1,2 1,2 LENA M. THORN, MD JONI A. TURUNEN, MD tients using an ABI Prism 7900 Se- 1,2 1,2 CAROL FORSBLOM, MD, DMSC MAIJA PARKKONEN, BSC 3,4 1,6 quence Detection System (Applied TIMO LAKKA, MD, DMSC HEIKKI TIKKANEN, MD, DMSC 1,2 1,2 Biosystems, Foster City, CA). MARKKU SARAHEIMO, MD PER-HENRIK GROOP, MD, DMSC 1,2 MILLA ROSENGÅRD-B¨ARLUND, MD ON BEHALF OF THE FINNDIANE STUDY 1,2 OUTI HEIKKILA¨, MD GROUP RESULTS — The mean Ϯ SD age was 36.4 Ϯ 11.5 years, duration of diabetes 21.3 Ϯ 11.7 years, A1C 8.4 Ϯ 1.4%, BMI he metabolic syndrome varies in Therefore, to further study the meta- 25.0 Ϯ 3.3 kg/m2, and 47% of patients prevalence among different popula- bolic syndrome in type 1 diabetes, we in- were men. Median (interquartile range) T tions. A common feature, however, vestigated whether physical activity LTPA was 19.7 (10.0–34.1) MET h/week. is a steep increase in prevalence along and/or the PPAR␥ Pro12Ala polymor- The prevalence of metabolic syndrome with a decrease in glucose tolerance (1–2). phism are associated with metabolic syn- was 29.5% (ratio of men to women 27.8: We have shown that 39% of adult drome in patients with type 1 diabetes in 31.0%, P ϭ 0.269); 31.8% had the Ala- type 1 diabetic patients have the meta- the Finnish Diabetic Nephropathy allele for PPAR␥ Pro12Ala (2.6% were bolic syndrome (3), and similar data were (FinnDiane) Study. homozygous). According to genotype, recently reported from Italy (4). How- there were no differences in BMI, waist- ever, whether the metabolic syndrome RESEARCH DESIGN AND to-hip ratio, lipid profile or, A1C (data not observed in type 1 diabetes is the same as METHODS — Using a cross-sectional shown). in nondiabetic and type 2 diabetic pa- study design, 1,028 type 1 diabetic pa- The prevalence of metabolic syn- tients is unclear. tients from the FinnDiane Study (3,14) drome did not differ by genotype Both lifestyle (5–8) and hereditary with data on leisure-time physical activity (Pro12Pro 30.4%, Pro12Ala 30.6%, factors (9) seem to be involved in the de- (LTPA) and metabolic syndrome were Ala12Ala 36.4%; P ϭ 0.836). LTPA in velopment of the metabolic syndrome in studied. Patients with end-stage renal dis- the presence versus absence of meta- nondiabetic and type 2 diabetic subjects. ease and/or cardiovascular events were bolic syndrome was 17.0 (8.6–31.6) vs. The PPAR␥ (peroxisome proliferator- excluded. 20.8 (10.8–34.7) MET h/week (age- activated receptor ␥) Pro12Ala polymor- Metabolic syndrome was defined adjusted P ϭ 0.038). Table 1 shows the phism has been associated with type 2 according to the NCEP/ATP III (Na- prevalences of the metabolic syndrome diabetes, the Ala allele being associated tional Cholesterol Education Program/ and its individual components accord- with a lower risk (10), and with the met- Adult Treatment Panel III) criteria (15). ing to LTPA and PPAR␥ genotype. abolic syndrome in some (11–12) but not LTPA (as MET h/week) was assessed by Among patients reporting LTPA of all (13) studies. However, whether life- a validated 12-month questionnaire low, moderate, or high intensity, 39.0, style or genetic factors also play a role in (16), and patients were grouped as sed- 28.3, and 23.2% (age-adjusted P ϭ the development and treatment of the entary, moderately active, or active as 0.008) had metabolic syndrome, re- metabolic syndrome in patients with type previously described (14). The PPAR␥ spectively. Regarding frequency of 1 diabetes is unknown. Pro12Ala (rs1801282) polymorphism LTPA, corresponding prevalences for ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Ͻ1, 1–2, or Ն3 sessions/week were From the 1Folkha¨lsan Institute of Genetics, Folkha¨lsan Research Center, Helsinki, Finland; the 2Division of 33.0, 29.9, and 27.7% (age-adjusted Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; the 3Depart- ϭ 4 P 0.325), respectively. ment of Physiology, Institute of Biomedicine, University of Kuopio; Kuopio Research Institute of Exercise In a multiple logistic regression Medicine, Kuopio, Finland; the 5Finnish Genome Center, University of Helsinki, Finland; and the 6Unit for Sports and Exercise Medicine, Institute of Clinical Medicine, University of Helsinki, Finland. model, LTPA as a log-transformed contin- Address correspondence and reprint requests to Per-Henrik Groop, Biomedicum Helsinki, POB 63, uous variable (odds ratio [OR] 0.73 [95% 00014 University of Helsinki, Finland. E-mail: per-henrik.groop@helsinki.fi. CI 0.58–0.92]) and laser-treated retinop- Received for publication 4 December 2006 and accepted in revised form 28 February 2007. athy (1.97 [1.19–3.27]) were indepen- Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2467. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ dently associated with the metabolic dc06-2467. syndrome. The model also included Abbreviations: FinnDiane, Finnish Diabetic Nephropathy; LTPA, leisure-time physical activity. PPAR␥ Pro12Pro genotype (0.99 [0.62– A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 1.58]), weekly doses (12 g/dose) of alco- factors for many substances. hol (1.26 [0.98–1.60]), male sex (0.98 © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby [0.62–1.56]), age (1.01 [0.99–1.03]), marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. low social class (1.09 [0.69–1.72]),
1618 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Wade´n and Associates
Table 1—Proportion of type 1 diabetic patients with the metabolic syndrome and its individual components* according to level of LTPA and genotype for PPAR␥ Pro12Ala
Sedentary Moderately active Active P† P‡ n 254 588 186 — — Metabolic syndrome (all) 35.0 28.4 25.3 0.058 0.021 Pro12Pro 33.6 29.4 28.6 0.600 0.358 Ala carrier 43.8 29.6 18.2 0.015 0.004 Individual components — — — — — Waist (all) 21.7 14.6 11.8 0.009 0.004 Pro12Pro 19.1 14.2 12.4 0.266 0.121 Ala carrier 29.7 15.1 6.8 0.004 0.001 Triglycerides (all) 16.1 12.6 11.3 0.259 0.120 Pro12Pro 15.1 13.0 13.3 0.813 — Ala carrier 15.6 9.4 2.3 0.070 0.021 HDL-cholesterol (all) 26.8 25.0 25.3 0.861 — Pro12Pro 28.9 27.2 27.6 0.926 — Ala carrier 31.3 24.5 27.3 0.586 — Hypertension (all) 66.5 60.2 60.8 0.209 — Pro12Pro 66.4 61.1 57.1 0.297 0.122 Ala carrier 73.4 59.1 65.9 0.125 — Data are percentages unless otherwise indicated. Ala carriers: Pro12Ala or Ala12Ala genotype. Patients: all, n ϭ 1028; Pro12Pro, n ϭ 573; Ala carrier, n ϭ 267. *According to the NCEP ATP III (National Cholesterol Education Program/Adult Treatment Panel III) criteria: waist circumference Ͼ102 cm (men), Ͼ88 cm (women); triglycerides Ն1.70 mmol/l; HDL cholesterol Ͻ1.00 mmol/l (men), Ͻ1.30 mmol/l (women); and blood pressure Ն130/85 mmHg or antihypertensive medication. All patients fulfilled the criteria for fasting blood glucose Ն6.11 mmol/l. A minimum of three criteria were requested for diagnosis of the metabolic syndrome. †2 test; ‡2 test for trend. smoking (0.76 [0.45–1.30]), and diabetic sures (18–19) in healthy individuals and assistance of Anna Sandelin, Sinikka Lindh, nephropathy (1.84 [0.92–3.68]). reduction in fasting plasma glucose in and Susanne Stro¨m is gratefully acknowl- type 2 diabetic patients (20). In the Finn- edged. Finally, we acknowledge physicians CONCLUSIONS — Low LTPA was ish Diabetes Prevention Study, a paradox- and nurses at each study center, presented in associated with a higher prevalence of the ical diabetogenic effect of the Ala allele in an online appendix (available at http:// dx.doi.org/10.2337/dc06-2467). metabolic syndrome, supporting our pre- subjects with impaired glucose tolerance vious findings on LTPA and insulin sen- was eliminated by lifestyle intervention sitivity in type 1 diabetes (14). Due to the (21). cross-sectional study design, LTPA could Based on our study and the findings References 1. Isomaa B, Almgren P, Tuomi T, Forse´n B, have been reduced by exercise-limiting of the Finnish Diabetes Prevention Lahti K, Nissen M, Taskinen MR, Groop factors associated with the metabolic syn- Study, the Ala allele might be viewed as L: Cardiovascular morbidity and mortal- drome. However, the likelihood of com- not exclusively beneficial for insulin ity associated with the metabolic syn- plication-derived physical activity bias sensitivity and glucose homeostasis be- drome. Diabetes Care 24:683–689, 2001 was reduced by controlling for diabetes cause the Ala allele, when combined 2. Ilanne-Parikka P, Eriksson JG, Lindstro¨m complications. with low physical activity, may on the J, Ha¨ma¨lainen H, Keina¨nen-Kiukaanni- The PPAR␥ Pro12Ala polymor- contrary be detrimental. In our study, emi S, Laakso M, Louheranta A, Mannelin phism was not associated with the met- sedentary Ala carriers more frequently M, Rastas M, Salminen V, Aunola S, Sund- abolic syndrome. Patients with the Ala had metabolic syndrome than sedentary vall J, Valle T, Lahtela J, Uusitupa M, allele, however, had a 2.4-fold higher patients with Pro12Pro genotype. Thus, Tuomilehto J, the Finnish Diabetes Pre- ␥ vention Study Group: Prevalence of the prevalence of the metabolic syndrome PPAR Pro12Ala may be a true exercise- metabolic syndrome and its components: when sedentary patients were com- response gene variant working in both findings from a Finnish general popula- pared with those who were physically directions, promoting insulin sensitiv- tion sample and the Diabetes Prevention active, while in patients with the ity in those who are physically active Study cohort. Diabetes Care 27:2135– Pro12Pro genotype, LTPA did not affect while impeding sensitivity in sedentary 2140, 2004 the prevalence of the metabolic syn- subjects. 3. Thorn LM, Forsblom C, Fagerudd J, drome. Of individual criteria, waist cir- Thomas MC, Pettersson-Fernholm K, cumference seemed important for this Saraheimo M, Wade´n J, Ro¨nnback M, genotype-dependent association, favor- Acknowledgments— This study was sup- Rosengård-Ba¨rlund M, Bjo¨rkesten CG, ing a pivotal role of insulin sensitivity, ported by the Folkha¨lsan Research Founda- Taskinen MR, Groop PH, the FinnDiane tion, Samfundet Folkha¨lsan, Wilhelm och Else Study Group: Metabolic syndrome in the key factor in the metabolic syn- Stockmann Foundation, Sigrid Juselius Foun- type 1 diabetes: association with dia- drome (17). dation, Waldemar von Frenckell Foundation, betic nephropathy and glycemic control Interestingly, the Ala allele has been Liv och Ha¨lsa Foundation, the Academy of (the FinnDiane study). Diabetes Care associated with greater exercise-induced Finland (no. 214335), and the European 28:2019–2024, 2005 improvement of insulin sensitivity mea- Commission (QLG2-CT-2001-01669). The 4. The Metascreen Writing Committee:
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1619 LTPA and metabolic syndrome in type 1 diabetes
The metabolic syndrome is a risk indi- longeville J: Association between peroxi- tance: a multifaceted syndrome responsible cator of microvascular and macrovascu- some proliferator-activated receptor ␥ for NIDDM, obesity, hypertension, dyslipi- lar complications in diabetes: results haplotypes and the metabolic syndrome demia, and atherosclerotic cardiovascular from Metascreen, a multicenter diabetes in French men and women. Diabetes 54: disease. Diabetes Care 14:173–194, 1991 clinic–based survey. Diabetes Care 29: 3043–3048, 2005 18. Kahara T, Takamura T, Hayakawa T, Na- 2701–2707, 2006 12. Frederiksen L, Brodbaek K, Fenger M, gai Y, Yamaguchi H, Katsuki T, Katsuki K, 5. Eriksson J, Taimela S, Koivisto VA: Exer- Jorgensen T, Borch-Johnsen K, Madsbad Katsuki M, Kobayashi K: PPARgamma cise and the metabolic syndrome. Diabe- S, Urhammer SA: Studies of the Pro12Ala gene polymorphism is associated with ex- tologia 40:125–135, 1997 polymorphism of the PPAR-gamma gene ercise-mediated changes of insulin resis- 6. Lakka TA, Laaksonen DE, Lakka HM, in the Danish MONICA cohort: homozy- tance in healthy men. Metabolism 52:209– Ma¨nnikko¨ N, Niskanen LK, Rauramaa R, gosity of the Ala allele confers a decreased 212, 2003 Salonen JT: Sedentary lifestyle, poor car- risk of the insulin resistance syndrome. 19. Weiss EP, Kulaputana O, Ghiu IA, Brand- diorespiratory fitness, and the metabolic J Clin Endocrinol Metab 87:3989–3992, syndrome. Med Sci Sports Exerc 35:1279– 2002 auer J, Wohn CR, Phares DA, Shuldiner 1286, 2003 13. Rhee EJ, Oh KW, Lee WY, Kim SY, Oh ES, AR, Hagberg JM: Endurance training-in- 7. Aude YW, Mego P, Mehta JL: Metabolic Baek KH, Kang MI, Kim SW: Effects of two duced changes in the insulin response to syndrome: dietary interventions. Curr common polymorphisms of peroxisome oral glucose are associated with the per- Opin Cardiol 19:473–479, 2004 proliferator-activated receptor-gamma gene oxisome proliferator-activated receptor- 8. Orchard TJ, Temprosa M, Goldberg R, on metabolic syndrome. Archives of Medical gamma2 Pro12Ala genotype in men but Haffner S, Ratner R, Marcovina S, Fowler Research 37:86–94, 2006 not in women. Metabolism 54:97–102, S, the Diabetes Prevention Program Re- 14. Wade´n J, Tikkanen H, Forsblom C, Fag- 2005 search Group: The effect of metformin erudd J, Pettersson-Fernholm K, Lakka T, 20. Adamo KB, Sigal RJ, Williams K, Kenny and intensive lifestyle intervention on the Riska M, Groop PH, the FinnDiane Study G, Prud’homme D, Tesson F: Influence metabolic syndrome: the Diabetes Pre- G: Leisure time physical activity is associ- of Pro12Ala peroxisome proliferator- vention Program randomized trial. Ann ated with poor glycemic control in type 1 activated receptor gamma2 polymor- Intern Med 142:611–619, 2005 diabetic women: the FinnDiane study. Di- phism on glucose response to exercise 9. Tang W, Hong Y, Province MA, Rich SS, abetes Care 28:777–782, 2005 training in type 2 diabetes. Diabetologia Hopkins PN, Arnett DK, Pankow JS, 15. Executive summary of the Third Report of 48:1503–1509, 2005 Miller MB, Eckfeldt JH: Familial cluster- the National Cholesterol Education Pro- 21. Lindi VI, Uusitupa MI, Lindstro¨m J, Lou- ing for features of the metabolic syn- gram (NCEP) Expert Panel on Detection, heranta A, Eriksson JG, Valle TT, Ha¨- drome. Diabetes Care 29:631–636, 2006 Evaluation, and Treatment of High Blood ma¨lainen H, Ilanne-Parikka P, Keina¨nen- 10. Altshuler D, Hirschhorn JN, Klannemark Cholesterol In Adults (Adult Treatment Kiukaanniemi S, Laakso M, Tuomilehto J, M, Lindgren CM, Vohl MC, Nemesh J, Panel III). JAMA 285:2486–2497, 2001 Lane CR, Schaffner SF, Bolk S, Brewer C, 16. Salonen JT, Lakka TA: Assessment of the Finnish Diabetes Prevention Study: Association of the Pro12Ala polymor- Tuomi T, Gaudet D, Hudson TJ, Daly M, physical activity in population studies: ␥ Groop L, Lander ES: The common PPAR- validity and consistency of the methods in phism in the PPAR- 2 gene with 3-year gamma Pro12Ala polymorphism is asso- the Kuopio Ishemic Heart Disease Risk incidence of type 2 diabetes and body ciated with decreased risk of type 2 Factor Study. Scand J Sports Sci 9:89–95, weight change in the Finnish Diabetes diabetes. Nat Genet 26:76–80, 2000 1987 Prevention Study. Diabetes 51:2581– 11. Meirhaeghe A, Cottel D, Amouyel P, Dal- 17. DeFronzo RA, Ferrannini E: Insulin resis- 2586, 2002
1620 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk BRIEF REPORT
Additive Effects of Obesity and TCF7L2 Variants on Risk for Type 2 Diabetes Among Cardiac Patients
1,2 3 QING LING DUAN. BSC PIERRE THEROUX´ , MD equipped with sequence detector soft- 3 1 MARIE-PIERRE DUBE´, PHD JUDITH ST-ONGE, DEC ware (SDS 2.2.2.). 4,5,6,7 1 NANCY FRASURE-SMITH, PHD GUY A. ROULEAU, MD, PHD, FRCP(C) 3 8 AMINA BARHDADI, PHD JEANNE M. MCCAFFERY, PHD 4,5,6,7 Statistical analysis FRANC¸ OIS LESPERANCE, MD Markers were tested for Hardy-Weinberg equilibrium by using the exact test (22). Three genetic models were used for case- microsatellite marker, DG10S478, in included. All participants were identified control association testing: the 2 geno- the transcription factor 7-like 2 between November 1998 and April 2002 at type test, the 2 allele test, and the A (TCF7L2) gene was previously asso- the Montreal Heart Institute and Hoˆpital Cochran-Armitage trend test on geno- ciated with type 2 diabetes in three Cauca- Sacre´-Coeur and gave written informed types, which tests for additive allele ef- sian populations (1). This association consent. Protocols were approved by the fects on disease risk. To obtain exact P followed earlier reports by the same group ethics committees at both institutions. value estimates, 100,000 Monte Carlo (2) and a separate team (3), which showed Type 2 diabetes was defined as the permutations were performed. Mantel- suggestive linkage to chromosomal 10q. use of diabetes medications or fasting Haenszel statistics were used for stratified Grant et al. (1) demonstrated that allele X (a blood glucose Ͼ126 mg/dl (7.0 mmol/l). analyses by obesity. Two-sided P values composite of all but the shortest allele) of BMI was calculated as the weight in kilo- are reported. Genotype by obesity inter- DG10S478 conferred an increased risk for grams divided by the square of height in action was evaluated by testing the signif- type 2 diabetes of 45 and 141% among het- meters. Obesity was defined as BMI Ն30 icance of the interaction term in a full 2 erozygotes and homozygotes, respectively. kg/m . logistic regression model with additive Since this report, numerous groups have genetic effects modeled as Ϫ1 (G/G), 0 replicated the association in various popu- Genotyping (G/T), and 1 (T/T) for the three genotype lations and extended it to include two in- DNA extraction from blood used a stan- categories. The association between tronic single nucleotide polymorphisms dard protocol (Gentra Systems). rs12255372 and BMI was measured using (rs12255372 and rs7903146) (4–20). In DG10S478 was genotyped by radiola- a genotype trend genetic model for an ad- 35 this study, we investigated the combined ef- beled (␣- S-dATP) PCR using a standard ditive allelic effect captured by a regres- fect of obesity and genotype at DG10S478 protocol and primers designed from the sion model for BMI. The model was built and rs12255372 in predicting type 2 diabe- genomic sequence of human TCF7L2 using the GLM procedure in SAS, which tes risk in a sample of French Canadian car- (NM_030756; http://www.ncbi.nlm.nih. gives a Fisher’s ANOVA and Student’s t diac patients. gov/). Products were separated by electro- test for regression coefficients. All data phoresis on 6% denaturing polyacrylamide were analyzed using SAS version 9.1.3 RESEARCH DESIGN AND gels. Allele sizes and frequencies were ob- and SAS/Genetics (SAS Institute, Cary, METHODS — Patients of French Ca- tained from the Centre d’Etude du Poly- NC). nadian descent with established coronary morphisme Humaine (CEPH) database artery disease recruited in two earlier (http://www.cephb.fr). Genotyping of RESULTS — In contrast to nondia- ϭ studies, Polymorphisme (n 484) and the rs12255372 used TaqMan assays de- betic patients, those with diabetes were Epidemiological Study of Acute Coronary signed by Applied Biosystems. Products significantly older, had fewer years of ed- Syndromes and the Pathophysiology of were analyzed with a spectrophotometer ucation, were more obese with signifi- ϭ Emotions (ESCAPE; n 596) (21), were (Applied Biosystems, Foster City, CA) cantly higher BMI, had greater systolic ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● blood pressure, and were more likely to From the 1Department of Medicine, Universite´ de Montre´al and Centre Hospitalier de l’Universite´de have undergone coronary artery bypass Montre´al, Montre´al, Canada; the 2Department of Human Genetics, McGill University, Montre´al, Canada; the surgery (P Ͻ 0.05). 3Montreal Heart Institute and Department of Medicine, Universite´ de Montre´al, Montre´al, Canada; the 4Department of Psychiatry and School of Nursing, McGill University, Montre´al, Canada; the 5Research Center, Montreal Heart Institute, Montre´al, Canada; the 6Department of Psychiatry, Universite´ de Montre´al, Genetic association tests Montre´al, Canada; the 7Research Center, Centre Hospitalier de l’Universite´ de Montre´al, Montre´al, Canada; Of the total population, 1,037 (96.2%) and the 8Weight Control and Diabetes Research Center, Brown Medical School and The Miriam Hospital, were successfully genotyped for Providence, Rhode Island. DG10S478 and 1,004 (93.1%) for Address correspondence and reprint requests to Jeanne M. McCaffery, PhD, Weight Control and Diabetes rs12255372. Both markers were in Research Center, 196 Richmond St., Providence, RI 02903. E-mail: [email protected]. ϭ Received for publication 7 November 2006 and accepted in revised form 28 February 2007. Hardy-Weinberg equillibrium (P Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2421. 0.9731 and 0.8557, respectively) and in A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion strong linkage disequilibrium (DЈϭ factors for many substances. 0.977 and r2 ϭ 0.970). Using the nomen- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby clature of Grant et al. (1), allele 0 of marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DG10S478 was the smallest, most fre-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1621 TCF7L2 is a risk for type 2 diabetes
Table 1—Rate of type 2 diabetes and odds ratios for each genotype stratified by obesity with corresponding genetic association test results
DG10S478 0/0 0/X X/X Allele test (P*) Genotype test (P*) Trend test (P*) All Diabetes 86 (17.6) 110 (25.1) 33 (30.0) 0.00057 0.00233 0.00057 No diabetes 402 (82.4) 329 (74.9) 77 (70.0) Nonobese Diabetes 43 (13.5) 61 (19.6) 24 (28.6) 0.0008 0.00296 0.0008 No diabetes 276 (86.5) 250 (80.4) 60 (71.4) Obese Diabetes 43 (25.4) 49 (38.3) 9 (34.6) 0.04858 0.0568 0.04858 No diabetes 126 (74.6) 79 (61.7) 17 (65.4) Mantel-Haenszel† Ͻ0.0001 0.0005 Odds ratio Nonobese 1 1.57 (1.02–2.40) 2.57 (1.45–4.55) Obese 2.19 (1.37–3.15) 3.98 (2.46–6.43) 3.39 (1.42–8.10) rs12255372 G/G G/T T/T Allele test (P*) Genotype test (P*) Trend test (P*)
All Diabetes 80 (17.2) 104 (23.9) 35 (34.0) 0.00009 0.00038 0.00009 No diabetes 386 (82.8) 331 (76.1) 68 (66.0) Nonobese Diabetes 38 (12.8) 58 (18.8) 24 (31.2) 0.00029 0.00079 0.00029 No diabetes 260 (87.2) 250 (81.2) 53 (68.8) Obese Diabetes 53 (29.6) 46 (36.2) 11 (42.3) 0.01824 0.04772 0.01824 No diabetes 126 (70.4) 81 (63.8) 15 (57.7) Mantel-Haenszel† Ͻ0.0001 0.0002 Odds ratio Nonobese 1 1.59 (1.02–2.48) 3.10 (1.72–5.59) Obese 2.28 (1.4–3.71) 3.88 (2.36–6.38) 5.02 (2.15–11.73) Data are n (%) or odds ratio (95% CI) unless otherwise noted. *100,000 Monte Carlo permutations were performed to obtain exact P value estimates. †Adjusted for stratification by obesity. quent (68.2%), and was strongly associ- risk allele. Within each genotype group, 2 diabetes. A recent study by the DE- ated with allele G of rs12255372. All obesity was strongly associated with an CODE (Diabetes Epidemiology: Collabo- other alleles (X) of DG10S478 (31.8%) increased risk of diabetes (P Ͻ 0.001). rative Analysis of Diagnostic Criteria in were strongly correlated with allele T of The regression model also showed an as- Europe) study group proposed that a sec- rs12255372. sociation between rs12255372 and BMI ond single nucleotide polymorphism, The rate of diabetes increased with an (P ϭ 0.0481) with a decrease of BMI to- rs7903146, correlated with DG10S478 increasing dose of allele X of DG10S478 ward the T/T genotype. This association and rs12255372 and may be the risk vari- or allele T of s12255372 and among was not detected using a dominant ge- ant or its closest known correlate (4). obese compared with nonobese partici- netic model. However, previous studies (1,10) showed pants (Table 1). The association was con- that none of these associated polymor- sistent for both groups but stronger in phisms explain the linkage of type 2 dia- nonobese coronary artery disease pa- CONCLUSIONS — Our study con- betes to this chromosome 10q region, tients. Also, rs12255372 was more closely firms that polymorphisms in TCF7L2 suggesting that another variant(s) nearby associated with type 2 diabetes, which (P Ͻ 0.0001) and obesity (P Ͻ 0.001) are accounts for this linkage, which may be may simply reflect the relative instability both associated with an increased risk for functional. Screening mRNA of TCF7L2 of the microsatellite. type 2 diabetes in our French Canadian might reveal splice variants or alternative Logistic regression modeling showed sample of cardiac patients. We observed exons that were undetected by screening that the interaction between obesity and that the genetic association was stronger the genomic DNA. genotype did not approach statistical sig- in nonobese patients and that genotype nificance (P Ͼ 0.34). Table 1 depicts the T/T at rs12255372 was associated with ϭ joint effects of these risk factors for type 2 reduced BMI (P 0.0481), confirming Acknowledgments— This work was funded diabetes using the nonobese group with- previous reports (4,10). Furthermore, we by the National Institutes of Health (Grant out a risk allele as the reference sample. did not detect an interaction between HL077442 to J.M.M.). Q.L.D. is funded by the The highest risk was observed among obesity and genotype, suggesting that Heart and Stroke Foundation of Canada. obese individuals who carried at least one these are independent risk factors for type G.A.R. is supported by the Canadian Institutes
1622 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Duan and Associates of Health Research. Collection of data for the polymorphisms and progression to diabe- Haeften TW, Hofker MH, Wijmenga C: ESCAPE study was supported by the Medical tes in the Diabetes Prevention Program. Association of variants of transcription Research Council of Canada and an unre- N Engl J Med 355:241–250, 2006 factor 7-like 2 (TCF7L2) with susceptibil- stricted grant from GlaxoSmithKline (POP- 6. Zhang C, Qi L, Hunter DJ, Meigs JB, Man- ity to type 2 diabetes in the Dutch Breda 37744), the Dana Foundation, the Montreal son JE, van Dam RM, Hu FB: Variant of cohort. Diabetologia 50:59–62, 2007 Heart Institute Research Fund, the Pierre transcription factor 7-like 2 (TCF7L2) 14. Humphries SE, Gable D, Cooper JA, Ire- David Fund, and the Foundation du Centre gene and the risk of type 2 diabetes in land H, Stephens JW, Hurel SJ, Li KW, Hospitalier de l’Universite´ de Montre´al. large cohorts of U.S. women and men. Di- Palmen J, Miller MA, Cappuccio FP, Elke- We would like to thank all the participants abetes 55:2645–2648, 2006 les R, Godsland I, Miller GJ, Talmud PJ: and Dr. Patrick A. Dion for careful review of 7. Groves CJ, Zeggini E, Minton J, Frayling Common variants in the TCF7L2 gene this manuscript. TM, Weedon MN, Rayner NW, Hitman and predisposition to type 2 diabetes in GA, Walker M, Wiltshire S, Hattersley UK European Whites, Indian Asians and AT, McCarthy MI: Association analysis of Afro-Caribbean men and women. J Mol References 6,736 U.K. subjects provides replication Med 84:1–10, 2006 1. Grant SF, Thorleifsson G, Reynisdottir I, and confirms TCF7L2 as a type 2 diabetes 15. Field SF, Howson JM, Smyth DJ, Walker Benediktsson R, Manolescu A, Sainz J, susceptibility gene with a substantial ef- NM, Dunger DB, Todd JA: Analysis of the Helgason A, Stefansson H, Emilsson V, fect on individual risk. Diabetes 55:2640– type 2 diabetes gene, TCF7L2, in 13,795 Helgadottir A, Styrkarsdottir U, Magnus- 2644, 2006 son KP, Walters GB, Palsdottir E, Jonsdot- 8. Scott LJ, Bonnycastle LL, Willer CJ, Sprau type 1 diabetes cases and control subjects. tir T, Gudmundsdottir T, Gylfason A, AG, Jackson AU, Narisu N, Duren WL, Diabetologia 50:212–213, 2007 Saemundsdottir J, Wilensky RL, Reilly Chines PS, Stringham HM, Erdos MR, 16. Chandak GR, Janipalli CS, Bhaskar S, MP, Rader DJ, Bagger Y, Christiansen C, Valle TT, Tuomilehto J, Bergman RN, Kulkarni SR, Mohankrishna P, Hattersley Gudnason V, Sigurdsson G, Thorsteins- Mohlke KL, Collins FS, Boehnke M: Asso- AT, Frayling TM, Yajnik CS: Common dottir U, Gulcher JR, Kong A, Stefansson ciation of transcription factor 7-like 2 variants in the TCF7L2 gene are strongly K: Variant of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in associated with type 2 diabetes mellitus in (TCF7L2) gene confers risk of type 2 dia- a Finnish sample. Diabetes 55:2649– the Indian population. Diabetologia 50: betes. Nat Genet 38:320–323, 2006 2653, 2006 63–67, 2007 2. Reynisdottir I, Thorleifsson G, Benedikts- 9. Damcott CM, Pollin TI, Reinhart LJ, Ott 17. Marzi C, Huth C, Kolz M, Grallert H, son R, Sigurdsson G, Emilsson V, Einars- SH, Shen H, Silver KD, Mitchell BD, Shul- Meisinger C, Wichmann HE, Rathmann dottir AS, Hjorleifsdottir EE, Orlygsdottir diner AR: Polymorphisms in the tran- W, Herder C, Illig T: Variants of the tran- GT, Bjornsdottir GT, Saemundsdottir J, scription factor 7-like 2 (TCF7L2) gene scription factor 7-like 2 gene (TCF7L2) Halldorsson S, Hrafnkelsdottir S, Sigur- are associated with type 2 diabetes in the are strongly associated with type 2 diabe- jonsdottir SB, Steinsdottir S, Martin M, Amish: replication and evidence for a role tes but not with the metabolic syndrome Kochan JP, Rhees BK, Grant SF, Frigge in both insulin secretion and insulin resis- in the MONICA/KORA surveys. Horm ML, Kong A, Gudnason V, Stefansson K, tance. Diabetes 55:2654–2659, 2006 Metab Res 39:46–52, 2007 Gulcher JR: Localization of a susceptibil- 10. Cauchi S, Meyre D, Dina C, Choquet H, 18. 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Saxena R, Gianniny L, Burtt NP, Lyssenko with type 2 diabetes in northern Sweden. 1140, 1999 V, Giuducci C, Sjogren M, Florez JC, Eur J Hum Genet 15:342–346, 2007 4. Helgason A, Palsson S, Thorleifsson G, Almgren P, Isomaa B, Orho-Melander M, 20. Yi F, Brubaker PL, Jin T: TCF-4 mediates Grant SF, Emilsson V, Gunnarsdottir S, Lindblad U, Daly MJ, Tuomi T, Hirsch- cell type-specific regulation of progluca- Adeyemo A, Chen Y, Chen G, Reynisdot- horn JN, Ardlie KG, Groop LC, Altshuler tir I, Benediktsson R, Hinney A, Hansen T, D: Common single nucleotide polymor- gon gene expression by beta-catenin and Andersen G, Borch-Johnsen K, Jorgensen phisms in TCF7L2 are reproducibly asso- glycogen synthase kinase-3beta. J Biol T, Schafer H, Faruque M, Doumatey A, ciated with type 2 diabetes and reduce the Chem 280:1457–1464, 2005 Zhou J, Wilensky RL, Reilly MP, Rader DJ, insulin response to glucose in nondiabetic 21. Lesperance F, Frasure-Smith N, Theroux Bagger Y, Christiansen C, Sigurdsson G, individuals. Diabetes 55:2890–2895, 2006 P, Irwin M: The association between ma- Hebebrand J, Pedersen O, Thorsteinsdot- 12. Weedon MN, McCarthy MI, Hitman G, jor depression and levels of soluble inter- tir U, Gulcher JR, Kong A, Rotimi C, Ste- Walker M, Groves CJ, Zeggini E, Rayner cellular adhesion molecule 1, interleukin-6, fansson K: Refining the impact of TCF7L2 NW, Shields B, Owen KR, Hattersley AT, and C-reactive protein in patients with re- gene variants on type 2 diabetes and Frayling TM: Combining information cent acute coronary syndromes. Am J Psy- adaptive evolution. Nat Genet 2:218–225, from common type 2 diabetes risk poly- chiatry 161:271–277, 2004 2007 morphisms improves disease prediction. 22. Guo SW, Thompson EA: Performing the 5. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1623 Cardiovascular and Metabolic Risk BRIEF REPORT
Metabolic Syndrome in Hypertensive Patients Correlation between anthropometric data and laboratory findings
KELMINDA BULHOES˜ , MD, MSC drome as the presence of three or more of LEILA ARAUJO´ , PHD the following associated conditions: fast- ing glucose Ն110 mg/dl, central obesity (waist circumference Ͼ102 cm for men ardiovascular disease is the princi- rial hypertension diagnosed according to and Ͼ88 cm for women), arterial pres- pal cause of morbidity and mortality the criteria defined by the IV Brazilian sure Ն130/85 mmHg or pharmacologi- in Brazil with a mortality coefficient Guidelines for Arterial Hypertension (5). cally treated hypertension, triglycerides C Ն of 442 per 100,000 inhabitants (1). In Exclusion criteria consisted of secondary 150 mg/dl or current use of fibrates, 90% of the individuals with a diagnosis of hypertension, clinical or laboratory evi- and HDL cholesterol Ͻ40 mg/dl for men arterial hypertension, no causal agent is dence of congestive heart failure, coro- and Ͻ50 mg/dl for women (6). identified; however, current knowledge nary disease, history of cerebral vascular IDF defines metabolic syndrome as tends to suggest the importance of in- accident, valve defect, or diabetes. waist circumference Ն90 cm for men creased BMI (particularly as a result of The following variables were evalu- and Ն80 cm for women, plus at least visceral fat) in the physiopathology of ated: age, sex, BMI, arterial pressure, two of the following factors: arterial this disease. In 1988, Reaven and Hoff- waist circumference, total cholesterol, pressure Ն130/85 mmHg or pharmaco- man (2) identified the following compo- HDL cholesterol, triglycerides, fasting logically treated, triglycerides Ն150 nents of a specific syndrome that would glucose, and glycemic levels 2 h after a mg/dl or current use of fibrates, HDL define increased cardiovascular risk: in- 75-g oral glucose load, fasting insulin, mi- cholesterol Ͻ40 mg/dl for men and sulin resistance, glucose intolerance, hy- croalbuminuria, and insulin resistance in- Ͻ50 mg/dl for women or the use of spe- perinsulinemia, elevated triglycerides, dex as determined by homeostasis model cific pharmacological therapy, and fast- reduced HDL cholesterol, and arterial assessment. Blood pressure was measured ing glucose Ն100 mg/dl or previously hypertension. using a previously calibrated aneroid diagnosed diabetes (7). The prevalence of metabolic syn- sphygmomanometer with a 12 ϫ 23 cm Biochemical evaluation was pre- drome increases substantially with aging, cuff or a 17 ϫ 32 cm cuff in the case of ceded by 3 days of normocaloric diet as does the incidence of diabetes (3). Met- obese patients. Following a 20-min rest with no carbohydrate restrictions and a abolic syndrome is strongly predictive of period, blood pressure was taken with the 12-h fasting period. Total cholesterol, future diabetes (4), and its presence in patient seated, with an empty bladder, HDL cholesterol, and triglycerides were hypertensive patients who may be at risk and without having smoked or consumed enzymatically measured. LDL choles- for diabetes should be investigated. The coffee or alcohol in the 30 min before the terol was calculated using Friedwald’s objective of the present study was to eval- test. Arterial hypertension was defined as formula [LDL cholesterol ϭ total cho- uate the prevalence of metabolic syn- arterial pressure Ն130/85 mmHg or lesterol Ϫ (HDL cholesterol ϩ triglyc- drome in hypertensive, nondiabetic treatment with antihypertensive medica- eride/5)] for triglyceride levels Ͻ400 outpatients. tion. Hypertensive patients were evalu- mg/dl. Diabetes was defined as fasting ated to define whether they fulfilled the glucose Ն126 mg/dl or glycemic levels RESEARCH DESIGN AND criteria for metabolic syndrome in accor- 2 h after a 75-g oral glucose load Ն200 METHODS — This cross-sectional dance with the definitions of the National mg/dl (8). study included 102 hypertensive outpa- Cholesterol Education Program (NCEP) Microalbuminuria was measured tients consecutively seen between De- Adult Treatment Panel III (ATPIII) and using immunoturbidimetry (APTEC, cember 2003 and May 2005 at a teaching the International Diabetes Federation intra-assay coefficient of variation [CV] hospital in Brazil. All patients included (IDF). 3.99% and interassay CV 3.35%), with were aged Ͼ18 years with systemic arte- NCEP/ATPIII defines metabolic syn- values Ն40 mg/24 h being considered positive. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil. Address correspondence and reprint requests to Kelminda Maria Bulho˜es Mendonc¸a, Avenida Princesa RESULTS — Table 1 lists the clinical Leopoldina, Edifı´cio Cidade de Manaus 66, Apto 501, Grac¸a, 40150-080 Salvador, Bahia, Brazil. E-mail: and laboratory data of the patients in this [email protected]. study. Prevalence of metabolic syndrome Recieved for publication 31 October 2006 and accepted in revised form 25 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2236. was 71.6 and 82.4% according to the Abbreviations: ATPIII, Adult Treatment Panel III; IDF, International Diabetes Federation; NCEP, Na- NCEP/ATPIII and IDF classification defi- tional Cholesterol Education Program. nitions, respectively. Concordance be- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tween the two classification systems factors for many substances. showed good reproducibility (k ϭ 0.67). © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby There was a statistically significant marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. difference between individuals with and
1624 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Bulho˜es and Arau´jo
Table 1—Clinical and biochemical characteristics of the study sample
MS according to NCEP criteria MS according to IDF criteria Variable Sample Absent Present Absent Present P NCEP P IDF n 102 29 73 18 84 Males 21 11 10 7 14 Females 81 18 63 11 70 Age (years) 60.71 Ϯ 10.45 61.17 Ϯ 12.44 60.52 Ϯ 9.64 59.67 Ϯ 12.57 60.93 Ϯ 10.02 0.778 0.729 Time since diagnosis 6.20 Ϯ 5.73 4.86 Ϯ 4.87 6.81 Ϯ 5.94 3.72 Ϯ 4.30 6.74 Ϯ 5.88 0.104 0.031 of hypertension (years) Weight (kg) 72.73 Ϯ 10.96 69.83 Ϯ 10.21 73.91 Ϯ 11.10 70.39 Ϯ 10.39 73.24 Ϯ 11.07 0.950 0.306 Height (m) 1.59 Ϯ 0.07 1.60 Ϯ 0.07 1.59 Ϯ 0.08 1.60 Ϯ 0.08 1.59 Ϯ 0.07 0.570 0.852 BMI (kg/m2) 28.70 Ϯ 4.20 27.38 Ϯ 3.76 29.23 Ϯ 4.28 27.66 Ϯ 4.03 28.92 Ϯ 4.23 0.950 0.249 Waist circumference 96.10 Ϯ 8.76 92.86 Ϯ 8.70 97.38 Ϯ 8.51 91.22 Ϯ 9.58 97.14 Ϯ 8.27 0.768 0.023 (cm) Hip (cm) 109.64 Ϯ 9.98 105.93 Ϯ 9.11 111.11 Ϯ 9.99 105.28 Ϯ 10.27 110.57 Ϯ 9.73 0.932 0.057 Glycemia (mg/dl) 106.63 Ϯ 33.98 90.97 Ϯ 12.69 104.53 Ϯ 38.77 87.06 Ϯ 11.91 103.54 Ϯ 36.44 0.053 0.004 Glycemia 2 h 146.71 Ϯ 56.36 115.96 Ϯ 40.20 158.25 Ϯ 57.43 110.94 Ϯ 28.91 154.13 Ϯ 57.91 0.000 0.002 following OGTT (mg/dl) HDL cholesterol 46.70 Ϯ 12.30 55.52 Ϯ 13.28 43.25 Ϯ 10.12 52.56 Ϯ 9.13 45.49 Ϯ 12.65 0.000 0.002 (mg/dl) Triglycerides (mg/dl) 169.02 Ϯ 123.78 97.03 Ϯ 27.67 197.62 Ϯ 135.20 102.11 Ϯ 40.89 183.36 Ϯ 130.86 0.000 0.000 Microalbuminuria 24.88 Ϯ 15.97 24.45 Ϯ 13.80 25.05 Ϯ 16.84 23.86 Ϯ 17.04 25.10 Ϯ 15.84 0.932 0.422 (mg/24 h) Insulin (U/ml) 8.18 Ϯ 6.08 6.87 Ϯ 6.54 8.69 Ϯ 5.87 6.30 Ϯ 6.05 8.58 Ϯ 6.05 0.006 0.012 Data are means Ϯ SD. MS, metabolic syndrome; OGTT, oral glucose tolerance test (75 g). without metabolic syndrome according to were obtained from an analysis of hyper- to investigate its presence in hypertensive the NCEP and IDF classifications when tensive patients in a reference hospital in patients who may be at risk for diabetes. the parameters of glucose levels 2 h after a which the waiting time for an appoint- The synergistic impact of arterial hyper- 75-g oral glucose load, HDL cholesterol, ment is long. tension and other components of meta- and triglycerides were evaluated (Table In a cross-sectional study (10), the bolic syndrome illustrate the need for 1). prevalence of metabolic abnormalities as- screening for the metabolic syndrome in According to the NCEP/ATPIII and sociated with arterial hypertension in in- hypertensive patients at initial diagnosis. IDF criteria, the prevalence of abnormal dividuals in the control and hypertensive In view of the relevance of this topic, waist circumference was 90.41 and groups ranged from 0.8 to 35.3%, respec- our objective with this study on the met- 100%, respectively, while low HDL cho- tively. Around 91.3% of the hypertensive abolic syndrome in hypertensive patients lesterol and hypertriglyceridemia had a patients had at least one associated car- was to describe the high prevalence of this prevalence of 76.71 and 67.12% and diovascular risk factor. The combination syndrome in patients receiving care at a 64.29 and 57.14%, respectively. Abnor- most frequently found was arterial hyper- university teaching hospital in the city of mal fasting glucose was the variable with tension and hypertriglyceridemia. Salvador, Brazil, and, based on data from the lowest prevalence in the study sample In the present study, the most fre- the literature that show the metabolic syn- according to both criteria (32.88% ac- quent combination was arterial hyperten- drome to be an important predictor of di- cording to NCEP/ATPIII and 57.14% ac- sion and increased waist circumference abetes, to call attention to the need to cording to IDF). followed by low HDL cholesterol, which investigate this condition in hypertensive When the percentage of risk factors of is the factor of the metabolic syndrome individuals. the patients with metabolic syndrome is most associated with hypertension. analyzed according to the NCEP/ATPIII The presence of metabolic syndrome classification, 46% of patients in the study is highly predictive of new-onset diabetes. References sample had three of the defining criteria Many studies show that hyperglycemia at 1. Mansur AP, Souza MFM, Timerman A, for metabolic syndrome, whereas 35.7% pre-diabetes levels is an independent risk Ramires JAF: Tendeˆncia do risco de morte had two and 17.9% had five of the asso- fator for cardiovascular diseases (11,12), por doenc¸as circulato´rias, cerebrovascu- ciated conditions. and diabetes is accompanied by a signifi- lares e isqueˆmicas do corac¸a˜o em 11 capi- tais do Brasil, de 1980 a 1998. Ar Qbras cantly increased prevalence of hyperten- Cardiol 79:269–276, 2002 (in Portu- CONCLUSIONS — The high preva- sion and dyslipidemia (13). guese) lence of metabolic syndrome found in this Detecting metabolic syndrome is a 2. Reaven GM, Hoffman BB: A role for insu- study may be related to the mean age of simple method of evaluating individuals lin in the aetiology and course of hyper- the study sample and the fact that the data at high risk of diabetes, and it is important tension? Lancet 2:435–437, 1987
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1625 Metabolic syndrome in hypertensive patients
3. Grant RW, Meigs JB: Should the insulin of High Blood Cholesterol in Adults 1649, 1998 resistance syndrome be treated in the el- (Adult Treatment Panel III). JAMA 285: 10. Rantala AO, Kauma H, Lilja M, Savol- derly? Drugs Aging 21:141–151, 2004 2486–2497, 2001 ainen MJ, Reunanen A, Kesaniemi YA: 4. Lorenzo C, Williams K, Hunt KJ, Haffner 7. Alberti KG, Zimmet P, Shaw J; IDF Epide- Prevalence of the metabolic syndrome in SM: The National Cholesterol Education miology Task Force Consensus Group: drug-treated hypertensive patients and Program-Adult Treatment Panel III, Inter- The metabolic syndrome: a new world- control subjects. J Intern Med 245:163– national Diabetes Federation, and World wide definition. Lancet 366:1059–1062, 174, 1999 Health Organization definitions of the 2005 11. Meigs JB, Nathan DM, D’Agostino RB Sr, metabolic syndrome as predictors of inci- 8. Genuth S, Alberti KG, Bennett P, Buse J, Wilson PW: Fasting and postchallenge dent cardiovascular disease and diabetes. Defronzo R, Kahn R, Kitzmiller J, Knowler glycemia and cardiovascular disease risk: Diabetes Care 30:8–13, 2007 WC, Lebovitz H, Lernmark A, Nathan D, the Framingham Offspring Study. Diabe- 5. Mion D, Machado CA, Gomes MAM, No- Palmer J, Rizza R, Saudek C, Shaw J, tes Care 25:1845–1850, 2002 bre F, Kohlmann O, Amodeo C, Praxedes Steffes M, Stern M, Tuomilehto J, Zimmet JN, Pascoal I, Magalha˜es L: IV Diretrizes P; Expert Committee on the Diagnosis 12. Brunner EJ, Shipley MJ, Witte DR, Fuller Brasileiras de Hipertensa˜o Arterial. Ar and Classification of Diabetes Mellitus: JH, Marmot MG: Relation between blood Qbras Cardiol 82 (suplemento IV):1–14, Follow-up report on the diagnosis of dia- glucose and coronary mortality over 33 2004 (in Portuguese) betes mellitus. Diabetes Care 26: years in the Whitehall Study. Diabetes 6. Expert Panel on Detection, Evaluation 3160–3167, 2003 Care 29: 26–31,2006 and Treatment of High Blood Cholesterol 9. Bonora E, Kiechl S, Willeit J, Oberhollen- 13. Mokdad AH, Ford ES, Bowman BA, Dietz in Adults: Executive summary of the zer F, Egger G, Targher G, Alberiche M, WH, Vinicor F, Bales VS, Marks JS: Prev- Third Report of the National Cholesterol Bonadonna R, Muggeo M: Prevalence of alence of obesity, diabetes, and obesity- Education Program (NCEP) Expert Panel insulin resistance in metabolic disorders: related health risk factors, 2001. JAMA on Detection, Evaluation, and Treatment the Bruneck Study. Diabetes 47:1643– 289:76–79, 2003
1626 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Cardiovascular and Metabolic Risk BRIEF REPORT
C-Reactive Protein Is Independently Associated With Glucose but Not With Insulin Resistance in Healthy Men
1,2 1,2 ANNE G. NIEHOFF, MD CLARA C. ELBERS, MSC sion analysis was used to estimate the 3 2 TIMON W. VAN HAEFTEN, MD, PHD CISCA WIJMENGA, PHD relation of CRP with insulin resistance 1,2 1 N. CHARLOTTE ONLAND-MORET, PHD YVONNE T. VAN DER SCHOUW, PHD and the individual components of meta- bolic syndrome. The P value for linear trend was calculated with the median of ecent studies have shown that low- were excluded because their level of CRP the CRP level in each quartile. Multivari- grade inflammation is linked both was above 10 mg/l and 2 because blood ate analyses were adjusted for age, smok- R to insulin resistance (1,2) and the samples had been taken in a nonfasting ing, and physical activity. To explore the metabolic syndrome (3,4) and may even state. Our final study population com- relationship between CRP and insulin re- predict the development of type 2 diabe- prised 364 participants. sistance and between CRP and metabolic tes (5–8). Various measures of obesity were ob- syndrome independently of markers of However, adipose tissue might play tained: weight, BMI, waist circumference, obesity, the models were also adjusted for an important role in these relationships. waist-to-hip ratio, visceral and subcuta- various different body composition pa- There is still controversy about whether neous fat using ultrasound measurement rameters. Statistical analyses were per- low-grade inflammation is an intermedi- (10), and total body fat mass using dual- formed using SPSS, version 12.0.1 for ate factor between obesity and insulin re- energy X-ray absorptiometry. Windows. sistance or whether it has an independent Information on prevalent diseases, effect on the development of type 2 dia- medication use, and lifestyle factors was RESULTS — In general, men with betes through a mechanism separate from available. Peripheral blood pressure was higher CRP levels were older, scored obesity. measured. Physical activity was assessed higher on markers of obesity, were less The aim of this study was to explore using the Voorrips score (11). physically active, and had higher glucose whether low-grade inflammation (mea- High-sensitivity–CRP, HDL choles- levels and insulin resistance. They also sured by plasma C-reactive protein (CRP) terol, triglycerides, glucose, and insulin fulfilled the criteria for metabolic syn- levels) was related to insulin resistance were measured in fasting blood samples. drome more often (Online Appendix and to parameters of metabolic syn- Details about the precision of the assays Table 1 [available at http://dx.doi.org/ drome, independent of obesity. have been reported (9,12,13). Insulin 10.2337/dc06-2531]). sensitivity was determined with the ho- After adjusting for confounders (age, RESEARCH DESIGN AND meostasis model assessment of insulin re- smoking, and physical activity), insulin METHODS — We conducted a cross- sistance (HOMA-IR): [fasting insulin resistance was significantly higher in the sectional, single-center study on 400 men (mU/l) ϫ fasting glucose (mmol/l)]/22.5. 4th quartile of CRP compared to the 1st, aged between 40 and 80 years. The sub- The presence of metabolic syndrome was but after adjusting for the various param- jects, methods of recruitment, study pro- defined according to the National Choles- eters of obesity, the difference in cedures and anthropometrical and terol Education Program criteria (14). HOMA-IR between the quartiles of CRP laboratory measurements have been de- was no longer evident (Table 1). How- scribed elsewhere (9). Twenty-one partic- Statistical analysis ever, adjustment for subcutaneous fat at- ipants had prevalent diabetes and were Subjects were divided into quartiles ac- tenuated the relationship between CRP excluded from the study; 13 participants cording to their CRP level. Linear regres- and HOMA-IR to a lesser extent than the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● other parameters of obesity. Of the individual components of met- From the 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; the 2Complex Genetics Section, DBG-Department of Medical Genetics, University Medical abolic syndrome, waist circumference, Center Utrecht, the Netherlands; the 3Department of Internal Medicine, University Medical Center Utrecht, glucose, and HDL-cholesterol showed a the Netherlands. statistically significant association with Address correspondence and reprint requests to Yvonne T. van der Schouw, PhD, Julius Center for Health CRP (data not shown). When we further Sciences and Primary Care, University Medical Center Utrecht, Room 6.131 Stratenum, P.O. Box 85500, 3508 GA Utrecht, Netherlands. E-mail: [email protected]. adjusted the relationship between CRP Received for publication 14 December 2006 and accepted in revised form 9 March 2007. and the individual components of meta- Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2531. bolic syndrome for measures of obesity, Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ only glucose remained statistically signif- dc06-2531. icantly higher in the 4th quartile of CRP C.W. is currently affiliated with the Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands. compared to the 1st quartile (Table 1). Abbreviations: CRP, C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion CONCLUSIONS — CRP was not re- factors for many substances. lated to insulin resistance after adjust- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby ment for parameters of body marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. composition, whereas CRP was indepen-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1627 CRP, insulin resistance, and glucose
dently associated with glucose, but not ‡
P with the other components of metabolic 0.001 0.001 Ͻ Ͻ syndrome. Recently Kahn et al. (15) showed that the relationship between CRP and the number of components of metabolic syn- drome markedly attenuated and became iles as reference nonsignificant after adjusting for BMI in drug-naive type 2 diabetes patients. Be- cause all the patients in their study satis-
for trend. WC, waist circumference; fied the glucose criteria of metabolic P syndrome by definition, this criterion did not contribute to the correlation between CRP and components of metabolic syn- 0.31 to 0.25) 0.39 (0.08 to 0.71) 0.006 0.30 to 0.26) 0.36 (0.10 to 0.66) 0.012 0.31 to 0.24) 0.41 (0.11 to 0.70)0.22 to 0.35) 0.53 0.003 (0.23 to 0.83) 0.32 to 0.23) 0.37 (0.07 to 0.67) 0.005 0.29 to 0.27) 0.44 (0.14 to 0.73)0.27 to 0.28) 0.39 0.001 (0.10 to 0.69) 0.003 0.15 to 0.41) 0.57 (0.27 to 0.87) drome. Our study therefore broadens Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ what is known about this topic, since it ) 2.6–10.0 mg/l. ‡
4 shows that CRP is associated with plasma 0.03 ( 0.02 ( 0.04 ( 0.04 ( 0.01 ( glucose, independently of obesity. Fur- Ϫ Ϫ Ϫ Ϫ Ϫ thermore, in healthy elderly men we con- -coefficient (95% CI) per quartile of CRP†
 firmed Kahn et al.’s finding that CRP is not independently related to other com- ) 1.2–2.6, and 3 ponents of metabolic syndrome. Conflicting results have been found 0.25 to 0.32) 0.19 to 0.39) 0.07 ( 0.18 to 0.38) 0.20 to 0.35) 0.24 to 0.32) 0.01 ( 0.24 to 0.31) 0.22 to 0.35) 0.12 to 0.45) 0.13 ( Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ regarding the correlation between CRP
) 0.6–1.2, and insulin resistance (2,16–20). How- 2 ever most of these studies did not have the prime aim of exploring the underlying
) 0–0.6, pathways. Some of these studies did not 1 therefore adjust for parameters of obesity
‡1 2 3 4 at all, while others did not investigate the P effect of a separate adjustment for obesity. A limitation of our study is its cross- sectional design, and, therefore, we can only suggest, but not prove, the causality of the observed relationships. We used 0.37 to 0.50) 0.764 Ref. 0.04 ( 0.30 to 0.58) 0.730 Ref. 0.10 ( 0.18 to 0.67) 0.293 Ref. 0.07 ( 0.19 to 0.72) 0.229 Ref. 0.04 ( 0.27 to 0.59) 0.396 Ref. 0.03 ( 0.14 to 0.75) 0.163 Ref. 0.07 ( HOMA-IR and ultrasound instead of hy- Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ perinsulinemic-euglycemic clamp and computed tomography scan, respectively, for assessing insulin sensitivity and vis- ceral and subcutaneous fat. However, these measurements have proven to be strongly correlated with the gold stan- dards (correlation coefficients Ϫ0.82 and 0.42 to 0.37) 0.06 ( 0.42 to 0.38) 0.24 ( 0.30 to 0.56) 0.49 (0.03 to 0.94) 0.020 Ref. 0.10 ( 0.40 to 0.42) 0.14 ( 0.46 to 0.35) 0.16 ( 0.31 to 0.53) 0.27 ( 0.39 to 0.46) 0.30 ( 0.07 to 0.82) 0.62 (0.15 to 1.09) 0.023 Ref. 0.17 ( 0.81, respectively) (10,21) Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Our data point to an obesity-indepen- dent mechanism which relates CRP and 0.02 ( 0.02 ( 0.06 ( -coefficient (95% CI) per quartile of CRP† Glucose:  Ϫ Ϫ Ϫ glucose. One explanation might be the proinflammatory effects of glucose: In it- self, glucose is proinflammatory (22), and it can increase IL (interleukin)-6, tumor necrosis factor-␣, and IL-18 release in 0.38 to 0.42) 0.37 to 0.51) 0.13 ( 0.23 to 0.58) 0.01 ( 0.26 to 0.53) 0.36 to 0.49) 0.11 ( 0.38 to 0.42) 0.33 to 0.51) 0.04 ( 0.13 to 0.77) 0.38 ( healthy subjects and persons with im- Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ
Insulin resistance: paired glucose tolerance (23). Further- more, prolonged hyperglycemia and the accompanying production of excess amounts of advanced glycation end prod- 1234 Ref. 0.02 ( Ref. 0.07 ( Ref. 0.32 ( ucts can activate nuclear factor-B (24). This will lead to an inflammatory reac- Relationship between CRP (in quartiles) and insulin resistance as assessed by HOMA-IR and between CRP (in quartiles) and glucose, with the first quart tion, independently of adipose tissue. In conclusion, our findings strongly fat mass fat only point to low-grade inflammation as an in- Percentage of Subcutaneous Visceral fat Ref. 0.18 ( BMI Ref. 0.13 ( WHR Ref. 0.07 ( WC Ref. 0.02 ( Weight Ref. 0.09 ( Confounders Adjustments* WHR, waist-to-hip ratio. Table 1— *All analyses are adjusted for the following confounders: age, physical activity, and smoking. †CRP quartile ranges: termediate factor in the relationship be-
1628 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Niehoff and Associates tween adipose tissue and insulin resistance. erosclerosis study. Diabetes 51:1131–1137, W, Hanefeld M: Subclinical inflammation The independent association of glucose 2002 is strongly related to insulin resistance but with CRP suggests an additional mecha- 7. Barzilay JI, Abraham L, Heckbert SR, not to impaired insulin secretion in a high nism by which glucose and CRP are related, Cushman M, Kuller LH, Resnick HE, risk population for diabetes. Metabolism independent of obesity. Tracy RP: The relation of markers of in- 51:743–749, 2002 flammation to the development of glucose 17. Hak AE, Stehouwer CD, Bots ML, Polder- disorders in the elderly: the Cardiovascu- man KH, Schalkwijk CG, Westendorp IC, lar Health Study. Diabetes 50:2384– Hofman A, Witteman JC: Associations of Acknowledgments— We thank Jackie Se- 2389, 2001 C-reactive protein with measures of obe- nior for critically reading the manuscript. This 8. Pradhan AD, Manson JE, Rifai N, Buring sity, insulin resistance, and subclinical work was supported by an Innovatieve Onder- JE, Ridker PM: C-reactive protein, inter- zoeks Programma’s (Innovative Research Pro- atherosclerosis in healthy, middle-aged leukin 6, and risk of developing type 2 women. Arterioscler Thromb Vasc Biol 19: grams) grant from the Dutch Ministry of diabetes mellitus. JAMA 286:327–334, Economic Affairs (grant no. IGE05012). 1986–1991, 1999 2001 18. Kriketos AD, Greenfield JR, Peake PW, 9. Muller M, Grobbee DE, den Tonkelaar I, Furler SM, Denyer GS, Charlesworth JA, Lamberts SW, van der Schouw YT: En- Campbell LV: Inflammation, insulin re- References dogenous sex hormones and metabolic sistance, and adiposity: a study of first- 1. Yudkin JS, Stehouwer CD, Emeis JJ, Cop- syndrome in aging men. J Clin Endocrinol degree relatives of type 2 diabetic pack SW: C-reactive protein in healthy sub- Metab 90:2618–2623, 2005 subjects. Diabetes Care 27:2033–2040, jects: associations with obesity, insulin 10. Stolk RP, Wink O, Zelissen PM, Meijer R, 2004 resistance, and endothelial dysfunction: a van Gils AP, Grobbee DE: Validity and 19. Forouhi NG, Sattar N, McKeigue PM: Re- potential role for cytokines originating from reproducibility of ultrasonography for the lation of C-reactive protein to body fat adipose tissue? Arterioscler Thromb Vasc Biol measurement of intra-abdominal adipose distribution and features of the metabolic 19:972–978, 1999 tissue. Int J Obes Relat Metab Disord 25: syndrome in Europeans and South 2. Festa A, D’Agostino R Jr, Howard G, Myk- 1346–1351, 2001 Asians. Int J Obes Relat Metab Disord 25: kanen L, Tracy RP, Haffner SM: Chronic 11. Voorrips LE, Ravelli AC, Dongelmans PC, 1327–1331, 2001 subclinical inflammation as part of the in- Deurenberg P, Van Staveren WA: A phys- 20. Pradhan AD, Cook NR, Buring JE, Man- sulin resistance syndrome: the Insulin Re- ical activity questionnaire for the elderly. son JE, Ridker PM: C-reactive protein is sistance Atherosclerosis Study (IRAS). Med Sci Sports Exerc 23:974–979, 1991 independently associated with fasting in- Circulation 102:42–47, 2000 12. Nakhai Pour HR, Grobbee DE, Muller M, sulin in nondiabetic women. Arterioscler 3. Florez H, Castillo-Florez S, Mendez A, van der Schouw YT: Association of endog- Casanova-Romero P, Larreal-Urdaneta C, enous sex hormone with C-reactive pro- Thromb Vasc Biol 23:650–655, 2003 Lee D, Goldberg R: C-reactive protein is tein levels in middle-aged and elderly 21. Bonora E, Targher G, Alberiche M, Bona- elevated in obese patients with the meta- men. Clin Endocrinol 65:621–622, 2007 donna RC, Saggiani F, Zenere MB, bolic syndrome. Diabetes Res Clin Pract 13. 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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1629 Reviews/Commentaries/ADA Statements STANDARDS AND REVIEW CRITERIA
National Standards for Diabetes Self- Management Education
1 8 MARTHA M. FUNNELL, MS, RN, CDE MARK PEYROT, PHD ciples based on existing evidence that 2 9,10 TAMMY L. BROWN, MPH, RD, BC-ADM, CDE JOHN D. PIETTE, PHD would be used to guide the review and 3 11 BELINDA P. CHILDS, ARNP, MN, CDE, BC-ADM DIANE READER, RD, CDE revision of the DSME Standards. These 4 12 LINDA B. HAAS, PHC, CDE, RN LINDA M. SIMINERIO, PHD, RN, CDE are: 5 7 GWEN M. HOSEY, MS, ARNP, CDE KATIE WEINGER, EDD, RN 6 13 BRIAN JENSEN, RPH ICHAEL EISS JD 7 M A. W , 1. Diabetes education is effective for im- MELINDA MARYNIUK, MED, RD, CDE proving clinical outcomes and quality of life, at least in the short-term (1–7). 2. DSME has evolved from primarily di- iabetes self-management education The Task Force was charged with re- dactic presentations to more theoreti- (DSME) is a critical element of care viewing the current DSME standards for cally based empowerment models D for all people with diabetes and is their appropriateness, relevance, and sci- (3,8). necessary in order to improve patient out- entific basis. The Standards were then re- 3. There is no one “best” education pro- comes. The National Standards for DSME viewed and revised based on the available gram or approach; however, programs are designed to define quality diabetes evidence and expert consensus. The com- incorporating behavioral and psycho- self-management education and to assist mittee convened on 31 March 2006 and 9 social strategies demonstrate im- diabetes educators in a variety of settings September 2006, and the Standards were proved outcomes (9–11). Additional to provide evidence-based education. Be- approved 25 March 2007. studies show that culturally and age- cause of the dynamic nature of health care appropriate programs improve out- and diabetes-related research, these Stan- DEFINITION AND comes (12–16) and that group dards are reviewed and revised approxi- OBJECTIVES — Diabetes self-man- education is effective (4,6,7,17,18). mately every 5 years by key organizations agement education (DSME) is the ongo- 4. Ongoing support is critical to sustain and federal agencies within the diabetes ing process of facilitating the knowledge, progress made by participants during education community. skill, and ability necessary for diabetes the DSME program (3,13,19,20). A Task Force was jointly convened by self-care. This process incorporates the the American Association of Diabetes Edu- needs, goals, and life experiences of the 5. Behavioral goal-setting is an effective cators and the American Diabetes Associa- person with diabetes and is guided by ev- strategy to support self-management tion in the summer of 2006. Additional idence-based standards. The overall ob- behaviors (21). organizations that were represented in- jectives of DSME are to support informed cluded the American Dietetic Association, decision-making, self-care behaviors, STANDARDS the Veteran’s Health Administration, the problem-solving and active collaboration Centers for Disease Control and Prevention, with the health care team and to improve Structure the Indian Health Service, and the Ameri- clinical outcomes, health status, and qual- Standard 1. The DSME entity will have can Pharmaceutical Association. Members ity of life. documentation of its organizational struc- of the Task Force included a person with ture, mission statement, and goals and will diabetes; several health services researchers/ GUIDING PRINCIPLES — Before recognize and support quality DSME as an behaviorists, registered nurses, and regis- the review of the individual Standards, integral component of diabetes care. tered dietitians; and a pharmacist. the Task Force identified overriding prin- Documentation of the DSME organi- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● zational structure, mission statement, and goals can lead to efficient and effective The previous version of the “National Standards for Diabetes Self-Management Education” was originally provision of services. In the business lit- published in Diabetes Care 23:682–689, 2000. This version received final approval in March 2007. From the 1Department of Medical Education, Diabetes Research and Training Center, University of erature, case studies and case report in- Michigan, Ann Arbor, Michigan; 2Indian Health Service, Albuquerque, New Mexico; 3MidAmerica Diabetes vestigations on successful management Associates, Wichita, Kansas; the 4VA Puget Sound Health Care System, Seattle, Washington; the 5Division of strategies emphasize the importance of Diabetes Translation, National Center for Chronic Diseases Prevention and Health Promotion, Centers for clear goals and objectives, defined rela- Disease Control and Prevention, Atlanta, Georgia; 6Lakeshore Apothacare, Two Rivers, Wisconsin; the 7Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; 8Loyola College, Baltimore, Mary- tionships and roles, and managerial sup- land; the 9VA Ann Arbor Health Care System, Ann Arbor, Michigan; the 10Department of Internal Medicine, port (22–25). While this concept is Diabetes Research and Training Center, University of Michigan, Ann Arbor, Michigan; the 11International relatively new in health care, business and Diabetes Center, Minneapolis, Minnesota; the 12Diabetes Institute, University of Pittsburgh Medical Center, 13 health policy experts and organizations Pittsburgh, Pennsylvania; and Patient Centered Solutions, Pittsburgh, Pennsylvania. have begun to emphasize written com- Address correspondence to Martha M. Funnell, 300 N. Ingalls, 3D06, Box 0489, University of Michigan, Ann Arbor, MI 48109-0489. E-mail: [email protected]. mitments, policies, support, and the im- Abbreviations: CQI, continuous quality improvement; DSME, diabetes self-management education; portance of outcome variables in quality DSMS, diabetes self-management support; FHL, functional health literacy; JCAHO, Joint Commission on improvement efforts (22,26–37). The Accreditation of Health Care Organizations. continuous quality improvement litera- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. ture also stresses the importance of devel- DOI: 10.2337/dc07-9923 oping policies, procedures, and © 2007 by the American Diabetes Association. guidelines (22,26).
1630 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Standards and Review Criteria
Documentation of the organizational educational needs of all individuals with 79). Reviews comparing the effectiveness structure, mission statement, and goals diabetes, not just those who frequently of different disciplines for education re- can lead to efficient and effective provi- attend clinical appointments (51). DSME port mixed results (3,5,6). Generally, the sion of DSME. Documentation of an orga- is a critical component of diabetes treat- literature favors current practice that uti- nizational structure that delineates ment (2,54,55), yet the majority of indi- lizes the registered nurse, registered die- channels of communication and repre- viduals with diabetes do not receive any titian, and the registered pharmacist as sents institutional commitment to the ed- formal diabetes education (56,57). Thus, the key primary instructors for diabetes ucational entity is critical for success (38– identification of access issues is an essen- education and members of the multidis- 42). According to the Joint Commission tial part of the assessment process (58). ciplinary team responsible for designing on Accreditation of Health Care Organi- Demographic variables, such as ethnic the curriculum and assisting in the deliv- zations (JCAHO) (26), this type of docu- background, age, formal educational ery of DSME (1–7,77). In addition to reg- mentation is equally important for small level, reading ability, and barriers to par- istered nurses, registered dietitians, and and large health care organizations. ticipation in education, must also be con- pharmacists, a number of studies reflect Health care and business experts over- sidered to maximize the effectiveness of the ever-changing and evolving health whelmingly agree that documentation of DSME for the target population (13– care environment and include other the process of providing services is a crit- 19,43–47,59–61). health professionals (e.g., a physician, be- ical factor in clear communication and Standard 4. A coordinator will be desig- haviorist, exercise physiologist, ophthal- provides a solid basis from which to de- nated to oversee the planning, implementa- mologist, optometrist, podiatrist) liver quality diabetes education (22,26, tion, and evaluation of diabetes self- (48,80–84) and, more recently, lay 33,35–37). In 2005, JACHO published management education. The coordinator will health and community workers (85–91) the Joint Commission International Stan- have academic or experiential preparation in and peers (92) to provide information, dards for Disease or Condition-Specific chronic disease care and education and in behavioral support, and links with the Care, which outlines national standards program management. health care system as part of DSME. and performance measurements for dia- The role of the coordinator is essential Expert consensus supports the need betes and addresses diabetes self- to ensure that quality diabetes education for specialized diabetes and educational management education as one of seven is delivered through a coordinated and training beyond academic preparation for critical elements (26). systematic process. As new and creative the primary instructors on the diabetes Standard 2. The DSME entity shall appoint methods to deliver education are ex- team (64,93–97). Certification as a diabe- an advisory group to promote quality. This plored, the coordinator plays a pivotal tes educator by the National Certification group shall include representatives from the role in ensuring accountability and conti- Board for Diabetes Educators (NCBDE) is health professions, people with diabetes, the nuity of the educational process (23,60– one way a health professional can demon- community, and other stakeholders. 62). The individual serving as the strate mastery of a specific body of knowl- Established and new systems (e.g., coordinator will be most effective if there edge, and this certification has become an committees, governing bodies, advisory is familiarity with the lifelong process of accepted credential in the diabetes com- groups) provide a forum and a mecha- managing a chronic disease (e.g., diabe- munity (98). An additional credential that nism for activities that serve to guide and tes) and with program management. indicates specialized training beyond ba- sustain the DSME entity (30,39–41). sic preparation is board certification in Broad participation of organization(s) Process advanced Diabetes Management (BC- and community stakeholders, including Standard 5. DSME will be provided by one ADM) offered by the American Nurses health professionals, people with diabe- or more instructors. The instructors will have Credentialing Center (ANCC), which is tes, consumers, and other community in- recent educational and experiential prepara- available for master’s prepared nurses, di- terest groups, at the earliest possible tion in education and diabetes management etitians, and pharmacists (48,84,99). moment in the development, ongoing or will be a certified diabetes educator. The DSME has been shown to be most ef- planning, and outcomes evaluation pro- instructor(s) will obtain regular continuing fective when delivered by a multidisci- cess (22,26,33,35,36,41) can increase education in the field of diabetes manage- plinary team with a comprehensive plan knowledge and skills about the local com- ment and education. At least one of the in- of care (7,31,52,100–102). Within the munity and enhance collaborations and structors will be a registered nurse, dietitian, multidisciplinary team, team members joint decision-making. The result is a or pharmacist. A mechanism must be in place work interdependently, consult with one DSME program that is patient-centered, to ensure that the participant’s needs are met another, and have shared objectives more responsive to consumer-identified if those needs are outside the instructors’ (7,103,104). The team should have a col- needs and the needs to the community, scope of practice and expertise. lective combination of expertise in the more culturally relevant, and of greater Diabetes education has traditionally clinical care of diabetes, medical nutrition personal interest to consumers (43–50). been provided by nurses and dietitians. therapy, educational methodologies, Standard 3. The DSME entity will deter- Nurses have been utilized most often as teaching strategies, and the psychosocial mine the diabetes educational needs of the instructors in the delivery of formal and behavioral aspects of diabetes self- target population(s) and identify resources DSME (2,3,5,63–67). With the emer- management. A referral mechanism necessary to meet these needs. gence of medical nutrition therapy (66– should be in place to ensure that the in- Clarifying the target population and 70), registered dietitians became an dividual with diabetes receives education determining its self-management educa- integral part of the diabetes education from those with appropriate training and tional needs serve to focus resources and team. In more recent years, the role of the credentials. It is essential in this collabo- maximize health benefits (51–53). The diabetes educator has expanded to other rative and integrated team approach that assessment process should identify the disciplines, particularly pharmacists (73– individuals with diabetes are viewed as
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1631 Standards and Review Criteria leaders of their team and assume an active tings and represent topics that can be de- modalities, including telephone fol- role in designing their educational expe- veloped in basic, intermediate, and low-up and other information technolo- rience (7,20,31,100–102,104). advanced levels. Approaches to education gies (e.g., Web-based, automated phone Standard 6. A written curriculum reflecting that are interactive and patient-centered calls), may augment face-to-face assess- current evidence and practice guidelines, with have been shown to be effective ments (97,99). criteria for evaluating outcomes, will serve as (83,119,121,122,125–127). While there is little direct evidence on the framework for the DSME entity. Assessed These content areas are presented in the impact of documentation on patient needs of the individual with pre-diabetes and behavioral terms and thereby exemplify outcomes, it is required to receive pay- diabetes will determine which of the content ar- the importance of action-oriented, behav- ment for services. In addition, documen- eas listed below are to be provided: ioral goals and objectives (13,21,55,121– tation of patient encounters guides the 123,128,129). Creative, patient-centered educational process, provides evidence of ● Describing the diabetes disease process experience-based delivery methods are communication among instructional and treatment options effective for supporting informed deci- staff, may prevent duplication of services, ● Incorporating nutritional management sion-making and behavior change and go and provides information on adherence into lifestyle beyond the acquisition of knowledge. to guidelines (37,64,100,131,153). Pro- ● Incorporating physical activity into life- Standard 7. An individual assessment and viding information to other members of style education plan will be developed collabora- the patient’s health care team through ● Using medication(s) safely and for max- tively by the participant and instructor(s) to documentation of educational objectives imum therapeutic effectiveness direct the selection of appropriate educa- and personal behavioral goals increases ● Monitoring blood glucose and other pa- tional interventions and self-management the likelihood that all of the members will rameters and interpreting and using the support strategies. This assessment and edu- address these issues with the patient results for self-management decision cation plan and the intervention and out- (37,98,153). making comes will be documented in the education The use of evidence-based perfor- ● Preventing, detecting, and treating record. mance and outcome measures has been acute complications Multiple studies indicate the impor- adopted by organizations and initiatives ● Preventing detecting, and treating tance of individualizing education based such as the Centers for Medicare and Med- chronic complications on the assessment (1,56,68,131–135). icaid Services (CMS), the National Com- ● Developing personal strategies to ad- The assessment includes information mittee for Quality Assurance (NCQA), the dress psychosocial issues and concerns about the individual’s relevant medical Diabetes Quality Improvement Project ● Developing personal strategies to pro- history, age, cultural influences, health (DQIP), the Health Plan Employer Data mote health and behavior change beliefs and attitudes, diabetes knowledge, and Information Set (HEDIS), the Veter- self-management skills and behaviors, ans Administration Health System, and People with diabetes and their families readiness to learn, health literacy level, JCAHO (26,154). and caregivers have a great deal to learn in physical limitations, family support, and Research suggests that the development order to become effective self-managers of financial status (10–17,19,131,136– of standardized procedures for documenta- their diabetes. A core group of topics are 138). The majority of these studies sup- tion, training health professionals to docu- commonly part of the curriculum taught port the importance of attitudes and ment appropriately, and the use of in comprehensive programs that have health beliefs in diabetes care outcomes structured standardized forms based on demonstrated successful outcomes (1,68,134,135,138,139). current practice guidelines can improve (1,2,3,6,105–109). The curriculum, a co- In addition, functional health literacy documentation and may ultimately im- ordinated set of courses and educational (FHL) level can affect patients’ self- prove quality of care (100,153–155). experiences, includes learning outcomes management, communication with clini- Standard 8. A personalized follow-up plan and effective teaching strategies (110– cians, and diabetes outcomes (140,141). for ongoing self management support will be 112). The curriculum is dynamic and Simple tools exist for measuring FHL as developed collaboratively by the participant needs to reflect current evidence and part of an overall assessment process and instructor(s). The patient’s outcomes and practice guidelines (112–117). Current (142–144). goals and the plan for ongoing self manage- educational research reflects the impor- Many people with diabetes experi- ment support will be communicated to the tance of emphasizing practical, problem- ence problems due to medication costs, referring provider. solving skills, collaborative care, and asking patients about their ability to While DSME is necessary, it is not psychosocial issues, behavior change, and afford treatment is important (144). Co- sufficient for patients to sustain a lifetime strategies to sustain self-management ef- morbid chronic illness (e.g., depression of diabetes self-care (55). Initial improve- forts (31,39,42,48,98,118–122). and chronic pain) as well as more general ments in metabolic and other outcomes The content areas delineated above psychosocial problems can pose signifi- diminish after ϳ6 months (3). To sustain provide instructors with an outline for de- cant barriers to diabetes self-management behavior at the level of self-management veloping this curriculum. It is important (104,146–151); considering these issues needed to effectively manage diabetes, that the content be tailored to match each in the assessment may lead to more effec- most patients need ongoing diabetes self- individual’s needs and adapted as neces- tive planning (149–151). management support (DSMS). sary for age, type of diabetes (including Periodic reassessment determines at- DSMS is defined as activities to assist pre-diabetes and pregnancy), cultural in- tainment of the educational objectives or the individual with diabetes to implement fluences, health literacy, and other co- the need for additional and creative inter- and sustain the ongoing behaviors needed morbidities (123,124). The content areas ventions and future reassessment to manage their illness. The type of sup- are designed to be applicable in all set- (7,97,100,152). A variety of assessment port provided can include behavioral, ed-
1632 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Standards and Review Criteria ucational, psychosocial, or clinical needs to be in place to communicate per- Kidney Diseases of the National Institutes of (13,121–123). sonal goals and progress to other team Health. A variety of strategies are available for members. The Task Force gratefully acknowledges the providing DSMS both within and outside The AADE Outcome Standards for Di- assistance and support of Paulina Duker, the DSME entity. Some patients benefit MPH, APRN-BC, CDE, and Nathanial Clark, abetes Education specify self-management MD, CDE, of the American Diabetes Associa- from working with a nurse case manager behavior as the key outcome (112,160). tion; Lori Porter, MBA, RD, CAE, of the Amer- (7,20,98,157). Case management for Knowledge is an outcome to the degree that ican Association of Diabetes Educators; and DSMS can include reminders about it is actionable (i.e., knowledge that can be Karmeen Kulkarni, MS, RD, BC-ADM, Past needed follow-up care and tests, medica- translated into self-management behavior). President, Health Care and Education of the tion management, education, behavioral In turn, effective self-management is one American Diabetes Association; Malinda goal-setting, and psychosocial support/ (but not the only) contributor to longer- Peeples, MS, RN, CDE, Past President of the connection to community resources. term, higher-order outcomes such as clini- American Association of Diabetes Educators; The effectiveness of providing DSMS and Carole’ Mensing, RN, MA, CDE, for their cal status (e.g., control of glycemia, blood insights and helpful suggestions. through disease-management programs, pressure, and cholesterol), health status trained peers and health community We also gratefully acknowledge the work of (e.g., avoidance of complications), and sub- the previous Task Force for the National Stan- workers, community-based programs, jective quality of life. Thus, patient self- dards for DSME: Carole’ Mensing, RN, MA, use of technology, ongoing education and management behaviors are at the core of the CDE; Jackie Boucher, MS, RD, LD, CDE; Mar- support groups, and medical nutrition outcomes evaluation. jorie Cypress, MS, C-ANP, CDE; Katie therapy has also been established Standard 10. The DSME entity will mea- Weinger, EdD, RN; Kathryn Mulcahy, MSN, (7,13,89–92,101,121–123,158–159). sure the effectiveness of the education process RN, CDE; Patricia Barta, RN, MPH, CDE; While the primary responsibility for and determine opportunities for improve- Gwen Hosey, MS, ARNP, CDE; Wendy Ko- pher, RN, C, CDE, HTP; Andrea Lasichak, MS, diabetes education belongs to the DSME ment using a written continuous quality im- entity, patients benefit by receiving rein- RD, CDE; Betty Lamb, RN, MSN; Mavourneen provement plan that describes and Mangan, RN, MS, ANP, C, CDE; Jan Norman, forcement of content and behavioral goals documents a systematic review of the entities’ from their entire health care team (100). RD, CDE; Jon Tanja, BS, MS, RPH; Linda process and outcome data. Yauk, MS, RD, LD, CDE; Kimberlydawn Wis- Additionally, many patients receive Diabetes education must be respon- dom, MD, MS; and Cynthia Adams, PhD DSMS through their provider. Thus, com- sive to advances in knowledge, treatment munication is essential to ensure that pa- strategies, educational strategies, psycho- tients receive the support they need. social interventions, and the changing References 1. Brown SA: Interventions to promote di- Outcomes health care environment. Continuous quality improvement (CQI) is an iterative, abetes self-management: state of the sci- Standard 9. The DSME entity will measure ence. Diabetes Educ 25 (6 Suppl.):52– attainment of patient-defined goals and pa- planned process (161) that leads to im- 61, 1999 tient outcomes at regular intervals using ap- provement in the delivery of patient edu- 2. Norris SL, Engelgau MM, Naranyan propriate measurement techniques to cation (162). The CQI plan should define KMV: Effectiveness of self-management evaluate the effectiveness of the educational quality based on and consistent with the training in type 2 diabetes: a systematic intervention. organization’s mission, vision, and strate- review of randomized controlled trials. gic plan and include identifying and pri- Diabetes Care 24:561–587, 2001 In addition to program-defined goals 3. Norris SL, Lau J, Smith SJ, Schmid CH, and objectives (e.g., learning goals, meta- oritizing improvement opportunities (163). Once improvement projects are Engelgau MM: Self-management educa- bolic, and other health outcomes), the tion for adults with type 2 diabetes: a DSME entity needs to assess each patient’s identified and selected, the plan should meta-analysis on the effect on glycemic personal self-management goals and his/ incorporate timelines and important control. Diabetes Care 25:1159–1171, her progress toward those personal goals. milestones including data collection, 2002 The AADE7 self-care behaviors provide a analysis, and presentation of results 4. Norris SL: Self-management education useful framework for assessment and doc- (163). Outcome measures indicate the re- in type 2 diabetes. Practical Diabetology umentation. Diabetes self-management sult of a process (i.e., whether changes are 22:713, 2003 behaviors include physical activity, actually leading to improvement), while 5. Gary TL, Genkinger JM, Guallar E, Pey- process measures provide information rot M, Brancati FL: Meta-analysis of ran- healthy eating, medication taking, moni- domized educational and behavioral toring blood glucose, diabetes self-care about what caused those results (163– interventions in type 2 diabetes. Diabetes related problem solving, reducing risks of 164). Process measures are often targeted Educ 29:488–501, 2003 acute and chronic complications, and to those processes that typically impact 6. Deakin T, McShane CE, Cade JE, et al. psychosocial aspects of living with diabe- the most important outcomes. Measuring Review: group based education in self- tes (112,160). Assessments of patient out- both process and outcomes helps to en- management strategies improves out- comes should occur at appropriate sure that change is successful without comes in type 2 diabetes mellitus. intervals. The interval depends on the causing additional problems in the system Cochrane Database Syst Rev (2): outcome itself and the timeframe pro- (164). CD003417, 2005 vided within the selected goals. For some 7. Renders CM, Valk GD, Griffin SJ, Wag- ner EH, Eijk van JThM, Assendelft WJJ: areas, the indicators, measures, and time- Interventions to improve the manage- frames may be based on guidelines from Acknowledgments— Work on this article ment of diabetes in primary care, outpa- professional organizations or government was supported in part by grant nos. NIH5P60 tient, and community settings: a agencies. In addition to assessing progress DK20572 and 1 R18 0K062323 from the Na- systematic review. Diabetes Care 24: toward personal behavioral goals, a plan tional Institute of Diabetes and Digestive and 1821–1833, 2001
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1637 Reviews/Commentaries/ADA Statements ADA WORKGROUP REPORT
Computer Modeling of Diabetes and Its Complications A report on the Fourth Mount Hood Challenge Meeting
THE MOUNT HOOD 4MODELING GROUP* opment. The Fourth Mount Hood Chal- lenge was the first to ask participating modelers to perform simulations based Computer simulation models are mathematical equations combined in a structured framework on published clinical trials, thereby allow- to represent some real or hypothetical system. One of their uses is to allow the projection of ing comparison of all eight participating short-term data from clinical trials to evaluate clinical outcomes and costs over a long-term models against “real life” data (2–12). period. This technology is becoming increasingly important to assist decision making in modern Treatments and interventions, long-term medicine in situations where there is a paucity of long-term clinical trial data, as recently management of patients, cohort charac- acknowledged in the American Diabetes Association Consensus Panel Guidelines for Computer teristics, cost, and health state utilities Modeling of Diabetes and its Complications. The Mount Hood Challenge Meetings provide a were defined to minimize the number of forum for computer modelers of diabetes to discuss and compare models and identify key areas potentially disparate assumptions re- of future development to advance the field. The Fourth Mount Hood Challenge in 2004 was the first meeting of its kind to ask modelers to perform simulations of outcomes for patients in quired to make reliable forecasts. The published clinical trials, allowing comparison against “real life” data. Eight modeling groups working hypothesis for the Mount Hood participated in the challenge. Each group was given three of the following challenges: to simulate Challenge was that this process of stan- a trial of type 2 diabetes (CARDS [Collaborative Atorvastatin Diabetes Study]); to simulate a trial dardized comparison is the best method of type 1 diabetes (DCCT [Diabetes Control and Complications Trial]); and to calculate out- to identify differences between models as comes for a hypothetical, precisely specified patient (cross-model validation). The results of the well as assessing the models’ reliability in models varied from each other and for methodological reasons, in some cases, from the pub- terms of projecting the “real life” situation lished trial data in important ways. This approach of performing systematic comparisons and (clinical trials). validation exercises has enabled the identification of key differences among the models, as well The aim of this article is to report the as their possible causes and directions for improvement in the future. proceedings of the Fourth Mount Hood Diabetes Care 30:1638–1646, 2007 Challenge held in Basel, Switzerland, in 2004. It is not intended to provide a de- tailed description of the models pre- he growing importance of computer the projection of short-term data from sented, as in most cases this information simulation modeling in decision clinical trials to evaluate clinical outcomes has been previously published elsewhere, T making in modern medicine was re- and costs over the long term. This tech- and it does not purport to address the cently acknowledged in the American Di- nology is designed to provide information need for validation outlined in the ADA abetes Association (ADA) Consensus for health care decision makers and al- Consensus Panel Modeling Guidelines. Panel Guidelines for Computer Modeling lows them to make the most informed However, the proceedings of the Fourth of Diabetes and its Complications (1). Al- choices between available interventions. Mount Hood Challenge are reported here though clinical studies, in particular Increasingly, the health care industry is to provide an overview of how current large-scale randomized controlled trials, relying on modeling to make more in- models match up to data from published remain the main data source for decision formed decisions. It is therefore of central clinical studies as well as to each other, to makers, modeling is gaining acceptance importance that there is confidence in highlight differences between models, as a valuable tool to provide information models to provide an accurate reflection Ͼ and to describe a process for comparing on long-term ( 5–10 years) clinical and of disease progression in real life. models that may also be valuable in other economic outcomes, which is often un- The Mount Hood Challenge Meetings research areas. available directly from clinical studies. have been held regularly since 2000 and Computer simulation models, in essence provide a forum for computer modelers of a series of mathematical equations com- diabetes to discuss and compare models RESEARCH DESIGN AND bined in a structured framework, allow and to identify key areas of future devel- METHODS — In July 2004, partici- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● pating modelers received instructions Address correspondence and reprint requests to Dr. Andrew J. Palmer, CORE—Center for Outcomes outlining the Fourth Mount Hood Chal- Research, Bu¨ ndtenmattstrasse 40, 4102 Binningen, Switzerland. E-mail: [email protected]. lenge. The challenge had three parts: simu- *A complete list of the Mount Hood 4 Modeling Group members can be found in the APPENDIX. lation of a trial of type 2 diabetes Abbreviations: ADA, American Diabetes Association; CARDS, Collaborative Atorvastatin Diabetes Study; (Collaborative Atorvastatin Diabetes Study CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; CORE, Center for Outcomes Research; CVD, cardiovascular disease; DiDACT, Diabetes Decision Analysis of Cost of Type 2; DCCT, [CARDS]) that had not been used by any of Diabetes Control and Complications Trial; EAGLE, Economic Assessment of Glycemic Control and Long- the modelers to build their model, simula- term Effects; MI, myocardial infarction; RTI, Research Triangle Institute; UKPDS, U.K. Prospective Diabetes tion of a trial of type 1 diabetes (Diabetes Study; WESDR, Wisconsin Epidemiological Study of Diabetic Retinopathy. Control and Complications Trial [DCCT]) A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. that had been used by the three groups who DOI: 10.2337/dc07-9919 model type 1 diabetes to build models of © 2007 by the American Diabetes Association. that disease; and estimation of outcomes for
1638 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 The Mount Hood 4 Modeling Group a precisely defined hypothetical person changes in risk factor values (e.g., HDL tions is provided on the Mount Hood 4 with type 2 diabetes, with and without gly- cholesterol) in the treatment and control Web site (13). In the present article, we cemic control. This article reports the re- groups and to report the cumulative inci- report only selected outcomes for micro- sults of the first and second challenges. dence of cardiovascular events, all-cause vascular complications that can be com- Results of simulating the third challenge are mortality, and quality-adjusted life ex- pared against published DCCT data. described on the Mount Hood 4 Web site pectancy taking into account macrovas- (13). cular complications and the costs of Overview of models participating in complications by therapy allocation over the Fourth Mount Hood Challenge Type 2 diabetes: simulating CARDS time horizons of 4 years (trial duration 3.9 The format of the Fourth Mount Hood The first part of the challenge was to sim- years) and 20 years. Each modeling group Challenge Meeting was decided in August ulate the outcomes of CARDS, which in- was requested to use only the source in- 2003 at the Third Mount Hood Chal- vestigated the role of lipid-lowering formation indicated in order to standard- lenge. Eight modeling groups partici- therapy in the primary prevention of car- ize the inputs for each model (as far as was pated in Third Mount Hood Challenge: diovascular disease (CVD) in patients possible with the different models’ struc- the Cardiff Diabetes Model, the Sheffield with type 2 diabetes. This challenge was tures and designs). Each group was in- Diabetes Model, the U.K. Prospective Di- undertaken to compare modeling results structed to carefully record the abetes Study (UKPDS) Model, the Eco- in a well-defined cohort receiving an in- assumptions used when defining the sim- nomic Assessment of Glycemic Control tervention to control the progression of ulations. More information on the simu- and Long-term Effects (EAGLE) Model, cardiovascular complications of type 2 di- lation settings is provided online at the the Center for Outcomes Research abetes. CARDS was a randomized place- Mount Hood Challenge 4 Web site (13). (CORE) Diabetes Model, the Archimedes bo-controlled trial that compared 10 mg Although modelers were asked to Model, the Global Diabetes Model, the atorvastatin with placebo in 2,838 pa- simulate all complications of diabetes University of Michigan Model, and the tients aged 40–75 years with no clinical over 4- and 20-year time horizons, this Diabetes Decision Analysis and Cost of history of coronary, cerebrovascular, or article only presents data that can be com- Type 2 (DiDACT) Model. An open invita- severe peripheral vascular disease (LDL pared with the published CARDS results tion to all diabetes modelers was extended cholesterol Յ4.14 mmol/l [Յ160 mg/dl]; with the primary and secondary end to participate in the Fourth Mount Hood triglycerides Յ6.78 mmol/l [Յ600 mg/ points at 4 years. The interested reader is Challenge. Seven models participated in dl]) and at least one of the following: hy- referred to the online documentation the fourth challenge: the Cardiff Diabetes pertension (systolic blood pressure Ͼ140 from the meeting for results on other Model, the Sheffield Diabetes Model, the mmHg or diastolic blood pressure Ͼ80 complications and health economic out- UKPDS Outcomes Model, the UKPDS mmHg or taking antihypertensive medi- comes and for the 20-year horizon (13). Risk Engine, the EAGLE Model, the cation), retinopathy, micro- or mac- CORE Diabetes Model, and the CDC/RTI roalbuminuria, or current smoker (14). Type 1 diabetes: simulating the (Centers for Disease Control/Research The combined primary end point com- DCCT Triangle Institute) Type 2 Diabetes Pro- prised acute coronary heart disease The second part of the Mount Hood Chal- gression Model. An eighth model pre- (CHD) death, nonfatal myocardial infarc- lenge was to simulate the outcomes of the sented data from previous analyses (the tion (MI) including silent myocardial in- DCCT. Modelers were asked to simulate Archimedes Model). farction, hospitalized unstable angina, the DCCT type 1 diabetes interventions in resuscitated cardiac arrest, coronary re- the primary prevention cohort and the Cardiff Diabetes Model vascularization, and stroke. combined cohort (primary prevention The Cardiff Diabetes Model was pre- Results from CARDS were first re- and secondary interventions groups) over sented for the first time at the Fourth ported at the ADA 64th Annual Scientific time horizons of 9 (trial duration) and 20 Mount Hood Challenge Meeting and is a Sessions and posted on the CARDS Web years (17–24). Simulations were designed discrete event model that runs stochastic site (http://www.cardstrial.org) on 3 June to compare conventional with intensive simulations. It was programmed in Visual 2004 (15). For the challenge, modelers insulin therapy and were based on pub- Basic script embedded in Microsoft Excel (except Archimedes, see below) were sent lished DCCT data. Modelers were given and is structurally based on the Eastman information on 22 July 2004 by the various data from the trial to form the ba- Model of type 2 diabetes first published in Mount Hood 4 Steering Group on the de- sis of their simulations. This included the 1997 (22). It is designed to evaluate the sign of the trial, baseline characteristics of observations that A1C levels remained impact of new therapies typically in sim- people in the two groups, and, based on constant in the conventional group but ulated populations of up to 10,000 newly the ADA presentation, the effects of treat- decreased by 1.9% points in the intensive diagnosed type 2 diabetic patients. The ment on the most important biological therapy group; that separation in A1C model can accommodate type 2 diabetic outcomes over the duration of the trial, as curves was evident after 6 months and and nondiabetic populations using the well as the results for the primary and sec- was maintained over the long term; that UKPDS Risk Engine formula (3–5) and ondary end points (14). Archimedes per- major hypoglycemic event rates were 19 the Framingham risk equation, respec- formed its calculations before any per 100 patient-years on conventional tively. Standard outputs from model sim- postrandomization results were known. therapy and 62 per 100 patient-years in ulations include the incidence of The findings of CARDS were subse- the intensive therapy group; and that microvascular (retinopathy, neuropathy, quently published by Colhoun et al. (16). body weight increased by 4.6 kg more in or nephropathy) and macrovascular com- Modelers were challenged to simulate the the intensive therapy group than in the plications (congestive heart disease, MI, trial outcomes using information on the conventional group. Additional detail on sudden death, and cerebrovascular dis- baseline cohort characteristics and the assumptions made for these simula- ease defined as neurological deficit with
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1639 ADA Workgroup Report symptoms or signs lasting Ն1 month), with additional data from the Rochester UKPDS Risk Engine software provides a mortality, cost-effectiveness and cost- Epidemiology Project and the DCCT diabetes-specific alternative to the many utility data, and acceptability curves. (22). Similarly, the retinopathy and neu- existing coronary risk tools for the general Source data for the model have been ropathy submodels are based on the East- population. The UKPDS Risk Engine taken from DCCT and UKPDS report 64 man Model, with the former including equations have also been published (3– for nephropathy, and from UKPDS re- additional data from the UKPDS 50 report 5), in part so that they could be used in ports 56 and 60 for macrovascular com- (22,28). The Sheffield Diabetes Model developing simulation models for health plications (3,4,21,25). Risk factors was used to perform the CARDS challenge decision making. Although the UKPDS included in the simulations (dictated by at Mount Hood Challenge 4, but as this group has subsequently published their the risk formula used) include total cho- model is designed only to simulate the own simulation model (see UKPDS Out- lesterol, HDL cholesterol, A1C, systolic progression of type 2 diabetes, no results comes Model above), other models use blood pressure, smoking status, age, sex, for the DCCT challenge are presented. UKPDS Risk Engine equations in this ethnicity, and duration of diabetes. The way, including several reported here. Cardiff Diabetes Model includes health UKPDS Outcomes Model The Risk Engine equations available utility data (using the EQ-5D and the The UKPDS Outcomes Model was devel- at the time of the meeting estimated the SF-36 instruments) drawn from the oped at the University of Oxford on the risk of CHD, stroke, fatal CHD, and fatal Health Outcomes Data Repository data- basis of survival equations estimated us- stroke. (This corresponds to version 2 of base in Cardiff that includes data on ing 3,642 patients from the UKPDS, and the software; version 1 lacked fatal CHD 40,000 primary and secondary care pa- an article providing a full description of and fatal stroke, but otherwise gave iden- tients, of whom 3,000 have diabetes. As the model was published in Diabetologia tical results.) These currently available risk the model is not designed to simulate the (2). In summary, the UKPDS Outcomes equations use risk factors measured in the progression of type 1 diabetes, no data for Model is a probabilistic discrete-time first 2 years after diagnosis of diabetes. Sup- the DCCT challenge were presented at model that uses an integrated set of para- porting evidence for their use in cohorts Mount Hood Challenge 4. metric proportional hazard models to with recently diagnosed type 2 diabetes is predict absolute risk of first occurrence of available elsewhere (see the RESULTS AND DIS- Sheffield Diabetes Model seven major diabetes-related complica- CUSSION section). The CARDS challenge Work on the Sheffield Diabetes Model be- tions (ischemic heart disease, MI [fatal tested whether they could also be used in a gan in the School of Health and Related and nonfatal], heart failure, stroke, blind- cohort with several years since diagnosis of Research at the University of Sheffield, ness, renal failure, and amputation). diabetes. The forthcoming cardiovascular Sheffield, U.K., at the end of 2003, and These predictions are based on patient version of the UKPDS Risk Engine, which is the model was presented at the Fourth characteristics (such as age and sex) and designed for use at any time after diagnosis Mount Hood Challenge, even though it risk factors that vary with time (such as of diabetes, was not available at the time of was still considered to be under develop- A1C level and systolic blood pressure). the meeting (29). Like the Framingham ment. This model is designed to simulate Simulated patients start with a prespeci- equations, the UKPDS Risk Engine reports the progression of type 2 diabetes and fied health status and can experience one risk from censored survival models. It was consists of five submodels representing or more nonfatal complications or die incorporated into a simple simulation comorbidity classifications (CHD, stroke, during any of the annual cycles as the sim- model for the CARDS challenge. The nephropathy, retinopathy, and neuropa- ulation progresses. As a model of type 2 UKPDS Risk Engine is specific to type 2 di- thy). The effects of therapy are simulated diabetes, the UKPDS Outcomes Model abetes and did not participate in the DCCT on the progression of the three main risk was used to simulate the CARDS chal- challenge. factors—-A1C, lipids (total cholesterol lenge at the Mount Hood Challenge 4 but and HDL), and blood pressure. Smoking did not perform the DCCT challenge. The EAGLE Model status, age, sex, ethnicity, and duration of UKPDS Outcomes Model is available as The EAGLE Model was presented at the diabetes are also taken into consideration software from the UKPDS Web site Fourth Mount Hood Challenge Meeting in the CVD (CHD and stroke) submodels, (http://www.dtu.ox.ac.uk/). by Analytica International, Lo¨rrach, Ger- as these are primarily based on the For the CARDS challenge, the UKPDS many. The EAGLE Model has been out- UKPDS Risk Engine (UKPDS reports 56 Outcomes Model (and the UKPDS Risk lined at previous Mount Hood Challenge and 60) (3,4). Engine [see below]) used a simulated co- Meetings and is an object-oriented prob- For the CHD and stroke submodels, hort with mean risk factors, male-to- abilistic Monte Carlo simulation applica- source data were taken from various female ratio, smoking prevalence, and tion (30,31). A description of an updated UKPDS publications (3–5,26,27), British ethnic mix exactly equal to those reported version of the model (version 2.0) that Heart Foundation statistics, the PRAIS- for CARDS, with risk factor variances ap- captures the effects of more parameters/ U.K. (Prospective Registry of Acute Isch- proximately equal to those reported for variables has been recently published emic Syndromes in the U.K.) study, CARDS, and with correlations between (32). A Markov process with yearly inter- Minnesota population and NICE (Na- risk factors based on the UKPDS. vals and first- and second-order calcula- tional Institute for Clinical Excellence) tions was the basic structure for guidelines, the PROGRESS (Perindopril UKPDS Risk Engine development. Transition probabilities are Protection Against Recurrent Stroke The UKPDS Risk Engine is a coronary risk dependent on the status of the simulated Study) trial, and the Heart Protection calculator for clinical use. It is derived patient, with related calculations defined Study. The nephropathy submodel is from UKPDS data but designed to reflect internally. Among various demographics largely based on published data from the risk in the general type 2 diabetic popu- (e.g., age, duration of diabetes, and sex), Eastman Model of diabetes progression, lation, not to reproduce the UKPDS (3). physiologic characteristics (e.g., A1C and
1640 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 The Mount Hood 4 Modeling Group systolic blood pressure), preexisting com- connectivity and interaction between in- and inclusion of probabilistic sensitivity plications, and lifestyle input parameters dividual complication submodels. analyses. As the CDC/RTI Type 2 Diabetes (e.g., smoking), the main determinant of Separate transition probabilities and Progression Model was not designed to events is A1C, which is simulated over management strategies are used for type 1 simulate type 1 diabetes, only the CARDS time with regard to predefined target and type 2 diabetes wherever differential challenge simulations were performed for A1C. Twenty outcomes (e.g., hypoglyce- data exist. Source data for the model have the Fourth Mount Hood Challenge. mia, retinopathy, macular edema, end- been taken from a broad range of pub- stage renal disease, neuropathy, diabetic lished clinical and epidemiological stud- Archimedes Model foot syndrome, MI, and stroke) are pro- ies (7). The economics module allows Another model represented at the Fourth jected based on data from epidemiological estimation of direct and indirect costs, ap- Mount Hood Challenge was the and clinical trials including the DCCT, plies quality-of-life utilities/disutilities, Archimedes Model. Developed at Kaiser UKPDS, and WESDR (Wisconsin Epidemi- and allows users to perform cost- Permanente, the Archimedes Model has ological Study of Diabetic Retinopathy). It is effectiveness, cost-utility, budget impact, been presented at previous Mount Hood capable of simulating the progression of and cost-benefit analyses. The model has Meetings and described in a recent publi- type 1 and type 2 diabetes. The model gen- been validated against epidemiological cation (11). In essence, it is a mathemati- erates a virtual patient cohort of up to and clinical studies of type 1 diabetes (8). cal representation of the anatomy, 50,000 patients for each simulation apply- The CORE Diabetes Model was used to pathophysiology, signs, symptoms, behav- ing distribution assumptions to determine simulate the CARDS and DCCT chal- iors, tests, treatments, logistics, resources, patient characteristics. Events are assigned lenges at the Mount Hood Challenge 4 and outcomes associated with type 1 and to individual patients at the time of occur- Meeting. type 2 diabetes, as well as several other dis- rence. Results are reported as average values eases and conditions (CHD, congestive for each cohort simulation and as average CDC/RTI Type 2 Diabetes heart failure, asthma, stroke, hypertension, values for multiple iterations (of identical Progression Model and obesity). The model uses an object- simulations) as required. The model also The CDC/RTI Type 2 Diabetes Progres- oriented approach and differential equa- has a health economics module to provide sion Model was developed by the CDC tions to recreate a level of detail cor- output data on costs (of treatment and com- and RTI International. The model was de- responding to that in patient charts, medical plications), cost-consequence, quality of signed to assess interventions important textbooks, clinical practice guidelines, and life, and cost-effectiveness of interventions. to public health and has been presented at clinical trials. It covers a spectrum of The EAGLE Model version 2.0, with many previous Mount Hood Meetings and out- disease-related areas, taking into account more influence parameters and features, lined in several recent publications biological details, care processes, patient has been developed (documentation can be (9,10,33,34). Full details are in the Tech- and practitioner behaviors, logistics, re- obtained upon request from Analytica). nical Report for the CDC/RTI Type 2 Di- sources, costs, and quality of life. The model EAGLE Model version 1.2 was used to per- abetes Progression Model available represents biological variables and time form the simulations for the CARDS and directly from the CDC. The model is a continuously (any event can occur at any DCCT challenges at Mount Hood Chal- Markov simulation programmed in Cϩϩ time) and, unlike Markov modeling, has no lenge 4. that begins at the diagnosis of type 2 dia- distinct states or strata. It is capable of mod- betes and tracks a cohort until death. It is eling diseases and complications simulta- CORE Diabetes Model based on data from the UKPDS and sev- neously, enabling it to address comor- The CORE Diabetes Model was devel- eral other published sources. Patients bidities, syndromes, multiple treatments, oped by the Center for Outcomes Re- progress simultaneously through five dif- and treatments with multiple effects. Vali- search, Basel, Switzerland, and has been ferent disease paths in the model to sim- dation of the Archimedes Model against previously described in detail (7). It is an ulate the complications of diabetes clinical trials has been published, providing interactive computer model developed to (nephropathy, neuropathy, retinopathy, details of 74 validation exercises involving determine the long-term health outcomes CHD, and stroke). Transition probabili- 18 trials (12). and economic consequences of interven- ties for progression through these paths At the Fourth Mount Hood Chal- tions in type 1 or type 2 diabetes. The are dependent on time of diagnosis of lenge, the Archimedes Model presented model structure comprises 14 interde- type 2 diabetes, age, sex, ethnic group, the results of a publicly announced, pendent submodels that simulate the A1C level, smoking status, serum choles- blinded prospective prediction of the complications of diabetes (angina, MI, terol levels, and blood pressure. CARDS trial outcomes based on trial de- congestive heart failure, stroke, periph- For reporting clinical outcomes and sign information (e.g., inclusion/ eral vascular disease, diabetic retinopa- mortality, the CDC/RTI Type 2 Diabetes exclusion criteria, treatment protocols, thy, macula edema, cataract, hypo- Progression Model includes a health eco- and definitions of end points) and the glycemia, ketoacidosis, lactic acidosis, nomics module that allows calculation of prerandomization baseline patient char- nephropathy and end-stage renal disease, incremental cost-effectiveness ratios for acteristics, but without any postrandom- neuropathy, foot ulcer, and amputation) selected interventions. Cohorts can be de- ization data (14). The CARDS inves- and another simulating nonspecific mor- fined by age, sex, race, hypertension, cho- tigators conducted a specific analysis of tality. Each submodel is a Markov model lesterol, and smoking status. Updates the outcomes estimated by the using time, state, and diabetes type– since the Third Mount Hood Meeting in Archimedes Model (35). For type 1 dia- dependent probabilities. Monte Carlo Oxford, U.K., include incorporation of betes, the Archimedes modelers pre- simulation using tracker variables over- the UKPDS Risk Engine for simulation of sented the results of a previously comes the memory-less properties of the CVD, a facility to simulate screening for published validation of the model against standard Markov model and allows inter- type 2 diabetes and pre-diabetic states, the primary end points of the DCCT trial:
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1641 ADA Workgroup Report microalbuminuria, proteinuria, and reti- of values from 1.5% (CDC/RTI Type 2 tured via their impact on included risk nopathy in the primary prevention and Diabetes Progression Model) to 3.5% factors such as systolic blood pressure. secondary intervention cohorts (12). (Sheffield Diabetes Model) in the partici- (See Mount Hood 4 Web site for summary pating model simulations. statistics of the patient population used by RESULTS AND DISCUSSION In terms of reproducing the CARDS each group in their simulations.) The in- results, most of the models appeared to fluence of such differences on the re- CARDS comparisons slightly overestimate the incidence of ma- ported results could not be fully resolved The first challenge for the Mount Hood 4 crovascular complications. One reason during the meeting but is an important modelers was to simulate the progress of for this might be that the type 2 diabetic area for further research, as are the meth- the cohorts in the CARDS trial over a time population in CARDS was a specially se- ods used to construct these populations. horizon of 4 years taking into account ma- lected “low mortality risk” group, with no This point also highlights the importance crovascular complications by therapy al- previously documented history of CVD or of clinical detail in diabetes models. Out- location. The end points simulated by the preexisting major illnesses. As a result, comes such as CVD are affected by a va- models did not exactly accord with the the incidence of macrovascular complica- riety of risk factors. All of these risk factors reported CARDS end points (16) (Table tions may be lower than in other type 2 need to be considered in a model to accu- 1), and further details can be found on the diabetic populations such as the UKPDS. rately simulate disease progression, and, Mount Hood 4 Web site (13). For exam- Previous studies have indicated that using of course, accurate input data are essential ple, while most models attempted to sim- the Framingham risk formula in diabetic to producing realistic outcomes using any ulate total MI (fatal plus nonfatal MI), the populations underestimates the incidence simulation model. relevant published CARDS end point for of CVD (36–39). Many of the models par- comparison was “acute coronary events,” ticipating in the meeting used the UKPDS DCCT comparisons which also included hospitalized unstable Risk Engine to estimate the incidence of Three models at the Fourth Mount Hood angina, silent MI, and resuscitated cardiac cardiovascular complications. (Excep- Challenge were designed to specifically arrest. Full definitions of end points for tions were EAGLE, UKPDS Outcomes simulate type 1 diabetes: the EAGLE each model and those used in the CARDS Model, and Archimedes.) The version of Model, the CORE Diabetes Model, and study are available on the Mount Hood 4 the Risk Engine available in 2004 is opti- the Archimedes Model. In the cases of the Web site (13). mized for use in the early years of diabetes EAGLE and CORE Models, this was The 3.9-year total event rate of acute (3), whereas the CARDS population had a achieved using a modular approach, with coronary events in CARDS was 5.5% in mean duration of diagnosed diabetes of distinct approaches applied to the simu- the control group and 3.6% in the inter- almost 8 years. The Cardiff Diabetes Fore- lation of type 1 versus type 2 diabetes in vention arm (10 mg atorvastatin daily). caster, which adjusts the Risk Engine for keeping with the distinct etiologies of dis- Most of the models taking part in the chal- duration of diabetes, overestimated coro- ease. The Archimedes Model includes both lenge reported total event rates of MI over nary risk to a lesser extent than the Risk type 1 and type 2 diabetes in a single inte- a 4-year time horizon in the range of 5.3% Engine itself (Table 1). grated model. All of the other models at (UKPDS Outcomes Model) to 8.0% Another possible reason for the ap- Mount Hood 4 were designed only to sim- (UKPDS Risk Engine) for the control parent discrepancy is that when under- ulate the progression of type 2 diabetes. The group and 3.4% (Archimedes Model) to taking the CARDS challenge, each group Archimedes group performed its validation 5.7% (Sheffield Diabetes Model) for the had to make assumptions regarding the against the DCCT 2 years ago and reported intervention group (Table 1). (The characteristics of the population used in those previously calculated results at the Archimedes group presented 4.5-year cu- the simulation. Groups used a variety of Mount Hood 4 meeting. mulative incidence rates for acute coro- different methods that ranged from as- For the simulation of nephropathy nary events at the meeting; 4-year results suming patients had characteristics such complications, the DCCT reported a cu- were also reported and are shown here for as A1C equal to the reported mean values mulative incidence of microalbuminuria comparability with other models.) for the CARDS population and to the cre- (urinary albumin excretion rate 30–300 Model estimates of absolute risks of ation of synthetic populations using ex- mg/24 h) of 27.3% in the conventional stroke were close to those experienced in ternal data. We have provided summary treatment arm compared with 16.0% in the trial by either the control or interven- statistics for the patient characteristics the intensive treatment arm for the pri- tion group. However, the models did not used by each group in their simulations mary prevention cohort. These values generally predict the large reduction in on the Mount Hood 4 Web site. In some were projected to be 27.6 and 14.9% by risk experienced by the intervention instances there were significant differ- the CORE Diabetes Model and 28 and group in the trial (Table 1). In the control ences between the mean values for some 15% by the Archimedes Model. The group, CARDS reported a cumulative in- characteristics and those reported for the EAGLE Model projected higher cumula- cidence of total stroke (fatal plus nonfatal) CARDS population. For example, the tive incidence rates due to the fact that the of 3.2% over a median 4-year follow-up Archimedes Model created a population secondary prevention cohort was used as period. This compared with model simu- in which 42% of the population was fe- basis for simulations (41.7 and 25.3% in lation values ranging between 1.7% male, compared with only 32% in the the conventional and intensive treatment (CDC/RTI Type 2 Diabetes Progression CARDS study population. Other models, arms, respectively). The DCCT reported Model) and 3.9% (Sheffield Diabetes for example, the UKPDS Outcomes 9-year cumulative incidences of mi- Model) for the participating models. In Model, did not directly incorporate any croalbuminuria of 42.1% in the conven- the atorvastatin intervention group, the therapy-specific information, such as tional treatment arm and 26.2% in the cumulative incidence of stroke was 1.7% whether patients were on ACE inhibitors, intensive treatment arm in the secondary in CARDS, which compared with a range on the assumption that their effect is cap- prevention cohort. As all groups had used
1642 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 The Mount Hood 4 Modeling Group
Table 1—CARDS cumulative incidence of cardiovascular events challenge: observed rates of disease in CARDS
Observed event rates reported by CARDS Acute coronary Any acute events Stroke CVD events Comments CARDS total event rate* Number of events during a median 3.9 years Control† 5.5 (4.3–6.6) 2.8 (1.9–3.6) 13.4 (11.6–15.2) divided by number of patients at baseline. The Intervention‡ 3.6 (2.6–4.5) 1.5 (0.8–2.1) 9.4 (7.9–10.9) best comparison for model results available at the time of the meeting. CARDS 4-year cumulative Cumulative hazard at 4.0 years estimated by the incidence§ Nelson-Aalen method. The best possible Control 5.1 (4.0–6.2) 3.2 (2.3–4.1) 4.9 (12.8–16.4) comparison for model-calculated results. Intervention 3.2 (2.3–4.1) 1.4 (0.8–2.0) 9.6 (8.1–11.1)
Model-predicted 4-year total event rates for the CARDS cohort, presented at the fourth Mount Hood Challenge Meeting Fatal plus Any acute CVD nonfatal MI‡ Stroke event Comments CDC/RTI Control 6.4 1.7 10.2 Intervention 4.3 1.5 6.9 EAGLE Results available only for pooled data. Control 3.9# 0.8** 8.4 Intervention — — — CARDIFF Control 6.7 2.5 9.2 Intervention 4.5 2.2 6.7 SHEFFIELD Model was still under development at time Control 7.8 3.9 12.4 of analysis. Unstable angina and Intervention 5.7 3.5 9.6 secondary events included. UKPDS Outcomes Model MI is defined as nonfatal MI, fatal vascular Control 5.3 2.3 — cardiac event, or sudden death. Intervention 3.6 2.0 — UKPDS Risk Engine Successful validation results for the Risk Control 8.0 2.9 10.4 Engine, against observational data, are Intervention 5.2 2.5 7.4 reported in the text. CORE MI is defined as nonfatal or fatal vascular Control 6.4 2.0 — cardiac event or sudden death. Intervention 4.5 1.7 —
Model-predicted 4-year cumulative incidence rates Acute coronary Any acute CVD events Stroke event Comments Archimedes Control 5.4 3.2 — 4.5-year cumulative incidence rates reported at the meeting for acute coronary events were placebo predicted, 6.0% (actual, 6.0%); atorvastatin predicted, 4.0% (actual, 4.0%). Intervention 3.4 2.7 — Data are % (95% CI) where available, for comparison to the rates predicted by the models (estimated cumulative incidence rates by 4.0 years except where indicated. *Reference 16; acute coronary events included: MI, silent MI, unstable angina, acute CHD, death, and unresucitated cardiac arrest, all hospital verified. Stroke and any acute CVD events were also hospital verified. †Control was a placebo. ‡Intervention was atorvostatin. §Reference 35 and unpublished correspondence from Prof. Helen Colhoun on behalf of the CARDS Group. Acute coronary events were defined as above for note*, except for omission of unstable angina. Stroke and any acute CVD events as “note 1.” ʈUnless otherwise indicated, the predicted rates for fatal plus nonfatal MI do not include any of the following: silent MI, unstable angina, and some forms of acute CHD death. #Nonfatal MI. **Nonfatal stroke.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1643 ADA Workgroup Report
Table 2—DCCT cumulative incidence of complications challenge (9-year time horizon in the primary prevention cohort)
DCCT EAGLE CORE Archimedes* Conventional Intensive Conventional Intensive Conventional Intensive Conventional Intensive therapy therapy therapy therapy therapy therapy therapy therapy Microalbuminuria† 27.3 16.0 41.7‡ 25.3‡ 27.6 14.9 28.0 15.0 Background retinopathy 52.2 14.3 76.9§ 69.6§ 39.4 14.4 40.0 13.0 Peripheral neuropathyʈ 63.2, 21.3 27.7, 10.0 18.1 5.2 64.0 25.0 —— Data are %. *Archimedes data are from a previously published validation exercise (ref. 12). †Urinary albumin excretion rate 30–300 mg/24 h. ‡EAGLE Model used the second prevention cohort as the basis for simulations. §Events were modeled according to WESDR data (see DCCT comparisons). ʈBold face data refer to neuropathy defined as abnormal curve condition in the DCCT; data not in bold face refer to neuropathy defined as confirmed clinical neuropathy (identifiedby clinical examination). the DCCT to develop their model, these ripheral neuropathy identified by clinical Archimedes group presented previously should be regarded as internal validation examination and confirmed by subse- published results for of external valida- exercises (1). quent investigation (21.3 and 10.0% in tions against nine clinical trials, of which The development of background the conventional and intensive groups of eight were completely successful and the retinopathy, defined as a three-step the extrapolated DCCT data, respec- ninth partially successful (12). Of the change in patients without retinopathy tively) and projected cumulative inci- other models, for EAGLE and the UKPDS at baseline using the retinopathy assess- dences of 18.1 and 5.2% for the Outcomes Model results were reported ment scale for the DCCT, was also pro- conventional and intensive groups, re- from successful internal validations: tests jected (Table 2). The CORE Diabetes spectively (derived from the weighted against the data on which the model was Model projection of cumulative inci- mean of the intensive group). The re- built. The ADA guidelines for diabetes dence of diabetic retinopathy in the in- ported cumulative incidences of periph- modeling encourage validation, prefera- tensive treatment group corresponded eral neuropathy after 5 years were 15.2 bly external validation, wherever possible closely to the DCCT data (14.4 vs. and 6.9% for the conventional and inten- (1). The DiDACT group argued that vali- 14.3%, respectively), but less so in the sive arm, respectively, in the DCCT. For dation has limited value because valida- conventional treatment group (39.4 vs. neuropathy, the Archimedes Model cal- tion exercises (e.g., comparison to 4-year 52.2%, respectively). The Archimedes culates the Semmes-Weinstein 20 g test results from CARDS) are narrow com- Model projected comparable values of (40), which was not reported by the pared with real applications (e.g., estimat- 13 and 40% for the two groups, respec- DCCT. ing lifetime outcomes). Others argued tively. The EAGLE group, which used that a limited test of a model is preferable data from the WESDR to build its model General discussion and future to no test. of retinopathy (proliferative and non- directions The second methodological session proliferative), calculated higher inci- In a methodological session at the Mount was used by different speakers to empha- dence rates for retinopathy than Hood Challenge 4 Meeting, modelers size different aspects of statistical uncer- reported by the DCCT, providing values were invited to summarize their valida- tainty. The UKPDS group presented of 69.6 and 76.9% in the intensive and tion results to date. Several groups re- results from their Outcomes Model that conventional treatment groups, respec- ported “external validations”— tests demonstrated the importance of eliminat- tively. It is worth noting that for this end against data independent from the model. ing first-order uncertainty, which is the point, the 9-year value from the DCCT The Cardiff group reported that their uncertainty that arises when Monte Carlo had a wide range of uncertainty due to model had successfully predicted cardio- simulation is the method used for model the very small number of patients in the vascular event rates in the Cardiff Diabe- calculations. Some models (CDC, UKPDS study for that duration (Ͻ50 people). tes Registry. Since the model derives Risk Engine, and DiDACT) use calcula- A similar pattern was observed for the cardiovascular risk from the UKPDS Risk tion methods that are not subject to first- onset of peripheral neuropathy end point. Engine, not Cardiff data, this is an exter- order uncertainty. Others (CORE, The 9-year cumulative incidence of neu- nal validation. The UKPDS group re- Cardiff, EAGLE, Sheffield Diabetes ropathy values (defined as abnormal ported a validation of the current Risk Model, UKPDS Outcomes Model, and nerve conduction) extrapolated from Engine by an independent group in a Global Diabetes Model) eliminate first- DCCT data for the primary prevention co- community-based cohort with newly di- order uncertainty by averaging over mul- hort were 63.2 and 27.7% for conven- agnosed diabetes. The CHD event rate tiple simulation runs. Results from tional therapy and intensive therapy, predicted by the Risk Engine was close to Archimedes are based on single simula- respectively (22). Projections using the the observed rate (within the 95% confi- tion runs. “Second-order” uncertainty, CORE Diabetes Model produced values of dence interval) (37). The Cardiff result statistical uncertainty in model parame- 64.0 and 25.0%, respectively, for periph- mentioned above also supports use of the ters, is addressed via confidence intervals eral neuropathy. The reported cumulative current Risk Engine. The CORE group in some models and via probabilistic sen- incidence after 5 years was 40.2 and presented a mixture of external and inter- sitivity analysis in others (1). No single 16.5% for the conventional and intensive nal validation results against many stud- group presented results on model uncer- arms, respectively, in the DCCT. The ies, with the external validations tainty or variation in results due to differ- EAGLE Model used the definition of pe- predominantly successful (8). The ent design decisions in modeling (41).
1644 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 The Mount Hood 4 Modeling Group
The Mount Hood Meetings can be seen as With this drive toward validity for end Additional contributions an investigation of this important source users and the growing demand for accu- Alan Brennan, MSc (University of Shef- of uncertainty that is often overlooked be- rate diabetes models, especially for a dis- field, Sheffield, U.K.); Wiley Chan, MD cause it is difficult to quantify in any sin- ease with such a huge financial burden in (Global Diabetes Model, Kaiser Perma- gle model (1). a global climate of limited health care re- nente, Northwest Region, Portland, OR); An important discussion point at the sources, meetings such as the Mount Alan Russell, PhD (Kaiser Permanente, Fourth Mount Hood Challenge was the Hood Challenge, where competing mod- Southern CA); Thomas Hoerger, PhD issue of the meeting’s limitations and eling groups compare and contrast mod- (Centers for Disease Control and Preven- whether it offers a fair comparison across els with clinical trial data, could have an tion, Atlanta, GA); Katherine Hicks, MSc all diabetes models. The DiDACT Model increasingly important role to play in (Centers for Disease Control and Preven- group declined to compete in Mount coming years. tion, Atlanta, GA); Roman Casciano, MSc Hood Challenge 4, arguing that none of (EAGLE Model, Analytica International, the end points presented in the challenge Lo¨rrach, Germany); Rito Bergemann, MD were comparable with their model out- Acknowledgments— The Fourth Mount (EAGLE Model, Analytica International, puts (as in most cases they did not use the Hood Challenge Meeting was supported by an Lo¨rrach, Germany). same measures). It was emphasized that, unrestricted grant from Novo Nordisk and although discrete event simulation mod- hosted by the Center for Outcomes Research els are most widely used, other types of in Basel, Switzerland. Richard Stevens is funded by the Health Foundation. References model exist that have a serious and signif- The Mount Hood 4 modelers thank Novo 1. American Diabetes Association Consen- icant contribution to make to diabetes Nordisk A/S for the provision of an unre- sus Panel: Guidelines for computer mod- modeling. stricted grant to support the Fourth Mount eling of diabetes and its complications In past Mount Hood Challenge meet- Hood Challenge and Professor Helen Colhoun (Consensus Statement). Diabetes Care 27: ings, participants have compared out- and the CARDS group for their support in pre- 2262–2265, 2004 comes for hypothetical diabetes cohorts paring this article. We would also like to thank 2. Clarke PM, Gray AM, Briggs A, Farmer AJ, and interventions. While interesting com- the Center for Outcomes Research and in par- Fenn P, Stevens RJ, Matthews DR, Strat- parisons were made and important differ- ticular Josh Ray for their work behind the ton IM, Holman RR: A model to estimate ences between models identified, the scenes to ensure the smooth running of the the lifetime health outcomes of patients meeting. with type 2 diabetes, UK Prospective Di- format of previous Mount Hood Chal- abetes Study (UKPDS): the United King- lenges was limited in that there were no dom Prospective Diabetes Study (UKPDS) “real-life” data to use as a yardstick. As a APPENDIX Outcomes Model (UKPDS no. 68). Diabe- result, it was not possible to test the ex- tologia 47:1747–1759, 2004 ternal validity of the participating models’ The Mount Hood 4 Modelers 3. Stevens RJ, Kothari V, Adler AI, Stratton forecasts. Previous Mount Hood Chal- Andrew J. Palmer, MBBS (CORE, Basel, IM, Holman RR: The UKPDS risk engine: lenges were restricted by incomplete co- Switzerland); Ste´phane Roze, MSc a model for the risk of coronary heart dis- hort and treatment definitions; therefore, (CORE, Basel, Switzerland); William J. ease in type II diabetes (UKPDS 56). Clin assumptions on key input parameters had Valentine, PhD (CORE, Basel, Switzer- Sci (Lond) 101:671–679, 2001 to be made. Moreover, each modeling land); Philip McEwan, PhD (University of 4. Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, Holman RR: UKPDS group applied its own utility functions Cardiff, Cardiff, U.K.); Michael Gillett, 60: risk of stroke in type 2 diabetes esti- and cost settings, leading to different as- BSc, CIMA (University of Sheffield, Shef- mated by the UK Prospective Diabetes sumptions being made by each group, field, U.K.); Michael Holmes, BSc (Uni- Study risk engine. Stroke 33:1776–1781, which contributed to the divergence in versity of Sheffield, Sheffield, U.K.); 2002 forecast outcomes. Philip Clarke, PhD (UKPDS, University of 5. Stevens RJ, Coleman RL, Adler AI, Strat- Mount Hood Challenge 4 was de- Oxford, Oxford, U.K.); Richard Stevens, ton IM, Matthews DR, Holman RR: Risk signed with these previous limitations in PhD (UKPDS, University of Oxford, Ox- factors for myocardial infarction case fa- mind and taking into consideration the ford, U.K.); Alastair M. Gray, PhD tality and stroke case fatality in type 2 di- fact that key steps toward having diabetes (UKPDS, University of Oxford, Oxford, abetes: UKPDS 66. Diabetes Care 27:201– models widely accepted by decision- U.K.); Ruth Coleman, MSc (UKPDS, Uni- 207, 2004 6. Stevens RJ: Evaluation of methods for in- makers and physicians are those of trans- versity of Oxford, Oxford, U.K); Stephen terval estimation of model outputs, with parency and validity. Models must be Sorensen, PhD (Centers for Disease Con- application to survival models. J Appl Stat understood by their target audience and trol and Prevention, Atlanta, GA); Elvira 30:967–981, 2003 trusted by the end users. It therefore Mu¨ ller, PhD, MPH (EAGLE Model, Ana- 7. Palmer AJ, Roze S, Valentine WJ, Minshall seems essential that modelers make every lytica International, Lo¨rrach, Germany); ME, Foos V, Lurati FM, Lammert M, Spi- effort to clearly describe and validate their Stefan Walzer, MA (EAGLE Model, Ana- nas GA: The CORE Diabetes Model: pro- models and quantify and explain predic- lytica International, Lo¨rrach, Germany); jecting long-term clinical outcomes, costs tive differences between models. Such is- David M. Eddy, MD (Archimedes Model, and cost-effectiveness of interventions in sues are not confined to diabetes Kaiser Permanante, San Francisco, CA); diabetes mellitus (types 1 and 2) to sup- modeling; a recent exercise in which re- Richard Kahn, PhD (ADA, Alexandria, port clinical and reimbursement decision- making. Curr Med Res Opin 20 (Suppl. 1): searchers developed seven independent VA); Adrian Bagust, PhD (DiDACT S5–S26, 2004 statistical models of breast cancer inci- Model, University of Liverpool, Liver- 8. Palmer AJ, Roze S, Valentine W, Minshall dence and mortality to assess the effects of pool, U.K.); and Jonathan Brown, PhD M, Foos V, Lurati F, Lammert M, Spinas screening and adjuvant therapy reported (Global Diabetes Model, Kaiser Perma- GA: Validation of the CORE Diabetes substantial variability across models (42). nente, Northwest Region, Portland, OR). Model against epidemiological and clini-
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American Diabetes Association: The Diabe- lator for type 2 diabetes (Abstract). Diabe- monofilaments to the Weinstein Enhanced tes Control and Complications Trial tes 54 (Suppl. 1):A172, 2005 Sensory Test. J Hand Ther 6:11–22, 1993 (DCCT): design and methodological con- 30. Mu¨ ller E, Maxion-Bergemann S, Gultyaev 41. Chatfield C: Model uncertainty, data min- siderations for the feasibility phase: the D, Walzer S, Bergemann R: EAGLE Dia- ing and statistical inference. J R Stat Ser DCCT Research Group. Diabetes 35:530– betes Model: basic features and internal Stat Soc A:419–466, 1995 545, 1986 validation of simulating long-term dia- 42. Berry DA, Cronin KA, Plevritis SK, Fry- 19. American Diabetes Association: Imple- betic outcomes and related costs (Ab- back DG, Clarke L, Zelen M, Mandelblatt mentation of treatment protocols in the stract). Value Health 7:745, 2004 JS, Yakovlev AY, Habbema JD, Feuer EJ: Diabetes Control and Complications 31. 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1646 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Reviews/Commentaries/ADA Statements CONSENSUS STATEMENT
Waist Circumference and Cardiometabolic Risk A Consensus Statement from Shaping America’s Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; the American Society for Nutrition; and the American Diabetes Association
1 5 SAMUEL KLEIN, MD RUDOLPH L. LEIBEL, MD tant risk factor for obesity-related dis- 2 6 DAVID B. ALLISON, PHD CATHY NONAS, MS, RD, CDE eases. Excess abdominal fat (also known 3 7 STEVEN B. HEYMSFIELD, MD RICHARD KAHN, PHD 4 as central or upper-body fat) is associated DAVID E. KELLEY, MD with an increased risk of cardiometabolic disease. However, precise measurement of abdominal fat content requires the use besity is an important risk factor for plications and mortality rate (e.g., 3,4). of expensive radiological imaging tech- cardiometabolic diseases, including Men and women who have a BMI Ն30 niques. Therefore, waist circumference O diabetes, hypertension, dyslipide- kg/m2 are considered obese and are gen- (WC) is often used as a surrogate marker mia, and coronary heart disease (CHD). erally at higher risk for adverse health of abdominal fat mass, because WC cor- Several leading national and international events than are those who are considered relates with abdominal fat mass (subcuta- institutions, including the World Health overweight (BMI between 25.0 and 29.9 neous and intra-abdominal) (5) and is Organization (WHO) and the National kg/m2) or lean (BMI between 18.5 and associated with cardiometabolic disease Institutes of Health, have provided guide- 24.9 kg/m2). Therefore, BMI has become risk (6). Men and women who have waist lines for classifying weight status based on the “gold standard” for identifying pa- circumferences greater than 40 inches BMI (1,2). Data from epidemiological tients at increased risk for adiposity- (102 cm) and 35 inches (88 cm), respec- studies demonstrate a direct correlation related adverse health outcomes. tively, are considered to be at increased between BMI and the risk of medical com- Body fat distribution is also an impor- risk for cardiometabolic disease (7). These cut points were derived from a re- gression curve that identified the waist ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● circumference values associated with a BMI Ն30 kg/m2 in primarily Caucasian From the 1Division of Geriatrics and Nutritional Science, Center for Human Nutrition, Washington Uni- versity School of Medicine, St. Louis, Missouri; the 2Clinical Nutrition Research Unit, University of Alabama men and women living in north Glasgow at Birmingham, Birmingham, Alabama; the 3Clinical Research Department, Metabolism, Merck Pharmaceu- (8). tical Company, Rahway, New Jersey; the 4Obesity and Nutrition Research Center, University of Pittsburgh, 5 An expert panel, organized by the Na- Pittsburgh, Pennsylvania; the Naomi Berrie Diabetes Center, Columbia University, New York, New York; tional Heart, Lung and Blood Institute, the 6Obesity and Diabetes Programs, North General Hospital, New York, New York; and the 7American Diabetes Association, Alexandria, Virginia. has recommended that WC be measured Address correspondence and reprint requests to Samuel Klein, MD, Washington University School of as part of the initial assessment and be Medicine, 660 South Euclid Ave., Campus Box 8031, St. Louis, MO 63110. E-mail: [email protected]. used to monitor the efficacy of weight loss Approved for publication 7 March 2007. therapy in overweight and obese patients D.B.A. has received research grants from Frito-Lay and OMP; has served as a consultant to Kraft Foods, Ͻ 2 Pfizer, Bristol-Myers Squibb, and Bio Era; and has received financial support from Lilly, Pfizer, Merck who have a BMI 35 kg/m (7). How- Pharmaceutical Company, Unilever, Coca-Cola, General Mills, International Life Sciences Institute, Glaxo- ever, measurement of WC has not been SmithKline, OMP, Jansen Pharmaceuticals, and Frito-Lay. S.K. has received research grants from Sanofi- widely adopted in clinical practice, and Aventis, Merck, and Takeda for clinical trials; has served as a consultant to Sanofi-Aventis, Amylin the anatomical, metabolic, and clinical Pharmaceuticals, EnteroMedics, Dannon-Yakult, and Merck Pharmaceutical Company. S.B.H. is an em- ployee of Merck Pharmaceutical Company. D.E.K. has received research grants from Novartis Pharmaceu- implications of WC data can be confus- ticals, Sanofi-Aventis, and Pfizer; has served as a consultant/advisor to Novartis Pharmaceuticals, Sanofi- ing. Therefore, Shaping America’s Health: Aventis, Pfizer, Merck Pharmaceutical Company, and GlaxoSmithKline; and has been on speaker’s bureaus Association for Weight Management and for Novartis Pharmaceuticals, Sanofi-Aventis, and Merck Pharmaceutical Company. R.L.L. has received Obesity Prevention; NAASO: The Obesity research grants from GlaxoSmithKline and has been a consultant/advisor to Amylin Pharmaceuticals, Merck Pharmaceutical Company, Arisaph Pharmaceuticals, and Genaera Corporation. C.N. has been a consultant/ Society; and the American Diabetes Asso- advisor to Amylin Pharmaceuticals, GlaxoSmithKline, and Slim Fast. ciation convened a panel, comprised of Abbreviations: CHD, coronary heart disease; CT, computed tomography; IAAT, intra-abdominal adi- members with expertise in obesity man- pose tissue; MRI, magnetic resonance imaging; NHANES III, National Health and Nutrition Examination agement, obesity-related epidemiology, Survey III; SAAT, subcutaneous abdominal adipose tissue; WC, waist circumference; WHO, World Health Organization. adipose tissue metabolic pathophysiol- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ogy, statistics, and nutrition science to re- factors for many substances. view the published scientific literature DOI: 10.2337/dc07-9921 and hear presentations from other experts © 2007 by NAASO and the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby in these fields. The Consensus Panel met marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. from December 17 to 20, 2006, in Wash-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1647 Consensus Statement ington, DC, and was charged to provide Table 1—Distribution of adipose tissue mass commonly used to describe intra- answers to the following four questions: in lean and obese men abdominal fat and includes both intra- 1. What does waist circumference peritoneal fat (mesenteric and omental measure? Lean Obese fat), which drains directly into the portal 2. What are the biological mecha- men men circulation, and retroperitoneal fat, which nisms responsible for the associa- drains into the systemic circulation. tion between waist circumference BMI (kg/m2) 23 37 Magnetic resonance imaging (MRI) and cardiometabolic risk? Body weight (kg) 71 116 and computed tomography (CT) are con- 3. What is the power of waist cir- Body fat (%) 15 32 sidered the gold-standard methods for cumference to predict adverse car- Total body fat (kg) 10 37 determining the quantity of subcutaneous diometabolic outcomes? How Total subcutaneous fat (kg) 9 32 abdominal adipose tissue (SAAT) and in- does the predictive power of waist Abdominal fat (kg) 4.3 12.3 tra-abdominal adipose tissue (IAAT) (17). circumference compare with that Subcutaneous (kg) 2.4 7.2 Most MRI and CT methods involve acqui- of BMI? Does measuring waist cir- Intra-abdominal (kg) 1.9 5.1 sition of cross-sectional abdominal im- cumference in addition to BMI im- Intraperitoneal (kg) 1.1 3.5 ages, which are then analyzed for fat prove predictability? Retroperitoneal (kg) 0.8 1.6 content. A single slice is often acquired at 4. Should waist circumference be Adapted from reference 16. the L4-L5 intervertebral level to estimate measured in clinical practice? SAAT and IAAT volume, expressed as 3 cm . However, L4-L5 imaging does not surements are typically taken three times provide the best estimate of total IAAT QUESTION 1: What does waist and recorded to the nearest 0.1 cm. Al- mass, which is more reliably estimated circumference measure? though specific techniques have been rec- several centimeters cephalad of the L4-L5 Measurement technique. Waist cir- ommended for measuring WC in the intervertebral space (17,18). In addition, cumference is actually a perimeter, which clinical setting (2,10), there is no uni- measurement site influences the relation- provides an estimate of body girth at the formly accepted approach. Training tech- ship between IAAT volume and cardio- level of the abdomen. Different anatomi- nicians and even patients to use an metabolic risk; the association between cal landmarks have been used to deter- appropriate technique for measuring WC IAAT volume and presence of the meta- mine the exact location for measuring WC is essential to obtain reliable data; special bolic syndrome is greater when IAAT vol- in different clinical studies, including: 1) tape measures, instructional manuals, ume is determined at the L1-L2 than at the midpoint between the lowest rib and the and videotapes are available for this pur- L4-L5 level (19). Currently, there is no iliac crest; 2) the umbilicus; 3) narrowest pose (11). universally accepted site for measuring (minimum) or widest (maximum) waist The reproducibility of WC measure- IAAT and SAAT. circumference; 4) just below the lowest ments at all sites is high for both men and The relationship between WC, rib; and 5) just above the iliac crest. The women (e.g., iliac crest site, intra-class weight, and BMI can be conceptualized specific site used to measure WC influ- correlation coefficient, r ϭ 0.998 and r ϭ by using simple geometric relationships ences the absolute WC value that is ob- 0.999, respectively) (9,12,13). The corre- that consider the body as a cylinder; WC tained (9). The most commonly used sites lation between technician- and self- is the cylinder’s circumference, height is reported in studies that evaluated the re- measured WC after proper training can its length, and weight is a measure of lationship between morbidity or mortal- also be high for both men (r ϭ 0.95) and mass. Therefore, BMI provides informa- ity rate and WC were at the midpoint women (0.89), respectively (14). How- tion about body volume and mass, and between the lowest rib and the iliac crest ever, self-reported measurements are WC provides information about body (29%), umbilicus (28%), and narrowest prone to a systematic bias, and there is a shape. In general, BMI and WC are highly waist circumference (22%). Although nontrivial underestimate of self-measured correlated, typically with r values in the sites that use an easily identifiable and re- WC at all anatomic sites (15). range of 0.80–0.95 (20), and WC reflects producible landmark (e.g., just above the Anatomical relationships. Adipose tis- both SAAT and IAAT volumes (21). The bony landmark of the lilac crest) might be sue consists of adipocytes, inflammatory relationships among WC, BMI, and adi- more precise and easier to use than other cells, and vascular, connective, and neu- pose tissue compartments in primarily sites, we are not aware of data from any ral tissues. Adipose tissue is distributed Caucasian and African-American men studies that demonstrate an advantage of throughout the body, as large homoge- and women are shown in Table 2 (18). one measurement site over others. neous discrete compartments and as These data demonstrate that both BMI Waist circumference measurements small numbers of cells “marbling” or ad- and WC are strongly correlated with total should be made around a patient’s bare jacent to other tissues. Most adipose tis- body adipose tissue mass but that WC is a midriff, after the patient exhales while sue (ϳ85% of total adipose tissue mass) is better predictor of IAAT than is BMI. standing without shoes, both feet touch- located under the skin (subcutaneous Assessment of WC provides a mea- ing, and arms hanging freely. The measur- fat), and a smaller amount (ϳ15%) is lo- sure of fat distribution that cannot be ob- ing tape should be made of a material that cated within the abdomen (intra- tained by measuring BMI. However, there is not easily stretched, such as fiberglass. abdominal fat) in lean and obese persons is no standardized approach for measur- The tape should be placed perpendicular (Table 1) (16). The relative contribution ing WC and different anatomical land- to the long axis of the body and horizontal of intra-abdominal fat mass to total body marks have been used to measure WC in to the floor and applied with sufficient fat is influenced by sex, age, race/ different studies. Moreover, the measure- tension to conform to the measurement ethnicity, physical activity, and total adi- ment site that provides the best correla- surface. In a research setting, WC mea- posity. The term “visceral fat” is tion with disease risk and best reflects
1648 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Klein and Associates
Table 2—Relationships among waist circumference, BMI, and adipose tissue compartments in volved in the association between abdom- men and women inal fat mass and adverse metabolic consequences. Men Women QUESTION 3: What is the power of Waist Waist waist circumference to predict BMI circumference BMI circumference adverse cardiometabolic outcomes? Total adipose tissue 0.82 0.87 0.91 0.87 How does the predictive power of Percent body fat 0.70 0.79 0.86 0.82 waist circumference compare with Total subcutaneous 0.82 0.83 0.91 0.86 that of BMI? Does waist adipose tissue circumference measurement in Total intra-abdominal 0.59 0.79 0.69 0.77 addition to BMI improve adipose tissue predictability? The importance of WC in predicting car- Data are correlation coefficients. Adapted from reference 18. diometabolic risk factors (e.g., elevated blood pressure, dyslipidemia, and hyper- changes in abdominal adipose tissue mass limited ability of subcutaneous fat depots glycemia) and adverse outcomes (e.g., di- has not been established. Nonetheless, to store excess energy results in “over- abetes, CHD, and death rate) has been the precision of WC measurement is high flow” of chemical energy to IAAT and “ec- examined in many large epidemiological at any given landmark. Even self- topic” sites, such as liver and skeletal studies (7,24–33). Specific relative risks measurement can be highly reproducible muscle. Excessive ectopic fat accumula- between WC and these outcomes vary, when performed by properly trained sub- tion then causes metabolic dysfunction in depending on the population sampled jects, although self-measurement results those organs. In fact, increased intrahe- and the outcome measured. The relation- in an underestimation of true WC. Mea- patic fat is associated with dyslipidemia ship between WC and clinical outcome is surement of WC cannot determine the in- and hepatic insulin resistance (23), and consistently strong for diabetes risk, and dividual contributions of SAAT and IAAT increased intramyocellular fat is associ- WC is a stronger predictor of diabetes to abdominal girth, which require imag- ated with skeletal muscle insulin resis- than is BMI. The relative risk of develop- ing by MRI or CT. The value of these scan- tance (24). In this paradigm, IAAT is ing diabetes between subjects in the high- ning techniques in clinical practice has primarily a marker of the magnitude of est and lowest categories of reported WC not been determined. overflow of fatty acids from subcutaneous often exceeds 10 and remains statistically depots. Therefore, increased WC could be a significant after adjusting for BMI. These QUESTION 2: What are the discernible marker of a system-wide im- data demonstrate that WC can identify biological mechanisms responsible pairment in energy storage regulation, in persons who are at greater cardiometa- for the association between waist which an increase in IAAT reflects a re- bolic risk than those identified by BMI circumference and metabolic and duced capacity for energy storage in other alone. Values for WC are also consistently cardiometabolic risk? adipose tissues. A third hypothesis pro- related to the risk of developing CHD, It is not known whether the storage of an poses a direct effect of omental and mesen- and the relative risk of developing CHD absolute or relative excess amount of tri- teric adipose tissue depots on insulin between subjects in the highest and low- glycerides in abdominal fat depots is di- resistance, lipoprotein metabolism, and est categories of WC ranges from 1.5 to rectly responsible for increased disease blood pressure. Metabolic products of 2.5 and remains statistically significant af- risk or whether such deposition is simply omental and mesenteric adipose tissue de- ter adjusting for BMI. Values for WC are associated with other processes that cause pots are released into the portal vein, which usually strongly associated with all-cause risk, or both. In addition, WC values pro- provides direct delivery to the liver. Lipoly- and selected cause-specific mortality vide a measure of both SAAT and IAAT sis of omental and mesenteric adipose tissue rates. Data from several studies support masses. Therefore, the relationship be- triglycerides release free fatty acids that can the notion that WC is an important pre- tween WC and cardiometabolic risk can- induce hepatic insulin resistance and dictor of diabetes, CHD, and mortality not determine whether risk is associated provide substrate for lipoprotein synthesis rate, independent of traditional clinical with SAAT, IAAT, or both. and neutral lipid storage in hepatocytes. In tests, such as blood pressure, blood glu- The mechanism(s) responsible for the addition, specific proteins and hormones cose, and lipoproteins (7,26). However, relationship between excess abdominal produced by omental and mesenteric adi- there is not yet a compelling body of evi- fat distribution and cardiometabolic dis- pose tissue, such as inflammatory adipo- dence demonstrating that WC provides ease is not known, but several hypotheses kines, angiotensinogen, and cortisol clinically meaningful information that is have been proposed. One of the earliest (generated by local activity of 11 -hydrox- independent of well-known cardiometa- hypotheses that implicated IAAT as a met- ysteroid dehydrogenase), can also contrib- bolic risk factors. abolic risk factor suggested that activation ute to cardiometabolic disease. A fourth The relationships between WC and of the central nervous system–adrenal hypothesis is that genes that predispose to health outcomes are affected by demo- axis by environmental stressors caused preferential deposition of fat in abdominal graphic variables, including sex, race/ both the preferential deposition of adi- depots independently cause cardiometa- ethnicity, and age. WC is an important pose tissue in the trunk and the cardio- bolic disease. predictor of health outcomes in men and vascular and metabolic disorders These hypotheses are not mutually women; Caucasians, African Americans, associated with that deposition (22). exclusive, and it is possible that all, and Asians, and Hispanics; and adults of all More recently, it has been suggested that a other unknown mechanisms, are in- age-groups. In fact, the relationship be-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1649 Consensus Statement tween WC and health outcome changes incremental value in these predictions clinical management if NHLBI obesity much less with increasing age than does above and beyond that offered by BMI treatment guidelines are followed? An- the relationship between BMI and health and commonly evaluated cardiometa- swer: Probably not. outcome (31). However, it is not known bolic risk factors, such as blood glucose Measurement of WC in clinical prac- whether WC can provide a better assess- concentration, lipid profile and blood tice is not trivial, because providing this ment of health risk in one sex, racial/ pressure? Answer: Uncertain. assessment competes for the limited time ethnic group, or age category than Data from many large population available in a busy office practice and re- another. studies have found waist circumference to quires specific training to ensure that re- The shape of the relationship between be a strong correlate of clinical outcome, liable data are obtained. Therefore, waist WC and health outcomes (e.g., linear, particularly diabetes, and to be indepen- circumference should only be measured if monotonic, step-function, or U-shaped) dent of BMI. In addition, data from a lim- it can provide additional information that influences the WC value that can most ited number of studies demonstrates that influences patient management. Based on efficiently distinguish between “normal” WC remains a predictor of diabetes, NHANES III data, 99.9% of men and and “abnormal” and serve as a basis for CHD, and mortality rate, even after ad- 98.4% of women would have received the considering clinical action. Data from justing for BMI and several other cardio- same treatment recommendations pro- most studies suggest that the shape of the metabolic risk factors. Additional studies posed by the NHLBI Expert Panel by eval- relationship between WC and health out- are needed to confirm that WC remains uating BMI and other cardiovascular risk come lends itself to identifying clinically an independent predictor of risk. factors, without an assessment of WC meaningful cut point values because risk 3. Do the current definitions used to (37). However, it is likely that different often accelerates monotonically above, determine a high WC identify a nontrivial WC cut point values could provide more and can be relatively flat below, a specific number of patients who are at increased useful clinical information. For example, WC value. Optimum WC cut points will cardiometabolic risk, but who would not an analysis of data obtained from the likely vary according to the population otherwise be identified by having a BMI NHANES III and the Canadian Heart studied, the health outcome of interest, Ն25 kg/m2 and an assessment of com- Health Surveys found that BMI-specific and demographic factors. monly evaluated cardiometabolic risk fac- WC cut points provided a better indicator Data from most clinical weight loss tors? Answer: Yes. of cardiometabolic risk than the recom- and exercise training trials have shown The recommended WC thresholds mended WC thresholds (35). For nor- that reductions in WC occur concomi- for increased cardiometabolic risk in men mal-weight (BMI 18.5–24.9 kg/m2), tantly with reductions in obesity-related (Ͼ40 inches [102 cm]) and women (Ͼ35 overweight (BMI 25.0–29.9 kg/m2), class cardiometabolic risk factors and disease. inches [88 cm]) were derived from WC I obesity (BMI 30.0–34.9 kg/m2), and However, these results do not prove that values that correlated with a BMI Ն30 class II/class III obesity (BMI Ն35.0 kg/ the reduction in WC was responsible for kg/m2 (2). The National Health and Nu- m2), the optimal WC cut points were 87, the beneficial effect on health outcome. trition Examination Survey III (NHANES 98, 109, and 124 cm in men and 79, 92, Additional studies are needed to evaluate III) found that about 14% of women and 103, and 115 cm in women, respectively. the effect of decreasing WC on cardio- about 1% of men had a “high” WC but a Therefore, it is possible that WC measure- metabolic outcomes. normal BMI (18.5–24.9 kg/m2) (36). In ment could be an effective clinical tool for addition, ϳ70% of women who were identifying “metabolically obese, lean” QUESTION 4: Should waist overweight (BMI 25.0–29.9 kg/m2) had a patients who might benefit from lifestyle circumference be measured in WC Ͼ35 inches and ϳ25% of men who therapy but would not have been consid- clinical practice? were overweight had a WC Ͼ40 inches. ered for treatment because of a normal The panel concluded that determining An estimate based on data available from BMI. Waist circumference could also whether waist circumference should be the WHO Monica Project, conducted in identify “metabolically normal, obese” measured in clinical practice depends on more than 32,000 men and women from subjects who do not require aggressive the responses to the following four key Europe, Australia, and New Zealand, sug- obesity therapy because they do not have questions: gest that about 10% of participants who a marked increase in cardiometabolic 1. Can waist circumference be reli- had BMI values Ͻ30 kg/m2 hadaWC risk. ably measured? Answer: Yes. above the recommended cut points for in- Health care personnel and even pa- creased risk (36). It is not known what CONCLUSIONS tients themselves, who are given appro- portion of subjects who had a large WC Waist circumference provides a unique priate training in technique, can provide would have been identified as having in- indicator of body fat distribution, which highly reproducible measurements of creased cardiometabolic risk based on can identify patients who are at increased WC in men and women. However, it is findings from a standard medical evalua- risk for obesity-related cardiometabolic not know whether measurement of one tion. Therefore, the optimal WC criteria disease, above and beyond the measure- anatomical site is a better indicator of car- needed to identify patients at increased ment of BMI. However, the current WC diometabolic risk than measurement at risk of metabolic disease, who would oth- cut points recommended to determine other sites. erwise not be identified by evaluating BMI health risk (2) were derived by regression 2. Does waist circumference provide: and/or other standard cardiometabolic from an “obese” BMI and are unlikely to a) good prediction of diabetes, CHD, and risk factors, is not known and will likely affect clinical management when BMI and mortality rate? Answer: Yes; b) incremen- require adjustments based on BMI, sex, other obesity-related cardiometabolic risk tal value in predicting diabetes, CHD, and age, and race/ethnicity. factors are already being determined. mortality rate above and beyond that pro- 4. Would assessment of WC in pa- Therefore, the clinical usefulness of mea- vided by BMI? Answer: Yes; c) sufficient tients who have a BMI Ն25 kg/m2 affect suring WC, when risk is based on the cur-
1650 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Klein and Associates rently accepted guidelines, is limited. Evans DJ, Hartz AJ, Kalkhoff RK, Adams inal subcutaneous adipose tissue alter as- However, WC measurement can some- PW: Relation of body fat distribution to sociations with the metabolic syndrome? times provide additional information to metabolic complications of obesity. J Clin Diabetes Care 29:679–684, 2006 help the clinician determine which pa- Endocrinol Metab 54:254–260, 1982 20. Ford ES, Mokdad AH, Giles WH: Trends tients should be evaluated for the pres- 7. Wang Y, Rimm EB, Stampfer MJ, Willett in waist circumference among U.S. adults. WC, Hu FB: Comparison of abdominal Obes Res 11:1223–1231, 2003 ence of cardiometabolic risk factors, such adiposity and overall obesity in predicting 21. Chan DC, Watts GF, Barrett PH, Burke V: as dyslipidemia, and hyperglycemia. In risk of type 2 diabetes among men. 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Seppala-Lindroos A, Vehkavaara S, Hak- can assess cardiometabolic risk, not ade- M, Kolter D, Laferrere B, Mayer L, Pi-Su- kinen AM, Goto T, Westerbacka J, Sovi- nyer FX, Pierson RN Jr: Comparison of jarvi A, Halavaara J, Yki-Jarvinen H: Fat quately captured by BMI and routine clin- waist circumferences measured at 4 sites. accumulation in the liver is associated ical assessments. Selection of the most Am J Clin Nutr 77:379–384, 2003 with defects in insulin suppression of glu- appropriate WC values will be complex 10. Douketis JD, Paradis G, Keller H, Martin- cose production and serum free fatty acids because they are likely influenced by sex, eau C: Canadian guidelines for body independent of obesity in normal men. race/ethnicity, age, BMI, and other fac- weight classification in adults: application J Clin Endocrinol Metab 87:3023–3028, tors. Nonetheless, it should be possible to in clinical practice to screen for over- 2002 determine more useful WC cut points weight and obesity and to assess disease 24. Sinha R, Dufour S, Petersen KF, LeBon V, than are currently recommended, by risk. CMAJ 172:995–998, 2005 Enoksson S, Ma YZ, Savoye M, Rothman carefully reviewing published data and 11. NHANES III Anthropometric Procedures DL, Shulman GI, Caprio S: Assessment of reevaluating datasets available from exist- Video. Available from http://www.cdc. skeletal muscle triglyceride content by ing population studies. These additional gov/nchs/about/major/nhanes/avideo.htm. (1)H nuclear magnetic resonance spec- 12. Nordhamn K, Sodergren E, Olsson E, troscopy in lean and obese adolescents: analyses will define the future role of WC Karlstrom B, Vessby B, Berglund L: Reli- relationships to insulin sensitivity, total measurement in clinical practice. ability of anthropometric measurements body fat, and central adiposity. Diabetes in overweight and lean subjects: conse- 51:1022–1027, 2002 quences for correlations between anthro- 25. Katzmarzyk PT, Craig CL: Independent Acknowledgments— This conference was pometric and other variables. Int J Obes effects of waist circumference and physi- supported in part by an educational grant from Relat Metab Disord 24:652–657, 2000 cal activity on all-cause mortality in Cana- the Campbell Soup Company. 13. Chen MM, Lear SA, Gao M, Frohlich JJ, dian women. Appl Physiol Nut Metal 31: Birmingham CL: Intraobserver and inter- 271–276, 2006 observer reliability of waist circumference 26. Yusuf S, Hawken S, Ounpuu S, Bautista L, References and the waist-to-hip ratio. Obes Res 9:651, Franzosi MG, Commerford P, Lang CC, 1. World Health Organization: Obesity: Pre- 2001 Rumboldt Z, Onen CL, Lisheng L, Tan- venting and Managing the Global Epidemic: 14. Rimm EB, Stampfer MJ, Colditz GA, omsup S, Wangai P Jr, Razak F, Sharma Report of a WHO Consultation on Obesity. Chute CG, Litin LB, Willett WC: Validity AM, Anand SS; INTERHEART Study In- Geneva, World Health Organization, 1998 of self-reported waist and hip circumfer- vestigators: Obesity and the risk of myo- 2. National Institutes of Health, National ences in men and women. Epidemiology cardial infarction in 27,000 participants Heart, Lung, and Blood Institute: Clinical 1:466–473, 1990 from 52 countries: a case-control study. guidelines on the identification, evalua- 15. Bigaard J, Spanggaard I, Thomsen BL, Lancet 366:1640–1649, 2005 tion, and treatment of overweight and Overvad K, Tjonneland A: Self-reported 27. Hu G, Tuomilehto J, Silventoinen K, obesity in adults—the evidence report. and technician-measured waist circum- Barengo N, Jousilahti P: Joint effects of Obes Res 6 (Suppl. 2):51S–209S, 1998 ferences differ in middle-aged men and physical activity, body mass index, waist 3. Colditz GA, Willett WC, Rotnitzky A, women. J Nutr 135:2263–2270, 2005 circumference and waist-to-hip ratio with Manson JE: Weight gain as a risk factor for 16. Abate N, Garg A, Peshock RM, Stray-Gun- the risk of cardiovascular disease among clinical diabetes mellitus in women. Ann dersen J, Grundy SM: Relationships of middle-aged Finnish men and women. Intern Med 122:481–486, 1995 generalized and regional adiposity to in- Eur Heart J 24:2212–2219, 2004 4. Calle EE, Thun MJ, Petrelli JM, Rodriguez sulin sensitivity in men. J Clin Invest 96: 28. Lofgren I, Herron K, Zern T, West K, Pata- C, Heath CW Jr: Body-mass index and 88–98, 1995 lay M, Shachter NS, Koo SI, Fernandez mortality in a prospective cohort of U.S. 17. Shen W, Wang Z, Punyanyita M, Lei J, ML: Waist circumference is a better pre- adults. N Engl J Med 341:1097–1105, Sinav A, Kral JG, Imielinska C, Ross R, dictor than body mass index of coronary 1999 Heymsfield SB: Adipose tissue quantifica- heart disease risk in overweight premeno- 5. Pouliot MC, Despres JP, Lemieux S, tion by imaging methods: a proposed pausal women. J Nutr 134:1071–1076, Moorjani S, Bouchard C, Tremblay A, classification. Obes Res 11:5–16, 2003 2004 Nadeau A, Lupien PJ: Waist circumfer- 18. Shen W, Punyanitya M, Wang Z, Gal- 29. Suk SH, Sacco RL, Boden-Albala B, ence and abdominal saggital diameter: lagher D, St-Onge MP, Albu J, Heymsfield Cheun JF, Pittman JG, Elkind MS, Paik best simple anthropometric indices of ab- SB: Total body skeletal muscle and adi- MC; Northern Manhattan Stroke Study: dominal visceral adipose tissue accumu- pose tissue volumes: estimation from a Abdominal obesity and risk of ischemic lation and related cardiovascular risk in single abdominal cross-sectional image. stroke: the Northern Manhattan Stroke men and women. Am J Cardiol 73:460– J Appl Physiol 97:2333–2338, 2004 Study. Stroke 34:1586–1592, 2003 468, 1994 19. Kuk JL, Church TS, Blair SN, Ross R: Does 30. Carey VJ, Walters EE, Colditz GA, So- 6. Kissebah AH, Vydelingum N, Murray R, measurement site for visceral and abdom- lomon CG, Willett WC, Rosner BA,
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Speizer FE, Manson JE: Body fat distribu- the Iowa Women’s Health Study. Arch In- of type 2 diabetes in the general popula- tion and risk of non-insulin-dependent tern Med 160:2117–2128, 2000 tion: are there differences between men diabetes mellitus in women: the Nurses’ 33. Hu FB, Willett WC, Li T, Stampfer MJ, and women? The MONICA/KORA Augs- Health Study. Am J Epidemiol 145:614– Colditz GA, Manson JE: Adiposity as burg cohort study. Am J Clin Nutr 84:483– 619, 1997 compared with physical activity in pre- 489, 2006 31. Visscher TL, Seidell JC, Molarius A, van dicting mortality among women. N Engl 37. Kiernan M, Winkleby MA: Identifying pa- der Kuip D, Hofman A, Witteman JC: A J Med 351:2694–2703, 2004 tients for weight-loss treatment: an empir- comparison of body mass index, waist- 34. Baik I, Ascherio A, Rimm EB, Giovan- ical evaluation of the NHLBI Obesity hip ratio and waist circumference as pre- nucci E, Spiegelman D, Stampfer MJ, Wil- Education Initiative Expert Panel treat- dictors of all-cause mortality among the lett WC: Adiposity and mortality in men. ment recommendations. Arch Intern Med elderly: the Rotterdam study. Int J Obes Am J Epidemiol 152:264–271, 2000 160:2169–2176, 2000 Relat Metab Disord 25:1730–1735, 2001 35. Ardern CI, Janssen I, Ross R, Katzmarzyk 38. Dekker MJ, Lee S, Hudson R, Kilpatrick K, 32. Folsom AR, Kushi LH, Anderson KE, PT: Development of health-related waist Graham TE, Ross R, Robinson LE: An exer- Mink PJ, Olson JE, Hong CP, Sellers TA, circumference thresholds within BMI cat- cise intervention without weight loss de- Lazovich D, Prineas RJ: Associations of egories. Obes Res 12:1094–1103, 2004 creases circulating interleukin-6 in lean and general and abdominal obesity with mul- 36. Meisinger C, Doring A, Thorand B, Heier obese men with and without type 2 diabetes tiple health outcomes in older women: M, Lowel H: Body fat distribution and risk mellitus. Metabolism 56:332–338, 2007
1652 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Reviews/Commentaries/ADA Statements CONSENSUS STATEMENT
Use of Insulin Pump Therapy in the Pediatric Age-Group Consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes
1 4 MOSHE PHILLIP, MD THOMAS DANNE, MD gained increasing popularity among pa- 2 5 TADEJ BATTELINO, MD, PHD FRANCINE KAUFMAN tients with diabetes. CSII is the most 3 HENRY RODRIGUEZ FOR THE CONSENSUS FORUM PARTICIPANTS* physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin se- oung patients with diabetes, their verse effects on cognitive function and cretion, namely continuous 24-h adjust- families, and their diabetes care lead to hypoglycemia unawareness and able “basal” delivery of insulin upon Y providers continue to be faced with may be associated with significant emo- which are superimposed prandial “bo- the challenge of striving to maintain tional morbidity for the child and parents. luses.” In addition, CSII offers the possi- blood glucose levels in the near-normal Fear of hypoglycemia, especially during bility of more flexibility and more precise range. High blood glucose levels with el- the night, may compromise quality of life insulin delivery than multiple daily injec- evated A1C levels are associated with (QOL) for the family and jeopardize ef- tion (MDI). However, there is still debate long-term microvascular and macrovas- forts to achieve optimal metabolic among diabetes care practitioners around cular complications. Recurrent episodes control. the world as to whether CSII has advan- of hypoglycemia, especially at young Over the past decade, continuous tages over MDI in terms of reduction in ages, may cause short- and long-term ad- subcutaneous insulin infusion (CSII) has A1C levels, occurrence of severe hypogly- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● cemic events, episodes of diabetic ketoac- From the 1Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider idosis (DKA), and frequency of hos- Children’s Medical Center of Israel, Petah Tikva, Israel; the 2Department of Pediatric Endocrinology, Dia- pitalizations in young patients. Further- betes and Metabolism, University Children’s Hospital, Ljubljana, Slovenia; the 3Section of Pediatric Endo- more, no clear criteria have been estab- crinology, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana; 4Diabeteszentrum fur Kinder und Jugendliche, Kinderkrankenhaus auf der Bult, lished to help the physician choose the Hannover, Germany; and the 5Center for Diabetes, Endocrinology and Metabolism, Childrens Hospital, Los “appropriate” patient for CSII therapy. Angeles, California. To address these issues, the European Address correspondence and reprint requests to Prof. Moshe Phillip, Institute for Endocrinology and Society for Pediatric Endocrinology Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, 14 Kaplan St., Petah Tikva 49202, Israel. E-mail: [email protected]. (ESPE), the Lawson Wilkins Pediatric En- Approved for publication 7 March 2007. docrine Society (LWPES), and the Inter- This consensus statement was written in collaboration with the participants in the Consensus Meeting national Society for Pediatric and held in Berlin in April 2006 on the Use of Insulin Pumps Therapy in the Pediatric Age Group organized by Adolescent Diabetes (ISPAD) convened a the LoopClub on behalf of the European Society for Paediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes panel of expert physicians for a consensus (ISPAD) and endorsed by the American Diabetes Association (ADA) and the European Association for the conference endorsed by the American Di- Study of Diabetes (EASD). abetes Association (ADA) and the Euro- *A complete list of the participants in the forum can be found in the ACKNOWLEDGMENTS. pean Association for the Study of Diabetes M.P. has received honoraria from Medtronic, consulting fees from D-Medical and Nilimedix, speakers fees from Medtronic, and a research grant from Animas and holds stock in D-Medical and Nilimedix. T.B. has (EASD). received consulting and speaker fees from Medtronic MiniMed, Johnson and Johnson, Abbott, Novo Nor- For each major topic area, clinical ex- disk, and Elli Lilly. H.R. is on the healthcare professional advisory board of Disetronic Medical Systems and perts were chosen to review the literature has received honoraria from Disetronic Medical Systems and consulting fees from Roche Diagnostics. T.D. and provide evidence-based recommen- has received speaker fees from Abbott, Lifescan, Medtronic, Roche, and Bayer and has received a research grant from Medtronic. F.K. has received research funds from Medtronic MiniMed and Johnson and Johnson dations according to criteria used by the and is on the medical advisory boards of and has received consulting fees from Lifescan, Medtronic MiniMed, ADA. Key citations identified for each and Novo Nordisk. topic were assigned a level of evidence Abbreviations: ADA, American Diabetes Association; CSII, continuous subcutaneous insulin infusion; (indicated in bold throughout the text) DCCT, Diabetes Control and Complications Trial; DKA, diabetic ketoacidosis; EASD, European Association for the Study of Diabetes; ESPE, European Society for Paediatric Endocrinology; ISPAD, International Society and verified by the expert panel (Table 1). for Pediatric and Adolescent Diabetes; LWPES, Lawson Wilkins Pediatric Endocrine Society; MDI, multiple This article summarizes the consensus daily injection; QALY, quality-adjusted life year; QOL, quality of life; RCT, randomized controlled trial. recommendations of the expert panel and A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion represents the current state of knowledge factors for many substances. DOI: 10.2337/dc07-9922 about CSII in pediatric and adolescent pa- © 2007 by the American Diabetes Association. tients with type 1 diabetes.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1653 Insulin pump use in pediatrics
Table 1—ADA evidence grading system for clinical practice recommendations [reprinted from trol after in average almost 4 years of ther- Diabetes Care 26 (Suppl. 1):S1, 2003] apy (B: 28). Several RCTs have assessed the bene- Level of evidence Description fits of CSII compared with MDI. No sig- nificant difference in A1C was reported A Clear evidence from well-conducted, generalizable, randomized controlled with CSII versus MDI using NPH as basal trials that are adequately powered, including: insulin in an open crossover RCT of chil- • Evidence from a well-conducted multicenter trial dren (B: 32) and adolescents (B: 33) with • Evidence from a meta-analysis that incorporated quality ratings in the type 1 diabetes. In a study of preschool- analysis age children with diabetes, A1C was • Compelling nonexperimental evidence, i.e., “all or none” rule developed slightly lower in the CSII group compared by the Center for Evidence Based Medicine at Oxford* with the MDI group at 3 months, but not Supportive evidence from well-conducted randomized controlled trials at 6 months (B: 34). In a 1-year RCT of that are adequately powered, including: toddlers and preschool-age children, • Evidence from a well-conducted trial at one or more institutions there was no difference in A1C between • Evidence from a meta-analysis that incorporated quality ratings in the the CSII and MDI groups (B: 35). A analysis 6-month RCT failed to demonstrate a sig- nificant decrease in A1C between groups B Supportive evidence from well-conducted cohort studies, including: of children aged 1–6 years treated with • Evidence from a well-conducted prospective cohort study or registry either CSII or MDI (B: 36). One RCT re- • Evidence from a well-conducted meta-analysis of cohort studies ported that after 16 weeks, A1C was sig- Supportive evidence from a well-conducted case-control study nificantly lower in children and adolescents receiving CSII compared with C Supportive evidence from poorly controlled or uncontrolled studies, their initial A1C level, as well as being including: significantly lower than the level observed • Evidence from randomized clinical trials with one or more major or in patients receiving MDI with glargine three or more minor methodological flaws that could invalidate the (B: 37). In addition, there was a statisti- results cally significant difference in the number • Evidence from observational studies with high potential for bias (such as of patients achieving the ADA treatment case series with comparison with historical controls) goal of A1C Յ7% between the CSII group • Evidence from case series or case reports (8 of 16 patients) and the MDI/glargine Conflicting evidence with the weight of evidence supporting the group (2 of 16). Because all of the RCT recommendation studies were of short duration (up to 1 E Expert consensus or clinical experience year), it is difficult to determine whether pump therapy per se was beneficial or *Either all patients died before therapy and at least some survived with therapy or some patients died without therapy and none died with therapy. Example: use of insulin in the treatment of diabetic ketoacidosis. whether improved control resulted from increased motivation associated with the use of novel technology. BENEFITS AND RISKS OF trolled trials (RCTs) in adults have dem- Recommendation. As only one short- CSII IN PEDIATRIC AND onstrated an average decrease in A1C of term RCT has demonstrated improve- ADOLESCENT PATIENTS— 0.5–1.2% with CSII compared with MDI ment in A1C in pediatric patients treated WHAT WE KNOW SO FAR (3), but their generalizability to the pedi- with CSII versus MDI, further well- Since its introduction, there have been a atric population has been questioned. controlled trials are needed. number of real and perceived risks and Numerous observational studies, in- benefits of CSII compared with conven- volving more than 760 pediatric patients tional MDI. Ascertainment of the relative with type 1 diabetes, have reported de- Severe hypoglycemia risk is hampered by limited data compar- creases in A1C with CSII (C: 4–27, B: Achieving optimal blood glucose control ing CSII with MDI in toddlers, preschool- 28). The mean A1C reported in these is especially challenging in younger pa- aged children, and adolescents with type studies is comparable with or lower than tients with type 1 diabetes. Inadequate 1 diabetes (C:1,B: 2). Despite this limi- glucose control can lead to wide glycemic the mean A1C reported in the adolescent tation, collective experience can help ad- excursions or frequent hypoglycemia. Re- group in the Diabetes Control and Com- dress questions regarding the relative current episodes of hypoglycemia at a risks associated with the use of CSII in plications Trial (DCCT) (A: 29). How- very young age have been associated with these age-groups. ever, most of these studies have been of neurocognitive dysfunction (E: 38). Fear limited duration (6–12 months), and of hypoglycemia is prevalent in adoles- Impact on A1C only four of the studies reported a fol- cents and families of children with type 1 Treatment targets for blood glucose levels low-up period of 2–5 years (5,10,16, C: diabetes and may pose a barrier to im- for children and adolescents are those that 30). A recent, large 3-year observational proved glycemic control (C: 39,40). The achieve a near-normal A1C (ISPAD study demonstrated a significant im- threat of pump malfunction, resulting in 2000), which serves as a surrogate marker provement in A1C after initiation of CSII excessive insulin delivery, was an early for a low risk of late complications. Most (C: 31) and another demonstrated the concern after the introduction of CSII. adequately powered randomized con- sustained benefit of CSII on glycemic con- This is not an issue with the current gen-
1654 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Phillip and Associates eration of pumps, which are equipped Physical activity and exercise as with MDI, DKA is preventable in CSII with numerous safety features. Although children and adolescents with using published DKA prevention guide- In adults, RCTs have demonstrated a type 1 diabetes are encouraged to exercise lines (E: 57) that recommend frequent significant decrease in the rate of severe regularly, plasma glucose concentrations monitoring of urine or serum ketones and hypoglycemia with CSII (A: 41). In chil- are often difficult to manage during pro- blood glucose with appropriate interven- dren, however, reports of the frequency of longed periods of physical activity. Recent tion when ill. In Norwegian children with hypoglycemia on CSII are highly variable. studies from the Diabetes Research in diabetes, the nationwide incidence of Several observational pediatric trials, Children Network (DirecNet) demon- DKA (ϳ4 per 100 patient-years) did not mostly of short-term duration (up to 1 strate that the risk of hypoglycemia is in- change despite an increase in CSII use year), have shown a decrease in the rate of creased both during and on the night from 5% in 2001 to 38% in 2005 (C: 58). severe hypoglycemia with CSII concomi- following a 75-min period of moderate- Recommendations. RCT trials are tant with a reduction in A1C (C: 1,31,42; intensity aerobic exercise in children and needed to evaluate whether young pa- B: 28). However, RCTs have not shown adolescents maintained on a fixed basal tients treated with CSII are more vulner- evidence of a significant difference in the insulin replacement regimen (B: 52,53). able to metabolic deterioration. However, frequency of severe hypoglycemia be- In a follow-up study (C: 54), the DirecNet DKA should be preventable in CSII using tween CSII and MDI in children (B: 32– study group has shown that the risk of published DKA prevention guidelines. 37). A possible explanation for this hypoglycemia with exercise can be mark- finding is that these studies were not pow- edly reduced with CSII by suspending the Infusion site reactions ered to detect differences in hypoglyce- basal insulin infusion during exercise. De- Although few studies have systematically mia. Another explanation might be that in spite the cessation of insulin delivery dur- recorded the incidence of lipohypertro- the short-term, patients are motivated to ing exercise, few subjects developed phy, skin irritation, infusion site infec- measure their blood glucose more fre- hyperglycemia and their blood ketone tions, and scarring in children, more than quently and during the night, therefore levels remained suppressed throughout 15 studies in adults have reported the fre- reducing the frequency and severity of hy- the exercise period. quency of episodes of infections and skin poglycemia with CSII. Another study compared prolonged irritation at catheter sites. Rates of irrita- Recommendation. Pediatric observa- standardized exercise in patients with tion and/or infection ranged from 0.06 to tional studies, but not RCTs, have dem- CSII with either half of the regular basal 12 per patient per year (B: 2). onstrated that CSII decreases the rate (temporary basal) during the exercise Conclusion. Efforts to minimize the risk frequency of severe hypoglycemia. Con- or temporary interruption of insulin de- of irritation, scarring, and infection tinuous glucose monitoring will un- livery. The rate of hypoglycemia during should include strict adherence to proper doubtedly improve the ability to monitor exercise was similar in both groups, but a infusion site preparation, catheter inser- patients for hypoglycemia, and future trend toward an increased rate of late hy- tion, and site rotation. controlled studies will allow us to better poglycemia was observed in the tempo- characterize the hypoglycemic risk and rary basal group (B: 55). Psychosocial issues benefits in young patients using CSII. Conclusions. After subcutaneous injec- The adoption of CSII can weigh heavily tion, the action of long-acting insulin an- on the patient and their family. Sources of alogs cannot be interrupted, whereas with familial stress may include the constant Blood glucose variability CSII, insulin delivery can be temporarily need to be accessible to other caregivers Treatment targets for blood glucose levels suspended during prolonged physical ac- and the additional monetary costs of CSII. in pediatric patients are the same whether tivity. This feature should decrease the Furthermore, for the school-aged child, they are using CSII or MDI, as published risk of exercise-related hypoglycemia in the additional skills and supervision re- in guidelines from several organizations patients using CSII. quired of school personnel can add stress (ISPAD and ADA). Although A1C is the and strain the relationship between the most generally accepted marker for the Weight gain child’s family and school personnel. risk of long-term complications, the ad- Although concerns have been raised re- Evidence from studies using different verse effect of glycemic variability is in- garding CSII and weight gain, studies in assessment tools indicates that QOL, pa- creasingly becoming recognized (C: 43), pediatric patients have shown that CSII tient satisfaction, and disease-related sat- although this has been questioned in the either decreases BMI SD score or results in isfaction are unchanged or improved with DCCT (A: 44). no excess weight gain over a study period CSII therapy (B: 34,36; C: 25,59–65). A In adults, CSII has been shown to re- of 3.5–12 months (B: 32; C: 7,56) and meta-analysis that examined the meta- duce blood glucose variability (C: 45). In over 3–4 years of follow-up (C: 31; B: bolic and psychosocial impact of CSII and children, CSII monitored with continu- 28). included five pediatric studies reported ous glucose sensors has shown a decrease Conclusions. Short-term studies have no consistent differences in anxiety, de- in glucose variability in some but not all not shown weight gain with CSII; how- pression, QOL, self-esteem, and family trials (C: 15,16,46–51). ever, well-controlled long-term trials are functioning (B: 2). In qualitative studies Recommendations. The determination needed. using standardized interview techniques, of the impact of glucose variability on the on switching from MDI to CSII, parents of risk for complications must await the re- Metabolic deterioration infants and toddlers reported more free- sults of ongoing and future studies. More Individuals using CSII are potentially at dom, flexibility, and spontaneity in their RCT trials are needed to confirm whether increased risk of developing DKA, with lives as well as reduced parental stress and CSII reduces blood glucose variability in DKA rates varying from 2.7–9 episodes worry regarding their child’s overall care children. per 100 patient-years (C: 56). However, (C: 66). Several other studies have found
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1655 Insulin pump use in pediatrics that CSII reduces parental anxiety (C: The timing of pump initiation remains an pervise and manage pump therapy 61,62,67). In addition, adolescent pa- important consideration for the family (C: 10). tients using CSII report high levels of sat- and health care team in optimizing the isfaction due to a greater sense of control, likelihood of successful implementation CSII supportive care independence, fewer physical com- and outcomes (B: 28). CSII should be The child and caregivers should be edu- plaints, and increased flexibility in diet considered in the conditions listed below: cated on the following concepts: and daily schedule (C: 20). One nonran- domized study using the Diabetes Quality 1. Recurrent severe hypoglycemia (C: 1. Nutrition therapy including carbohy- of Life for Youth (DQOL) and the Chil- 1,4) drate counting/estimation dren’s Depression Inventory (C: 1) and a 2. Wide fluctuations in blood glucose 2. Principles of basal-bolus therapy second RCT of young children with dia- levels regardless of A1C (C: 50) 3. Insulin kinetics and pump failure betes using the Parenting Stress Index and 3. Suboptimal diabetes control (i.e., A1C 4. Recognition and management of hy- the Brief Symptom Inventory (C: 46) did exceeds target range for age) (C:1) poglycemia and hyperglycemia not find a significant improvement in 4. Microvascular complications and/or 5. The effects of activity and exercise on QOL for children or their parents after risk factors for macrovascular compli- blood glucose initiation of CSII therapy. The authors cations (A: 68,69) 6. Sick day management commented, however, that the use of less 5. Good metabolic control but insulin objective and more open-ended question- regimen that compromises lifestyle (E) Recommendations naires and interviews may have yielded different results. Other circumstances in which CSII may 1. Caregivers must be assessed to ensure Most of the studies evaluating QOL be beneficial include: proper supervision and responsibility were done in infants and toddlers where for pump management and frequent the parents are completely in charge, and 1. Young children and especially infants blood glucose monitoring (E). very few of the studies were done with and neonates (B: 34–36;C: 10,12,13) 2. Children and their caregivers must re- teenagers. Therefore, CSII may be helpful 2. Adolescents with eating disorders (E) ceive initial and ongoing education re- to the anxious parent; however, its bene- 3. Children and adolescents with a pro- garding warning symptoms and fits to the adolescent should be further nounced dawn phenomenon (E) strategies for prevention of DKA and studied. 4. Children with needle phobia (E) problem-solving strategies for pump Concerns about the complexity of 5. Pregnant adolescents, ideally precon- problems. pump therapy and consequent problems ception (A: 70) 3. Children, adolescents, and caregivers in management of children by less knowl- 6. Ketosis-prone individuals (C: 71) must receive initial and ongoing edu- edgeable and experienced caregivers have 7. Competitive athletes (E) cation regarding pump functions, proven to be unfounded. On the contrary, proper infusion set insertion, and children Ͻ7 years of age using CSII had Recommendations pump catheter maintenance by a pro- greater A1C reduction and less severe hy- fessional very knowledgeable about poglycemia when daytime care was pro- 1. A pediatric multidisciplinary diabetes pumps (E). vided by paid providers rather than the team experienced in insulin pump ● Patients and families should be in- mother (C: 10). therapy is required to initiate CSII and structed to notify their diabetes care Conclusion. Despite the intensive na- supervise the ongoing management of provider if pain, inflammation, pu- ture of CSII, QOL with CSII therapy is a child on CSII (E). rulent discharge, or recurrent irrita- similar to or higher than that reported in 2. Frequent contact between the family/ tion occurs at the infusion site. youth treated with MDI. child and diabetes team is required af- ● Adequate training for adolescents Clinical experience has shown that ter initiating pump therapy, and 24-h and young adults using CSII should instances of patient/family choice to dis- access to a diabetes team member is include a discussion about handling continue CSII and return to MDI are not desirable (E). the pump in intimate situations. common in any of the pediatric age- 3. CSII can be safely initiated at diagnosis groups (B: 28,35,36; C: 64,56). (A: 72; C: 73; B: 74) or anytime there- 4. Children and their caregivers should after (A: 70; B: 34–36). be counseled as to the possibility of 4. The child’s parent/s, guardian, and weight gain with improved glycemic CSII USE IN THE PEDIATRIC daytime care provider must be willing control. PATIENT and able to provide the supportive The following summarizes the consensus care necessary for successful CSII im- PERSONALIZING CSII recommendations convened by the ex- plementation. pert panel. ● Psychosocial instability within the Selecting an insulin pump family or emotional problems in the The choice of a specific pump will be in- Initiating CSII child are reasons to consider post- fluenced by the experience and comfort of The decision to begin pump therapy poning initiation of pump therapy the diabetes team with a particular model, should be made jointly by the child, par- (E). as well as by the personal preference of ent(s)/guardians, and diabetes team. All ● Lack of an available parent during the patient and family. Pumps that auto- pediatric patients with type 1 diabetes are the day is not a contraindication to matically calculate meal or correction bo- potential candidates for CSII, and there is initiating CSII in the young child, as luses based on insulin-to-carbohydrate no lower age limit for initiating CSII (E). other caregivers can be taught to su- ratios and insulin sensitivity factors are
1656 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Phillip and Associates useful features that aid other caregivers, rapid-acting insulin analogs for CSII is 2. Needle type such as grandparents, nannies, and day recommended (E). ● Children fearful of an indwelling steel care workers. The ability to review insulin ● Selected “ketosis-prone” patients needle may prefer Teflon catheters; boluses, carbohydrate intake used in bo- may benefit from the longer lasting however, catheter obstruction may lus calculations, and blood glucose levels effect of regular insulin. Alterna- occur less frequently with steel nee- from pump memory may be useful for tively, one could add an injection of dles (controlled studies are lacking). counseling patients on their diabetes basal insulin, such as insulin management, particularly for adoles- glargine or levemir, to decrease the 3. Tubing length cents, who often omit boluses and have risk of DKA. ● The infusion set tubing length difficulty with manual record keeping (C: should be tailored for the individual 19). 2. Particularly in neonates or toddlers, or child and his/her activities. during low insulin requirements such Pump features requiring as the “honeymoon period,” insulin Recommendations consideration include: dilution with a compatible diluent may be required (E). 1. Trials with different catheter tubing 1. Small basal rate increments for infants ● In a simulated continuous insulin lengths may be necessary, and when in and toddlers infusion, U10 and U50 dilutions of doubt, the shorter catheter length ● Some pumps allow for 0.025 or U100 insulin aspart were found to should be tried first (E). 0.05 unit/h incremental changes, be stable for 7 days at 37°C (C: 76). 2. For infants and toddlers, the tubing which is important when there is a ● Although similar studies with di- should not be so long that it could low total daily insulin dose. luted insulin lispro (using Sterile Di- pose a risk of strangulation (E). luent ND-800) are not yet 2. Sufficient reservoir volume published, diluted insulin lispro has 3. To prevent accidental dislodgement of ● Sufficient reservoir volume may be been successfully used in single the pump catheter secondary to pull- important, particularly in teenagers, cases (B: 35; C: 77). ing, a catheter loop (pig tail) or a sec- who may have high total daily insu- ond piece of tape should be used to secure the tubing close to the insertion lin requirements. 3. To avoid dosing errors or bacterial site (E). contamination, U50 or U10 dilutions 3. Direct communication with a home should only be used in those cases re- blood glucose meter quiring very low hourly insulin infu- Calculating the total daily insulin ● Direct communication with a home sions (Ͻ0.2 IU/h) (E). requirements when switching from blood glucose meter may be benefi- MDI to CSII cial for pumps that assist with bolus The starting insulin dose is based on the Selecting a catheter dose calculation; however, the accu- prepump total daily dose and is guided by Selection of catheters, adhesives, and tub- racy of the blood glucose meter continued frequent blood glucose mea- ing is dependent on age and individual must be considered. surements before and after meals and dur- circumstances. Children and adolescents ing the night. The higher the insulin dose involved in frequent physical exercise and 4. Alarm features required with MDI (in insulin units per outdoor activities prefer catheters that can ● Alarm features remind a child that a kilogram), the more pronounced the in- be disconnected. meal bolus has been missed. sulin reduction should be when switching Several approaches have been used to to CSII. minimize the discomfort of inserting in- 5. Waterproof casing fusion catheters, including topical anes- Recommendations ● Waterproof casing should be con- thetics, application of ice, autoinsertion sidered for youth active in water devices, distraction, and insertion while sports where inadvertent submer- 1. In children with good glycemic con- the child is asleep. sion is likely. trol and a low frequency of hypoglyce- mia, the total dose may need to be Determining which concentration Catheter features requiring reduced by 10–20% (C: 12,42,78). and type of insulin to use consideration include: 2. In a patient who has been experienc- Rapid-acting insulin analogs result in a ing frequent hypoglycemia, the dose modest but significant reduction in A1C 1. Needle length should be reduced by 20% (E). compared with soluble (regular) insulin ● Children usually have significantly when used in CSII and are preferred by less subcutaneous fat than adults. Calculating the basal insulin rate adult patients (B: 75). Both insulin lispro Therefore, the preferred needle The basal rate of insulin delivery ad- and insulin aspart are approved for CSII length is 6–8 mm. dresses the child’s food-independent in- in most countries. Rapid-acting analogs ● If frequent catheter dislodgement sulin requirement and regulates hepatic are only available in a concentration of occurs or if the overall success of glucose production. As with MDI, this com- 100 IU/ml (U100). CSII is less than expected, one prises 30–50% of the total daily dose. With Recommendations should consider the use of longer the correct dose of basal insulin, all food needles/catheters or catheter in- intake (even small snacks) will necessitate a 1. Although there are no data from con- sertion angles Ͻ90°, especially in food bolus, and, conversely, skipping a trolled studies in children, the use of adolescents. meal will not lead to hypoglycemia.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1657 Insulin pump use in pediatrics
Recommendations in postprandial blood glucose, i.e., ● If the pump does not have an “insu- blood glucose ϳ30–40 mg/dl (1.67– lin on board” function, a second cor- 1. The basal rate is typically 30–50% of 2.2 mmol/l) higher 2 h after a meal and rection dose should not be given the total daily dose (E). returning to the preprandial level by within2hofthefirst. 2. The total daily basal rate should be 4 h after a meal (E). programmed in hourly intervals, ac- 3. In very young children or fussy eaters, 3. If a correction bolus fails to reduce the cording to the patient’s circadian vari- parents may prefer to administer the blood glucose within 2 h, and partic- ation in insulin sensitivity (E). bolus after the meal (C: 85) in order to ularly in the presence of ketosis, a cor- ● The circadian variations in basal in- choose an insulin dose that is appro- rection dose with a pen or syringe sulin are age dependent (C:78;B: priate for the amount of food actually should be given immediately and the 79). eaten. However, if postprandial insu- infusion set should be changed (E). ● Adolescents and young adults typi- lin doses are frequently forgotten, ad- This is most important, since most ep- cally have a two-waved basal rate ministration of the bolus after the meal isodes of DKA in pump users could profile (decreased insulin sensitivity should not be encouraged (C: 86). have been avoided by this simple mea- from ϳ5:00–9:00 A.M. and, to a sure. Ketones should be tested when- lesser extent, in the late afternoon Calculating the correction dose ever there are continued high blood [dawn-dusk phenomenon]). The correction insulin dose depends on glucose readings or the patient feels ● Young children often need more insulin sensitivity and the blood glucose unwell or has nausea/vomiting (E).  basal insulin between 9:00 P.M. and target. It is calculated based on the differ- Blood ketone testing (measures -hy- midnight (C: 78,80,81). ence between the current blood glucose droxybutyrate) is more appropriate for and the desired target blood glucose level. preventing metabolic deterioration, 3. Extreme care is required if prandial As with meal boluses, formulae are avail- but urine ketones (measures acetoace- boluses are programmed into the basal able to calculate insulin sensitivity factors tate) will be sufficient if this is not rate for meals that occur at the same (C: 83). Some pump models offer calcu- available (C: 88). time every day, as hypoglycemia will lation tools for this purpose, whereas occur if this meal is missed or delayed other models require manual calculation Monitoring patients on CSII (E). or the use of other devices (C: 25,87). Recommendations. After initiation of Insulin analogs have a total duration CSII, frequent contact with the diabetes Calculating and timing the prandial of activity of 4–6 h, with the main activity team is required to review and optimize (bolus) insulin requirement occurring during the first 3 h after injec- CSII (E). Scheduled outpatient visits A method of accurately estimating the tion, followed by a prolonged tail of de- should address the following: carbohydrate content of meals and snacks creasing insulin effect. Many new pumps (carbohydrate counting) is a prerequisite allow the user to set the “insulin on board” 1. Glycemic control (A1C, blood glucose for successfully determining the bolus in- duration to a variable length, and most values, and hypoglycemic episodes) sulin requirement (C: 82). Prandial bo- patients use between 3 and 6 h. Subjects 2. Weight gain luses are dependent on carbohydrate seeking very tight control prefer a shorter 3. Average (7 days) total daily insulin intake as well as circadian variation of in- duration of action, whereas subjects con- dose—compared with body weight sulin sensitivity, current blood glucose cerned about hypoglycemia tend to 4. Average total daily basal dose (should levels, and planned physical activity. The choose a longer duration of insulin action. be ϳ0.2–0.4 IU/h for toddlers, 0.4– amount of insulin per gram of carbohy- Frequent administration of boluses is 0.6 IU/h for prepubertal children, and drate is usually highest in the morning associated with better glycemic control 0.8–1.2 IU/h for adolescents) (breakfast). (80). The putative benefits of different bo- 5. Insulin-to-carbohydrate ratio lus modes and timing obtained with bolus Recommendations 6. Correction dose and target blood calculators has yet to be established in the glucose pediatric age-group. 1. Patients with CSII must have a method 7. Average number of boluses per day (to to calculate the appropriate insulin Recommendations assess for missed boluses) dose. 8. Basal-to-bolus ratio ● Various algorithms exist that assist 1. Infants and toddlers typically are more 9. Postprandial and overnight blood glu- in calculating insulin to carbohy- sensitive to insulin than older children cose values drate ratios (C: 83). and adolescents and therefore require 10. Are the total carbohydrates entered ● Receiving more than seven daily bo- less insulin to correct hyperglycemia into the bolus calculator appropriate luses has been associated with a sig- (E). for the child’s age? nificantly lower A1C levels (C: 80). 2. “Active insulin” or “insulin on board” ● A dual-wave bolus may be beneficial from a previous insulin bolus should Terminating CSII when eating foods that are gradually be taken into consideration when de- Recommendations. Discontinuation of absorbed, such as pizza, beans, and termining the subsequent bolus dose CSII should be considered temporarily or meals with a high fat content (C: to prevent “stacking” of correction in- permanently under the following circum- 84). sulin boluses (E). stances (E). ● The duration of action of large bo- 2. The prandial bolus should be designed luses is generally longer than small 1. Child wishes to return to injection to preserve the physiological variation doses of insulin. therapy
1658 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Phillip and Associates
2. Conditions that put the child at undue introduction of currently available Acknowledgments— The ESPE, the LWPES, risk pumps, and, more importantly, these and the ISPAD gratefully acknowledge the ● Recurrent DKA due to pump mis- models have never been validated against support for the consensus meeting from management real long-term prospective controlled tri- Medtronic Minimed, Animas Corporation, ● Ineffective pump management (e.g., als, so their value is questionable. Fur- Novo Nordisk A/S, Abbott Diabetes Care, Eli recurrent missed boluses, inade- thermore, more recent studies show that Lilly & Company, Amylin Pharmaceuticals quate frequency of blood glucose CSII therapy is associated with fewer se- Inc., Roche Diagnostics GmbH, Sooil De- monitoring, or set changes) vere hypoglycemic events (A: 89; C: 92– velopment Co. Ltd, and Smith Medical ● Intentional insulin overdosing to 94). Even if these models were accurate, Deutschland GmbH. cause hypoglycemia what is cost-effective in adults may not be ● Recurrent site infections cost-effective in children given the addi- Participants in the consensus forum tional health team interventions required The following experts were coauthors in Cost-effectiveness for children and their families. the production of this consensus state- There are no published cost-effectiveness The following variables should be ment: Holley Allen (Springfield, MA), analyses or cost-benefit studies compar- considered in analyzing the cost benefit of Shin Amemiya (Saitama, Japan), Bruce ing CSII with MDI in children or adoles- CSII: acute complications, i.e., the fre- Buckingham (Stanford, CA), Fergus cents with type 1 diabetes; such analyses quency of severe hypoglycemia and DKA Cameron (Parkville, Victoria, Australia), are needed. Studies performed in adults (including emergency department visits Francesco Chiarelli (Chiety, Italy), have calculated the expense of insulin and hospitalizations [C: 58]); chronic Nathaniel Clark (Alexandria, VA), Carine pumps, infusion sets, batteries, and insu- complications, both micro- and macro- de Beaufort (Luxembourg), Dorothee lin cartridges compared with that of insu- vascular (EDIC macrovascular study [B: Deiss (Berlin, Germany), Knut Dahl- lin (vials and cartridges) and syringes 95]); direct costs of supplies; indirect Joergrsen (Oslo, Norway), Larry Fox used in MDI. In most countries, the cost costs related to lost earnings of parents; (Jacksonville, FL), Ragnar Hanas (Udde- of a pump and related supplies is higher and costs of other caregivers and addi- valla, Sweden), Przemyslawa Jarosz- than the cost of MDI therapy. Further- tional care team resources. Chobot (Katowice, Poland), Lori Laffel more, the diabetes care team should an- Conclusions. There are insufficient data (Boston, MA), Margaret Lawson (Ottawa, ticipate additional personnel costs for at this time to make a definitive statement Ontario, Canada), Johnny Ludvigsson time spent in the initial education and about cost-effectiveness of CSII in pediat- (Linkoeping, Sweden), Michel Polak training and subsequent support of pump ric patients. (Paris, France), Kenneth Robertson (Glas- users. gow, U.K.), Shlomit Shalitin (Petah Tikva, Two meta-analyses in adults (A: 89; Israel), William Tamborlane (New Ha- B: 2) found that in comparison with MDI CONCLUSIONS — There are very ven, CT), and Joseph Wolfsdorf (Boston, therapy, CSII is associated with a signifi- few published long-term studies on pump MA). cant reduction in mean A1C. Using an use in children and adolescents, and al- A1C reduction of 0.5% with CSII, Scuff- most all of those are observational studies. ham et al. (90) constructed a Markov The vast majority of the studies cited References model to estimate the cost and outcomes use a multidisciplinary trained team that 1. Boland EA, Grey M, Oesterle A, Fredrick- son L, Tamborlane WV: Continuous sub- of CSII compared with MDI. The primary usually is not available to the general pe- cutaneous insulin infusion: a new way to outcome measure was quality-adjusted diatrician or nonacademic pediatric en- lower risk of severe hypoglycemia, im- life years (QALYs). Using Monte Carlo docrinologist. This may be a caveat to prove metabolic control, and enhance simulations for 10,000 hypothetical pa- prescribing CSII. However, based on the coping in adolescents with type 1 diabe- tients over 8 years of monthly cycles (con- available evidence and the experience of tes. Diabetes Care 22:1779–1784, 1999 sidered to be the expected life of a pump), the expert panel, CSII therapy may be ap- 2. Weissberg-Benchell J, Antisdel-Lomaglio the average patient using CSII could ex- propriate for children and youth of all J, Seshadri R: Insulin pump therapy: a pect to gain 0.48 Ϯ 0.2 QALYs compared ages provided that appropriate support meta-analysis. Diabetes Care 26:1079– with MDI at an incremental cost of personnel are available. CSII use in chil- 1087, 2003 £11,461 Ϯ 3,656 (ϳ22,800 Ϯ 7,200$ dren and adolescents may be associated 3. Hanaire-Broutin H, Melki V, Bessieres-La- combe S, Tauber JP: Comparison of con- U.S.) per QALY. Using the Center for with improved glycemic control and im- tinuous subcutaneous insulin infusion Outcomes Research, Basel, Switzerland, proved QOL and poses no greater, and and multiple daily injection regimens diabetes model to describe the incidence possibly less, risk than MDI. Minimizing using insulin lispro in type 1 diabetic pa- and progression of diabetes-related com- risks of CSII entails the same interven- tients on intensified treatment: a random- plications, Roze et al. (C: 91) found that tions that promote safety in all patients ized study: the Study Group for the treatment with CSII was associated with with type 1 diabetes, including proper ed- Development of Pump Therapy in Diabe- an improvement in mean quality- ucation, frequent blood glucose monitor- tes. Diabetes Care 23:1232–1235, 2000 adjusted life expectancy of 0.76 Ϯ 0.19 ing, attention to diet and exercise, and the 4. Maniatis AK, Klingensmith GJ, Slover RH, years compared with MDI and an incre- maintenance of communication with a di- Mowry CJ, Chase HP: Continuous subcu- mental cost-effectiveness ratio of £25,648 abetes team. Additional risk reduction taneous insulin infusion therapy for chil- ϳ dren and adolescents: an option for ( 51,000$ U.S.) per QALY gained. It may be possible with current continuous routine diabetes care. Pediatrics 107:351– must be noted, however, that many of the glucose sensors and will almost certainly 356, 2001 studies included in these meta-analyses decline further with advances in this tech- 5. Plotnick LP, Clark LM, Brancati FL, Er- and for calculating cost-effectiveness nology and the eventual development of linger T: Safety and effectiveness of insu- were published several years before the “closed-loop” insulin delivery systems. lin pump therapy in children and
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1659 Insulin pump use in pediatrics
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Margeirsdottir HD, Larsen JR, Brunborg tions and Complications (DCCT/EDIC) Holzum MK: Continuous subcutaneous C, Dahl-Jorgensen K: Nationwide im- Study Research Group: Intensive diabetes insulin infusion and multiple dose of in- provement in HbA1c and complication treatment and cardiovascular disease in sulin regimen display similar patterns of screening in a benchmarking project in patients with type 1 diabetes. N Engl J Med blood glucose excursions in pediatric type childhood diabetes (Abstract). Pediatr Di- 353:2643–2653, 2005 1 diabetes. Diabetes Technol Ther 7:587– abetes 7 (Suppl. 5):18, 2006 70. Burkart W, Hanker JP, Schneider HPG: 596, 2005 59. McMahon SK, Airey FL, Marangou DA, Complications and fetal outcome in dia- 48. Heptulla RA, Allen HF, Gross TM, Reiter McElwee KJ, Carne CL, Clarey AJ, Davis betic pregnancy: intensified conventional EO: Continuous glucose monitoring in EA, Jones TW: Insulin pump therapy in versus insulin pump therapy. Gynecol Ob- children with type 1 diabetes: before and children and adolescents: improvements stet Invest 26:104–112, 1998 after insulin pump therapy. Pediatr Diabe- in key parameters of diabetes manage- 71. Steindel BS, Roe TR, Costin G, Carlson M, tes 5:10–15, 2004 ment including quality of life. Diabet Med Kaufman FR: Continuous subcutaneous 49. Lepore G, Dodesini AR, Nosari I, Trevisan 22:92–96, 2005 insulin infusion (CSII) in children and ad- R: Effect of continuous subcutaneous in- 60. Hoogma RP, Spijker AJ, van Doorn- olescents with chronic poorly controlled sulin infusion vs multiple daily insulin in- Scheele M, van Doorn TT, Michels RP, type 1 diabetes mellitus. Diabetes Res Clin jection with glargine as basal insulin: an van Doorn RG, Levi M, Hoekstra JB: Qual- Pract 27:199–204, 1995 open parallel long-term study. Diabetes ity of life and metabolic control in patients 72. Pozzilli P, Crino A, Schiaffini R, Manfrini Nutr Metab 17:84–89, 2004 with diabetes mellitus type 1 treated by S, Fioriti E, Coppolino G, Pitocco D, Vis- 50. Weintrob N, Schechter A, Benzaquen H, continuous subcutaneous insulin infu- alli N, Corbi S, Spera S, Suraci C, Cervoni Shalitin S, Lilos P, Galatzer A, Phillip M: sion or multiple daily insulin injections. M, Matteoli MC, Patera IP, Ghirlanda G, Glycemic patterns detected by continu- Neth J Med 62:383–387, 2004 The IMDIAB Group: A 2-year pilot trial of ous subcutaneous glucose sensing in chil- 61. Kamoi K, Miyakoshi M, Maruyama R: A continuous subcutaneous insulin infu- dren and adolescents with type 1 diabetes quality-of-life assessment of intensive in- sion versus intensive insulin therapy in mellitus treated by multiple daily injec- sulin therapy using insulin lispro patients with newly diagnosed type 1 di- tions vs continuous subcutaneous insulin switched from short-acting insulin and abetes (IMDIAB 8). Diabetes Technol Ther infusion. Arch Pediatr Adolesc Med 158: measured by an ITR-QOL questionnaire: 5:965–974, 2003 677–684, 2004 a prospective comparison of multiple 73. De Beaufort CE, Houtzagers CM, Bruin- 51. Schaepelynck-Belicar P, Vague P, Simo- daily insulin injections and continuous ing GJ, Aarsen RS, den Boer NC, Grose nin G, Lassmann-Vague V: Improved subcutaneous insulin infusion. Diabetes WF, van Strik R, de Visser JJ: Continuous metabolic control in diabetic adolescents Res Clin Pract 64:19–25, 2004 subcutaneous insulin infusion (CSII) ver- using the continuous glucose monitoring 62. Peyrot M, Rubin RR: Validity and reliabil- sus conventional injection therapy in
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newly diagnosed diabetic children: two- the PedPump Study Group: The Ped- young people with type 1 diabetes: a ran- year follow-up of a randomized, prospec- Pump Study: a low percentage of basal domized clinical trial. Diabet Med tive trial. Diabet Med 6:766–771, 1989 insulin and more than five daily boluses 23:278–284, 2006 74. Skogsberg L, Lindman E, Fors H, for the are associated with better centralized 89. Pickup J, Mattock M, Kerry S: Glycaemic International Society for Pediatric and HbA1c in 1041 children on CSII from 17 control with continuous subcutaneous in- Adolescent Diabetes: Comparison in met- countries (Abstract). Diabetes 54 (Suppl. sulin infusion compared with intensive abolic control and quality of life of con- 1):A453, 2005 insulin injections in patients with type 1 tinuous subcutaneous insulin infusion 81. Boland E, Ahern JH, Aher JJ, Vincent MR: diabetes: meta-analysis of randomised and multiple daily injections in children Pumps and kids: basal requirements for controlled trials. BMJ 324:705, 2002 at onset of type 1 diabetes mellitus (Ab- excellent metabolic control (Abstract). 90. Scuffham P, Carr L: The cost-effectiveness stract). Pediatr Diabetes 7 (Suppl. 5):65, Diabetes 51 (Suppl. 2):A3, 2002 of continuous subcutaneous insulin infu- 2006 82. Waldron S, Hanas R, Palmvig B: How do sion compared with multiple daily injec- 75. Colquitt J, Royle P, Waugh N: Are ana- we educate young people to balance car- tions for the management of diabetes. logue insulins better than soluble in con- bohydrate intake with adjustments of in- Diabet Med 20:586–593, 2003 tinuous subcutaneous insulin infusion? sulin? Horm Res 57 (Suppl. 1):62–65, 91. Roze S, Valentine WJ, Zakrzewska KE, Results of a meta-analysis. Diabet Med 20: 2002 Palmer AJ: Health-economic comparison 863–866, 2003 83. Davidson PC: The Insulin Pump Therapy of continuous subcutaneous insulin infu- 76. Jorgensen D, Solbeck H, Harboe E: Dilu- Book: Insights from the Experts. Fredrick- sion with multiple daily injection for the tion of Novolog (insulin aspart 100 U/ml) son L, Ed. Sylmar, CA, MiniMed Technol- treatment of type 1 diabetes in the UK. with NPH medium for small dose use in ogies, 1995 Diabet Med 22:1239–12345, 2005 continuous subcutaneous insulin infu- 84. Chase HP, Saib SZ, MacKenzie T, Hansen 92. Bode BW, Sabbah HT, Gross TM, sion does not affect in-vitro stability (Ab- MM, Garg SK: Post-prandial glucose ex- Fredrickson LP, Davidson PC: Diabetes stract). Diabetes 54 (Suppl. 1):A102, 2005 cursions following four methods of bolus management in the new millennium us- 77. Bharucha T, Brown J, McDonnell C, Ge- insulin administration in subjects with ing insulin pump therapy. Diabete Metab bert R, McDougall P, Cameron F, Werther type 1 diabetes. Diabet Med 19:317–321, Res Rev 18 (Suppl. 1):S14–S20, 2002 G, Zacharin M: Neonatal diabetes melli- 2002 93. Linkeschova R, Raoul M, Bott U, Berger tus: insulin pump as an alternative man- 85. Rutledge KS, Chase HP, Klingensmith GJ, agement strategy. J Paediatr Child Health Walravens PA, Slover RH, Garg SK: Effec- M, Spraul M: Less severe hypoglycaemia, 41:522–526, 2005 tiveness of postprandial Humalog in tod- better metabolic control, and improved 78. Conrad SC, McGrath MT, Gitelman SE: dlers with diabetes. Pediatrics 100:968– quality of life in type 1 diabetes mellitus Transition from multiple daily injections 972, 1997 with continuous subcutaneous insulin in- to continuous subcutaneous insulin infu- 86. Burdick J, Chase HP, Slover RH, Knievel fusion (CSII) therapy: an observational sion in type 1 diabetes mellitus. J Pediatr K, Scrimgeour L, Maniatis AK, Klingen- study of 100 consecutive patients fol- 140:235–240, 2002 smith GJ: Missed insulin meal boluses and lowed for a mean of 2 years. Diabet Med 79. Danne T, Battelino T, Kordonouri O, Ha- elevated hemoglobin A1c levels in chil- 19:746–751, 2002 nas R, Klinkert C, Ludvigsson J, Barrio R, dren receiving insulin pump therapy. Pe- 94. DeWitt DE, Hirsch IB: Outpatient insulin Aebi C, Gschwend S, Mullis PE, Schuma- diatrics 113:e221–e224, 2004 therapy in type 1 and type 2 diabetes mel- cher U, Zumsteg U, Morandi A, Rabbone 87. Kaufman FR, Halvorson M, Carpenter S: litus: scientific review. JAMA 289:2254– I, Cherubini V, Toni S, de Beaufort C, Use of a plastic insulin dosage guide to 2264, 2003 Hindmarsh P, Sumner A, van Waarde correct blood glucose levels out of the tar- 95. Nathan DM, Cleary PA, Backlund JY, Ge- WM, van den Berg N, Phillip M: A cross- get range and for carbohydrate counting nuth SM, Lachin JM, Orchard TJ, Raskin sectional international survey of continu- in subjects with type 1 diabetes. Diabetes P, Zinman B, Diabetes Control and Com- ous subcutaneous insulin infusion in 377 Care 8:1252–1257, 1999 plications Trial/Epidemiology of Diabetes children and adolescents with type 1 dia- 88. Laffel LM, Wentzell K, Loughlin C, Tovar Interventions and Complications (DCCT/ betes mellitus from 10 countries. Pediatr A, Motltz K, Brink S: Sick day manage- EDIC) Study Research Group: Intensive Diabetes 6:193–198, 2005 ment using blood 3-hydroxybutyrate (3- diabetes treatment and cardiovascular 80. Danne T, Battelino T, Jarosz-Chobot P, OHB) compared with urine ketone disease in patients with type 1 diabetes. Kordonouri O, Pankowska E, Phillip M, monitoring reduces hospital visits in N Engl J Med 353:2643–2653, 2005
1662 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS
Nonalcoholic Fatty Liver Disease and Insulin Resistance in Youth
ZACHARY T. BLOOMGARDEN, MD abnormality of peroxisomes or by iron overload. NASH is associated with paracrystalline mitochondrial inclusions Perspectives on the News commentaries are from the endoplasmic reticulum. NAFLD is similar to those in mitochondrial gene ab- now part of a new, free monthly CME activ- associated with depletion of polyunsatu- normalities, with decreased mitochon- ity. The Mount Sinai School of Medicine, rated fatty acids, particularly ␥-linoleic acid, drial respiratory chain activity (2). New York, New York, is designating this ac- but with increased overall availability of Oxidative stress in turn causes liver in- tivity for 2.0 AMA PRA Category 1 credits. If fatty acids and reduced fatty acid oxidation, jury, directly by damaging cellular or- you wish to participate, review this article although there is no specific abnormality in ganelles and DNA, by depleting and visit www.diabetes.procampus.net to fatty acid -oxidative capacity. Thus, the mitochondrial DNA, and by inducing of complete a posttest and receive a certificate. condition appears to be a function of in- redox-sensitive genes such as those of the The Mount Sinai School of Medicine is ac- creased fat accumulation from importation nuclear factor-B pathway, while increas- credited by the Accreditation Council for and synthesis, with reduced export. Tran- ing the degradation of inhibitors of B, Continuing Medical Education (ACCME) to scriptional regulators include liver X recep- potentially explaining the increased apop- provide continuing medical education for tor and SREBP, as well as the farnesyl X tosis found in NASH (3). Another area physicians. receptor and peroxisome proliferator– receiving attention is the unfolded protein activated receptors, which in turn are mod- response, a signal transduction network his is the second in a series of four ulated by endocrine, paracrine, and activated by inhibition of protein folding articles on presentations at the autocrine, factors such as insulin, tumor ne- in the endoplasmic reticulum, triggered T World Congress on the insulin resis- crosis factor-␣, adiponectin, and resistin, all by low cellular levels of ATP and calcium tance syndrome (IRS), reviewing the rela- of which are affected by diet, physical activ- depletion, with free cholesterol poten- tionship between insulin resistance and ity, genetics, and adipocyte mass. tially playing a role. This endoplasmic re- nonalcoholic fatty liver disease, and as- There is a stepwise and significant in- ticulum stress phenomenon leads to pects of insulin resistance in children and crease in hepatic free cholesterol in NAFLD, release of mediators such as activating adolescents. and, to an even greater extent, in NASH, transcription factor 6 from the endoplas- which Sanyal suggested may mediate cellu- mic reticulum, leading to expression of Nonalcoholic fatty liver disease lar injury, while hepatic esterified choles- “adaptation” and “alarm” genes, with sub- Arun Sanyal (Richmond, VA) reviewed the terol levels are similar to those in individuals sequent inflammation as well as apopto- spectrum of disorders constituting nonalco- without NAFLD. Free cholesterol can be sis, worsened by cellular necrosis, holic fatty liver disease (NAFLD), from fatty converted to cholesterol esters by acyl-CoA: cytokines, and further oxidative stress, liver to nonalcoholic steatohepatitis cholesterol acyltransferase, can be secreted then further activating nuclear factor-B (NASH). Analysis of liver fat content in ste- directly into bile, or can be converted into and mitogenic pathways. All of this oc- atosis, mainly di- and triglycerides, shows bile acids. No genomic abnormality has curs in the setting of insulin resistance, fatty acids derived from circulation as well been demonstrated in cholesterol and bile which itself worsens inflammation, caus- as fatty acid synthesized de novo from acid synthetic pathways in NAFLD, but he- ing macrophages to migrate into adipose Acetyl-CoA, derived from glucose, acetate, patic cholesterol esters are enriched in poly- tissue with proinflammatory cytokine re- and oxidation of circulating fatty acids, unsaturated rather than saturated fatty lease, increasing systemic inflammation ϳ60% are from plasma free fatty acids acids, suggesting the presence of an abnor- and fibrosis, particularly in the liver. He- (FFAs), 15% from dietary sources, and 25% mality in cholesterol metabolism in patic fibrosis is mediated by stellate cells, from de novo lipogenesis. The latter process NAFLD, leading to increased biliary choles- which produce matrix. These cells are ac- is controlled by sterol regulatory element– terol, which may underlie the association tivated by oxidative stress, by cytokines, binding protein (SREBP)1c, which is in- between the IRS and gallstones. and by activation of the cannabinoid 1 duced by overfeeding, an effect of insulin There is increased lipid peroxidation receptor. As a subsequent step, insulin and the nuclear liver X receptor, to facilitate in NAFLD (1) reflecting hepatic oxidative and leptin are needed to increase stellate conversion of glucose to fatty acids and tri- stress, which may be caused by mitochon- cell matrix production, while endocan- glycerides for the storage. SREBP-1c acts at drial dysfunction, by activation of the cy- nabinoids are among the factors produc- the levels of transcription and of cleavage tochrome P 450 system, or, less likely, by ing stellate cell apoptosis. Another ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● potential abnormality in NASH may be deficiency of stem cell–based reparative Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. processes, which have the potential to re- Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CVD, cardiovascular disease; store normal hepatic architecture and FFA, free fatty acid; IGT, impaired glucose tolerance; IMCL, intramyocellular lipid; IRS, insulin resistance physiology. syndrome; IUGR, intrauterine growth retardation; NAFLD, nonalcoholic fatty liver disease; NASH, nonal- Mary Rinella (Chicago, IL) discussed coholic steatohepatitis; NHANES, National Health and Nutrition Examination Survey; SREBP, sterol regu- latory element–binding protein. the evaluation and management of DOI: 10.2337/dc07-zb06 NAFLD. The distinction between simple © 2007 by the American Diabetes Association. steatosis and NASH is important. For in-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1663 Perspectives on the News dividuals with NASH, over a 5-year pe- from NASH. It is, she stated, important to alone, 45 mg pioglitazone daily was asso- riod 25% will develop fibrosis and 15% exclude hepatic decompensation and to ciated with improvement in glycemia and cirrhosis (4). Histological signs such bal- assess the stage of disease in an individual transaminase levels, with decreased histo- looning degeneration indicate active dis- with NASH, with “liver biopsy . . . the logical evidence of steatosis, ballooning ease, with a proposed NASH activity score only way at this time to stage disease ac- necrosis, and inflammation, although not allowing discrimination between mild curately.” There is a 66% prevalence of with significant difference in fibrosis and more severe disease, although there is bridging fibrosis, the stage just before cir- [12].) Metformin has been administered disagreement at the intermediate stages rhosis, in individuals aged Ͼ50 years in a number of studies (13,14). In a com- (5). Typically, levels of alanine transami- with diabetes or with obesity (7,8). She parison of metformin with rosiglitazone, nase (ALT) exceed those of aspartate suggested that specialist referral is appro- only the latter agent was associated with transaminase (AST), the opposite finding priate in accurately staging disease and improvement of hepatic fat content and to that of alcoholic fatty liver; the presence before initiating therapy that might lead reduction in transaminase levels (15). of an increased alkaline phosphatase sug- to adverse outcome, as well as for clinical Given the evidence that administration of gests that another disease process may be trials. metformin with thiazolidinediones re- present. Six of 10 individuals with NASH Management approaches include duces the likelihood of weight gain are asymptomatic, 30% have fatigue, 30% avoidance of alcohol and drugs causing among individuals with diabetes, Rinella have right upper abdominal pain, and steatohepatitis, correction of underlying suggested that consideration should be 25% have enlargement of the liver on risk factors with lipid-lowering agents given to studying the combination in the physical examination. A normal ALT is and insulin sensitizers, and weight loss, treatment of NAFLD. Another potentially seen in 30% of individuals with NASH with diet, exercise, and pharmacologic useful approach is intervention in the re- and in 60% of those with cirrhosis, and approaches including orlisat, sibutra- nin-angiotensin-aldosterone system. when the ALT is normal with NASH, mine, GLP-1 receptor agonists, and an- Mineralcorticoid blockade reduces car- Rinella commented that diabetes is partic- tagonists of endogenous cannabinoids diac fibrosis. Animal models show im- ularly likely to be present. NASH should having potentially beneficial effects, with provement in hepatic steatosis with then be suspected in high-risk individu- consideration potentially given to bariat- losartan, and in the DREAM (Diabetes RE- als, particularly with metabolic syndrome ric surgery in morbidly obese individuals. duction Assessment with ramipril and and obesity, even with normal liver en- There may, however, be harm from rapid rosiglitazone Medication) trial ALT levels zymes, as well as in individuals with per- weight loss, as seen with jejeuno-ileal by- decreased with ramipril (16). Given the sistently abnormal liver enzymes, pass, and as has been found in diabetes evidence of toxicity of free cholesterol, recognizing that other causes must be ex- prevention trials relatively small degrees statins might be of benefit, with promis- cluded, such as alcohol, chronic viral of weight loss may be effective, recogniz- ing preliminary results using atorvastatin. hepatitis B (particularly in individuals of ing the many barriers that exist to achiev- Consideration should always be given, Asian origin), hepatitis C (particularly ing this goal. Other pharmacologic Rinella noted, to excluding the presence with a history of drug use or with a tat- approaches being explored include anti- of hepatitis C, which is associated with too), autoimmune hepatitis (which may oxidants such as vitamin E, pentoxifyl- NAFLD, with the presence of NAFLD af- be associated with positive antinuclear or line, agents blocking tumor necrosis fecting the response to antiviral treat- antismooth muscle antibodies), or with factor-␣, betaine, S-adenosyl-methio- ment. abnormality on serum protein electro- nine, and ursodeoxycholic acid. phoresis, iron overload, and drugs in- Rinella reviewed a number of studies Insulin resistance in childhood and cluding tamoxifen, prednisone, of these approaches. In analysis of the ef- adolescence diltiazem, and amiodarone. Using such fect of bariatric surgery in individuals Alan Sinaiko (Minneapolis, MN) intro- an approach, in a study of 354 individuals with morbid obesity, the prevalence of duced a symposium on insulin resistance with persistently abnormal liver enzymes, hepatic steatosis decreased from 88% be- in pediatrics preceding the Annual World 34 and 32% had NAFL and NASH, with fore to 8% after the procedure, with the Congress on the IRS with the observation more than one-third having other etiolo- prevalences of fibrosis decreasing from 31 that “the roots of the metabolic syndrome gies (6). Imaging may be useful in exclud- to13% and that of inflammation from 23 go back into childhood.” Proper appreci- ing other liver diseases. Ultrasound to 2% (9). Another study used gastric ation of its complexities, then, must in- features include a “bright” liver with echo banding, again showing improvement of clude the study of children with insulin texture increased compared with that of steatosis and fibrosis (10). The majority of resistance. Stephen Cook (Rochester, NY) the kidney and with vascular blurring, al- individuals with NASH, however, do not examined the characterization of meta- though ultrasound suffers from low sen- have morbid obesity, and there are no bolic syndrome in children and adoles- sitivity, as it may be normal with fat long-term follow-up studies showing cents. Certainly, cardiovascular disease comprising Ͻ30% of the liver, as well as continued benefit. In studies of thiazo- (CVD) risk factors cluster in families, and low specificity as it may be difficult to dis- lidinediones, pioglitazone administration in individual children, and tracking these tinguish fat from fibrosis. Computerized has been associated with decreased fat, factors over time in children provides in- tomography detects the presence of ste- ballooning, Mallory bodies, and pericel- sight into their development. Over several atosis by decreased attenuation compared lular fibrosis (11), although the potential decades, progressive increase has been with spleen, a finding exaggerated with for weight gain has been a concern. (A seen in overweight among children and contrast, and magnetic resonance imag- 6-month study of 55 individuals with adolescents (17). Mean waist circumfer- ing is the most sensitive test in detecting NASH who had diabetes or glucose intol- ence increased by 1.6 and 2.4 cm for male steatosis; however, Rinella noted that no erance was reported subsequent to Rinel- and female children, respectively, from imaging modality distinguishes NAFLD la’s talk; compared with hypocaloric diet the time of the National Health and Nu-
1664 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Bloomgarden trition Examination Survey (NHANES) III with overweight and with the metabolic “self-regulate better.” A therapeutic impli- survey in 1988–1994 to the next survey syndrome, suggesting another contribu- cation is the need to focus on measures to in 1999–2000, with the prevalence of el- tory factor. improve self-regulation and on nutrients evated waist circumference increasing by Studies of preadolescent girls, using that improve regulation of energy bal- Ͼ70% (18,19). Similar studies in British modified Adult Treatment Panel III and ance, rather than on efforts to increase children have shown increased central World Health Organization criteria, body weight in infants with IUGR, as this adiposity (20). found IRS prevalence ranging from may promote the development of obesity. Analysis of the NHANES III data Ͻ0.5 to 25% (27). Applying a common Devaskar reviewed cross-sectional com- shows that 23.7% of adults have meta- set of criteria, 3% of Korean, 4% of puted tomography scan studies showing bolic syndrome, including 6–7% of those North American, 6% of Brazilian, and that offspring with IUGR exhibiting aged 20–29 years (21). Using 110 mg/dl 10% of Iranian children had metabolic catch-up growth have increases both in for both triglyceride and glucose cutoff syndrome. Interestingly, analyses of subcutaneous and visceral fat, while those levels, 40 and 50 mg/dl HDL, respec- 1,826 adolescents in the NHANES with lower childhood weight have lesser tively, in male and female adolescents, 1999–2002 dataset using three differ- increase in visceral fat, without increased and the 90th percentiles of abdominal cir- ent definitions showed IRS prevalence subcutaneous fat. The infants with IUGR cumference and blood pressure, 4% of varying from 2 to 9.4%, with 12–44% exhibiting catch-up have the greatest de- adolescents had metabolic syndrome of the overweight group meeting the cri- gree of postload hyperinsulinemia when (22). In studies of younger children using teria for the syndrome, suggesting the tested in adulthood. This leads to the con- 90 mg/dl as triglyceride cutoff, 40 mg/dl need to design definitions having cept of transgenerational propagation, for HDL cholesterol, and A1C Ͼ6% greater agreement with one another. which has been explored in animal stud- (rather than fasting glucose) as criteria, Sherin Devaskar (Los Angeles, CA) ies, with either over- or undernutrition 4.3% of 5- to 11-year-old children had described the fetal origins of the IRS, with predisposing the infant to insulin resis- metabolic syndrome, including 20% of multiple complex contributory factors, tance. With intervention in the grand- those who were overweight. including intrauterine growth retardation mother, mothers show IUGR, and their There is evidence that risk factor clus- (IUGR), which may reflect a gene- infants, even with optimal maternal nutri- tering tracks over time (23). The Young environment interaction leading to obe- tion during pregnancy, have normal Finns study followed high-risk children sity and type 2 diabetes, so that increased growth pattern but postload hyperinsu- with increased cholesterol, low HDL, and energy intake and inactivity may “propa- linemia, lower hepatic glucose produc- increased diastolic blood pressure, find- gate what was already set in utero.” A tion, and altered insulin signaling. A ing that one-quarter still had high-risk ab- number of maternal factors influence potential mechanism may be epigenetic normality in these parameters after 6 postnatal outcome, including maternal change, perhaps with DNA methylation years of follow-up (24). A 12-year Cana- prepregnancy weight/body composition, of genes leading to abnormality of nutri- dian study similarly showed the IRS to weight gain during pregnancy, ethnicity, ent metabolism. continue in young individuals over a 12- pregestational and gestational diabetes, Donna M. Dabelea (Denver, CO) dis- year period. In the Bogalusa study, abnor- whether diet- or insulin-controlled, pre- cussed ethnic differences in the IRS in malities of insulin sensitivity index, BMI, gestational and gestational hypertension, youth, emphasizing that the syndrome blood pressure, triglyceride, and HDL and dyslipidemia. Maternal obesity is as- represents clustering of CVD risk factors cholesterol clustered after 8 years. Similar sociated with still birth and both with including central obesity, abnormal glu- studies show that IRS tracks into adult- macrosomia and with IUGR. Presenta- cose tolerance, dyslipidemia with high tri- hood (25). Furthermore, offspring stud- tions at birth may include injuries, such as glyceride and low HDL cholesterol, and ies in Minnesota and Bogalusa show that shoulder dystocia and nerve palsies, and hypertension and rapid heart rate, all re- parents with IRS have children with prematurity leading to respiratory dis- flecting insulin resistance. The associa- higher BMI, waist circumference, insulin, tress syndrome. Long-term outcome has tion of pulse pressure and heart rate was and blood pressure levels, presumably re- been studied in Pima Indian and Chicago shown in the Bogalusa study (32), with flecting both genetic and environmental observations of adolescents born to dia- autopsy of children who died accidentally influences. Interesting, not only those betic or obese mothers, showing in- in this study showing an association of the children with high levels of CVD risk fac- creased likelihood of hyperinsulinemia, number of IRS components with the like- tors, but also those in the lowest quartile elevated leptin levels, and childhood obe- lihood of aortic and coronary artery fatty levels of risk factors track together, sug- sity. IUGR is also common in the devel- streaks and fibrous plaques (33). A num- gesting that with appropriate intervention oping world in the setting of low maternal ber of studies in adults have shown there is the potential to offer long-term caloric intake, and here too it is associated greater prevalence of insulin resistance protection. with long-term complications including and of CVD risk factors in ethnic minori- Cook reviewed other studies suggest- insulin resistance, central obesity, hyper- ties, in part related to obesity. There is ing further factors reflecting metabolic tension, and CVD (28,29). One possibil- evidence of elevated fasting insulin in Af- risk. Children who survive malignancy ity is that IUGR leads to exaggerated rican-American versus non-Hispanic have increased risk of developing IRS, “catch-up growth,” with excessive conse- white children ages 7–11 (34), with sim- with greater likelihood of obesity, high quent energy balance causing the insulin- ilar findings in American Indian and in triglyceride levels, and low HDL choles- resistant state (30). Conversely, an Hispanic children, to some extent inde- terol levels. Analysis of C-reactive protein important postnatal influence on insulin pendent of obesity. Dabelea suggested showed levels of 3.8 vs. 1.4 mg/l in indi- sensitivity is breast-feeding, which is as- that obesity may influence the develop- viduals with versus without IRS, respec- sociated with lower BMI at age 6 through ment of IRS to greater extent in white and tively (26). Cigarette use is associated 72 months (31), suggesting that they Hispanic than African-American chil-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1665 Perspectives on the News dren. African-American and Hispanic American Indians, lower in those of CoA, and protein kinase C-, leading to youth have lower insulin sensitivity than Asian-Pacific island ethnicity, with some- decreased insulin receptor substrate 1 ac- non-Hispanic white youth, with higher what lower prevalence among Hispanics, tivity (44). acute insulin response in African- and then among African American, and NAFLD is the major cause of unex- American than in Hispanic or in non- lowest among non-Hispanic white (41). plained increased ALT in adults and chil- Hispanic white youth and total insulin Although evidence of insulin resistance is dren, termed by Caprio “the hepatic secretion higher in Hispanic children common among type 2 diabetic youth, it component of the metabolic syndrome,” (35). There may be both genetic and so- also is seen in 30% of youth with type 1 present in 2–3% of nonobese and 30– cial class components to the reduced in- diabetes. The prevalence of microalbu- 50% of obese children and in 70% of chil- sulin sensitivity and greater acute insulin minuria is also higher in type 2 than type dren with IRS. Hepatic fat accumulation is response to glucose in African American 1 diabetic youth, varying with race in seen in the setting of increased circulating than non-Hispanic white (36), with the youth with type 2 diabetes but not in FFAs, leading to increased hepatic VLDL greater insulin response associated with those with type 1 diabetes. production and glucose production, per- reduced hepatic insulin extraction, while Sonia Caprio (New Haven, CT) re- haps mediated to a large part by an asso- Hispanic youth have greater levels of in- viewed the spectrum of insulin resistance ciated decrease in levels of adiponectin, sulin secretion. There is a stronger rela- among obese children. Given the predic- which has metabolic and anti-inflamma- tionship of total body fat to insulin tion that diabetes is growing in epidemic tory effects including actions on adeno- secretion (37) and to triglyceride levels proportions in Asia, South America, and sine monophosphate–activated protein (38) in non-Hispanic white than in Afri- Africa, she speculated that the “hidden kinase and on peroxisome proliferator– can-American youth. This data suggests, epidemic” of impaired glucose tolerance activated receptor-␥ (45). This phenome- Dablea commented, that minority chil- (IGT) may be of even greater conse- non led Caprio’s group to study 392 obese dren might be more likely than non- quence, as there are currently some 200 adolescents, none receiving medications, Hispanic white children to develop type 2 million individuals with diabetes and comparing ALT tertiles. The highest ALT diabetes due to obesity-independent in- Ͼ300 million with IGT worldwide. An level was seen in 14% of African- crease in insulin resistance but may be important consideration is the mecha- American, but in 43% of non-Hispanic less likely to develop obesity-dependent nism of the effect of obesity in causing white and 37% of Hispanic, adolescents insulin resistance, although this conclu- insulin resistance. Obesity is associated in the group, with stepwise worsening of sion appears somewhat at variance with with excess tissue lipid deposition, caus- glucose tolerance and of hyperinsulin- clinical experience. In terms of IRS, one ing increased hepatic glucose production emia as ALT increased, in association with must recognize that it is difficult to com- and impaired muscle insulin-mediated decreasing insulin sensitivity and increas- pare studies, as different definitions are glucose disposal, both contributing to in- ing triglyceride and FFA levels (46). Mag- used. There appears to be a higher preva- sulin resistance and eventually to hyper- netic resonance imaging studies in 72 of lence of the syndrome in African- glycemia. Skeletal muscle specimens these children allowed quantitation of American than in non-Hispanic white or obtained from adults with type 2 diabetes liver, visceral, and subcutaneous fat. The Hispanic children (22). Comparing non- contain droplets of ectopic lipid (42), and African-American children had less and Hispanic white with African-American Caprio reviewed studies in children and the Hispanic children more hepatic fat, and Hispanic children in the NHANES III adolescents using 1H nuclear magnetic and different subcutaneous fat patterns study, the prevalence of central obesity resonance spectroscopy to quantitate ex- were seen in the two groups, with African appeared to increase over time in the lat- tra- and intramyocellular lipid (IMCL), Americans having more superficial ab- ter group, blood pressure levels increased the latter associated with insulin resis- dominal and less deep subcutaneous fat, in all, and HDL cholesterol levels were tance. In her study of adolescents with while the Hispanic children had more lower in the minority groups (39). IGT, euglycemic and hyperglycemic deep subcutaneous fat. Children with in- Type 2 diabetes in youth may be con- clamps were performed to assess insulin creased hepatic fat had lower adiponec- sidered “the extreme manifestation of the sensitivity and secretion, and body com- tin, higher visceral fat, and a greater ratio IRS,” and, although increasing in inci- position measurements were made in 14 of deep-to-superficial subcutaneous fat. dence, it remains sufficiently rare on a adolescents with IGT and 14 control sub- Jeffrey Schwimmer (San Diego, CA) population basis that it has not been pos- jects with normal glucose tolerance, further reviewed the association of liver sible to directly ascertain whether it be- matched for obesity. Fasting glucose lev- disease with obesity and metabolic syn- gins in children with insulin resistance. els were identical, but the 2-h glucose drome in children. The normal liver is The Search for Diabetes in Youth data has level was 111 vs. 162 mg/dl, fasting and ϳ1% fat. NAFLD is associated with large given some information on the topic. For 2-h insulin levels were ϳ1.5- and 3-fold fat droplets in liver, with steatosis (Ն5% children up to 9 years of age developing higher, and adiponectin 25% lower in the fat content) the defining feature. The diabetes, the prevalence is 0.79 cases per IGT group. Insulin sensitivity was re- mechanism of NASH may involve excess 1,000, somewhat higher among non- duced in the nonoxidative pathway in a delivery of fat to the liver, with increased Hispanic white, with Ͼ80% having type 1 fashion similar to that seen in individuals FFA uptake, or potentially caused by in- diabetes, while among those aged 10–19 with type 2 diabetes, and IMCL was 30% creased de novo lipogenesis, although an years the prevalence is 2.80 cases per higher in the IGT children (43). Total alternative concept is that increased liver 1,000, with type 2 diabetes in 6% of non- body fat was similar in the two groups, fat reflects decreased oxidation or de- Hispanic white but in 76% of American but those with IGT had more visceral and creased VLDL secretion. Inflammation is Indian youth (40). Among youth with di- less subcutaneous fat. IMCL may directly present in some individuals with NAFLD abetes, the prevalence of insulin resis- reduce insulin signaling by increasing lev- and may reach the level of NASH. Other tance and of IRS components is highest in els of ceramide, diacyl glycerol, fatty acyl- individuals with NAFLD develop fibrosis,
1666 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Bloomgarden some with cirrhosis, and 3–10% of chil- Alan Sinaiko presented his studies of pressure, triglyceride, and fasting insulin dren with NAFLD have cirrhosis at the the natural history of insulin resistance and lower HDL but similar insulin sensi- time of a diagnostic liver biopsy. Schwim- and its relationship to the IRS in children tivity to that seen in the thinner half, mer commented that one should never and adolescents. The prevalence of “over- while, comparing those with low versus consider NAFLD “just fatty liver,” stating weight” (the term used to designate obe- high insulin sensitivity, triglyceride levels that NASH progresses to cirrhosis as fre- sity among children) increased from 4 were higher and HDL cholesterol lower, quently as hepatitis C. to10% from 1971 to 1994. Pediatric over- but blood pressure was similar. Those In Schwimmer’s studies of pediatric weight is associated with abnormal ca- who were both in the heavier and less in- NASH, the disease typically presents rotid intima-media thickness and flow- sulin-sensitive halves of the population around 12 years of age (47). On autopsy mediated vasodilation, the findings of the had higher blood pressure, higher triglyc- studies the prevalence of NASH increases IRS in adults. Sinaiko reviewed his three eride, lower HDL, and higher fasting in- with age, with twice as many boys than cohort studies, started in 1978, in 1986, sulin, suggesting this to be the key group girls (48). ALT levels are typically higher and in 1997. The first study showed an displaying all the metabolic abnormali- than levels of AST, but Schwimmer extremely high correlation of BMI at age 7 ties, an observation that became more ap- pointed out that a normal level does not years with that at age 24 years (49), so that parent using the Z-score measure (52). exclude NASH. Most pediatric NASH is the notion that when children “go Sinaiko pointed out that the goal of an associated with obesity, and abnormal through their growth spurt” they lose analysis of the sort he described is to de- liver function is seen in 10–20% of obese weight is incorrect. HDL cholesterol, tri- rive approaches to the prediction of future children, while half of obese children glyceride, and blood pressure track simi- risk. In addition to baseline insulin resis- have ultrasound findings suggesting larly from age 13 to 23 years, but insulin tance, an important predictive factor is NASH, with some of these probably false- levels do not track as well, leading Sinaiko the degree of change in insulin resistance, positive given the 38% prevalence of to conclude that the “fasting insulin falls and although the baseline BMI is not a NASH on liver biopsy of obese children. far short of other measures of insulin sen- significant predictor of CVD risk in mul- Morbid obesity is an important risk factor sitivity.” Insulin sensitivity measured by tivariate analysis, the change in BMI from for progression; interestingly, hypopitu- euglycemic clamp shows somewhat bet- age 13 to 19 years was strongly correlated itarism also increases the likelihood of ter correlation at the two time points than with blood pressure and triglyceride (53), progression of NASH. Of children with fasting insulin, with an insulin resistance suggesting that initiatives to change obe- NAFLD, 8–10% have diabetes, 75% have score based on “Z-scores” of triglyceride, sity are important, although we do not hyperinsulinemia, and 95% have insulin HDL, systolic blood pressure, and fasting know how to reproducibly achieve this resistance using homeostasis model as- insulin showing the greatest correlation. goal. sessment. Conversely, half of type 2 dia- Sinaiko reviewed other evidence that the Sinakio described the relationship be- betic children have NAFLD. Half of fasting insulin correlates poorly with tween the metabolic syndrome and insu- children with NAFLD have acanthosis, clamp insulin sensitivity (50) and noted lin resistance in his studies. The and dyslipidemia is common. Approxi- that given the low variability in fasting syndrome was present in 2–6%, 4–9%, mately one-quarter of children have pain glucose, homeostasis model assessment and 8% of children in his survey at ages from NASH, with Schwimmer character- (calculated from the ratio of insulin to 13, 15, and 19 years, depending on the izing these as “the lucky ones [who] get glucose) is no better than the fasting insu- approach used, with waist, triglyceride, picked up.” lin. and HDL cholesterol more important Two types of NASH are seen in chil- Insulin sensitivity decreases at the be- than elevated blood pressure and glucose dren: the first type with fat particularly in ginning of of puberty, particularly for levels as contributors to the diagnosis. Al- the central vein area, similar to the typical boys, returning to baseline at end of pu- most all of the children with metabolic appearance in adults, affects 20%, while berty (51). During the period from age 8 syndrome had BMI above and insulin sen- in the second, more common type lipid is to 19 years, blood pressure and triglycer- sitivity below the median, and this group mainly present in hepatocytes, with por- ide levels increase, particularly in boys, tended not to show improvement during tal inflammation and fibrosis (47). Non- and HDL cholesterol levels decrease. In- the period of follow-up, further suggest- Hispanic white children typically have the sulin sensitivity, however, decreases in ing the importance of developing mea- first type, while the second form of NASH boys and increases in girls, and the pro- sures to achieve weight loss or to improve in children is typically seen in those of portion of body fat decreases in boys and insulin sensitivity. Comparing insulin- Asian, particularly Filipino and Japanese, increases in girls, suggesting that al- sensitive with insulin-resistant children and Hispanic ethnicity, with obese Afri- though insulin sensitivity is related to whose BMI was below median, visceral fat can-American children having NASH rel- obesity, there must be determinants other measured at age 23 years was lower atively infrequently. than fatness. The degree of obesity does, among the former group, suggesting that Schwimmer described a trial of 10 however, correlate with levels of insulin, fatness may be important even among nondiabetic children aged 8–17 years triglyceride, HDL, blood pressure, and in- those in the thinner group. Differences with NASH treated for 24 weeks with 500 flammatory markers. between these groups in triglyceride and mg metformin twice daily, with ALT and Grouping children into four catego- in the insulin sensitivity Z-score contin- AST decreased to normal levels in half. ries, based on BMI and on insulin sensi- ued to be present over time. Sinaiko con- Liver fat by magnetic resonance spectros- tivity above versus below the median cluded that the metabolic syndrome does copy decreased in all cases, with a direct gives another approach to dissecting the begin in childhood, that it is related to dose-response effect between metformin relative contributions of obesity versus in- increased risk, and that its treatment will (in milligrams per kilograms per day) and sulin resistance to CVD risk factors. The require measures both to address obesity the decrease in liver fat. heavier half of children had higher blood and to improve insulin sensitivity.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1667 Perspectives on the News
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DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1669 Editorials EDITORIAL (SEE YATURU ET AL., P. 1574)
Thiazolidinedione Therapy Gets Complicated Is bone loss the price of improved insulin resistance?
n escalating number of recent pub- not reported but did not differ statistically bone loss among diabetic men without lications suggest that the thiazo- between the pioglitazone and comparison TZD use. Changes in bone with TZD use A lidinedione (TZD) medications may groups. in men have not been investigated in a have a negative effect on the skeleton. The Results of a randomized controlled randomized clinical trial. Thus, our manufacturers of the two currently avail- trial, published electronically in January knowledge of the effects of TZDs on bone able TZDs, rosiglitazone and pioglita- 2007, added to the evidence that TZDs in men is quite limited. The results re- zone, have both issued letters to health have negative effects on the skeleton. In a ported by Yaturu et al. (6) indicate that care providers, warning that these medi- trial that enrolled 50 postmenopausal further study in men is warranted. cations may cause an increased risk of women without diabetes or osteoporosis, Studies with rodent models have fracture in women (1,2). TZDs improve Grey et al. (4) reported bone loss with found increased bone loss with rosiglita- insulin sensitivity and are widely pre- rosiglitazone. After 14 weeks of treatment zone and pioglitazone treatment and sug- scribed for type 2 diabetes, but we are just (8 mg/day), total hip bone density de- gest that the mechanism is decreased beginning to understand their clinical ef- creased significantly in the rosiglitazone osteoblast function (7–10). TZDs activate fects on bone. group (Ϫ1.9% rosiglitazone vs. Ϫ0.2% the nuclear hormone receptor, peroxi- In December 2006, the ADOPT trial placebo). Markers of bone formation were some proliferator–activated receptor-␥ reported a higher risk of fractures in dia- also reduced (Ϫ8toϪ13%), while no (PPAR-␥), improving insulin sensitivity. betic women randomized to rosiglitazone change was seen in resorption markers. PPAR-␥ activation also influences the lin- than in women randomized to metformin Although these results were found in eage allocation of mesenchymal stem cells or glyburide (3). The ADOPT trial fol- women without diabetes, the fracture re- (MSCs) in the bone marrow. With rosiglit- lowed 4,360 (42% women) participants sults cited above suggest that the findings azone treatment, MSCs are increasingly with a mean age of 57 years for a median apply to those with diabetes as well. In allocated toward adipocytes, and differ- of 4 years. The primary outcome was time addition, we have shown that older dia- entiation toward osteoblasts is decreased to monotherapy failure as determined by betic women taking any TZD (rosiglita- (11). The effect of PPAR-␥ activation on fasting glucose. An imbalance in fracture zone, pioglitazone, and troglitazone) in osteoclasts has not been elucidated, with rates was identified in a final review of the observational Health, Aging and Body some studies finding no effect (7–9) but adverse event reports. The proportion of Composition (Health ABC) study had an others finding increased bone resorption women reporting a fracture was 9.3% for increased rate of bone loss (5). (12). In one animal model, ovariecto- rosiglitazone, 5.1% for metformin, and In this issue Yaturu et al. (6) provide mized, but not intact, rats experienced 3.5% for glyburide, corresponding to an evidence that rosiglitazone may also cause bone loss with rosiglitazone treatment, approximate relative risk (RR) of 2.18 bone loss in older men. This observa- suggesting that low levels of endogenous (95% CI 1.52–3.13) for rosiglitazone ver- tional study compared changes in bone estrogen may enhance the negative effect sus the other treatments combined. density over an average of 16 months in of rosiglitazone on bone (12). This effect Among male participants, 89 reported a 160 older (average age 68 years) men with modification with estrogen levels is one fracture, distributed similarly across diabetes, 32 using rosiglitazone and 128 possible explanation for the sex differ- treatments (rosiglitazone 3.9%, met- who had not used any TZD. Those using ences seen in fracture rates with TZD ther- formin 3.4%, and glyburide 3.3%), corre- rosiglitazone lost bone more rapidly. In apy since postmenopausal women tend to sponding to an approximate RR of 1.18 unadjusted models, the difference in an- have lower endogenous estrogen levels (0.77–1.80), for rosiglitazone versus the nual bone loss was Ϫ1.05% at the total than men of a similar age. other treatments combined. hip, Ϫ1.02% at the femoral neck, and The short trial by Grey et al. (4) found Pioglitazone, the other currently Ϫ1.24% at the spine. This study has im- 1.7% more bone loss in the rosiglitazone- available TZD, may also have negative portant limitations, including its observa- treated group compared with placebo skeletal effects. In March 2007, Takeda tional design and the lack of adjustment over just 14 weeks. If this rate of bone loss (2) reported increased fracture risk in for potential confounders. The only other continued, the additional loss with ros- women, but not men, using pioglitazone, data available on men is from the Health iglitazone therapy would be Ͼ6% per based on an analysis of their clinical trial ABC observational study, reporting a year. However, in both the Health ABC database, including 24,000 person-years modest increase in bone loss that was not study and the study in this issue by Yaturu of follow-up. Among women, fracture in- statistically significant (5). Older diabetic et al., the additional annual bone loss for cidence was 1.9 per 100 person-years for men using any TZD had additional annual women or men attributable to TZD use pioglitazone and 1.1 per 100 person- bone loss of Ϫ0.25% (95% CI Ϫ1.10 to was considerably lower, on the order of years for those using placebo or another 0.60) at the spine and Ϫ0.19% (Ϫ0.61 to Յ1.2% per year for the hip and spine active drug. The incidence for men was 0.22) at the total hip, compared with (5,6). These differences might be due to
1670 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Schwartz and Sellmeyer different study population characteristics pause and instituting osteoporosis treat- 2007 and study design; however, they do raise ment in women found to be at increased 3. Kahn SE, Haffner SM, Heise MA, Herman the question of the overall magnitude of risk for fracture. WH, Holman RR, Jones NP, Kravitz BG, bone loss that might occur with TZD ther- The value of screening bone density Lachin JM, O’Neill MC, Zinman B, Viberti testing in younger individuals and men is G: Glycemic durability of rosiglitazone, apy. The evidence from bone markers, metformin, or glyburide monotherapy. bone density scans, and fracture risk sug- not as well established. Currently, these N Engl J Med 355:2427–2443, 2006 gests that the TZDs cause clinically patients are selected for testing based on 4. Grey A, Bolland M, Gamble G, Wattie important bone loss, at least in postmeno- clinical risk factors or the presence of a D, Horne A, Davidson J, Reid IR: The pausal women, but the degree of bone secondary cause of bone loss. The study peroxisome-proliferator-activated receptor- loss remains a question. in this issue by Yaturu et al. (6) is the first gamma agonist rosiglitazone decreases Longer-term clinical trials are needed to suggest that men may also be suscepti- bone formation and bone mineral density to clarify the extent of bone loss poten- ble to bone loss associated with TZD ther- in healthy postmenopausal women: a ran- tially related to TZD therapy, to deter- apy. At this time, it would seem prudent domized, controlled trial. J Clin Endocrinol Metab 92:1305–1310, 2007 mine whether men are also susceptible, to consider the presence of TZD therapy when developing an overall impression of 5. Schwartz AV, Sellmeyer DE, Vittinghoff and to identify the effects in younger E, Palermo L, Lecka-Czernik B, Feingold adults. Additional work using animal and fracture risk for each patient and deter- KR, Strotmeyer ES, Resnick HE, Carbone in vitro models will also be needed to elu- mining whether screening bone density L, Beamer BA, Park SW, Lane NE, Harris cidate the underlying mechanisms by testing is necessary. Nutrition and life- TB, Cummings SR: Thiazolidinedione use which TZDs interact with the skeleton. style recommendations for bone health and bone loss in older diabetic adults. More investigation is needed; how- should be implemented in all patients and J Clin Endocrinol Metab 91:3349–3354, ever, at this time, health care providers specific osteoporosis therapy initiated in 2006 should be made aware of the potential for those individuals who appear to be at in- 6. Yaturu S, Bryant B, Jain S: Thiazolidinedio- creased fracture risk based on clinical risk nes treatment decreases bone mineral den- increased bone loss and fracture risk with sity in type 2 diabetic men. Diabetes Care TZD use. In ADOPT, where the mean age factors and the results of bone density testing. The benefits of TZD therapy to 2007 Mar 15 [Epub ahead of print] was 57 years, the annual fracture rate 7. Rzonca SO, Suva LJ, Gaddy D, Montague among women using rosiglitazone was improve glycemic control and prevent DC, Lecka-Czernik B: Bone is a target for 2.7%, about double the 1.3% rate in the complications of diabetes are well estab- the antidiabetic compound rosiglitazone. glyburide group. The absolute increase in lished. Further data are needed to deter- Endocrinology 145:401–406, 2004 fracture risk will vary depending on age, mine the magnitude of the potential 8. Soroceanu MA, Miao D, Bai XY, Su H, bone density, and other risk factors for skeletal effects and the overall risk benefit Goltzman D, Karaplis AC: Rosiglitazone ratio for individuals with diabetes. impacts negatively on bone by promoting fracture. For example, in an older cohort 1 osteoblast/osteocyte apoptosis. J Endocri- of diabetic women (average age 72 years), ANN V. SCHWARTZ, PHD nol 183:203–216, 2004 2 the reported fracture rate was 4.3% (13). DEBORAH E. SELLMEYER, MD 9. Ali AA, Weinstein RS, Stewart SA, Parfitt If the same RR observed in the ADOPT From the 1Division of Epidemiology and Biostatis- AM, Manolagas SC, Jilka RL: Rosiglita- trial holds and this rate doubles with TZD tics, University of California San Francisco, San zone causes bone loss in mice by sup- use, then the absolute fracture rate would Francisco, California; and the 2Division of Endocri- pressing osteoblast differentiation and increase to ϳ8–9%. To provide perspec- nology and Metabolism, University of California San bone formation. Endocrinology 146:1226– Francisco, San Francisco, California. 1235, 2005 tive, this relative increase in fracture risk Address correspondence to Ann V. Schwartz, is similar to what has been observed with 10. Syversen U, Stunes A, Gustafsson B, PhD, 185 Berry St., Suite 5700, San Francisco, CA Waarsing J, van Leeuwen H, Weinans H, a 1 SD decrease in bone density, i.e., a T 94107. E-mail: [email protected]. Westbroek I: The PPAR gamma agonist score decrease of one point. These esti- A.V.S. has been a consultant for GlaxoSmithKline. DOI: 10.2337/dc07-0554 fenofibrate prevents bone loss, while the mates are necessarily very approximate, © 2007 by the American Diabetes Association. PPAR alpha agonist pioglitazone exagger- given the limited research on TZDs and ates bone loss in ovarectomized rats (Ab- fracture, but provide a sense of the possi- ●●●●●●●●●●●●●●●●●●●●●●● stract). J Bone Miner Res 21 (Suppl. ble increase in fracture risk that can be References 1):S216, 2006 weighed against the proven benefits of 1. GlaxoSmithKline (GSK): Clinical trial ob- 11. Lecka-Czernik B, Gubrij I, Moerman EJ, TZDs in treating diabetes. servation of an increased incidence of Kajkenova O, Lipschitz DA, Manolagas The data to date are probably not suf- fractures in female patients who received SC, Jilka RL: Inhibition of Osf2/Cbfa1 ex- long-term treatment with Avandia (ros- pression and terminal osteoblast differen- ficient to recommend widespread osteo- iglitazone maleate) tablets for type 2 dia- tiation by PPARgamma2. J Cell Biochem porosis screening for all patients being betes mellitus (Letter to Health Care 74:357–371, 1999 considered for TZD therapy or those al- Providers), February 2007. Available from 12. Sottile V, Seuwen K, Kneissel M: En- ready on a TZD. However, older post- www.fda.gov/MedWatch/safety/2007/ hanced marrow adipogenesis and bone menopausal women are at the greatest Avandia_GSK_Ltr.pdf. Accessed 15 March resorption in estrogen-deprived rats treated risk for fracture and also the group for 2007 with the PPARgamma agonist BRL49653 whom data on the adverse skeletal effects 2. Takeda: Observation of an increased inci- (rosiglitazone). Calcif Tissue Int 75:329– of TZD therapy are the most consistent. dence of fractures in female patients who 337, 2004 received long-term treatment with AC- 13. Schwartz AV, Sellmeyer DE, Ensrud KE, For postmenopausal women using or TOS (pioglitazone HCl) tablets for type 2 Cauley JA, Tabor HK, Schreiner PJ, Jamal starting TZD therapy, a conservative ap- diabetes mellitus (Letter to Health Care SA, Black DM, Cummings SR: Older proach to osteoporosis screening would Providers), March 2007. Available from women with diabetes have an increased seem warranted, initiating screening for www.fda.gov/medwatch/safety/2007/ risk of fracture: a prospective study. J Clin low bone density at the time of meno- Actosmar0807.pdf. Accessed 19 March Endocrinol Metab 86:32–38, 2001
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1671 Point-Counterpoint SEE AL-OZAIRI ET AL. (P. 1677)
Point: Recent Long-Term Clinical Studies Support an Enhanced Role for Thiazolidinediones in the Management of Type 2 Diabetes
he treatment options for type 2 diabe- today, so that “rescue” therapy for partic- reached 10 mmol/l (180 mg/dl) (12), and tes were for many years limited to sul- ipants randomized to the conventional this therefore formed the basis for the T fonylureas, metformin, and insulin. treatment arm was only instituted at a choice of this glucose level for the primary However, in the last decade or so, a number fasting plasma glucose level of 15 mmol/l outcome. While the choice of this threshold of new oral and injectable agents have been (270 mg/dl). has been criticized based on today’s targets introduced including the thiazolidinedi- The UKPDS confirmed the findings of (13), the robustness of the ADOPT outcome ones, incretin-related compounds, and “de- the Diabetes Control and Complications in relation to current clinical practice rec- signer” insulins. Despite these additions to Trial (DCCT) in patients with type 2 dia- ommendations was demonstrated by the practitioners’ armamentarium, attainment betes; namely, glucose control is critically similar relative effectiveness of the three of optimal glucose control has remained important in preventing the microvascu- agents when the prespecified secondary largely elusive, in large part because type 2 lar complications of diabetes. In addition, outcomes, namely fasting glucose 7.8 diabetes is a progressive disease and health the UKPDS underscored the realization mmol/l (140 mg/dl) and glycated hemoglo- care professionals have failed to initiate that loss of -cell function is characteristic bin 7% (11), were examined. ADOPT also combination therapy, including insulin, in of type 2 diabetes, and slowing this loss indicated that the differences in outcome a timely fashion. With near-normoglycemia could potentially delay diabetes and its were related to the differing effects of the treatment targets, the approach to glycemic complications. As a result, a number of  management currently being advocated by major clinical trials were spawned. These medications on -cell function and insulin the American Diabetes Association (ADA), included four large studies that systemat- sensitivity. As in the UKPDS, glyburide in-  the European Association for the Study of ically asked whether lifestyle, metformin, creased -cell function, but this effect was Diabetes (EASD), and the Canadian Diabe- acarbose,orthethiazolidinedionestroglit- rapidly lost as function declined at 6.1% per tes Association (CDA) includes earlier com- azone and rosiglitazone can slow or even year compared with 3.1 and 2.0% annually mencement of treatment and more prevent the development of type 2 diabe- for metformin and rosiglitazone, respec- aggressive use of combination therapy tes in individuals at increased risk (5–9). tively. Rosiglitazone and metformin also (1,2). With few exceptions, most of these They clearly showed it is possible to slow improved insulin sensitivity with greater ef- therapeutic recommendations are based on the development of diabetes with lifestyle fect than rosiglitazone, while glyburide had relatively short-term studies and expert and that the thiazolidinediones were no such benefit. opinion, as there are few long-term, head- more effective then either metformin or ADOPT once again taught us that use to-head comparisons that provide definitive acarbose. Further, the recognition that of these medications is not “free.” The evidence. the insulin-sensitizing effect of the thiazol- well-recognized adverse events of weight idinediones could decrease -cell secre- gain and edema occurred with rosiglita- Impact of the UK Prospective tory demand led to the logical question zone, unpleasant gastrointestinal effects Diabetes Study and the Diabetes whether these agents would reduce the with metformin, and weight gain along  Control and Complications Trial loss of -cell function and thereby pro- with hypoglycemia with glyburide. In ad- The UK Prospective Diabetes Study vide more durable control of glycemia. To dition, rosiglitazone was linked to an in- (UKPDS) helped fashion the current ap- answer this question, A Diabetes Out- creased risk of upper- and lower- proach to diabetes management. This come Progression Trial (ADOPT) was un- extremity fractures in women. Of interest, long-term study reported in 1998 and dertaken (10). a recent report indicated that thiazol- demonstrated that improved glucose con- idinediones may reduce bone mass (14). trol is associated with a reduced risk of What were the results of ADOPT Somewhat unexpectedly, the reported microvascular complications (3,4). Fur- and what has it taught us? ther, it suggested that none of the thera- ADOPT, by comparing metformin, gly- adverse cardiovascular event of conges- pies used in the study—sulfonylureas, buride, and rosiglitazone in a large glycemia tive heart failure did not differ in subjects metformin, and insulin—were able to outcome study, has provided important receiving rosiglitazone or metformin, yet slow the progressive nature of type 2 dia- new evidence to help guide our choices of the event rates for these two parameters betes. Thus, over the course of more than therapy. In a cohort of over 4,000 recently were lower in those on glyburide. 10 years, glycemic control deteriorated in diagnosed, drug-naı¨ve, type 2 diabetic sub- Thus, ADOPT has clearly demon- all treatment arms at a rate that paralleled jects, rosiglitazone reduced the need for the strated for the first time that the progres- that in the cohort that received the con- addition of a second agent by 32% com- sion of hyperglycemia in type 2 diabetes ventional lifestyle intervention. At the pared with metformin and by 63% versus can be slowed. Clearly the magnitude of time this landmark study was under- glyburide (11). At the time ADOPT was de- this effect is of clinical importance, partic- taken, the recommendations for glucose signed, the ADA was recommending addi- ularly when comparing rosiglitazone to control differed markedly from those of tion of medication when fasting glucose glyburide.
1672 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kahn and Zinman
What have we learned from other large study in individuals with estab- 2 diabetes disease process. The longitudi- recent, long-term studies in type 2 lished type 2 diabetes and cardiovascu- nal data on glycemia in ADOPT are par- diabetes? lar disease was undertaken to determine ticularly instructive. In the first 6 months The realization that there is a long latent whether pioglitazone reduced macro- following institution of treatment, gly- period during which individuals transition vascular disease events; the composite buride was clearly superior in improving from normal glucose tolerance to type 2 di- primary outcome failed to reach clinical glycemic control to both metformin and abetes prompted the undertaking of long- significance. However, the number of rosiglitazone (Fig. 1). At 2 years, glycated term studies focused on preventing the events for the more-focused composite hemoglobin showed there was no clear progression from states of impaired glucose secondary outcome (all cause mortality, glycemic benefit of any of the three metabolism (pre-diabetes) to diabetes. myocardial infarction, and stroke) was agents. However, there can be no doubt These studies have demonstrated variable significantly reduced. Despite these po- that from a statistical and, more impor- effectiveness of lifestyle intervention, met- tential benefits on cardiovascular out- tantly, clinical standpoint, beyond 2 years formin, acarbose, orlistat, and the thiazo- comes, fluid retention and congestive glyburide proved to be inferior and pro- lidinediones in reducing the development heart failure were significantly more gressively so. of diabetes. The thiazolidinedione troglita- prevalent in those receiving pioglita- Now turn to surrogate markers, and zone proved effective in women with a his- zone in the PROACTIVE Study (19). A of great relevance, cardiovascular disease. tory of gestational diabetes (15) and in similar observation of an increase in All three thiazolidinediones have been subjects with impaired glucose tolerance heart failure was made with rosiglita- shown irrefutably to rapidly reduce the (8); however, both these trials were prema- zone in the DREAM Trial (9), but this progression of carotid intima-media turely discontinued because of the hepatic was not observed with troglitazone in thickness, with a recent report in a large toxicity of troglitazone, which resulted in its the DPP, possibly because the patient number of subjects with type 2 diabetes withdrawal from the market. More recently, years of exposure was less (8), or in showing this effect was different than that the results of the Diabetes Reduction As- ADOPT, where the rate of heart failure with the sulfonylurea glimepiride (20). sessment With Ramipril and Rosiglitazone assessed by independent cardiologists This marker has been extensively utilized Medication (DREAM) Trial (9) were an- (unlike the investigator-reported ad- because it is believed to provide a good nounced and demonstrated that rosiglita- verse events of heart failure) was similar indication of not only what is happening zone was also effective and reduced the rate with rosiglitazone, metformin, and to the cerebral vessels but also what is of progression to diabetes by 60%, a risk glyburide. occurring at sites such as the coronary reduction similar to that seen with lifestyle vasculature. Therefore, a reduction in car- in both the Diabetes Prevention Program What have long-term studies in diovascular events would be anticipated. (DPP) (6) and the Finnish Diabetes Study diabetes taught us compared with Unfortunately, however, despite its long- (5) and greater than reported with met- short-term studies? term time frame, the PROACTIVE Study formin in the DPP (6), acarbose in the Study The results of research over the last de- failed to conclusively demonstrate such to Prevent Non–Insulin-Dependent Diabe- cade have provided great insight and si- dramatic effects on vascular outcomes. tes Mellitus (STOP-NIDDM) program (7), multaneously raised new questions. This Thus, although still possible, it remains to and orlistat in the XENical in the Prevention period has seen the development of a be demonstrated that thiazolidinediones of Diabetes in Obese Subjects (XENDOS) number of glucose-lowering compounds do in fact reduce cardiovascular disease. Study (16). that have proven useful as therapeutic in- In addition, the significance of changes in In spite of their ability to lower terventions in patients with type 2 diabe- intima-media thickness with these agents plasma glucose, the thiazolidinediones tes. The proof of their ability to improve needs to be revisited. have not achieved wide-ranging accep- glycemic control, resulting in their regis- Undoubtedly, studies in animals have tance, in part because of the weight gain tration, has been based on short-term been critical in understanding human and fluid retention observed with these studies, typically lasting 3 to 6 months. type 2 diabetes and formulating ap- agents. With these unwanted effects has Further, their mechanisms of action have proaches to its therapy. In fact, in some also come the observation of an in- usually been determined using sophisti- instances it is the work in animals that has creased incidence of congestive heart cated approaches in small numbers of redirected the usefulness of pharmaco- failure, especially in those also using in- subjects treated for a limited period of therapeutics. A case in point is the dipep- sulin or sulfonylureas (17). While the time. And finally, their potential benefit tidyl petidase-4 (DPP-4) inhibitors. The presentation of heart failure with thia- beyond simply glucose control has been development of this class of compounds zolidinediones appears to differ from suggested using surrogate markers that was driven by the belief that inhibiting that typically observed in individuals frequently change rather rapidly or data this enzyme could alter the inflammatory with type 2 diabetes (18), the long-term from animal studies. While the value of response and prove beneficial in diseases implications of an episode of cardiac de- these short-term studies is great, the ne- completely unrelated to type 2 diabetes. It compensation as a consequence of fluid cessity for long-term clinical outcome is only based on animal work that their overload remain unknown. On the flip studies in type 2 diabetes has now been, glucose-lowering ability and subse- side, there are data suggesting that thia- more than ever, firmly established. To quently their effect to slow degradation of zolidinediones may be beneficial in re- support this opinion we focus on glucose the incretins was recognized (21). Fur- ducing cardiovascular disease. Most control, surrogate markers, and animal ther, animal studies have also demon- powerful, but yet not conclusive, were work. strated that the DPP-4 inhibitors and the the findings of the Prospective Pioglita- Consider first glycemic control. The incretin analogue exenatide reduce -cell zone Clinical Trial In Macrovascular UKPDS and ADOPT both clearly high- loss by decreasing apoptosis and fostering Events (PROACTIVE) Study (19). This lighted the progressive nature of the type cell regeneration (21), thereby abating a
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1673 Thiazolidinediones and type 2 diabetes
we are going to fully understand the po- tential value of these agents.
Have long-term clinical trials changed the treatment paradigm for type 2 diabetes, at least as far as glycemic control is concerned? It is our conviction that the additional knowledge gained from recent long-term clinical trials suggests that modification of the latest recommendations of the ADA and EASD (1) may already be in order. It is now clear that metformin and the thia- zolidinediones can slow progression of glycemia in individuals with impaired glucose tolerance and type 2 diabetes through their dual effects of enhancing insulin sensitivity and slowing -cell function loss (8,11,15). On the other hand, sulfonylureas only affect the -cells, improving secretion initially but not being able to sustain this effect, result- ing in the progressive loss of glycemic control at a rate beyond that of either met- formin or rosiglitazone (11). Further, there is an additional practical disadvan- tage to sulfonylurea use. With recommen- dations that pharmacological therapy be instituted earlier and with target glycated hemoglobin values that are lower, the risk of sulfonylurea-induced hypoglycemia is increased and therewith compliance will be more difficult. While clearly met- formin and thiazolidinediones are them- selves not without adverse effects, the troubling nature of these adverse effects
Figure 1—Fasting plasma glucose (A) and glycated hemoglobin (B) over time according to treatment group assignment in ADOPT. The typical durations of short-, medium- and long- term clinical trials are indicated by the shaded areas and highlight the important differences in glucose control observed when studies vary in duration. The total number of patients included for each measurement at annual time points is indicated below each graph. Data are presented as means Ϯ SE and the annualized rate of change (slope) from 0.5 to 5 years. *Significant differences between the rosiglitazone group and the other two treatment groups. For fasting plasma glucose, treatment differences (95% CI) at 4 years for rosiglitazone vs. metformin were Ϫ9.8 mg/dl (Ϫ12.6 to Ϫ7.0), P Ͻ 0.001, and for rosiglitazone vs. glyburide Ϫ17.4 mg/dl (Ϫ20.4 to Ϫ14.5), P Ͻ 0.001. For glycated hemoglobin, treatment differences for rosiglita- zone vs. metformin were Ϫ0.13% (Ϫ0.22 to Ϫ0.05), P ϭ 0.002, and for rosiglitazone vs. glyburide Ϫ0.42% (Ϫ0.50 to Ϫ0.33), P Ͻ critical contributor to the loss of insulin and may never, as sampling pancreas in 0.001. Adapted with permission in 2007 from release in type 2 diabetes (22). Does this living subjects is clearly inappropriate. ref. 11. (Copyright 2006 Massachusetts Medi- effect occur in humans? We do not know But some insight into this issue is critical if cal Society. All rights reserved.)
1674 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Kahn and Zinman can be reduced when they are used at less ing the loss of -cell function observed Affairs. S.E.K. is the recipient of an ADA Dis- than maximal doses and/or as low-dose with sulfonylureas. As mentioned, these tinguished Clinical Scientist Award. combination therapies early in individu- newer agents clearly improve insulin re- als with relatively moderate hyperglycemia. lease in humans by enhancing incretin ac- NOTE ADDED IN PROOF Based on these observations, we agree tion and have in animal studies also been Since submission of this manuscript, the with the recent recommendations that shown to reduce cell death and enhance manufacturer of pioglitazone has re- metformin be considered as first-line -cell regeneration (21). Whether -cell ported that the use of this medication is therapy for individuals with recently di- number increases in humans and/or a sus- also associated with an increased risk of agnosed diabetes in whom glycated he- tained improvement in -cell function re- fractures in women. moglobin levels are Ͼ7%. However, in sults are unknown and will not likely be contrast to these guidelines, we would ad- discernable by short-term studies. We ●●●●●●●●●●●●●●●●●●●●●●● vocate that the role of sulfonylureas will ultimately require long-term clinical References should be supplanted by the thiazol- trial evidence of durability, and direct 1. Nathan DM, Buse JB, Davidson MB, Heine idinediones. Thus, should metformin not comparisons with other therapeutic RJ, Holman RR, Sherwin R, Zinman B: be suitable as initial therapy or if use of agents would be particularly informative. Management of hyperglycemia in type 2 dual agents is warranted, it would be rea- diabetes: a consensus algorithm for the sonable to prescribe a thiazolidinedione initiation and adjustment of therapy: a Conclusions consensus statement from the American instead of a sulfonylurea. Evidence-based medicine has certainly Diabetes Association and the European In considering these guidelines and contributed to a changing landscape in Association for the Study of Diabetes the recent data, we also recognize that clinical practice, and large, long-term (Consensus Statement). Diabetes Care 29: there is greater acceptance of early inter- clinical trials have added to this process. 1963–1972, 2006 vention with more than a single agent and In the area of diabetes, that which we have 2. Harris SB, Lank CN: Recommendations that the natural history of the disease has from the Canadian Diabetes Association: learned from clinical studies reported 2003 guidelines for prevention and man- not been well defined in the face of dual over the last decade has been tremendous, therapy, whether it is introduced early or agement of diabetes and related cardio- and there is no doubt that as more data vascular risk factors. Can Fam Physician late in the course of the disease. However, from these trials are reported, we will gain what is abundantly clear from short-term 50:425–433, 2004 greater insights. With this additional in- 3. UK Prospective Diabetes Study (UKPDS) studies is that a number of combinations formation we have also been provided the Group: Effect of intensive blood-glucose of agents that address different aspects of opportunity to develop and amend clini- control with metformin on complications the pathophysiology are capable of effec- cal guidelines, and it is our conviction in overweight patients with type 2 diabe- tively improving glucose control and fre- that the time has arrived for us to take the tes (UKPDS 34). Lancet 352:854–865, quently do so with smaller doses of each evidence and reconsider the role of thia- 1998 agent and less unwanted effects, although 4. UK Prospective Diabetes Study (UKPDS) zolidinediones and sulfonylureas in the Group: Intensive blood-glucose control this is not always the case. Whether such treatment of type 2 diabetes. effects can be sustained for longer periods with sulphonylureas or insulin compared with conventional treatment and risk of of time requires data from additional clin- 1 STEVEN E. KAHN, MB, CHB complications in patients with type 2 di- ical trials. 2 BERNARD ZINMAN, MD, FRCPC abetes (UKPDS 33). Lancet 352:837–853, 1998 What have long-term clinical trials From the 1Division of Metabolism, Endocrinology, 5. Tuomilehto J, Lindstrom J, Eriksson JG, taught us about future research on and Nutrition, Department of Medicine, Veterans Valle TT, Hamalainen H, Ilanne-Parikka therapeutics for type 2 diabetes? Affairs Puget Sound Health Care System and Uni- P, Keinanen-Kiukaanniemi S, Laakso M, To this the answer is relatively simple. versity of Washington, Seattle, Washington; and Louheranta A, Rastas M, Salminen V, Large clinical trials performed over a pe- 2Samuel Lunenfeld Research Institute, Mount Sinai Uusitupa M: Prevention of type 2 diabetes Ն Hospital, University of Toronto, Ontario, Canada. mellitus by changes in lifestyle among riod of 3 years provide insight that Address correspondence and reprint requests to short-term studies designed for registra- subjects with impaired glucose tolerance. Steven E. Kahn, MB, ChB, VA Puget Sound Health N Engl J Med 344:1343–1350, 2001 tion of single or combinations of agents Care System (151), 1660 S. Columbian Way, Seat- simply cannot. That is not to say that tle, WA 98108. Email: [email protected]. 6. The Diabetes Prevention Program Re- search Group: Reduction in the incidence these shorter studies are not valuable, just Published ahead of print at http://care.diabetes journals.org on 10 March 2007. DOI: 10.2337/ of type 2 diabetes with lifestyle interven- that they have a different niche in inform- dc07-0168. tion or metformin. N Engl J Med 346:393– ing us about diabetes therapeutics. S.K. receives consulting fees from Bristol-Myers 403, 2002 A case in point is the development of Squibb; consulting fees, grant support, and lecture 7. Chiasson JL, Josse RG, Gomis R, Hanefeld newer agents targeting the -cell. This fees from GlaxoSmithKline and Novartis; and con- M, Karasik A, Laakso M: Acarbose for pre- area of investigation is logical and impor- sulting and lecture fees from Merck. B.Z. receives vention of type 2 diabetes mellitus: the research support from Eli Lilly, GlaxoSmithKline, STOP-NIDDM randomised trial. Lancet tant based on our understanding of the Merck, Novartis, and Novo Nordisk. He is a member vital role of impaired insulin release in of scientific advisory boards and/or has received 359:2072–2077, 2002 type 2 diabetes. Short-term improvement honoraria for speaking for Amylin, Eli Lilly, Glaxo- 8. The Diabetes Prevention Program Re- in -cell function is associated with im- SmithKline, Johnson & Johnson, Merck, Novartis, search Group: Prevention of type 2 diabe- Novo Nordisk, Pfizer, and Sanofi-Aventis. tes with troglitazone in the Diabetes proved glycemic control. However, as © 2007 by the American Diabetes Association. Prevention Program. Diabetes 54:1150– practitioners, it is now critical that we 1156, 2005 know whether the glucagon-like pep- 9. The DREAM Trial Investigators: Effect of tide-1 analogues and DPP-4 inhibitors do Acknowledgments— This work was sup- rosiglitazone on the frequency of diabetes or do not reproduce the findings regard- ported in part by the Department of Veterans in patients with impaired glucose toler-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1675 Thiazolidinediones and type 2 diabetes
ance or impaired fasting glucose: a ran- and bone loss in older diabetic adults. failure. J Am Coll Cardiol 41:1394–1398, domised controlled trial. Lancet 368: J Clin Endocrinol Metab 91:3349–3354, 2003 1096–1105, 2006 2006 19. Dormandy JA, Charbonnel B, Eckland DJ, 10. Viberti G, Kahn SE, Greene DA, Herman 15. Buchanan TA, Xiang AH, Peters RK, Kjos Erdmann E, Massi-Benedetti M, Moules WH, Zinman B, Holman RR, Haffner SM, SL, Marroquin A, Goico J, Ochoa C, Tan IK, Skene AM, Tan MH, Lefebvre PJ, Mur- Levy D, Lachin JM, Berry RA, Heise MA, S, Berkowitz K, Hodis HN, Azen SP: Pres- ray GD, Standl E, Wilcox RG, Wilhelmsen Jones NP, Freed MI: A Diabetes Outcome ervation of pancreatic -cell function and L, Betteridge J, Birkeland K, Golay A, Progression Trial (ADOPT): an interna- prevention of type 2 diabetes by pharma- Heine RJ, Koranyi L, Laakso M, Mokan M, tional multicenter study of the compara- cological treatment of insulin resistance in Norkus A, Pirags V, Podar T, Scheen A, tive efficacy of rosiglitazone, glyburide, high-risk Hispanic women. Diabetes 51: Scherbaum W, Schernthaner G, Schmitz and metformin in recently diagnosed type 2796–2803, 2002 O, Skrha J, Smith U, Taton J: Secondary 2 diabetes. Diabetes Care 25:1737–1743, 16. Torgerson JS, Hauptman J, Boldrin MN, prevention of macrovascular events in pa- 2002 Sjostrom L: XENical in the prevention of tients with type 2 diabetes in the PRO- 11. Kahn SE, Haffner SM, Heise MA, Herman diabetes in obese subjects (XENDOS) active Study (PROspective pioglitAzone WH, Holman RR, Jones NP, Kravitz BG, study: a randomized study of orlistat as an Clinical Trial In macroVascular Events): a Lachin JM, O’Neill MC, Zinman B, Viberti adjunct to lifestyle changes for the pre- randomised controlled trial. Lancet 366: G: Glycemic durability of rosiglitazone, vention of type 2 diabetes in obese pa- metformin, or glyburide monotherapy. tients. Diabetes Care 27:155–161, 2004 1279–1289, 2005 N Engl J Med 355:2427–2443, 2006 17. Nesto RW, Bell D, Bonow RO, Fonseca V, 20. Mazzone T, Meyer PM, Feinstein SB, Da- 12. American Diabetes Association: Stan- Grundy SM, Horton ES, Le Winter M, vidson MH, Kondos GT, D’Agostino RB, dards of medical care for patients with di- Porte D, Semenkovich CF, Smith S, Sr, Perez A, Provost JC, Haffner SM: Effect abetes mellitus (Position Statement). Young LH, Kahn R: Thiazolidinedione of pioglitazone compared with glimepiride Diabetes Care 22 (Suppl. 1):S32–S41, 1999 use, fluid retention, and congestive heart on carotid intima-media thickness in type 2 13. Nathan DM: Thiazolidinediones for initial failure: a consensus statement from the diabetes: a randomized trial. JAMA 296: treatment of type 2 diabetes? N Engl J Med American Heart Association and Ameri- 2572–2581, 2006 355:2477–2480, 2006 can Diabetes Association. Circulation 108: 21. Drucker DJ: The biology of incretin hor- 14. Schwartz AV, Sellmeyer DE, Vittinghoff 2941–2948, 2003 mones. Cell Metab 3:153–165, 2006 E, Palermo L, Lecka-Czernik B, Feingold 18. Tang WH, Francis GS, Hoogwerf BJ, 22. Kahn SE: The relative contributions of in- KR, Strotmeyer ES, Resnick HE, Carbone Young JB: Fluid retention after initiation sulin resistance and beta-cell dysfunction L, Beamer BA, Park SW, Lane NE, Harris of thiazolidinedione therapy in diabetic to the pathophysiology of type 2 diabetes. TB, Cummings SR: Thiazolidinedione use patients with established chronic heart Diabetologia 46:3–19, 2003
1676 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Point-Counterpoint SEE KAHN AND ZINMAN (P. 1672)
Counterpoint: A Diabetes Outcome Progression Trial (ADOPT): Good for Sulfonylureas?
Diabetes Outcome Progression lowering drugs were compared in mono- ology of Diabetes Interventions and Com- Trial (ADOPT) was conceived in therapy or in various combinations, plications) Study outcomes (in A the hope that the seemingly inexo- suggesting that outcomes are not different individuals with type 1 diabetes) remind rable decline in islet B-cell function de- except for the exacerbation of hypoglyce- us that early and tight blood glucose con- scribed with metformin, sulfonylureas, mia. Accordingly, in this review it will be trol can effectively delay the point at and insulin in the UK Prospective Diabe- assumed that the findings of a mono- which a cardiovascular event occurs (7); tes Study (UKPDS) might be stopped or therapy study (ADOPT) can be extended that study and the epidemiological analy- inhibited to a major degree by peroxi- to the more usual role of sulfonylureas sis of the UKPDS suggest that a useful pe- some proliferator–activated receptor-␥ and thiazolidinediones in combination riod of good blood glucose control in agonists, in particular rosiglitazone (1,2). with metformin. preventing a cardiovascular event (an im- It was already well recognized that the A valid review of ADOPT and other provement in A1C Ն1.0%) is as short as 2 rapid early efficacy of sulfonylureas in longer-term studies of oral glucose- years and would be proportionately lowering glucose was not retained to 12 lowering drugs is hampered by three ma- shorter for larger improvements (7,8). months, and that metformin and thiazol- jor issues. First, both the readers of the Balancing improved overall blood idinediones had slow onset of action over papers and the authors of this review only glucose control is an issue that might months, so the design of the study neces- have access to averaged data. This can dis- worsen health or perceived well-being. sarily had to enable decline of measures of guise the true nature of the changes oc- The familiar health issues that affect sul- blood glucose control to be assessed for a curring in individuals, particularly where fonylureas and thiazolidinediones are considerable period from 1 year onwards. rescue therapies are introduced and/or putative worsening of cardiovascular However, the extent (degree and time) to data are censored at some point in deteri- outcomes (possible adverse cardiac ef- which this early efficacy of the sulfonyl- oration of glucose control (Fig. 1). Sec- fects on one hand and exacerbation of ureas in protecting against hyperglycemia ond, very high dropout rates from studies cardiac failure from fluid retention on would persist was not accurately known. as in ADOPT are of concern, particularly the other) and of hypoglycemia with the where the major outcome variable might The study also provided a good opportu- sulfonylureas, concerns arising from the nity to compare durability of effect of the cause dropout through dissatisfaction (as DREAM (Diabetes Reduction Assess- three classes of drugs directly in the con- in studies of blood glucose control and ment With Ramipril and Rosiglitazone text of some shorter-term studies since body weight); no amount of data snoop- Medication) Trial regarding noncardiac published (3). ing can provide absolute reassurance over failure cardiovascular outcomes and os- Metformin is currently well estab- hidden biases. Third, data on changes in teoporotic effects (9,10) of rosiglita- lished as first-line therapy in people with islet B-cell function may be problematic type 2 diabetes, usually after lifestyle mea- where an insulin secretagogue (including zone. Regarding well-being, the issues sures fail to achieve A1C levels Ͻ6.5%, sulfonylureas) is used and with ho- that arise again include fluid retention although some consensus (as opposed to meostasis model assessment analysis once (edema) and hypoglycemia but, in ad- evidence-based) guidelines have sug- glucose control has deteriorated with time dition, body weight gain. The last may gested initiation immediately from diag- (6). also have add-on health consequences nosis (4,5). This review will not challenge outside the metabolic area through non- those ideas, although the evidence is not Criteria for successful glucose- linear exacerbation of such conditions as strong as sometimes assumed. The ex- lowering medication as knee osteoarthrosis and sleep apnea, ceptions to first-line metformin use are The primary purpose of ADOPT was not with significant impact on future quality where metformin is contraindicated, per- to answer the question as to whether ei- of life. haps where someone is not overweight, ther of the three medications was better Assessment of the success of a medi- and where presentation glucose levels are overall than the others, but rather to ad- cation can only be made in the context of high and the rapid effect of a sulfonylurea dress specifically the issue of durability of its cost-effectiveness. Newer medications, is needed. In situations where metformin blood glucose control in the longer term. such as thiazolidinediones, are only easily is contraindicated, or as second-line In their analysis, the authors have not, for available to the well insured, those in add-on therapy to metformin when target example, addressed the question of which some socialist medical systems that have levels are no longer met, the alternative medication gave the best control over 1, approved reimbursement, and in some choice to a sulfonylurea would be a thia- 2, 3, and 4 years. Clinically, however, the countries where patent laws are not ap- zolidinedione or possibly a gliptin (it is issue of success at varying intervals is the plied. Even where insurance or reim- assumed insulin would not usually be the critical one; health in chronic disease is bursement is available, health care preference of a person with diabetes at not judged by health outcomes at any one resources are not unlimited, and it be- this stage) (4,5). ADOPT was not a com- time (and ultimately everyone dies), but hooves funders in the interest of the pop- bination therapy study, but a host of rather by quality of life over periods of ulations they serve to determine where a studies in recent years, where glucose- years. Furthermore, the EDIC (Epidemi- medication is properly positioned on the
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1677 ADOPT and sulfonylureas
formin line occurring at the end of 1 cess rates for medications in many areas of year and only at 18 months with rosiglit- medicine. azone (Fig. 2). Notably, overall glucose Therapy side effects. The main side ef- control really only began to diverge be- fects to be considered are hypoglycemia tween the three groups at 3 years and in for sulfonylureas, fluid retention and car- years 2 and 3 differed little between the diac failure for the thiazolidinediones, three treatments. Accordingly, average and other cardiovascular safety for both. glucose control over the first 3 years was This review is not concerned with the almost exactly the same for the three thiazolidinediones, but since the drugs do Figure 1—Diagram to show how very nonlin- therapies (Table 1), with a possible compete for a role in second-line therapy ear deterioration in individual blood glucose slight advantage to the sulfonylureas. (and increasingly also with the gliptins), it control with censoring on starting insulin None of the three therapies proved should be noted that the issues of fluid (solid lines, five patients) can produce an ap- satisfactory as monotherapy in the major- retention, use of loop diuretics (which parently linear average decline (dashed line). ity of individuals, as judged by the mean carry morbidity), and bone changes with Many other nonlinear examples can produce A1C and a criterion of Ͻ6.5%. However, that class of drugs are confirmed by linear averages. the data suggest that these agents lower ADOPT as real, while concerns over an A1C by ϳ0.5% from the kind of baseline adverse non–cardiac failure cardiovascu- levels reported in the ADOPT study, a re- lar profile raised in the DREAM study has patient-care pathway. That issue will sult almost exactly consistent with 18- been ameliorated (9). therefore also be addressed in this article. month data with these groups of Even after subtraction of cardiac In comparing glucose-lowering ther- medications in the RECORD (Rosiglita- failure events, numerically there were apies the following questions can then be zone Evaluated for Cardiac Outcomes fewer cardiovascular disease events in set: 1) Over time courses of 1, 2, 3, and 4 and Regulation of Glycaemia in Diabetes) ADOPT in the glibenclamide group years, how do sulfonylureas match up to Study (11). As an approximation, it is than in the metformin and rosiglitazone thiazolidinediones (and metformin) in then possible, with reservations, to use groups, namely, 32, 40, and 39 patients terms of amelioration of hyperglycemia the ADOPT paper’s data on time to failure affected, respectively. Figures for myo- (avoidance of A1C Ͼ6.5%)? 2) How sig- at an A1C of 7.0% for glibenclamide alone cardial infarction are 18, 27, and 23 pa- nificant are the direct side effects of the as if it was used in combination with met- tients, respectively, with three, two, and therapies, and in particular hypoglycemia formin with a failure criterion of Ն6.5%. two fatalities; data on stroke and pe- and fluid retention, to both other health This shows that on average the sulfonyl- ripheral arterial disease were unremark- risks and current quality of life? 3) How urea would be successful in the ADOPT able. It should be noted that these data does ADOPT impact on concerns over population for up to 2.75 years, a useful should be interpreted as safety data and cardiovascular safety of sulfonylureas duration of effect clinically. Using the not subject to forms of statistical analy- (and thiazolidinediones)? 4) Of what im- ADOPT authors’ secondary criterion of sis, which would be unsafe given the portance are issues of weight gain, and success in maintaining fasting plasma glu- low statistical power for outcomes that how does the large quantitative difference cose at Ͻ7.8 mmol/l (140 mg/dl) as were not part of the study design. Nev- between sulfonylureas and thiazol- monotherapy, glibenclamide was suc- ertheless, the data do strongly suggest idinediones affect patient choice? 5) What cessful at 4 years in 67% of patients, a that long-held theoretical concerns is the balance of cost-impact and cost- useful result and far in excess of the suc- about adverse effects of sulfonylureas, effectiveness issues? Table 1—Blood glucose control with glibenclamide (glyburide) compared with metformin and Judgement on the medications rosiglitazone in the ADOPT study (ref. 2) Glucose-lowering efficacy. In ADOPT, blood glucose control was considerably better with the sulfonylurea than with Glibenclamide Metformin Rosiglitazone metformin or rosiglitazone over the first 2 Mean A1C (%)* months of therapy, although the effect is Year 1† 6.5 6.7 6.8 difficult to quantify accurately, as the first Year 2 6.8 6.7 6.8 published data point is at 2 months and Year 3 7.0 6.9 6.8 A1C is a lagging measure. Nevertheless, Years 1–3† 6.7 6.8 6.8 comparison of the fasting plasma glucose A1C Ͻ7.0% and A1C results would suggest that the At 4 years (% patients) 26 36 40 effect of the sulfonylurea was nearly in- Time to Ն7.0% (years) 2.75 3.75 4.75 stantaneous, as the latter has already FPG fallen markedly by 2 months, a fall two to Ͻ10.0 mmol/l (180 mg/dl) three times greater than for the other At 3 years (% patients) 84 92 93 medications (2). At 4 years (% patients) 78 88 90 This change is echoed over the first Ͻ7.8 mmol/l (140 mg/dl) year (Table 1). Indeed, the average At 4 years (% patients) 67 76 85 blood glucose control was better with Baseline A1C was 7.4% in all groups and FPG 8.4 mmol/l (151–152 mg/dl). *Data is read from graphs and the sulfonylurea in the period of 2–12 is thus subject to small errors. †Excludes the baseline measurement and thus glucose control over 0–2 months, the intercept with the met- months, when it is considerably better with the sulfonylurea. FPG, fasting plasma glucose.
1678 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Al-Ozairi and Associates
in blood glucose concentration–driven glucose metabolism (15). Thereafter, body weight fell slowly over the rest of the study, consistent with the slow deteriora- tion of blood glucose control and secular trends of weight with age in the general population. This was true despite stimu- lation of endogenous insulin secretion, which by homeostasis model assessment analysis was nearly normalized by gliben- clamide at 6 months (this assumes equiv- alence between the ADOPT and Oxford insulin assays) and remained above base- line and numerically higher than for the other medications for up to 4 years. This weight change would not then be expected to have any adverse meta- bolic effect. Little confirmatory informa- Figure 2—Time course of A1C in ADOPT redrawn to show average blood glucose control over the tion is available from the study itself, first 3 years (ref. 2). Data from 4 years onward is omitted as invalid (only 55% falling to 20% of though overall insulin sensitivity seems to randomized participants continuing). ‚, glibenclamide; E, metformin; , rosiglitazone. have improved with glibenclamide dur- ing the study. Data on lipids are not avail- able through the study, but at 4 years and in particular glibenclamide, on pre- its continued, widespread usage glo- serum LDL cholesterol concentration was vention of ischemic preconditioning in bally. Data on the extent of this problem not different from metformin, though cardiac muscle are unwarranted (12). are difficult to come by, but the inci- HDL cholesterol was marginally (3%) The issue of hypoglycemia with sul- dence of events is probably 2–10 times lower. fonylureas is important and in some peo- higher than with other sulfonylureas In cosmetic terms, a weight gain of ple can have a significant impact on (12). In the 2-year pioglitazone- 2.5 kg in one year is a minor but signifi- quality of life through employment, rec- gliclazide study, gliclazide seems to cant problem, but stabilization of body reation, or even falls and coma, particu- have been associated with 10–13% of weight over a period of 4 years subse- larly in the infirm elderly (13). In the patients having an event in 2 years (n ϭ quently is likely to be welcomed by many general diabetic population treated with 952 exposed), with no mention of people with diabetes. these medications, it is not such an issue, events giving rise to serious health Costs and cost-effectiveness. Costs of as evidenced for example by the UKPDS problems (3). The UKPDS used only the diabetes care are coming into ever- (1). Unfortunately, the hypoglycemia two drugs with the worst reputation in sharper focus at present, driven by three data available from the ADOPT study are this field (glibenclamide and chlorpro- issues. The first of these is the welcome of very poor quality and small in quantity. pamide), finding a serious hypoglyce- acknowledgment of the reality that the Thus hypoglycemia was not confirmed by mia rate of ϳ0.5% patients per year (1). real costs of diabetes come from failures of a plasma glucose measurement as is usual The impression then is that ADOPT preventative medicine, that is, when com- in insulin studies, so that a prevalence rate does not worsen our impression that plications develop. The second is the ex- (patients affected) of ϳ10–12% was re- hypoglycemia is a problem in only a mi- panding prevalence of diabetes, driven by corded even for people on rosiglitazone or nority of people using sulfonylureas, overeating and underactivity, together metformin monotherapy. Subtraction of and that careful choice of agent and self- with increased life expectancy through this figure suggests that perhaps 28% of monitoring are important in avoiding better application of those preventative people on glibenclamide might have had the issue in routine clinical practice. measures and the longer survival of peo- hypoglycemic symptoms, and just 0.6% Weight gain. The body weight trajectory ple developing diabetes at a younger age an investigator-defined serious event, at in participants randomized to gliben- (16). However, the third issue is the in- some time during the 5 years of the study. clamide in ADOPT is reassuring (unlike creased costs of new technologies, nota- It is not possible from the data given to that for the thiazolidinedione) and cannot bly, medications and methods of giving calculate the event rate (episodes per really be called a side effect. Again it must them. To put this in perspective, in the year) or the number of people with a re- be noted that stimulation of appetite is a uncomplicated patient, items such as in- current problem. particular problem with glibenclamide sulin pumps, inhaled insulin, new oral Glibenclamide is easily the most no- compared with other sulfonylureas be- agents, new antiplatelet drugs, and new torious member of its class as far as hy- cause of its hypoglycemic tendency lipid-lowering drugs can easily double or poglycemia is concerned, not just in around lunchtime in individuals with triple the total costs (not just the drug clinical practice but also in terms of na- good blood glucose control. Initial weight costs) of diabetes care. tional serious adverse event reporting, gain appears (graphically) to be 2.5 kg in ADOPT is positive for sulfonylureas particularly in association with renal ϳ1 year, not inconsistent with the aver- because the sister drugs of glibenclamide disease (12,14). Indeed, this is one rea- age improvement of 0.8% in A1C and en- such as gliclazide and glipizide are widely son it is often chosen as a comparator in tirely consistent with amelioration of available at generic prices while having a oral therapy drug trials, the other being urinary glycosuria and a Ͼ10% reduction better safety profile regarding hypoglyce-
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1679 ADOPT and sulfonylureas mia (12). Put another way, over 3 years ●●●●●●●●●●●●●●●●●●●●●●● 9. The DREAM (Diabetes REduction Assess- the glucose-lowering effect may be iden- References ment with ramipril and rosiglitazone tical to a thiazolidinedione, but the cost– 1. United Kingdom Prospective Diabetes Medication) Trial Investigators: Effect of to–glucose-lowering ratio is some six Study (UKPDS) Group: Intensive blood- rosiglitazone on the frequency of diabetes times or so better for the sulfonylurea. At glucose control with sulphonylureas or in patients with impaired glucose toler- insulin compared with conventional ance or impaired fasting glucose: a ran- present, the comparative side effect pro- treatment and risk of complications in pa- domised controlled trial. Lancet 368: files would not suggest that any added tients with type 2 diabetes (UKPDS 33). 1096–1105, 2006 costs of therapy were higher for the sulfo- Lancet 352:837–853, 1998 10. Watts NB, D’Alessio DA: Type 2 diabetes, nylurea—and perhaps the reverse. The 2. Kahn SE, Haffner SM, Heise MA, Herman thiazolidinediones: bad to the bone? J Clin only thing that could change this analysis WH, Holman RR, Jones NP, Krawitz BG, Endocrinol Metab 91:3276–3278, 2006 would be demonstration of a fundamental Lachin JM, O’Neill C, Zinman B, Viberti 11. Home PD, Jones NP, Pocock SJ, Beck- improvement in preservation of islet B- G, for the ADOPT Study Group: Glycemic Nielsen H, Gomis R, Hanefeld M, Koma- cells that could reduce the need for fur- durability of rosiglitazone, metformin, or jda M, Curtis P, for the RECORD Study ther (expensive) therapies later in the glyburide monotherapy. N Engl J Med Group: Rosiglitazone RECORD study: course of the disease, but meanwhile the 355:2427–2443, 2006 glucose control outcomes at 18 months. 3. Charbonnel B, Schernthaner G, Brunetti Diabet Med. In press argument is more centered on the order of P, Matthews DR, Urquhart R, Tan MH, 12. Lebowitz HE, Melander A: Sulfonylureas: use of therapies as second or third line. Hanefeld M: Long-term efficacy and tol- basic aspects and clinical uses. In Interna- erability of add-on pioglitazone therapy to tional Textbook of Diabetes Mellitus. 3rd ed. Conclusions failing monotherapy compared with addi- DeFronzo RA, Ferrannini E, Keen H, Zim- ADOPT presents good news for sulfonyl- tion of gliclazide or metformin in patients met P, Eds. Chichester, U.K., John Wiley, ureas. In the guise of glibenclamide, they with type 2 diabetes. Diabetologia 2004, p. 801–831 are found to be safe, very effective ini- 48:1093–1104, 2005 13. Thomson FJ, Masson EA, Leeming JT, tially, and equally effective over 3 years to 4. International Diabetes Federation Clinical Boulton AJM: Lack of knowledge of Guidelines Task Force: Global guideline symptoms of hypoglycemia by elderly di- the competitor medications. Weight gain for type 2 diabetes [article online], 2005. abetic patients. Age Ageing 20:404–406, is moderate and physiological, and insu- Brussels, International Diabetes Federa- 1991 lin sensitivity and islet B-cell function are tion. Available from www.idf.org. Ac- 14. Asplund K, Wiholm B-E, Lithner F: Glib- not adversely affected. They remain inex- cessed 6 January 2007 enclamide-associated hypoglycemia: a re- pensive and highly cost-effective (17,18). 5. Nathan DM, Buse JB, Davidson MB, Heine port on 57 Cases. Diabetologia 24:412– But combination therapy with metformin RJ, Holman RR, Sherwin R, Zinman B: 417, 1983 will be needed for most people within the Management of hyperglycemia in type 2 15. Ravikumar B, Gerrard J, Carey PE, Taylor first year of diagnosis if glucose-control diabetes: a consensus algorithm for the R: Tighter blood glucose control de- targets are to be met. initiation and adjustment of therapy: a creases resting energy expenditure in type consensus statement from the American 2 diabetes: implications for weight con- Diabetes Association and the European trol (Abstract). Diabet Med 20 (Suppl. 2): EBAA AL-OZAIRI, MD Association for the Study of Diabetes. Di- A11, 2003 LATIKA SIBAL, MD abetes Care 29:1963–1972, 2006 16. International Diabetes Federation: Diabe- PHILIP HOME, MA, DM, DPHIL 6. Wallace TM, Levy JC, Matthews DR: Use tes Atlas. 3rd ed. [article online], 2006. and abuse of HOMA modeling. Diabetes Brussels, International Diabetes Federa- From the Newcastle Diabetes Centre and Newcastle Care 27:1487–1495, 2004 tion. Available from www.eatlas.org. Ac- University, Newcastle upon Tyne, U.K. Address correspondence and reprint requests to 7. Diabetes Control and Complications Tri- cessed 6 January 2007 Prof. Philip Home, SCMS-Diabetes, The Medical al/Epidemiology of Diabetes Interven- 17. UKPDS Group: Cost effectiveness of an School, Framlington Place, Newcastle upon Tyne, tions and Complications Research Group: intensive blood glucose control policy in NE2 4HH, U.K. E-mail: [email protected]. Intensive diabetes treatment and cardio- patients with type 2 diabetes: economic Published ahead of print at http://care.diabetes vascular disease in patients with type 1 analysis alongside randomised controlled journals.org on 10 March 2007. DOI: 10.2337/ diabetes. N Engl J Med 353:2643–2653, trial (UKPDS 41): United Kingdom Pro- dc07-0339. 2005 spective Diabetes Study Group. BMJ 320: P.H. has provided consultation advice on be- 8. Stratton IM, Adler AI, Neil HA, Matthews 1373–1378, 2000 half of Newcastle University to manufacturers of DR, Manley SE, Cull CA, Hadden D, 18. The CDC Diabetes Cost-Effectiveness sulfonylureas, peroxisome proliferator–activated receptor-␥ agonists, gliptins, endocannabinoid Turner RC, Holman RR: Association of Group: Cost-effectiveness of intensive receptor blockers, and metformin. He is involved glycemia with macrovascular and micro- glycemic control, intensified hyperten- in major sponsored clinical trials of some of these vascular complications of type 2 diabetes sion control, and serum cholesterol re- medications. (UKPDS 35): prospective observational duction for type 2 diabetes. JAMA 287: © 2007 by the American Diabetes Association. study. BMJ 321:405–412, 2000 2542–2551, 2002
1680 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Errata
Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, Dobs A, Basaria S, Hill Golden S, Platz EA: Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30:234–238, 2007
In Table 1 of the above-listed article, n values under the columns “Diabetes” and “No diabetes” should be switched. The correct table appears below.
Table 1—Selected characteristics of the study population in men aged >20 years by diabetes status, U.S. 1988–1994, NHANES III
Overall No diabetes Diabetes n 1,413 1,312 101 Age (years) 42.4 Ϯ 0.8 41.8 Ϯ 0.8 57.0 Ϯ 2.8 Race/ethnicity Non-Hispanic white 84.2 Ϯ 2.6 84.6 Ϯ 2.5 74.5 Ϯ 6.6 Non-Hispanic black 10.3 Ϯ 2.0 9.9 Ϯ 1.9 19.6 Ϯ 5.9 Mexican American 5.5 Ϯ 1.5 5.5 Ϯ 1.5 5.9 Ϯ 2.3 BMI (kg/m2) 26.4 Ϯ 0.2 26.2 Ϯ 0.2 29.5 Ϯ 1.4 Waist-to-hip ratio 0.95 Ϯ 0.003 0.95 Ϯ 0.003 1.02 Ϯ 0.01 Data are means or proportions Ϯ SE.
DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1683 Errata
Vinik AI, Zhang Q: Adding insulin glargine versus rosiglitazone: health-related quality-of-life impact in type 2 diabetes. Diabetes Care 30:795–800, 2007
In Fig. 1A of the above-listed article, the y-axis should have been labeled “Improvement From Baseline in Total Symptom Score, Value (%).” The correct figure appears below.
Figure 1—Unadjusted improvement from baseline in total symptom and symptom distress scores. A: Adjusted difference in change from baseline at week 24, 7.59. P ϭ 0.005. B: Adjusted difference in change from baseline at week 24, 1.92. P ϭ 0.03. f, insulin glargine; o, rosiglitazone.
1684 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 ONLINE LETTERS
of total and high–molecular weight metabolism or inflammation. Our data OBSERVATIONS (HMW) adiponectin were measured us- strongly support the primary effect of ing commercially available enzyme- pioglitazone on the regulation of circu- linked immunosorbent assay kits (Otsuka lating adiponectin. Pioglitazone Rapidly Pharmaceuticals, Tokyo, Japan and Fu- 1 Increases Serum jirebio, Tokyo, Japan, respectively). YUKIO IKEDA, MD, PHD 1 Total and HMW adiponectin levels HIROSHI TAKATA, MD Adiponectin Levels 1 both rapidly increased within 3 days of KOSUKE INOUE, MD 1 in Men With Normal pioglitazone treatment in all subjects and MASAYUKI SHINAHARA, MD 1 Glucose Tolerance continued to increase throughout the SHOJIRO INADA, MD Ϯ Ϯ 1 study (total adiponectin 6.6 1.0, 7.9 HIROSHI MARUYAMA, MD Ϯ Ϯ Ϯ 2 1.2, 9.9 1.6, 11.8 1.9, and 13.7 FUMIAKI OSAKI, MD, PHD Ͻ 1 he thiazolidinedione class of an- 2.2 g/ml [P 0.05, repeated-measures TADASHI SUEHIRO, MD, PHD Ϯ 1 tidiabetes drugs has various pleio- ANOVA] and HMW adiponectin 4.3 KOZO HASHIMOTO, MD, PHD tropic effects on cardiovascular 0.8, 5.2 Ϯ 1.0, 7.0 Ϯ 1.3, 8.4 Ϯ 1.5, and T Ϯ Ͻ 1 diseases and lipid metabolism (1). Thia- 10.4 1.9 g/ml [P 0.05] at days 0, 3, From the Department of Endocrinology, Metabo- 7, 10, and 14, respectively). In addition, lism, and Nephrology, Kochi Medical School, Kochi zolidinediones including pioglitazone 2 have been shown to increase circulating the HMW–to–total adiponectin ratio, University, Nankoku, Japan; and the Department of Internal Medicine, Kochi Prefectural Aki Hospi- adiponectin in diabetic subjects, although which may be a useful predictor of insulin tal, Aki, Japan. the mechanism is not well understood resistance and metabolic syndrome (4), Address correspondence to Yukio Ikeda, MD, (2,3). Since, in previous studies, adi- was significantly increased after 14 days PhD, Department of Endocrinology, Metabolism, ponectin levels in diabetic patients were (0.59 Ϯ 0.06 to 0.72 Ϯ 0.04, P Ͻ 0.01). and Nephrology, Kochi Medical School, Kochi Uni- Ն On the other hand, pioglitazone treat- versity, Kohasu, Oko-cho, Nankoku, Kochi 783- evaluated after 3 weeks of pioglitazone 8505, Japan. E-mail: [email protected]. treatment, elevated adiponectin may be, ment for 14 days did not change fasting DOI: 10.2337/dc07-0308 in part, secondary to improved lipid and plasma glucose (5.4 Ϯ 0.1 to 5.4 Ϯ 0.1 © 2007 by the American Diabetes Association. glucose handling in these studies. In this mmol/l), C-reactive protein (0.31 Ϯ 0.07 Ϯ study, we examined short-term effects of to 0.30 0.07 mg/l), or lipid profile (data ●●●●●●●●●●●●●●●●●●●●●●● pioglitazone on serum adiponectin in not shown). Small decreases in fasting nondiabetic subjects to assess the effect of plasma insulin (7.0 Ϯ 0.7 to 6.3 Ϯ 0.8 References U/ml), homeostasis model assessment 1. Yki-Ja¨rvinen H: Thiazolidinediones. N Engl pioglitazone independently of glycolipid J Med 351:1106–1118, 2004 metabolism. of insulin resistance (1.7 Ϯ 0.2 to 1.5 Ϯ Ϯ Ϯ 2. Kadowaki T, Yamauchi T, Kubota N, Hara The study comprised 10 men aged 0.2), and leptin levels (4.2 0.5 to 3.4 K, Ueki K, Tobe K: Adiponectin and adi- 28–42 years (mean Ϯ SE age 34 Ϯ 2 0.3 ng/ml) were detected after 14 days, ponectine receptors in insulin resistance, years) with normal glucose tolerance, but they were not statistically significant. diabetes, and the metabolic syndrome. which was confirmed by a 75-g oral glu- We cannot overlook the possibility that J Clin Invest 116:1784–1792, 2006 cose tolerance test. Subjects gave written the combination of these minor metabolic 3. Kadowaki T, Yamauchi T: Adiponectin informed consent, and the study was ap- effects may contribute to the increased and adiponectin receptors. Endocr Rev 26: proved by the institutional review board adiponectin; however, these parameters 439–451, 2005 of the University of Kochi Medical School. had not changed after 7 days pioglitazone 4. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai Study participants were treated with 30 treatment, when adiponectin levels were R, Kadowaki T: Measurement of the high– mg/day pioglitazone for 14 days, and fast- already elevated (data not shown). molecular weight form of adiponectin in ing blood samples were obtained at base- Thus, pioglitazone rapidly increases plasma is useful for the prediction of in- line and at days 3, 7, 10, and 14 of serum adiponectin levels, which pre- sulin resistance and metabolic syndrome. pioglitazone treatment. The serum levels cedes changes in the status of glycolipid Diabetes Care 29:1357–1362, 2006
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tors in the hippocampus (4), and it is said Masserini B, Beck-Peccoz P, Orsi E, Am- COMMENTS AND that cortisol predicts cognitive functions brosi B, Arosio M: Cortisol secretion in (5). Glucocorticoids have been shown to patients with type 2 diabetes: relationship RESPONSES increase the pathogenic features of Alz- with chronic complications. Diabetes Care heimer’s disease (6), and in addition, ro- 30:83–88, 2007 2. Forget H, Lacroix A, Somma M, Cohen H: Cortisol Secretion in siglitazone, an insulin sensitizer, has Cognitive decline in patients with Cush- shown to reverse memory deficits in a ing’s syndrome. J Int Neuropsychol Soc 6: Patients With Type 2 transgenic model of Alzheimer’s disease 20–29, 2000 Diabetes: by reducing glucocorticoid actions (7). 3. Simon GE, Katon WJ, Lin EH, Rutter C, Earlier, Sandeep et al. (8) showed that Manning WG, Von Korff M, Ciech- Relationship With blocking 11-hydroxisteroid dehydroge- anowski P, Ludman EJ, Young BA: Cost- Chronic nase, which normally regenerates corti- effectiveness of systematic depression sone to cortisol, improved cognitive treatment among people with diabetes Complications performance in a diabetic group. mellitus. Arch Gen Psychiatry 64:65–72, In light of the finding made by Chio- 2007 4. Roozendaal B, Griffith QK, Buranday J, de Response to Chiodini et al. dini et al. (1), cortisol should become a Quervain DJ, McGaugh JL: The hip- focal point in researching diabetes com- pocampus mediates glucocorticoid-in- plications. duced impairment of spatial memory hiodini and colleagues (1) reported retrieval: dependence on the basolateral that increased levels of cortisol se- amygdale. Proc Natl Acad SciUSA100: C cretion are related to diabetes com- Acknowledgments— J.M.P.-O. is partially 1328–1333, 2003 plications but did not evaluate central supported by PRIORI-UADY (FMED 06-004). 5. Egeland J, Lund A, Landro NI, Rund BR, nervous system complications. It has Sundet K, Asbjornsen A, Mjellem N, Ron- 1,2,3 been increasingly recognized that diabe- JORGE I. CASTILLO-QUAN, BSC, BM ess A, Stordal KI: Cortisol predicts execu- 2,3 tes is related to several neurological and JULIA M. PE´ REZ-OSORIO, MD tive and memory function in depression, symptom level predicts psychomotor psychiatric disorders. Mild cognitive im- 1 pairment, Alzheimer’s disease, and de- From the Department of Clinical Sciences, Auton- speed. Acta Psychiatr Scand 112:434–441, omous University of Yucata´n, Me´rida, Yucata´n, 2005 pression have been associated with 2 Mexico; the Department of Psychopedagogy, Au- 6. Green KN, Billings LM, Roozendaal B, diabetes, and these are also related to ab- tonomous University of Yucata´n, Me´rida, Yucata´n, 3 McGaugh JL, LaFerla FM: Glucocorti- normal cortisol levels. The discovery of Mexico; and the Metabolic Syndrome Psychoendo- coids increase amyloid- and tau pathol- how hypercortisolism is related to diabe- crinology Study Group (GENES), Me´rida, Yucata´n, Mexico. ogy in a mouse model of Alzheimer’s tes complications could help us under- Address correspondence and reprint requests to disease. J Neurosci 26:9047–9056, 2006 stand these associations. Jorge I. Castillo-Quan, Department of Clinical Sci- 7. Pedersen WA, McMillan PJ, Kulstad JJ, It has been known that Cushing’s syn- ences, Faculty of Medicine, Autonomous University Leverenz JB, Craft S, Haynatzki GR: Ro- drome (a hypercortisolemic condition) is of Yucata´n, Av. Itza´es x 59 no. 498. Col. Centro, siglitazone attenuates learning and mem- related to neuropsychological impair- Me´rida, Yucata´n, Me´xico C.P. 97240. E-mail: ory deficits in Tg2576 Alzheimer disease. [email protected]. Exp Neurol 199:265–273, 2006 ment, probably mediated by cortisol del- DOI: 10.2337/dc07-0104 eterious effects in the brain (2). Moreover, 8. Sandeep TC, Yau JL, MacLullich AM, No- © 2007 by the American Diabetes Association. ble J, Deary IJ, Walker BR, Seckl JR: 11 treatment of depression in diabetic pa- -hidroxysteroid dehydrogenase inhibi- tients has led to improvement in glycemic ●●●●●●●●●●●●●●●●●●●●●●● tion improves cognitive function in and diabetes complications (3). Glu- References healthy elderly men and type 2 diabetics. cocorticoid-related memory impairment 1. Chiodini I, Adda G, Scillitani A, Coletti F, Proc Natl Acad SciUSA101:6734–6739, has been linked to glucocorticoid recep- Morelli V, Di Lembo S, Epaminonda P, 2004
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psychological conditions between the two clinico, Mangiagalli e Regina Elena, IRCCS, Milan, 2 COMMENTS AND groups of patients (i.e., complicated and Italy; the Department of Endocrinology, San Giuseppe-Milanocuore Hospital, Fatebenefratelli not complicated). Nevertheless, since the 3 RESPONSES Research Association, Milan, Italy; the Unit of En- two groups were comparable as far as age, docrinology, Department of Medical and Surgical a difference in age-related cerebral func- Sciences, University of Milan, IRCCS Policlinico San tion between the two groups is unlikely. Donato Institute, San Donato Milanese, Milan, Italy. Cortisol Secretion in On the basis of our findings, it is not Address correspondence to Iacopo Chiodini, MD, Endocrine Unit, Department of Medical Sciences, Uni- Patients With Type 2 possible to draw conclusions about cau- versity of Milan, Fondazione Policlinico, Mangiagalli e Diabetes: sality. Indeed, the presence of enhanced Regina Elena, IRCCS, Via Francesco Sforza 35, 20122 HPA axis activity may be constitutive or Milan, Italy. E-mail: [email protected]. Relationship With a precocious sign of cerebral aging (1), DOI: 10.2337/dc07-0271 Chronic contributing in worsening the meta- © 2007 by the American Diabetes Association. bolic control of type 2 diabetes and, ●●●●●●●●●●●●●●●●●●●●●●● Complications therefore, inducing a higher prevalence References of diabetes complications. On the other 1. Ferrari E, Cravello L, Muzzoni B, Casa- Response to Castillo-Quan and hand, increased HPA axis activity may rotti D, Paltro M, Solerte SB, Fioravanti M, Pe´rez-Osorio be a response to a stress condition (4), Cuzzoni G, Pontiggia B, Magri F: Age-re- determined by the presence of diabetes lated changes of the hypothalamic-pitu- complications. Similarly, the possible itary-adrenal axis: pathophysiological everal papers focused on the possi- causal relationship between the HPA correlates. Eur J Endocrinol 144:319–329, ble link between cortisol secretion axis secretion and the psychoneurologi- 2001 S and physiological and pathological cal status has not been ascertained. 2. Sapolsky RM, Krey LC, McEwen BS: The cerebral aging (1,2). The neurological Thus, we completely agree with the neuroendocrinology of stress and ageing: (mainly limbic-hippocampal) degenera- suggestion by Castillo-Quan and Pe´rez- the glucocorticoid cascade hypothesis. tive modification during aging has been Endocr Rev 7:284–301, 1986 Osorio (5) that it would be important to 3. Chiodini I, Adda G, Scillitani A, Coletti F, suggested to be responsible for a hyperac- evaluate the effect of therapies able to Morelli V, Di Lembo S, Epaminonda P, tivity of hypothalamic-pituitary-adrenal modulate HPA axis activity on the devel- Masserini B, Beck-Peccoz P, Orsi E, Am- (HPA) axis, and an age-related decrease of oping and the progression of type 2 dia- brosi B, Arosio M: Cortisol secretion in HPA sensitivity to cortisol feedback has betes complications and physiological patients with type 2 diabetes: relationship been reported (2). and pathological cerebral aging. with chronic complications. Diabetes Care In our study (3), although overt alter- 30:83–88, 2007 1 4. Richardson AP, Tayek JA: Type 2 diabetic ations of the sleep-wake cycle and depres- IACOPO CHIODINI, MD 2 patients may have a mild form of an injury sion were exclusion criteria, we did not GUIDO ADDA, MD perform a deep evaluation of the psycho- 1 response: a clinical research center study. PAOLO BECK-PECCOZ Am J Physiol Endocrinol Metab 282:1286– logical status and cerebral function of our 1 EMANUELA ORSI, MD 1290, 2002 3 subjects with type 2 diabetes. Thus, we BRUNO AMBROSI 5. Castillo-Quan JI, Pe´rez-Osorio JM: Cor- 1,2 cannot exclude that our findings of an en- MAURA AROSIO tisol secretion in patients with type 2 hanced HPA axis activity in patients with diabetes: relationship with chronic com- complicated type 2 diabetes may have From the 1Endocrine Unit, Department of Medical plications (Letter). Diabetes Care 30:e49, been influenced by a difference in neuro- Sciences, University of Milan, Fondazione Poli- 2007. DOI: 10.2337/dc07-0104
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Recently, we have reevaluated the this association appears to be principally COMMENTS AND CVD outcomes among 2,103 type 2 dia- explained by occurrence of hypertension betic participants of the Valpolicella Heart and proteinuria. Moreover, our results do RESPONSES Diabetes Study during an extended fol- not support any significant sex difference low-up of 6.5 years. A total of 384 partic- in the adverse impact of retinopathy on ipants (63% men, mean age 62 Ϯ 4 years, incident CVD events. Retinopathy Predicts with diabetes duration 16 Ϯ 3 years) de- Cardiovascular veloped incident CVD events (myocardial 1,2 GIOVANNI TARGHER, MD infarction, ischemic stroke, coronary re- 1 Mortality in Type 2 LORENZO BERTOLINI, MD vascularization, or cardiovascular death), 2 Diabetic Men and GIACOMO ZOPPINI, MD whereas 1,719 participants remained free 3 GIUSEPPE LIPPI, MD Women of diagnosed CVD during follow-up. At 1 LUCIANO ZENARI, MD baseline, a single ophthalmologist diag- nosed retinopathy after pupillary dilation, Response to Juutilainen et al. 1 according to a clinical disease severity From the Diabetes Unit, “Sacro Cuore” Hospital of Negrar, Negrar, Verona, Italy; the 2Section of Endo- scale (3). crinology, Department of Biomedical and Surgical e read with interest the recent ar- Overall, 987 (46.9%) participants Sciences, University Hospital of Verona, Verona, It- ticle by Juutilainen et al. (1) had retinopathy, of whom 798 had non- aly; and the 3Section of Clinical Chemistry, Depart- showing that proliferative reti- proliferative and 189 had proliferative ment of Biomedical and Morphological Sciences, W University Hospital of Verona, Verona, Italy. retinopathy (confirmed by fluorescein an- nopathy in both sexes and nonprolifera- Address correspondence to Giovanni Targher, tive retinopathy in women independently giography). After adjustment for age, MD, Diabetes Unit, Ospedale “Sacro Cuore – don predict all-cause and cardiovascular dis- BMI, smoking status, lipids, A1C, and di- Calabria”, Via Sempreboni, 5, 37024 Negrar (VR), ease (CVD)-associated death. The authors abetes duration and treatment, those with Italy. E-mail: [email protected]. have cautiously concluded that the sex nonproliferative or proliferative retinopa- DOI: 10.2337/dc07-0265 © 2007 by the American Diabetes Association. difference observed in the association be- thy had a higher risk (P Ͻ 0.001) of inci- tween nonproliferative retinopathy and dent CVD than those without retinopathy cardiovascular death needs to be con- (hazard ratio 1.57 [95% CI 1.18–2.51] ●●●●●●●●●●●●●●●●●●●●●●● firmed in larger studies. Indeed, I think and 3.72 [2.11–7.58] for men; 1.63 [1.23–2.56] and 3.77 [2.15–7.83] for References the relatively low frequency of retinopa- 1. Juutilainen A, Letho S, Ronnemaa T, thy (23%) and the relatively high cut-off women, respectively). Further adjust- Pyorala K, Laakso M: Retinopathy pre- chosen for diagnosing hypertension ment for hypertension (blood pressure Ն dicts cardiovascular mortality in type 2 (blood pressure Ն160/95 mmHg or treat- 130/85 mmHg or treatment) and mac- diabetic men and women. Diabetes Care ment) could be some possible explana- roalbuminuria (urinary albumin-to- 30:292–299, 2007 tions for these apparently unexpected creatinine ratio Ն25 mg/mmol) 2. Targher G, Bertolini L, Tessari R, Zenari L, results. considerably attenuated these associa- Arcaro G: Retinopathy predicts future car- Previously, we found that retinopathy tions, particularly among those with non- diovascular events among type 2 diabetic is associated with an increased CVD inci- proliferative retinopathy; the risk of patients: the Valpolicella Heart Diabetes dence among 744 type 2 diabetic patients incident CVD remained approximately Study (Letter). Diabetes Care 29:1178, followed for 5 years (2). This association twofold greater—but statistically nonsig- 2006 was largely explained by occurrence of nificant (P Ͼ 0.07)—among men (1.95 3. Wilkinson CP, Ferris FL, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik traditional risk factors, especially hyper- [0.89–4.41]) and women (1.99 [0.94– A, Pararajasegaram R, Verdaguer JT, the tension (defined as blood pressure 4.82]) with proliferative retinopathy. Ն Global Diabetic Retinopathy Project 130/85 mmHg or treatment) and pro- These results extend our previous Group: Proposed international clinical di- teinuria. However, in this study no sepa- findings showing that retinopathy is asso- abetic retinopathy and diabetic macular rate statistical analyses had been made for ciated with an increased CVD incidence edema disease severity scales. Ophthalmol- men and women (2). in people with type 2 diabetes. However, ogy 110:1677–1682, 2003
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1 (23%) was lower than in the Valpolicella AUNI JUUTILAINEN, MD 1 COMMENTS AND Heart Diabetes Study, which reflects the SEPPO LEHTO, MD 2 shorter duration of diabetes in our study TAPANI RONNEMAA¨ , MD RESPONSES 1 (mean Ϯ SD 8 Ϯ 4 years) in comparison KALEVI PYOR¨ AL¨ A¨, MD 1 with the Valpolicella Heart Diabetes MARKKU LAAKSO, MD Study (14 Ϯ 3 years). This may lower the Retinopathy Predicts statistical power of our study. From the 1Department of Medicine, Kuopio Univer- Targher et al. demonstrated a central sity Hospital, University of Kuopio, Kuopio, Fin- Cardiovascular 2 role of hypertension and proteinuria as land; and the Department of Medicine, University Mortality in Type 2 of Turku, Turku, Finland. risk factors for prevalent retinopathy and Address correspondence to Markku Laakso, Diabetic Men and incident CVD. When we adjusted for Academy Professor, Department of Medicine, Uni- Women other risk factors, including hyperten- versity of Kuopio and Kuopio University Hospital, sion, urinary protein, and A1C, the haz- 70210 Kuopio, Finland. E-mail: markku.laakso@ ard ratios slightly decreased in women kuh.fi. Response to Targher et al. DOI: 10.2337/dc07-0424 but increased in men (2). We found a sex © 2007 by the American Diabetes Association. difference in the association of retinopa- e thank Targher et al. (1) for their thy with CVD (2), which was not ob- ●●●●●●●●●●●●●●●●●●●●●●● interest in our recent article (2). served in the Valpolicella Heart Diabetes W They compared the results from Study. Sex differences in diabetes-related References the Valpolicella Heart Diabetes Study (3) CVD have been observed in several previ- 1. Targher G, Bertolini L, Zoppini G, Lippi to our findings (2) and concluded that the ous studies, including ours (4), and there- G, Zenari L: Retinopathy predicts car- fore the sex difference in the retinopathy- diovascular mortality in type 2 diabetic association of retinopathy with cardiovas- men and women (Letter). Diabetes Care cular disease (CVD) in type 2 diabetic associated risk of CVD is not surprising. We conclude that retinopathy pre- 30:e51, 2007. DOI: 10.2337/dc07-0265 subjects is principally explained by the 2. Juutilainen A, Lehto S, Ro¨nnemaa T, occurrence of hypertension and protein- dicts CVD in Finns (2) independently of Pyo¨ra¨la¨ K, Laakso M: Retinopathy pre- uria. Furthermore, they did not find a sig- other risk factors, including blood pres- dicts cardiovascular mortality in type 2 nificant sex difference in the association sure and proteinuria, indicating that there diabetic men and women. Diabetes Care of retinopathy with incident CVD events. is a “common soil” for diabetic micro- and 30:292–299, 2007 Targher et al. suggested that the rela- macrovascular complications associated 2. Targher G, Bertolini L, Tessari R, Zenari L, tively high cut-off for hypertension and a with hyperglycemia. Because several pre- Arcaro G: Retinopathy predicts future car- low frequency of retinopathy could partly vious studies have shown a sex difference diovascular events among type 2 diabetic explain our results. However, even after in the risk of CVD in type 2 diabetic sub- patients: the Valpolicella Heart Diabetes jects, we believe that our finding that Study (Letter). Diabetes Care 29: 1178, the adjustment for systolic blood pressure 2006 or pulse pressure as a continuous vari- there is a sex difference in the role of ret- 3. Juutilainen A, Kortelainen S, Lehto S, able, our results remained essentially un- inopathy to predict CVD is likely to be a Ro¨nnemaa T, Pyo¨ra¨la¨ K, Laakso M: Gen- changed. The number of type 2 diabetic true observation. However, other popula- der difference in the impact of type 2 di- subjects in our study was 824, and the tion-based longitudinal studies are abetes on coronary heart disease risk. percentage of subjects with retinopathy needed to confirm this conclusion. Diabetes Care 27:2898–2904, 2004
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Ϫ min 1 per pmol/l) with HOMA-IR (r ϭ From the 1Department of Internal Medicine, Uni- COMMENTS AND Ͻ versity Medical Center, Utrecht, the Netherlands; 0.573, P 0.0005). As expected, plasma 2 IGFBP-1 inversely correlated with fasting the Department of Medical Physiology, University RESPONSES ϭ Medical Center Utrecht, Utrecht, the Netherlands; plasma insulin levels and HOMA-IR (r the 3Department of Rehabilitation Medicine, Aca- Ϫ0.448 and Ϫ0.446, respectively; both demic Medical Center Amsterdam, Amsterdam, the P Ͻ 0.0005), but the correlation of Netherlands; and the 4Department of Metabolic and IGF-Binding Protein- plasma IGFBP-1 with insulin sensitivity Endocrine Diseases, University Center Utrecht, (clamp) had an appreciably lower corre- Utrecht, the Netherlands. 1 Levels Are Related ϭ ϭ Address correspondence to Dr. T.W. van lation coefficient (r 0.228, P 0.074). Haeften, Department of Internal Medicine F02.126, to Insulin-Mediated Similarly, plasma IGFBP-2 correlated University Medical Center Utrecht, P.O. Box 85500, Glucose Disposal and with plasma insulin levels and HOMA-IR NL 3508 GA Utrecht, Netherlands. E-mail: (r ϭϪ0.271, P ϭ 0.027 and r ϭϪ0.262, [email protected]. Are a Potential P ϭ 0.032, respectively) but not with in- DOI: 10.2337/dc07-0176 © 2007 by the American Diabetes Association. Serum Marker of sulin sensitivity (r ϭ 0.141, P ϭ 0.28).To Insulin Resistance study whether plasma IGFBP-1 levels could be of further use in assessing insulin ●●●●●●●●●●●●●●●●●●●●●●● sensitivity from basal values, we assessed Response to Maddux et al. References the relationship of insulin sensitivity with 1. Maddux BA, Chan A, Mandarino LJ, age, BMI, waist circumference, fasting Goldfine ID, DeFilippis EA: IGF-binding e were interested in the article of plasma insulin, and fasting plasma glu- protein-1 levels are related to insulin-me- Maddux et al. (1) in which they cose with multiple linear correlation with diated glucose disposal and are a potential found a correlation coefficient of and without the inclusion of IGFBP-1. In- serum marker of insulin resistance. Dia- W clusion of IGFBP-1 did not improve the betes Care 29:1535–1537, 2006 0.75 for the relationship of IGF-binding regression (nor did IGFBP-2, waist cir- 2. Stumvoll M, van Haeften T, Fritsche A, protein (IGFBP)-1 with insulin sensitiv- Gerich J: Oral glucose tolerance test in- ity. Often, the homeostasis model assess- cumference, or fasting plasma glucose): insulin sensitivity ϭ 0.141 Ϫ 0.0005 ϫ dexes for insulin sensitivity and secretion ment of insulin resistance (HOMA-IR) or Ϫ ϫ Ϫ ϫ based on various availabilities of sampling other assessments such as the Stumvoll age 0.00185 BMI 0.000773 fasting insulin (overall R ϭ 0.646, P times (Letter). Diabetes Care 24:796–797, Index (2) are used. Because hepatic pro- 2001 Ͻ 0.0005; insulin in pmol/l). duction of IGFBP-1 is under direct in- 3. Sabelis LWE, Senden PJ, Zonderland ML, hibitory influence of insulin, plasma We conclude that plasma IGFBP-1 van de Wiel A, Wielders JP, Huisveld IA, IGFBP-1 levels could potentially be of use has only a very modest relation with in- van Haeften TW, Mosterd WL: Determi- for the assessment of insulin sensitivity. sulin sensitivity; in our experience, nants of insulin sensitivity in chronic IGFBP-2 has also been associated with the plasma IGFBP-1 (or IGFBP-2) does not heart failure. Eur J Heart Failure 5:759– metabolic syndrome and nutritional sta- improve the assessment of an index for 765, 2003 tus. For 62 nondiabetic subjects who un- insulin sensitivity as performed with our 4. Bannink EMN, van Doorn J, Stijnen T, modification of the Stumvoll Index (2). Drop SLS, de Muinck Keizer-Schrama derwent a hyperinsulinemic-euglycemic SMPF: Free-dissociable insulin-like growth clamp (3), we determined plasma IG- 1 factor I (IGF-I), total IGF-I and their bind- FBP-1 and IGFBP-2 levels through estab- TIMON W. VAN HAEFTEN, MD ing proteins in girls with Turner Syn- 2 lished radioimmunoassays (4). We found MARIA L. ZONDERLAND, PHD drome during long-term growth hormone 3 a linear correlation of insulin sensitivity LOUISE W.E. SABELIS, MD treatment. Clin Endocrinol 65:310–319, Ϫ1 4 (clamp; m kg lean body mass JAAP VAN DOORN, PHD 2006
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information about the patients other than From the 1Diabetes Center, Department of Medi- COMMENTS AND cine, University of California, San Francisco, Cali- that they were not diabetic. They cite a 2 reference concerning their study of insu- fornia; and the School of Life Science, Arizona State RESPONSES University, Tempe, Arizona. lin resistance in heart failure patients on Address correspondence to Dr. Ira Goldfine, various medications (3), and it would ap- UCSF, 2200 Post, C415, San Francisco, CA 94143- pear that these patients were the ones 1616. E-mail: ira.goldfi[email protected]. IGF-Binding Protein- studied. In contrast to sick patients, we DOI: 10.2337/dc07-0385 1 Levels Are Related studied healthy nondiabetic individuals © 2007 by the American Diabetes Association. to Insulin-Mediated with a broad range of insulin sensitivity. Thus, the difference between the studies Glucose Disposal and could be the difference in patient popula- ●●●●●●●●●●●●●●●●●●●●●●● Are a Potential tions and/or the medications their pa- References Serum Marker of tients were taking. We drew samples for 1. van Haeften TW, Zonderland ML, Sabelis IGFBP-1 between 7 A.M. and 9 A.M. in fast- LWE, van Doorn J: IGF-binding protein-1 Insulin Resistance ing subjects. It is unknown whether their levels are related to insulin-mediated glu- patients were fasting when the protein cose disposal and are a potential serum Response to van Haeften et al. was measured and at what times the sam- marker of insulin resistance (Letter). Dia- ples were drawn. Since there is a diurnal betes Care 30:e53, 2007. DOI: 10.2337/ dc07-0176 e appreciate the interest of van variation for IGF-binding protein 1, it is Haeflen et al. (1) in our article (2) 2. Maddux BA, Chan A, Mandarino LJ, possible that they drew samples at differ- Goldfine ID, DeFilippis EA: IGF-binding concerning IGF-binding protein W ent times during the day, which would protein-1 levels are related to insulin-me- (IGFBP)-1 as a maker of insulin resistance alter the results. Considering all these un- diated glucose disposal and are a potential in healthy nondiabetic subjects. In con- known variables, we believe it is not pos- serum marker of insulin resistance. Dia- trast to our study, they did not find a sible to compare our study with theirs. betes Care 29:1535–1537, 2006 strong a correlation between insulin ac- 1 3. Sabelis LWE, Senden PJ, Zonderland ML, tion as determined by the hyperinsuline- BETTY A. MADDUX, BS van de Wiel A, Wielders JP, Huisveld IA, 1 mic clamp and levels of IGFBP-1. There ADELINE CHAN, BS van Haeften TW, Mosterd WL: Determi- 2 are several possible explanations for the ELENA A. DE FILIPPIS, MD nants of insulin sensitivity in chronic 2 difference in results between their study LAWRENCE J. MANDARINO, PHD heart failure. Eur J Heart Failure 5:759– 1 and ours. First, they provided no direct IRA D. GOLDFINE, MD 765, 2003
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fatty acids and is a determinant of Parkin- holic fatty liver disease and its association COMMENTS AND son’s disease. The same applies to diabe- with cardiovascular disease among type 2 tes (7), and the benefit of n-3 fat in CVD is diabetic patients. Diabetes Care 30:1212– RESPONSES also well known. Long-chain n-3 PUFAs 1218, 2007 decrease triglycerides, inflammatory eico- 2. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J: Type 2 diabetes and the risk sanoids and cytokines, blood pressure, Prevalence of of Parkinson’s disease. Diabetes Care 30: and thrombosis and increase nitric oxide 842–847, 2007 Nonalcoholic Fatty production and endothelial relaxation 3. Svegliati-Baroni G, Candelaresi C, Sac- Liver Disease and Its (8). comnno S, Ferretti G, Bachetti T, Marzi- A problem in Parkinson’s disease is oni M, De Minicis S, Nobili L, Salzano R, Association With the decrease in dopamine. Studies also Omenetti A, Pacetti D, Sigmund S, Cardiovascular show that Parkinson’s patients who expe- Benedetti A, Casini A: A model of insulin Disease Among Type rienced motor complications due to levo- resistance and nonalcoholic steatohepati- dopa had higher arachidonic acid tis in rats: role of peroxisome prolifera- 2 Diabetic Patients concentrations in the cortex compared tors-activated receptor alpha and n-3 with control subjects and levodopa- polyunsaturated fatty acid treatment on treated patients devoid of motor compli- liver injury. Am J Pathol 169:846–860, Response to Targher et al. and Hu 2006 cations (6). et al. 4. Cortez-Pinto H, Jesus L, Barros H, Lopes PUFAs are required in the ratio of Ͻ C, Moura M, Camilo M: How different is n6:n3 of 5:1. Arachidonic acid and the dietary pattern in non-alcoholic ste- read with interest the articles by docosahexanoic acid are longer PUFAs of atohepatitis patients? Clin Nutr 25:816– Targher et al. (1), which shows that n-6 and n-3, respectively. In proper pro- 823, 2006 I nonalcoholic fatty liver disease portion, their intake determines ho- 5. Ebbeson S, Ebbesson L, Swenson M, Ken- (NAFLD) is extremely common in type 2 meostasis of various body tissues nish J, Robbins DA: Successful diabetes diabetes and is associated with a higher including nervous tissue. Animal studies prevention study in Eskimos: the Alaska prevalence of cardiovascular disease reveal that n-3 fatty acid deficiency de- Siberia Project. Int J Circumpolar Health (CVD), and by Hu et al. (2), which shows creases dopamine receptor binding (9) 64:409–424, 2005 6. Julien C, Berthiaume L, Hadj-Tahar A, Ra- that type 2 diabetes is associated with an and alters dopamine metabolism (10), and supplementation with long-chain jput A, Bedard P, Di Paolo T, Julien P, increased risk of Parkinson’s disease. Nei- Calon F: Postmortem brain fatty acid pro- ther is surprising, considering society’s PUFAs prevents the decrease in dopami- file of levodopa-treated Parkinson disease excessive use of polyunsaturated n-6– nergic neurotransmitters in the frontal patients and parkinsonian monkeys. Neu- rich vegetable oils (a source of linoleic cortex caused by deficiency in alphalino- rochem Int 48:404–414, 2006 acid, a short-chain n-6 polyunsaturated lenic acid (n-3 fat) (11). 7. Raheja B, Talim M: Dietary fats and their fatty acid [PUFA]) in place of saturated Universal recommendations to cor- lipid toxicity: role in pathogenesis of fats, in addition to a deficiency of n-3 fat. rect PUFA imbalance are needed to pre- CHD, diabetes and cancer. J Diab Assoc It is possible to hypothesize that Parkin- vent diabetes and a host of diseases India 38:1–11, 1998 son’s disease, CVD, and diabetes share including Parkinson’s disease, heart dis- 8. Calder P: n-3 Fatty acids and cardiovas- common ground linked by improper diet. ease, and NAFLD. Implications point to a cular disease: evidence explained and solution for preventing all the four dis- mechanisms explored. Clin Sci (Lond)107: Svegliati-Baroni et al. (3) have dem- 1–11, 2004 onstrated that supplementation of n-3 eases: correction of inadequate or im- proper diet; therefore there is an urgent 9. Delion S, Chalon S, Herault J, Gulloteau D, PUFA ameliorates fatty liver and degree of Besnaud J, Durand G: Chronic alpha-lino- liver injury in rats. In humans, a high-fat need for large-scale studies in this respect. lenic acid deficiency alters dopaminergic intake, particularly of n-6 fat and a high and serotonergic neurotransmission in rats. n-6:n-3 ratio, was found in patients of MANISHA TALIM, MBBS, DD J Nutr 124:2466–2476, 1994 10. De la Presa O, Innis S: Docosahexanoic nonalcoholic steatohepatitis (4). From Shushrusha Hospital, Mumbai, India. A diabetes prevention study in Eski- Address correspondence to Dr. Manisha Talim, and arachidonic acid prevent a decrease mos demonstrated that a higher con- Shushrusha Hospital, 698B Ranade Rd., Dadar, in dopaminergic and serotoninergic neu- sumption of long-chain n-3 fatty acids Mumbai 400028, India. E-mail: drmanishatalim@ rotransmitters in frontal cortex caused by was associated with improved glucose tol- yahoo.com. linoleic and alphalinolenic acid deficient DOI: 10.2337/dc07-0361 erance, insulin resistance, and compo- diet in formula fed piglets. J Nutr 129: © 2007 by the American Diabetes Association. 2088–2093, 1999 nents of the metabolic syndrome (5). 11. Zimmer I, Hembert S, Dward G, Breton P, Diabetes, heart disease, and NAFLD ●●●●●●●●●●●●●●●●●●●●●●● Guilloteau D, Besnard J-C, Chalon S: appear to be chronic inflammatory condi- References Chronic n-3 polyunsaturated fatty acid tions in response to inadequate or im- 1. Targher G, Bertolini L, Padovani R, deficiency acts on dopamine metabolism proper diet. As demonstrated by Julien et Rodella S, Tessari R, Zenari L, Christo- in the rat frontal cortex: a microdialysis al. (6), nutritional intake affects brain pher D, Arcaro G: Prevalence of nonalco- study. Neurosci Lett 240:177–181, 1998
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a lower risk of type 2 diabetes in the sity of Tampere, Tampere, Finland; and the 4South COMMENTS AND Nurses’ Health Study and the Iowa Wom- Ostrobothnia Central Hospital, Seina¨joki, Finland. en’s Study (3,4). In the pooled analyses of Address correspondence to Gang Hu, MD, PhD, RESPONSES Department of Health Promotion and Chronic Dis- the Health Professionals Follow-up Study eases Prevention, National Public Health Institute, and the Nurses’ Health Study, the associ- Mannerheimintie 166, FIN-00300 Helsinki, Fin- ations of total and individual polyunsatu- land. E-mail: hu.gang@ktl.fi. Prevalence of rated fatty acid intake on the risk of DOI: 10.2337/dc07-0375 Nonalcoholic Fatty Parkinson’s disease were examined (5). © 2007 by the American Diabetes Association. Liver Disease and Its No significant associations were found between the risk of Parkinson’s disease ●●●●●●●●●●●●●●●●●●●●●●● Association With and intake of total polyunsaturated fatty Cardiovascular acids, linoleic, ␣-linolenic, or long-chain References n-3 fatty acids, including eicosapenta- 1. Talim M: Prevalence of nonalcoholic fatty Disease Among Type liver disease and its association with car- enoic acid and docosahexaenoic acid. A 2 Diabetic Patients diovascular disease among type 2 diabetic higher baseline intake of arachidonic acid patients (Letter). Diabetes Care 30:e55, tended to be associated with a lower risk 2007. DOI: 10.2337/dc07-0361 Response to Talim of Parkinson’s disease. However, no stud- 2. Hu G, Jousilahti P, Bidel S, Antikainen R, ies assess the association between specific Tuomilehto J: Type 2 diabetes and the risk types of fat consumed and the risk of both of Parkinson’s disease. Diabetes Care 30: e appreciate Dr. Talim’s com- type 2 diabetes and Parkinson’s disease. 842–847, 2007 ments (1) on the results of our Further studies are needed to test this as- 3. Salmeron J, Hu FB, Manson JE, Stampfer W study (2) on type 2 diabetes and sociation, since we do not have data on fat MJ, Colditz GA, Rimm EB, Willett WC: the risk of Parkinson’s disease. We agree consumption. Dietary fat intake and risk of type 2 dia- that polyunsaturated rich vegetable oils betes in women. Am J Clin Nutr 73:1019– 1,2 1026, 2001 may be associated with the risk of both GANG HU, MD, PHD 1,3 4. Meyer KA, Kushi LH, Jacobs DR Jr, Fol- type 2 diabetes and Parkinson’s disease. PEKKA JOUSILAHTI, MD, PHD 1,2,4 som AR: Dietary fat and incidence of type In recent years, several prospective stud- JAAKKO TUOMILEHTO, MD, PHD 2 diabetes in older Iowa women. Diabetes ies have assessed the association between 1 Care 24:1528–1535, 2001 specific types of fat consumed and the risk From the Department of Health Promotion and Chronic Diseases Prevention, National Public 5. Chen H, Zhang SM, Hernan MA, Willett of type 2 diabetes and Parkinson’s disease Health Institute, Helsinki, Finland; the 2Department WC, Ascherio A: Dietary intakes of fat and separately. Higher vegetable fat and poly- of Public Health, University of Helsinki, Helsinki, risk of Parkinson’s disease. Am J Epidemiol unsaturated fat intake are associated with Finland; 3Tampere School of Public Health, Univer- 157:1007–1014, 2003
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pirin was associated with a nonsignificant From the Department of Clinical Pharmacology and COMMENTS AND 10% reduction in the risk of major cardio- Epidemiology, Consorzio Mario Negri Sud, S. Maria vascular events as compared with placebo Imbaro, Chieti, Italy. RESPONSES Address correspondence to Antonio Nicolucci, (0.90 [0.63–1.29]). The overall effect was MD, Department of Clinical Pharmacology and Ep- the result of a reduction in the risk of idemiology, Consorzio Mario Negri Sud, Via Nazio- stroke (0.46 [0.25–0.85]), associated nale 8/A, 66030 S. Maria Imbaro (CH), Italy. E-mail: Primary Prevention with an increased risk of myocardial in- [email protected]. DOI: 10.2337/dc07-0220 of Cardiovascular farction (1.48 [0.88–2.49]) (6). © 2007 by the American Diabetes Association. Diseases in People Overall, existing data suggest that With Diabetes the clinical efficacy of low-dose aspirin in patients with diabetes is substantially ●●●●●●●●●●●●●●●●●●●●●●● Mellitus: A Scientific lower than in individuals without dia- References Statement From the betes. Indeed, a growing body of evi- 1. Buse JB, Ginsberg HN, Bakris GL, Clark dence supports the hypothesis that NG, Costa F, Eckel R, Fonseca V, Gerstein American Heart diabetes might represent a special case HC, Grundy S, Nesto RW, Pignone MP, Association and the of aspirin resistance (7). Therefore, ex- Plutzky J, Porte D, Redberg R, Stitzel KF, American Diabetes isting recommendations seem mainly Stone NJ: Primary prevention of cardio- based on extrapolations from data on vascular diseases in people with diabetes Association other high-risk groups, rather than a mellitus: a scientific statement from the comprehensive review of pertinent American Heart Association and the American Diabetes Association. Diabetes Response to Buse et al. data, under the assumption that diabe- Care 30:162–172, 2007 tes is a cardiovascular disease risk 2. American Diabetes Association: Aspirin equivalent. therapy in diabetes (Position Statement). he recent American Diabetes Associ- The need for sound, reliable evidence is Diabetes Care 27 (Suppl. 1):S72–S73, 2004 ation/American Heart Association underlined by the activation of several 3. ETDRS Investigators: Aspirin effects on T statement recommends the use of large-scale randomized trials (ASCEND [A mortality and morbidity in patients with low doses of aspirin as a strategy for pri- Study of Cardiovascular Events in Diabe- diabetes mellitus: Early Treatment Dia- mary prevention of cardiovascular dis- tes], POPADAD [Prevention of Progression betic Retinopathy Study report 14. JAMA eases in all individuals with diabetes aged of Asymptomatic Diabetic Arterial Disease], 268:1292–1300, 1992 Ͼ 4. Antithrombotic Trialists’ Collaboration: 40 years or who have additional risk ACCEPT-D [Aspirin and Simvastatin Com- factors (1). Like in previous recommen- Collaborative meta-analysis of random- bination for Cardiovascular Events Preven- ised trials of antiplatelet therapy for pre- dations (2), only selected pieces of evi- tion Trial in Diabetes], and J-PAD [Japanese dence are mentioned to support this vention of death, myocardial infarction, Primary Prevention of Atherosclerosis With and stroke in high risk patients. BMJ 324: statement. The data used to sustain the Aspirin for Diabetes]) currently under way. 71–86, 2002 efficacy of aspirin come from the Early In the meantime, the decision to prescribe 5. Sacco M, Pellegrini F, Roncaglioni MC, Treatment Diabetic Retinopathy Study, aspirin should be taken on an individual Avanzini F, Tognoni G, Nicolucci A, on the only study specifically conducted in patient basis, after a careful evaluation of the behalf of the PPP Collaborative Group: diabetic patients with and without previ- balance between the expected benefits and Primary prevention of cardiovascular ous cardiovascular disease (3). In this the risk of major bleeding (8). Will aspirin events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the trial, treatment with 650 mg aspirin for 5 benefits outweigh the risks in patients Primary Prevention Project (PPP) trial. Di- years was associated with a nonsignificant younger than 50 years of age, without addi- 9% reduction in the primary end point abetes Care 26:3264–3272, 2003 tional cardiovascular risk factors? Should 6. Ridker PM, Cook NR, Lee IM, Gordon D, (vascular death, nonfatal myocardial in- aspirin be prescribed to patients over 70 farction, or nonfatal stroke). On the other Gaziano JM, Manson JE, Hennekens CH, years of age, considering the lack of reliable Buring JE: A randomized trial of low-dose hand, the results of the last meta-analysis information in this age-group and the sharp aspirin in the primary prevention of car- on the efficacy of antiplatelet therapy in increase in the risk of upper gastrointestinal diovascular disease in women. N Engl the prevention of major cardiovascular bleeding? (9). If the lower-than-expected J Med 352:1293–1304, 2005 events are not discussed (4). The meta- benefit of aspirin in diabetes will be con- 7. Evangelista V, Totani L, Rotondo S, analysis documented a clear benefit for firmed by ongoing trials, its use for primary Lorenzet R, Tognoni G, De Berardis G, the whole population (22% reduction in Nicolucci A: Prevention of cardiovascular prevention of vascular disease in unselected the risk of major cardiovascular events) disease in type-2 diabetes: how to im- people will result in net harm. To this re- but not for the subgroup of diabetic pa- prove the clinical efficacy of aspirin. spect, it is worth noting that the Food and tients (7% risk reduction). Likewise, the Thromb Haemost 93:8–16, 2005 Drug Administration did not support using Primary Prevention Project, involving 8. McQuaid KR, Laine L: Systematic review aspirin for the primary prevention of heart over 1,000 diabetic patients, showed that and meta-analysis of adverse events of attacks in moderate-risk patients. low-dose aspirin and clopidogrel in ran- low-dose aspirin only marginally reduced domized controlled trials. Am J Med 119: the risk of major cardiovascular events 624–638, 2006 (RR 0.90 [95% CI 0.50–1.62]) (5). More ANTONIO NICOLUCCI, MD 9. Patrono C, Garcia Rodriguez LA, Landolfi recently, results of the Women’s Health GIORGIA DE BERARDIS, MSC PHARM CHEM R, Baigent C: Low-dose aspirin for the Study documented in 1,027 women with MICHELE SACCO, MD prevention of atherothrombosis. N Engl diabetes that treatment with low-dose as- GIANNI TOGNONI, MD J Med 353:2373–2383, 2005
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tions of the American Diabetes Associa- JOHN B. BUSE, MD, PHD COMMENTS AND tion and the American Heart Association MICHAEL P. PIGNONE, MD, MPH RESPONSES by consensus of those at the table. As we FOR THE ADA/AHA PRIMARY PREVENTION mention in the section entitled “Compre- CONSENSUS PANEL hensive Risk Assessment” (2), patients with diabetes can have a range of cardio- From the Department of Medicine, University of Primary Prevention vascular risk levels, although most men North Carolina School of Medicine, Chapel Hill, of Cardiovascular over 40 and women over 50 years of age North Carolina. with diabetes have a sufficient level of risk Address correspondence to John B. Buse, MD, Diseases in People University of North Carolina, 8025 Burnett Wo- to benefit from aspirin if it is effective for mack Building, CB# 7110, Chapel Hill, NC 27599. With Diabetes cardiovascular risk reduction. In contrast, E-mail: [email protected]. Mellitus: A Scientific some people with diabetes will not benefit DOI: 10.2337/dc07-0463 Statement From the from aspirin therapy over age 40 years— © 2007 by the American Diabetes Association. American Heart e.g., a physically active thin woman with type 1 diabetes of recent onset and no ●●●●●●●●●●●●●●●●●●●●●●● Association and the other cardiovascular risk factors. The References American Diabetes clinical trials that Nicolucci et al. cite will certainly expand the evidence base on as- 1. Nicolucci A, De Berardis G, Sacco M, Tog- Association noni G: Primary prevention of cardiovas- pirin’s efficacy and thus help support or cular diseases in people with diabetes refute the recommendations. mellitus: a scientific statement from the Response to Nicolucci et al. Until then, we stand by the recom- American Heart Association and the mendations to routinely employ low-dose American Diabetes Association (Letter). aspirin therapy in patients with diabetes Diabetes Care 30:e57, 2007. DOI:10.2337/ e believe that the currently avail- over age 40 years or with other cardiovas- dc07-0220 able evidence is insufficient to cular risk factors in the absence of contra- 2. Buse JB, Ginsberg HN, Bakris GL, Clark determine whether aspirin is indications or recognized adverse events. NG, Costa F, Eckel R, Fonseca V, Gerstein W HC, Grundy S, Nesto RW, Pignone MP, more, equally, or less effective in people These recommendations are designed to with diabetes as compared to those with- provide easily translated advice for pri- Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ: Primary prevention of cardio- out diabetes. In their letter, Nicolucci et mary care providers and community vascular diseases in people with diabetes al. (1) correctly point out that the recom- health workers about the likely beneficial mellitus: a scientific statement from the mendation statement was not the product and cost-effective strategies to reduce car- American Heart Association and the of a new systematic review but an effort to diovascular disease–related morbidity American Diabetes Association. Diabetes align previously published recommenda- and mortality. Care 30:162–172, 2007
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