2016 Standards of Medical Care in Diabetes

THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION VOLUME 39 | SUPPLEMENT 1

WWW.DIABETES.ORG/DIABETESCARE JANUARY 2016

PLE M E P N U T S 1 AMERICAN DIABETES ASSOCIATION STANDARDS OF MEDICAL CARE IN DIABETES—2016

ISSN 0149-5992 American Diabetes Association Standards of Medical Care in Diabetesd2016

January 2016 Volume 39, Supplement 1

[T]he simple word Care may sufﬁce to express [the journal’s] philosophical mission. The new journal is designed to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes. As such, the American Diabetes Association views Diabetes Care as a reafﬁrmation of Francis Weld Peabody’s contention that “the secret of the care of the patient is in caring for the patient.” —Norbert Freinkel, Diabetes Care, January-February 1978

EDITOR IN CHIEF William T. Cefalu, MD

ASSOCIATE EDITORS EDITORIAL BOARD George Bakris, MD Nicola Abate, MD Rita Rastogi Kalyani, MD, MHS, FACP Lawrence Blonde, MD, FACP Silva Arslanian, MD Rory J. McCrimmon, MBChB, MD, FRCP Andrew J.M. Boulton, MD Angelo Avogaro, MD, PhD Harold David McIntyre, MD, FRACP David D’Alessio, MD Ananda Basu, MD, FRCP Gianluca Perseghin, MD Sherita Hill Golden, MD, MHS, FAHA John B. Buse, MD, PhD Anne L. Peters, MD Mary de Groot, PhD Sonia Caprio, MD Jonathan Q. Purnell, MD Eddie L. Greene, MD Robert Chilton, DO Peter Reaven, MD Frank B. Hu, MD, MPH, PhD Kenneth Cusi, MD, FACP, FACE Helena Wachslicht Rodbard, MD Derek LeRoith, MD, PhD Paresh Dandona, MD, PhD David J. Schneider, MD Robert G. Moses, MD Stefano Del Prato, MD Elizabeth R. Seaquist, MD Stephen Rich, PhD Dariush Elahi, PhD Norbert Stefan, MD Matthew C. Riddle, MD Franco Folli, MD, PhD Jeff Unger, MD Julio Rosenstock, MD Robert G. Frykberg, DPM, MPH Ram Weiss, MD, PhD William V. Tamborlane, MD W. Timothy Garvey, MD Deborah J. Wexler, MD, MSc Katie Weinger, EdD, RN Ronald B. Goldberg, MD Joseph Wolfsdorf, MD, BCh Judith Wylie-Rosett, EdD, RD Margaret Grey, DrPH, RN, FAAN Tien Yin Wong, MBBS, FRCSE, FRANZCO, Richard Hellman, MD MPH, PhD

AMERICAN DIABETES ASSOCIATION OFFICERS CHAIR OF THE BOARD PRESIDENT-ELECT, MEDICINE & SCIENCE Robin J. Richardson Alvin C. Powers, MD PRESIDENT, MEDICINE & SCIENCE PRESIDENT-ELECT, HEALTH CARE & Desmond Schatz, MD EDUCATION Brenda Montgomery, RN, MSHS, CDE PRESIDENT, HEALTH CARE & EDUCATION Margaret A. Powers, PhD, RD, CDE SECRETARY/TREASURER-ELECT Umesh Verma SECRETARY/TREASURER Lorrie Welker Liang CHIEF EXECUTIVE OFFICER Kevin L. Hagan CHAIR OF THE BOARD-ELECT David A. DeMarco, PhD CHIEF SCIENTIFIC & MEDICAL OFFICER Robert E. Ratner, MD, FACP, FACE

The mission of the American Diabetes Association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes. Diabetes Care is a journal for the health care practitioner that is intended to increase knowledge, stimulate research, and promote better management of people with diabetes. To achieve these goals, the journal publishes original research on human studies in the following categories: Clinical Care/Education/Nutrition/ Psychosocial Research, Epidemiology/Health Services Research, Emerging Technologies and Therapeutics, Pathophysiology/Complications, and Cardiovascular and Metabolic Risk. The journal also publishes ADA statements, consensus reports, clinically relevant review articles, letters to the editor, and health/medical news or points of view. Topics covered are of interest to clinically oriented physicians, researchers, epidemiologists, psychologists, diabetes educators, and other health professionals. More information about the journal can be found online at care.diabetesjournals.org.

Copyright © 2016 by the American Diabetes Association, Inc. All rights reserved. Printed in the USA. Requests for permission to reuse content should be sent to Copyright Clearance Center at www.copyright.com or 222 Rosewood Dr., Danvers, MA 01923; phone: (978) 750-8400; fax: (978) 646-8600. Requests for permission to translate should be sent to Permissions Editor, American Diabetes Association, at [email protected]. The American Diabetes Association reserves the right to reject any advertisement for any reason, which need not be disclosed to the party submitting the advertisement. Commercial reprint orders should be directed to Sheridan Content Services, (800) 635-7181, ext. 8065. Single issues of Diabetes Care can be ordered by calling toll-free (800) 232-3472, 8:30 A.M. to 5:00 P.M. EST, Monday through Friday. Outside the United States, call (703) 549-1500. Rates: $75 in the United States, $95 in Canada and Mexico, and $125 for all other countries. Diabetes Care is available online at care.diabetesjournals.org. Please call the numbers listed above, e-mail [email protected], or visit the online journal for PRINT ISSN 0149-5992 more information about submitting manuscripts, publication charges, ordering reprints, ONLINE ISSN 1935-5548 subscribing to the journal, becoming an ADA member, advertising, permission to reuse PRINTED IN THE USA content, and the journal’s publication policies.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS

EDITORIAL OFFICE DIRECTOR PRODUCTION MANAGER DIRECTOR, MEMBERSHIP/SUBSCRIPTION Lyn Reynolds Amy S. Gavin SERVICES Donald Crowl PEER REVIEW MANAGER TECHNICAL EDITOR PHARMACEUTICAL DIGITAL ADVERTISING Shannon Potts Oedipa Rice e-Healthcare Solutions John Burke EDITORIAL OFFICE SECRETARIES Chief Revenue Ofﬁcer Raquel Castillo MANAGING DIRECTOR, MEDIA SALES Clare Liberis [email protected] Joan Garrett [email protected] (609) 882-8887, ext. 149 (212) 725-4925, ext. 3448 MANAGING DIRECTOR, SCHOLARLY PHARMACEUTICAL PRINT ADVERTISING JOURNAL PUBLISHING The Jackson-Gaeta Group, Inc. Christian S. Kohler ADVERTISING MANAGER B. Joseph Jackson Julie DeVoss Graff [email protected] DIRECTOR, SCHOLARLY JOURNAL PUBLISHING [email protected] Heather Norton Blackburn Paul Nalbandian (703) 299-5511 [email protected] EDITORIAL MANAGERS Tina Auletta Valentina Such ASSOCIATE DIRECTOR, BILLING & COLLECTIONS [email protected] Nancy C. Baldino Laurie Ann Hall (973) 403-7677 January 2016 Volume 39, Supplement 1

Standards of Medical Care in Diabetes—2016

S1 Introduction S60 8. Cardiovascular Disease and Risk S3 Professional Practice Committee Management S4 Standards of Medical Care in Diabetes—2016: Hypertension/Blood Pressure Control Summary of Revisions Lipid Management S6 1. Strategies for Improving Care Antiplatelet Agents Coronary Heart Disease Diabetes Care Concepts Care Delivery Systems S72 9. Microvascular Complications and Foot Care When Treatment Goals Are Not Met Diabetic Kidney Disease Tailoring Treatment to Vulnerable Populations Diabetic Retinopathy S13 2. Classification and Diagnosis of Diabetes Neuropathy Classification Foot Care Diagnostic Tests for Diabetes S81 10. Older Adults Categories of Increased Risk for Diabetes (Prediabetes) Type 1 Diabetes Overview Type 2 Diabetes Neurocognitive Function Gestational Diabetes Mellitus Hypoglycemia Monogenic Diabetes Syndromes Treatment Goals Cystic Fibrosis–Related Diabetes Pharmacological Therapy Treatment in Skilled Nursing Facilities S23 3. Foundations of Care and Comprehensive Medical Evaluation and Nursing Homes End-of-Life Care Foundations of Care S86 11. Children and Adolescents Basis for Initial Care Ongoing Care Management Type 1 Diabetes Diabetes Self-management Education and Support Type 2 Diabetes Medical Nutrition Therapy Transition From Pediatric to Adult Care Physical Activity S94 12. Management of Diabetes in Pregnancy Smoking Cessation: Tobacco and e-Cigarettes Immunization Diabetes in Pregnancy Psychosocial Issues Preconception Counseling Comprehensive Medical Evaluation Glycemic Targets in Pregnancy Comorbidities Management of Gestational Diabetes Mellitus Management of Pregestational Type 1 Diabetes S36 4. Prevention or Delay of Type 2 Diabetes and Type 2 Diabetes in Pregnancy Lifestyle Modification Postpartum Care Pharmacological Interventions Pregnancy and Antihypertensive Drugs Diabetes Self-management Education and Support S99 13. Diabetes Care in the Hospital S39 5. Glycemic Targets Hospital Care Delivery Standards Assessment of Glycemic Control Considerations on Admission A1C Testing Glycemic Targets in Hospitalized Patients A1C Goals Antihyperglycemic Agents in Hospitalized Hypoglycemia Patients Intercurrent Illness Standards for Special Situations Treating and Preventing Hypoglycemia S47 6. Obesity Management for the Treatment of Type 2 Diabetes Self-management in the Hospital Medical Nutrition Therapy in the Hospital Look AHEAD Transition From the Acute Care Setting Assessment Diabetes Care Providers in the Hospital Diet, Physical Activity, and Behavioral Therapy Bedside Blood Glucose Monitoring Pharmacotherapy S105 14. Diabetes Advocacy Bariatric Surgery S52 7. Approaches to Glycemic Treatment Advocacy Position Statements S107 Professional Practice Committee for the Standards Pharmacological Therapy for Type 1 Diabetes of Medical Care in Diabetes—2016 Pharmacological Therapy for Type 2 Diabetes Bariatric Surgery S109 Index

This issue is freely accessible online at care.diabetesjournals.org.

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Diabetes Care Volume 39, Supplement 1, January 2016 S1 INTRODUCTION

Introduction Diabetes Care 2016;39(Suppl. 1):S1–S2 | DOI: 10.2337/dc16-S001

Diabetes is a complex, chronic illness re- diabetes care standards, guidelines, and to diabetes. Workgroup reports fall into quiring continuous medical care with related documents for over 25 years. this category. Scientific statements are multifactorial risk-reduction strategies ADA’s clinical practice recommenda- published in the ADA journals and other beyond glycemic control. Ongoing patient tions are viewed as important resources scientific/medical publications, as ap- self-management education and support for health care professionals who care propriate. Scientific statements also are critical to preventing acute complica- for people with diabetes. ADA’s “Stan- undergo a formal review process. tions and reducing the risk of long-term dards of Medical Care in Diabetes,” complications. Significant evidence exists position statements, and scientific Consensus Report that supports a range of interventions to statements undergo a formal review A consensus report contains a compre- improve diabetes outcomes. process by ADA’s Professional Practice hensive examination by an expert panel The American Diabetes Association’s Committee (PPC) and the Executive (i.e., consensus panel) of a scientificor (ADA’s) “Standards of Medical Care in Committee of the Board of Directors. medical issue related to diabetes. A con- Diabetes” is intended to provide clini- The Standards and all ADA position sensus report is not an ADA position and cians, patients, researchers, payers, statements, scientific statements, and represents expert opinion only. The cat- and other interested individuals with consensus reports are available on the As- egory may also include task force and the components of diabetes care, gen- sociation’s Web site at http://professional expert committee reports. The need eral treatment goals, and tools to eval- .diabetes.org/adastatements. for a consensus report arises when clini- uate the quality of care. The Standards cians or scientists desire guidance on a of Care recommendations are not in- “Standards of Medical Care in subject for which the evidence is contra- tended to preclude clinical judgment Diabetes” dictory or incomplete. A consensus re- Standards of Care: ADA position state- and must be applied in the context of port is developed following a consensus ment that provides key clinical practice excellent clinical care, with adjustments conference where the controversial issue recommendations. for individual preferences, comorbid- The PPC performs an is extensively discussed. The report ities, and other patient factors. For extensive literature search and updates represents the panel’s collective anal- more detailed information about man- the Standards annually based on the ysis, evaluation, and opinion at that agement of diabetes, please refer to quality of new evidence. point in time based in part on the con- Medical Management of Type 1 Diabe- ADA Position Statement ference proceedings. A consensus re- tes (1) and Medical Management of A position statement is an official ADA port does not undergo a formal ADA Type 2 Diabetes (2). point of view or belief that contains clin- review process. The recommendations include ical or research recommendations. Posi- GRADING OF SCIENTIFIC EVIDENCE screening, diagnostic, and therapeutic tion statements are issued on scientific fi actions that are known or believed to or medical issues related to diabetes. Since the ADA rst began publishing favorably affect health outcomes of pa- They are published in the ADA journals practice guidelines, there has been con- tients with diabetes. Many of these in- and other scientific/medical publica- siderable evolution in the evaluation of fi terventions have also been shown to be tions. ADA position statements are typ- scienti c evidence and in the develop- cost-effective (3). ically based on a systematic review or ment of evidence-based guidelines. In fi The ADA strives to improve and up- other review of published literature. 2002, the ADA developed a classi cation fi date the Standards of Care to ensure Position statements undergo a formal system to grade the quality of scienti c that clinicians, health plans, and policy- review process. They are updated every evidence supporting ADA recommenda- makers can continue to rely on them as 5 years or as needed. tions for all new and revised ADA posi- the most authoritative and current tion statements. A recent analysis of the guidelines for diabetes care. ADA Scientific Statement evidence cited in the Standards of Care Ascientific statement is an official ADA found steady improvement in quality ADA STANDARDS, STATEMENTS, point of view or belief that may or may over the past 10 years, with the 2014 AND REPORTS not contain clinical or research recom- Standards for the first time having the The ADA has been actively involved in mendations. Scientific statements con- majority of bulleted recommendations the development and dissemination of tain scholarly synopsis of a topic related supported by A-orB-level evidence

“Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: November 2015. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. S2 Introduction Diabetes Care Volume 39, Supplement 1, January 2016

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” dence may be equally important but Level of are not as well supported. Of course, evidence Description evidence is only one component of clinical decision making. Clinicians care for A Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered, including patients, not populations; guidelines c Evidence from a well-conducted multicenter trial must always be interpreted with the in- c Evidence from a meta-analysis that incorporated quality ratings in the dividual patient in mind. Individual cir- analysis cumstances, such as comorbid and Compelling nonexperimental evidence, i.e., “all or none” rule developed by the coexisting diseases, age, education, dis- Centre for Evidence-Based Medicine at the University of Oxford ability, and, above all, patients’ values Supportive evidence from well-conducted randomized controlled trials that are and preferences, must be considered adequately powered, including c Evidence from a well-conducted trial at one or more institutions and may lead to different treatment tar- c Evidence from a meta-analysis that incorporated quality ratings in the gets and strategies. Furthermore, con- analysis ventional evidence hierarchies, such as B Supportive evidence from well-conducted cohort studies the one adapted by the ADA, may miss c Evidence from a well-conducted prospective cohort study or registry nuances important in diabetes care. For c Evidence from a well-conducted meta-analysis of cohort studies example, although there is excellent ev- Supportive evidence from a well-conducted case-control study idence from clinical trials supporting C Supportive evidence from poorly controlled or uncontrolled studies the importance of achieving multiple c Evidence from randomized clinical trials with one or more major or three or risk factor control, the optimal way to more minor methodological flaws that could invalidate the results achievethisresultislessclear.Itisdif- c Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls) ficult to assess each component of c Evidence from case series or case reports such a complex intervention. Conflicting evidence with the weight of evidence supporting the recommendation References E Expert consensus or clinical experience 1. American Diabetes Association. Medical Management of Type 1 Diabetes.6thed. Kaufman FR, Ed. Alexandria, VA, American Di- abetes Association, 2012 2. American Diabetes Association. Medical (4). A grading system (Table 1) devel- in which clinical trials may be impracti- Management of Type 2 Diabetes.7thed. oped by the ADA and modeled after ex- cal, or in which there is conflicting evi- Burant CF, Young LA, Eds. Alexandria, VA, Amer- isting methods was used to clarify and dence. Recommendations with an A ican Diabetes Association, 2012 3. Li R, Zhang P, Barker LE, Chowdhury FM, codify the evidence that forms the basis rating are based on large well-designed Zhang X. Cost-effectiveness of interventions to for the recommendations. ADA recom- clinical trials or well-done meta-analyses. prevent and control diabetes mellitus: a sys- mendations are assigned ratings of A, B, Generally, these recommendations tematic review. Diabetes Care 2010;33:1872– or C, depending on the quality of evi- have the best chance of improving out- 1894 E 4. Grant RW, Kirkman MS. Trends in the evidence. Expert opinion is a separate comes when applied to the population dence level for the American Diabetes Associa- category for recommendations in which to which they are appropriate. Recom- tion’s “Standards of Medical Care in Diabetes” there is no evidence from clinical trials, mendations with lower levels of evi- from 2005 to 2014. Diabetes Care 2015;38:6–8 RFSINLPATC COMMITTEE PRACTICE PROFESSIONAL Diabetes Care Volume 39, Supplement 1, January 2016 S3

Professional Practice Committee Diabetes Care 2016;39(Suppl. 1):S3 | DOI: 10.2337/dc16-S002

The Professional Practice Committee for human studies related to each sec- Emma Morton-Eggleston, MD, MPH; (PPC) of the American Diabetes Associ- tion and published since 1 January Margaret A. Powers, PhD, RD, CDE; ation (ADA) is responsible for the “Stan- 2015. Recommendations were revised Robert E. Ratner, MD; Erinn Rhodes, dards of Medical Care in Diabetes” basedonnewevidenceor,insome MD, MPH; Amy Rothberg, MD; Sharon position statement, referred to as the cases, to clarify the prior recommenda- D. Solomon, MD; Guillermo E. Umpierrez, “Standards of Care.” The PPC is a multi- tion or match the strength of the word- MD; Willy Valencia, MD; and Kristina F. disciplinary expert committee coming to the strength of the evidence. A Zdanys, MD. prised of physicians, diabetes educators, table linking the changes in recommen- registered dietitians, and others who dations to new evidence can be re- have expertise in a range of areas, in- viewed at http://professional.diabetes Members of the PPC cluding adult and pediatric endocrinol- .org/SOC. As for all position statements, William H. Herman, MD, MPH (Chair)* ogy, epidemiology, public health, lipid the Standards of Care position state- research, hypertension, preconception ment was reviewed and approved by Thomas W. Donner, MD planning, and pregnancy care. Appoint- the Executive Committee of ADA’s R. James Dudl, MD ment to the PPC is based on excellence Board of Directors, which includes Hermes J. Florez, MD, PhD, MPH* in clinical practice and research. Al- health care professionals, scientists, though the primary role of the PPC is and lay people. Judith E. Fradkin, MD to review and update the Standards of Feedback from the larger clinical Charlotte A. Hayes, MMSc, MS, RD, CDE, Care, it is also responsible for oversee- community was valuable for the 2016 ACSM CCEP ’ ing the review and revisions of ADA s revision of the Standards of Care. Readers Rita Rastogi Kalyani, MD, MHS, FACP position statements and scientific who wish to comment on the Standards statements. of Medical Care in Diabetesd2016 are Suneil Koliwad, MD, PhD The ADA adheres to the Institute of invited to do so at http://professional Joseph A. Stankaitis, MD, MPH* Medicine Standards for Developing .diabetes.org/SOC. Tracey H. Taveira, PharmD, CDOE, Trustworthy Clinical Practice Guidelines. The ADA funds development of the CVDOE* All members of the PPC are required to Standards of Care and all ADA position Deborah J. Wexler, MD, MSc* disclose potential conflicts of interest statements out of its general revenues with industry and/or other relevant or- and does not use industry support for Joseph Wolfsdorf, MB, BCh* ganizations. These disclosures are dis- these purposes. The PPC would like to *Subgroup leaders cussed at the onset of each Standards thank the following individuals who of Care revision meeting. Members of the provided their expertise in reviewing committee, their employer, and their dis- and/or consulting with the committee: ADA Staff fl Lloyd Paul Aiello, MD, PhD; Sheri closed con icts of interest are listed in Jane L. Chiang, MD “ Colberg-Ochs, PhD; Jo Ellen Condon, RD, the Professional Practice Committee (Corresponding author: Standards of Medical Care in CDE; Donald R. Coustan, MD; Silvio E. for the [email protected]) Diabetesd2016” table (see p. S107). Inzucchi, MD; George L. King, MD; For the current revision, PPC mem- Shihchen Kuo, RPh, PhD; Ira B. Lamster, DDS, Erika Gebel Berg, PhD bers systematically searched MEDLINE MMSc; Greg Maynard, MD, MSc, SFHM; Allison T. McElvaine, PhD

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. S4 Diabetes Care Volume 39, Supplement 1, January 2016

Standards of Medical Care in Diabetesd2016: SUMMARY OF REVISIONS Summary of Revisions Diabetes Care 2016;39(Suppl. 1):S4–S5 | DOI: 10.2337/dc16-S003

GENERAL CHANGES screening recommendations. The rec- the ADA added the recommendation In alignment with the American Diabe- ommendation is now to test all adults that people who use continuous glucose tes Association’s(ADA’s) position that beginning at age 45 years, regardless monitoring and insulin pumps should diabetes does not define people, the of weight. have continued access after they turn word “diabetic” will no longer be used Testing is also recommended for 65 years of age. when referring to individuals with dia- asymptomatic adults of any age who Section 6. Obesity Management for betes in the “Standards of Medical Care are overweight or obese and who have the Treatment of Type 2 Diabetes in Diabetes.” The ADA will continue to one or more additional risk factors for This new section, which incorporates use the term “diabetic” as an adjective diabetes. Please refer to Section 2 for prior recommendations related to bari- for complications related to diabetes testing recommendations for gesta- atric surgery, has new recommenda- (e.g., diabetic retinopathy). tional diabetes mellitus. Although levels of evidence for several For monogenic diabetes syndromes, tions related to the comprehensive recommendations have been updated, there is specific guidance and text on assessment of weight in diabetes and these changes are not included below as testing, diagnosing, and evaluating indi- to the treatment of overweight/obesity fi the clinical recommendations have re- viduals and their family members. with behavior modi cation and pharma- mained the same. Changes in evidence cotherapy. level from, for example, C to E are not Section 3. Foundations of Care and This section also includes a new table noted below. The “Standards of Medical Comprehensive Medical Evaluation of currently approved medications for “ Care in Diabetesd2016” contains, in addi- Section 3 Initial Evaluation and Diabe- the long-term treatment of obesity. ” tion to many minor changes that clarify tes Management Planning and Section 4 “Foundations of Care: Education, Nu- Section 7. Approaches to Glycemic recommendations or reflect new evidence, Treatment the following more substantive revisions. trition, Physical Activity, Smoking Cessa- tion, Psychosocial Care, and Immunization” Bariatric surgery was removed from this from the 2015 Standards were com- section and placed in a new section en- SECTION CHANGES “ bined into one section for 2016 to re- titled Obesity Management for the Section 1. Strategies for Improving Care ” flect the importance of integrating Treatment of Type 2 Diabetes. This section was revised to include rec- medical evaluation, patient engage- ommendations on tailoring treatment Section 8. Cardiovascular Disease and ment, and ongoing care that highlight to vulnerable populations with diabetes, Risk Management the importance of lifestyle and behav- including recommendations for those “Atherosclerotic cardiovascular disease” ioral modification. The nutrition and with food insecurity, cognitive dysfunc- (ASCVD) has replaced the former term vaccination recommendations were tion and/or mental illness, and HIV, “cardiovascular disease” (CVD), as streamlined to focus on those aspects and a discussion on disparities related ASCVD is a more specificterm. of care most important and most rele- to ethnicity, culture, sex, socioeconomic A new recommendation for pharma- vant to people with diabetes. differences, and disparities. cological treatment of older adults was Section 4. Prevention or Delay of added. Section 2. Classification and Diagnosis Type 2 Diabetes To reflect new evidence on ASCVD of Diabetes To reflect the changing role of technology risk among women, the recommenda- The order and discussion of diagnostic in the prevention of type 2 diabetes, a re- tion to consider aspirin therapy in . tests (fasting plasma glucose, 2-h plasma commendation was added encouraging women aged 60 years has been $ glucose after a 75-g oral glucose tolerance the use of new technology such as apps changed to include women aged 50 test, and A1C criteria) were revised to and text messaging to affect lifestyle years. A recommendation was also make it clear that no one test is preferred modification to prevent diabetes. added to address antiplatelet use in pa- over another for diagnosis. tients aged ,50 years with multiple risk To clarify the relationship between Section 5. Glycemic Targets factors. age, BMI, and risk for type 2 diabetes Because of the growing number of older A recommendation was made to re- and prediabetes, the ADA revised the adults with insulin-dependent diabetes, flect new evidence that adding ezetimibe

to moderate-intensity statin provides ad- includes neurocognitive function, hypo- from a recommendation of ,6% (42 ditional cardiovascular benefits for select glycemia, treatment goals, care in skilled mmol/mol) to a target of 6–6.5% (42– individuals with diabetes and should be nursing facilities/nursing homes, and 48 mmol/mol), although depending on considered. end-of-life considerations. hypoglycemia risk the target may be A new table provides efficacy and tightened or relaxed. Section 11. Children and Adolescents dose details on high- and moderate- Glyburide in gestational diabetes The scope of this section is more com- intensity statin therapy. mellitus was deemphasized based on prehensive, capturing the nuances of di- new data suggesting that it may be in- abetes care in the pediatric population. Section 9. Microvascular ferior to insulin and metformin. Complications and Foot Care This includes new recommendations addressing diabetes self-management “Nephropathy” was changed to “dia- education and support, psychosocial Section 13. Diabetes Care in the betic kidney disease” to emphasize issues, and treatment guidelines for Hospital that, while nephropathy may stem type 2 diabetes in youth. This section was revised to focus solely from a variety of causes, attention is The recommendation to obtain a fast- on diabetes care in the hospital setting. placed on kidney disease that is directly ing lipid profile in children starting at This comprehensive section addresses related to diabetes. There are several age 2 years has been changed to age hospital care delivery standards, more minor edits to this section. The signifi- 10 years, based on a scientificstatement detailed information on glycemic tar- cant ones, based on new evidence, are on type 1 diabetes and cardiovascular gets and antihyperglycemic agents, as follows: disease from the American Heart Asso- standards for special situations, and Diabetic kidney disease: guidance was ciation and the ADA. transitions from the acute care setting. addedonwhentoreferforrenalre- This section also includes a new table placement treatment and when to refer Section 12. Management of Diabetes on basal and bolus dosing recommenda- to physicians experienced in the care of in Pregnancy tions for continuous enteral, bolus en- diabetic kidney disease. The scope of this section is more com- teral, and parenteral feedings. Diabetic retinopathy: guidance was prehensive, providing new recommen- added on the use of intravitreal anti- dations on pregestational diabetes, Section 14. Diabetes Advocacy VEGF agents for the treatment of gestational diabetes mellitus, and gen- “Diabetes Care in the School Setting: A center-involved diabetic macular edema, eral principles for diabetes management Position Statement of the American Di- as they were more effective than mono- in pregnancy. abetes Association” was revised in 2015. therapy or combination therapy with A new recommendation was added to This position statement was previously laser. highlight the importance of discussing fam- called “Diabetes Care in the School and Section 10. Older Adults ily planning and effective contraception Day Care Setting.” The ADA intentionally The scope of this section is more compre- with women with preexisting diabetes. separated these two populations be- hensive, capturing the nuances of diabe- A1C recommendations for pregnant cause of the significant differences in di- tes care in the older adult population. This women with diabetes were changed, abetes care between the two cohorts. S6 Diabetes Care Volume 39, Supplement 1, January 2016

1. Strategies for Improving Care American Diabetes Association

Diabetes Care 2016;39(Suppl. 1):S6–S12 | DOI: 10.2337/dc16-S004

Recommendations c A patient-centered communication style that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care should be used. B c Treatment decisions should be timely and based on evidence-based guidelines that are tailored to individual patient preferences, prognoses, and comorbidities. B c Care should be aligned with components of the Chronic Care Model to ensure productive interactions between a prepared proactive practice team and an informed activated patient. A c When feasible, care systems should support team-based care, community involvement, patient registries, and decision support tools to meet patient needs. B

DIABETES CARE CONCEPTS In the following sections, different components of the clinical management of patients with (or at risk for) diabetes are reviewed. Clinical practice guidelines are key to improving population health; however, for optimal outcomes, diabetes care must be individualized for each patient. The American Diabetes Association high- 1. STRATEGIES FOR IMPROVING CARE lights the following three themes that clinicians, policymakers, and advocates should keep in mind:

1. Patient-Centeredness: Practice recommendations, whether based on evidence or expert opinion, are intended to guide an overall approach to care. The science and art of medicine come together when the clinician is facedwithmakingtreatmentrecommendations for a patient who would not have met eligibility criteria for the studies on which guidelines were based. Recognizing that one size does not fit all, these Standards provide guidance for when and how to adapt recommendations. Because patients with diabetes have greatly increased risk for cardiovascular disease, a patient- centered approach should include a comprehensive plan to reduce cardiovascular risk by addressing blood pressure and lipid control, smoking prevention and cessation, weight management, physical activity, and healthy lifestyle choices. 2. Diabetes Across the Life Span: An increasing proportion of patients with type 1 diabetes are adults. For less salutary reasons, the incidence of type 2 diabetes is increasing in children and young adults. Patients with type 1 diabetes and those with type 2 diabetes are living well into older age, a stage of life for which there is little evidence from clinical trials to guide therapy. All these demographic changes highlight another challenge to high-quality diabetes care, which is the need to improve coordination between clinical teams as patients transition through different stages of the life span. 3. Advocacy for Patients With Diabetes: Advocacy can be defined as active support and engagement to advance a cause or policy. Advocacy is needed to improve the lives of patients with (or at risk for) diabetes. Given the tremendous toll that Suggested citation: American Diabetes Associa- obesity, physical inactivity, and smoking have on the health of patients with tion.Strategiesforimprovingcare.Sec.1.In Standards of Medical Care in Diabetesd2016. diabetes, efforts are needed to address and change the societal determinants Diabetes Care 2016;39(Suppl. 1):S6–S12 at the root of these problems. Within the narrower domain of clinical practice © 2016 by the American Diabetes Association. guidelines, the application of evidence level grading to practice recommenda- Readers may use this article as long as the work tions can help to identify areas that require more research (1). Refer to Section is properly cited, the use is educational and not 14 “Diabetes Advocacy.” for profit, and the work is not altered. care.diabetesjournals.org Strategies for Improving Care S7

CARE DELIVERY SYSTEMS 2. Self-management support 1. Healthy lifestyle choices (physical There has been steady improvement in 3. Decision support (basing care on activity, healthy eating, tobacco ces- the proportion of patients with diabetes evidence-based, effective care guide- sation, weight management, and ef- treated with statins and achieving recom- lines) fective coping) mended levels of A1C, blood pressure, 4. Clinical information systems (using 2. Disease self-management (taking and LDL cholesterol in the last 10 years registries that can provide patient- and managing medications and, when (2). The mean A1C nationally has declined specific and population-based sup- clinically appropriate, self-monitoring from 7.6% (60 mmol/mol) in 1999–2002 port to the care team) of glucose and blood pressure) to 7.2% (55 mmol/mol) in 2007–2010 5. Community resources and policies 3. Prevention of diabetes complica- based on the National Health and Nutri- (identifying or developing resources tions (self-monitoring of foot health; tion Examination Survey (NHANES), with to support healthy lifestyles) active participation in screening for younger adults less likely to meet treat- 6. Health systems (to create a quality- eye, foot, and renal complications; ment targets compared with older adults oriented culture) and immunizations) (2). This has been accompanied by improvements in cardiovascular outcomes Redefining the roles of the health care High-quality diabetes self-management andhasledtosubstantialreductionsin delivery team and promoting self- education (DSME) has been shown to end-stage microvascular complications. management on the part of the patient improve patient self-management, Nevertheless, 33–49% of patients still are fundamental to the successful imple- satisfaction, and glucose control. Na- do not meet targets for glycemic, blood mentation of the CCM (8). Collaborative, tional DSME standards call for an inte- pressure, or cholesterol control, and multidisciplinary teams are best suited to grated approach that includes clinical only 14% meet targets for all three mea- provide care for people with chronic con- content and skills, behavioral strategies sures and nonsmoking status (2). Evi- ditions such as diabetes and to facilitate (goal setting, problem solving), and en- dence also suggests that progress in patients’ self-management (9–11). gagement with psychosocial concerns cardiovascular risk factor control (par- Key Objectives (23). ticularly tobacco use) may be slowing The National Diabetes Education Pro- Objective 3: Change the Care System (2,3). Certain patient groups, such as gram (NDEP) maintains an online re- An institutional priority in most success- young adults and patients with complex source (www.betterdiabetescare.nih ful care systems is providing high quality comorbidities, financial or other social .gov) to help health care professionals of care (24). Changes that have been hardships, and/or limited English profi- to design and implement more effective shown to increase quality of diabetes ciency, may present particular chal- health care delivery systems for those care include basing care on evidence- lenges to goal-based care (4–6). Even fi with diabetes. Three speci c objectives, based guidelines (18); expanding the after adjusting for patient factors, with references to literature outlining role of teams to implement more inten- the persistent variation in quality of di- practical strategies to achieve each, are sive disease management strategies abetes care across providers and prac- as follows: (6,21,25); redesigning the care process tice settings indicates that there is potential for substantial system-level Objective 1 : Optimize Provider and Team (26); implementing electronic health improvements. Behavior record tools (27,28); activating and Thecareteamshouldprioritizetimely educating patients (29,30); removing fi- Chronic Care Model and appropriate intensification of life- nancial barriers and reducing patient Numerous interventions to improve ad- style and/or pharmacological therapy out-of-pocket costs for diabetes educa- herence to the recommended standards for patients who have not achieved ben- tion, eye exams, self-monitoring of have been implemented. However, a ma- eficial levels of glucose, blood pressure, blood glucose, and necessary medica- jor barrier to optimal care is a delivery or lipid control (12). Strategies such as tions (6); and identifying/developing/ system that is often fragmented, lacks explicit goal setting with patients (13); engaging community resources and clinical information capabilities, dupli- identifying and addressing language, nu- public policy that support healthy life- cates services, and is poorly designed for meracy, or cultural barriers to care (14– styles (31). the coordinated delivery of chronic care. 17); integrating evidence-based guide- Initiatives such as the Patient-Centered The Chronic Care Model (CCM) has been lines and clinical information tools into Medical Home show promise for improv- showntobeaneffectiveframeworkfor the process of care (18–20); and incor- ing outcomes through coordinated pri- improving the quality of diabetes care (7). porating care management teams in- mary care and offer new opportunities Six Core Elements cluding nurses, pharmacists, and other for team-based chronic disease care The CCM includes six core elements for providers (21,22) have each been shown (32). Additional strategies to improve di- the provision of optimal care of patients to optimize provider and team behavior abetes care include reimbursement with chronic disease: and thereby catalyze reductions in A1C, structures that, in contrast to visit-based blood pressure, and LDL cholesterol. billing, reward the provision of appropriate 1. Delivery system design (moving Objective 2: Support Patient Behavior and high-quality care (33), and incen- from a reactive to a proactive care Change tives that accommodate personalized delivery system where planned visits Successful diabetes care requires a sys- care goals (6,34). are coordinated through a team- tematic approach to supporting patients’ Optimal diabetes management re- based approach) behavior change efforts, including quires an organized, systematic approach S8 Strategies for Improving Care Diabetes Care Volume 39, Supplement 1, January 2016

and the involvement of a coordinated pressure, or lipids (40). Although there TAILORING TREATMENT TO team of dedicated health care profes- are many ways to measure adherence VULNERABLE POPULATIONS sionals working in an environment where (40), Medicare uses percent of days cov- Health Disparities patient-centered high-quality care is a ered (PDC), which is a measure of the The causes of health disparities are com- priority (6). number of pills prescribed divided by plex and include societal issues such as the days between first and last prescrip- institutional racism, discrimination, socio- WHEN TREATMENT GOALS ARE tions. “Adequate” adherence is defined economic status, poor access to health NOT MET as 80% (40). This metric can be used to care, and lack of health insurance. Disparities In general, providers should seek evidence- find and track poor adherence and help are particularly well documented for car- based approaches that improve the to guide system improvement efforts to diovascular disease. clinical outcomes and quality of life of pa- overcome the barriers to adherence. tients with diabetes. Recent reviews of Barriers to adherence may include pa- Ethnic/Cultural/Sex/Socioeconomic quality improvement strategies in diabe- tient factors (remembering to obtain Differences tes care (24,35,36) have not identified a or take medications, fears, depression, Ethnic, cultural, religious, and sex differ- particular approach that is more effective or health beliefs), medication factors ences and socioeconomic status may than others. However, the Translating Re- (complexity, multiple daily dosing, affect diabetes prevalence and out- search Into Action for Diabetes (TRIAD) cost, or side effects), and system factors comes. Type 2 diabetes develops more study provided objective data from large (inadequate follow-up or support). frequently in women with prior gesta- managed care systems demonstrating ef- tional diabetes mellitus (42), in individu- fective tools for specific targets (6). TRIAD Improving Adherence als with hypertension or dyslipidemia, found it useful to divide interventions into Simplifying a complex treatment regi- andincertainracial/ethnicgroups those that affected processes of care and men may improve adherence. Nurse- (African American, Native American, intermediate outcomes. directed interventions, home aides, Hispanic/Latino, and Asian American) (43). diabetes education, and pharmacy- Access to Health Care Processes of Care derived interventions improved ad- Ethnic, cultural, religious, sex, and socio- Processes of care included periodic test- herence but had a very small effect on economic differences affect health care ing of A1C, lipids, and urinary albumin; outcomes, including metabolic control accessandcomplicationriskinpeople examining the retina and feet; advising (41). Success in overcoming barriers on aspirin use; and smoking cessation. with diabetes. Recent studies have rec- may be achieved if the patient and pro- ommended lowering the BMI cut point TRIADresultssuggestthatproviders vider agree on a targeted treatment control these activities. Performance for testing for Asian Americans to $23 for a specific barrier. For example, one 2 feedback, reminders, and structured kg/m (44). Women with diabetes, com- study found that when depression was pared with men with diabetes, have a care (e.g., guidelines, formal case man- fi identi ed as a barrier, agreement on 40% greater risk of incident coronary agement, and patient education re- antidepressant treatment subsequently fl heart disease (45). Socioeconomic and sources) may in uence providers to allowed for improvements in A1C, improve processes of care (6). ethnic inequalities exist in the provision blood pressure, and lipid control (10). of health care to individuals with diabe- Intermediate Outcomes and Thus, to improve adherence, systems tes (46). As a result, children with type 1 Treatment Intensification should continually monitor and prevent diabetes from racial/ethnic populations For intermediate outcomes, such as or treat poor adherence by identifying with lower socioeconomic status are at A1C, blood pressure, and lipid goals, barriers and implementing treatments risk for poor metabolic control and poor fi tools that improved processes of care that are barrier speci c and effective. emotional functioning (47). Significant did not perform as well in addressing A systematic approach to achieving in- racial differences and barriers exist in barriers to treatment intensification termediate outcomes involves three steps: self-monitoring and outcomes (48). and adherence (6). In 35% of cases, un- Assess adherence. controlled A1C, blood pressure, or lipids 1. Adherence should Addressing Disparities fi were associated with a lack of treatment be addressed as the rst priority. If Therefore, diabetes management re- intensification, defined as a failure to adherence is 80% or above, then treat- quires individualized, patient-centered, fi either increase a drug dose or change a ment intensi cation should be consid- and culturally appropriate strategies. To drug class (37). Treatment intensifica- ered (e.g., up-titration). If medication overcome disparities, community health tion was associated with improvement up-titration is not a viable option, then workers (49), peers (50,51), and lay lead- in A1C, hypertension, and hyperlipid- consider initiating or changing to a dif- ers (52) may assist in the delivery of emia control (38). A large multicenter ferent medication class. DSME and diabetes self-management Explore barriers study confirmed the strong association 2. to adherence with support services (53). Strong social sup- fi between treatment intensification and the patient/caregiver and nd a mutu- port leads to improved clinical outcomes, improved A1C (39). ally agreeable approach to overcom- reduced psychosocial symptomatology, ing the barriers. and adoption of healthier lifestyles (54). Intermediate Outcomes and 3. Establish a follow-up plan that con- Structured interventions, tailored to eth- Adherence firms the planned treatment change nic populations that integrate culture, In 23% of cases, poor adherence was and assess progress in reaching the language, religion, and literacy skills, pos- associated with uncontrolled A1C, blood target. itively influence patient outcomes (55). care.diabetesjournals.org Strategies for Improving Care S9

To decrease disparities, all providers and Providers should recognize that FI com- Additionally, homeless patients with dia- groups are encouraged to use the National plicates diabetes management and seek betes need secure places to keep their Quality Forum’s National Voluntary Con- local resources that can help patients and diabetes supplies and refrigerator access sensus Standards for Ambulatory Cared the parents of patients with diabetes to to properly store their insulin. Measuring Healthcare Disparities (56). more regularly obtain nutritious food (59). Literacy and Numeracy Deficiencies. FI and Lack of Health Insurance Food Insecurity and Hyperglycemia. Hy- diabetes are more common among non- Not having health insurance affects the perglycemia is more common in those English speaking individuals and those processes and outcomes of diabetes with diabetes and FI. Reasons for this with poor literacy and numeracy skills. care. Individuals without insurance include the steady consumption of Therefore, it is important to consider coverage for blood glucose monitoring carbohydrate-rich processed foods, screening for FI, proper housing, and di- supplies have a 0.5% higher A1C than binge eating, not filling antidiabetes med- abetes in this population. Programs that those with coverage (57). The afford- ication prescriptions owing to financial see such patients should work to develop able care act has improved access to constraint, and anxiety/depression that services in multiple languages with the fi health care; however, many remain lead to poor diabetes self-care behaviors. speci c goal of preventing diabetes and without coverage. In a recent study of Providers should be well versed in these building diabetes awareness in people predominantly African American or risk factors for hyperglycemia and take who cannot easily read or write in English. Hispanic uninsured patients with dia- practical steps to alleviate them in order Cognitive Dysfunction betes, 50–60% were hypertensive, but to improve glucose control. only 22–37% had systolic blood pres- Recommendations Food Insecurity and Hypoglycemia sure controlled by treatments to under c Intensive glucose control is not ad- 130 mmHg (58). Type 1 Diabetes. Individuals with type 1 vised for the improvement of poor diabetes and FI may develop hypoglycemia cognitive function in hyperglycemic Food Insecurity as a result of inadequate or erratic carbo- individuals with type 2 diabetes. B Recommendations hydrate consumption following insulin c In individuals with poor cognitive c Providers should evaluate hyper- administration. Long-acting insulin, as op- function or severe hypoglycemia, glycemia and hypoglycemia in the posed to shorter-acting insulin that may glycemic therapy should be tailored context of food insecurity and pro- peak when food is not available, may to avoid significant hypoglycemia. C pose solutions accordingly. A lowertheriskforhypoglycemiainthose c In individuals with diabetes at high c Providers should recognize that with FI. Short-acting insulin analogs, cardiovascular risk, the cardiovascular homelessness, poor literacy, and preferably delivered by a pen, may be benefits of statin therapy outweigh poor numeracy often occur with used immediately after consumption the risk of cognitive dysfunction. A food insecurity, and appropriate of a meal, whenever food becomes c If a second-generation antipsychotic resources should be made avail- available. Unfortunately, the greater medication is prescribed, changes in able for patients with diabetes. A cost of insulin analogs should be weighed weight, glycemic control, and cho- against their potential advantages. Caring lesterol levels should be carefully Food insecurity (FI) is the unreliable for those with type 1 diabetes in the set- monitored and the treatment regi- availability of nutritious food and the ting of FI may mirror “sick day” manage- men should be reassessed. C inability to consistently obtain food ment protocols. without resorting to socially unaccept- Dementia Type 2 Diabetes. Those with type 2 diabe- able practices. Over 14% (or one out of The most severe form of cognitive tes and FI can develop hypoglycemia for every seven people in the U.S.) are food dysfunction is dementia. A recent meta- similar reasons after taking certain oral insecure. The rate is higher in some analysis of prospective observational stud- hypoglycemic agents. If using a sulfonyl- racial/ethnic minority groups including iesinpeoplewithdiabetesshoweda73% urea, glipizide is the preferred choice African American and Latino popula- increased risk of all types of dementia, a due to the shorter half-life. Glipizide tions, in low-income households, and 56% increased risk of Alzheimer dementia, can be taken immediately before meal in homes headed by a single mother. FI and 127% increased risk of vascular de- may involve a tradeoff between purchas- consumption, thus limiting its tendency mentia compared with individuals without ing nutritious food for inexpensive and to produce hypoglycemia as compared diabetes (60). The reverse is also true: peo- more energy- and carbohydrate-dense with longer-acting sulfonylureas (e.g., ple with Alzheimer dementia are more processed foods. glyburide). likely to develop diabetes than people In people with FI, interventions should Homelessness. Homelessness often ac- without Alzheimer dementia. focus on preventing diabetes and, in companies the most severe form of FI. Hyperglycemia. In those with type 2 those with diabetes, limiting hyperglyce- Therefore, providers who care for those diabetes, the degree and duration of mia and preventing hypoglycemia. The with FI who are uninsured and homeless hyperglycemia are related to dementia. risk for type 2 diabetes is increased two- and individuals with poor literacy and nu- More rapid cognitive decline is associated fold in those with FI. The risks of uncontrolled meracy should be well versed or have with both increased A1C and longer du- hyperglycemia and severe hypoglycemia access to social workers to facilitate tem- ration of diabetes (61). The Action to are increased in those with diabetes who porary housing for their patients as a Control Cardiovascular Risk in Diabetes are also food insecure. means to prevent and control diabetes. (ACCORD) study found that each 1% S10 Strategies for Improving Care Diabetes Care Volume 39, Supplement 1, January 2016

higher A1C level was associated with analysis showed a significantly increased progression toward diabetes. Among lower cognitive function in individuals risk of incident depression (relative risk HIV patients with diabetes, preventive with type 2 diabetes (62). However, the [RR] 5 1.15), and, in turn, depression was health care using an approach similar ACCORD study found no difference in associated with a significantly increased to that used in patients without HIV is cognitive outcomes between intensive risk of diabetes (RR 5 1.6) (71). Depression critical to reduce the risks of microvas- and standard glycemic control, support- and psychosocial issues are discussed cular and macrovascular complications. ing the recommendation that intensive more extensively in Section 3 “Founda- For patients with HIV and ARV- glucose control should not be advised for tions of Care and Comprehensive Medical associated hyperglycemia, it may be the improvement of cognitive function in Evaluation.” appropriate to consider discontinuing individuals with type 2 diabetes (63). the problematic ARV agents if safe and Medications effective alternatives are available (76). Hypoglycemia. In type 2 diabetes, severe Diabetes medications are effective, re- Before making ARV substitutions, carefully hypoglycemia is associated with reduced gardless of mental health status. Treat- cognitive function, and those with poor consider the possible effect on HIV viro- ments for depression are effective in logical control and the potential adverse cognitive function have more severe hy- patients with diabetes, and treating de- poglycemia. In a long-term study of older effects of new ARV agents. In some cases, pression may improve short-term glyce- antidiabetes agents may still be necessary. patients with type 2 diabetes, individuals mic control (72). If a second-generation with one or more recorded episode of antipsychotic medication is prescribed, References severe hypoglycemia had a stepwise in- changes in weight, glycemic control, and 1. Grant RW, Kirkman MS. Trends in the evi- crease in risk of dementia (64). Likewise, cholesterol levels should be carefully dence level for the American Diabetes Associa- the ACCORD trial found that as cognitive monitored and the treatment regimen tion’s “Standards of Medical Care in Diabetes” – function decreased, the risk of severe hy- should be reassessed if significant changes from 2005 to 2014. Diabetes Care 2015;38:6 8 poglycemia increased (65). Tailoring gly- 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, are noted (73). Awareness of an individu- Imperatore G, Gregg EW. Achievement of goals cemic therapy may help to prevent al’s medication profile, especially if an in- hypoglycemia in individuals with cogni- in U.S. diabetes care, 1999-2010. N Engl J Med dividual takes psychotropic medications, is 2013;368:1613–1624 tive dysfunction. key to effective management. 3. Wang J, Geiss LS, Cheng YJ, et al. Long-term Nutrition. In one study, adherence to the and recent progress in blood pressure levels Mediterranean diet correlated with im- Diabetes Care in Patients With HIV among U.S. adults with diagnosed diabetes, 1988-2008. Diabetes Care 2011;34:1579–1581 proved cognitive function (66). However, Recommendation 4. Kerr EA, Heisler M, Krein SL, et al. Beyond fi a recent Cochrane review found insuf - c Patients with HIV should be screened comorbidity counts: how do comorbidity type cient evidence to recommend any dietary for diabetes and prediabetes with a and severity influence diabetes patients’ treat- change for the prevention or treatment of fasting glucose level before starting ment priorities and self-management? J Gen cognitive dysfunction (67). Intern Med 2007;22:1635–1640 antiretroviral therapy and 3 months 5. Fernandez A, Schillinger D, Warton EM, et al. Statins. Given the controversy over a po- after starting or changing it. If initial Language barriers, physician-patient language tential link between statins and demen- screening results are normal, check- concordance, and glycemic control among in- tia, it is worth noting that a Cochrane ing fasting glucose each year is ad- sured Latinos with diabetes: the Diabetes Study systematic review has reported that data vised. If prediabetes is detected, of Northern California (DISTANCE). J Gen Intern – do not support an adverse effect of sta- continue to measure levels every Med 2011;26:170 176 – 6. TRIAD Study Group. Health systems, patients tins on cognition. The U.S. Food and Drug 3 6 months to monitor for pro- factors, and quality of care for diabetes: a syn- E Administration (FDA) postmarketing sur- gression to diabetes. thesis of findings from the TRIAD study. Diabe- veillance databases have also revealed a tes Care 2010;33:940–947 low reporting rate for cognitive-related Diabetes risk is increased with certain 7. Stellefson M, Dipnarine K, Stopka C. The adverse events, including cognitive dys- protease inhibitors (PIs) and nucleoside Chronic Care Model and diabetes management in US primary care settings: a systematic review. function or dementia, with statin therapy, reverse transcriptase inhibitors (NRTIs). New-onset diabetes is estimated to occur Prev Chronic Dis 2013;10:E26 similar to rates seen with other com- 8. Coleman K, Austin BT, Brach C, Wagner EH. monly prescribed cardiovascular medica- in more than 5% of HIV-infected patients Evidence on the Chronic Care Model in the tions (68). Therefore individuals with on PIs, whereas more than 15% may have new millennium. Health Aff (Millwood) 2009; diabetes and a high risk for cardiovascular prediabetes (74). PIs are associated with 28:75–85 disease should be placed on statin ther- insulin resistance and may also lead to 9. Piatt GA, Anderson RM, Brooks MM, et al. 3-year follow-up of clinical and behavioral apy regardless of cognitive status. apoptosis of pancreatic b-cells. NRTIs also affect fat distribution (both lipohy- improvements following a multifaceted diabetes care intervention: results of a randomized con- Mental Illness pertrophy and lipoatrophy), which is as- trolled trial. Diabetes Educ 2010;36:301–309 Severe mental disorder that includes sociated with insulin resistance. 10. Katon WJ, Lin EHB, Von Korff M, et al. Col- schizophrenia, bipolar disorder, and de- Individuals with HIV are at higher risk laborative care for patients with depression and pression is increased 1.7-fold in people for developing prediabetes and diabetes chronic illnesses. N Engl J Med 2010;363:2611– with diabetes (69). The prevalence of on antiretroviral (ARV) therapies, so a 2620 11. Parchman ML, Zeber JE, Romero RR, Pugh type 2 diabetes is two–three times higher proper screening protocol is recom- JA. Risk of coronary artery disease in type 2 di- in people with schizophrenia, bipolar dis- mended (75). In those with prediabetes, abetes and the delivery of care consistent with order, and schizoaffective disorder than weight loss through healthy nutrition the chronic care model in primary care settings: in the general population (70). A meta- and physical activity may reduce the a STARNet study. Med Care 2007;45:1129–1134 care.diabetesjournals.org Strategies for Improving Care S11

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Curr ment of the American Diabetes Association, the Saf 2014;23:699–710 Diab Rep 2012;12:769–781 American Association of Diabetes Educators, 40. Raebel MA, Schmittdiel J, Karter AJ, 55. Zeh P, Sandhu HK, Cannaby AM, Sturt JA. and the Academy of Nutrition and Dietetics. Di- Konieczny JL, Steiner JF. Standardizing terminol- The impact of culturally competent diabetes abetes Care 2015;38:1372–1382 ogy and definitions of medication adherence and care interventions for improving diabetes- 24. Tricco AC, Ivers NM, Grimshaw JM, et al. persistence in research employing electronic da- related outcomes in ethnic minority groups: a Effectiveness of quality improvement strategies tabases. Med Care 2013;51(Suppl. 3):S11–S21 systematic review. Diabet Med 2012;29:1237– on the management of diabetes: a systematic 41. Vermeire E, Wens J, Van Royen P, Biot Y, 1252 review and meta-analysis. Lancet 2012;379: Hearnshaw H, Lindenmeyer A. Interventions 56. National Quality Forum. National Voluntary 2252–2261 for improving adherence to treatment recom- Consensus Standards for Ambulatory Cared 25. Peikes D, Chen A, Schore J, Brown R. Effects mendations in people with type 2 diabetes mel- Measuring Healthcare Disparities [Internet], of care coordination on hospitalization, quality litus. Cochrane Database Syst Rev 2005;2: 2008. Available from https://www.qualityforum of care, and health care expenditures among CD003638 .org/Publications/2008/03/National_Voluntary_ Medicare beneficiaries: 15 randomized trials. 42. Kim C, Newton KM, Knopp RH. Gestational Consensus_Standards_for_Ambulatory_Care% JAMA 2009;301:603–618 diabetes and the incidence of type 2 diabetes: a E2%80%94Measuring_Healthcare_Disparities 26. Feifer C, Nemeth L, Nietert PJ, et al. Differ- systematic review. Diabetes Care 2002;25: .aspx. Accessed 2 September 2015 ent paths to high-quality care: three archetypes 1862–1868 57. Bowker SL, Mitchell CG, Majumdar SR, Toth of top-performing practice sites. Ann Fam Med 43. Hutchinson RN, Shin S. Systematic review of EL, Johnson JA. Lack of insurance coverage for 2007;5:233–241 health disparities for cardiovascular diseases testing supplies is associated with poorer S12 Strategies for Improving Care Diabetes Care Volume 39, Supplement 1, January 2016

glycemic control in patients with type 2 diabe- 64. Whitmer RA, Karter AJ, Yaffe K, Quesenberry depression and bipolar disorder. World Psychi- tes. CMAJ 2004;171:39–43 CP Jr, Selby JV. Hypoglycemic episodes and risk of atry 2015;14:119–136 58. Baumann LC, Chang M-W, Hoebeke R. Clinical dementia in older patients with type 2 diabetes 71. Mezuk B, Eaton WW, Albrecht S, Golden SH. outcomes for low-income adults with hyperten- mellitus. JAMA 2009;301:1565–1572 Depression and type 2 diabetes over the lifespan: a sion and diabetes. Nurs Res 2002;51:191–198 65. Punthakee Z, Miller ME, Launer LJ, et al.; meta-analysis. Diabetes Care 2008;31:2383–2390 59. Seligman HK, Schillinger D. Hunger and so- ACCORD Group of Investigators; ACCORD- 72. Baumeister H, Hutter N, Bengel J. Psycho- cioeconomic disparities in chronic disease. N MIND Investigators. Poor cognitive function logical and pharmacological interventions for Engl J Med 2010;363:6–9 and risk of severe hypoglycemia in type 2 dia- depression in patients with diabetes mellitus 60. Gudala K, Bansal D, Schifano F, Bhansali A. betes: post hoc epidemiologic analysis of the and depression. Cochrane Database Syst Rev Diabetes mellitus and risk of dementia: a meta- ACCORD trial. Diabetes Care 2012;35:787–793 2012;12:CD008381 analysis of prospective observational studies. J 66. Scarmeas N, Stern Y, Mayeux R, Manly JJ, 73. American Diabetes Association; American Diabetes Investig 2013;4:640–650 Schupf N, Luchsinger JA. Mediterranean diet Psychiatric Association; American Association 61. Rawlings AM, Sharrett AR, Schneider AL, and mild cognitive impairment. Arch Neurol of Clinical Endocrinologists; North American As- – et al. Diabetes in midlife and cognitive change 2009;66:216 225 sociation for the Study of Obesity. Consensus over 20 years: a cohort study. Ann Intern Med 67. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Car- development conference on antipsychotic bohydrates for improving the cognitive per- drugs and obesity and diabetes. Diabetes Care 2014;161:785–793 formance of independent-living older adults 2004;27:596–601 62. Cukierman-Yaffe T, Gerstein HC, Williamson with normal cognition or mild cognitive impair- 74. Dube´ MP. Disorders of glucose metabo- JD, et al.; Action to Control Cardiovascular Risk ment. Cochrane Database Syst Rev 2011;4: lism in patients infected with human immuno- in Diabetes-Memory in Diabetes (ACCORD- CD007220 deﬁciency virus. Clin Infect Dis 2000;31: MIND) Investigators. Relationship between 68. Richardson K, Schoen M, French B, et al. 1467–1475 baseline glycemic control and cognitive func- Statins and cognitive function: a systematic re- 75. Schambelan M, Benson CA, Carr A, et al.; tion in individuals with type 2 diabetes and view. Ann Intern Med 2013;159:688–697 International AIDS Society-USA. Management other cardiovascular risk factors: the action to 69. Osborn DPJ, Wright CA, Levy G, King MB, of metabolic complications associated with control cardiovascular risk in diabetes-memory Deo R, Nazareth I. Relative risk of diabetes, dys- antiretroviral therapy for HIV-1 infection: rec- in diabetes (ACCORD-MIND) trial. Diabetes lipidaemia, hypertension and the metabolic syn- ommendations of an International AIDS Society- Care 2009;32:221–226 drome in people with severe mental illnesses: USA panel. J Acquir Immune Deﬁc Syndr 2002;31: 63. Launer LJ, Miller ME, Williamson JD, et al.; systematic review and metaanalysis. BMC Psy- 257–275 ACCORD MIND investigators. Effects of intensive chiatry 2008;8:84 76. Wohl DA, McComsey G, Tebas P, et al. glucose lowering on brain structure and function 70. Correll CU, Detraux J, De Lepeleire J, De Current concepts in the diagnosis and man- in people with type 2 diabetes (ACCORD MIND): a Hert M. Effects of antipsychotics, antidepres- agement of metabolic complications of HIV randomised open-label substudy. Lancet Neurol sants and mood stabilizers on risk for physi- infection and its therapy. Clin Infect Dis 2011;10:969–977 cal diseases in people with schizophrenia, 2006;43:645–653 Diabetes Care Volume 39, Supplement 1, January 2016 S13

2. Classiﬁcation and Diagnosis of American Diabetes Association Diabetes Diabetes Care 2016;39(Suppl. 1):S13–S22 | DOI: 10.2337/dc16-S005

CLASSIFICATION Diabetes can be classiﬁed into the following general categories:

1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin deficiency) DIABETES OF DIAGNOSIS AND CLASSIFICATION 2. 2. Type 2 diabetes (due to a progressive loss of insulin secretion on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS or after organ transplantation)

This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position statement “Diagnosis and Classification of Diabetes Mellitus” (1). Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, patients with type 2 diabetes may present with diabetic ketoacidosis (DKA). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia and approximately one-third with DKA (2). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in children. Although difficulties in distinguishing diabetes type may occur in all age- groups at onset, the true diagnosis becomes more obvious over time. DIAGNOSTIC TESTS FOR DIABETES Diabetes may be diagnosed based on the plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT) or the A1C criteria (1,3) (Table 2.1). The same tests are used to screen for and diagnose diabetes and to detect individuals with prediabetes. Diabetes may be identified anywhere along the spectrum of clinical scenarios: in seemingly low-risk individuals who happen to have glucose testing, in individuals tested based on diabetes risk assessment, and in symptomatic patients. Fasting and 2-Hour Plasma Glucose Table 2.1 Suggested citation: American Diabetes Associa- The FPG and 2-h PG may be used to diagnose diabetes ( ). The concordance tion. Classification and diagnosis of diabetes. between the FPG and 2-h PG tests is imperfect, as is the concordance between A1C Sec. 2. In Standards of Medical Care in and either glucose-based test. Numerous studies have confirmed that, compared Diabetesd2016. Diabetes Care 2016;39(Suppl. 1): with FPG cut points and A1C, the 2-h PG value diagnoses more people with diabetes. S13–S22 © 2016 by the American Diabetes Association. A1C Readers may use this article as long as the work The A1C test should be performed using a method that is certified by the NGSP is properly cited, the use is educational and not (www.ngsp.org) and standardized or traceable to the Diabetes Control and for profit, and the work is not altered. S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.1—Criteria for the diagnosis of diabetes the test result that is above the diagnos- FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* tic cut point should be repeated. The diagnosis is made on the basis of the OR confirmed test. For example, if a patient 2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in meets the diabetes criterion of the A1C water.* (two results $6.5% [48 mmol/mol]) but not OR FPG (,126 mg/dL [7.0 mmol/L]), that A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is person should nevertheless be consid- NGSP certified and standardized to the DCCT assay.* ered to have diabetes. OR Since all the tests have preanalytic and In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma analytic variability, it is possible that an glucose $200 mg/dL (11.1 mmol/L). abnormal result (i.e., above the diagnostic *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. threshold), when repeated, will produce a value below the diagnostic cut point. This scenario is least likely for A1C, more likely Complications Trial (DCCT) reference as- of fructosamine and glycated albumin and for FPG, and most likely for the 2-h PG, say. Although point-of-care A1C assays lower levels of 1,5-anhydroglucitol, sug- especially if the glucose samples remain may be NGSP certified, proficiency testing gesting that their glycemic burden (partic- at room temperature and are not centri- is not mandated for performing the test, ularly postprandially) may be higher (8). fuged promptly. Barring laboratory error, so use of point-of-care assays for diagnos- Moreover, the association of A1C with such patients will likely have test results tic purposes is not recommended. risk for complications is similar in African near the margins of the diagnostic thresh- The A1C has several advantages com- Americans and non-Hispanic whites (9). old. The health care professional should pared with the FPG and OGTT, including follow the patient closely and repeat the Hemoglobinopathies/Anemias test in 3–6 months. greater convenience (fasting not re- Interpreting A1C levels in the presence of quired), greater preanalytical stability, certain hemoglobinopathies and anemia CATEGORIES OF INCREASED RISK and less day-to-day perturbations during may be problematic. For patients with an FOR DIABETES (PREDIABETES) stress and illness. However, these advan- abnormal hemoglobin but normal red blood tages may be offset by the lower sensitiv- cell turnover, such as those with the sickle Recommendations c ity of A1C at the designated cut point, cell trait, an A1C assay without interference Testing to assess risk for future di- greater cost, limited availability of A1C from abnormal hemoglobins should be abetes in asymptomatic people testing in certain regions of the develop- used. An updated list of interferences is should be considered in adults of ing world, and the imperfect correlation available at www.ngsp.org/interf.asp. any age who are overweight or between A1C and average glucose in cer- obese (BMI $25 kg/m2 or $23 tain individuals. National Health and Red Blood Cell Turnover kg/m2 in Asian Americans) and Nutrition Examination Survey (NHANES) In conditions associated with increased who have one or more additional data indicate that an A1C cut point of red blood cell turnover, such as pregnancy risk factors for diabetes. B $6.5% (48 mmol/mol) identifies one- (second and third trimesters), recent blood c For all patients, testing should begin third fewer cases of undiagnosed diabe- loss or transfusion, erythropoietin therapy, at age 45 years. B tes than a fasting glucose cut point of or hemolysis, only blood glucose criteria c If tests are normal, repeat testing $126 mg/dL (7.0 mmol/L) (4). should be used to diagnose diabetes. carried out at a minimum of 3-year It is important to take age, race/ intervals is reasonable. C ethnicity, and anemia/hemoglobinop- Confirming the Diagnosis c To test for prediabetes, fasting athies into consideration when using Unless there is a clear clinical diagnosis plasma glucose, 2-h plasma glucose the A1C to diagnose diabetes. (e.g., patient in a hyperglycemic crisis or after 75-g oral glucose tolerance test, with classic symptoms of hyperglycemia and A1C are equally appropriate. B Age and a random plasma glucose $200 c The epidemiological studies that formed In patients with prediabetes, iden- mg/dL [11.1 mmol/L]), a second test is re- the basis for recommending A1C to di- tify and, if appropriate, treat other quired for confirmation. It is recom- B agnose diabetes included only adult cardiovascular disease risk factors. mended that the same test be repeated c populations. Therefore, it remains un- Testing to detect prediabetes should without delay using a new blood sample clear if A1C and the same A1C cut point be considered in children and ado- for confirmation because there will be a should be used to diagnose diabetes in lescents who are overweight or greater likelihood of concurrence. For ex- children and adolescents (4,5). obese and who have two or more ample, if the A1C is 7.0% (53 mmol/mol) additional risk factors for diabetes. E Race/Ethnicity and a repeat result is 6.8% (51 mmol/mol), A1C levels may vary with patients’ race/ the diagnosis of diabetes is confirmed. If ethnicity (6,7). For example, African Amer- two different tests (such as A1C and FPG) Description icans may have higher A1C levels than are both above the diagnostic threshold, In 1997 and 2003, the Expert Committee non-Hispanic whites despite similar fast- this also confirms the diagnosis. On the on the Diagnosis and Classification of Di- ing and postglucose load glucose levels. other hand, if a patient has discordant abetes Mellitus (10,11) recognized a African Americans also have higher levels results from two different tests, then group of individuals whose glucose care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

levels did not meet the criteria for di- Hence, it is reasonable to consider an islet cell autoantibodies and autoanti- abetes but were too high to be consid- A1C range of 5.7–6.4% (39–46 mmol/mol) bodies to insulin, GAD (GAD65), the ty- ered normal. “Prediabetes” is the term as identifying individuals with prediabe- rosine phosphatases IA-2 and IA-2b, and used for individuals with impaired fast- tes. As with those with IFG and/or IGT, ZnT8. Type 1 diabetes is defined by one ing glucose (IFG) and/or impaired glu- individuals with an A1C of 5.7–6.4% or more of these autoimmune markers. cose tolerance (IGT) and indicates an (39–46 mmol/mol) should be informed The disease has strong HLA associations, increased risk for the future develop- of their increased risk for diabetes and with linkage to the DQA and DQB genes. ment of diabetes. IFG and IGT should CVD and counseled about effective strate- These HLA-DR/DQ alleles can be either not be viewed as clinical entities in their gies to lower their risks (see Section 4 “Pre- predisposing or protective. own right but rather risk factors for di- vention or Delay of Type 2 Diabetes”). Therateofb-cell destruction is quite abetes (Table 2.2) and cardiovascular Similar to glucose measurements, the con- variable, being rapid in some individu- disease (CVD). IFG and IGT are associ- tinuum of risk is curvilinear, so as A1C rises, als (mainly infants and children) and ated with obesity (especially abdominal the diabetes risk rises disproportionately slow in others (mainly adults). Children or visceral obesity), dyslipidemia with (12). Aggressive interventions and vigilant and adolescents may present with ke- high triglycerides and/or low HDL cho- follow-up should be pursued for those toacidosis as the first manifestation of lesterol, and hypertension. considered at very high risk (e.g., those the disease. Others have modest fast- with A1C .6.0% [42 mmol/mol]). ing hyperglycemia that can rapidly Diagnosis Table 2.3 summarizes the categories change to severe hyperglycemia and/or In 1997 and 2003, the Expert Committee of prediabetes and Table 2.2 the criteria ketoacidosis with infection or other on the Diagnosis and Classification of Di- for prediabetes testing. For recommen- stress. Adults may retain sufficient b-cell abetes Mellitus (10,11) defined IFG as dations regarding risk factors and function to prevent ketoacidosis for FPG levels 100–125 mg/dL (5.6–6.9 screening for prediabetes, see pp. S17– many years; such individuals eventually mmol/L) and IGT as 2-h PG after 75-g S18 (“Testing for Type 2 Diabetes and Pre- become dependent on insulin for survival OGTT levels 140–199 mg/dL (7.8–11.0 diabetes in Asymptomatic Adults” and and are at risk for ketoacidosis. At this mmol/L). It should be noted that the “Testing for Type 2 Diabetes and Pre- latter stage of the disease, there is little World Health Organization (WHO) and diabetes in Children and Adolescents”). or no insulin secretion, as manifested by numerous diabetes organizations define low or undetectable levels of plasma C- TYPE 1 DIABETES the IFG cutoff at 110 mg/dL (6.1 mmol/L). peptide. Immune-mediated diabetes As with the glucose measures, several Recommendations commonly occurs in childhood and ado- prospective studies that used A1C to c Blood glucose rather than A1C should lescence, but it can occur at any age, even predict the progression to diabetes be used to diagnose acute onset of in the 8th and 9th decades of life. demonstrated a strong, continuous as- type 1 diabetes in individuals with Autoimmune destruction of b-cells sociation between A1C and subsequent symptoms of hyperglycemia. E has multiple genetic predispositions diabetes. In a systematic review of c Inform the relatives of patients with and is also related to environmental fac- 44,203 individuals from 16 cohort stud- type 1 diabetes of the opportunity tors that are still poorly defined. Al- ies with a follow-up interval averaging to be tested for type 1 diabetes risk, though patients are not typically obese 5.6 years (range 2.8–12 years), those but only in the setting of a clinical when they present with type 1 diabetes, with an A1C between 5.5–6.0% (37–42 research study. E obesity should not preclude the diagno- mmol/mol) had a substantially in- sis. These patients are also prone to creased risk of diabetes (5-year inci- other autoimmune disorders such as Diagnosis dence from 9% to 25%). An A1C range Hashimoto thyroiditis, celiac disease, In a patient with acute symptoms, mea- of 6.0–6.5% (42–48 mmol/mol) had a Graves disease, Addison disease, viti- surement of blood glucose is part of the 5-year risk of developing diabetes be- ligo, autoimmune hepatitis, myasthenia definition of diabetes (classic symptoms of tween25%and50%andarelative gravis, and pernicious anemia. hyperglycemia or hyperglycemic crisis plus risk 20 times higher compared with an a random plasma glucose $200 mg/dL A1C of 5.0% (31 mmol/mol) (12). In a Idiopathic Type 1 Diabetes [11.1 mmol/L]). In these cases, knowing community-based study of African Some forms of type 1 diabetes have no the blood glucose level is critical because, American and non-Hispanic white adults known etiologies. These patients have in addition to confirming that symptoms without diabetes, baseline A1C was a permanent insulinopenia and are prone are due to diabetes, this will inform man- stronger predictor of subsequent diabe- to ketoacidosis, but have no evidence of agement decisions. Some providers may tes and cardiovascular events than fast- b-cell autoimmunity. Although only a also want to know the A1C to determine ing glucose (13). Other analyses suggest minority of patients with type 1 diabetes how long a patient has had hyperglycemia. that an A1C of 5.7% (39 mmol/mol) is fall into this category, of those who do, associated with a diabetes risk similar Immune-Mediated Diabetes most are of African or Asian ancestry. to that of the high-risk participants in This form, previously called “insulin- Individuals with this form of diabetes the Diabetes Prevention Program (DPP) dependent diabetes” or “juvenile-onset suffer from episodic ketoacidosis and (14), and A1C at baseline was a strong diabetes,” accounts for 5–10% of diabe- exhibit varying degrees of insulin defi- predictor of the development of glucose- tes and is due to cellular-mediated auto- ciency between episodes. This form of defined diabetes during the DPP and its immune destruction of the pancreatic diabetes is strongly inherited and is not follow-up (15). b-cells. Autoimmune markers include HLA associated. An absolute requirement S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.2—Criteria for testing for diabetes or prediabetes in asymptomatic adults being conducted to test various meth- 1. Testing should be considered in all adults who are overweight (BMI $25 kg/m2 or $23 kg/m2 in ods of preventing type 1 diabetes in Asian Americans) and have additional risk factors: those with evidence of autoimmunity c physical inactivity (www.clinicaltrials.gov). c first-degree relative with diabetes c high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, TYPE 2 DIABETES Pacific Islander) c women who delivered a baby weighing .9 lb or were diagnosed with GDM Recommendations c hypertension ($140/90 mmHg or on therapy for hypertension) c Testing to detect type 2 diabetes in c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL asymptomatic people should be con- (2.82 mmol/L) sidered in adults of any age who are c women with polycystic ovary syndrome overweight or obese (BMI $25 c $ A1C 5.7% (39 mmol/mol), IGT, or IFG on previous testing 2 $ 2 c other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis kg/m or 23 kg/m in Asian Amer- nigricans) icans) and who have one or more c history of CVD additional risk factors for diabetes. B 2. For all patients, testing should begin at age 45 years. c For all patients, testing should be- 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with gin at age 45 years. B consideration of more frequent testing depending on initial results (e.g., those with c If tests are normal, repeat testing prediabetes should be tested yearly) and risk status. carried out at a minimum of 3-year intervals is reasonable. C c To test for type 2 diabetes, fasting for insulin replacement therapy in af- type 1 diabetes within 10 years and 84% plasma glucose, 2-h plasma glucose fected patients may be intermittent. within 15 years (19,20). These findings are after 75-g oral glucose tolerance test, highly significant because, while the and A1C are equally appropriate. B Testing for Type 1 Diabetes Risk German group was recruited from off- c In patients with diabetes, identify The incidence and prevalence of type 1 spring of parents with type 1 diabetes, and, if appropriate, treat other car- diabetes is increasing (16). Patients with the Finnish and American groups were diovascular disease risk factors. B type 1 diabetes often present with acute recruited from the general population. c Testing to detect type 2 diabetes symptoms of diabetes and markedly el- Remarkably, the findings in all three should be considered in children evated blood glucose levels, and ap- groups were the same, suggesting that andadolescentswhoareoverweight proximately one-third are diagnosed the same sequence of events led to clin- or obese and who have two or more with life-threatening ketoacidosis (2). ical disease in both “sporadic” and famil- additional risk factors for diabetes. E Several studies indicate that measuring ial cases of type 1 diabetes. islet autoantibodies in relatives of those Although there is currently a lack of Description with type 1 diabetes may identify individ- accepted screening programs, one Type 2 diabetes, previously referred to uals who are at risk for developing type 1 should consider referring relatives of as “non–insulin-dependent diabetes” or diabetes (17). Such testing, coupled with those with type 1 diabetes for antibody “adult-onset diabetes,” accounts for education about diabetes symptoms and testing for risk assessment in the setting 90–95% of all diabetes. This form en- close follow-up in an observational clini- of a clinical research study (http://www2 compasses individuals who have insulin fi cal study, may enable earlier identi ca- .diabetestrialnet.org). Widespread clini- resistance and usually relative (rather tion of type 1 diabetes onset (18). There cal testing of asymptomatic low-risk in- than absolute) insulin deficiency. At is evidence to suggest that early diagnosis dividuals is not currently recommended least initially, and often throughout may limit acute complications (19). due to lack of approved therapeutic in- their lifetime, these individuals may A recent study reported the risk of pro- terventions. Higher-risk individuals may not need insulin treatment to survive. gression to type 1 diabetes from the be tested, but only in the context of a There are various causes of type 2 di- time of seroconversion to autoantibody clinical research setting. Individuals abetes. Although the specific etiologies positivity in three pediatric cohorts from who test positive will be counseled are not known, autoimmune destruction Finland, Germany, and the U.S. Of the 585 about the risk of developing diabetes, of b-cells does not occur, and patients do children who developed more than two diabetes symptoms, and DKA preven- not have any of the other known causes autoantibodies, nearly 70% developed tion. Numerous clinical studies are of diabetes. Most, but not all, patients with type 2 diabetes are overweight or Table 2.3—Categories of increased risk for diabetes (prediabetes)* obese. Excess weight itself causes some FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) degree of insulin resistance. Patients who OR are not obese or overweight by traditional 2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) weight criteria may have an increased OR percentage of body fat distributed predominantly in the abdominal region. A1C 5.7–6.4% (39–46 mmol/mol) Ketoacidosis seldom occurs sponta- *For all three tests, risk is continuous, extending below the lower limit of the range and neously in type 2 diabetes; when seen, becoming disproportionately greater at the higher end of the range. it usually arises in association with the care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

stress of another illness such as infec- individuals to identify those with predi- (sensitivity of 80%) for nearly all Asian tion. Type 2 diabetes frequently goes abetes or diabetes might seem reason- American subgroups (with levels slightly undiagnosed for many years because hy- able, rigorous clinical trials to prove the lower for Japanese Americans). This perglycemia develops gradually and, at effectiveness of such screening have not makes a rounded cut point of 23 kg/m2 earlier stages, is often not severe enough been conducted and are unlikely to occur. practical. In determining a single BMI cut for the patient to notice the classic diabe- A large European randomized con- point, it is important to balance sensitivity tes symptoms. Nevertheless, even undi- trolled trial compared the impact of and specificity so as to provide a valuable agnosed patients are at increased risk of screening for diabetes and intensive screening tool without numerous false developing macrovascular and microvas- multifactorial intervention with that of positives. An argument can be made to cular complications. screening and routine care (22). General push the BMI cut point to lower than Whereas patients with type 2 diabetes practice patients between the ages of 23 kg/m2 in favor of increased sensitivity; may have insulin levels that appear nor- 40–69 years were screened for diabetes however, this would lead to an unaccept- mal or elevated, the higher blood glucose and randomly assigned by practice to ably low specificity (13.1%). Data from the levels in these patients would be expected intensive treatment of multiple risk fac- WHO also suggest that a BMI $23 kg/m2 to result in even higher insulin values had tors or routine diabetes care. After 5.3 should be used to define increased risk their b-cell function been normal. Thus, years of follow-up, CVD risk factors were in Asian Americans (27). The finding insulin secretion is defective in these pa- modestly but significantly improved that half of diabetes in Asian Americans tients and insufficient to compensate for with intensive treatment compared is undiagnosed suggests that testing is not insulin resistance. Insulin resistance may with routine care, but the incidence of occurring at lower BMI thresholds (21). improve with weight reduction and/or first CVD events or mortality was not Evidence also suggests that other pharmacological treatment of hypergly- significantly different between the populations may benefitfromlower cemia but is seldom restored to normal. groups (22). The excellent care provided BMI cut points. For example, in a large The risk of developing type 2 diabetes to patients in the routine care group and multiethnic cohort study, for an equiva- increases with age, obesity, and lack of the lack of an unscreened control arm lent incidence rate of diabetes, a BMI of physical activity. It occurs more fre- limited the authors’ ability to prove that 30 kg/m2 in non-Hispanic whites was quently in women with prior GDM, in screening and early intensive treatment equivalent to a BMI of 26 kg/m2 in Afri- those with hypertension or dyslipidemia, impact outcomes. Mathematical model- can Americans (28). and in certain racial/ethnic subgroups ing studies suggest that major benefits (African American, American Indian, are likely to accrue from the early diag- Medications Certain medications, such as glucocorti- Hispanic/Latino, and Asian American). It nosis and treatment of glycemia and car- coids, thiazide diuretics, and atypical an- is often associated with a strong genetic diovascular risk factors in type 2 diabetes tipsychotics (29), are known to increase predisposition, more so than type 1 dia- (23); moreover, screening, beginning at the risk of diabetes and should be con- betes. However, the genetics of type 2 age 30 or 45 years and independent sidered when ascertaining a diagnosis. diabetes is poorly understood. of risk factors, may be cost-effective (,$11,000 per quality-adjusted life- Diagnostic Tests Testing for Type 2 Diabetes and year gained) (24). FPG, 2-h PG after 75-g OGTT, and A1C Prediabetes in Asymptomatic Adults Additional considerations regarding are equally appropriate for testing.It Prediabetes and type 2 diabetes meet cri- testing for type 2 diabetes and predia- should be noted that the tests do not teria for conditions in which early detec- betes in asymptomatic patients include necessarily detect diabetes in the same tion is appropriate. Both conditions are the following: individuals. The efficacy of interventions fi common and impose signi cant clinical Age for primary prevention of type 2 diabe- and public health burdens. There is often Testing recommendations for diabetes tes (30,31) has primarily been demon- a long presymptomatic phase before the in asymptomatic adults are listed in strated among individuals with IGT, not diagnosis of type 2 diabetes. Simple tests Table 2.2. Age is a major risk factor for for individuals with isolated IFG or for to detect preclinical disease are readily diabetes. Testing should begin at age 45 those with prediabetes defined by A1C available. The duration of glycemic burden years for all patients. criteria. is a strong predictor of adverse outcomes. Testing Interval There are effective interventions that pre- BMI and Ethnicity The appropriate interval between tests is vent progression from prediabetes to dia- Testing should be considered in adults not known (32). The rationale for the betes (see Section 4 “Prevention or Delay of any age with BMI $25 kg/m2 and one 3-year interval is that with this interval, of Type 2 Diabetes”)andreducetheriskof or more additional risk factors for dia- the number of false-positive tests that re- diabetes complications (see Section 8 betes. However, recent data (25) and quire confirmatory testing will be reduced “Cardiovascular Disease and Risk Man- evidence from the ADA position state- and individuals with false-negative tests agement” and Section 9 “Microvascular ment “BMI Cut Points to Identify At-Risk will be retested before substantial time Complications and Foot Care”). Asian Americans for Type 2 Diabetes elapses and complications develop (32). Approximately one-quarter of people Screening” (26) suggest that the BMI with diabetes in the U.S. and nearly half cut point should be lower for the Asian Community Screening of Asian and Hispanic Americans with American population. For diabetes Ideally, testing should be carried out diabetes are undiagnosed (21). Al- screening purposes, the BMI cut points within a health care setting because of though screening of asymptomatic fall consistently between 23 and 24 kg/m2 the need for follow-up and treatment. S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Community testing outside a health care 1. “One-step” 75-g OGTT or using the oral glucose tolerance setting is not recommended because 2. “Two-step” approach with a 50-g (non- test and clinically appropriate non- people with positive tests may not fasting) screen followed by a 100-g pregnancy diagnostic criteria. E seek, or have access to, appropriate OGTT for those who screen positive c Women with a history of gesta- follow-up testing and care. Community tional diabetes mellitus should testing may also be poorly targeted; i.e., Different diagnostic criteria will identify have lifelong screening for the de- it may fail to reach the groups most at different degrees of maternal hyperglyce- velopment of diabetes or predia- risk and inappropriately test those at mia and maternal/fetal risk, leading some betes at least every 3 years. B very low risk or even those who have experts to debate, and disagree on, opti- c Women with a history of gesta- already been diagnosed. mal strategies for the diagnosis of GDM. tional diabetes mellitus found to Testing for Type 2 Diabetes and have prediabetes should receive lifestyle interventions or metfor- One-Step Strategy Prediabetes in Children and In the 2011 Standards of Care (39), the min to prevent diabetes. A Adolescents ADA for the first time recommended In the last decade, the incidence and that all pregnant women not known to prevalence of type 2 diabetes in ado- Definition have prior diabetes undergo a 75-g lescents has increased dramatically, es- Formanyyears,GDMwasdefined as any OGTT at 24–28 weeks of gestation, based pecially in ethnic populations (16). degree of glucose intolerance that was first on a recommendation of the Interna- Recent studies question the validity of recognized during pregnancy (10), regard- tional Association of the Diabetes and A1C in the pediatric population, espe- less of whether the condition may have pre- Pregnancy Study Groups (IADPSG) (40). cially among certain ethnicities, and dated the pregnancy or persisted after the The IADPSG defined diagnostic cut points suggest OGTT or FPG as more suitable pregnancy. This definition facilitated a uni- for GDM as the average glucose values diagnostic tests (33). However, many of form strategy for detection and classification (fasting, 1-h, and 2-h PG) in the HAPO these studies do not recognize that di- of GDM, but it was limited by imprecision. study at which odds for adverse out- abetes diagnostic criteria are based on The ongoing epidemic of obesity and comes reached 1.75 times the estimated long-term health outcomes, and valida- diabetes has led to more type 2 diabetes odds of these outcomes at the mean glu- tions are not currently available in the in women of childbearing age, with an in- cose levels of the study population. This pediatric population (34). The ADA ac- crease in the number of pregnant women one-step strategy was anticipated to sig- knowledges the limited data support- with undiagnosed type 2 diabetes (37). Be- nificantly increase the incidence of GDM ing A1C for diagnosing type 2 diabetes cause of the number of pregnant women (from 5–6% to 15–20%), primarily be- in children and adolescents. Although with undiagnosed type 2 diabetes, it is rea- cause only one abnormal value, not two, A1C is not recommended for diagnosis sonable to test women with risk factors for became sufficient to make the diagnosis. fi of diabetes in children with cystic bro- type 2 diabetes (Table 2.2) at their initial The ADA recognized that the anticipated sisorsymptomssuggestiveofacuteon- prenatal visit, using standard diagnostic increase in the incidence of GDM would set of type 1 diabetes and only A1C criteria (Table 2.1).Womenwithdiabetes have significant impact on the costs, med- assays without interference are appro- in the first trimester would be classified as ical infrastructure capacity, and potential priate for children with hemoglobinopa- having type 2 diabetes. GDM is diabetes for increased “medicalization” of preg- thies, the ADA continues to recommend diagnosed in the second or third trimester nancies previously categorized as normal, A1C for diagnosis of type 2 diabetes in of pregnancy that is not clearly either but recommended these diagnostic crite- fi this cohort (35,36). The modi ed recom- type 1 or type 2 diabetes (see Section 12 ria changes in the context of worrisome mendations of the ADA consensus “Management of Diabetes in Pregnancy”). worldwide increases in obesity and diabe- report “Type 2 Diabetes in Children tes rates with the intent of optimizing and Adolescents” are summarized in Diagnosis gestational outcomes for women and Table 2.4. GDM carries risks for the mother and ne- their offspring. onate. Not all adverse outcomes are of The expected benefits to these preg- GESTATIONAL DIABETES equal clinical importance. The Hypergly- nancies and offspring are inferred from MELLITUS cemia and Adverse Pregnancy Outcome intervention trials that focused on (HAPO) study (38), a large-scale (25,000 women with lower levels of hyperglyce- Recommendations pregnant women) multinational cohort mia than identified using older GDM di- c Test for undiagnosed type 2 diabe- study, demonstrated that risk of adverse agnostic criteria and that found modest tes at the first prenatal visit in maternal, fetal, and neonatal outcomes benefits including reduced rates of those with risk factors, using stan- continuously increased as a function of large-for-gestational-age births and pre- dard diagnostic criteria. B maternal glycemia at 24–28 weeks, even eclampsia (41,42). It is important to c Test for gestational diabetes mel- within ranges previously considered nor- note that 80–90% of women being litus at 24–28 weeks of gestation mal for pregnancy. For most complica- treated for mild GDM in two random- in pregnant women not previously tions, there was no threshold for risk. ized controlled trials (whose glucose val- known to have diabetes. A These results have led to careful reconsid- ues overlapped with the thresholds c Screen women with gestational di- eration of the diagnostic criteria for GDM. recommended by the IADPSG) could abetes mellitus for persistent diabe- GDM diagnosis (Table 2.5)canbeaccom- be managed with lifestyle therapy tes at 6–12 weeks postpartum, plished with either of two strategies: alone. Data are lacking on how the care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Table 2.4—Testing for type 2 diabetes or prediabetes in asymptomatic children* c Because a diagnosis of maturity- Criteria onset diabetes of the young may c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or impact therapy and lead to identi- . weight 120% of ideal for height) fication of other affected family Plus any two of the following risk factors: members, consider referring indi- c Family history of type 2 diabetes in first- or second-degree relative viduals with diabetes not typical of c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis type 1 or type 2 diabetes and oc- nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational- curing in successive generations age birth weight) (suggestive of an autosomal dom- c Maternal history of diabetes or GDM during the child’s gestation inant pattern of inheritance) to a Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age specialist for further evaluation. E Frequency: every 3 years *Persons aged #18 years. Monogenic defects that cause b-cell dysfunction, such as neonatal diabetes treatment of lower levels of hyperglyce- its guidelines in 2013 and supported the and MODY, represent a small fraction of , mia affects a mother’sriskforthedevel- two-step approach (45). patients with diabetes ( 5%). These opment of type 2 diabetes in the future forms of diabetes are frequently charac- Future Considerations terized by onset of hyperglycemia at an and her offspring’s risk for obesity, di- fl The con icting recommendations from early age (generally before age 25 years). abetes, and other metabolic dysfunc- expert groups underscore the fact that tion. Additional well-designed clinical there are data to support each strategy. Neonatal Diabetes studies are needed to determine the op- The decision of which strategy to imple- Neonatal diabetes is a monogenic form of timal intensity of monitoring and treatment must therefore be made based on diabetes with onset in the first 6 months of ment of women with GDM diagnosed by the relative values placed on factors that life. It can be mistaken for the more com- the one-step strategy. have yet to be measured (e.g., cost–benefit mon type 1 diabetes, but type 1 diabetes estimation, willingness to change prac- rarely occurs before 6 months of age. Neo- Two-Step Strategy tice based on correlation studies rather natal diabetes can either be transient or In 2013, the National Institutes of Health than clinical intervention trial results, rel- permanent. The most common genetic (NIH) convened a consensus develop- ative role of cost considerations, and avail- defect causing transient disease is a defect ment conference on diagnosing GDM. able infrastructure locally, nationally, and on ZAC/HYAMI imprinting, whereas per- The 15-member panel had representatives internationally). manent neonatal diabetes is most com- from obstetrics/gynecology, maternal- As the IADPSG criteria have been adop- monly an autosomal dominant defect in fetal medicine, pediatrics, diabetes re- ted internationally, further evidence has the gene encoding the Kir6.2 subunit of search, biostatistics, and other related emerged to support improved pregnancy the b-cell K channel. Correct diagnosis fields to consider diagnostic criteria (43). ATP outcomes with cost savings (46) and may has important implications, because chil- The panel recommended the two-step be the preferred approach. In addition, dren with neonatal diabetes due to muta- approach of screening with a 1-h 50-g pregnancies complicated by GDM per tions affecting Kir6.2 should be treated glucose load test (GLT) followed by a 3-h IADPSG criteria, but not recognized as with sulfonylureas rather than insulin. 100-g OGTT for those who screen posi- such, have comparable outcomes to preg- tive, a strategy commonly used in the U.S. Maturity-Onset Diabetes of the Young nancies diagnosed as GDM by the more Key factors reported in the NIH pan- MODYischaracterizedbyimpairedinsulin stringent two-step criteria (47). There el’s decision-making process were the secretion with minimal or no defects in remains strong consensus that estab- lack of clinical trial interventions dem- insulin action. It is inherited in an autoso- lishing a uniform approach to diagnosing onstrating the benefits of the one-step mal dominant pattern. Abnormalities at GDM will benefit patients, caregivers, strategy and the potential negative con- six genetic loci on different chromosomes and policymakers. Longer-term outcome sequences of identifying a large new have been identified to date. The most studies are currently under way. group of women with GDM, including common form (MODY 3) is associated medicalization of pregnancy with in- MONOGENIC DIABETES with mutations on chromosome 12 in a creased interventions and costs. More- SYNDROMES hepatic transcription factor referred to as over, screening with a 50-g GLT does not hepatocyte nuclear factor (HNF)-1a and Recommendations require fasting and is therefore easier to also referred to as transcription factor-1 c All children diagnosed with diabe- accomplish for many women. Treat- (TCF-1). The second most common form tes in the first 6 months of life ment of higher threshold maternal (MODY 2) is associated with mutations in should have genetic testing. B hyperglycemia, as identified by the two- the glucokinase gene on chromosome 7p c Maturity-onset diabetes of the step approach, reduces rates of neonatal and results in a defective glucokinase mol- young should be considered in indi- macrosomia, large-for-gestational-age ecule. Glucokinase converts glucose to viduals who have mild stable fasting births (44), and shoulder dystocia, with- glucose-6-phosphate, the metabolism of hyperglycemia and multiple family out increasing small-for-gestational-age which, in turn, stimulates insulin secretion members with diabetes not charac- births. The American College of Obstetri- by the b-cell. The less common forms of teristic of type 1 or type 2 diabetes. E cians and Gynecologists (ACOG) updated MODY result from mutations in other S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.5—Screening for and diagnosis of GDM occurring in about 20% of adolescents – One-step strategy and 40 50% of adults. Diabetes in this population, compared with individuals Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2h,at24–28 weeks of gestation in women not previously diagnosed with overt diabetes. with type 1 or type 2 diabetes, is asso- The OGTT should be performed in the morning after an overnight fast of at least 8 h. ciated with worse nutritional status, fl The diagnosis of GDM is made when any of the following plasma glucose values are met or more severe in ammatory lung dis- exceeded: ease, and greater mortality. Insulin in- c Fasting: 92 mg/dL (5.1 mmol/L) sufficiency is the primary defect in c 1 h: 180 mg/dL (10.0 mmol/L) CFRD. Genetically determined b-cell c 2 h: 153 mg/dL (8.5 mmol/L) function and insulin resistance associ- Two-step strategy ated with infection and inflammation Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 may also contribute to the develop- weeks of gestation in women not previously diagnosed with overt diabetes. ment of CFRD. Milder abnormalities If the plasma glucose level measured 1 h after the load is $140 mg/dL* (7.8 mmol/L), proceed of glucose tolerance are even more to a 100-g OGTT. common and occur at earlier ages Step 2: The 100-g OGTT should be performed when the patient is fasting. than CFRD. Although screening for di- The diagnosis of GDM is made if at least two of the following four plasma glucose levels abetes before the age of 10 years can (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded: identify risk for progression to CFRD Carpenter/Coustan (55) or NDDG (56) in those with abnormal glucose toler- fi c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) ance, no bene t has been established c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) with respect to weight, height, BMI, c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) or lung function. Continuous glucose c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) monitoring may be more sensitive NDDG, National Diabetes Data Group. *The ACOG recommends a lower threshold of 135 mg/dL than OGTT to detect risk for progres- (7.5 mmol/L) in high-risk ethnic populations with higher prevalence of GDM; some experts also sion to CFRD, but evidence linking recommend 130 mg/dL (7.2 mmol/L). continuous glucose monitoring results tolong-termoutcomesislacking transcription factors, including HNF-4a, without typical clinical features of and its use is not recommended for HNF-1b, insulin promoter factor-1 (IPF-1), type 2 diabetes screening (50). and NeuroD1. CRFD mortality has significantly de- CYSTIC FIBROSIS–RELATED Diagnosis creased over time, and the gap in mor- DIABETES A diagnosis of MODY should be consid- tality between cystic fibrosis patients ered in individuals who have atypical di- Recommendations with and without diabetes has consider- abetes and multiple family members c Annual screening for cystic fibrosis– ably narrowed (51). There are limited with diabetes not characteristic of related diabetes with oral glucose clinical trial data on therapy for CFRD. type 1 or type 2 diabetes. These individ- tolerance test should begin by age The largest study compared three regi- uals should be referred to a specialist for 10 years in all patients with cystic mens: premeal insulin aspart, repagli- further evaluation. Readily available fibrosis who do not have cystic nide, or oral placebo in cystic fibrosis commercial genetic testing now enables fibrosis–related diabetes. B patients with diabetes or abnormal a genetic diagnosis. It is important to cor- c A1C as a screening test for cystic glucose tolerance. Participants all had rectly diagnose one of the monogenic fibrosis–related diabetes is not weight loss in the year preceding treat- forms of diabetes because these patients recommended. B ment; however, in the insulin-treated may be incorrectly diagnosed with type 1 c Patients with cystic fibrosis–related group, this pattern was reversed, and or type 2 diabetes, leading to suboptimal diabetes should be treated with patients gained 0.39 (6 0.21) BMI units treatment regimens and delays in diag- insulin to attain individualized gly- (P 5 0.02). The repaglinide-treated nosing other family members (48,49). cemic goals. A group had initial weight gain, but this The diagnosis of monogenic diabetes c In patients with cystic fibrosis and was not sustained by 6 months. The pla- should be considered in children with impaired glucose tolerance with- cebo group continued to lose weight the following findings: out confirmed diabetes, prandial (52). Insulin remains the most widely insulin therapy should be consid- used therapy for CFRD (53). ○ Diabetes diagnosed within the first ered to maintain weight. B Recommendations for the clinical 6monthsoflife c Beginning 5 years after the diagnosis management of CFRD can be found in ○ Strong family history of diabetes but with- of cystic fibrosis–related diabetes, the ADA position statement “Clinical out typical features of type 2 diabetes annual monitoring for complications Care Guidelines for Cystic Fibrosis– (nonobese, low-risk ethnic group) of diabetes is recommended. E Related Diabetes: A Position Statement ○ Mild fasting hyperglycemia (100–150 of the American Diabetes Association mg/dL [5.5–8.5 mmol/L]), especially if and a Clinical Practice Guideline of young and nonobese Cystic fibrosis–related diabetes the Cystic Fibrosis Foundation, En- ○ Diabetes with negative diabetes- (CFRD) is the most common comor- dorsed by the Pediatric Endocrine associated autoantibodies and bidity in people with cystic fibrosis, Society” (54). care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

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Diabetes Care 2011;34: drate Intolerance Study in Pregnant Women Examination Survey 2005-2006. Am J Prev 1741–1748 (ACHOIS) Trial Group. Effect of treatment of Med 2011;40:11–17 29. Erickson SC, Le L, Zakharyan A, et al. New- gestational diabetes mellitus on pregnancy out- 15. Diabetes Prevention Program Research onset treatment-dependent diabetes mellitus comes. N Engl J Med 2005;352:2477–2486 Group. HbA1c as a predictor of diabetes and and hyperlipidemia associated with atypical an- 43. Vandorsten JP, Dodson WC, Espeland MA, as an outcome in the Diabetes Prevention Pro- tipsychotic use in older adults without schizo- et al. NIH consensus development confer- gram: a randomized clinical trial. Diabetes Care phrenia or bipolar disorder. J Am Geriatr Soc ence: diagnosing gestational diabetes melli- 2015;38:51–58 2012;60:474–479 tus. NIH Consens State Sci Statements 2013; 16. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; 30. Knowler WC, Barrett-Connor E, Fowler SE, 29:1–31 SEARCH for Diabetes in Youth Study. Prevalence et al.; Diabetes Prevention Program Research 44. Horvath K, Koch K, Jeitler K, et al. Effects of of type 1 and type 2 diabetes among children Group. Reduction in the incidence of type 2 di- treatment in women with gestational diabetes and adolescents from 2001 to 2009. JAMA 2014; abetes with lifestyle intervention or metformin. mellitus: systematic review and meta-analysis. 311:1778–1786 N Engl J Med 2002;346:393–403 BMJ 2010;340:c1395 S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

45. Committee on Practice Bulletins–Obstetrics. 49. Rubio-Cabezas O, Hattersley AT, Njølstad Therapy trial. Diabetes Care 2009;32:1783– Practice Bulletin No. 137: gestational diabetes PR, et al.; International Society for Pediatric 1788 mellitus. Obstet Gynecol 2013;122:406–416 and Adolescent Diabetes. ISPAD Clinical Practice 53. Onady GM, Stolfi A. Insulin and oral agents 46. Duran A, Saenz´ S, Torrejon´ MJ, et al. Intro- Consensus Guidelines 2014. The diagnosis and for managing cystic fibrosis-related diabetes. duction of IADPSG criteria for the screening and management of monogenic diabetes in children Cochrane Database Syst Rev 2013;7:CD004730 diagnosis of gestational diabetes mellitus re- and adolescents. Pediatr Diabetes 2014;15 54. Moran A, Brunzell C, Cohen RC, et al.; CFRD sultsinimprovedpregnancy outcomes at a (Suppl. 20):47–64 Guidelines Committee. Clinical care guidelines lower cost in a large cohort of pregnant women: 50. Ode KL, Moran A. New insights into cystic for cystic fibrosis-related diabetes: a position the St. Carlos Gestational Diabetes Study. fibrosis-related diabetes in children. Lancet Di- statement of the American Diabetes Associa- Diabetes Care 2014;37:2442–2450 abetes Endocrinol 2013;1:52–58 tion and a clinical practice guideline of the Cystic 47. Ethridge JK Jr, Catalano PM, Waters TP. Peri- 51. Moran A, Dunitz J, Nathan B, Saeed A, Fibrosis Foundation, endorsed by the Pediatric natal outcomes associated with the diagnosis of Holme B, Thomas W. Cystic fibrosis-related di- Endocrine Society. Diabetes Care 2010;33: gestational diabetes made by the International abetes: current trends in prevalence, incidence, 2697–2708 Association of the Diabetes and Pregnancy Study and mortality. Diabetes Care 2009;32:1626– 55. Carpenter MW, Coustan DR. Criteria for Groups criteria. Obstet Gynecol 2014;124:571– 1631 screening tests for gestational diabetes. Am J 578 52. Moran A, Pekow P, Grover P, et al.; Cystic Obstet Gynecol 1982;144:768–773 48. Hattersley A, Bruining J, Shield J, Njolstad P, Fibrosis Related Diabetes Therapy Study Group. 56. National Diabetes Data Group. Classifica- Donaghue KC. The diagnosis and management of Insulin therapy to improve BMI in cystic fibrosis- tion and diagnosis of diabetes mellitus and monogenic diabetes in children and adolescents. related diabetes without fasting hyperglycemia: other categories of glucose intolerance. Diabe- Pediatr Diabetes 2009;10(Suppl. 12):33–42 results of the Cystic Fibrosis Related Diabetes tes 1979;28:1039–1057 Diabetes Care Volume 39, Supplement 1, January 2016 S23

3. Foundations of Care and American Diabetes Association Comprehensive Medical Evaluation Diabetes Care 2016;39(Suppl. 1):S23–S35 | DOI: 10.2337/dc16-S006

The foundations of care include self-management education, nutrition, counseling, physical activity, smoking cessation, immunizations, psychosocial care, and medications (covered in other sections). The comprehensive medical evaluation includes the initial and ongoing evaluations, assessment of complications, management of comorbid conditions, and engagement of the patient throughout the process.

FOUNDATIONS OF CARE CARE OF FOUNDATIONS 3. Optimal diabetes management starts with laying down the foundations of care. The health care provider must take a holistic approach in providing care, accounting for all aspects of the patient’s life circumstances. A team approach to diabetes management facilitates a comprehensive assessment and development of a plan that addresses the patient’s values and circumstances. The investment of time and collaboration can facilitate, and potentially expedite, care delivery and achieve and maintain outcomes. The initial clinical evaluation should be as comprehensive as possible as the patient will now have to address behavioral, dietary, lifestyle, and pharmaceutical interventions to effectively manage this newly identified chronic condition. The components for the comprehensive medical evaluation (Table 3.1) will provide the health care team with information necessary to optimally support a patient with diabetes. In addition to the medical history and physical examination, laboratory tests, nutrition, and psychosocial assessments should be obtained. Patient Engagement As discussed in Section 1 “Strategies for Improving Care,” the Chronic Care Model (CCM) has been shown to be an effective framework for improving the quality of diabetes care (1–3). This is a patient-centered approach to care that requires a close working relationship between the patient and clinicians involved in care planning and delivery. The foundation of successful diabetes management includes ongoing individual lifestyle and behavioral changes, engagement of the patient, and assessment of the patient’s level of understanding about the disease and level of pre- paredness for self-management. BASIS FOR INITIAL CARE Diabetes self-management education (DSME), diabetes self-management support (DSMS), medical nutrition therapy (MNT), counseling on smoking cessation, education on physical activity, guidance on routine immunizations, and psychosocial care are the cornerstone of diabetes management. Patients should be referred for such services if not readily available in the clinical care setting, i.e., referral for DSME, DSMS, MNT, and emotional health concerns. Additionally, specialty and lifestyle change services and programs may Suggested citation: American Diabetes Associa- be beneficial (Table 3.2). Patients should also receive recommended prevention. Foundations of care and comprehensive tive care services (e.g., cancer screening and immunizations); referral for smok- medical evaluation. Sec. 3. In Standards of Med- ical Care in Diabetesd2016. Diabetes Care ing cessation, if needed; and podiatric, ophthalmological, and dental referrals. 2016;39(Suppl. 1):S23–S35 Clinicians should ensure that individuals with diabetes are screened for com- © 2016 by the American Diabetes Association. plications and comorbidities. Identifying and implementing the initial approach Readers may use this article as long as the work to glycemic control with the patient is one part, not the sole aspect, of the is properly cited, the use is educational and not comprehensive care strategy. for profit, and the work is not altered. S24 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Table 3.1—Components of the comprehensive diabetes medical evaluation psychosocial care). Various strategies Medical history and techniques should be used to enable c Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic patients to self-manage diabetes, includ- laboratory finding) ing providing education on problem- c Eating patterns, nutritional status, weight history, and physical activity habits; nutrition solving skills for all aspects of diabetes education and behavioral support history and needs management. Treatment goals and plans c Presence of common comorbidities, psychosocial problems, and dental disease should be individualized and take patient c Screen for depression using PHQ-2 (PHQ-9 if PHQ-2 is positive) or Edinburgh Postnatal Depression Scale (EPDS) preferences into account. In developing c Screen for diabetes distress using DDS or PAID-1 the plan, health care providers should c History of smoking, alcohol consumption, and substance use consider the patient’s age, school/work c Diabetes education, self-management, and support history and needs schedule and conditions, physical activ- c Review of previous treatment regimens and response to therapy (A1C records) ity, eating patterns, social situation, cul- ’ c Results of glucose monitoring and patient s use of data tural factors, diabetes complications, c Diabetic ketoacidosis frequency, severity, and cause health priorities, other medical condi- c Hypoglycemia episodes, awareness, and frequency and causes c History of increased blood pressure, increased lipids, and tobacco use tions, preferences for care and self- c Microvascular complications: retinopathy, nephropathy, and neuropathy (sensory, management, and life expectancy. including history of foot lesions; autonomic, including sexual dysfunction and gastroparesis) DIABETES SELF-MANAGEMENT c Macrovascular complications: coronary heart disease, cerebrovascular disease, and peripheral arterial disease EDUCATION AND SUPPORT Physical examination Recommendations c Height, weight, and BMI; growth and pubertal development in children and adolescents c c Blood pressure determination, including orthostatic measurements when indicated In accordance with the national c Fundoscopic examination standards for diabetes self-man- c Thyroid palpation agement education (DSME) and c Skin examination (e.g., for acanthosis nigricans, insulin injection or infusion set insertion support (DSMS), all people with di- sites) abetes should participate in DSME c Comprehensive foot examination to facilitate the knowledge, skills, c Inspection and ability necessary for diabetes c Palpation of dorsalis pedis and posterior tibial pulses c Presence/absence of patellar and Achilles reflexes self-care and in DSMS to assist with c Determination of proprioception, vibration, and monofilament sensation implementing and sustaining skills Laboratory evaluation and behaviors needed for ongoing c A1C, if the results are not available within the past 3 months self-management, both at diagnosis c If not performed/available within the past year andasneededthereafter.B c Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides, as needed c Effective self-management, im- c Liver function tests proved clinical outcomes, health c Spot urinary albumin–to–creatinine ratio status, and quality of life are key c Serum creatinine and estimated glomerular filtration rate c Thyroid-stimulating hormone in patients with type 1 diabetes or dyslipidemia or women outcomes of DSME and DSMS and aged .50 years should be measured and monitored as part of care. C c DSME and DSMS should be patient centered, respectful, and respon- ONGOING CARE MANAGEMENT with diabetes must assume an active sive to individual patient prefer- People with diabetes should receive role in their care. ences, needs, and values, which medical care from a collaborative, inte- The patient, family, physician, and should guide clinical decisions. A grated team with diabetes expertise. other members of the health care team c DSME and DSMS programs should This team may include physicians, nurse should formulate the management plan. have the necessary elements in practitioners, physician assistants, Integral components of the management their curricula that are needed to nurses, dietitians, exercise specialists, plan include the foundations of care prevent the onset of diabetes. pharmacists, dentists, podiatrists, and (DSME, DSMS, MNT, smoking cessation, DSME and DSMS programs should mental health professionals. Individuals physical activity, immunizations, and therefore tailor their content specifically when prevention of diabetes is the desired goal. B Table 3.2—Referrals for initial care management c Because DSME and DSMS can re- c Eye care professional for annual dilated eye exam sult in cost savings and improved c Family planning for women of reproductive age outcomes B,DSMEandDSMS c Registered dietitian for MNT should be adequately reimbursed c DSME/DSMS by third-party payers. E c Dentist for comprehensive dental and periodontal examination c Mental health professional, if indicated DSME and DSMS are the ongoing processes of facilitating the knowledge, care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S25

skills, and ability necessary for diabetes (10,13), healthy coping (14,15), and types of diabetes and be supportive of self-care. These processes incorporate lower costs (16,17). Better outcomes their implementation. See Table 3.3 for the needs, goals, and life experiences were reported for DSME interventions specific nutrition recommendations. of the person with diabetes. The overall that were longer (.10 h) and included Goals of Medical Nutrition Therapy objectives of DSME and DSMS are to follow-up support (DSMS) (18,19), were for Adults With Diabetes support informed decision making, culturally (20,21) and age appropriate 1. To promote and support healthful eat- self-care behaviors, problem solving, (22,23), were tailored to individual ing patterns, emphasizing a variety of and active collaboration with the health needs and preferences, and addressed nutrient-dense foods in appropriate care team to improve clinical outcomes, psychosocial issues and incorporated portion sizes, in order to improve health status, and quality of life in a behavioral strategies (5,14,24,25). Both overall health and specifically to cost-effective manner (4). individual and group approaches have ○ Achieve and maintain body weight DSME and DSMS are essential ele- been found effective (12,26). There is goals ments of diabetes care (5,6), and the growing evidence for the role of com- ○ Attain individualized glycemic, current national standards for DSME munity health workers (27), as well as blood pressure, and lipid goals and DSMS (4) are based on the evidence peer (27–29) and lay (30) leaders, in pro- ○ Delay or prevent complications of of their benefits. Education helps people viding ongoing support. diabetes with diabetes to initiate effective self- DSME is associated with increased pri- 2. To address individual nutrition needs management and cope with diabetes mary and preventive service use based on personal and cultural prefer- when they are first diagnosed. Ongoing (16,31,32) and lower acute, inpatient hos- ences, health literacy and numeracy, DSMS helps people with diabetes to pital service use (11). Patients who partic- access to healthful foods, willingness maintain effective self-management ipate in DSME are more likely to follow and ability to make behavioral changes, throughout a lifetime of diabetes as best practice treatment recommenda- andbarrierstochange they face new challenges and as treat- tions, particularly among the Medicare 3. To maintain the pleasure of eating by ment advances become available. population, and have lower Medicare providing nonjudgmental messages The DSME and DSMS algorithm de- and insurance claim costs (17,31). about food choices fines four critical time points for DSME 4. To provide an individual with diabe- and DSMS delivery (7): Reimbursement DSME and DSMS, when provided by a tes with practical tools for develop- 1. At diagnosis program that meets the national stan- ing healthful eating patterns rather 2. Annually for assessment of educa- dards (4) and is recognized by the Amer- than focusing on individual macronu- tion, nutrition, and emotional needs ican Diabetes Association (ADA) or other trients, micronutrients, or single 3. When new complicating factors arise approval bodies, are reimbursed as part foods fl that in uence self-management of the Medicare program as overseen by 4. When transitions in care occur the Centers for Medicare & Medicaid Ser- MNT is an integral component of diabe- vices. DSME is also covered by most tes prevention, management, and self- Current best practice of DSME is a skill- health insurance plans. Although DSMS management education. All individuals based approach that focuses on helping has been shown to be instrumental for with diabetes should receive individual- those with diabetes to make informed improving outcomes and can be provided ized MNT, preferably provided by a reg- self-management choices (4,5). DSME has via phone calls and telehealth, it currently istered dietitian who is knowledgeable fi changed from a didactic approach that has limited reimbursement as compared and skilled in providing diabetes-speci c focusedonprovidinginformationtoem- with in-person follow-up to DSME. MNT. MNT delivered by a registered di- powerment models that focus on helping etitian shows A1C decreases of 0.3–1% those with diabetes to make informed self- MEDICAL NUTRITION THERAPY for people with type 1 diabetes (35–37) management decisions (5). Diabetes care and 0.5–2% for people with type 2 di- For many individuals with diabetes, the has shifted to an approach that is more abetes (38–41). patient centered and places the person most challenging part of the treatment Weight Management with diabetes and his or her family at the plan is determining what to eat. It is the center of the care model, working in col- position of the ADA that there is not a Intensive lifestyle programs with fre- fi laboration with health care professionals. one-size- ts-all eating pattern for individ- quent follow-up are required to achieve fi Patient-centered care is respectful of and uals with diabetes. The ADA recognizes signi cant reductions in excess body responsive to individual patient prefer- the integral role of MNT in overall diabe- weight and improve clinical indicators. ences, needs, and values. It ensures that tes management and recommends that There is strong and consistent evidence patient values guide all decision making (8). each person with diabetes be actively en- that obesity management can delay pro- gaged in self-management, education, gression from prediabetes to type 2 di- and treatment planning with his or her abetes (42,43) and benefits type 2 Evidence for the Benefits health care team, including the collabora- diabetes treatment. Studies have found that DSME is associ- tive development of an individualized In overweight and obese patients ated with improved diabetes knowl- eating plan (33,34). Therefore, it is impor- with type 2 diabetes, modest weight edge, improved self-care behaviors (4), tant that each member of the health care loss, defined as sustained reduction of lower A1C (6,9,10), lower self-reported team be knowledgeable about nutrition 5% of initial body weight, has been weight (11,12), improved quality of life therapy principles for people with all showntoimproveglycemiccontrol S26 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Table 3.3—Nutrition therapy recommendations Topic Recommendations Evidence rating Effectiveness of nutrition therapy c An individualized MNT program, preferably provided by a registered dietitian, is A recommended for all people with type 1 or type 2 diabetes. c For people with type 1 diabetes or those with type 2 diabetes who are prescribed A a flexible insulin therapy program, education on how to use carbohydrate counting or estimation to determine mealtime insulin dosing can improve glycemic control. c For individuals whose daily insulin dosing is fixed, having a consistent pattern of B carbohydrate intake with respect to time and amount can result in improved glycemic control and a reduced risk of hypoglycemia. c A simple and effective approach to glycemia and weight management C emphasizing healthy food choices and portion control may be more helpful for those with type 2 diabetes who are not taking insulin, who have limited health literacy or numeracy, and who are elderly and prone to hypoglycemia. c Because diabetes nutrition therapy can result in cost savings B and improved B, A, E outcomes (e.g., A1C reduction) A, MNT should be adequately reimbursed by insurance and other payers. E Energy balance c Modest weight loss achievable by the combination of lifestyle modification and A the reduction of energy intake benefits overweight or obese adults with type 2 diabetes and also those at risk for diabetes. Interventional programs to facilitate this process are recommended. Eating patterns and macronutrient c As there is no single ideal dietary distribution of calories among carbohydrates, E distribution fats, and proteins for people with diabetes, macronutrient distribution should be individualized while keeping total calorie and metabolic goals in mind. c Carbohydrate intake from whole grains, vegetables, fruits, legumes, and dairy B products, with an emphasis on foods higher in fiber and lower in glycemic load, should be advised over other sources, especially those containing sugars. c People with diabetes and those at risk should avoid sugar-sweetened beverages B, A in order to control weight and reduce their risk for CVD and fatty liver B and should minimize the consumption of sucrose-containing foods that have the capacity to displace healthier, more nutrient-dense food choices. A Protein c In individuals with type 2 diabetes, ingested protein appears to increase insulin B response without increasing plasma glucose concentrations. Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia. Dietary fat c Whereas data on the ideal total dietary fat content for people with diabetes are B inconclusive, an eating plan emphasizing elements of a Mediterranean-style diet rich in monounsaturated fats may improve glucose metabolism and lower CVD risk and can be an effective alternative to a diet low in total fat but relatively high in carbohydrates. c Eating foods rich in long-chain omega-3 fatty acids, such as fatty fish (EPA and B, A DHA) and nuts and seeds (ALA), is recommended to prevent or treat CVD B; however, evidence does not support a beneficial role for omega-3 dietary supplements. A Micronutrients and herbal supplements c There is no clear evidence that dietary supplementation with vitamins, minerals, C herbs, or spices can improve diabetes, and there may be safety concerns regarding the long-term use of antioxidant supplements such as vitamins E and C and carotene. Alcohol c Adults with diabetes who drink alcohol should do so in moderation (no more C than one drink per day for adult women and no more than two drinks per day for adult men). c Alcohol consumption may place people with diabetes at increased risk for B delayed hypoglycemia, especially if taking insulin or insulin secretagogues. Education and awareness regarding the recognition and management of delayed hypoglycemia are warranted. Sodium c As for the general population, people with diabetes should limit sodium B consumption to ,2,300 mg/day, although further restriction may be indicated for those with both diabetes and hypertension. care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S27

and to reduce the need for glucose- from meal to meal and improving glycemic omega-3 fatty acids did not improve glyce- lowering medications (44–46). Weight control (36,51,57,58). For individuals on a mic control in individuals with type 2 di- loss can be attained with lifestyle programs fixed daily insulin schedule, meal planning abetes (53). Randomized controlled trials that achieve a 500–750 kcal/day energy should emphasize a relatively fixed carbo- also do not support recommending deficit or provide ;1,200–1,500 kcal/day hydrate consumption pattern with respect omega-3 supplements for primary or sec- for women and 1,500–1,800 kcal/day for to both time and amount (34). By ondary prevention of CVD (69–73). People men, adjusted for the individual’s baseline contrast, a simpler diabetes meal planning with diabetes should be advised to follow body weight. Although benefits may be approach emphasizing portion control and the guidelines for the general population seen with as little as 5% weight loss, sus- healthful food choices may be better for the recommended intakes of saturated tained weight loss of $7% is optimal. suited for some elderly individuals, those fat, dietary cholesterol, and trans fat (64). These diets may differ in the types of with cognitive dysfunction, and those for In general, trans fats should be avoided. foods they restrict (such as high-fat or whom there are concerns over health lit- high-carbohydrate foods) but are effec- eracy and numeracy (34–36,38,51,57). Sodium tive if they create the necessary energy As for the general population, people with deficit (47–50). The diet choice should Protein diabetes should limit their sodium consumption to ,2,300 mg/day. Lowering be based on the patients’ health status For individuals without evidence of dia- sodium intake (i.e., 1,500 mg/day) may and preferences. betic kidney disease, the evidence is incon- benefit blood pressure in certain circum- clusive about recommending an ideal stances (74). The American Heart Associa- Carbohydrates amount of protein for optimizing glycemic tion recommends 1,500 mg/day for Studies examining the ideal amount of control or for improving one or more CVD African Americans; people diagnosed carbohydrate intake for people with dia- risk measures (53). Therefore, these goals with hypertension, diabetes, or chronic betes are inconclusive, although monitor- should be individualized. For those with di- kidney disease; and people over 51 years ing carbohydrate intake and considering abetic kidney disease (with albuminuria, of age (75). However, other studies (76,77) thebloodglucoseresponsetodietarycar- reduced estimated glomerular filtration have recommended caution for universal bohydrate are key for improving post- rate), dietary protein should be maintained sodium restriction to 1,500 mg in this pop- prandial glucose control (51,52). The at the recommended daily allowance of ulation. Sodium intake recommendations literature concerning glycemic index and 0.8 g/kg body weight per day. Reducing should take into account palatability, avail- glycemic load in individuals with diabetes the amount of dietary protein below ability, affordability, and the difficulty of is complex. Although in some studies low- the recommended daily allowance is achieving low-sodium recommendations ering the glycemic load of consumed not recommended because it does not in a nutritionally adequate diet (78). carbohydrates has demonstrated A1C alter glycemic measures, cardiovascular For complete discussion and refer- reductions of 20.2% to 20.5% (53,54), a risk measures, or the rate at which glo- ences of all recommendations, see the systematic review (53) found that whole- merular filtration rate declines (59,60). ADA position statement “Nutrition Ther- grain consumption was not associated In individuals with type 2 diabetes, in- apy Recommendations for the Manage- with improvements in glycemic control gested protein may enhance the insulin ment of Adults With Diabetes” (34). in type 2 diabetes. One study did find a response to dietary carbohydrates (61). potential benefit of whole-grain intake in Therefore, carbohydrate sources high in PHYSICAL ACTIVITY reducing mortality and cardiovascular dis- protein should not be used to treat or pre- ease (CVD) among individuals with type 2 vent hypoglycemia. The effects of protein Recommendations diabetes (55). As for all Americans, indi- intake on blood glucose levels in type 1 c Children with diabetes or predia- viduals with diabetes should be encour- diabetes are less clear. betes should be encouraged to en- aged to replace refined carbohydrates gage in at least 60 min of physical and added sugars with whole grains, Fats activity each day. B legumes, vegetables, and fruits. The con- Limited research exists concerning the c Adults with diabetes should be ad- sumption of sugar-sweetened beverages ideal amount of fat for individuals with di- visedtoperformatleast150min/ and “low-fat” or “nonfat” products with abetes. The Institute of Medicine has week of moderate-intensity aerobic high amounts of refined grains and added defined an acceptable macronutrient dis- physical activity (50–70% of maxi- sugars should be discouraged (56). tribution range for all adults for total fat of mum heart rate), spread over at least Individuals with type 1 or type 2 diabe- 20–35% of energy with no tolerable upper 3 days/week with no more than 2 tes taking insulin at mealtimes should be intake level defined (62). The type of fatty consecutive days without exercise. A offered intensive education on coupling acids consumed is more important than c All individuals, including those with insulin administration with carbohydrate total amount of fat when looking at meta- diabetes, should be encouraged to intake. For people whose meal schedules bolic goals and CVD risk (63–65). Multiple reduce sedentary time, particularly or carbohydrate consumption is variable, randomized controlled trials including pa- by breaking up extended amounts regular counseling to help them to under- tients with type 2 diabetes have reported of time (.90 min) spent sitting. B stand the complex relationship between that a Mediterranean-style eating pattern c In the absence of contraindications, carbohydrate intake and insulin needs, as (63,66–68), rich in monounsaturated fats, adults with type 2 diabetes should be well as the carbohydrate-counting ap- can improve both glycemic control and encouraged to perform resistance proach to meal planning, can assist them blood lipids. However, a systematic review training at least twice per week. A with effectively modifying insulin dosing concluded that dietary supplements with S28 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Physical activity is a general term that over age 18 years do 150 min/week of careful history being aware of the atyp- includes all movement that increases en- moderate-intensity or 75 min/week of ical presentation of coronary artery dis- ergy use and is an important part of the vigorous-intensity aerobic physical activ- ease in patients with diabetes and assess diabetes management plan. Exercise is a ity, or an equivalent combination of the other cardiovascular risk factors. Cer- more specific form of physical activity two. In addition, the guidelines suggest tainly, high-risk patients should be en- that is structured and designed to im- that adults do muscle-strengthening activ- couraged to start with short periods of prove physical fitness. Although both ities that involve all major muscle groups 2 low-intensity exercise and slowly in- are important, exercise has been shown or more days/week. The guidelines sug- crease the intensity and duration. Pro- to improve blood glucose control, reduce gest that adults over age 65 years or those viders should assess patients for cardiovascular risk factors, contribute to with disabilities follow the adult guide- conditions that might contraindicate weight loss, and improve well-being. lines if possible or, if this is not possible, certain types of exercise or predis- Physical activity is as important for those be as physically active as they are able. pose to injury, such as uncontrolled with type 1 diabetes as it is for the general Recent evidence supports that all indi- hypertension, autonomic neuropathy, population, but its specific role in pre- viduals, including those with diabetes, peripheral neuropathy, a history of venting diabetes complications and con- should be encouraged to reduce the foot lesions, and untreated proliferative trolling blood glucose is not as clear as it is amount of time spent being sedentary retinopathy. The patient’s age and pre- for those with type 2 diabetes. (e.g., working at a computer, watching vious physical activity level should be Furthermore, regular exercise may TV), particularly, by breaking up extended considered. The provider should cus- prevent type 2 diabetes in high-risk in- amounts of time (.90 min) spent sitting tomize the exercise regimen to the dividuals (43,79,80) (see Section 4 “Pre- by briefly standing or walking (87). individual’s needs. Those with compli- vention or Delay of Type 2 Diabetes”). cations may require a more thorough Structured exercise interventions of at Physical Activity and Glycemic evaluation (81). least 8 weeks’ duration have been Control Hypoglycemia showntolowerA1Cbyanaverageof On the basis of physical activity studies In individuals taking insulin and/or insu- 0.66% in people with type 2 diabetes, that include people with diabetes, it is lin secretagogues, physical activity may even with no significant change in BMI reasonable to recommend that people cause hypoglycemia if the medication (80). There are also considerable data with diabetes will specifically benefit dose or carbohydrate consumption is for the health benefits (e.g., increased from following the U.S. Department of not altered. Individuals on these thera- cardiovascular fitness, muscle strength, Health and Human Services’ physical ac- pies may need to ingest some added improved insulin sensitivity, etc.) of reg- tivity guidelines. For example, studies in- carbohydrate if pre-exercise glucose lev- ular exercise for those with type 1 dia- cluded in the meta-analysis of the effects els are ,100 mg/dL (5.6 mmol/L), de- betes (81). Higher levels of exercise of exercise interventions on glycemic con- pending on whether they can lower intensity are associated with greater im- trol (80) reported a mean of 3.4 sessions/ insulin levels during the workout (such provements in A1C and in fitness (82). week, with a mean of 49 min/session. as with an insulin pump or reduced pre- Other benefits include slowing the de- Clinical trials have provided strong evi- exercise insulin dosage), the time of day cline in mobility among overweight pa- dence for the A1C-lowering value of resis- exercise is done, and the intensity and tients with diabetes (83). “Exercise and tance training in older adults with type 2 duration of the activity. Hypoglycemia is Type 2 Diabetes: The American College diabetes (84) and for an additive benefitof less common in patients with diabetes of Sports Medicine and the American combined aerobic and resistance exercise who are not treated with insulin or in- Diabetes Association: Joint Position in adults with type 2 diabetes (88,89). If sulin secretagogues, and no preventive Statement” (84) reviews the evidence not contraindicated, patients with type 2 measures for hypoglycemia are usually for the benefits of exercise in people diabetes should be encouraged to do at advised in these cases. Intense activities with type 2 diabetes. least two weekly sessions of resistance ex- may actually raise blood glucose levels ercise (exercise with free weights or Exercise and Children instead of lowering them (91). weight machines), with each session con- As is recommended for all children, chil- sisting of at least one set of five or more dren with diabetes or prediabetes should Exercise in the Presence of Specific different resistance exercises involving the be encouraged to engage in at least 60 Long-term Complications of Diabetes largemusclegroups(84). minofphysicalactivityeachday.Included Retinopathy in the 60 min each day, children should Pre-exercise Evaluation If proliferative diabetic retinopathy or se- engage in vigorous-intensity aerobic ac- As discussed more fully in Section 8 “Car- vere nonproliferative diabetic retinopa- tivity, muscle-strengthening activities, diovascular Disease and Risk Manage- thy is present, then vigorous-intensity and bone-strengthening activities at least ment,” the best protocol for screening aerobic or resistance exercise may be 3 of those days (85). asymptomatic patients with diabetes contraindicated because of the risk of forcoronaryarterydiseaseremains triggering vitreous hemorrhage or retinal Frequency and Type of Physical unclear. The ADA consensus report detachment (92). Activity “Screening for Coronary Artery Disease Peripheral Neuropathy The U.S. Department of Health and Hu- in Patients With Diabetes” (90) con- Decreased pain sensation and a higher man Services’ physical activity guidelines cluded that routine testing is not recom- pain threshold in the extremities result for Americans (86) suggest that adults mended. Providers should perform a in an increased risk of skin breakdown, care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S29

infection, and Charcot joint destruction Results from epidemiological, case-control, c Administer hepatitis B vaccine to with some forms of exercise. There- and cohort studies provide convincing ev- unvaccinated adults with diabetes fore, a thorough assessment should idence to support the causal link between who are aged 19–59 years. C be done to ensure that neuropathy cigarette smoking and health risks (97). c Consider administering hepatitis B does not alter kinesthetic or propriocep- Other studies of individuals with diabetes vaccine to unvaccinated adults tive sensation during physical activity. consistently demonstrate that smokers with diabetes who are aged $60 Studies have shown that moderate- (and people exposed to secondhand years. C intensity walking may not lead to an smoke) have a heightened risk of CVD, increased risk of foot ulcers or reulcera- premature death, and microvascular As for the general population, all chil- tion in those with peripheral neuropa- complications. Smoking may have a role dren and adults with diabetes should re- thy who use proper footwear (93). In in the development of type 2 diabetes ceive routine vaccinations (105,106) addition, 150 min/week of moderate (98). One study in smokers with newly according to age-specific recommenda- exercise was reported to improve out- diagnosed type 2 diabetes found that tions (see the adult vaccination sched- comes in patients with milder forms smoking cessation was associated with ule available from http://www.cdc.gov/ of neuropathy (94). All individuals with amelioration of metabolic parameters vaccines/schedules/hcp/imz/adult.html peripheral neuropathy should wear and reduced blood pressure and albumin- and the child and adolescent vaccina- proper footwear and examine their uria at 1 year (99). tion schedule available from http:// feet daily to detect lesions early. Any- The routine and thorough assessment www.cdc.gov/vaccines/schedules/hcp/ one with a foot injury or open sore of tobacco use is essential to prevent imz/child-adolescent.html). should be restricted to non–weight- smoking or encourage cessation. Nu- The Centers for Disease Control and bearing activities. merous large randomized clinical trials Prevention (CDC) Advisory Committee have demonstrated the efficacy and cost- Autonomic Neuropathy on Immunization Practices recommends effectiveness of brief counseling in smoking Autonomic neuropathy can increase the influenza and pneumococcal vaccines cessation, including the use of telephone risk of exercise-induced injury or ad- for all individuals with diabetes (http:// quit lines, in reducing tobacco use. For the verse events through decreased cardiac www.cdc.gov/vaccines/schedules). responsiveness to exercise, postural hy- patient motivated to quit, the addition of potension, impaired thermoregulation, pharmacological therapy to counseling Influenza impaired night vision due to impaired is more effective than either treatment Influenza is a common, preventable in- papillary reaction, and greater suscepti- alone. Special considerations should in- fectious disease associated with high bility to hypoglycemia (95). Cardiovas- clude assessment of level of nicotine mortality and morbidity in vulnerable cular autonomic neuropathy is also an dependence, which is associated with populations, such as the young and fi independent risk factor for cardiovascu- dif culty in quitting and relapse (100). the elderly and people with chronic lar death and silent myocardial ischemia Although some patients may gain weight diseases. Regardless of sex, race, and (96). Therefore, individuals with dia- in the period shortly after smoking ces- socioeconomic status, adults with diabetic autonomic neuropathy should un- sation, recent research has demon- betes 25–64yearsofagewhodiedare dergo cardiac investigation before strated that this weight gain does not four times more likely to have pneu- fi beginning physical activity more intense diminish the substantial CVD bene t re- monia and influenza recorded on their than that to which they are accustomed. alized from smoking cessation (101). death certificates than adults without Nonsmokers should be advised not to diabetes who died at comparable ages Albuminuria and Nephropathy use e-cigarettes. Physical activity can acutely increase uri- (107). In a case-control series, the in- There are no rigorous studies that have fluenza vaccine was shown to reduce nary protein excretion. However, there demonstrated that e-cigarettes are a is no evidence that vigorous-intensity diabetes-related hospital admission healthier alternative to smoking or that fl exercise increases the rate of progres- by as much as 79% during uepidemics e-cigarettes can facilitate smoking cessa- (108). sion of diabetic kidney disease, and tion. More extensive research of their fi there appears to be no need for speci c short- and long-term effects is needed Pneumococcal Pneumonia exercise restrictions for people with di- to determine their safety and their car- Like influenza, pneumococcal pneumo- abetic kidney disease (92). diopulmonary effects in comparison nia is a common, preventable disease. with smoking and standard approaches People with diabetes may be at in- SMOKING CESSATION: TOBACCO to smoking cessation (102–104). creased risk for the bacteremic form of AND e-CIGARETTES pneumococcal infection and have been reported to have a high risk of nosoco- Recommendations IMMUNIZATION mial bacteremia, with a mortality rate c Advise all patients not to use ciga- as high as 50% (109). All patients with rettes, other tobacco products, or Recommendations diabetes 2 years of age and older should e-cigarettes. A c Provide routine vaccinations for receive the pneumococcal polysaccha- c Include smoking cessation coun- children and adults with diabetes ride vaccine 23 (PPSV23). There is suffi- seling and other forms of treat- as for the general population ac- cient evidence to support that people ment as a routine component of cording to age-related recommen- with diabetes have appropriate sero- diabetes care. B dations. C logic and clinical responses to these S30 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

vaccinations. The ADA endorses the appropriate services. A systematic re- with depression without significant CDC advisory panel recommendation view and meta-analysis showed that DD, and those with DD without signifi- that both pneumococcal conjugate vac- psychosocial interventions modestly cant depression. Understanding the cine 13 (PCV13) and PPSV23 should be but significantly improved A1C (stan- category in which a particular patient administered routinely in series to all dardized mean difference 20.29%) belongs facilitates a customized care adults aged $65 years. and mental health outcomes. However, approach that may include DSME, there was a limited association be- DSMS, cognitive therapy, or treatment Hepatitis B tween the effects on A1C and mental for depression (psychotherapy and/ Compared with the general population, health, and no intervention characteris- or psychotropic medications). The people with type 1 or type 2 diabetes tics predicted benefit on both outcomes screening of all patients with diabetes have higher rates of hepatitis B. This (114). with the Patient Health Questionnaire-2 may be due to contact with infected (PHQ-2) and either the Diabetes Dis- blood or through improper equipment Screening tress Scale (DDS) or Problem Areas in use (glucose monitoring devices or in- Key opportunities for psychosocial Diabetes (PAID)-1 scale can help to fected needles). Because of the higher screening occur at diabetes diagnosis, facilitate this (24,123,124). likelihood of transmission, hepatitis B during regularly scheduled manage- Other issues known to affect self- vaccine is recommended for adults ment visits, during hospitalizations, management and health outcomes with diabetes. with new onset of complications, or include attitudes about the illness, ex- when problems with glucose control, PSYCHOSOCIAL ISSUES pectations for medical management and quality of life, or self-management are outcomes, anxiety, general and diabetes- fi Recommendations identi ed. Patients are likely to exhibit related quality of life, resources (financial, c The patient’s psychological and psychological vulnerability at diagnosis, social, and emotional) (125), and psychi- social situation should be ad- when their medical status changes atric history (126). dressedinthemedicalmanage- (e.g., end of the honeymoon period), fi ment of diabetes. B when the need for intensi ed treat- Referral to a Mental Health Specialist c Psychosocial screening and follow- ment is evident, and when complica- Indications for referral to a mental up may include, but are not lim- tions are discovered. Depression health specialist familiar with diabetes ; – ited to, attitudes about the illness, affects 20 25% of people with diabe- management may include possibility of expectations for medical man- tes (115). Individuals with both diabe- self-harm, gross disregard for the med- agement and outcomes, affect/ tes and major depressive disorder ical regimen (by self or others) (127), mood, general and diabetes-related have a twofold increased risk for new- depression, overall stress related to quality of life, resources (financial, onset myocardial infarction compared work-life balance, debilitating anxiety social, and emotional), and psy- with either disease state alone (116). (alone or with depression), indications chiatric history. E There appears to be a bidirectional re- of an eating disorder (128), or cognitive c Routinely screen for psychoso- lationship between both diabetes (117) functioning that significantly impairs cial problems such as depression, and metabolic syndrome (118) and judgment. It is preferable to incorpo- diabetes-related distress, anxiety, depression. rate psychological assessment and eating disorders, and cognitive im- treatment into routine care rather pairment. B Diabetes Distress than waiting for a specific problem or c Older adults (aged $65 years) Diabetes-related distress (DD) is dis- deterioration in metabolic or psycho- with diabetes should be consid- tinct from depressive disorders and is logical status (24,119). In the second Di- ered for evaluation of cognitive very common (119–121) in people abetes Attitudes, Wishes and Needs function and depression screening with diabetes and their family mem- (DAWN2) study, significant DD was re- and treatment. B bers (113). DD refers to significant neg- ported by 45% of the participants, but c Patients with comorbid diabetes ative psychological reactions related only 24% reported that their health care and depression should receive a to emotional burdens and worries spe- team asked them how diabetes affected stepwise collaborative care ap- cifictoanindividual’sexperiencein their life (119). proach for the management of de- having to manage a severe, compli- Although the clinician may not feel pression. A cated, and demanding chronic dis- qualified to treat psychological prob- ease such as diabetes (120–122). Its lems (129), optimizing the patient– Emotional well-being is an important part prevalence is reported to be 18–45%, provider relationship as a foundation of diabetes care and self-management. with an incidence of 38–48% over 18 may increase the likelihood of the pa- Psychological and social problems can months. High levels of distress are tient accepting referral for other ser- impair the individual’s (110–112) or significantly linked to medication non- vices. Collaborative care interventions family’s (113) ability to carry out adherence (122), higher A1C, lower and a team approach have demonstrated diabetes care tasks and therefore com- self-efficacy, and poorer dietary and efficacy in diabetes and depression promise health status. There are oppor- exercise behaviors (15,120). The clini- (130,131). Interventions to enhance tunities for the clinician to routinely cian needs to understand that individuals self-management and address severe assess psychosocial status in a timely may fall into one of three categories: distress have demonstrated efficacy and efficient manner for referral for those with depression and DD, those in DD (15). care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S31

COMPREHENSIVE MEDICAL Obstructive Sleep Apnea For patients with type 2 diabetes with EVALUATION Age-adjusted rates of obstructive sleep fracture risk factors, thiazolidinediones apnea, a risk factor for CVD, are signifi- (148) and sodium–glucose cotransporter Recommendations cantly higher (4- to 10-fold) with obe- 2 inhibitors should be avoided as their use A complete medical evaluation should sity, especially with central obesity has been associated with a higher risk of be performed at the initial visit to (139). The prevalence of obstructive fractures (149). c Confirm the diagnosis and classify sleep apnea in the population with diabetes. B type 2 diabetes may be as high as 23% Low Testosterone in Men c Detect diabetes complications and (140). In obese participants enrolled in Mean levels of testosterone are lower in potential comorbid conditions. E the Action for Health in Diabetes (Look men with diabetes compared with age- c Review previous treatment and AHEAD) trial, it exceeded 80% (141). matched men without diabetes, but risk factor control in patients Sleep apnea treatment significantly im- obesity is a major confounder (150). with established diabetes. E proves quality of life and blood pressure Treatment in asymptomatic men is con- c Begin patient engagement in the control. The evidence for a treatment troversial. The evidence that testoster- formulation of a care manage- effect on glycemic control is mixed one replacement affects outcomes is ment plan. B (142). mixed, and recent guidelines do not rec- c Develop a plan for continuing care. B ommend testing and treating men with- Cancer out symptoms (151). Diabetes (possibly only type 2 diabetes) Besides assessing diabetes-related is associated with increased risk of Periodontal Disease complications and comorbidities, clini- cancers of the liver, pancreas, endome- Periodontal disease is more severe, but cians and their patients need to be trium, colon/rectum, breast, and blad- not necessarily more prevalent, in pa- aware of other common conditions der (143). The association may result tients with diabetes than in those with- that affect people with diabetes. Im- from shared risk factors between out (152). Current evidence suggests proved disease prevention and treat- type 2 diabetes and cancer (older age, that periodontal disease adversely af- ment mean that people with diabetes obesity, and physical inactivity) but fects diabetes outcomes, although evi- are living longer and developing heart may also be due to hyperinsulinemia dence for treatment benefits remains failure, fatty liver disease, obstructive or hyperglycemia (144). Patients with controversial (136). sleep apnea, and arthritisdconditions diabetes should be encouraged to un- Hearing Impairment that affect people with diabetes more dergo recommended age- and sex-ap- Hearing impairment, both in high-frequency often than age-matched people without propriate cancer screenings and to and low/mid-frequency ranges, is more diabetes and that may complicate dia- reduce their modifiable cancer risk fac- betes management (132–136). tors (smoking, obesity, and physical in- common in people with diabetes than Adults who develop type 1 diabetes activity). in those without, perhaps due to neu- ropathyand/orvasculardisease.Ina may develop additional autoimmune dis- Fractures orders including thyroid or adrenal dys- National Health and Nutrition Examina- Age-specific hip fracture risk is signifi- tion Survey (NHANES) analysis, hearing function and celiac disease, although the cantly increased in both type 1 (relative risk of coexisting autoimmunity is lower in impairment was about twice as preva- risk 6.3) and type 2 (relative risk 1.7) di- lent in people with diabetes compared adults than for youth with type 1 diabe- abetes in both sexes (145). Type 1 dia- with those without, after adjusting for tes. For additional details on autoimmune betes is associated with osteoporosis, “ age and other risk factors for hearing conditions, see Section 11 Children and but in type 2 diabetes, an increased ” impairment (153). Adolescents. risk of hip fracture is seen despite higher bone mineral density (BMD) (146). In Cognitive Impairment COMORBIDITIES three large observational studies of Diabetes is associated with a signifi- Fatty Liver Disease older adults, femoral neck BMD T-score cantly increased risk and rate of cogni- Elevations of hepatic transaminase con- and the World Health Organization Frac- tive decline and an increased risk of centrations are significantly associated ture Risk Assessment Tool (FRAX) score dementia (154,155). In a 15-year pro- with higher BMI, waist circumference, were associated with hip and nonspine spective study of community-dwelling and triglyceride levels and lower HDL fractures. Fracture risk was higher in people aged .60 years, the presence cholesterol levels. In a prospective anal- participants with diabetes compared of diabetes at baseline significantly ysis, diabetes was significantly associ- with those without diabetes for a given increased the age- and sex-adjusted ated with incident nonalcoholic chronic T-score and age for a given FRAX score incidence of all-cause dementia, Alz- liver disease and with hepatocellular (147). Providers should assess fracture heimer disease, and vascular dementia carcinoma (137). Interventions that im- history and risk factors in older patients compared with rates in those with prove metabolic abnormalities in pa- with diabetes and recommend measure- normal glucose tolerance (156). In a tients with diabetes (weight loss, ment of BMD if appropriate for the pa- substudy of the Action to Control Car- glycemic control, and treatment with tient’s age and sex. Fracture prevention diovascular Risk in Diabetes (ACCORD) specific drugs for hyperglycemia or dys- strategies for people with diabetes are clinical trial, there were no differences lipidemia) are also beneficial for fatty the same as for the general population in cognitive outcomes between the in- liver disease (138). and include vitamin D supplementation. tensive and standard glycemic control S32 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

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U.S. Department of Health and Human and the Council on Nutrition, Physical Activity, and 83. Rejeski WJ, Ip EH, Bertoni AG, et al.; Look Services, U.S. Department of Agriculture. Scientific Metabolism; Council on Cardiovascular Nursing; AHEAD Research Group. Lifestyle change and Report of the 2015 Dietary Guidelines Advisory and Council on Epidemiology and Prevention. mobility in obese adults with type 2 diabetes. Committee [Internet], 2015. Available from http:// Circulation 2009;119:902–907 N Engl J Med 2012;366:1209–1217 health.gov/dietaryguidelines/2015-scientific- 70. Crochemore ICC, Souza AFP, de Souza ACF, 84. Colberg SR, Sigal RJ, Fernhall B, et al.; Amer- report. Accessed 18 November 2015 Rosado EL. Omega-3 polyunsaturated fatty acid ican College of Sports Medicine; American S34 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

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126. Zhang X, Norris SL, Gregg EW, Cheng YJ, hepatocellular carcinoma. Gastroenterology with risk of fracture in older adults with type 2 Beckles G, Kahn HS. Depressive symptoms and 2004;126:460–468 diabetes. JAMA 2011;305:2184–2192 mortality among persons with and without di- 138. American Gastroenterological Associa- 148. Kahn SE, Zinman B, Lachin JM, et al.; Di- abetes. Am J Epidemiol 2005;161:652–660 tion. American Gastroenterological Association abetes Outcome Progression Trial (ADOPT) 127. Rubin RR, Peyrot M. Psychological issues medical position statement: nonalcoholic fatty Study Group. Rosiglitazone-associated fractures and treatments for people with diabetes. J Clin liver disease. Gastroenterology 2002;123:1702– in type 2 diabetes: an Analysis from A Diabetes Psychol 2001;57:457–478 1704 Outcome Progression Trial (ADOPT). Diabetes 128. Young-Hyman DL, Davis CL. Disordered 139. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, Care 2008;31:845–851 eating behavior in individuals with diabetes: im- Mokdad AH. Prevalence of self-reported clini- 149. Taylor SI, Blau JE, Rother KI. Possible ad- portance of context, evaluation, and classifica- cally diagnosed sleep apnea according to obe- verse effects of SGLT2 inhibitors on bone. Lan- tion. Diabetes Care 2010;33:683–689 sity status in men and women: National Health cet Diabetes Endocrinol 2015;3:8–10 129. Beverly EA, Hultgren BA, Brooks KM, and Nutrition Examination Survey, 2005-2006. 150. Dhindsa S, Miller MG, McWhirter CL, et al. Ritholz MD, Abrahamson MJ, Weinger K. Under- Prev Med 2010;51:18–23 Testosterone concentrations in diabetic and ’ standing physicians challenges when treating 140. West SD, Nicoll DJ, Stradling JR. Preva- nondiabetic obese men. Diabetes Care 2010; ’ – type 2 diabetic patients social and emotional lence of obstructive sleep apnoea in men with 33:1186 1192 fi dif culties: a qualitative study. Diabetes Care type 2 diabetes. Thorax 2006;61:945–950 151. Bhasin S, Cunningham GR, Hayes FJ, et al.; – 2011;34:1086 1088 141. Foster GD, Sanders MH, Millman R, et al.; Endocrine Society Task Force. Testosterone fi 130. Ciechanowski P. Diapression: an inte- Sleep AHEAD Research Group. Obstructive therapy in men with androgen de ciency syn- grated model for understanding the experience sleep apnea among obese patients with type 2 dromes: an Endocrine Society clinical practice of individuals with co-occurring diabetes and diabetes. Diabetes Care 2009;32:1017–1019 guideline. J Clin Endocrinol Metab 2010;95: – – depression. Clin Diabetes 2011;29:43 49 142. Shaw JE, Punjabi NM, Wilding JP, Alberti 2536 2559 131. Katon WJ, Lin EH, Von Korff M, et al. Col- 152. Khader YS, Dauod AS, El-Qaderi SS, Alkafajei KG, Zimmet PZ; International Diabetes Federa- laborative care for patients with depression and A, Batayha WQ. Periodontal status of diabetics tion Taskforce on Epidemiology and Prevention. chronic illnesses. N Engl J Med 2010;363:2611– compared with nondiabetics: a meta-analysis. J Sleep-disordered breathing and type 2 diabetes: 2620 Diabetes Complications 2006;20:59–68 a report from the International Diabetes Feder- 132. Selvin E, Coresh J, Brancati FL. The burden 153. Bainbridge KE, Hoffman HJ, Cowie CC. Di- ation Taskforce on Epidemiology and Preven- and treatment of diabetes in elderly individuals abetes and hearing impairment in the United – in the U.S. Diabetes Care 2006;29:2415–2419 tion. Diabetes Res Clin Pract 2008;81:2 12 States: audiometric evidence from the National 133. Grant RW, Ashburner JM, Hong CS, Chang 143. Suh S, Kim K-W. Diabetes and cancer: is Health and Nutrition Examination Survey, 1999 Y, Barry MJ, Atlas SJ. Defining patient complex- diabetes causally related to cancer? Diabetes to 2004. Ann Intern Med 2008;149:1–10 – ity from the primary care physician’s perspec- Metab J 2011;35:193 198 154. Cukierman T, Gerstein HC, Williamson JD. tive: a cohort study. Ann Intern Med 2011;155: 144. Giovannucci E, Harlan DM, Archer MC, Cognitive decline and dementia in diabetesd 797–804 et al. Diabetes and cancer: a consensus report. systematic overview of prospective observational – 134.TinettiME,FriedTR,BoydCM.Design- Diabetes Care 2010;33:1674 1685 studies. Diabetologia 2005;48:2460–2469 ing health care for the most common chronic 145. Janghorbani M, Van Dam RM, Willett WC, 155. Biessels GJ, Staekenborg S, Brunner E, conditiondmultimorbidity. JAMA 2012;307: Hu FB. Systematic review of type 1 and type 2 Brayne C, Scheltens P. Risk of dementia in di- 2493–2494 diabetes mellitus and risk of fracture. Am J Epi- abetes mellitus: a systematic review. Lancet 135. 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J Periodontol 2013;84 search Group; Osteoporotic Fractures in Men sive glucose lowering on brain structure and (Suppl.):S135–S152 (MrOS) Research Group; Health, Aging, and function in people with type 2 diabetes 137. El-Serag HB, Tran T, Everhart JE. Diabetes Body Composition (Health ABC) Research (ACCORD MIND): a randomised open-label sub- increases the risk of chronic liver disease and Group. Association of BMD and FRAX score study. Lancet Neurol 2011;10:969–977 S36 Diabetes Care Volume 39, Supplement 1, January 2016

4. Prevention or Delay of Type 2 American Diabetes Association Diabetes Diabetes Care 2016;39(Suppl. 1):S36–S38| DOI: 10.2337/dc16-S007

Recommendations c Patients with prediabetes should be referred to an intensive diet and physical activity behavioral counseling program adhering to the tenets of the Diabetes Prevention Program (DPP) targeting a loss of 7% of body weight and should increase their moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A c Follow-up counseling and maintenance programs should be offered for long- term success in preventing diabetes. B c Based on the cost-effectiveness of diabetes prevention, such programs should be covered by third-party payers. B c Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially in those with BMI .35 kg/m2, those aged ,60 years, and women with prior gestational diabetes mellitus. A c At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E c Screening for and treatment of modifiable risk factors for cardiovascular disease is suggested. B c Diabetes self-management education and support programs are appropriate venues for people with prediabetes to receive education and support to de- 4. PREVENTION OR DELAY OF TYPE 2 DIABETES velop and maintain behaviors that can prevent or delay the onset of diabetes. B c Technology-assisted tools including Internet-based social networks, distance learning, DVD-based content, and mobile applications can be useful elements of effective lifestyle modification to prevent diabetes. B LIFESTYLE MODIFICATION Randomized controlled trials have shown that individuals at high risk for developing type 2 diabetes (impaired fasting glucose, impaired glucose tolerance, or both) can significantly decrease the rate of diabetes onset with particular interventions (1–7). These include intensive lifestyle modification programs that have been showntobeveryeffective(;58% reduction after 3 years). Follow-up of all three large studies of lifestyle intervention has shown sustained reduction in the rate of conversion to type 2 diabetes: 43% reduction at 20 years in the Da Qing study (8), 43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS) (9), and 34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS) (10). A cost-effectiveness model suggested that lifestyle interventions in the Diabetes Prevention Program (DPP) are cost-effective (11). Actual cost data from the DPP and DPPOS also confirm this (12). Group delivery of DPP content into community settings has the potential to reduce overall program costs while still producing weight loss and diabetes risk reduction (13,14). The Centers for Disease Control and Prevention (CDC) helps to coordinate the National Diabetes Prevention Program, a resource designed to bring evidence-based lifestyle change programs for preventing type 2 diabetes to communities (http://www.cdc.gov/diabetes/ Suggested citation: American Diabetes Associa- prevention/index.htm). tion. Prevention or delay of type 2 diabetes. Sec. 4. In Standards of Medical Care in Diabetesd2016. Given the clinical trial results and the known risks of progression from prediabetes Diabetes Care 2016;39(Suppl. 1):S36–S38 to diabetes, people with an A1C 5.7–6.4% (39–46 mmol/mol), impaired glucose © 2016 by the American Diabetes Association. tolerance, or impaired fasting glucose should be counseled on lifestyle changes Readers may use this article as long as the work with goals similar to those of the DPP (7% weight loss and moderate-intensity is properly cited, the use is educational and not physical activity of at least 150 min/week). for profit, and the work is not altered. care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S37

Nutrition health care providers should inform PHARMACOLOGICAL As for people with diabetes (see Section 3 at-risk patients of these benefits in or- INTERVENTIONS “Foundations of Care and Comprehen- der to motivate them to engage Pharmacological agents, such as metfor- sive Medical Evaluation”), evidence sup- in regular moderate-intensity physical min, a-glucosidase inhibitors, orlistat, ports the importance of maintaining a activity. and thiazolidinediones, have each healthy diet in order to prevent diabetes Moderate exercise, such as brisk been shown to decrease incident dia- onset. Unlike past recommendations walking or other activities of equivalent betes to various degrees. Metformin that focused on simply reducing total di- intensity, has been also observed to im- has the strongest evidence base and etary fat and cholesterol consumption, prove insulin sensitivity and reduce ab- demonstrated long-term safety as more recent evidence argues against dominal fat content in children and pharmacological therapy for diabetes the preventative effects of lowering fat young adults (22,23). The DPP included prevention (34). For other drugs, cost, and cholesterol intake across the board 150 min/week of moderate-intensity ex- side effects, and durable efficacy re- and supports instead that the quality of ercise and showed beneficial effect on quire consideration. fats consumed in the diet is more impor- glycemia in those with prediabetes (1). Metformin was less effective than tant than the total quantity of dietary fat. Both resistance training and endurance lifestyle modification in the DPP and For example, recent work supports the exercise appear to have beneficial ef- DPPOS but may be cost-saving over a Mediterranean diet, which is relatively fects on waist circumference, insulin 10-year period (12). It was as effective rich in monounsaturated fats, as a means sensitivity, and thus diabetes risk as lifestyle modification in participants to help to prevent type 2 diabetes (15). (24,25). The preventative effects of exer- with BMI $35 kg/m2 but not signifi- Studies evaluating glycemic index to cise appear to extend to the prevention cantly better than placebo in those guide carbohydrate recommendations of gestational diabetes mellitus (GDM) over 60 years of age (1). In the DPP, have been inconsistent (16,17); however, as well (26). for women with a history of GDM, met- data suggest that consumption of a diet formin and intensive lifestyle modifica- enriched in whole grains is helpful in pre- Prevention of Cardiovascular Disease tion led to an equivalent 50% reduction venting type 2 diabetes (18). Finally, in- People with prediabetes often have other in diabetes risk (35), and both inter- creased consumption of nuts (19) and cardiovascular risk factors, such as obe- ventions remained highly effective berries (20) in the context of a diet high sity, hypertension, and dyslipidemia during a 10-year follow-up period in vegetables and whole fruits has been and are at increased risk for cardiovas- (36). Metformin may be recommended correlated with reduced diabetes risk. In- cular disease events. While treatment for high-risk individuals (e.g., those dividualized medical nutrition therapy goals for people with prediabetes are with a history of GDM, those who are (see Section 3 “Foundations of Care and thesameasforthegeneralpopulation, very obese, and/or those with more Comprehensive Medical Evaluation” for increased vigilance is warranted to severe or progressive hyperglycemia) more detailed information) has been identify and treat these and other risk and/or those with rising A1C despite shown to be effective in lowering A1C in factors (e.g., smoking). lifestyle intervention. individuals diagnosed with prediabetes (7). This indicates that nutritional inter- Technology Assistance to Deliver ventions are potentially effective in stav- Lifestyle Modification DIABETES SELF-MANAGEMENT ing off the progression toward type 2 Technology may be an effective means EDUCATION AND SUPPORT diabetes (e.g., individuals showing signs to deliver the core components of the As for those with established diabetes, the of metabolic syndrome). DPP (27,28). Initial studies have vali- standards for diabetes self-management dated DVD-based content delivery education and support (see Section 3 Physical Activity and Exercise (29). This has been corroborated in a “Foundations of Care and Comprehen- Physical activity and exercise are impor- primary care patient population (30). sive Medical Evaluation”) can also apply tant for those living with diabetes (see Recent studies support content delivery to the education and support of people Section 3 “Foundations of Care and Com- through virtual small groups (31), Internet- with prediabetes. Currently, there are prehensive Medical Evaluation”), but they driven social networks (32,33), cellular significant barriers to the provision of have also been evaluated for diabetes pre- phones, and other mobile devices. Mo- education and support to those with prevention. Physical activity is a more general bile applications for weight loss and di- diabetes. However, the strategies for term that covers all types of activity, abetes prevention have been validated supporting successful behavior change whereas exercise refers to structured or for their ability to reduce A1C in the and the healthy behaviors recom- planned activities. Although not well stud- setting of prediabetes (33). The CDC’s Di- mended for people with prediabetes ied in isolation, exercise and physical ac- abetes Prevention Recognition Program are comparable to those for diabetes. tivity have been validated to prevent or (DPRP) (http://www.cdc.gov/diabetes/ Although reimbursement remains a delay diabetes development as part of a prevention/recognition/index.htm) has barrier, studies show that providers of comprehensive approach to lifestyle mod- begun to certify electronic and mobile diabetes self-management education ification (21). These studies suggest that health-based modalities as effective ve- and support are particularly well equip- while exercise treatment programs may hicles for DPP-style prevention content pedtoassistpeoplewithprediabetesin not reduce body weight, programs of suf- that may be considered alongside more developing and maintaining behaviors ficient intensity have been shown to de- traditional face-to-face and coach-driven that can prevent or delay the onset of crease diabetes risk (21). Therefore, programs. diabetes (7,37). S38 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

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Lancet 2002;359:2072–2077 iterranean diet: results of the PREDIMED-Reus 29. Kramer MK, Kriska AM, Venditti EM, et al. A 4. Lin JS, O’Connor E, Evans CV, Senger CA, nutrition intervention randomized trial. Diabe- novel approach to diabetes prevention: evalua- Rowland MG, Groom HC. Behavioral counseling tes Care 2011;34:14–19 tion of the Group Lifestyle Balance program de- to promote a healthy lifestyle in persons with 16. Bhupathiraju SN, Tobias DK, Malik VS, et al. livered via DVD. Diabetes Res Clin Pract 2010; cardiovascular risk factors: a systematic review Glycemic index, glycemic load, and risk of type 2 90:e60–e63 for the U.S. Preventive Services Task Force. Ann diabetes: results from 3 large US cohorts and an 30. Ma J, Yank V, Xiao L, et al. Translating the Intern Med 2014;161:568–578 updated meta-analysis. Am J Clin Nutr 2014; Diabetes Prevention Program lifestyle interven- 5. Paulweber B, Valensi P, Lindstrom¨ J, et al. A 100:218–232 tion for weight loss into primary care: a random- European evidence-based guideline for the pre- 17. Sacks FM, Carey VJ, Anderson CAM, et al. ized trial. JAMA Intern Med 2013;173:113–121 vention of type 2 diabetes. Horm Metab Res Effects of high vs low glycemic index of dietary 31. Azar KMJ, Aurora M, Wang EJ, Muzaffar A, 2010;42(Suppl. 1):S3–S36 carbohydrate on cardiovascular disease risk fac- Pressman A, Palaniappan LP. Virtual small 6. Diabetes Prevention Program Research tors and insulin sensitivity: the OmniCarb ran- groups for weight management: an innovative – Group. HbA1c as a predictor of diabetes and as domized clinical trial. JAMA 2014;312:2531 2541 delivery mechanism for evidence-based lifestyle an outcome in the Diabetes Prevention Pro- 18. Montonen J, Knekt P, Jarvinen¨ R, Aromaa A, interventions among obese men. Transl Behav gram: a randomized clinical trial. Diabetes Reunanen A. Whole-grain and fiber intake and Med 2015;5:37–44 Care 2015;38:51–58 the incidence of type 2 diabetes. Am J Clin Nutr 32. Sepah SC, Jiang L, Peters AL. Translating the 7. Parker AR, Byham-Gray L, Denmark R, Winkle 2003;77:622–629 Diabetes Prevention Program into an online so- PJ. The effect of medical nutrition therapy by a 19. Afshin A, Micha R, Khatibzadeh S, cial network: validation against CDC standards. registered dietitian nutritionist in patients with Mozaffarian D. Consumption of nuts and legumes Diabetes Educ 2014;40:435–443 prediabetes participating in a randomized con- and risk of incident ischemic heart disease, stroke, 33. Sepah SC, Jiang L, Peters AL. Long-term out- trolled clinical research trial. J Acad Nutr Diet and diabetes: a systematic review and meta- comes of a Web-based diabetes prevention pro- 2014;114:1739–1748 analysis. Am J Clin Nutr 2014;100:278–288 gram: 2-year results of a single-arm longitudinal 8. Li G, Zhang P, Wang J, et al. The long-term 20. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi study. J Med Internet Res 2015;17:e92 effect of lifestyle interventions to prevent dia- T, Voutilainen S. Intake of fruit, berries, and 34. Group TDPPR; Diabetes Prevention Pro- betes in the China Da Qing Diabetes Prevention vegetables and risk of type 2 diabetes in Finnish gram Research Group. Long-term safety, tol- Study: a 20-year follow-up study. Lancet 2008; men: the Kuopio Ischaemic Heart Disease Risk erability, and weight loss associated with 371:1783–1789 Factor Study. Am J Clin Nutr 2014;99:328–333 metforminintheDiabetesPreventionPro- 9. Lindstrom¨ J, Ilanne-Parikka P, Peltonen M, 21. Swift DL, Johannsen NM, Lavie CJ, Earnest gram Outcomes Study. Diabetes Care 2012; et al.; Finnish Diabetes Prevention Study Group. CP, Church TS. The role of exercise and physical 35:731–737 Sustained reduction in the incidence of type 2 activity in weight loss and maintenance. Prog 35. Ratner RE, Christophi CA, Metzger BE, et al.; diabetes by lifestyle intervention: follow-up of Cardiovasc Dis 2014;56:441–447 Diabetes Prevention Program Research Group. the Finnish Diabetes Prevention Study. Lancet 22. Fedewa MV, Gist NH, Evans EM, Dishman Prevention of diabetes in women with a history 2006;368:1673–1679 RK. Exercise and insulin resistance in youth: a of gestational diabetes: effects of metformin 10. Knowler WC, Fowler SE, Hamman RF, et al.; meta-analysis. Pediatrics 2014;133:e163–e174 and lifestyle interventions. J Clin Endocrinol Diabetes Prevention Program Research Group. 23. Davis CL, Pollock NK, Waller JL, et al. Exer- Metab 2008;93:4774–4779 10-year follow-up of diabetes incidence and cise dose and diabetes risk in overweight and 36. Aroda VR, Christophi CA, Edelstein SL, et al.; weight loss in the Diabetes Prevention Program obese children: a randomized controlled trial. Diabetes Prevention Program Research Group. Outcomes Study. Lancet 2009;374:1677–1686 JAMA 2012;308:1103–1112 The effect of lifestyle intervention and metfor- 11. Herman WH, Hoerger TJ, Brandle M, et al.; 24. Sigal RJ, Alberga AS, Goldfield GS, et al. Ef- min on preventing or delaying diabetes among Diabetes Prevention Program Research Group. fects of aerobic training, resistance training, or women with and without gestational diabetes: The cost-effectiveness of lifestyle modification both on percentage body fat and cardiometa- the Diabetes Prevention Program outcomes or metformin in preventing type 2 diabetes in bolic risk markers in obese adolescents: the study 10-year follow-up. J Clin Endocrinol adults with impaired glucose tolerance. Ann In- healthy eating aerobic and resistance training Metab 2015;100:1646–1653 tern Med 2005;142:323–332 in youth randomized clinical trial. JAMA Pediatr 37. Butcher MK, Vanderwood KK, Hall TO, 12. Diabetes Prevention Program Research 2014;168:1006–1014 Gohdes D, Helgerson SD, Harwell TS. Capacity Group. The 10-year cost-effectiveness of life- 25. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, of diabetes education programs to provide both style intervention or metformin for diabetes Arslanian S. Effects of aerobic versus resistance diabetes self-management education and to im- prevention: an intent-to-treat analysis of the exercise without caloric restriction on abdomi- plement diabetes prevention services. J Public DPP/DPPOS. Diabetes Care 2012;35:723–730 nal fat, intrahepatic lipid, and insulin sensitivity Health Manag Pract 2011;17:242–247 Diabetes Care Volume 39, Supplement 1, January 2016 S39

5. Glycemic Targets American Diabetes Association Diabetes Care 2016;39(Suppl. 1):S39–S46 | DOI: 10.2337/dc16-S008

ASSESSMENT OF GLYCEMIC CONTROL Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) and A1C. Continuous glucose monitoring (CGM) or interstitial glucose may be a useful adjunct to SMBG in selected patients.

Recommendations c When prescribed as part of a broader educational context, self-monitoring of blood glucose (SMBG) results may help to guide treatment decisions and/or self-management for patients using less frequent insulin injections B or noninsulin therapies. E c When prescribing SMBG, ensure that patients receive ongoing instruction and TARGETS GLYCEMIC 5. regular evaluation of SMBG technique, SMBG results, and their ability to use SMBG data to adjust therapy. E c Most patients on intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should consider SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. B c When used properly, continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens is a useful tool to lower A1C in selected adults (aged $25 years) with type 1 diabetes. A c Although the evidence for A1C lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. B c CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. C c Given variable adherence to CGM, assess individual readiness for continuing CGM use prior to prescribing. E c When prescribing CGM, robust diabetes education, training, and support are required for optimal CGM implementation and ongoing use. E c People who have been successfully using CGM should have continued access after they turn 65 years of age. E Self-monitoring of Blood Glucose Major clinical trials of insulin-treated patients have included SMBG as part of the multifactorial interventions to demonstrate the benefit of intensive glycemic control on diabetes complications. SMBG is thus an integral component of effective therapy (1). SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Integrating SMBG results into diabetes management can be a useful tool for guiding medical nutrition therapy and physical activity, preventing hypoglycemia, and adjusting medications (particularly prandial insulin doses). Among patients with type 1 diabetes, there is a correlation between greater SMBG frequency and lower A1C (2). The patient’s specific needs and goals should dictate SMBG frequency and timing. Suggested citation: American Diabetes Associa- tion. Glycemic targets. Sec. 5. In Optimization Standards of Medical Care in Diabetesd2016. Diabetes Care SMBG accuracy is dependent on the instrument and user, so it is important to 2016;39(Suppl. 1):S39–S46 evaluate each patient’s monitoring technique, both initially and at regular intervals © 2016 by the American Diabetes Association. thereafter. Optimal use of SMBG requires proper review and interpretation of the Readers may use this article as long as the work data, by both the patient and the provider. Among patients who check their blood is properly cited, the use is educational and not glucose at least once daily, many report taking no action when results are high or for profit, and the work is not altered. S40 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

low. In a yearlong study of insulin-na¨ıve suggested that SMBG reduced A1C by automatic low glucose suspend feature patients with suboptimal initial glycemic 0.25% at 6 months (13), but the effect was has been approved by the FDA. The Auto- control, a group trained in structured attenuated at 12 months (14). A key con- mation to Simulate Pancreatic Insulin Re- SMBG (a paper tool was used at least sideration is that performing SMBG alone sponse (ASPIRE) trial of 247 patients quarterly to collect and interpret 7-point does not lower blood glucose levels. To be showed that sensor-augmented insulin SMBG profiles taken on 3 consecutive useful, the information must be integrated pump therapy with a low glucose sus- days) reduced their A1C by 0.3 percent- into clinical and self-management plans. pend significantly reduced nocturnal hy- age points more than the control group poglycemia, without increasing A1C (3). Patients should be taught how to use Continuous Glucose Monitoring levels for those over 16 years of age SMBG data to adjust food intake, exer- Real-time CGM measures interstitial (23). These devices may offer the oppor- cise, or pharmacological therapy to glucose (which correlates well with tunity to reduce severe hypoglycemia for achieve specific goals. The ongoing need plasma glucose) and includes sophisti- those with a history of nocturnal hypo- for and frequency of SMBG should be cated alarms for hypo- and hyperglycemic glycemia. Due to variable adherence, op- reevaluated at each routine visit to avoid excursions, but the U.S. Food and Drug timal CGM use requires an assessment of overuse (4–6). SMBG is especially impor- Administration (FDA) has not approved individual readiness for the technology tant for insulin-treated patients to monitor these devices as a sole agent to monitor as well as initial and ongoing education for and prevent asymptomatic hypoglyce- glucose. CGMs require calibration with and support (16,24). Additionally, providers mia and hyperglycemia. SMBG, with the latter still required for need to provide robust diabetes education, making acute treatment decisions. training, and support for optimal CGM For Patients on Intensive Insulin Regimens A 26-week randomized trial of 322 pa- implementation and ongoing use. As Most patients on intensive insulin regimens tients with type 1 diabetes showed that people with type 1 or type 2 diabetes (multiple-dose insulin or insulin pump ther- adults aged $25 years using intensive in- are living longer healthier lives, individu- apy) should consider SMBG prior to meals sulintherapyandCGMexperienceda0.5% als who have been successfully using and snacks, occasionally postprandially, at reduction in A1C (from ;7.6% to 7.1% CGM should have continued access after bedtime, prior to exercise, when they sus- [;60 mmol/mol to 54 mmol/mol]), com- they turn 65 years of age. pect low blood glucose, after treating low pared with those using intensive insulin blood glucose until they are normoglyce- therapy with SMBG (15). Sensor use in A1C TESTING mic, and prior to critical tasks such as driv- those aged ,25 years (children, teens, Recommendations ing. For many patients, this will require and adults) did not result in significant c Perform the A1C test at least two – testing 6 10 (or more) times daily, al- A1C lowering, and there was no significant timesayearinpatientswhoare though individual needs may vary. A data- difference in hypoglycemia in any group. meeting treatment goals (and who base study of almost 27,000 children and The greatest predictor of A1C lowering have stable glycemic control). E adolescents with type 1 diabetes showed for all age-groups was frequency of sensor c Perform the A1C test quarterly in that, after adjustment for multiple con- use, which was highest in those aged $25 patients whose therapy has changed founders, increased daily frequency of years and lower in younger age-groups. or who are not meeting glycemic fi SMBG was signi cantly associated with A registry study of 17,317 participants goals. E 2 lower A1C ( 0.2% per additional test per confirmed that more frequent CGM use is c Point-of-care testing for A1C pro- day) and with fewer acute complications. associated with lower A1C (16), whereas vides the opportunity for more For Patients Using Basal Insulin or Oral another study showed that children with timely treatment changes. E Agents .70% sensor use missed fewer school The evidence is insufficient regarding days (17). Small randomized controlled A1C reflects average glycemia over when to prescribe SMBG and how often trials in adults and children with baseline several months and has strong predic- testing is needed for patients who do A1C 7.0–7.5% (53–58 mmol/mol) have tive value for diabetes complications not use an intensive insulin regimen, confirmed favorable outcomes (A1C and (25,26). Thus, A1C testing should be such as those with type 2 diabetes using hypoglycemia occurrence) in groups us- performed routinely in all patients with oral agents or on basal insulin. For patients ing CGM, suggesting that CGM may pro- diabetesdat initial assessment and as on basal insulin, lowering of A1C has been vide further benefit for individuals with part of continuing care. Measurement demonstrated for those who adjust their type 1 diabetes who already have tight approximately every 3 months deter- dose to attain a fasting glucose within a control (18,19). mines whether patients’ glycemic targets targeted range (7,8). A meta-analysis suggests that, com- have been reached and maintained. The For individuals with type 2 diabetes on paredwithSMBG,CGMisassociated frequency of A1C testing should depend less intensive insulin therapy, more fre- with short-term A1C lowering of ;0.26% on the clinical situation, the treatment quent SMBG (e.g., fasting, before/after (20). The long-term effectiveness of CGM regimen, and the clinician’s judgment. Pa- meals) may be helpful, as increased fre- needs to be determined. This technology tients with type 2 diabetes with stable quency has been shown to be inversely maybeparticularlyusefulinthosewith glycemia well within target may do well correlated with glycemic control (9). hypoglycemia unawareness and/or fre- with testing only twice per year. Unstable or Several randomized trials have called quent hypoglycemic episodes, although highly intensively managed patients (e.g., into question the clinical utility and cost- studies have not shown consistent re- pregnant women with type 1 diabetes) effectiveness of routine SMBG in noninsulin- ductions in severe hypoglycemia (20– may require testing more frequently than treated patients (10–12). A meta-analysis 22). A CGM device equipped with an every 3 months (27). care.diabetesjournals.org Glycemic Targets S41

Table 5.1—Mean glucose levels for speciﬁed A1C levels (24,28) Mean plasma glucose* Mean fasting glucose Mean premeal glucose Mean postmeal glucose Mean bedtime glucose A1C % (mmol/mol) mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L 6 (42) 126 7.0 ,6.5 (48) 122 6.8 118 6.5 144 8.0 136 7.5 6.5–6.99 (48–53) 142 7.9 139 7.7 164 9.1 153 8.5 7 (53) 154 8.6 .7.0–7.49 (53–58) 152 8.4 152 8.4 176 9.8 177 9.8 7.5–7.99 (58–64) 167 9.3 155 8.6 189 10.5 175 9.7 8 (64) 183 10.2 .8.0–8.5 (64–69) 178 9.9 179 9.9 206 11.4 222 12.3 9 (75) 212 11.8 10 (86) 240 13.4 11 (97) 269 14.9 12 (108) 298 16.5 A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG. *These estimates are based on ADAG data of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (28).

A1C Limitations type 2, and no diabetes (28), and an em- A1C GOALS The A1C test is subject to certain limita- pirical study of the average blood glucose For glycemic goals in children, please refer tions. Conditions that affect red blood levels at premeal, postmeal, and bedtime to Section 11 “Children and Adolescents.” cell turnover (hemolysis, blood loss) associated with specified A1C levels using For glycemic goals in pregnant women, and hemoglobin variants must be consid- data from the ADAG trial (24). The Amer- please refer to Section 12 “Management ered, particularly when the A1C result does ican Diabetes Association (ADA) and the of Diabetes in Pregnancy.” not correlate with the patient’sbloodglu- American Association for Clinical Chemis- cose levels. For patients in whom A1C/ try have determined that the correlation Recommendations estimated average glucose (eAG) and (r 5 0.92) in the ADAG trial is strong c A reasonable A1C goal for many , measured blood glucose appear discrep- enough to justify reporting both the A1C nonpregnant adults is 7% (53 A ant, clinicians should consider the possi- result and the eAG result when a clinician mmol/mol). bilities of hemoglobinopathy or altered orders the A1C test. Clinicians should c Providers might reasonably sug- red blood cell turnover and the options note that the mean plasma glucose num- gest more stringent A1C goals of more frequent and/or different timing bers in the table are based on ;2,800 (such as ,6.5% [48 mmol/mol]) of SMBG or CGM use. Other measures of readings per A1C in the ADAG trial. for selected individual patients if chronic glycemia such as fructosamine are this can be achieved without signif- A1C Differences in Ethnic Populations and available, but their linkage to average glu- icant hypoglycemia or other adverse Children cose and their prognostic significance are effects of treatment. Appropriate In the ADAG study, there were no signif- not as clear as for A1C (see Section 2 “Clas- patients might include those with icant differences among racial and ethnic sification and Diagnosis of Diabetes”). short duration of diabetes, type 2 groups in the regression lines between A1C does not provide a measure of gly- diabetes treated with lifestyle or A1C and mean glucose, although there cemic variability or hypoglycemia. For metformin only, long life expec- was a trend toward a difference between patients prone to glycemic variability, es- tancy, or no significant cardiovascu- the African/African American and non- pecially patients with type 1 diabetes or lar disease. C Hispanic white cohorts. A small study type 2 diabetes with severe insulin defi- c Less stringent A1C goals (such as comparing A1C to CGM data in children ciency, glycemic control is best evaluated ,8% [64 mmol/mol]) may be ap- with type 1 diabetes found a highly sta- by the combination of results from SMBG propriate for patients with a his- tistically significant correlation between and A1C. A1C may also confirm the accu- tory of severe hypoglycemia, A1C and mean blood glucose, although racy of the patient’s meter (or the patient’s limited life expectancy, advanced the correlation (r 5 0.7) was signifi- reported SMBG results) and the adequacy microvascular or macrovascular cantly lower than in the ADAG trial (29). of the SMBG testing schedule. complications, extensive comor- Whether there are significant differences bid conditions, or long-standing A1C and Mean Glucose in how A1C relates to average glucose in diabetes in whom the general Table 5.1 shows the correlation between children or in different ethnicities is an goal is difficult to attain despite A1C levels and mean glucose levels based area for further study (30,31). For the diabetes self-management educa- on two studies: the international A1C- time being, the question has not led to tion, appropriate glucose monitor- Derived Average Glucose (ADAG) trial, different recommendations about testing ing, and effective doses of multiple which based the correlation with A1C on A1C or to different interpretations of the glucose-lowering agents including frequent SMBG and CGM in 507 adults clinical meaning of given levels of A1C in insulin. B (83% non-Hispanic whites) with type 1, those populations. S42 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

A1C and Microvascular Complications poor control to fair/good control. These events (combined fatal or nonfatal MI Type 1 Diabetes analyses also suggest that further lower- and sudden death) in the intensive glyce- Hyperglycemia defines diabetes, and ing of A1C from 7% to 6% [53 mmol/mol mic control arm that did not reach statis- glycemic control is fundamental to dia- to 42 mmol/mol] is associated with fur- tical significance (P 5 0.052), and there betes management. The Diabetes Con- ther reduction in the risk of microvascular was no suggestion of benefit on other trol and Complications Trial (DCCT) (1), a complications, although the absolute risk CVD outcomes (e.g., stroke). However, af- prospective randomized controlled trial reductions become much smaller. Given ter 10 years of follow-up, those originally of intensive versus standard glycemic the substantially increased risk of hypo- randomly assigned to intensive glycemic control in patients with relatively recently glycemia in type 1 diabetes trials and control had significant long-term reduc- diagnosed type 1 diabetes, showed defin- with polypharmacy in type 2 diabetes, tions in MI (15% with sulfonylurea or in- itively that improved glycemic control is the risks of lower glycemic targets outweigh sulin as initial pharmacotherapy, 33% associated with significantly decreased the potential benefits on microvascular with metformin as initial pharmacother- rates of microvascular (retinopathy [32] complications. apy) and in all-cause mortality (13% and and diabetic kidney disease) and neuro- The concerning mortality findings in 27%, respectively) (37). pathic complications. Follow-up of the the ACCORD trial (42), discussed below, The ACCORD, ADVANCE, and VADT DCCT cohorts in the Epidemiology of and the relatively intense efforts required suggested no significant reduction in Diabetes Interventions and Complications to achieve near-euglycemia should also CVD outcomes with intensive glycemic (EDIC) study (33) demonstrated persis- be considered when setting glycemic tar- control in participants followed for tence of these microvascular benefits in gets. However, on the basis of physician 3.525.6 years who had more advanced previously intensively treated subjects, judgment and patient preferences, select type 2 diabetes than UKPDS partici- even though their glycemic control ap- patients, especially those with little co- pants. All three trials were conducted proximated that of previous standard morbidity and long life expectancy, may in participants with more long-standing arm subjects during follow-up. benefit from adopting more intensive gly- diabetes (mean duration 8–11 years) cemic targets (e.g., A1C target ,6.5% and either known CVD or multiple car- Type 2 Diabetes [48 mmol/mol]) as long as significant hy- diovascular risk factors. The target The Kumamoto Study (34) and UK Pro- poglycemia does not become a barrier. A1C among intensive control subjects spective Diabetes Study (UKPDS) (35,36) was ,6% (42 mmol/mol) in ACCORD, confirmed that intensive glycemic control A1C and Cardiovascular Disease ,6.5% (48 mmol/mol) in ADVANCE, was associated with significantly de- Outcomes and a 1.5% reduction in A1C compared creased rates of microvascular and neu- Cardiovascular Disease and Type 1 with control subjects in VADT, with ropathic complications in patients with Diabetes achieved A1C of 6.4% versus 7.5% type 2 diabetes. Long-term follow-up of Cardiovascular disease (CVD) is a more (46 mmol/mol vs. 58 mmol/mol) in the UKPDS cohorts showed enduring ef- common cause of death than microvas- ACCORD, 6.5% versus 7.3% (48 mmol/mol fects of early glycemic control on most cular complications in populations with vs. 56 mmol/mol) in ADVANCE, and microvascular complications (37). diabetes. There is evidence for a cardio- 6.9% versus 8.4% (52 mmol/mol vs. 68 Therefore, achieving glycemic control vascular benefit of intensive glycemic mmol/mol) in VADT. Details of these of A1C targets of ,7% (53 mmol/mol) control after long-term follow-up of studies are reviewed extensively in the has been shown to reduce microvascular study cohorts treated early in the course ADA position statement “Intensive Glyce- complications of diabetes and, in patients of type 1 and type 2 diabetes. In the mic Control and the Prevention of Cardio- with type 1 diabetes, mortality. If imple- DCCT, there was a trend toward lower vascular Events: Implications of the mented soon after the diagnosis of diabetes, risk of CVD events with intensive control. In ACCORD, ADVANCE, and VA Diabetes this target is associated with long-term the 9-year post-DCCT follow-up of the EDIC Trials: A Position Statement of the Amer- reduction in macrovascular disease. cohort, participants previously randomly ican Diabetes Association and a Scientific ACCORD, ADVANCE, and VADT assigned to the intensive arm had a signif- Statement of the American College of Three landmark trials (Action to Control icant 57% reduction in the risk of nonfatal Cardiology Foundation and the American Cardiovascular Risk in Diabetes [ACCORD], myocardial infarction (MI), stroke, or CVD Heart Association” (46). Action in Diabetes and Vascular Disease: death compared with those previously in The glycemic control comparison in Preterax and Diamicron MR Controlled thestandardarm(43).Thebenefitofin- ACCORD was halted early due to an in- Evaluation [ADVANCE], and Veterans Af- tensive glycemic control in this cohort with creased mortality rate in the intensive fairs Diabetes Trial [VADT]) showed that type 1 diabetes has been shown to persist compared with the standard arm lower A1C levels were associated with for several decades (44) and to be associ- (1.41% vs. 1.14% per year; hazard ratio reduced onset or progression of micro- ated with a modest reduction in all-cause 1.22 [95% CI 1.01–1.46]), with a similar vascular complications (38–40). mortality (45). increase in cardiovascular deaths. Anal- Epidemiological analyses of the DCCT Cardiovascular Disease and Type 2 ysis of the ACCORD data did not identify a (1) and UKPDS (41) demonstrate a cur- Diabetes clear explanation for the excess mortality vilinear relationship between A1C and In type 2 diabetes, there is evidence that in the intensive arm (42). microvascular complications. Such analyses more intensive treatment of glycemia in Longer-term follow-up has shown no suggest that, on a population level, the newly diagnosed patients may reduce evidence of cardiovascular benefitor greatest number of complications will be long-term CVD rates. During the UKPDS harm in the ADVANCE trial (47), which is averted by taking patients from very trial, there was a 16% reduction in CVD perhaps not unexpected given the narrow care.diabetesjournals.org Glycemic Targets S43

separation in A1C between groups. The Table 5.2—Summary of glycemic recommendations for nonpregnant adults with end-stage renal disease rate was lower diabetes in the intensive group over follow-up. A1C ,7.0% (53 mmol/mol)* However, 10-year follow-up of the VADT Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) cohort (48) showed a reduction in the risk Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L) of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] *More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, events per 1,000 person-years) with no known CVD or advanced microvascular complications, hypoglycemia unawareness, and benefit in cardiovascular or overall mor- individual patient considerations. tality. Heterogeneity of mortality effects †Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the beginning of across studies was noted, which may re- the meal, generally peak levels in patients with diabetes. flect differences in glycemic targets, therapeutic approaches, and population characteristics (49). of ,7% (53 mmol/mol). The issue of pre- and landmark glycemic control trials Mortality findings in ACCORD (42) and prandial versus postprandial SMBG targets such as the DCCT and UKPDS relied subgroup analyses of VADT (50) suggest is complex (54). Elevated postchallenge (2-h overwhelmingly on preprandial SMBG. that the potential risks of intensive glyce- oral glucose tolerance test) glucose values Additionally, a randomized controlled mic control may outweigh its benefits in have been associated with increased cardio- trial in patients with known CVD found higher-risk patients. In all three trials, se- vascular risk independent of fasting plasma no CVD benefit of insulin regimens tar- vere hypoglycemia was significantly more glucose in some epidemiological studies. In geting postprandial glucose compared likely in participants who were randomly subjects with diabetes, surrogate measures with those targeting preprandial glucose assigned to the intensive glycemic control of vascular pathology, such as endothelial (55). Therefore, it is reasonable for post- arm. Those patients with long duration of dysfunction, are negatively affected by prandial testing to be recommended for diabetes, a known history of severe hypo- postprandial hyperglycemia. It is clear that individuals who have premeal glucose val- glycemia, advanced atherosclerosis, or postprandial hyperglycemia, like prepran- ues within target but have A1C values advanced age/frailty may benefit from dial hyperglycemia, contributes to elevated above target. Taking postprandial plasma less aggressive targets (51,52). A1C levels, with its relative contribution be- glucose measurements 1–2 h after the Providers should be vigilant in pre- ing greater at A1C levels that are closer to start of a meal and using treatments aimed venting severe hypoglycemia in patients 7% (53 mmol/mol). However, outcome at reducing postprandial plasma glucose with advanced disease and should not studies have clearly shown A1C to be values to ,180mg/dL(10.0mmol/L) aggressively attempt to achieve near- the primary predictor of complications, may help to lower A1C. normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals. Many factors, including patient preferences, should be taken into account when developing a patient’sindi- vidualized goals (Table 5.2).

A1C and Glycemic Targets Numerous aspects must be considered when setting glycemic targets. The ADA proposes optimal targets, but each target must be individualized to the needs of each patient and his or her disease factors. When possible, such decisions should be made with the patient, reﬂecting his or her preferences, needs, and values. Figure 5.1 is not designed to be applied rigidly but to be used as a broad construct to guide clinical decision making (53), both in type 1 and type 2 diabetes. Recommended glycemic targets for many nonpregnant adults are shown in Table 5.2. The recommendations in- Figure 5.1—Depicted are patient and disease factors used to determine optimal A1C targets. clude blood glucose levels that appear Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those to correlate with achievement of an A1C toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (53). S44 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

An analysis of data from 470 partici- (e.g., bedtime snack to prevent overnight c Ongoing assessment of cognitive pants of the ADAG study (237 with hypoglycemia), exercise management, function is suggested with in- type 1 diabetes and 147 with type 2 dia- medication adjustment, glucose monitor- creased vigilance for hypoglyce- betes) found that actual average glucose ing, and routine clinical surveillance may mia by the clinician, patient, and levels associated with conventional A1C improve patient outcomes (61). Docu- caregivers if low cognition or de- targets were higher than older DCCT and mented symptomatic hypoglycemia and clining cognition is found. B ADA targets (Table 5.1) (24,28). These find- asymptomatic hypoglycemia are defined ings support that premeal glucose targets as occurring at a plasma glucose concen- Hypoglycemia is the major limiting fac- may be relaxed without undermining over- tration of #70 mg/dL (3.9 mmol/L) (61). tor in the glycemic management of type all glycemic control as measured by A1C. This level remains a general threshold for 1 and insulin-treated type 2 diabetes. These data have prompted a revision in defining hypoglycemia. Mild hypoglycemia may be inconve- the ADA-recommended premeal target In 2014, the ADA changed its glycemic nient or frightening to patients with to 80–130 mg/dL (4.4–7.2 mmol/L). target to 80–130 mg/dL (4.4–7.2 mmol/L). diabetes. Severe hypoglycemia is defined This change reflects the results of the as hypoglycemia requiring assistance HYPOGLYCEMIA ADAG study, which demonstrated that from another person. It is characterized higher glycemic targets corresponded to Recommendations by cognitive impairment that may be rec- A1C goals (24). An additional goal of rais- c Individuals at risk for hypogly- ognized or unrecognized and can prog- ing the lower range of the glycemic tar- cemia should be asked about ress to loss of consciousness, seizure, get was to limit overtreatment and symptomatic and asymptomatic coma, or death, and it is reversed by ad- provide a safety margin in patients ti- hypoglycemia at each encoun- ministration of rapid-acting glucose. Se- ter. C trating glucose-lowering drugs such as vere hypoglycemia can cause acute insulin to glycemic targets. c Glucose (15–20 g) is the preferred harm to the person with diabetes or treatment for the conscious in- others, especially if it causes falls, motor Hypoglycemia Treatment dividual with hypoglycemia, al- vehicle accidents, or other injury. A large Hypoglycemia treatment requires in- though any form of carbohydrate cohort study suggested that among older gestion of glucose- or carbohydrate- that contains glucose may be adults with type 2 diabetes, a history of containing foods. The acute glycemic used. Fifteen minutes after treat- severe hypoglycemia was associated with response correlates better with the glu- ment, if SMBG shows continued greater risk of dementia (56). Conversely, cose content of food than with the car- hypoglycemia, the treatment in a substudy of the ACCORD trial, cogni- bohydrate content of food. Pure glucose should be repeated. Once SMBG tive impairment at baseline or decline in is the preferred treatment, but any form returns to normal, the individual cognitive function during the trial was sig- of carbohydrate that contains glucose should consume a meal or snack nificantly associated with subsequent ep- will raise blood glucose. Added fat may to prevent recurrence of hypogly- isodes of severe hypoglycemia (57). retard and then prolong the acute gly- E cemia. Evidence from DCCT/EDIC, which in- cemic response. Ongoing insulin activity c Glucagon should be prescribed for volved younger adults and adolescents or insulin secretagogues may lead to recurrent hypoglycemia unless further all individuals at increased risk of with type 1 diabetes, found no associa- fi food is ingested after recovery. severe hypoglycemia, de ned as tion between frequency of severe hypo- hypoglycemia requiring assis- glycemia and cognitive decline (58), as Glucagon tance, and caregivers, school per- discussed in Section 11 “Children and Those in close contact with, or having sonnel, or family members of these Adolescents.” custodial care of, people with hypoglyce- individuals should be instructed in Severe hypoglycemia was associated mia-prone diabetes (family members, its administration. Glucagon admin- with mortality in participants in both the roommates, school personnel, child care istrationisnotlimitedtohealth standard and the intensive glycemia providers, correctional institution staff, or care professionals. E arms of the ACCORD trial, but the relation- coworkers) should be instructed on the use c Hypoglycemia unawareness or ships between hypoglycemia, achieved of glucagon kits. An individual does not one or more episodes of severe A1C, and treatment intensity were not need to be a health care professional to hypoglycemia should trigger re- straightforward. An association of severe safely administer glucagon. Care should evaluation of the treatment regi- hypoglycemia with mortality was also betakentoensurethatglucagonkitsare men. E found in the ADVANCE trial (59). An asso- not expired. c Insulin-treated patients with hy- ciation between self-reported severe hy- Hypoglycemia Prevention poglycemia unawareness or an ep- poglycemia and 5-year mortality has also isode of severe hypoglycemia Hypoglycemia prevention is a critical been reported in clinical practice (60). should be advised to raise their component of diabetes management. Young children with type 1 diabetes glycemic targets to strictly avoid SMBG and, for some patients, CGM are and the elderly are noted as particularly further hypoglycemia for at least essential tools to assess therapy and de- vulnerable to severe hypoglycemia be- several weeks in order to partially tect incipient hypoglycemia. Patients cause of their reduced ability to recognize reverse hypoglycemia unaware- should understand situations that in- hypoglycemic symptoms and effectively ness and reduce risk of future ep- crease their risk of hypoglycemia, such communicate their needs. Individualized isodes. A as fasting for tests or procedures, during patient education, dietary intervention or after intense exercise, and during care.diabetesjournals.org Glycemic Targets S45

sleep. Hypoglycemia may increase the hyperglycemic nonketotic hyperosmo- HbA1c by 0.25%. Ann Intern Med 2012;156:JC6– risk of harm to self or others, such as lar state, please refer to the ADA con- JC12 with driving. Teaching people with diabetes sensus report “Hyperglycemic Crises in 14. Malanda UL, Welschen LM, Riphagen II, Dekker JM, Nijpels G, Bot SD. Self-monitoring to balance insulin use and carbohydrate in- Adult Patients With Diabetes” (63). of blood glucose in patients with type 2 diabetes take and exercise are necessary, but these mellitus who are not using insulin. Cochrane strategies are not always sufficient for References Database Syst Rev 2012;1:CD005060 15. Tamborlane WV, Beck RW, Bode BW, et al.; prevention. 1. The Diabetes Control and Complications Trial Juvenile Diabetes Research Foundation Contin- In type 1 diabetes and severely insulin- Research Group. The effect of intensive treatment uous Glucose Monitoring Study Group. Contin- of diabetes on the development and progression deficient type 2 diabetes, hypoglycemia uous glucose monitoring and intensive treatment of long-term complications in insulin-dependent unawareness (or hypoglycemia-associated of type 1 diabetes. N Engl J Med 2008;359: diabetes mellitus. N Engl J Med 1993;329:977–986 1464–1476 autonomic failure) can severely compro- 2. Miller KM, Beck RW, Bergenstal RM, et al.; 16. Wong JC, Foster NC, Maahs DM, et al.; T1D mise stringent diabetes control and quality T1D Exchange Clinic Network. Evidence of a Exchange Clinic Network. Real-time continuous of life. This syndrome is characterized by strong association between frequency of self- glucose monitoring among participants in the monitoring of blood glucose and hemoglobin deficient counterregulatory hormone re- T1D Exchange clinic registry. Diabetes Care A1c levels in T1D Exchange clinic registry partic- lease, especially in older adults, and a di- 2014;37:2702–2709 ipants. Diabetes Care 2013;36:2009–2014 minished autonomic response, which 3. Polonsky WH, Fisher L, Schikman CH, et al. 17. Hommel E, Olsen B, Battelino T, et al.; both are risk factors for, and caused by, Structured self-monitoring of blood glucose sig- SWITCH Study Group. Impact of continuous glu- hypoglycemia. A corollary to this “vicious nificantly reduces A1C levels in poorly con- cose monitoring on quality of life, treatment satisfaction, and use of medical care resources: cycle” is that several weeks of avoidance trolled, noninsulin-treated type 2 diabetes: results from the Structured Testing Program analyses from the SWITCH study. Acta Diabetol – of hypoglycemia has been demonstrated study. Diabetes Care 2011;34:262–267 2014;51:845 851 to improve counterregulation and aware- 4. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good 18. Battelino T, Phillip M, Bratina N, Nimri R, ness to some extent in many patients (62). CB,FineMJ.DualuseofDepartmentofVet- Oskarsson P, Bolinder J. Effect of continuous Hence, patients with one or more episodes erans Affairs and Medicare benefits and use of glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care 2011;34:795–800 of severe hypoglycemia may benefitfrom test strips in veterans with type 2 diabetes mellitus. JAMA Intern Med 2015;175:26–34 19. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile at least short-term relaxation of glycemic 5. Grant RW, Huang ES, Wexler DJ, et al. Pa- Diabetes Research Foundation Continuous Glu- targets. tients who self-monitor blood glucose and their cose Monitoring Study Group. The effect of con- unused testing results. Am J Manag Care 2015; tinuous glucose monitoring in well-controlled INTERCURRENT ILLNESS 21:e119–e129 type 1 diabetes. Diabetes Care 2009;32:1378– 1383 For further information on management 6. Endocrine Society. Choosing wisely [Internet], 20. Yeh H-C, Brown TT, Maruthur N, et al. Com- of patients with hyperglycemia in the 2013. Available from http://www.choosingwisely .org/societies/endocrine-society/. Accessed 18 parative effectiveness and safety of methods of hospital, please refer to Section 13 August 2015 insulin delivery and glucose monitoring for di- “Diabetes Care in the Hospital.” 7. Rosenstock J, Davies M, Home PD, Larsen J, abetes mellitus: a systematic review and meta- – Stressful events (e.g., illness, trauma, Koenen C, Schernthaner G. A randomised, analysis. Ann Intern Med 2012;157:336 347 21. Choudhary P, Ramasamy S, Green L, et al. surgery, etc.) frequently aggravate glycemic 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when adminis- Real-time continuous glucose monitoring signif- control and may precipitate diabetic keto- tered as add-on to glucose-lowering drugs in icantly reduces severe hypoglycemia in hypogly- acidosis or nonketotic hyperosmolar state, insulin-naive people with type 2 diabetes. Dia- cemia-unaware patients with type 1 diabetes. life-threatening conditions that require im- betologia 2008;51:408–416 Diabetes Care 2013;36:4160–4162 mediate medical care to prevent complica- 8. Garber AJ. Treat-to-target trials: uses, inter- 22. Choudhary P, Rickels MR, Senior PA, et al. pretation and review of concepts. Diabetes Evidence-informed clinical practice recommen- tions and death. Any condition leading to Obes Metab 2014;16:193–205 dations for treatment of type 1 diabetes com- deterioration in glycemic control necessi- 9. Elgart JF, Gonzalez´ L, Prestes M, Rucci E, plicated by problematic hypoglycemia. Diabetes tates more frequent monitoring of blood Gagliardino JJ. Frequency of self-monitoring Care 2015;38:1016–1029 glucose; ketosis-prone patients also require blood glucose and attainment of HbA1c target 23. Bergenstal RM, Klonoff DC, Garg SK, et al.; urine or blood ketone monitoring. If accom- values. Acta Diabetol. 5 April 2015 [Epub ahead ASPIRE In-Home Study Group. Threshold-based of print] insulin-pump interruption for reduction of hy- panied by ketosis, vomiting, or alteration in 10. Farmer A, Wade A, Goyder E, et al. Impact poglycemia. N Engl J Med 2013;369:224–232 the level of consciousness, marked hyper- of self monitoring of blood glucose in the man- 24. Wei N, Zheng H, Nathan DM. Empirically glycemia requires temporary adjustment of agement of patients with non-insulin treated establishing blood glucose targets to achieve the treatment regimen and immediate in- diabetes: open parallel group randomised trial. HbA1c goals. Diabetes Care 2014;37:1048– 1051 teraction with the diabetes care team. The BMJ 2007;335:132 11. O’Kane MJ, Bunting B, Copeland M, Coates 25. Albers JW, Herman WH, Pop-Busui R, et al.; patient treated with noninsulin therapies VE; ESMON Study Group. Efficacy of self moni- Diabetes Control and Complications Trial/ or medical nutrition therapy alone may toring of blood glucose in patients with newly Epidemiology of Diabetes Interventions and temporarily require insulin. Adequate diagnosed type 2 diabetes (ESMON study): Complications Research Group. Effect of prior fluid and caloric intake must be ensured. randomised controlled trial. BMJ 2008;336: intensive insulin treatment during the Diabetes – Control and Complications Trial (DCCT) on pe- Infection or dehydration is more likely to 1174 1177 12. Simon J, Gray A, Clarke P, Wade A, Neil A, ripheral neuropathy in type 1 diabetes during necessitate hospitalization of the person Farmer A; Diabetes Glycaemic Education and the Epidemiology of Diabetes Interventions with diabetes than the person without Monitoring Trial Group. Cost effectiveness of and Complications (EDIC) Study. Diabetes Care diabetes. self monitoring of blood glucose in patients 2010;33:1090–1096 A physician with expertise in diabetes with non-insulin treated type 2 diabetes: eco- 26. Stratton IM, Adler AI, Neil HAW, et al. As- nomic evaluation of data from the DiGEM trial. sociation of glycaemia with macrovascular and management should treat the hospital- BMJ 2008;336:1177–1180 microvascular complications of type 2 diabetes ized patient. For further information on 13. Willett LR. Meta-analysis: self-monitoring (UKPDS 35): prospective observational study. diabetic ketoacidosis management or in non-insulin-treated type 2 diabetes improved BMJ 2000;321:405–412 S46 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

27. Jovanovicˇ L, Savas H, Mehta M, Trujillo A, glucose control and vascular outcomes in patients 50. Duckworth WC, Abraira C, Moritz TE, et al.; Pettitt DJ. Frequent monitoring of A1C during with type 2 diabetes. N Engl J Med 2008;358:2560– Investigators of the VADT. The duration of di- pregnancy as a treatment tool to guide therapy. 2572 abetes affects the response to intensive glucose Diabetes Care 2011;34:53–54 40. Ismail-Beigi F, Craven T, Banerji MA, et al.; control in type 2 subjects: the VA Diabetes Trial. 28. Nathan DM, Kuenen J, Borg R, Zheng H, ACCORD Trial Group. Effect of intensive treatment J Diabetes Complications 2011;25:355–361 Schoenfeld D, Heine RJ; A1c-Derived Average of hyperglycaemia on microvascular out- 51. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Glucose Study Group. Translating the A1C assay comesintype2diabetes:ananalysisofthe Steinman MA. Potential overtreatment of diabetes into estimated average glucose values. Diabetes ACCORD randomised trial. Lancet 2010;376: mellitus in older adults with tight glycemic control. Care 2008;31:1473–1478 419–430 JAMA Intern Med 2015;175:356–362 29. Wilson DM, Kollman; Diabetes Research in 41. Adler AI, Stratton IM, Neil HAW, et al. As- 52. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Children Network (DirecNet) Study Group. Re- sociation of systolic blood pressure with macro- Effect of patients’ risks and preferences on lationship of A1C to glucose concentrations in vascular and microvascular complications of health gains with plasma glucose level lowering children with type 1 diabetes: assessments by type 2 diabetes (UKPDS 36): prospective obser- in type 2 diabetes mellitus. JAMA Intern Med high-frequency glucose determinations by sen- vational study. BMJ 2000;321:412–419 2014;174:1227–1234 sors. Diabetes Care 2008;31:381–385 42. Gerstein HC, Miller ME, Byington RP, et al.; 53. Inzucchi SE, Bergenstal RM, Buse JB, et al. 30. Buse JB, Kaufman FR, Linder B, Hirst K, El Action to Control Cardiovascular Risk in Diabe- Management of hyperglycemia in type 2 diabe- Ghormli L, Willi S; HEALTHY Study Group. Dia- tes Study Group. Effects of intensive glucose tes, 2015: a patient-centered approach. Update betes screening with hemoglobin A(1c) versus lowering in type 2 diabetes. N Engl J Med to a position statement of the American Diabe- fasting plasma glucose in a multiethnic middle- 2008;358:2545–2559 tes Association and the European Association school cohort. Diabetes Care 2013;36:429–435 43. Nathan DM, Cleary PA, Backlund J-YC, et al.; for the Study of Diabetes. Diabetes Care 2015; 31. Kamps JL, Hempe JM, Chalew SA. Racial dis- Diabetes Control and Complications Trial/ 38:140–149 parity in A1C independent of mean blood glu- Epidemiology of Diabetes Interventions and 54. American Diabetes Association. Postpran- cose in children with type 1 diabetes. Diabetes Complications (DCCT/EDIC) Study Research dial blood glucose. Diabetes Care 2001;24: Care 2010;33:1025–1027 Group. Intensive diabetes treatment and cardio- 775–778 32. Lachin JM, White NH, Hainsworth DP, Sun W, vascular disease in patients with type 1 diabetes. 55. Raz I, Wilson PWF, Strojek K, et al. Effects of Cleary PA, Nathan DM; Diabetes Control and N Engl J Med 2005;353:2643–2653 prandial versus fasting glycemia on cardiovas- Complications Trial (DCCT)/Epidemiology of Dia- 44. Nathan DM, Zinman B, Cleary PA, et al.; cular outcomes in type 2 diabetes: the HEART2D betes Interventions and Complications (EDIC) Re- Diabetes Control and Complications Trial/ trial. Diabetes Care 2009;32:381–386 search Group. Effect of intensive diabetes therapy Epidemiology of Diabetes Interventions and 56. Whitmer RA, Karter AJ, Yaffe K, Quesenberry on the progression of diabetic retinopathy in pa- Complications (DCCT/EDIC) Research Group. CP Jr, Selby JV. 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Orchard TJ, Nathan DM, Zinman B, et al.; ACCORD trial. Diabetes Care 2012;35:787–793 34. Ohkubo Y, Kishikawa H, Araki E, et al. Inten- Writing Group for the DCCT/EDIC Research 58. Jacobson AM, Musen G, Ryan CM, et al.; sive insulin therapy prevents the progression of Group. Association between 7 years of intensive Diabetes Control and Complications Trial/ diabetic microvascular complications in Japa- treatment of type 1 diabetes and long-term Epidemiology of Diabetes Interventions and nese patients with non-insulin-dependent dia- mortality. JAMA 2015;313:45–53 Complications Study Research Group. Long- betes mellitus: a randomized prospective 6-year 46. Skyler JS, Bergenstal R, Bonow RO, et al.; term effect of diabetes and its treatment on study. Diabetes Res Clin Pract 1995;28:103–117 American Diabetes Association; American Col- cognitive function. N Engl J Med 2007;356: 35. UK Prospective Diabetes Study (UKPDS) lege of Cardiology Foundation; American Heart 1842–1852 Group. Effect of intensive blood-glucose control Association. Intensive glycemic control and the 59. Zoungas S, Patel A, Chalmers J, et al.; with metformin on complications in overweight prevention of cardiovascular events: implica- ADVANCE Collaborative Group. Severe hypogly- patients with type 2 diabetes (UKPDS 34). Lan- tions of the ACCORD, ADVANCE, and VA Diabe- cemia and risks of vascular events and death. N cet 1998;352:854–865 tes Trials: a position statement of the American Engl J Med 2010;363:1410–1418 36. UK Prospective Diabetes Study (UKPDS) Diabetes Association and a scientiﬁc statement 60. McCoy RG, Van Houten HK, Ziegenfuss JY, Group. Intensive blood-glucose control with sul- of the American College of Cardiology Founda- ShahND,WermersRA,SmithSA.Increased phonylureas or insulin compared with conven- tion and the American Heart Association. mortality of patients with diabetes reporting tional treatment and risk of complications in Diabetes Care 2009;32:187–192 severe hypoglycemia. Diabetes Care 2012;35: patients with type 2 diabetes (UKPDS 33). Lan- 47. Zoungas S, Chalmers J, Neal B, et al.; 1897–1901 cet 1998;352:837–853 ADVANCE-ON Collaborative Group. Follow-up of 61. Seaquist ER, Anderson J, Childs B, et al. Hy- 37. Holman RR, Paul SK, Bethel MA, Matthews blood-pressure lowering and glucose control in poglycemia and diabetes: a report of a work- DR, Neil HAW. 10-year follow-up of intensive type 2 diabetes. N Engl J Med 2014;371:1392–1406 group of the American Diabetes Association glucose control in type 2 diabetes. N Engl 48. Hayward RA, Reaven PD, Wiitala WL, et al.; and the Endocrine Society. Diabetes Care J Med 2008;359:1577–1589 VADT Investigators. Follow-up of glycemic con- 2013;36:1384–1395 38. Duckworth W, Abraira C, Moritz T, et al.; trol and cardiovascular outcomes in type 2 62. Cryer PE. Diverse causes of hypoglycemia- VADT Investigators. Glucose control and vascu- diabetes. N Engl J Med 2015;372:2197–2206 associated autonomic failure in diabetes. N Engl lar complications in veterans with type 2 diabetes. 49. Turnbull FM, Abraira C, Anderson RJ, et al. J Med 2004;350:2272–2279 N Engl J Med 2009;360:129–139 Intensive glucose control and macrovascular 63. Kitabchi AE, Umpierrez GE, Miles JM, Fisher 39. Patel A, MacMahon S, Chalmers J, et al.; outcomes in type 2 diabetes. Diabetologia JN. Hyperglycemic crises in adult patients with ADVANCE Collaborative Group. Intensive blood 2009;52:2288–2298 diabetes. Diabetes Care 2009;32:1335–1343 Diabetes Care Volume 39, Supplement 1, January 2016 S47

6. Obesity Management for the American Diabetes Association Treatment of Type 2 Diabetes

Diabetes Care 2016;39(Suppl. 1):S47–S51 | DOI: 10.2337/dc16-S009

There is strong and consistent evidence that obesity management can delay progression from prediabetes to type 2 diabetes (1,2) and may be beneﬁcial in the treatment of type 2 diabetes. In overweight and obese patients with type 2 diabetes, modest and sustained weight loss has been shown to improve glycemic control and to reduce the need for glucose-lowering medications (3–5). Small studies have demonstrated that in obese patients with type 2 diabetes more extreme dietary energy DIABETES 2 TYPE IN MANAGEMENT OBESITY 6. restriction with very low-calorie diets can reduce A1C to ,6.5% (48 mmol/mol) and fasting glucose to ,126 mg/dL (7.0 mmol/L) in the absence of pharmacological therapy or ongoing procedures (6,7). Weight loss–induced improvements in glycemia are most likely to occur early in the natural history of type 2 diabetes when obesity- associated insulin resistance has caused reversible b-cell dysfunction but insulin secretory capacity remains relatively preserved (5,8). Although the Action for Health in Diabetes (Look AHEAD) trial did not show that an intensive lifestyle intervention reduced cardiovascular events in overweight or obese adults with type 2 diabetes (9), it did show the feasibility of achieving and maintaining long-term weight loss in patients with type 2 diabetes. LOOK AHEAD In the Look AHEAD intensive lifestyle intervention group, mean weight loss was 4.7% (SE 0.2) at 8 years (10). Approximately 50% of intensive lifestyle intervention participants lost $5% and 27% lost $10% of their initial body weight at 8 years (10). Participants randomly assigned to the intensive lifestyle group achieved equivalent risk factor control but required fewer glucose-, blood pressure–, and lipid-lowering medications than those randomly assigned to standard care. Secondary analyses of the Look AHEAD trial and other large cardiovascular outcome studies document other beneﬁts of weight loss in patients with type 2 diabetes, including improvements in mobility, physical and sexual functioning, and health-related quality of life (11). The goal of this section is to provide evidence-based recommendations for dietary, pharmacological, and surgical interventions for obesity management as treatments for hyperglycemia in type 2 diabetes.

ASSESSMENT

Recommendation c At each patient encounter, BMI should be calculated and documented in the medical record. B

At each routine patient encounter, BMI should be calculated from the height and weight. BMI should be classified to determine the presence of overweight or obesity, discussedwiththepatient,anddocumentedinthepatientrecord(Table 6.1). In Asian Americans, the BMI cutoff points to define overweight and obesity are lower: normal (,23 kg/m2), overweight (23.0–27.4 kg/m2), obese (27.5–37.4 kg/m2), and extremely Suggested citation: American Diabetes Associa- obese ($37.5 kg/m2) (12). Providers should advise overweight and obese patients that tion. Obesity management for the treatment of higherBMIsincreasetheriskofcardiovascular disease and all-cause mortality. Providers type 2 diabetes. Sec. 6. In Standards of Medical ’ Care in Diabetesd2016. Diabetes Care 2016; should assess each patient s readiness to achieve weight loss and jointly determine 39(Suppl. 1):S47–S51 weight loss goals and intervention strategies. Strategies include diet, physical activity, Table 6.1 © 2016 by the American Diabetes Association. behavioral therapy, pharmacological therapy, and bariatric surgery ( ). The latter Readers may use this article as long as the work two strategies may be prescribed for carefully selected patients as adjuncts to diet, is properly cited, the use is educational and not physical activity, and behavioral therapy. for profit, and the work is not altered. S48 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

DIET, PHYSICAL ACTIVITY, AND control, and/or other obesity-related consumption of a reduced calorie diet, BEHAVIORAL THERAPY medical conditions, lifestyle changes and participation in high levels of phys- that result in modest and sustained ical activity (200–300 min/week). Some Recommendations weight loss produce clinically meaning- commercial and proprietary weight loss c Diet, physical activity, and behavioral ful reductions in blood glucose, A1C, and programs have shown promising weight therapy designed to achieve 5% triglycerides (3–5). Greater weight loss loss results (18). weight loss should be prescribed produces even greater benefits, including When provided by trained practi- for overweight and obese patients reductions in blood pressure, improve- tioners in medical care settings with with type 2 diabetes ready to ments in LDL and HDL cholesterol, and close medical monitoring, short-term achieve weight loss. A reductions in the need for medications (3-month) high-intensity lifestyle inter- c Such interventions should be high in- to control blood glucose, blood pressure, ventions that use very low-calorie diets tensity ($16 sessions in 6 months) and lipids (9,10). (defined as #800 kcal/day) and total and focus on diet, physical activity, meal replacements may achieve greater and behavioral strategies to achieve short-term weight loss (10–15%) than a 500–750 kcal/day energy deficit. A Lifestyle Interventions intensive behavioral lifestyle interven- c Diets that provide the same caloric Weight loss can be attained with life- tions that typically achieve 5% weight restriction but differ in protein, style programs that achieve a 500–750 loss. Weight regain following the cessation carbohydrate, and fat content are kcal/day energy deficit or provide ap- of high-intensity lifestyle interventions is equally effective in achieving proximately 1,200–1,500 kcal/day for greater than following intensive behavioral weight loss. A women and 1,500–1,800 kcal/day for lifestyle interventions unless a long-term c For patients who achieve short- men, adjusted for the individual’s base- comprehensive weight loss maintenance term weight loss goals, long-term line body weight. Although benefits may program is provided (19,20). ($1-year) comprehensive weight be seen with as little as 5% weight loss, maintenance programs should be sustained weight loss of $7% is optimal. PHARMACOTHERAPY prescribed. Such programs should These diets may differ in the types of provide at least monthly contact foods they restrict (such as high-fat or Recommendations c When choosing glucose-lowering and encourage ongoing monitoring high-carbohydrate foods) but are effec- medications for overweight or of body weight (weekly or more fre- tive if they create the necessary energy obese patients with type 2 diabetes, quently), continued consumption deficit (13–16). The diet choice should consider their effect on weight. E of a reduced calorie diet, and par- be based on the patient’shealthstatus c Whenever possible, minimize the ticipation in high levels of physical and preferences. medications for comorbid condi- activity (200–300 min/week). A Intensive behavioral lifestyle inter- tions that are associated with weight c To achieve weight loss of .5%, ventions should include $16 sessions gain. E short-term (3-month) high-intensity in 6 months and focus on diet, physical c Weight loss medications may be lifestyle interventions that use activity, and behavioral strategies to effective as adjuncts to diet, physical very low-calorie diets (#800 achieve an ;500–750 kcal/day energy activity, and behavioral counseling kcal/day) and total meal replace- deficit. Interventions should be pro- forselectedpatientswithtype2di- ments may be prescribed for vided by trained interventionists in ei- abetes and BMI $27 kg/m2.Potential carefully selected patients by ther individual or group sessions (17). benefits must be weighed against the trained practitioners in medical Overweight and obese patients with potential risks of the medications. A care settings with close medical type 2 diabetes who have lost weight c If a patient’s response to weight loss monitoring. To maintain weight during the 6-month intensive behavioral medications is ,5% after 3 months loss, such programs must incorpo- lifestyle intervention should be enrolled or if there are any safety or tolerabil- rate long-term comprehensive in long-term ($1-year) comprehensive ity issues at any time, the medication weight maintenance counseling. B weight loss maintenance programs should be discontinued and alterna- that provide at least monthly contact tive medications or treatment ap- Among overweight or obese patients with a trained interventionist and focus proaches should be considered. A with type 2 diabetes and inadequate on ongoing monitoring of body weight glycemic, blood pressure and lipid (weekly or more frequently), continued When considering pharmacological treatments for overweight or obese patients Table 6.1—Treatment for overweight and obesity in type 2 diabetes with type 2 diabetes, providers should first consider their choice of glucose- BMI category (kg/m2) lowering medications. Whenever possi- Treatment 23.0* or 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40 ble, medications should be chosen to Diet, physical activity, and promote weight loss or to be weight neu- behavioral therapy ┼┼┼┼┼ tral. Agents associated with weight loss Pharmacotherapy ┼┼┼┼ include metformin, a-glucosidase inhibi- Bariatric surgery ┼┼ tors, glucagon-like peptide 1 agonists, ┼Treatment may be indicated for selected motivated patients. amylin mimetics, and sodium–glucose *Cutoff points for Asian American individuals. cotransporter 2 inhibitors. Dipeptidyl care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S49

peptidase 4 inhibitors appear to be In general, pharmacological treatment education, lifestyle counseling, and weight neutral. Unlike these agents, insu- of obesity has been limited by low adher- encouragement to participate in Weight lin secretagogues, thiazolidinediones, and ence, modest efficacy, adverse effects, Watchers) in achieving a target A1C #6% insulin have often been associated with and weight regain after medication cessa- (42 mmol/mol) at 3 years among obese weight gain (see Section 7 “Approaches tion (21). patients with uncontrolled type 2 diabe- to Glycemic Treatment”). tes (mean A1C 9.3% [78 mmol/mol]). This BARIATRIC SURGERY A1C target was achieved by 38% (P , Concomitant Medications Recommendations 0.001) in the gastric bypass group, 24% Providers should carefully review the (P 5 0.01) in the sleeve gastrectomy patient’s concomitant medications c Bariatric surgery may be considered . 2 group, and 5% in the group that received and, whenever possible, minimize or for adults with BMI 35 kg/m and type 2 diabetes, especially if diabe- only medical therapy (26). Diabetes re- provide alternatives for medications mission rates tend to be higher with pro- that promote weight gain. The latter intes or associated comorbidities are fi cedures that bypass portions of the small clude atypical antipsychotics (clozapine, dif cult to control with lifestyle and B intestine and lower with procedures that olanzapine, risperidone, etc.) and an- pharmacological therapy. c Patients with type 2 diabetes who only restrict the stomach. tidepressants (tricyclic antidepressants, Younger age, shorter duration of selective serotonin reuptake inhibitors, have undergone bariatric surgery need lifelong lifestyle support type 2 diabetes, lower A1C, higher and monoamine oxidase inhibitors), serum insulin levels, and nonuse of glucocorticoids, oral contraceptives and annual medical monitoring, at a minimum. B insulin have all been associated with that contain progestins, anticonvulsants higher remission rates after bariatric including gabapentin, and a number of c Although small trials have shown a fi surgery (27). antihistamines and anticholinergics. glycemic bene tofbariatricsur- gery in patients with type 2 dia- Although bariatric surgery has been fi Approved Medications betes and BMI 30–35 kg/m2, shown to improve the metabolic pro les The U.S. Food and Drug Administration there is currently insufficient evi- of morbidly obese patients with type 1 (FDA) has approved five weight loss dence to generally recommend diabetes, the role of bariatric surgery in medications (or combination medica- surgeryinpatientswithBMI such patients will require larger and tions) for long-term use by patients #35 kg/m2. E longer studies (28). with BMI $27 kg/m2 with one or more obesity-associated comorbid conditions Bariatric and metabolic surgeries, either Disadvantages and by patients with BMI $30 kg/m2 gastric banding or procedures that involve Bariatric surgery is costly and has asso- who are motivated to lose weight (21– resecting, bypassing, or transposing sec- ciated risks. Morbidity and mortality 23). Medications approved for long-term tions of the stomach and small intestine, rates directly related to the surgery weight loss and weight loss mainte- can be effective weight loss treatments have decreased considerably in recent nance and their advantages and disad- for severe obesity when performed as years, with 30-day mortality rates vantages are summarized in Table 6.2. part of a comprehensive weight manage- now 0.2% for laparoscopic procedures, The rationale for weight loss medica- ment program with lifelong lifestyle sup- similar to those for laparoscopic cholecys- tions is to help patients to more consis- port and medical monitoring. In one tectomy, and 2.1% for open procedures tently adhere to low-calorie diets and to meta-analysis, gastric banding resulted (29,30). Outcomes vary depending on reinforce lifestyle changes including phys- in less weight loss than sleeve gastrec- the procedure and the experience of ical activity. Providers should be knowl- tomy and Roux-en-Y gastric bypass the surgeon and center. Longer-term edgeable about the product label and (1-year excess weight loss ;33% vs. concerns include dumping syndrome should balance the potential benefits of ;70%) (24). National guidelines sup- (nausea, colic, diarrhea), vitamin and fi successful weight loss against the poten- port consideration of bariatric surgery mineral de ciencies, osteoporosis, and, tial risks of the medication for each pa- for people with type 2 diabetes with rarely, severe hypoglycemia from insulin tient. All medications are FDA pregnancy BMI .35 kg/m2. hypersecretion. More recent studies also category X. These medications are con- suggest that patients who undergo bari- traindicated in women who are or may Advantages atric surgery may be at increased risk for become pregnant. Women in their repro- Treatment with bariatric surgery has substance use, including drug and alcohol ductive years must be cautioned to use a been shown to achieve near or complete use and cigarette smoking (31). Cohort reliable method of contraception. normalization of glycemia 2 years follow- studies attempting to match surgical ing surgery in 72% of patients (compared and nonsurgical subjects suggest that Assessing Efficacy and Safety with 16% in a matched control group the procedure may reduce longer-term Efficacy and safety should be assessed at treated with lifestyle and pharmacologi- mortality (25). least monthly for the first 3 months of treat- cal interventions) (25). A study evaluated In contrast, a propensity score– ment. If a patient’s response is deemed in- the effectiveness of surgical intervention adjusted analysis of older, severely obese sufficient (weight loss ,5%) or if there are (Roux-en-Y gastric bypass or sleeve gas- patients in Veterans Affairs Medical Cen- any safety or tolerability issues at any time, trectomy) and medical therapy compared ters found that bariatric surgery was not the medication should be discontinued and with medical therapy alone (quarterly associated with decreased mortality com- alternative medications or treatment ap- visits, pharmacological therapy, self- pared with usual care (mean follow-up proaches should be considered. monitoring of blood glucose, diabetes 6.7 years) (32). Retrospective analyses 5 bst aaeetfrteTeteto ye2Diabetes 2 Type of Treatment the for Management Obesity S50

Table 6.2—Medications approved by the FDA for the long-term treatment of obesity 1-Year weight change status2–5 – Generic drug name, % Patients with $5% Adverse effects2,6 12 (proprietary name[s]) and Average wholesale Average weight loss loss of baseline dosage strength and form Adult dosing frequency price (per month)1 relative to placebo weight Common7 Serious7 Lipase inhibitor Orlistat (Alli) 60 mg caps or 60 mg or 120 mg t.i.d. $41–82 (60 mg) 2.5 kg (60 mg) 35–73% Abdominal pain/discomfort, oily Liver failure and oxalate orlistat (Xenical) 120 mg caps (during or up to 1 h $615 (120 mg) 3.4 kg (120 mg) spotting/stool, fecal urgency, nephropathy after a low-fat meal) malabsorption of fat-soluble vitamins (A, D, E, K) and medications (e.g., cyclosporine, thyroid hormone replacement, or anticonvulsants), potentiation of the effects of warfarin

Selective serotonin (5-HT) 5-HT2C receptor agonist Lorcaserin (Belviq) 10 mg tabs 10 mg b.i.d. $263 3.2 kg 38–48% Hypoglycemia, headache, fatigue Serotonin syndrome or NMS-like reactions, heart valve disorder (,2.4%), bradycardia Sympathomimetic amine anorectic/antiepileptic combination Phentermine/topiramate ER (Qsymia) Recommended dose: 3.75 mg/23 mg $239 (maximum 6.7 kg (7.5 mg/46 mg) 45–70% Paresthesia, xerostomia, constipation, Topiramate is teratogenic and 3.75 mg/23 mg caps, q.d. for 14 days, then increase to dose using the 8.9 kg (15 mg/92 mg) headache has been associated with 7.5 mg/46 mg caps, 7.5 mg/46 mg q.d. highest strength) cleft lip/palate 11.25 mg/69 mg caps, Maximum dose: 15 mg/92 mg q.d. 15 mg/92 mg caps Opioid antagonist/aminoketone antidepressant combination Naltrexone/bupropion (Contrave) Maximum dose: two tablets of Contrave $239 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, headache, Depression, precipitation 8 mg/90 mg tabs b.i.d. for a total daily dosage of naltrexone (32 mg/360 mg) vomiting of mania 32 mg/bupropion 360 mg Acylated human glucagon-like peptide 1 receptor agonist Liraglutide (Saxenda) Maintenance dose: 3 mg s.c. q.d. $1,282 5.8–5.9 kg 51–73% Hypoglycemia, nausea, vomiting, Pancreatitis, thyroid C-cell ﬁ

6 mg/mL pre lled pen diarrhea, constipation, headache tumors in rodents, Care Diabetes contraindicated in patients with personal/family history of MTC or MEN2, acute renal failure

All medications are FDA pregnancy category X; these medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method 2016 January 1, Supplement 39, Volume of contraception. Caps, capsules; ER, extended release; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets. 1RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO. 2Physicians’ Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO. 3Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86. 4Astrup A, Carraro R, Finer N, et al.; NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012;36:843–854. 5Wadden TA, Hollander P, Klein S, et al.; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443–1451. 6DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. 7Selective common (deﬁned as an incidence of .5%) and serious adverse effects are noted. Refer to the medication package inserts for full information about adverse effects, cautions, and contraindications. 8Data of common adverse effects for Xenical were derived from seven double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes), but the percentage of patients with type 2 diabetes was not reported. In clinical trials in obese patients with diabetes, hypoglycemia and abdominal distension were also observed. 9Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes. 10 Data of common adverse effects for Qsymia were derived from four clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2 diabetes. 11 Data of common adverse effects for Contrave were derived from ﬁve double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2diabetes. 12 Data of common adverse effects for Saxenda were derived from clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes). Percentage of patients with type 2 diabetes was not reported. care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S51

and modeling studies suggest that bariat- intervention: the Look AHEAD study. Obesity 23. Pi-Sunyer X, Astrup A, Fujioka K, et al.; ric surgery may be cost-effective or even (Silver Spring) 2014;22:5–13 SCALE Obesity and Prediabetes NN8022-1839 cost-saving for patients with type 2 di- 11. Wilding JPH. The importance of weight Study Group. A randomized, controlled trial of management in type 2 diabetes mellitus. Int J 3.0 mg of liraglutide in weight management. abetes, but the results are largely de- Clin Pract 2014;68:682–691 N Engl J Med 2015;373:11–22 pendent on assumptions about the 12. WHO Expert Consultation. Appropriate 24. Chang S-H, Stoll CRT, Song J, Varela JE, long-term effectiveness and safety of body-mass index for Asian populations and its Eagon CJ, Colditz GA. The effectiveness and risks the procedures (33,34). Understanding implications for policy and intervention strate- of bariatric surgery: an updated systematic re- – fi gies. Lancet 2004;363:157 163 view and meta-analysis, 2003-2012. JAMA Surg the long-term bene ts and risks of bari- 13. Sacks FM, Bray GA, Carey VJ, et al. Compar- 2014;149:275–287 atric surgery in individuals with type 2 ison of weight-loss diets with different compo- 25. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. diabetes, especially those who are not sitions of fat, protein, and carbohydrates. N Engl Association of bariatric surgery with long-term severely obese, will require well-de- J Med 2009;360:859–873 remission of type 2 diabetes and with microvas- signed clinical trials, with optimal med- 14. de Souza RJ, Bray GA, Carey VJ, et al. Effects cular and macrovascular complications. JAMA of 4 weight-loss diets differing in fat, protein, 2014;311:2297–2304 ical therapy as the comparator (35). and carbohydrate on fat mass, lean mass, vis- 26. Schauer PR, Bhatt DL, Kirwan JP, et al.; Unfortunately, such studies may not ceral adipose tissue, and hepatic fat: results STAMPEDE Investigators. Bariatric surgery be feasible (36). from the POUNDS LOST trial. Am J Clin Nutr versus intensive medical therapy for diabetesd 2012;95:614–625 3-year outcomes. N Engl J Med 2014;370:2002– 15. Johnston BC, Kanters S, Bandayrel K, et al. 2013 References Comparison of weight loss among named diet 27. Still CD, Wood GC, Benotti P, et al. Preop- 1. Tuomilehto J, Lindstrom¨ J, Eriksson JG, et al.; programs in overweight and obese adults: a erative prediction of type 2 diabetes remission Finnish Diabetes Prevention Study Group. Pre- meta-analysis. JAMA 2014;312:923–933 after Roux-en-Y gastric bypass surgery: a retro- vention of type 2 diabetes mellitus by changes 16. Jensen MD, Ryan DH, Apovian CM, et al.; spective cohort study. Lancet Diabetes Endocri- in lifestyle among subjects with impaired glu- American College of Cardiology/American Heart nol 2014;2:38–45 cose tolerance. N Engl J Med 2001;344:1343– Association Task Force on Practice Guidelines; 28. Brethauer SA, Aminian A, Rosenthal RJ, 1350 Obesity Society. 2013 AHA/ACC/TOS guideline Kirwan JP, Kashyap SR, Schauer PR. Bariatric sur- 2. Knowler WC, Barrett-Connor E, Fowler SE, for the management of overweight and obesity gery improves the metabolic profile of morbidly et al.; Diabetes Prevention Program Research in adults: a report of the American College of obese patients with type 1 diabetes. Diabetes Group. Reduction in the incidence of type 2 Cardiology/American Heart Association Task Force Care 2014;37:e51–e52 diabetes with lifestyle intervention or metfor- on Practice Guidelines and The Obesity Society. J 29. Buchwald H, Estok R, Fahrbach K, Banel D, min. N Engl J Med 2002;346:393–403 Am Coll Cardiol 2014;63(25 Pt B):2985–3023 Sledge I. Trends in mortality in bariatric surgery: 3. UK Prospective Diabetes Study 7. UK Pro- 17. Selph S, Dana T, Bougatsos C, Blazina I, Patel a systematic review and meta-analysis. Surgery spective Diabetes Study 7: response of fasting H, Chou R. Screening for abnormal glucose and 2007;142:621–632 plasma glucose to diet therapy in newly pre- type 2 diabetes mellitus: a systematic review to 30. The Longitudinal Assessment of Bariatric senting type II diabetic patients, UKPDS Group. update the 2008 U.S. Preventive Services Task Surgery (LABS) Consortium. Peri-operative Metabolism 1990;39:905–912 Force Recommendation [Internet], 2015. safety in the longitudinal assessment of bari- 4. Goldstein DJ. Beneficial health effects of Rockville, MD, Agency for Healthcare Research atric surgery. N Engl J Med 2009;361:445– modest weight loss. Int J Obes Relat Metab Dis- and Quality (Report No.: 13-05190-EF-1. U.S. 454 ord 1992;16:397–415 Preventive Services Task Force Evidence Syn- 31. Conason A, Teixeira J, Hsu C-H, Puma L, 5. Pastors JG, Warshaw H, Daly A, Franz M, theses, formerly Systematic Evidence Reviews) Knafo D, Geliebter A. Substance use following Kulkarni K. The evidence for the effectiveness 18. Gudzune KA, Doshi RS, Mehta AK, et al. Ef- bariatric weight loss surgery. JAMA Surg 2013; of medical nutrition therapy in diabetes man- ficacy of commercial weight-loss programs: an 148:145–150 agement. Diabetes Care 2002;25:608–613 updated systematic review. Ann Intern Med 32. Maciejewski ML, Livingston EH, Smith VA, 6. Lim EL, Hollingsworth KG, Aribisala BS, Chen 2015;162:501–512 et al. Survival among high-risk patients after MJ,MathersJC,TaylorR.Reversaloftype2 19. Tsai AG, Wadden TA. The evolution of bariatric surgery. JAMA 2011;305:2419–2426 diabetes: normalisation of beta cell function in very-low-calorie diets: an update and meta- 33. Hoerger TJ, Zhang P, Segel JE, Kahn HS, association with decreased pancreas and liver tri- analysis. Obesity (Silver Spring) 2006;14: Barker LE, Couper S. Cost-effectiveness of acylglycerol. Diabetologia 2011;54:2506–2514 1283–1293 bariatric surgery for severely obese adults 7. Jackness C, Karmally W, Febres G, et al. Very 20. Johansson K, Neovius M, Hemmingsson E. with diabetes. Diabetes Care 2010;33:1933– low-calorie diet mimics the early beneficial ef- Effects of anti-obesity drugs, diet, and exercise 1939 fect of Roux-en-Y gastric bypass on insulin sen- on weight-loss maintenance after a very- 34. Keating CL, Dixon JB, Moodie ML, Peeters sitivity and b-cell function in type 2 diabetic low-calorie diet or low-calorie diet: a systematic A, Playfair J, O’Brien PE. Cost-efficacy of sur- patients. Diabetes 2013;62:3027–3032 review and meta-analysis of randomized con- gically induced weight loss for the manage- 8. Rothberg AE, McEwen LN, Kraftson AT, trolled trials. Am J Clin Nutr 2014;99:14–23 ment of type 2 diabetes: a randomized Fowler CE, Herman WH. Very-low-energy diet 21. Yanovski SZ, Yanovski JA. Long-term drug controlled trial. Diabetes Care 2009;32:580– for type 2 diabetes: an underutilized therapy? treatment for obesity: a systematic and clinical 584 J Diabetes Complications 2014;28:506–510 review. JAMA 2014;311:74–86 35. Wolfe BM, Belle SH. Long-term risks and 9. Wing RR, Bolin P, Brancati FL, et al.; Look 22. Greenway FL, Fujioka K, Plodkowski RA, benefits of bariatric surgery: a research chal- AHEAD Research Group. Cardiovascular effects et al.; COR-I Study Group. Effect of naltrexone lenge. JAMA 2014;312:1792–1793 of intensive lifestyle intervention in type 2 plus bupropion on weight loss in overweight 36. Courcoulas AP, Goodpaster BH, Eagleton JK, diabetes. N Engl J Med 2013;369:145–154 and obese adults (COR-I): a multicentre, rando- et al. Surgical vs medical treatments for type 2 10. Look AHEAD Research Group. Eight-year mised, double-blind, placebo-controlled, phase diabetes mellitus: a randomized clinical trial. weight losses with an intensive lifestyle 3 trial. Lancet 2010;376:595–605 JAMA Surg 2014;149:707–715 S52 Diabetes Care Volume 39, Supplement 1, January 2016

7. Approaches to Glycemic American Diabetes Association Treatment Diabetes Care 2016;39(Suppl. 1):S52–S59 | DOI: 10.2337/dc16-S010

PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES

Recommendations c Most people with type 1 diabetes should be treated with multiple-dose insulin injections (three to four injections per day of basal and prandial insulin) or continuous subcutaneous insulin infusion. A c Consider educating individuals with type 1 diabetes on matching prandial insulin dose to carbohydrate intake, premeal blood glucose, and anticipated activity. E c Most individuals with type 1 diabetes should use insulin analogs to reduce hypoglycemia risk. A c Individuals who have been successfully using continuous subcutaneous insulin infusion should have continued access after they turn 65 years of age. E

Insulin Therapy Insulin is the mainstay of therapy for individuals with type 1 diabetes. There are excellent reviews to guide the initiation and management of insulin therapy to achieve desired glycemic goals (1). Although most studies of multiple-dose insulin

7. APPROACHES TO GLYCEMIC TREATMENT versus pump therapy have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favoring insulin pump therapy 20.30% [95% CI 20.58 to 20.02]) and severe hypoglycemia rates in children and adults (2). A large randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values (3). Intensive management through pump therapy/continuous glucose monitoring and active patient/family participation should be strongly encouraged (4–6). Selected individuals who have mastered carbohydrate counting should be educated that fat increases glucose concentrations and insulin requirements (7). The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive insulin therapy (three or more injections per day of insulin) or continuous subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part of improved glycemia and better outcomes (8,9). The study was carried out with short-acting and intermediate-acting human insulins. Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive insulin therapy was associated with a high rate of severe hypoglycemia (62 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia in type 1 diabetes, while matching the A1C lowering of human insulins (10,11). Rapid-acting inhaled insulin used before meals in type 1 diabetes leads to inferior A1C lowering when compared with aspart insulin, with less hypoglycemia across all A1C target categories (12). Suggested citation: American Diabetes Associa- Postprandial glucose excursions can be better controlled by adjusting the timing tion. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd2016. of prandial (bolus) insulin dose administration. The optimal time to inject prandial Diabetes Care 2016;39(Suppl. 1):S52–S59 insulin varies, based on the type of insulin injected (regular, rapid-acting analog, © 2016 by the American Diabetes Association. inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrate Readers may use this article as long as the work consumption. Recommendations for prandial insulin dose administration should is properly cited, the use is educational and not therefore be individualized. for proﬁt, and the work is not altered. care.diabetesjournals.org Approaches to Glycemic Treatment S53

Recommended therapy for type 1 di- insulin requirements (6.6 units/day, P , c A patient-centered approach abetes consists of the following: 0.001) and led to small reductions in should be used to guide the choice weight and total and LDL cholesterol but of pharmacological agents. Con- 1. Multiple-dose insulin injections (three not to improved glycemic control (abso- siderations include efficacy, cost, to four injections per day of basal and lute A1C reduction 0.11%, P 5 0.42) (14). potential side effects, weight, co- prandial insulin) or CSII therapy. Incretin-Based Therapies morbidities, hypoglycemia risk, 2. Match prandial insulin to carbohy- Therapies approved for the treatment of and patient preferences. E drate intake, premeal blood glucose, type 2 diabetes are currently being eval- c For patients with type 2 diabetes and anticipated physical activity. uated in type 1 diabetes. Glucagon-like who are not achieving glycemic 3. For most patients (especially those at peptide 1 (GLP-1) agonists and dipep- goals, insulin therapy should not elevated risk of hypoglycemia), use tidyl peptidase 4 (DPP-4) inhibitors are be delayed. B insulin analogs. not currently FDA approved for those 4. For patients with frequent nocturnal with type 1 diabetes but are being stud- An American Diabetes Association/ hypoglycemia, recurrent severe hy- ied in this population. European Association for the Study of poglycemia, and/or hypoglycemia – Diabetes position statement (17) evalu- unawareness, a sensor-augmented Sodium Glucose Cotransporter 2 ated the data and developed recom- low glucose threshold suspend pump Inhibitors Sodium–glucose cotransporter 2 (SGLT2) mendations, including advantages and may be considered. inhibitors provide insulin-independent disadvantages, for antihyperglycemic Pramlintide glucose lowering by blocking glucose re- agents for patients with type 2 diabetes. Pramlintide, an amylin analog, is an absorption in the proximal renal tubule A patient-centered approach is stressed, agent that delays gastric emptying, by inhibiting SGLT2. These agents including patient preferences, cost, and blunts pancreatic secretion of glucagon, provide modest weight loss and blood potential side effects of each class, effects and enhances satiety. It is a U.S. Food pressure reduction. There are three on body weight, and hypoglycemia risk. and Drug Administration (FDA)-approved FDA-approved agents for use in patients Lifestyle modifications that improve therapy for use in adults with type 1 di- with type 2 diabetes, but there are in- health (see Section 3 “Foundations of abetes. It has been shown to induce sufficient data to recommend treatment Care and Comprehensive Medical Eval- weight loss and lower insulin dose. Con- in type 1 diabetes (15). The FDA recently uation”) should be emphasized along current reduction of prandial insulin issued a warning about the risk of keto- with any pharmacological therapy. dosing is required to reduce the risk of acidosis with SGLT2 inhibitors in individ- Initial Therapy severe hypoglycemia. uals with type 1 or type 2 diabetes. Most patients should begin with life- Symptoms of ketoacidosis include nau- style changes, which may include life- Pancreas and Islet Cell Transplantation sea, vomiting, abdominal pain, tiredness, style counseling, setting a physical Pancreas and islet cell transplantation and dyspnea. Urinary tract infections activity goal of 150 min/week minimum, have been shown to normalize glucose leading to urosepsis and pyelonephritis and weight loss counseling to lose a min- levels but require lifelong immunosup- may also occur with SGLT2 inhibitors. Pa- imum of 7% of body weight (for details pression to prevent graft rejection and tients should stop taking their SGLT2 in- on lifestyle therapy, see Section 6 “Obe- recurrence of autoimmune islet destruc- hibitor and seek medical attention sity Management for the Treatment of tion. Given the potential adverse effects immediately if they have symptoms of Type 2 Diabetes”). When lifestyle efforts of immunosuppressive therapy, pan- ketoacidosis (16). creas transplantation should be reserved alone do not achieve or maintain glyce- for patients with type 1 diabetes under- PHARMACOLOGICAL THERAPY mic goals, metformin monotherapy going simultaneous renal transplanta- FOR TYPE 2 DIABETES should be added at, or soon after, diagnosis, unless there are contraindications tion, following renal transplantation, Recommendations or intolerance. Metformin has a long- or for those with recurrent ketoacidosis c Metformin, if not contraindicated standing evidence base for efficacy and or severe hypoglycemia despite aggres- and if tolerated, is the preferred safety, is inexpensive, and may reduce sive glycemic management (13). Islet initial pharmacological agent for risk of cardiovascular events and death cell transplantation remains investiga- type 2 diabetes. A (18). Accumulating observational data tional. Autoislet transplantation may c Consider initiating insulin therapy suggest that metformin may be safely be considered for patients requiring to- (with or without additional agents) continued down to glomerular filtration tal pancreatectomy who meet eligibility in patients with newly diagnosed rate(GFR)of45mL/min/1.73m2 or even criteria. type 2 diabetes and markedly symp- 30 mL/min/1.73 m2 (19). If metformin is tomatic and/or elevated blood glu- Investigational Agents used in the lower GFR range, the dose cose levels or A1C. E Metformin should be reduced and patients should c If noninsulin monotherapy at max- Adding metformin to insulin therapy may beadvisedtostopthemedicationfornau- imum tolerated dose does not reduce insulin requirements and improve sea, vomiting, and dehydration. In patients achieve or maintain the A1C target metabolic control in overweight/obese with metformin intolerance or contraindi- over 3 months, then add a second patients with poorly controlled type 1 dications, consider an initial drug from other oral agent, a glucagon-like peptide abetes. In a meta-analysis, metformin in classes depicted in Fig. 7.1 under “Dual 1 receptor agonist, or basal insulin. A type 1 diabetes was found to reduce therapy” and proceed accordingly. S54 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any speciﬁc preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 17 for description of efﬁcacy categorization. †Consider starting at this stage when A1C is $9% (75 mmol/mol). ‡Consider starting at this stage when blood glucose is $300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is $10–12% (86–108 mmol/mol), especially if symptomatic or catabolic features are present, in which case basal insulin 1 mealtime insulin is the preferred initial regimen. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (17).

Combination Therapy medical, psychosocial, and health eco- may be low-value based on high cost and Although there are numerous trials nomic outcomes (21). moderate glycemic effect (24). comparing dual therapy with metformin If the A1C target is not achieved after Rapid-acting secretagogues (megliti- alone, few directly compare drugs as approximately 3 months, consider a com- nides) may be used instead of sulfonyl- add-on therapy. A comparative effec- bination of metformin and one of these six ureas in patients with irregular meal tiveness meta-analysis (20) suggests treatment options: sulfonylurea, thiazolidi- schedules or those who develop late that overall each new class of noninsulin nedione, DPP-4 inhibitors (22), SGLT2 in- postprandial hypoglycemia on a sulfo- agents added to initial therapy lowers hibitors, GLP-1 receptor agonists, or basal nylurea. Other drugs not shown in the A1C around 0.9–1.1%. A comprehensive insulin (Fig. 7.1). Drug choice is based on figure (e.g., a-glucosidase inhibitors, co- listing, including the cost, is available in patient preferences (23), as well as various lesevelam, bromocriptine, pramlintide) Table 7.1. The ongoing Glycemia Reduc- patient, disease, and drug characteristics, may be tried in specific situations, but tion Approaches in Diabetes: A Compar- with the goal of reducing blood glucose are generally not favored due to modest ative Effectiveness Study (GRADE) will levels while minimizing side effects, espe- efficacy, the frequency of administra- compare the effect of four major drug cially hypoglycemia. Figure 7.1 emphasizes tion, and/or side effects. classes (sulfonylurea, DPP-4 inhibitor, drugs commonly used in the U.S. and/or For all patients, consider initiating GLP-1 analog, and basal insulin) over Europe. Cost-effectiveness models have therapy with a dual combination when 4 years on glycemic control and other suggested that some of the newer agents A1C is $9% (75 mmol/mol) to more care.diabetesjournals.org Table 7.1—Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes (17) Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Advantages Disadvantages Cost* Biguanides c Metformin Activates AMP-kinase (? other) c ↓ Hepatic glucose production c Extensive experience c Gastrointestinal side effects Low c No hypoglycemia (diarrhea, abdominal cramping) c ↓ CVD events (UKPDS) c Vitamin B12 deficiency c Contraindications: CKD, acidosis, hypoxia, dehydration, etc. c Lactic acidosis risk (rare)

Sulfonylureas 2nd Generation Closes KATP channels on b-cell c ↑ Insulin secretion c Extensive experience c Hypoglycemia Low c Glyburide/ plasma membranes c ↓ Microvascular risk c ↑ Weight glibenclamide (UKPDS) c Glipizide c Gliclazide† c Glimepiride

Meglitinides (glinides) c Repaglinide Closes KATP channels on b-cell c ↑ Insulin secretion c ↓ Postprandial glucose c Hypoglycemia Moderate c Nateglinide plasma membranes excursions c ↑ Weight c Dosing flexibility c Frequent dosing schedule TZDs c Pioglitazone‡ Activates the nuclear c ↑ Insulin sensitivity c No hypoglycemia c ↑ Weight Low c Rosiglitazone§ transcription factor PPAR-g c Durability c Edema/heart failure c ↑ HDL-C c Bone fractures c ↓ Triglycerides c ↑ LDL-C (rosiglitazone) (pioglitazone) c ? ↑ MI (meta-analyses, c ? ↓ CVD events rosiglitazone) (PROactive, pioglitazone) a-Glucosidase inhibitors c Acarbose Inhibits intestinal a-glucosidase c Slows intestinal carbohydrate c No hypoglycemia c Generally modest A1C efficacy Low to c Miglitol digestion/absorption c ↓ Postprandial glucose c Gastrointestinal side effects moderate excursions (flatulence, diarrhea) c ? ↓ CVD events (STOP- c Frequent dosing schedule NIDDM) c Nonsystemic DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, increasing c ↑ Insulin secretion (glucose c No hypoglycemia c Angioedema/urticaria and other High c Vildagliptin† postprandial active incretin dependent) c Well tolerated immune-mediated dermatological c Saxagliptin (GLP-1, GIP) concentrations c ↓ Glucagon secretion (glucose effects c Linagliptin dependent) c ? Acute pancreatitis

c Alogliptin c ? ↑ Heart failure hospitalizations S55 Treatment Glycemic to Approaches Bile acid sequestrants c Colesevelam Binds bile acids in intestinal tract, c ? ↓ Hepatic glucose production c No hypoglycemia c Generally modest A1C efﬁcacy High increasing hepatic bile acid c ? ↑ Incretin levels c ↓ LDL-C c Constipation production c ↑ Triglycerides c May ↓ absorption of other medications Dopamine-2 agonists c Bromocriptine Activates dopaminergic receptors c Modulates hypothalamic c No hypoglycemia c Generally modest A1C efﬁcacy High (quick release)§ regulation of metabolism c ? ↓ CVD events (Cycloset c Dizziness/syncope c ↑ Insulin sensitivity Safety Trial) c Nausea c Fatigue c Rhinitis Continued on p. S56 5 prahst lcmcTreatment Glycemic to Approaches S56

Table 7.1—Continued Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Advantages Disadvantages Cost* SGLT2 inhibitors c Canagliflozin Inhibits SGLT2 in the proximal c Blocks glucose reabsorption by c No hypoglycemia c Genitourinary infections High c Dapagliflozin‡ nephron the kidney, increasing c ↓ Weight c Polyuria c Empagliflozin glucosuria c ↓ Blood pressure c Volume depletion/hypotension/ c Effective at all stages of dizziness type 2 diabetes c ↑ LDL-C c Associated with lower c ↑ Creatinine (transient) CVD event rate and c DKA, urinary tract infections mortality in patients leading to urosepsis, pyelonephritis with CVD (EMPA-REG OUTCOME) GLP-1 receptor agonists c Exenatide Activates GLP-1 receptors c ↑ Insulin secretion (glucose c No hypoglycemia c Gastrointestinal side effects High c Exenatide extended dependent) c ↓ Weight (nausea/vomiting/diarrhea) release c ↓ Glucagon secretion (glucose c ↓ Postprandial glucose c ↑ Heart rate c Liraglutide dependent) excursions c ? Acute pancreatitis c Albiglutide c Slows gastric emptying c ↓ Some cardiovascular c C-cell hyperplasia/medullary c Lixisenatide† c ↑ Satiety risk factors thyroid tumors in animals c Dulaglutide c Injectable c Training requirements Amylin mimetics c Pramlintide§ Activates amylin receptors c ↓ Glucagon secretion c ↓ Postprandial glucose c Generally modest A1C efficacy High c Slows gastric emptying excursions c Gastrointestinal side effects c ↑ Satiety c ↓ Weight (nausea/vomiting) c Hypoglycemia unless insulin dose is simultaneously reduced c Injectable c Frequent dosing schedule c Training requirements c c ↑ c c

Insulins Rapid-acting analogs Activates insulin receptors Glucose disposal Nearly universal Hypoglycemia Moderate to Care Diabetes - Lispro c ↓ Hepatic glucose production response c Weight gain high# - Aspart c Theoretically unlimited c ? Mitogenic effects - Glulisine c Suppresses ketogenesis efﬁcacy c Training requirements - Inhaled insulin c ↓ Microvascular risk c Patient reluctance c Short-acting (UKPDS) c Injectable (except inhaled insulin) - Human Regular c Pulmonary toxicity (inhaled insulin) 2016 January 1, Supplement 39, Volume c Intermediate-acting - Human NPH c Basal insulin analogs - Glargine - Detemir - Degludec† c Premixed (several types) CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; EMPA-REG OUTCOME, BI 10773 (Empagliﬂozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (31); GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR-g, peroxisome proliferator–activated receptor g; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (32); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (33); TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (34,35). Cycloset trial of quick-release bromocriptine (36). *Cost is based on lowest-priced member of the class (see ref. 17). †Not licensed in the U.S. ‡Initial concerns regarding bladder cancer risk are decreasing after subsequent study. §Not licensed in Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs . human insulins) and dosage. Adapted with permission from Inzucchi et al. (17). care.diabetesjournals.org Approaches to Glycemic Treatment S57

Figure 7.2—Approach to starting and adjusting insulin in type 2 diabetes (17). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (17). expeditiously achieve the target A1C elevated blood glucose levels or A1C. control in patients with type 2 diabetes level. Insulin has the advantage of being Many patients with type 2 diabetes initiating insulin (25). fi effective where other agents may not be eventually require and bene tfromin- Basal Insulin and should be considered as part of any sulin therapy. Providers may wish to Basal insulin alone is the most conve- fl combination regimen when hyperglyce- consider regimen exibility when de nient initial insulin regimen, beginning mia is severe, especially if symptoms are vising a plan for the initiation and ad- at 10 units or 0.1–0.2 units/kg, depend- present or any catabolic features (weight justment of insulin therapy in people ing on the degree of hyperglycemia. loss, ketosis) are present. Consider ini- with type 2 diabetes (Fig. 7.2). The pro- Basal insulin is usually prescribed in con- tiating combination insulin injectable gressive nature of type 2 diabetes and junction with metformin and possibly therapy when blood glucose is $300– its therapies should be regularly and ob- one additional noninsulin agent. While 350 mg/dL (16.7–19.4 mmol/L) and/or jectively explained to patients. For pa- A1C is $10–12% (86–108 mmol/mol). As tients with type 2 diabetes who are not there is evidence for reduced risk of hy- the patient’s glucose toxicity resolves, the achieving glycemic goals, providers should poglycemia with newer, longer-acting, regimen may, potentially, be simplified. promptly initiate insulin therapy. basal insulin analogs, people with type Providers should avoid using insulin 2 diabetes without history of hypogly- Insulin Therapy asathreatordescribingitasafailureor cemia or severe hypoglycemia may use Consider initiating insulin therapy (with punishment. Equipping patients with an NPH safely at much lower cost (24,26). or without additional agents) in patients algorithm for self-titration of insulin Concentrated preparation of basal in- with newly diagnosed type 2 diabetes doses based on self-monitoring of blood sulinsuchasU-500regularisfive times and markedly symptomatic and/or glucose (SMBG) improves glycemic as potent per volume of insulin (i.e., S58 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

0.01 mL ;5 units of U-100 regular) and current insulin dose and then providing of hypoglycemia. N Engl J Med 2013;369:224– has a delayed onset and longer one-half of this amount as basal and 232 duration of action than U-100 regular. 4. Wood JR, Miller KM, Maahs DM, et al.; T1D one-half as mealtime insulin, the latter Exchange Clinic Network. Most youth with U-300 glargine and U-200 degludec are split evenly between three meals. It is crit- type 1 diabetes in the T1D Exchange clinic reg- three and two times, respectively, as ical that individuals who have been suc- istry do not meet American Diabetes Associa- potent per volume, have a longer dura- cessfully using CSII should have continued tion or International Society for Pediatric and tion of action, and may allow higher Adolescent Diabetes clinical guidelines. Diabe- access after they turn 65 years of age (30). tes Care 2013;36:2035–2037 doses of insulin administration in Inhaled Insulin 5. Kmietowicz Z. Insulin pumps improve control smaller volumes. These concentrated Inhaled insulin is now available for pran- and reduce complications in children with preparationsmaybemorecomfortable type 1 diabetes. BMJ 2013;347:f5154 dial use with a more limited dosing for the patient and allow better absorp- 6. Phillip M, Battelino T, Atlas E, et al. Nocturnal range and may require serial lung func- fi tion. However, they are more expen- glucose control with an arti cial pancreas at a dia- tion testing prior to and after starting betes camp. N Engl J Med 2013;368:824–833 sive, and accurate dosing may be more therapy. 7. Wolpert HA, Atakov-Castillo A, Smith SA, complicated. Steil GM. Dietary fat acutely increases glucose If basal insulin has been titrated to an Treatment Strategies concentrations and insulin requirements in Figure 7.2 acceptable fasting blood glucose level, focuses solely on sequential patients with type 1 diabetes: implications for but A1C remains above target, consider insulin strategies, describing the num- carbohydrate-based bolus dose calculation and ber of injections and the relative com- intensive diabetes management. Diabetes Care advancing to combination injectable – plexity and flexibility of each stage. Once 2013;36:810 816 therapy (Fig. 7.2) to cover postprandial 8. The Diabetes Control and Complications Trial glucose excursions. Options include an insulin regimen is initiated, dose ti- Research Group. The effect of intensive treat- adding a GLP-1 receptor agonist (27) or tration is important, with adjustments ment of diabetes on the development and progression of long-term complications in insulin- mealtime insulin, consisting of one to made in both mealtime and basal insulins based on the prevailing blood glu- dependent diabetes mellitus. N Engl J Med 1993; three injections of rapid-acting insulin – cose levels and an understanding of the 329:977 986 analog (lispro, aspart, or glulisine) ad- 9. Nathan DM, Cleary PA, Backlund J-YC, et al.; fi ministered just before eating. A less pharmacodynamic pro le of each for- Diabetes Control and Complications Trial/ studied alternative, transitioning from mulation (pattern control). Epidemiology of Diabetes Interventions and Noninsulin agents may be continued, Complications (DCCT/EDIC) Study Research basal insulin to twice-daily premixed Group. Intensive diabetes treatment and car- (or biphasic) insulin analogs (70/30 as- although sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are diovascular disease in patients with type 1 di- part mix, 75/25 or 50/50 lispro mix), abetes. N Engl J Med 2005;353:2643–2653 could also be considered; pharmacody- typically stopped once more complex in- 10. DeWitt DE, Hirsch IB. Outpatient insulin namic profiles make them suboptimal to sulin regimens beyond basal are used. In therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;289:2254–2264 cover postprandial glucose excursions. patients with suboptimal blood glucose control, especially those requiring in- 11. Rosenstock J, Dailey G, Massi-Benedetti M, Bolus Insulin creasing insulin doses, adjunctive use Fritsche A, Lin Z, Salzman A. Reduced hypoglyce- Some individuals with type 2 diabetes mia risk with insulin glargine: a meta-analysis com- of thiazolidinediones (usually pioglita- paring insulin glargine with human NPH insulin in may require bolus insulin dosing in ad- zone) or SGLT2 inhibitors may be helpful type 2 diabetes. Diabetes Care 2005;28:950–955 dition to basal insulin. Rapid-acting an- in improving control and reducing the 12. MannKind Corporation. Briefing Document: alogs are preferred due to their prompt amount of insulin needed. Comprehen- Endocrinologic and Metabolic Drug Advisory Committee. AFREZZA (insulin human [rDNA origin]) onset of action after dosing. The FDA sive education regarding SMBG, diet, ex- recently approved a more concentrated inhalation powder. An ultra-rapid acting insulin ercise, and the avoidance of and response treatment to improve glycemic control in adult formulation of rapid-acting insulin ana- to hypoglycemia are critically important patients with diabetes mellitus [Internet], 2014. log, U-200 (200 units/mL), dosed 15 min in any patient using insulin. Available from http://www.fda.gov/downloads/ or immediately prior to a meal. AdvisoryCommittees/CommitteesMeetingMaterials/ Regular human insulin and human BARIATRIC SURGERY Drugs/EndocrinologicandMetabolicDrugsAdvisory NPH-Regular premixed formulations Bariatric surgery also improves glycemic Committee/UCM390865.pdf. Accessed 6 November 2015 (70/30) are less costly alternatives to control in type 2 diabetes. Its effects are 13. American Diabetes Association. Pancreas rapid-acting insulin analogs and pre- discussed in Section 6 “Obesity Man- and islet transplantation in type 1 diabetes. Di- mixed insulin analogs, respectively, agement for the Treatment of Type 2 abetes Care 2006;29:935 but their pharmacodynamic profiles Diabetes.” 14. Vella S, Buetow L, Royle P, Livingstone S, make them suboptimal to cover post- Colhoun HM, Petrie JR. The use of metformin References in type 1 diabetes: a systematic review of effi- prandial glucose excursions. cacy. Diabetologia 2010;53:809–820 1. Wallia A, Molitch ME. Insulin therapy for 15. Chiang JL, Kirkman MS, Laffel LM, Peters AL; Continuous Subcutaneous Insulin Infusion type 2 diabetes mellitus. JAMA 2014;311: Type 1 Diabetes Sourcebook Authors. Type 1 di- A less commonly used and more costly 2315–2325 abetes through the life span: a position state- “ – ” 2. Yeh H-C, Brown TT, Maruthur N, et al. Com- alternative to basal bolus therapy ment of the American Diabetes Association. with multiple daily injections is CSII (in- parative effectiveness and safety of methods of Diabetes Care 2014;37:2034–2054 sulin pump) (28,29). In addition to the insulin delivery and glucose monitoring for di- 16. U.S. Food and Drug Administration. SGLT2 abetes mellitus: a systematic review and meta- suggestions provided for determining inhibitors: drug safety communication – labels analysis. Ann Intern Med 2012;157:336–347 to include warnings about too much acid the starting dose of mealtime insulin 3. Bergenstal RM, Klonoff DC, Garg SK, et al.; in the blood and serious urinary tract infec- under a basal–bolus regimen, another ASPIRE In-Home Study Group. Threshold- tions [Internet], 4 December 2015. Available method consists of adding up the total based insulin-pump interruption for reduction from http://www.fda.gov/safety/medwatch/ care.diabetesjournals.org Approaches to Glycemic Treatment S59

safetyinformation/safetyalertsforhumanmedical 24. Institute for Clinical and Economic Review. infusion versus multiple daily injections in older products/ucm475553.htm. Accessed 7 Decem- Controversies in the management of patients adults with type 2 diabetes. Diabetes Care 2005; ber 2015 with type 2 diabetes [Internet], 2014. Available 28:1568–1573 17. Inzucchi SE, Bergenstal RM, Buse JB, et al. from http://cepac.icer-review.org/wp-content/ 31. Zinman B, Wanner C, Lachin JM, et al.; Management of hyperglycemia in type 2 diabetes, uploads/2014/08/CEPAC-T2D-Final-Report- EMPA-REG OUTCOME Investigators. Empagli- 2015: a patient-centered approach. Update to a December-22.pdf. Accessed 6 November 2015 ﬂozin, cardiovascular outcomes, and mortality position statement of the American Diabetes As- 25. Blonde L, Merilainen M, Karwe V, Raskin P; in type 2 diabetes. N Engl J Med. 17 September sociation and the European Association for the TITRATE Study Group. Patient-directed titration 2015 [Epub ahead of print]. DOI: 10.1056/ Study of Diabetes. Diabetes Care 2015;38:140– for achieving glycaemic goals using a once-daily NEJMoa1504720 149 basal insulin analogue: an assessment of two 32. Dormandy JA, Charbonnel B, Eckland DJA, et al.; 18. Holman RR, Paul SK, Bethel MA, Matthews different fasting plasma glucose targetsdthe PROactive Investigators. Secondary prevention DR, Neil HA. 10-year follow-up of intensive glu- TITRATE study. Diabetes Obes Metab 2009;11: of macrovascular events in patients with type 2 cose control in type 2 diabetes. N Engl J Med 623–631 diabetes in the PROactive Study (PROspective 2008;359:1577–1589 26. Tricco AC, Ashoor HM, Soobiah C, et al. pioglitAzone Clinical Trial In macroVascular Events): 19. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, Safety, effectiveness, and cost of long-acting a randomised controlled trial. Lancet 2005;366: McGuire DK. Metformin in patients with versus intermediate-acting insulin for type 1 di- 1279–1289 type 2 diabetes and kidney disease: a systematic abetes: protocol for a systematic review and 33. Chiasson J-L, Josse RG, Gomis R, Hanefeld review. JAMA 2014;312:2668–2675 network meta-analysis. Syst Rev 2013;2:73 M, Karasik A, Laakso M; STOP-NIDDM Trial Re- 20. Bennett WL, Maruthur NM, Singh S, et al. 27. Eng C, Kramer CK, Zinman B, Retnakaran R. search Group. Acarbose for prevention of type 2 Comparative effectiveness and safety of medi- Glucagon-like peptide-1 receptor agonist and diabetes mellitus: the STOP-NIDDM randomised cations for type 2 diabetes: an update including basal insulin combination treatment for the trial. Lancet 2002;359:2072–2077 new drugs and 2-drug combinations. Ann Intern management of type 2 diabetes: a systematic 34. UK Prospective Diabetes Study (UKPDS) Group. Med 2011;154:602–613 review and meta-analysis. Lancet 2014;384: Intensive blood-glucose control with sulphonylureas 21. Nathan DM, Buse JB, Kahn SE, et al.; GRADE 2228–2234 or insulin compared with conventional treatment Study Research Group. Rationale and design of 28. Reznik Y, Cohen O, Aronson R, et al.; OpT2mise and risk of complications in patients with type 2 di- the glycemia reduction approaches in diabetes: Study Group. Insulin pump treatment compared abetes (UKPDS 33). Lancet 1998;352:837–853 a comparative effectiveness study (GRADE). with multiple daily injections for treatment of 35. UK Prospective Diabetes Study (UKPDS) Diabetes Care 2013;36:2254–2261 type 2 diabetes (OpT2mise): a randomised Group. Effect of intensive blood-glucose control 22. Green JB, Bethel MA, Armstrong PW, et al.; open-label controlled trial. Lancet 2014;384: with metformin on complications in overweight TECOS Study Group. Effect of sitagliptin on car- 1265–1272 patients with type 2 diabetes (UKPDS 34). Lan- diovascular outcomes in type 2 diabetes. N Engl 29. Johnson SL, McEwen LN, Newton CA, et al. The cet 1998;352:854–865 J Med 2015;373:232–242 impact of continuous subcutaneous insulin infusion 36. Gaziano JM, Cincotta AH, O’Connor CM, 23. Vijan S, Sussman JB, Yudkin JS, Hayward RA. and multiple daily injections of insulin on glucose et al. Randomized clinical trial of quick- Effect of patients’ risks and preferences on variability in older adults with type 2 diabetes. release bromocriptine among patients with health gains with plasma glucose level lowering J Diabetes Complications 2011;25:211–215 type 2 diabetes on overall safety and cardio- in type 2 diabetes mellitus. JAMA Intern Med 30. Herman WH, Ilag LL, Johnson SL, et al. A vascular outcomes. Diabetes Care 2010;33: 2014;174:1227–1234 clinical trial of continuous subcutaneous insulin 1503–1508 S60 Diabetes Care Volume 39, Supplement 1, January 2016

8. Cardiovascular Disease and Risk American Diabetes Association Management Diabetes Care 2016;39(Suppl. 1):S60–S71 | DOI: 10.2337/dc16-S011

For prevention and management of diabetes complications in children and adolescents, please refer to Section 11 “Children and Adolescents.” In all patients with diabetes, cardiovascular risk factors should be systematically assessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria. Abnor- mal risk factors should be treated as described elsewhere in these guidelines. Atherosclerotic cardiovascular disease (ASCVD)ddefined as acute coronary syndromes (ACSs), a history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clearriskfactorsforASCVD,anddiabetesitself confers independent risk. Numerous studieshaveshowntheefficacy of controlling individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed simultaneously. There is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade (1) and that ASCVD morbidity and mortality have decreased (2–4). HYPERTENSION/BLOOD PRESSURE CONTROL 8. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT Recommendations

Screening and Diagnosis c Blood pressure should be measured at every routine visit. Patients found to have elevated blood pressure should have blood pressure confirmed on a separate day. B Goals Systolic Targets c People with diabetes and hypertension should be treated to a systolic blood pressure goal of ,140 mmHg. A c Lower systolic targets, such as ,130 mmHg, may be appropriate for certain individuals with diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional atherosclerotic cardiovascular disease risk factors, if they can be achieved without undue treatment burden. C Diastolic Targets c Individuals with diabetes should be treated to a diastolic blood pressure goal of ,90 mmHg. A c Lower diastolic targets, such as ,80 mmHg, may be appropriate for certain individuals with diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional atherosclerotic cardiovascular disease risk factors, if they can be achieved without undue treatment burden. B Suggested citation: American Diabetes Associa- tion. Cardiovascular disease and risk manage- Treatment ment. Sec. 8. In . Standards of Medical Care in c Patients with blood pressure 120/80 mmHg should be advised on lifestyle Diabetesd2016. Diabetes Care 2016;39(Suppl. 1): changes to reduce blood pressure. B S60–S71 c Patients with confirmed office-based blood pressure .140/90 mmHg should, © 2016 by the American Diabetes Association. in addition to lifestyle therapy, have prompt initiation and timely subsequent Readers may use this article as long as the work titration of pharmacological therapy to achieve blood pressure goals. A is properly cited, the use is educational and not for profit, and the work is not altered. care.diabetesjournals.org Cardiovascular Disease and Risk Management S61

arm supported at heart level, after 5 min Diabetes and Vascular Disease: Preterax c In older adults, pharmacological ther- of rest. Cuff size should be appropriate for and Diamicron MR Controlled Evalua- apy to achieve treatment goals of the upper-arm circumference. Elevated tion–Blood Pressure (ADVANCE-BP), ex- ,130/70 mmHg is not recom- values should be confirmed on a separate amined the benefit of tighter blood mended; treating to systolic blood day. Postural changes in blood pressure pressure control in patients with type 2 pressure ,130 mmHg has not been and pulse may be evidence of autonomic diabetes. shown to improve cardiovascular out- neuropathy and therefore require adjust- comes and treating to diastolic blood ACCORD. The ACCORD trial examined ment of blood pressure targets. pressure ,70 mmHg has been asso- whether a lower SBP of ,120 mmHg in Home blood pressure self-monitoring ciated with higher mortality. C patients with type 2 diabetes at high risk and 24-h ambulatory blood pressure c Lifestyle therapy for elevated blood for ASCVD provided greater cardiovascular monitoring may provide evidence of pressure consists of weight loss, if protection than an SBP of 130–140 mmHg white-coat hypertension, masked hyper- overweight or obese; a Dietary Ap- (10). The study did not find a benefitin tension, or other discrepancies between proaches to Stop Hypertension primary end point (nonfatal MI, nonfatal office and “true” blood pressure. Studies (DASH)-style dietary pattern includ- stroke, and cardiovascular death) compar- in individuals without diabetes found ing reducing sodium and increasing ing intensive blood pressure treatment that home measurements may better potassium intake; moderation of al- (goal ,120 mmHg, average blood pres- correlate with ASCVD risk than office cohol intake; and increased physical sure achieved 5 119/64 mmHg on 3.4 measurements (5,6). However, most of activity. B medications) with standard treatment the evidence of benefits of hyperten- c Pharmacological therapy for patients (average blood pressure achieved 5 sion treatment in people with diabetes with diabetes and hypertension 143/70 mmHg on 2.1 medications). In isbasedonoffice measurements. should comprise a regimen that in- ACCORD, there was no benefitofag- cludes either an ACE inhibitor or an Treatment Goals gressive blood pressure lowering, de- angiotensin receptor blocker but not Epidemiological analyses show that spite the extra cost and efforts. B both. If one class is not tolerated, blood pressure .115/75 mmHg is asso- ADVANCE. In ADVANCE, the active blood the other should be substituted. C ciated with increased cardiovascular pressure intervention arm (a single-pill, c Multiple-drug therapy (including a event rates and mortality in individuals fixed-dose combination of perindopril thiazide diuretic and ACE inhibitor/ with diabetes and that systolic blood and indapamide) showed a significant angiotensin receptor blocker, at pressure (SBP) .120 mmHg predicts reductionintheriskoftheprimarycom- maximal doses) is generally required long-term end-stage renal disease. posite end point (major macrovascular to achieve blood pressure targets. B Randomized clinical trials have dem- or microvascular event) and significant c If ACE inhibitors, angiotensin recep- onstrated the benefit (reduction of reductions in the risk of death from any tor blockers, or diuretics are used, CHD events, stroke, and diabetic kidney cause and of death from cardiovascular serum creatinine/estimated glomer- disease) of lowering blood pressure to causes (11). The baseline blood pres- ular filtration rate and serum potas- ,140 mmHg systolic and ,90 mmHg sure among the study subjects was sium levels should be monitored. E diastolic in individuals with diabetes 145/81 mmHg. Compared with the pla- c In pregnant patients with diabetes (7). There is limited prespecified clinical cebo group, the patients treated with a and chronic hypertension, blood trial evidence for the benefits of lower single-pill, fixed-dose combination of pressure targets of 110–129/65–79 SBP or diastolic blood pressure (DBP) perindopril and indapamide experienced mmHg are suggested in the interest targets (8). A meta-analysis of random- an average reduction of 5.6 mmHg in SBP of optimizing long-term maternal ized trials of adults with type 2 diabetes and 2.2 mmHg in DBP. The final blood health and minimizing impaired fetal comparing intensive blood pressure pressure in the treated group was growth. E targets (upper limit of 130 mmHg systolic 136/73 mmHg, not quite the intensive and 80 mmHg diastolic) with standard or tight control achieved in ACCORD. Hypertension is a common diabetes comor- targets (upper limit of 140–160 mmHg Recently published 6-year follow-up bidity that affects many patients, with the systolic and 85–100 mmHg diastolic) of the ADVANCE–Post-Trial Observational prevalence depending on type of diabetes, foundnosignificant reduction in mortal- Study (ADVANCE-ON) reported that the age, BMI, and ethnicity. Hypertension is a ity or nonfatal MI. There was a statistically reductions in the risk of death from any major risk factor for both ASCVD and micro- significant 35% relative risk (RR) reduc- cause and of death from cardiovascular vascular complications. In type 1 diabetes, tion in stroke with intensive targets, but causes in the intervention group were hypertension is often the result of under- the absolute risk reduction was only 1%, attenuated, but remained significant (12). lying diabetic kidney disease, while in and intensive targets were associated SPRINT. Systolic Blood Pressure Interven- type 2 diabetes, it usually coexists with with an increased risk for adverse events tion Trial (SPRINT) was a multicenter, ran- other cardiometabolic risk factors. such as hypotension and syncope (9). domized controlled trial that compared Screening and Diagnosis ACCORD, ADVANCE, SPRINT, AND HOT two strategies for treating SBP with either Blood pressure measurement should be Given the epidemiological relationship be- the standard target of ,140 mmHg or an done by a trained individual and should tween lower blood pressure and better intensive target of ,120 mmHg; primary follow the guidelines established for the long-term clinical outcomes, two landmark outcomes were MI, ACS, stroke, heart general population: measurement in the trials, Action to Control Cardiovascular Risk failure, and death due to cardiovascular seated position, with feet on the floor and in Diabetes (ACCORD) and Action in disease. Of note, patients with diabetes S62 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

were excluded from participating in this additional ASCVD risk factors such as dysli- antihypertensive agents, including ACE in- trial, so the results have no direct impli- pidemia, smoking, or obesity (14). The hibitors, angiotensin receptor blockers cations for blood pressure management 2016 American Diabetes Association (ARBs), b-blockers, diuretics, and calcium in this population. The National Insti- (ADA) Standards of Care recommendations channel blockers, has been shown to be tutes of Health halted this study early have been revised to reflect the higher- effective in reducing cardiovascular because intensive therapy with a target quality evidence that exists to support a events. Several studies have suggested SBP of 120 mmHg demonstrated a risk goal of DBP ,90 mmHg, although lower that ACE inhibitors may be superior to reduction of cardiovascular events by targets may be appropriate for certain in- dihydropyridine calcium channel blockers almost a third and the risk of death dividuals. These targets are in harmoniza- in reducing cardiovascular events (18–20). by almost a quarter compared with a tion with a recent publication by the Eighth However, several studies have also shown target SBP of 140 mmHg (13). Joint National Committee that recom- no specific advantage to ACE inhibitors as mended for individuals over 18 years of an initial treatment of hypertension in the HOT. The results from the ACCORD and Hypertension Optimal Treatment (HOT) age with diabetes a DBP threshold of general hypertensive population, while , , (14) trials support the recommendation 90 mmHg and SBP 140 mmHg (8). showing an advantage of initial therapy to achieve blood pressure levels ,140/90 with low-dose thiazide diuretics on car- mmHg and underscore the important Treatment Strategies diovascular outcomes (17,21,22). clinical difference between patients who Lifestyle Modification Angiotensin Receptor Blockers. In people are able to easily achieve lower blood Although there are no well-controlled with diabetes, inhibitors of the renin- pressure levels (e.g., as seen in observa- studies of diet and exercise in the treat- angiotensin system (RAS) may have tional epidemiological studies) and pa- ment of elevated blood pressure or unique advantages for initial or early tients who require intensive medical hypertension in individuals with diabe- treatment of hypertension. In a trial of management to achieve lower blood tes, the Dietary Approaches to Stop individuals at high risk for ASCVD, pressure goals (e.g., the clinical trials). Hypertension (DASH) study evaluated including a large subset with diabetes, the impact of healthy dietary patterns an ACE inhibitor reduced ASCVD out- Systolic Blood Pressure in individuals without diabetes and has comes (23). In patients with congestive . There is strong evidence that SBP 140 shown antihypertensive effects similar to heart failure, including subgroups with mmHg is harmful, suggesting that clinicians those of pharmacological monotherapy. diabetes, ARBs have been shown to re- should promptly initiate and titrate ther- Lifestyle therapy consists of reducing duce major ASCVD outcomes (24–27). apy in an ongoing fashion to achieve and excess body weight, restricting sodium In patients with type 2 diabetes with , maintain SBP 140 mmHg in most pa- intake (,2,300 mg/day), increasing con- significant diabetic kidney disease, “ ” tients (see Section 10 Older Adults ). A sumption of fruits and vegetables (8–10 ARBs were superior to calcium channel recent systematic review and meta-anal- servings per day) and low-fat dairy blockers for reducing heart failure (28). ysis evaluating SBP lowering in adults with products (2–3 servings per day), avoiding Although evidence for distinct advantages type 2 diabetes showed that each 10-mmHg excessive alcohol consumption (no more of RAS inhibitors on ASCVD outcomes in reduction of SBP was associated with signif- than 2 servings per day in men and no diabetes remains conflicting (11,22), the icantly lower risk of mortality, cardiovascular more than 1 serving per day in women) high ASCVD risks associated with diabetes events, CHD, stroke, albuminuria, and reti- (16), and increasing activity levels (17). and the high prevalence of undiagnosed nopathy. However, when trials were strati- These lifestyle (nonpharmacological) ASCVD may still favor recommendations fi $ ed by mean baseline SBP 140 mmHg or strategies may also positively affect for their use as first-line antihypertensive , – 140 mmHg, blood pressure lowering glycemia and lipid control and should be therapy in people with diabetes (17). treatment was associated with lower risks encouraged in those with even mildly ele- However, the use of both ACE inhibitors of stroke and albuminuria, regardless of vated blood pressure, although the impact and ARBs in combination is not recom- initial SBP (15). Therefore, individuals in of lifestyle therapy on cardiovascular events mended given the lack of added ASCVD whom stroke risk is a concern may, as part has not been established. Nonpharmaco- benefit and increased rate of adverse of shared decision making, have lower logical therapy is reasonable in individuals eventsdnamely, hyperkalemia, syncope, , systolic targets such as 130 mmHg. with diabetes and mildly elevated blood and renal dysfunction (29). This is especially true if lower blood pres- . . pressure (SBP 120 mmHg or DBP 80 Other Pharmacological Interventions sure can be achieved with few drugs and mmHg). If the blood pressure is confirmed without side effects of therapy. The blood pressure arm of the ADVANCE to be $140 mmHg systolic and/or $90 trial demonstrated that routine adminis- Diastolic Blood Pressure mmHg diastolic, pharmacological therapy tration of a fixed combination of the ACE Similarly, strong evidence from random- should be initiated along with nonpharma- inhibitor perindopril and the diuretic ized clinical trials supports DBP targets cological therapy (17). To enable long-term indapamide significantly reduced com- of ,90 mmHg. Prior recommendations for adherence, lifestyle therapy should be adap- bined microvascular and macrovascular lower DBP targets (,80 mmHg) were based ted to suit the needs of the patient and outcomes, as well as death from cardio- primarily on a post hoc analysis of the HOT discussed as part of diabetes management. vascular causes and total mortality. trial (14). A DBP of ,80 mmHg may still be The improved outcomes could also appropriate for patients with long life expec- Pharmacological Interventions have been due to lower achieved blood tancy, those with chronic kidney disease, ACE Inhibitors. Lowering of blood pres- pressure in the perindopril–indapamide elevated urinary albumin excretion, and sure with regimens based on a variety of arm (11). Another trial showed a decrease care.diabetesjournals.org Cardiovascular Disease and Risk Management S63

in morbidity and mortality in those receiv- drugs known to be effective and safe in c For patients with diabetes aged ing benazepril and amlodipine versus be- pregnancy include methyldopa, labetalol, 40–75 years with additional ath- nazepril and hydrochlorothiazide (HCTZ) diltiazem, clonidine, and prazosin. Chronic erosclerotic cardiovascular dis- (30). The compelling benefits of RAS in- diuretic use during pregnancy is not rec- ease risk factors, consider using hibitors in patients with diabetes and al- ommended as it has been associated with high-intensity statin and lifestyle buminuria or renal insufficiency provide restricted maternal plasma volume, which therapy. B additional rationale for the use of these may reduce uteroplacental perfusion (33). c For patients with diabetes aged agents (see Section 9 “Microvascular .75 years without additional ath- Complications and Foot Care”). If needed LIPID MANAGEMENT erosclerotic cardiovascular dis- to achieve blood pressure targets, amlo- Recommendations ease risk factors, consider using dipine, HCTZ, or chlorthalidone can be c In adults not taking statins, it is moderate-intensity statin therapy added. If estimated glomerular filtration reasonable to obtain a lipid profile and lifestyle therapy. B rate is ,30 mL/min/1.73 m2, a loop di- at the time of diabetes diagnosis, at c For patients with diabetes aged uretic, rather than HCTZ or chlorthali- an initial medical evaluation, and .75 years with additional athero- done, should be prescribed. Titration of every 5 years thereafter, or more sclerotic cardiovascular disease risk and/or addition of further blood pressure frequently if indicated. E factors, consider using moderate- medications should be made in a timely c Obtain a lipid profile at initiation intensity or high-intensity statin fashion to overcome clinical inertia in of statin therapy and periodically therapy and lifestyle therapy. B achieving blood pressure targets. thereafter as it may help to mon- c In clinical practice, providers may Bedtime Dosing itor the response to therapy and need to adjust intensity of statin Growing evidence suggests that there is inform adherence. E therapy based on individual patient an association between increase in sleep- c Lifestyle modification focusing on response to medication (e.g., side time blood pressure and incidence of weight loss (if indicated); the reduc- effects, tolerability, LDL cholesterol ASCVD events. A randomized controlled tion of saturated fat, trans fat, and levels). E trial of 448 participants with type 2 di- cholesterol intake; increase of c The addition of ezetimibe to abetes and hypertension demonstrated omega-3 fatty acids, viscous fiber, moderate-intensity statin therapy reduced cardiovascular events and mor- and plant stanols/sterols intake; and has been shown to provide additional tality with median follow-up of 5.4 years increased physical activity should be cardiovascular benefitcompared if at least one antihypertensive medica- recommended to improve the lipid with moderate-intensity statin ther- tion was given at bedtime (31). Consider profile in patients with diabetes. A apy alone and may be considered administering one or more antihyper- c Intensify lifestyle therapy and opti- for patients with a recent acute cor- tensive medications at bedtime (32). mize glycemic control for patients onary syndrome with LDL cholesterol Other Considerations with elevated triglyceride levels $50 mg/dL (1.3 mmol/L) or for those An important caveat is that most patients ($150 mg/dL [1.7 mmol/L]) and/or patients who cannot tolerate high- with diabetes with hypertension require low HDL cholesterol (,40 mg/dL intensity statin therapy. A multiple-drug therapy to reach treatment [1.0 mmol/L] for men, ,50 mg/dL c Combination therapy (statin/fibrate) goals (16). Identifying and addressing [1.3 mmol/L] for women). C has not been shown to improve ath- barriers to medication adherence (such c For patients with fasting triglyceride erosclerotic cardiovascular disease as cost and side effects) should rou- levels $500 mg/dL (5.7 mmol/L), outcomes and is generally not rec- tinely be done. If blood pressure remains evaluate for secondary causes of ommended. A However, therapy uncontrolled despite confirmed adher- hypertriglyceridemia and consider with statin and fenofibrate may be ence to optimal doses of at least three medical therapy to reduce the risk considered for men with both tri- antihypertensive agents of different clas- of pancreatitis. C glyceride level $204 mg/dL (2.3 ses, one of which should be a diuretic, c For patients of all ages with diabetes mmol/L) and HDL cholesterol clinicians should consider an evaluation and atherosclerotic cardiovascular dis- level #34 mg/dL (0.9 mmol/L). B for secondary causes of hypertension. ease, high-intensity statin therapy c Combination therapy (statin/niacin) should be added to lifestyle therapy. A has not been shown to provide Pregnancy and Antihypertensive c For patients with diabetes aged additional cardiovascular benefit Medications ,40 years with additional athero- above statin therapy alone and In a pregnancy complicated by diabetes sclerotic cardiovascular disease risk may increase the risk of stroke and and chronic hypertension, target blood factors, consider using moderate- is not generally recommended. A pressure goals of SBP 110–129 mmHg intensity or high-intensity statin c Statin therapy is contraindicated and DBP 65–79 mmHg are reasonable, and lifestyle therapy. C in pregnancy. B as they contribute to improved long- c For patients with diabetes aged term maternal health. Lower blood 40–75 years without additional pressure levels may be associated with atherosclerotic cardiovascular dis- Lifestyle Intervention impaired fetal growth. During preg- ease risk factors, consider using Lifestyle intervention, including weight nancy, treatment with ACE inhibitors moderate-intensity statin and life- loss, increased physical activity, and and ARBs is contraindicated, as they style therapy. A medical nutrition therapy, allows some may cause fetal damage. Antihypertensive patients to reduce ASCVD risk factors. S64 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

Nutrition intervention should be tailored Table 8.1—Recommendations for statin and combination treatment in people according to each patient’s age, diabe- with diabetes tes type, pharmacological treatment, Age Risk factors Recommended statin intensity* lipid levels, and medical conditions. ,40 years None None Recommendations should focus on re- ASCVD risk factor(s)** Moderate or high ducing saturated fat, cholesterol, and ASCVD High trans fat intake and increasing plant 40–75 None Moderate stanols/sterols, omega-3 fatty acids, years ASCVD risk factors High and viscous fiber (such as in oats, le- ASCVD High gumes, and citrus). Glycemic control ACS and LDL cholesterol .50 mg/dL (1.3 mmol/L) Moderate plus ezetimibe can also beneficially modify plasma lipid in patients who cannot tolerate high-dose statins levels, particularly in patients with very .75 years None Moderate high triglycerides and poor glycemic ASCVD risk factors Moderate or high control. ASCVD High ACS and LDL cholesterol .50 mg/dL (1.3 mmol/L) in Moderate plus ezetimibe patients who cannot tolerate high-dose statins Statin Treatment *Inadditiontolifestyletherapy. Initiating Statin Therapy Based on Risk **ASCVD risk factors include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure, Patients with type 2 diabetes have an smoking, overweight and obesity, and family history of premature ASCVD. increased prevalence of lipid abnormalities, contributing to their high risk of ASCVD. Multiple clinical trials have The Risk Calculator. The American College Age >75 Years demonstrated the beneficial effects of of Cardiology/American Heart Association For adults with diabetes over 75 years of pharmacological (statin) therapy on ASCVD risk calculator may be a useful tool age, there are limited data regarding the ASCVD outcomes in subjects with and to estimate 10-year ASCVD (http://my benefits and risks of statin therapy. without CHD (34,35). Subgroup analy- .americanheart.org).Asdiabetesitself Statin therapy should be individualized ses of patients with diabetes in larger confers increased risk for ASCVD, the based on risk profile. High-intensity trials (36–40) and trials in patients risk calculator has limited use for statins, if well tolerated, are still appropri- with diabetes (41,42) showed signifi- assessing cardiovascular risk in indi- ate and recommended for older adults cant primary and secondary prevention viduals with diabetes. with ASCVD. High-intensity statin therapy may also be appropriate in adults with of ASCVD events and CHD death in Age ‡40 Years diabetes .75 years of age with additional patients with diabetes. Meta-analyses, In all patients with diabetes aged $40 ASCVD risk factors. However, the risk– including data from over 18,000 patients years, moderate-intensity statin treat- benefitprofile should be routinely evalu- with diabetes from 14 randomized trials ment should be considered in addition ated in this population, with downward of statin therapy (mean follow-up 4.3 to lifestyle therapy. Clinical trials in high- titration (e.g., high to moderate intensity) years), demonstrate a 9% proportional re- risk patients, such as those with ACS or performed as needed. See Section 10 duction in all-cause mortality and 13% re- previous cardiovascular events (47–49), “Older Adults” for more details on clinical duction in vascular mortality for each have demonstrated that more aggressive considerations for this population. mmol/L (39 mg/dL) reduction in LDL cho- therapy with high doses of statins led to a lesterol (43). significant reduction in further events. Age <40 Years and/or Type 1 Diabetes As in those without diabetes, abso- Therefore, high-dose statins are recom- Very little clinical trial evidence exists lute reductions in ASCVD outcomes mended in patients with increased car- for patients with type 2 diabetes under (CHD death and nonfatal MI) are great- diovascular risk (e.g., LDL cholesterol the age of 40 years or for patients with est in people with high baseline ASCVD $100 mg/dL [2.6 mmol/L], high blood type 1 diabetes of any age. In the Heart risk (known ASCVD and/or very high LDL pressure, smoking, albuminuria, and Protection Study (lower age limit cholesterol levels), but the overall ben- family history of premature ASCVD) or 40 years), the subgroup of ;600 patients efits of statin therapy in people with di- with ASCVD. with type 1 diabetes had a proportionately abetes at moderate or even low risk for ASCVD are convincing (44,45). Statins are the drugs of choice for LDL cholesterol lowering and cardioprotection. Table 8.2—High-intensity and moderate-intensity statin therapy* Most trials of statins and ASCVD out- High-intensity statin therapy Moderate-intensity statin therapy comes tested specificdosesofstatins Lowers LDL cholesterol by $50% Lowers LDL cholesterol by 30% to ,50% against placebo or other statins rather Atorvastatin 40–80 mg Atorvastatin 10–20 mg than aiming for specific LDL cholesterol Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg goals (46). In light of this fact, the 2016 Simvastatin 20–40 mg – ADA Standards of Care position state- Pravastatin 40 80 mg Lovastatin 40 mg ment was revised to recommend when Fluvastatin XL 80 mg to initiate and intensify statin therapy Pitavastatin 2–4mg (high vs. moderate intensity) based on *Once-daily dosing. risk profile (Table 8.1 and Table 8.2). care.diabetesjournals.org Cardiovascular Disease and Risk Management S65

similar, although not statistically signifi- be considered in adults with heterozygous levels, are the most prevalent pattern cant, reduction in risk as patients with familial hypercholesterolemia who require of dyslipidemia in individuals with type 2 diabetes (37). Even though the additional lowering of LDL cholesterol. type 2 diabetes. However, the evidence data are not definitive, similar statin for the use of drugs that target these treatment approaches should be consid- Combination Therapy for LDL lipid fractions is substantially less robust ered for patients with type 1 or type 2 Cholesterol Lowering than that for statin therapy (57). In a diabetes, particularly in the presence of Statins and Ezetimibe large trial in patients with diabetes, other cardiovascular risk factors. Please The IMProved Reduction of Outcomes: fenofibrate failed to reduce overall refer to “Type 1 Diabetes Mellitus and Vytorin Efficacy International Trial cardiovascular outcomes (58). Cardiovascular Disease: A Scientific (IMPROVE-IT) was a randomized con- Combination Therapy Statement From the American Heart As- trolled trial comparing the addition of Statin and Fibrate sociation and American Diabetes Associ- ezetimibe to simvastatin therapy versus Combination therapy (statin and fibrate) ation” (50) for additional discussion. simvastatin alone. Individuals were is associated with an increased risk for High-intensity statin therapy is recom- $50 years of age who experienced an abnormal transaminase levels, myositis, mended for all patients with diabetes and ACS within the preceding 10 days and and rhabdomyolysis. The risk of rhabdo- ASCVD. Treatment with a moderate dose had an LDL cholesterol level $50 mg/dL myolysis is more common with higher of statin should be considered if the (1.3 mmol/L). In those with diabetes doses of statins and renal insufficiency patient does not have ASCVD but has (27%), the combination of moderate- and appears to be higher when statins additional ASCVD risk factors. intensity simvastatin (40 mg) and ezetimibe are combined with gemfibrozil (59) (10 mg) showed a significant reduction (comparedwithfenofibrate). Ongoing Therapy and Monitoring of major adverse cardiovascular events In the ACCORD study, in patients with With Lipid Panel with an absolute risk reduction of type 2 diabetes who were at high risk for In adults with diabetes, it is reasonable to 5% (40% vs. 45%) and RR reduction of ASCVD, the combination of fenofibrate obtain a lipid profile (total cholesterol, 14% (RR 0.86 [95% CI 0.78–0.94]) over and simvastatin did not reduce the rate LDL cholesterol, HDL cholesterol, and moderate-intensity simvastatin (40 mg) of fatal cardiovascular events, nonfatal triglycerides) at the time of diagnosis, alone (53). Therefore, for people meeting MI, or nonfatal stroke as compared with at the initial medical evaluation, and at IMPROVE-IT eligibility criteria who can simvastatin alone. Prespecified subgroup least every 5 years thereafter. A lipid only tolerate a moderate-dose statin, the analyses suggested heterogeneity in panel should also be obtained immedi- addition of ezetimibe to statin therapy treatment effects with possible benefit ately before initiating statin therapy. should be considered. Onceapatientistakingastatin,testing for men with both a triglyceride level Statins and PCSK9 Inhibitors $ for LDL cholesterol may be considered 204 mg/dL (2.3 mmol/L) and an HDL Placebo-controlled trials evaluating the # on an individual basis (e.g., to monitor cholesterol level 34 mg/dL (0.9 addition of the novel PCSK9 inhibitors, for adherence and efficacy). In cases mmol/L) (60). evolocumab and alirocumab, to maxi- where patients are adherent, but the Statin and Niacin mally tolerated doses of statin therapy LDL cholesterol level is not responding, The Atherothrombosis Intervention in participants who were at high risk for clinical judgment is recommended to de- in Metabolic Syndrome With Low ASCVD demonstrated an average reduc- termine the need for and timing of lipid HDL/High Triglycerides: Impact on tion in LDL cholesterol ranging from 36% panels. In individual patients, the highly Global Health Outcomes (AIM-HIGH) tri- to 59%. These agents may therefore variable LDL cholesterol–lowering real randomized over 3,000 patients be considered as adjunctive therapy sponse seen with statins is poorly under- (about one-third with diabetes) with es- for patients with diabetes at high risk for stood (51). When maximally tolerated tablished ASCVD, low LDL cholesterol ASCVD events who require additional low- doses of statins fail to substantially lower levels (,180 mg/dL [4.7 mmol/L]), low ering of LDL cholesterol or who require LDL cholesterol (,30% reduction from HDL cholesterol levels (men ,40 mg/dL but are intolerant to high-intensity statin the patient’s baseline), there is no strong [1.0 mmol/L] and women ,50 mg/dL therapy (54,55). It is important to note evidence that combination therapy [1.3 mmol/L]), and triglyceride levels of that the effects of this novel class of agents should be used. Clinicians should attempt 150–400 mg/dL (1.7–4.5 mmol/L) to sta- on ASCVD outcomes are unknown as to find a dose or alternative statin that is tin therapy plus extended-release niacin phase 4 studies are currently under way. tolerable, if side effects occur. There is or placebo. The trial was halted early due evidence for benefitfromevenextremely Treatment of Other Lipoprotein to lack of efficacy on the primary ASCVD low, less than daily, statin doses (52). Fractions or Targets outcome (first event of the composite Increased frequency of LDL cholesterol Hypertriglyceridemia should be addressed of death from CHD, nonfatal MI, ische- monitoring should be considered for pa- with dietary and lifestyle changes includ- mic stroke, hospitalization for an ACS, or tients with new-onset ACS. A recent ran- ing abstinence from alcohol (56). Severe symptom-driven coronary or cerebral re- domized controlled trial evaluated the hypertriglyceridemia (.1,000 mg/dL) vascularization) and a possible increase addition of ezetimibe to moderate- may warrant immediate pharmacological in ischemic stroke in those on combina- intensity statin therapy and demon- therapy (fibric acid derivatives and/or fish tion therapy (61). Therefore, combina- strated ASCVD risk benefitoverstatin oil) to reduce the risk of acute pancreatitis. tion therapy with a statin and niacin is monotherapy (53). Increased frequency Low levels of HDL cholesterol, often not recommended given the lack of of LDL cholesterol monitoring may also associated with elevated triglyceride efficacy on major ASCVD outcomes, S66 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

possibleincreaseinriskofischemic stroke. There was some evidence of a dif- disease prevention for adults with stroke, and side effects. ference in aspirin effect by sex: aspirin diabetes at low atherosclerotic significantly reduced ASCVD events in Diabetes With Statin Use cardiovascular disease risk (10- men, but not in women. Conversely, as- Several studies have reported an increased year atherosclerotic cardiovascu- pirin had no effect on stroke in men but risk of incident diabetes with statin use lar disease risk ,5%), such as in significantly reduced stroke in women. (62,63), which may be limited to those men or women with diabetes aged However, there was no heterogeneity of with diabetes risk factors. An analysis of ,50yearswithnomajoradditional effect by sex in the risk of serious vascular one of the initial studies suggested that atherosclerotic cardiovascular dis- events (P 5 0.9). Sex differences in although statins were linked to diabetes ease risk factors, as the potential aspirin’s effects have not been observed risk, the cardiovascular event rate reduc- adverse effects from bleeding likely in studies of secondary prevention (66). tion with statins far outweighed the risk of offset the potential benefits. C In the six trials examined by the ATT incident diabetes even for patients at high- c In patients with diabetes ,50 years collaborators, the effects of aspirin on est risk for diabetes (64). The absolute risk of age with multiple other risk fac- major vascular events were similar for increase was small (over 5 years of follow- tors (e.g., 10-year risk 5–10%), clin- patients with or without diabetes: RR up, 1.2% of participants on placebo devel- ical judgment is required. E 0.88 (95% CI 0.67–1.15) and RR 0.87 oped diabetes and 1.5% on rosuvastatin c Use aspirin therapy (75–162 mg/day) (95% CI 0.79–0.96), respectively. The con- developed diabetes) (64). A meta-analysis as a secondary prevention strat- fidence interval was wider for those with of 13 randomized statin trials with 91,140 egyinthosewithdiabetesanda diabetes because of smaller numbers. participants showed an odds ratio of 1.09 history of atherosclerotic cardio- Aspirin appears to have a modest effect for a new diagnosis of diabetes, so that vascular disease. A on ischemic vascular events with the (on average) treatment of 255 patients c For patients with atherosclerotic absolute decrease in events depending with statins for 4 years resulted in one cardiovascular disease and docu- on the underlying ASCVD risk. The main additional case of diabetes, while simul- mented aspirin allergy, clopidog- adverse effects appear to be an increased taneously preventing 5.4 vascular events rel (75 mg/day) should be used. B risk of gastrointestinal bleeding. The excess among those 255 patients (63). c Dual antiplatelet therapy is reason- risk may be as high as 1–5per1,000per able for up to a year after an acute Statins and Cognitive Function year in real-world settings. In adults with coronary syndrome. B A recent systematic review of the U.S. ASCVD risk .1% per year, the number of ’ Food and Drug Administration s post- ASCVD events prevented will be similar to marketing surveillance databases, ran- Risk Reduction or greater than the number of episodes of domized controlled trials, and cohort, Aspirin has been shown to be effective bleeding induced, although these compli- case-control, and cross-sectional stud- in reducing cardiovascular morbidity cations do not have equal effects on long- ies evaluating cognition in patients re- and mortality in high-risk patients with term health (72). ceiving statins found that published previous MI or stroke (secondary preven- Treatment Considerations data do not reveal an adverse effect of tion). Its net benefit in primary prevention In 2010, a position statement of the statins on cognition. Therefore, a con- among patients with no previous cardio- ADA, the American Heart Association, cern that statins might cause cognitive vascular events is more controversial, and the American College of Cardiology dysfunction or dementia should not both for patients with diabetes and for Foundation recommended that low-dose prohibit their use in individuals with patients without diabetes (66,67). Previ- (75–162 mg/day) aspirin for primary diabetes at high risk for ASCVD (65). ous randomized controlled trials of aspi- prevention is reasonable for adults rin specifically in patients with diabetes with diabetes and no previous history ANTIPLATELET AGENTS failed to consistently show a significant of vascular disease who are at increased reduction in overall ASCVD end points, Recommendations ASCVD risk (10-year risk of ASCVD events raising questions about the efficacy of c Consider aspirin therapy (75–162 over 10%) and who are not at increased aspirin for primary prevention in people mg/day) as a primary prevention risk for bleeding. This previous recom- with diabetes, although some sex differ- strategy in those with type 1 or mendation included most men over age ences were suggested (68–71). type 2 diabetes who are at increased 50 years and women over age 60 years The Antithrombotic Trialists’ (ATT) cardiovascular risk (10-year risk who also have one or more of the follow- collaborators published an individual .10%). This includes most men or ing major risk factors: smoking, hyperten- patient-level meta-analysis of the six women with diabetes aged $50 sion, dyslipidemia, family history of large trials of aspirin for primary preven- years who have at least one addi- premature ASCVD, and albuminuria (73). tional major risk factor (family his- tion in the general population. These tri- tory of premature atherosclerotic als collectively enrolled over 95,000 Sex Considerations cardiovascular disease, hyperten- participants, including almost 4,000 Multiple recent well-conducted studies sion, smoking, dyslipidemia, or al- with diabetes. Overall, they found that and meta-analyses reported a risk of buminuria) and are not at increased aspirin reduced the risk of serious vascular heart disease and stroke that is equiva- – risk of bleeding. C events by 12% (RR 0.88 [95% CI 0.82 lent if not higher in women compared c Aspirin should not be recommended 0.94]). The largest reduction was for non- with men with diabetes, including among for atherosclerotic cardiovascular fatal MI, with little effect on CHD death nonelderly adults. Thus, the recommen- (RR 0.95 [95% CI 0.78–1.15]) or total dations for using aspirin as primary care.diabetesjournals.org Cardiovascular Disease and Risk Management S67

prevention are now revised to include Indications for P2Y12 Use the initial test. In adults with diabetes both men and women aged $50 years A P2Y12 receptor antagonist in combi- $40 years of age, measurement of cor- with diabetes and one or more major nation with aspirin should be used for at onary artery calcium is also reasonable risk factors to reflect these more recent least 1 year in patients following an ACS. for cardiovascular risk assessment. findings (74–77). Sex differences in the Evidence supports use of either ticagrelor Pharmacological stress echocardiography antiplatelet effect of aspirin have been or clopidogrel if no percutaneous cor- or nuclear imaging should be considered suggested in the general population onary intervention was performed and in individuals with diabetes in whom rest- (78); however, further studies are needed clopidogrel, ticagrelor, or prasugrel if a ing ECG abnormalities preclude exercise to investigate the presence of such differ- percutaneous coronary intervention stress testing (e.g., left bundle branch ences in individuals with diabetes. was performed (82). block or ST-T abnormalities). In addition, individuals who require stress testing and Aspirin Use in People <50 Years of Age CORONARY HEART DISEASE are unable to exercise should undergo Aspirin is not recommended for those at pharmacological stress echocardiography low risk of ASCVD (such as men and Recommendations , or nuclear imaging. women aged 50 years with diabetes Screening with no other major ASCVD risk factors; c In asymptomatic patients, routine Screening Asymptomatic Patients 10-year ASCVD risk ,5%) as the low screening for coronary artery dis- The screening of asymptomatic patients benefit is likely to be outweighed by ease is not recommended as it with high ASCVD risk is not recommended the risks of significant bleeding. Clinical does not improve outcomes as (44), in part because these high-risk judgment should be used for those at long as atherosclerotic cardiovascu- patients should already be receiving intermediate risk (younger patients lar disease risk factors are treated. A intensive medical therapydan approach with one or more risk factors or older c Consider investigations for coro- that provides similar benefit as invasive patients with no risk factors; those nary artery disease in the presence revascularization (83,84). There is also with 10-year ASCVD risk of 5–10%) until of any of the following: atypical car- some evidence that silent MI may reverse further research is available. Aspirin use diac symptoms (e.g., unexplained over time, adding to the controversy con- in patients aged ,21 years is contrain- dyspnea, chest discomfort); signs cerning aggressive screening strategies dicated due to the associated risk of or symptoms of associated vascular (85). In prospective trials, coronary artery Reye syndrome. disease including carotid bruits, calcium has been established as an inde- Aspirin Dosing transient ischemic attack, stroke, pendent predictor of future ASCVD Average daily dosages used in most clini- claudication, or peripheral arterial events in patients with diabetes and cal trials involving patients with diabetes disease; or electrocardiogram ab- is superior to both the UK Prospective ranged from 50 mg to 650 mg but were normalities (e.g., Q waves). E Diabetes Study (UKPDS) risk engine – mostly in the range of 100 325 mg/day. Treatment and the Framingham Risk Score in pre- There is little evidence to support any dicting risk in this population (86–88). c In patients with known atheroscle- specific dose, but using the lowest However, a randomized observational rotic cardiovascular disease, use as- possible dose may help to reduce side trial demonstrated no clinical benefit pirin and statin therapy (if not effects (79). In the U.S., the most com- to routine screening of asymptomatic contraindicated) A and consider mon low-dose tablet is 81 mg. Although patients with type 2 diabetes and normal ACE inhibitor therapy C to reduce platelets from patients with diabetes ECGs (89). Despite abnormal myocardial the risk of cardiovascular events. have altered function, it is unclear what, perfusion imaging in more than one in c In patients with prior myocardial in- if any, effect that finding has on the five patients, cardiac outcomes were farction, b-blockers should be con- required dose of aspirin for cardiopro- essentially equal (and very low) in tinued for at least 2 years after the tective effects in the patient with dia- screened versus unscreened patients. event. B betes. Many alternate pathways for Accordingly, indiscriminate screening c In patients with symptomatic platelet activation exist that are inde- is not considered cost-effective. Studies heart failure, thiazolidinedione pendent of thromboxane A and thus have found that a risk factor–based 2 treatment should not be used. A not sensitive to the effects of aspirin approach to the initial diagnostic eval- c In patients with type 2 diabetes with (80). “Aspirin resistance” appears higher uation and subsequent follow-up for stable congestive heart failure, met- in patients with diabetes when mea- coronary artery disease fails to identify formin may be used if renal function sured by a variety of ex vivo and in vitro which patients with type 2 diabetes will is normal but should be avoided in methods (platelet aggregometry, mea- have silent ischemia on screening tests unstable or hospitalized patients surement of thromboxane B ) (78). A re- (90,91). Any benefit of newer noninva- 2 with congestive heart failure. B cent trial suggested that more frequent sive coronary artery disease screening dosing regimens of aspirin may reduce Cardiac Testing methods, such as computed tomography platelet reactivity in individuals with dia- Candidates for advanced or invasive and computed tomography angiography, betes (81); however, these observations cardiac testing include those with 1)typ- to identify patient subgroups for different alone are insufficient to empirically rec- ical or atypical cardiac symptoms and 2) treatment strategies remains unproven. ommend that higher doses of aspirin be an abnormal resting electrocardiogram Although asymptomatic patients with di- used in this group at this time. It appears (ECG). Exercise ECG testing without or abetes with higher coronary disease bur- that 75–162 mg/day is optimal. with echocardiography may be used as den have more future cardiac events S68 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

(86,92,93), the role of these tests beyond Cardiovascular Outcomes with Sitagliptin other glucose-lowering treatments in risk stratification is not clear. Their routine (TECOS), recent multicenter, randomized, patients with diabetes and congestive use leads to radiation exposure and may double-blind, noninferiority trials, evalu- heart failure, even in those with reduced result in unnecessary invasive testing such ated heart failure and mortality outcomes left ventricular ejection fraction or con- as coronary angiography and revasculari- in patients with type 2 diabetes taking comitant chronic kidney disease; however, zation procedures. The ultimate balance of different DPP-4 inhibitors, alogliptin metformin should be avoided in hospi- benefit, cost, and risks of such an approach and sitagliptin, respectively, compared talized patients (105). in asymptomatic patients remains contro- with placebo. EXAMINE reported that References versial, particularly in the modern setting the hospital admission rate for heart fail- 1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, of aggressive ASCVD risk factor control. ure was 3.1% for patients randomly as- Imperatore G, Gregg EW. Achievement of goals Lifestyle and Pharmacological signed to alogliptin compared with 2.9% in U.S. diabetes care, 1999-2010. N Engl J Med 2013;368:1613–1624 Interventions for those randomly assigned to placebo (hazard ratio 1.07 [95% CI 0.79–1.46]) 2. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer- Intensive lifestyle intervention focusing (102). Alogliptin had no effect on the ican Heart Association; American Diabetes As- on weight loss through decreased calo- sociation. Primary prevention of cardiovascular composite end point of cardiovascular ric intake and increased physical activity diseases in people with diabetes mellitus: a sci- death and hospital admission for heart fi as performed in the Action for Health in enti c statement from the American Heart As- failure in the post hoc analysis (hazard sociation and the American Diabetes Association. Diabetes (Look AHEAD) trial may be con- ratio 1.00 [95% CI 0.82–1.21]) (102). Diabetes Care 2007;30:162–172 sidered for improving glucose control, TECOS showed a nonsignificant difference 3. Gaede P, Lund-Andersen H, Parving H-H, fitness, and some ASCVD risk factors. Pedersen O. Effect of a multifactorial interven- in the rate of heart failure hospitaliza- Patients at increased ASCVD risk should tion on mortality in type 2 diabetes. N Engl J tion for the sitagliptin group (3.1%; 1.07 – receive aspirin and a statin and ACE in- Med 2008;358:580 591 per 100 person-years) compared with 4. Centers for Disease Control and Prevention, hibitor or ARB therapy if the patient has the placebo group (3.1%; 1.09 per 100 National Center for Health Statistics, Division of hypertension, unless there are contrain- person-years) (103). Health Care Statistics. Crude and age-adjusted dications to a particular drug class. hospital discharge rates for major cardiovascu- While clear benefit exists for ACE inhib- lar disease as first-listed diagnosis per 1,000 di- EMPA-REG OUTCOME Study – itorandARBtherapyinpatientswithne- abetic population, United States, 1988 2006 The BI 10773 (Empagliflozin) Cardio- [Internet]. Available from http://www.cdc phropathy or hypertension, the benefits vascular Outcome Event Trial in .gov/diabetes/statistics/cvdhosp/cvd/fig3.htm. in patients with ASCVD in the absence of Type 2 Diabetes Mellitus Patients Accessed 27 August 2015 these conditions are less clear, especially 5. Bobrie G, Genes` N, Vaur L, et al. Is “isolated (EMPA-REG OUTCOME) was a random- when LDL cholesterol is concomitantly home” hypertension as opposed to “isolated ized, double-blind, placebo-controlled fi ” controlled (94,95). In patients with prior of ce hypertension a sign of greater cardiovas- trial that assessed the effect of cular risk? Arch Intern Med 2001;161:2205– MI, b-blockers should be continued for at empagliflozin, a sodium–glucose co- 2211 least 2 years after the event (96). transporter 2 inhibitor on cardiovascular 6. Sega R, Facchetti R, Bombelli M, et al. Prog- nostic value of ambulatory and home blood Diabetes and Heart Failure outcomes (stroke, MI, amputation, or pressures compared with office blood pressure Almost 50% of patients with type 2 di- coronary, carotid, or peripheral artery in the general population: follow-up results abetes will develop heart failure (97). obstruction) in patients with type 2 from the Pressioni Arteriose Monitorate e Data on the effects of glucose-lowering diabetes at high risk for cardiovascular Loro Associazioni (PAMELA) study. Circulation – disease. Study participants had a mean 2005;111:1777 1783 agents on heart failure outcomes have 7. Arguedas JA, Leiva V, Wright JM. Blood pres- demonstrated that thiazolidinediones age of 63 years, 57% had diabetes for sure targets for hypertension in people with di- have a strong and consistent relationship more than 10 years, and 70% had a his- abetes mellitus. Cochrane Database Syst Rev with heart failure (98–100). Therefore, tory of either stroke or MI. EMPA-REG 2013;10:CD008277 thiazolidinedione use should be avoided OUTCOME showed that the therapy re- 8. James PA, Oparil S, Carter BL, et al. 2014 duced the aggregate outcome of MI, evidence-based guideline for the management in patients with symptomatic heart failure. of high blood pressure in adults: report from the Recent studies have now examined stroke, and cardiovascular death by panel members appointed to the Eighth Joint the relationship between dipeptidyl 14% (absolute rate 10.5% vs. 12.1% in National Committee (JNC 8). JAMA 2014;311: peptidase 4 (DPP-4) inhibitors and the placebo group), due to a 38% reduc- 507–520 heart failure and have mixed results. tion in cardiovascular death (absolute rate 9. McBrien K, Rabi DM, Campbell N, et al. In- fl tensive and standard blood pressure targets in The Saxagliptin Assessment of Vascular 3.7% vs. 5.9%) (104). Empagli ozin is the patients with type 2 diabetes mellitus: system- Outcomes Recorded in Patients with Di- first of the recently approved diabetes atic review and meta-analysis. Arch Intern Med abetes Mellitus–Thrombolysis in Myo- treatments associated with a lower risk 2012;172:1296–1303 cardial Infarction 53 (SAVOR-TIMI 53) of cardiovascular disease. Whether empa- 10. Cushman WC, Evans GW, Byington RP, study showed that patients treated gliflozin or other sodium–glucose cotrans- et al.; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes melli- with saxagliptin (a DPP-4 inhibitor) were porter 2 inhibitors will have a similar tus. N Engl J Med 2010;362:1575–1585 more likely to be hospitalized for heart effect in lower-risk patients with diabetes 11. Patel A, MacMahon S, Chalmers J, et al.; failure than were those given placebo remains unknown. ADVANCE Collaborative Group. Effects of a fixed (3.5% vs. 2.8%, respectively) (101). How- combination of perindopril and indapamide on Metformin macrovascular and microvascular outcomes in ever, Examination of Cardiovascular patients with type 2 diabetes mellitus (the Outcomes with Alogliptin versus Standard A systematic review of 34,000 patients ADVANCE trial): a randomised controlled trial. of Care (EXAMINE) and Trial Evaluating showed that metformin is as safe as Lancet 2007;370:829–840 care.diabetesjournals.org Cardiovascular Disease and Risk Management S69

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Japanese Primary Prevention of Atherosclerosis domized controlled trial comparing impact on Efficacy and safety of alirocumab, a monoclonal With Aspirin for Diabetes (JPAD) Trial Investiga- platelet reactivity of twice-daily with once-daily antibody to PCSK9, in statin-intolerant patients: tors. Low-dose aspirin for primary prevention of aspirin in people with type 2 diabetes. Diabet design and rationale of ODYSSEY ALTERNATIVE, a atherosclerotic events in patients with type 2 Med. 4 June 2015 [Epub ahead of print]. DOI: randomized phase 3 trial. J Clin Lipidol 2014;8: diabetes: a randomized controlled trial. JAMA 10.1111/dme.12828 554–561 2008;300:2134–2141 82. Vandvik PO, Lincoff AM, Gore JM, et al.; 55. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and 69. Belch J, MacCuish A, Campbell I, Cobbe S, American College of Chest Physicians. Primary efficacy of anti-PCSK9 antibodies: a meta-analysis Taylor R, Prescott R, et al. The Prevention of and secondary prevention of cardiovascular of 25 randomized, controlled trials. BMC Med Progression of Arterial Disease and Diabetes disease: Antithrombotic Therapy and Preven- 2015;13:123 (POPADAD) trial: factorial randomised placebo tion of Thrombosis, 9th ed: American College 56. Berglund L, Brunzell JD, Goldberg AC, et al.; controlled trial of aspirin and antioxidants in of Chest Physicians Evidence-Based Clinical Endocrine Society. Evaluation and treatment of patients with diabetes and asymptomatic pe- Practice Guidelines. Chest 2012;141(Suppl.): hypertriglyceridemia: an Endocrine Society clin- ripheral arterial disease. BMJ 2008;337:a1840 e637S–e668S ical practice guideline. J Clin Endocrinol Metab 70. Zhang C, Sun A, Zhang P, et al. Aspirin for 83. Boden WE, O’Rourke RA, Teo KK, et al.; 2012;97:2969–2989 primary prevention of cardiovascular events in COURAGE Trial Research Group. Optimal medi- 57. Singh IM, Shishehbor MH, Ansell BJ. High- patients with diabetes: a meta-analysis. Diabe- cal therapy with or without PCI for stable coro- density lipoprotein as a therapeutic target: a tes Res Clin Pract 2010;87:211–218 nary disease. N Engl J Med 2007;356:1503–1516 systematic review. JAMA 2007;298:786–798 71. De Berardis G, Sacco M, Strippoli GF, et al. 84. BARI 2D Study Group. A randomized trial of 58. Keech A, Simes RJ, Barter P, et al.; FIELD Aspirin for primary prevention of cardiovascular therapies for type 2 diabetes and coronary ar- Study Investigators. Effects of long-term fenofi- events in people with diabetes: meta-analysis of tery disease. N Engl J Med 2009;360:2503–2515 brate therapy on cardiovascular events in 9795 randomised controlled trials. BMJ 2009;339: 85. Wackers FJT, Chyun DA, Young LH, et al.; people with type 2 diabetes mellitus (the FIELD b4531 DetectionofIschemiainAsymptomaticDia- study): randomised controlled trial. Lancet 72. Pignone M, Earnshaw S, Tice JA, Pletcher betics (DIAD) Investigators. Resolution of 2005;366:1849–1861 MJ. Aspirin, statins, or both drugs for the pri- asymptomatic myocardial ischemia in patients 59. Jones PH, Davidson MH. Reporting rate of mary prevention of coronary heart disease with type 2 diabetes in the Detection of Ische- rhabdomyolysis with fenofibrate 1 statin ver- events in men: a cost-utility analysis. Ann Intern mia in Asymptomatic Diabetics (DIAD) study. sus gemfibrozil 1 any statin. Am J Cardiol 2005; Med 2006;144:326–336 Diabetes Care 2007;30:2892–2898 95:120–122 73. Pignone M, Alberts MJ, Colwell JA, et al.; 86. Elkeles RS, Godsland IF, Feher MD, et al.; 60. Ginsberg HN, Elam MB, Lovato LC, et al.; American Diabetes Association; American Heart PREDICT Study Group. Coronary calcium mea- ACCORD Study Group. Effects of combination Association; American College of Cardiology surement improves prediction of cardiovascular lipid therapy in type 2 diabetes mellitus. N Foundation. Aspirin for primary prevention of events in asymptomatic patients with type 2 di- Engl J Med 2010;362:1563–1574 cardiovascular events in people with diabetes: abetes: the PREDICT study. Eur Heart J 2008;29: 61. Boden WE, Probstfield JL, Anderson T, et al.; a position statement of the American Diabetes 2244–2251 AIM-HIGH Investigators. Niacin in patients with Association, a scientific statement of the Ameri- 87. Raggi P, Shaw LJ, Berman DS, Callister TQ. low HDL cholesterol levels receiving intensive can Heart Association, and an expert consensus Prognostic value of coronary artery calcium statin therapy. N Engl J Med 2011;365:2255– document of the American College of Cardiology screening in subjects with and without diabetes. 2267 Foundation. Diabetes Care 2010;33:1395–1402 J Am Coll Cardiol 2004;43:1663–1669 62. Rajpathak SN, Kumbhani DJ, Crandall J, 74. Huxley RR, Peters SAE, Mishra GD, 88. Anand DV, Lim E, Hopkins D, et al. Risk strat- Barzilai N, Alderman M, Ridker PM. Statin ther- Woodward M. Risk of all-cause mortality and ification in uncomplicated type 2 diabetes: pro- apy and risk of developing type 2 diabetes: a vascular events in women versus men with spective evaluation of the combined use of meta-analysis. Diabetes Care 2009;32:1924– type 1 diabetes: a systematic review and coronary artery calcium imaging and selective 1929 meta-analysis. Lancet Diabetes Endocrinol myocardial perfusion scintigraphy. Eur Heart J 63. Sattar N, Preiss D, Murray HM, et al. Statins 2015;3:198–206 2006;27:713–721 and risk of incident diabetes: a collaborative 75. Peters SA, Huxley RR, Woodward M. Diabe- 89. Young LH, Wackers FJT, Chyun DA, et al.; meta-analysis of randomised statin trials. Lan- tes as risk factor for incident coronary heart DIAD Investigators. Cardiac outcomes after cet 2010;375:735–742 disease in women compared with men: a sys- screening for asymptomatic coronary artery dis- 64. Ridker PM, Pradhan A, MacFadyen JG, Libby tematic review and meta-analysis of 64 cohorts ease in patients with type 2 diabetes: the DIAD P, Glynn RJ. Cardiovascular benefits and diabe- including 858,507 individuals and 28,203 coro- study: a randomized controlled trial. JAMA tes risks of statin therapy in primary prevention: nary events. Diabetologia 2014;57:1542–1551 2009;301:1547–1555 an analysis from the JUPITER trial. Lancet 2012; 76. Kalyani RR, Lazo M, Ouyang P, et al. Sex 90. Wackers FJT, Young LH, Inzucchi SE, et al.; 380:565–571 differences in diabetes and risk of incident coro- Detection of Ischemia in Asymptomatic Dia- 65. Richardson K, Schoen M, French B, et al. nary artery disease in healthy young and middle- betics Investigators. Detection of silent myo- Statins and cognitive function: a systematic re- aged adults. Diabetes Care 2014;37:830–838 cardial ischemia in asymptomatic diabetic view. Ann Intern Med 2013;159:688–697 77. Peters SA, Huxley RR, Woodward M. Diabe- subjects: the DIAD study. Diabetes Care 2004; 66. Baigent C, Blackwell L, Collins R, et al.; An- tes as a risk factor for stroke in women com- 27:1954–1961 tithrombotic Trialists’ (ATT) Collaboration. Aspi- pared with men: a systematic review and 91. Scognamiglio R, Negut C, Ramondo A, rin in the primary and secondary prevention of meta-analysis of 64 cohorts, including 775,385 Tiengo A, Avogaro A. Detection of coronary care.diabetesjournals.org Cardiovascular Disease and Risk Management S71

artery disease in asymptomatic patients with enzyme inhibitors: a randomised controlled trial. 101. Scirica BM, Bhatt DL, Braunwald E, et al.; type 2 diabetes mellitus. J Am Coll Cardiol Lancet 2008;372:1174–1183 SAVOR-TIMI 53 Steering Committee and Inves- 2006;47:65–71 96. Kezerashvili A, Marzo K, De Leon J. Beta tigators. Saxagliptin and cardiovascular out- 92. Hadamitzky M, Hein F, Meyer T, et al. Prog- blocker use after acute myocardial infarction comesinpatientswithtype2diabetes nostic value of coronary computed tomographic in the patient with normal systolic function: mellitus. N Engl J Med 2013;369:1317–1326 angiography in diabetic patients without known when is it “ok” to discontinue? Curr Cardiol 102. Zannad F, Cannon CP, Cushman WC, et al.; coronary artery disease. Diabetes Care 2010;33: Rev 2012;8:77–84 EXAMINE Investigators. Heart failure and mor- 1358–1363 97. Kannel WB, Hjortland M, Castelli WP. Role tality outcomes in patients with type 2 diabetes 93. Choi E-K, Chun EJ, Choi S-I, et al. Assessment of diabetes in congestive heart failure: the Fra- taking alogliptin versus placebo in EXAMINE: a of subclinical coronary atherosclerosis in asymp- mingham study. Am J Cardiol 1974;34:29–34 multicentre, randomised, double-blind trial. tomatic patients with type 2 diabetes mellitus 98. Dormandy JA, Charbonnel B, Eckland DJA, Lancet 2015;385:2067–2076 with single photon emission computed tomogra- et al.; PROactive Investigators. Secondary pre- 103. Green JB, Bethel MA, Armstrong PW, phy and coronary computed tomography angiog- vention of macrovascular events in patients et al.; TECOS Study Group. Effect of sitagliptin raphy. Am J Cardiol 2009;104:890–896 with type 2 diabetes in the PROactive Study on cardiovascular outcomes in type 2 diabetes. 94. Braunwald E, Domanski MJ, Fowler SE, (PROspective pioglitAzone Clinical Trial In mac- N Engl J Med 2015;373:232–242 et al.; PEACE Trial Investigators. Angiotensin- roVascular Events): a randomised controlled trial. 104. Zinman B, Wanner C, Lachin JM, et al.; EMPA- converting-enzyme inhibition in stable coronary Lancet 2005;366:1279–1289 REG OUTCOME Investigators. Empagliﬂozin, cardio- artery disease. N Engl J Med 2004;351:2058– 99. Singh S, Loke YK, Furberg CD. Long-term risk vascular outcomes, and mortality in type 2 diabetes. 2068 of cardiovascular events with rosiglitazone: a N Engl J Med. 17 September 2015 [Epub ahead of 95. Telmisartan Randomised AssessmeNt meta-analysis. JAMA 2007;298:1189–1195 print]. DOI: 10.1056/NEJMoa1504720 Study in ACE iNtolerant subjects with cardiovas- 100. Lincoff AM, Wolski K, Nicholls SJ, Nissen 105. Eurich DT, Weir DL, Majumdar SR, et al. Com- cular Disease (TRANSCEND) Investigators. Ef- SE. Pioglitazone and risk of cardiovascular parative safety and effectiveness of metformin in fects of the angiotensin-receptor blocker events in patients with type 2 diabetes mellitus: patients with diabetes mellitus and heart failure: telmisartan on cardiovascular events in high- a meta-analysis of randomized trials. JAMA systematic review of observational studies involv- risk patients intolerant to angiotensin-converting 2007;298:1180–1188 ing 34,000 patients. Circ Heart Fail 2013;6:395–402 S72 Diabetes Care Volume 39, Supplement 1, January 2016

9. Microvascular Complications American Diabetes Association and Foot Care Diabetes Care 2016;39(Suppl. 1):S72–S80 | DOI: 10.2337/dc16-S012

DIABETIC KIDNEY DISEASE

Recommendations Screening c At least once a year, assess urinary albumin (e.g., spot urinary albumin–to– creatinine ratio) and estimated glomerular filtration rate in patients with type 1 diabetes with duration of $5 years, in all patients with type 2 diabetes, and in all patients with comorbid hypertension. B Treatment c Optimize glucose control to reduce the risk or slow the progression of diabetic kidney disease. A c Optimize blood pressure control (,140/90 mmHg) to reduce the risk or slow the progression of diabetic kidney disease. A c For people with nondialysis-dependent diabetic kidney disease, dietary protein intake should be 0.8 g/kg body weight per day (the recommended daily allowance). For patients on dialysis, higher levels of dietary protein intake should be considered. A c Either an ACE inhibitor or an angiotensin receptor blocker is recommended for the treatment of nonpregnant patients with diabetes and modestly elevated urinary albumin excretion (30–299 mg/day) B and is strongly recommended for those with urinary albumin excretion $300 mg/day and/or estimated glomerular filtration rate ,60 mL/min/1.73 m2. A 9. MICROVASCULAR COMPLICATIONS AND FOOT CARE c Periodically monitor serum creatinine and potassium levels for the development of increased creatinine or changes in potassium when ACE inhibitors, angiotensin receptor blockers, or diuretics are used. E c Continued monitoring of urinary albumin–to–creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment and progression of diabetic kidney disease. E c An ACE inhibitor or an angiotensin receptor blocker is not recommended for the primary prevention of diabetic kidney disease in patients with diabetes who have normal blood pressure, normal urinary albumin–to–creatinine ratio (,30 mg/g), and normal estimated glomerular filtration rate. B c When estimated glomerular filtration rate is ,60 mL/min/1.73 m2, evaluate and manage potential complications of chronic kidney disease. E c Patients should be referred for evaluation for renal replacement treatment if they have estimated glomerular filtration rate ,30 mL/min/1.73 m2. A c Promptly refer to a physician experienced in the care of kidney disease for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressing kidney disease. B

Suggested citation: American Diabetes Associ- Assessment of Albuminuria and Renal Function ation. Microvascular complications and foot Diabetic kidney disease, or kidney disease attributed to diabetes, occurs in 20–40% care.Sec.9.InStandards of Medical Care in Diabetesd2016. Diabetes Care 2016;39(Suppl. 1): of patients with diabetes and is the leading cause of end-stage renal disease S72–S80 (ESRD) (1). © 2016 by the American Diabetes Association. Screening for kidney damage (albuminuria) can be most easily performed by Readers may use this article as long as the work urinary albumin–to–creatinine ratio (UACR) in a random spot urine collection. is properly cited, the use is educational and not Timed or 24-h collections are more burdensome and add little to prediction or for proﬁt, and the work is not altered. care.diabetesjournals.org Microvascular Complications and Foot Care S73

accuracy (2,3). Measurement of a spot blood pressure control is a subject of notprogresstohigherlevelsover5–10 urine sample for albumin alone (whether debate. Continued surveillance can as- years of follow-up (5,9–11). Patients by immunoassay or by using a sensitive sess both response to therapy and dis- with persistent and severely increased dipstick test specific for albuminuria) ease progression and may aid in assessing ($300 mg/g Cr) levels of albuminuria without simultaneously measuring urine adherence to ACE inhibitor or ARB ther- are likely to develop ESRD (12,13). creatinine (Cr) is less expensive but sus- apy. Some suggest that reducing UACR to The presence of diabetic retinopathy ceptible to false-negative and false- normal (,30 mg/g Cr) or near normal in patients with UACR $300 mg/g Cr positive determinations as a result of may improve CKD and cardiovascular strongly suggests diabetic kidney dis- variation in urine concentration due to disease (CVD) prognosis, but this ap- ease, and its absence in those with re- hydration. proach has not been formally evaluated duced eGFR and UACR ,300 mg/g Cr Normal UACR is defined as ,30 mg/g in prospective trials, and evidence suggests nondiabetic CKD. Other causes Cr, and increased urinary albumin excre- demonstrates spontaneous remission of CKD should be considered in patients tion is defined as $30 mg/g Cr. Because of albuminuria in up to 40% of patients with diabetes and CKD but without di- of variability in urinary albumin excretion, with type 1 diabetes. abetic retinopathy and in those with an two of three specimens of UACR collected Progression of Diabetic Kidney Disease active urine sediment, with rapidly in- within a 3- to 6-month period should be Conversely, patients with increasing creasing proteinuria or nephrotic syn- abnormal before considering a patient to UACR, declining eGFR, retinopathy, in- drome with low or rapidly decreasing . have albuminuria. Exercise within 24 h, creasing blood pressure, macrovascular eGFR, with 30% reduction in eGFR – infection, fever, congestive heart failure, disease, elevated lipids and/or uric acid within 2 3 months of initiating ACE in- marked hyperglycemia, menstruation, concentrations, or a family history of hibitor or ARB therapy, with refractory and marked hypertension may elevate CKD are more likely to experience a pro- hypertension, or with signs or symp- UACR independently of kidney damage. gression of diabetic kidney disease (5). toms of other systemic diseases. Complications of kidney disease cor- Estimated Glomerular Filtration Rate Interventions Serum Cr should be used to estimate relate with level of kidney function. , 2 Nutrition glomerular filtration rate (GFR). Esti- When eGFR is 60 mL/min/1.73 m , For people with nondialysis-dependent mated GFR (eGFR) is commonly report- screening for complications of CKD is in- diabetic kidney disease, dietary protein Table 9.2 ed by laboratories or can be estimated dicated ( ). Early vaccination intake should be 0.8 g/kg body weight using formulae such as the Modification against hepatitis B virus is indicated in per day (the recommended daily allow- of Diet in Renal Disease (MDRD) study patients likely to progress to ESRD. ance). Compared with higher levels of equation (4) or the Chronic Kidney Identifying and monitoring diabetic dietary protein intake, this level slowed Disease Epidemiology Collaboration kidney disease relies on assessments of GFR decline with evidence of a greater (CKD-EPI) equation. The latter is the pre- kidney damage (albuminuria) and kid- effect over time. Higher levels of dietary ferred GFR estimating equation. GFR ney function (eGFR). Persistently in- protein intake (.20% of daily calories calculators are available at http:// creased UACR in the range of UACR from protein or .1.3 g/kg/day) have – www.nkdep.nih.gov. 30 299 mg/g Cr is an early indicator of been associated with increased albu- Abnormal urinary albumin excretion diabetic kidney disease in type 1 diabe- minuria, more rapid kidney function and eGFR may be used to stage chronic tes and a marker for development of di- loss, and CVD mortality and therefore kidney disease (CKD). The National Kid- abetic kidney disease in type 2 diabetes. should be avoided. Reducing the ney Foundation classification (Table 9.1) It is also a well-established marker of amount of dietary protein below the – is based on both kidney damage (UACR increased CVD risk (6 8). recommended daily allowance of 0.8 $30 mg/g Cr) and eGFR. Not all people with diabetes, kidney g/kg/day is not recommended because disease, and reduced eGFR have albumin- it does not alter glycemic measures, car- Surveillance uria. In addition, there is increasing evi- diovascular risk measures, or the course The need for annual quantitative as- dence that up to 40% of patients with of GFR decline. sessment of albumin excretion after di- type 1 diabetes and UACR levels 30–299 agnosis of albuminuria, institution of mg/g Cr have spontaneous remissions Glycemia ACE inhibitor or angiotensin receptor and approximately 30–40% remain with A number of interventions have been blocker (ARB) therapy, and achieving UACR levels of 30–299 mg/g Cr and do demonstrated to reduce the risk and slow the progression of diabetic kidney disease. Intensive diabetes manage- Table 9.1—Stages of CKD ment with the goal of achieving near- Stage Description GFR (mL/min/1.73 m2) normoglycemia has been shown in large 1 Kidney damage* with normal or increased eGFR $90 prospective randomized studies to delay 2 Kidney damage* with mildly decreased eGFR 60–89 the onset and progression of increased 3 Moderately decreased eGFR 30–59 urinary albumin excretion and reduced eGFR in patients with type 1 diabetes 4 Severely decreased eGFR 15–29 (13) and type 2 diabetes (1,14–17). 5 Kidney failure ,15 or dialysis Despite prior concerns and published *Kidney damage is defined as abnormalities on pathological, urine, blood, or imaging tests. case reports, current data indicate that Adapted from Levey et al. (3). the overall risk of metformin-associated S74 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

Table 9.2—Management of CKD in diabetes in hyperkalemic episodes in those on dual GFR (mL/min/1.73 m2) Recommended management therapy, and larger trials are needed before recommending such therapy. All patients Yearly measurement of Cr, UACR, potassium Diuretics, calcium channel blockers, – 45 60 Referraltoanephrologist if possibilityfornondiabetic kidney and b-blockers can be used as add-on disease exists (duration of type 1 diabetes ,10 years, therapy to achieve blood pressure goals persistent albuminuria, abnormal findings on renal ultrasound, resistant hypertension, rapid fall in eGFR, or in patients treated with maximum doses active urinary sediment on urine microscopic examination) of ACE inhibitors or ARBs (26) or as alter- Consider the need for dose adjustment of medications nate therapy in the rare individual unable Monitor eGFR every 6 months to tolerate ACE inhibitors and ARBs. Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, and parathyroid hormone at least yearly Referral to a Nephrologist Assure vitamin D sufficiency Consider referral to a physician experi- Consider bone density testing enced in the care of kidney disease when Referral for dietary counseling there is uncertainty about the etiology of 30–44 Monitor eGFR every 3 months kidney disease (absence of retinopathy, Monitor electrolytes, bicarbonate, calcium, phosphorus, heavy proteinuria, active urine sediment, parathyroid hormone, hemoglobin, albumin, and weight or rapid decline in GFR). Other triggers for – every 3 6 months referral may include difficult management Consider the need for dose adjustment of medications issues (anemia, secondary hyperparathy- ,30 Referral to a nephrologist roidism, metabolic bone disease, resistant hypertension, or electrolyte disturbances) lactic acidosis is low (1). GFR may be a ,130 mmHg to avoid diastolic blood or advanced kidney disease. The threshold more appropriate measure to assess pressure levels below 60–70 mmHg. for referral may vary depending on the continued metformin use than serum The UK Prospective Diabetes Study frequency with which a provider en- Cr, considering that the serum Cr level (UKPDS) provided strong evidence that counters patients with diabetes and can translate into widely varying blood pressure control can reduce the de- kidney disease. Consultation with a ne- eGFR levels depending on age, ethnic- velopment of diabetic kidney disease (22). phrologist when stage 4 CKD develops # 2 ity, and muscle mass (18). A review Interruption of the renin-angiotensin- (eGFR 30 mL/min/1.73 m ) has been (19) proposed that metformin use aldosterone system with either ACE found to reduce cost, improve quality of should be reevaluated at an eGFR inhibitors or ARBs contributes to reduc- care, and delay dialysis (27). However, ,45 mL/min/1.73 m2 with a reduction tions of kidney disease events in hy- other specialists and providers should in maximum dose to 1,000 mg/day. pertensive patients with diabetes and also educate their patients about the pro- Metformin should be discontinued eGFR ,60 mL/min/1.73 m2 and UACR gressive nature of diabetic kidney disease, fi when eGFR is ,30 mL/min/1.73 m2;in $300 mg/g Cr. the kidney preservation bene ts of pro- clinical situations in which there is an ACE inhibitors have been shown to reactive treatment of blood pressure and increased risk of lactic acidosis, such duce major CVD events in patients with blood glucose, and the potential need for as sepsis, hypotension, and hypoxia; or diabetes (23), thus further supporting the renal replacement therapy. when there is a high risk of acute kidney use of these agents in patients with albu- injury resulting in a worsening of GFR, such minuria, a CVD risk factor. In those with DIABETIC RETINOPATHY as administration of radiocontrast dye in diabetic kidney disease, some evidence Recommendations those with eGFR ,60 mL/min/1.73 m2. suggests that ARBs compared with ACE c Optimize glycemic control to re- inhibitors are associated with a smaller Blood Pressure duce the risk or slow the progres- increase in serum potassium levels (24). There are no randomized controlled tri- sion of diabetic retinopathy. A als of blood pressure levels in diabetes Combination Therapy c Optimize blood pressure and se- that have examined CKD events as out- Two clinical trials studied the combina- rum lipid control to reduce the comes. Blood pressure levels below tions of ACE inhibitors and ARBs and risk or slow the progression of di- 140/90 mmHg in diabetes are recom- found no benefits on CVD or diabetic abetic retinopathy. A mended to reduce CVD mortality and kidney disease, and the drug combina- Screening slow CKD progression. In individuals tion had higher adverse event rates (hy- c Adults with type 1 diabetes should with albuminuria, consider lower blood perkalemia and/or acute kidney injury) have an initial dilated and compre- pressure targets of ,130/80 mmHg (25). Therefore, the combined use of ACE hensive eye examination by an oph- (20,21). Of note, there is an adverse inhibitors and ARBs should be avoided. thalmologist or optometrist within safety signal in clinical trials of diabetic Mineralocorticoid receptor blockers 5 years after the onset of diabetes. B kidney disease when diastolic blood pres- (spironolactone) in combination with ACE c Patients with type 2 diabetes should sure is treated to below 70 mmHg and inhibitors or ARBs remain an area of great have an initial dilated and compre- especially below 60 mmHg in older pop- interest and have been explored in several hensive eye examination by an oph- ulations. As a result, clinical judgment short-term studies with a positive effect on thalmologist or optometrist at the should be used when attempting to albuminuria reduction in diabetic kidney time of the diabetes diagnosis. B achieve systolic blood pressure targets disease. There was, however, an increase care.diabetesjournals.org Microvascular Complications and Foot Care S75

type 2 diabetes, with prevalence controlled type 2 diabetes, there was c If there is no evidence of retinop- strongly related to both the duration essentially no risk of development of athy for one or more annual eye of diabetes and the level of glycemic significant retinopathy with a 3-year in- exams, then exams every 2 years control. Diabetic retinopathy is the terval after a normal examination (35). may be considered. If any level of most frequent cause of new cases of Examinations will be required more fre- diabetic retinopathy is present, blindness among adults aged 20–74 quently by the ophthalmologist if reti- subsequent dilated retinal exami- years in developed countries. Glaucoma, nopathy is progressing. nations for patients with type 1 or cataracts, and other disorders of the eye Retinal photography, with remote type 2 diabetes should be re- occur earlier and more frequently in reading by experts, has great potential peated at least annually by an people with diabetes. to provide screening services in areas ophthalmologist or optometrist. In addition to diabetes duration, where qualified eye care professionals If retinopathy is progressing or factors that increase the risk of, or are are not readily available (36). High-quality sight-threatening, then examina- associated with, retinopathy include fundus photographs can detect most tions will be required more fre- chronic hyperglycemia (28), nephropa- clinically significant diabetic retinopathy. quently. B thy (29), hypertension (30), and dys- Interpretation of the images should be c While retinal photography may lipidemia (31). Intensive diabetes performed by a trained eye care pro- serve as a screening tool for reti- management with the goal of achieving vider. Retinal photography may also en- nopathy, it is not a substitute for a near-normoglycemia has been shown in hance efficiency and reduce costs when comprehensive eye exam, which large prospective randomized studies to the expertise of ophthalmologists can be should be performed at least ini- prevent and/or delay the onset and pro- used for more complex examinations and tially and at intervals thereafter as gression of diabetic retinopathy (15,32). for therapy (37). In-person exams are still recommended by an eye care pro- Lowering blood pressure has been necessary when the retinal photos are un- fessional. E shown to decrease retinopathy progres- acceptable and for follow-up if abnormal- c Eye examinations should occur be- sion, although tight targets (systolic ities are detected. Retinal photos are fore pregnancy or in the first tri- ,120 mmHg) do not impart additional not a substitute for a comprehensive mester, and then patients should benefit (32). In patients with dyslipide- eye exam, which should be performed be monitored every trimester and mia, retinopathy progression may be at least initially and at intervals thereafter for 1 year postpartum as indicated slowed by the addition of fenofibrate, as recommended by an eye care profes- by the degree of retinopathy. B particularly with very mild nonprolifer- sional. Results of eye examinations should Treatment ative diabetic retinopathy (NPDR) at be documented and transmitted to the c Promptly refer patients with any baseline (31). Several case series and a referring health care professional. level of macular edema, severe controlled prospective study suggest Type 1 Diabetes nonproliferative diabetic retinop- that pregnancy in patients with type 1 Because retinopathy is estimated to athy (a precursor of proliferative diabetes may aggravate retinopathy and take at least 5 years to develop after diabetic retinopathy), or any pro- threaten vision, especially when glyce- the onset of hyperglycemia, patients liferative diabetic retinopathy to mic control is poor at the time of con- with type 1 diabetes should have an ini- an ophthalmologist who is knowl- ception (33,34). Laser photocoagulation tial dilated and comprehensive eye ex- edgeable and experienced in the surgery can minimize the risk of vision amination within 5 years after the management and treatment of di- loss (34). diagnosis of diabetes (38). abetic retinopathy. A c Laser photocoagulation therapy is Screening Type 2 Diabetes indicated to reduce the risk of vision The preventive effects of therapy and Patients with type 2 diabetes who may loss in patients with high-risk pro- the fact that patients with proliferative have had years of undiagnosed diabetes fi liferative diabetic retinopathy and, diabetic retinopathy (PDR) or macular and have a signi cant risk of prevalent in some cases, severe nonprolifera- edema may be asymptomatic provide diabetic retinopathy at the time of di- tive diabetic retinopathy. A strong support for screening to detect agnosis should have an initial dilated c Intravitreal injections of antivas- diabetic retinopathy. and comprehensive eye examination at cular endothelial growth factor An ophthalmologist or optometrist the time of diagnosis. are indicated for center-involved who is knowledgeable and experienced Pregnancy diabetic macular edema, which oc- in diagnosing diabetic retinopathy Pregnancy is associated with a rapid curs beneath the foveal center and should perform the examinations. If di- progression of diabetic retinopathy may threaten reading vision. A abetic retinopathy is present, prompt (39,40). Women with preexisting type c The presence of retinopathy is referral to an ophthalmologist is recom- 1 or type 2 diabetes who are planning not a contraindication to aspirin mended. Subsequent examinations for pregnancy or who have become preg- therapy for cardioprotection, as patients with type 1 or type 2 diabetes nant should be counseled on the risk aspirin does not increase the risk are generally repeated annually for pa- of development and/or progression of of retinal hemorrhage. A tients with minimal to no retinopathy. diabetic retinopathy. In addition, rapid Exams every 2 years may be cost- implementation of tight glycemic con- Diabetic retinopathy is a highly specific effective after one or more normal eye trol in the setting of retinopathy is asso- vascular complication of both type 1 and exams, and in a population with well- ciated with worsening of retinopathy S76 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

(34). Women who develop gestational di- replaced the need for laser photocoag- 3. Up to 50% of diabetic peripheral abetes mellitus do not require an eye ulationinthevastmajorityofpatients neuropathy (DPN) may be asymp- examination during pregnancy and do with diabetic macular edema (47). tomatic. If not recognized and if pre- not appear to be at increased risk of Most patients require near-monthly ventive foot care is not implemented, developing diabetic retinopathy during administration of intravitreal therapy patients are at risk for injuries to their pregnancy (41). with anti-VEGF agents during the first insensate feet. Treatment 12 months of treatment with fewer in- 4. Recognition and treatment of auto- jections needed in subsequent years to nomic neuropathy may improve Two of the main motivations for screen- maintain remission from center-involved symptoms, reduce sequelae, and im- ing for diabetic retinopathy are to pre- diabetic macular edema. Other emerging prove quality of life. vent loss of vision and to intervene with therapies for retinopathy that may use treatment when vision loss can be pre- sustained intravitreal delivery of phar- Specific treatment for the underlying vented or reversed. macological agents are currently under nerve damage, other than improved gly- Photocoagulation Surgery investigation. cemic control, is currently not available. Two large trials, the Diabetic Retinopathy Glycemic control can effectively prevent Study (DRS) in patients with PDR and the NEUROPATHY DPN and cardiac autonomic neuropathy Early Treatment Diabetic Retinopathy (CAN) in type 1 diabetes (48,49) and may Study (ETDRS) in patients with macular Recommendations modestly slow their progression in type 2 edema, provide the strongest support Screening diabetes (17) but does not reverse neuro- for the therapeutic benefits of photoco- c All patients should be assessed for nal loss. Therapeutic strategies (pharma- agulation surgery. The DRS (42) showed diabetic peripheral neuropathy cological and nonpharmacological) for that panretinal photocoagulation surgery starting at diagnosis of type 2 di- the relief of symptoms related to painful reduced the risk of severe vision loss from abetes and 5 years after the diag- DPN or autonomic neuropathy can poten- PDR from 15.9% in untreated eyes to nosis of type 1 diabetes and at tially reduce pain (50) and improve qual- 6.4% in treated eyes, with the greatest least annually thereafter. B ity of life. risk–benefit ratio in those with baseline c Assessment should include a care- disease (disc neovascularization or vitre- ful history and 10-g monofilament Diagnosis ous hemorrhage). The ETDRS also verified testing and at least one of the fol- Diabetic Peripheral Neuropathy fi the bene ts of panretinal photocoagula- lowing tests: pinprick, tempera- Patients with type 1 diabetes for 5 B tion for high-risk PDR and in older-onset ture, or vibration sensation. or more years and all patients with patients with severe NPDR or less-than- c Symptoms and signs of autonomic type 2 diabetes should be assessed an- high-risk PDR. Panretinal laser photoco- neuropathy should be assessed in nually for DPN using medical history agulation is still commonly used to patients with microvascular and and simple clinical tests. Symptoms E manage complications of diabetic reti- neuropathic complications. vary according to the class of sensory nopathy that involve retinal neovasculari- Treatment fibers involved. The most common zation and its complications. c Optimize glucose control to pre- early symptoms are induced by the in- Antivascular Endothelial Growth Factor vent or delay the development of volvement of small fibers and include Treatment neuropathy in patients with type 1 pain and dysesthesias (unpleasant While the ETDRS (43) established the diabetes A andtoslowthepro- sensations of burning and tingling). benefit of focal laser photocoagulation gression of neuropathy in patients The involvement of large fibers may surgery in eyes with clinically significant with type 2 diabetes. B cause numbness and loss of protective macular edema (defined as retinal c Assess and treat patients to reduce sensation (LOPS). LOPS indicates the edema located at or within 500 mmof pain related to diabetic peripheral presence of distal sensorimotor poly- the center of the macula), current data neuropathy B and symptoms of au- neuropathy and is a risk factor for di- from multiple well-designed clinical tri- tonomic neuropathy and to im- abetic foot ulceration. The following als demonstrate that intravitreal anti- prove quality of life. E clinical tests may be used to assess vascular endothelial growth factor small- and large-fiber function and (anti-VEGF) agents provide a more ef- The diabetic neuropathies are a hetero- protective sensation: fective treatment regimen for center- geneous group of disorders with diverse involved diabetic macular edema than clinical manifestations. The early recog- 1. Small-fiber function: pinprick and monotherapy or even combination ther- nition and appropriate management of temperature sensation apy with laser (44–46). neuropathy in the patient with diabetes 2. Large-fiber function: vibration per- Historically, laser photocoagulation is important. ception, 10-g monofilament, and an- surgery in both trials was beneficial in kle reflexes reducing the risk of further visual loss 1. Diabetic neuropathy is a diagnosis of 3. Protective sensation: 10-g monofilament in affected patients but generally not exclusion. Nondiabetic neuropathies beneficial in reversing already dimin- may be present in patients with di- These tests not only screen for the pres- ished acuity. Now, intravitreal therapy abetes and may be treatable. ence of dysfunctionbut also predict future with recombinant monoclonal neutralizing 2. Numerous treatment options exist for risk of complications. Electrophysiological antibody to VEGF improves vision and has symptomatic diabetic neuropathy. testing or referral to a neurologist is rarely care.diabetesjournals.org Microvascular Complications and Foot Care S77

needed, except in situations where the results are likely to be abnormal in the of painful DPN, may be effective and clinical features are atypical or the diag- setting of recent uncontrolled hypergly- considered for the treatment of painful nosis is unclear. cemia or diabetic ketoacidosis and often DPN. Comparative efficacy studies and In all patients with diabetes and DPN, correlate poorly with symptoms. Con- trials that include quality-of-life out- causes of neuropathy other than diabe- stipation is the most common lower- comes are rare, so treatment decisions tes should be considered, including gastrointestinal symptom but can must consider each patient’s presenta- toxins (alcohol), neurotoxic medications alternate with episodes of diarrhea. tion and comorbidities and often (chemotherapy), vitamin B12 deficiency, follow a trial-and-error approach. Given Genitourinary Disturbances hypothyroidism, renal disease, malig- the range of partially effective treatment Diabetic autonomic neuropathy may nancies (multiple myeloma, broncho- options, a tailored and stepwise pharma- also cause genitourinary disturbances. genic carcinoma), infections (HIV), cological strategy with careful attention In men, diabetic autonomic neuropathy chronic inflammatory demyelinating to relative symptom improvement, med- may cause erectile dysfunction and/or neuropathy, inherited neuropathies, ication adherence, and medication side retrograde ejaculation. Evaluation of and vasculitis (51). effects is recommended to achieve pain bladder function should be performed reduction and improve quality of life Diabetic Autonomic Neuropathy for individuals with diabetes who have (50,64,65). The symptoms and signs of autonomic recurrent urinary tract infections, pyelo- dysfunction should be elicited carefully nephritis, incontinence, or a palpable Orthostatic Hypotension during the history and physical exami- bladder. Treating orthostatic hypotension is chal- nation. Major clinical manifestations of lenging. The therapeutic goal is to min- diabetic autonomic neuropathy include Treatment imize postural symptoms rather than to hypoglycemia unawareness, resting Glycemic Control restore normotension. Most patients tachycardia, orthostatic hypotension, Near-normal glycemic control, imple- require both nonpharmacological mea- gastroparesis, constipation, diarrhea, mented early in the course of diabetes, sures (e.g., ensuring adequate salt intake, fecal incontinence, erectile dysfunction, has been shown to effectively delay or avoiding medications that aggravate hypo- neurogenic bladder, and sudomotor prevent the development of DPN and tension, or using compressive garments dysfunction with either increased or de- CAN in patients with type 1 diabetes over the legs and abdomen) and pharma- creased sweating. (55–58). Although the evidence for the cological measures. Midodrine is the only Cardiac Autonomic Neuropathy benefit of near-normal glycemic control drug approved by the FDA for the treat- CAN is associated with mortality inde- is not as strong for type 2 diabetes, some ment of orthostatic hypotension. pendent of other cardiovascular risk fac- studies have demonstrated a modest Gastroparesis tors (52,53). In its early stages, CAN may slowing of progression (59,60) without Gastroparesis may improve with a low- be completely asymptomatic and de- reversal of neuronal loss. Several obser- fat, low-fiber diet, optimized glycemic tected only by decreased heart rate var- vational studies suggest that neuro- control, and prokinetic agents such as iability with deep breathing. Advanced pathic symptoms improve not only metoclopramide or erythromycin. In disease may be associated with resting with optimization of glycemic control 2009, the FDA added a boxed warning tachycardia (.100 bpm) and orthostatic but also with the avoidance of extreme to the metoclopramide label highlighting hypotension (a fall in systolic or diastolic blood glucose fluctuations. the risks of irreversible tardive dyskinesia . . blood pressure by 20 mmHg or 10 Diabetic Peripheral Neuropathy after long-term use of metoclopramide. mmHg, respectively, upon standing DPN symptoms, and especially neuro- The chronic use of metoclopramide without an appropriate increase in heart pathic pain, can be severe and can im- should be avoided (66). Metoclopramide rate). CAN treatment is generally fo- pact quality of life, limit mobility, and should be reserved for patients with the cused on alleviating symptoms. contribute to depression and social dys- most severe symptoms that are unre- Gastrointestinal Neuropathies function (61). Several medications have sponsive to other therapies. The medica- Gastrointestinal neuropathies may in- been demonstrated to be effective for tion should be used at the lowest dose volve any portion of the gastrointestinal the treatment of pain associated with and for the shortest duration possible, tract with manifestations including DPN, but there is limited clinical evi- generally not to exceed 3 months, and esophageal dysmotility, gastroparesis, dence regarding which medication is side effects should be closely monitored. constipation, diarrhea, and fecal incon- most effective for an individual patient Erectile Dysfunction tinence. Gastroparesis should be sus- (62,63). Treatments for erectile dysfunction may pected in individuals with erratic The U.S. Food and Drug Administra- include phosphodiesterase type 5 inhib- glucose control or with upper gastroin- tion (FDA) has approved three medi- itors, intracorporeal or intraurethral testinal symptoms without another cations (pregabalin, duloxetine, and prostaglandins, vacuum devices, or pe- identified cause. Evaluation of gastric tapentadol) for the treatment of pain as- nile prostheses. Interventions for other emptying using the gastric emptying sociated with DPN, but none affords manifestations of autonomic neuropa- breath test, a new noninvasive test complete relief, even when used in com- thy are described in the American Dia- that does not use radiation-emitting bination. Tricyclic antidepressants, gaba- betes Association (ADA) statement on compounds (54), or the double-isotope pentin, venlafaxine, carbamazepine, neuropathy (67). As with DPN treat- scintigraphy may be performed if symp- tramadol, and topical capsaicin, al- ments, these interventions do not toms suggest gastroparesis, but test though not approved for the treatment change the underlying pathology and S78 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

natural history of the disease process recognition and treatment of patients brachial index testing should be per- but may improve the patient’s quality with diabetes and feet at risk for ulcers formed in patients with symptoms or of life. and amputations can delay or prevent signs of PAD. Due to the high estimated FOOT CARE adverse outcomes. prevalence of PAD in patients with di- The risk of ulcers or amputations is abetes and the fact that many patients Recommendations increased in people who have the fol- with PAD are asymptomatic, an ADA c Perform a comprehensive foot eval- lowing risk factors: consensus report on PAD (68) suggested uation each year to identify risk fac- that ankle-brachial index screening be tors for ulcers and amputations. B ○ History of foot ulcer performed in patients 50 years of age c Obtain a prior history of ulceration, ○ Amputation and older and be considered in patients amputation, Charcot foot, angio- ○ Foot deformities under 50 years of age who have other plasty or vascular surgery, cigarette ○ Peripheral neuropathy with LOPS PAD risk factors (e.g., smoking, hyper- smoking, retinopathy, and renal dis- ○ Preulcerative callus or corn tension, dyslipidemia, or duration of di- ease and assess current symptoms ○ PAD abetes .10 years). of neuropathy (pain, burning, ○ Poor glycemic control numbness) and vascular disease ○ Visual impairment Patient Education (leg fatigue, claudication). B ○ Diabetic nephropathy (especially pa- Patients with diabetes and high-risk foot c The examination should include in- tients on dialysis) conditions (history of ulcer or amputa- spection of the skin, assessment of ○ Cigarette smoking tion, deformity, LOPS, or PAD) should be foot deformities, neurological assess- educated about their risk factors and ment including 10-g monofilament Clinicians are encouraged to review ADA appropriate management. Patients at testing and pinprick or vibration test- screening recommendations for further risk should understand the implications ing or assessment of ankle reflexes, details and practical descriptions of how of foot deformities, LOPS, and PAD; the and vascular assessment including to perform components of the compre- proper care of the foot, including nail pulses in the legs and feet. B hensive foot examination (67). and skin care; and the importance of c foot monitoring on a daily basis. Pa- Patients with a history of ulcers or Evaluation for Loss of Protective tients with LOPS should be educated amputations, foot deformities, in- Sensation on ways to substitute other sensory mo- sensate feet, and peripheral arte- All adults with diabetes should un- dalities (palpation or visual inspection rial disease are at substantially dergo a comprehensive foot evaluation using a nonbreakable mirror) for sur- increased risk for ulcers and ampu- at least annually to identify high-risk veillance of early foot problems. tations and should have their feet conditions. Clinicians should ask about C The selection of appropriate foot- examined at every visit. history of foot ulcers or amputation, c wear and footwear behaviors at home Patients with symptoms of claudi- neuropathic and peripheral vascular should also be discussed. Patients’ un- cation or decreased or absent symptoms, impaired vision, renal dis- derstanding of these issues and their pedal pulses should be referred ease, tobacco use, and foot care prac- physical ability to conduct proper foot for ankle-brachial index and for tices. A general inspection of skin C surveillance and care should be as- further vascular assessment. integrity and musculoskeletal defor- c sessed. Patients with visual difficulties, A multidisciplinary approach is mities should be performed. Vascular physical constraints preventing move- recommended for individuals assessment should include inspection ment, or cognitive problems that impair with foot ulcers and high-risk feet and assessment of pedal pulses. their ability to assess the condition of (e.g., dialysis patients and those The neurological exam performed as the foot and to institute appropriate re- with Charcot foot, prior ulcers, or part of the foot examination is designed B sponses will need other people, such amputation). to identify LOPS rather than early neu- c as family members, to assist in their care. Refer patients who smoke or who ropathy. The 10-g monofilament is the have histories of prior lower- most useful test to diagnose LOPS. Ide- Treatment extremity complications, loss of ally, the 10-g monofilament test should People with neuropathy or evidence of protective sensation, structural be performed with at least one other increased plantar pressures (e.g., ery- abnormalities, or peripheral arte- assessment (pinprick, temperature or thema, warmth, or calluses) may be ade- rial disease to foot care specialists vibration sensation using a 128-Hz tun- quately managed with well-fitted walking for ongoing preventive care and ing fork, or ankle reflexes). Absent C shoes or athletic shoes that cushion the lifelong surveillance. monofilament sensation suggests LOPS, c feet and redistribute pressure. People Provide general foot self-care educa- while at least two normal tests (and no B with bony deformities (e.g., hammertoes, tion to all patients with diabetes. abnormal test) rule out LOPS. prominent metatarsal heads, bunions) Foot ulcers and amputation, which are Evaluation for Peripheral Arterial may need extra-wide or -deep shoes. Peo- consequences of diabetic neuropathy Disease ple with bony deformities, including Char- and/or peripheral arterial disease Initial screening for PAD should cot foot, who cannot be accommodated (PAD), are common and represent include a history for decreased walking with commercial therapeutic footwear major causes of morbidity and mor- speed, leg fatigue, claudication, and an will require custom-molded shoes. Spe- tality in people withdiabetes.Early assessment of the pedal pulses. Ankle- cial consideration and a thorough workup care.diabetesjournals.org Microvascular Complications and Foot Care S79

should be performed when patients with function, hypertension, and diabetes. Circulation 21. Cushman WC, Evans GW, Byington RP, neuropathy present with an acute onset 2004;110:32–35 et al.; ACCORD Study Group. Effects of intensive of a red, hot, swollen foot or ankle, and 9. de Boer IH, Rue TC, Cleary PA, et al.; Diabetes blood-pressure control in type 2 diabetes melli- Control and Complications Trial/Epidemiology tus. N Engl J Med 2010;362:1575–1585 Charcot neuroarthropathy should be ex- of Diabetes Interventions and Complications 22. UK Prospective Diabetes Study Group. Tight cluded. Early diagnosis and treatment of Study Research Group. Long-term renal out- blood pressure control and risk of macrovascu- Charcot neuroarthropathy is the best way comes of patients with type 1 diabetes mellitus lar and microvascular complications in type 2 to prevent deformities that increase the and microalbuminuria: an analysis of the diabetes: UKPDS 38. BMJ 1998;317:703–713 risk of ulceration and amputation. Diabetes Control and Complications Trial/ 23. Heart Outcomes Prevention Evaluation Epidemiology of Diabetes Interventions and Study Investigators. Effects of ramipril on car- Most diabetic foot infections are poly- Complications cohort. Arch Intern Med 2011; diovascular and microvascular outcomes in peo- microbial, with aerobic gram-positive 171:412–420 ple with diabetes mellitus: results of the HOPE cocci. Staphylococci are the most com- 10. Molitch ME, Steffes M, Sun W, et al.; Epi- study and MICRO-HOPE substudy. Lancet 2000; mon causative organisms. Wounds demiology of Diabetes Interventions and Com- 355:253–259 without evidence of soft-tissue or bone plications Study Group. Development and 24. Pepine CJ, Handberg EM, Cooper-DeHoff progression of renal insufficiency with and with- RM, et al.; INVEST Investigators. A calcium an- infection do not require antibiotic ther- out albuminuria in adults with type 1 diabetes in tagonist vs a non-calcium antagonist hyperten- apy. Empiric antibiotic therapy can be the Diabetes Control and Complications Trial sion treatment strategy for patients with narrowly targeted at gram-positive and the Epidemiology of Diabetes Interventions coronary artery disease. The International cocci in many patients with acute infec- and Complications study. Diabetes Care 2010; Verapamil-Trandolapril Study (INVEST): a ran- – tions, but those at risk for infection with 33:1536 1543 domized controlled trial. JAMA 2003;290: 11. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ 2805–2816 antibiotic-resistant organisms or with EDIC Research Group. Intensive diabetes ther- 25. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET chronic, previously treated, or severe apy and glomerular filtration rate in type 1 di- Investigators. Telmisartan, ramipril, or both in infections require broader-spectrum abetes. N Engl J Med 2011;365:2366–2376 patients at high risk for vascular events. N Engl J regimens and should be referred to spe- 12. Gall M-A, Hougaard P, Borch-Johnsen K, Med 2008;358:1547–1559 cialized care centers (69). Foot ulcers Parving H-H. Risk factors for development of 26. Berl T, Hunsicker LG, Lewis JB, et al.; Irbe- incipient and overt diabetic nephropathy in pa- sartan Diabetic Nephropathy Trial. Collabora- and wound care may require care by a tients with non-insulin dependent diabetes mel- tive Study Group. Cardiovascular outcomes in podiatrist, orthopedic or vascular sur- litus: prospective, observational study. BMJ the Irbesartan Diabetic Nephropathy Trial of pa- geon, or rehabilitation specialist experi- 1997;314:783–788 tients with type 2 diabetes and overt nephrop- enced in the management of individuals 13. The Diabetes Control and Complications athy. Ann Intern Med 2003;138:542–549 27. 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Diabetes Care 2005;28:956– 42. The Diabetic Retinopathy Study Research ease in patients with type 2 diabetes: the DIAD 962 Group. Preliminary report on effects of photo- study: a randomized controlled trial. JAMA 64. Griebeler ML, Morey-Vargas OL, Brito JP, coagulation therapy. Am J Ophthalmol 1976;81: 2009;301:1547–1555 et al. Pharmacologic interventions for painful 383–396 54. U.S. Food and Drug Administration. FDA ap- diabetic neuropathy: an umbrella systematic re- 43. Early Treatment Diabetic Retinopathy proves breath test to aid in diagnosis of delayed view and comparative effectiveness network Study Research Group. Photocoagulation for di- gastric emptying [Internet], 2015. Available from meta-analysis. Ann Intern Med 2014;161:639– abetic macular edema. Early Treatment Diabetic http://www.fda.gov/NewsEvents/Newsroom/ 649 Retinopathy Study report number 1. Arch Oph- PressAnnouncements/ucm441370.htm. Accessed 65. Ziegler D, Fonseca V. 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The effect of intensive diabetes ther- newsevents/newsroom/pressannouncements/ et al.; RESTORE Study Group. The RESTORE study: apy on measures of autonomic nervous system ucm149533.htm. Accessed 6 July 2015 ranibizumab monotherapy or combined with la- function in the Diabetes Control and Complications 67. Boulton AJM, Armstrong DG, Albert SF, ser versus laser monotherapy for diabetic macu- Trial (DCCT). Diabetologia 1998;41:416–423 et al.; American Diabetes Association; American lar edema. Ophthalmology 2011;118:615–625 57. Albers JW, Herman WH, Pop-Busui R, et al.; Association of Clinical Endocrinologists. Com- 46. Elman MJ, Bressler NM, Qin H, et al.; Dia- Diabetes Control and Complications Trial/Epi- prehensive foot examination and risk assess- betic Retinopathy Clinical Research Network. demiology of Diabetes Interventions and Com- ment: a report of the task force of the foot Expanded 2-year follow-up of ranibizumab plications Research Group. Effect of prior care interest group of the American Diabetes plus prompt or deferred laser or triamcinolone intensive insulin treatment during the Diabetes Association, with endorsement by the American plus prompt laser for diabetic macular edema. Control and Complications Trial (DCCT) on pe- Association of Clinical Endocrinologists. Diabe- Ophthalmology 2011;118:609–614 ripheral neuropathy in type 1 diabetes during tes Care 2008;31:1679–1685 47. Nguyen QD, Brown DM, Marcus DM, et al.; the Epidemiology of Diabetes Interventions and 68. American Diabetes Association. Peripheral RISE and RIDE Research Group. Ranibizumab for Complications (EDIC) Study. Diabetes Care arterial disease in people with diabetes. Diabe- diabetic macular edema: results from 2 phase III 2010;33:1090–1096 tes Care 2003;26:3333–3341 randomized trials: RISE and RIDE. Ophthalmol- 58. Pop-Busui R, Low PA, Waberski BH, et al.; 69. Lipsky BA, Berendt AR, Cornia PB, et al.; In- ogy 2012;119:789–801 DCCT/EDIC Research Group. Effects of prior in- fectious Diseases Society of America. 2012 In- 48. Ang L, Jaiswal M, Martin C, Pop-Busui R. tensive insulin therapy on cardiac autonomic fectious Diseases Society of America clinical Glucose control and diabetic neuropathy: les- nervous system function in type 1 diabetes mel- practice guideline for the diagnosis and treat- sons from recent large clinical trials. Curr Diab litus: the Diabetes Control and Complications ment of diabetic foot infections. Clin Infect Dis Rep 2014;14:528 Trial/Epidemiology of Diabetes Interventions 2012;54:e132–e173 Diabetes Care Volume 39, Supplement 1, January 2016 S81

10. Older Adults American Diabetes Association Diabetes Care 2016;39(Suppl. 1):S81–S85 | DOI: 10.2337/dc16-S013

Recommendations c Consider the assessment of medical, functional, mental, and social geriatric domains for diabetes management in older adults to provide a framework to determine targets and therapeutic approaches. E c Screening for geriatric syndromes may be appropriate in older adults experiencing limitations in their basic and instrumental activities of daily living, as they may affect diabetes self-management. E c Older adults ($65 years of age) with diabetes should be considered a high- priority population for depression screening and treatment. B c Hypoglycemia should be avoided in older adults with diabetes. It should be screened for and managed by adjusting glycemic targets and pharmacological

interventions. B ADULTS OLDER 10. c Older adults who are functional and cognitively intact and have significant life expectancy may receive diabetes care with goals similar to those developed for younger adults. E c Glycemic goals for some older adults might reasonably be relaxed, using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. E c Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. E c Other cardiovascular risk factors should be treated in older adults with consideration of the time frame of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid-lowering and aspirin therapy may benefit those with life expectancy at least equal to the time frame of primary or secondary prevention trials. E c When palliative care is needed in older adults with diabetes, strict blood pressure control may not be necessary, and withdrawal of therapy may be appropriate. Similarly, the intensity of lipid management can be relaxed, and withdrawal of lipid-lowering therapy may be appropriate. E c Consider diabetes education for the staff of long-term care facilities to improve the management of older adults with diabetes. E c Patients with diabetes residing in long-term care facilities need careful assessment to establish a glycemic goal and to make appropriate choices of glucose- lowering agents based on their clinical and functional status. E c Overall comfort, prevention of distressing symptoms, and preservation of quality of life and dignity are primary goals for diabetes management at the end of life. E

OVERVIEW Diabetes is an important health condition for the aging population; ;26% of patients over the age of 65 years have diabetes (1), and this number is expected to grow rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, and coexisting illnesses, such as hypertension, coronary heart disease, and stroke, than those without diabetes. Older Suggested citation: American Diabetes Associa- adults with diabetes also are at a greater risk than other older adults for several tion. Older adults. Sec. 10. In Standards of Med- ical Care in Diabetesd2016. Diabetes Care common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary 2016;39(Suppl. 1):S81–S85 incontinence, injurious falls, and persistent pain. Screening for diabetes complications © 2016 by the American Diabetes Association. in older adults also should be individualized and periodically revisited, since the results Readers may use this article as long as the work of screening tests may impact therapeutic approaches and targets. Older adults are at is properly cited, the use is educational and not increased risk for depression and should therefore be screened and treated accordingly for proﬁt, and the work is not altered. S82 Older Adults Diabetes Care Volume 39, Supplement 1, January 2016

(2). Diabetes management may require maintain cognitive function in older no complications. Some older adults assessment of medical, functional, mental, adults. However, studies examining the with diabetes are frail and have other and social domains. This may provide a effects of intensive glycemic and blood underlying chronic conditions, substan- framework to determine targets and pressure control to achieve specific tar- tial diabetes-related comorbidity, or therapeutic approaches. Particular at- gets have not demonstrated a reduction limited physical or cognitive function- tention should be paid to complications in brain function decline (12). ing. Other older individuals with diabe- that can develop over short periods of Older adults with diabetes should be tes have little comorbidity and are time and/or that would significantly carefully screened and monitored for cog- active. Life expectancies are highly vari- impair functional status, such as visual nitive impairment (3). Several organiza- able for this population but are often and lower-extremity complications. Please tions have released simple assessment longer than clinicians realize. Providers refer to the American Diabetes Associa- tools, such as the Mini-Mental State Ex- caring for older adults with diabetes tion (ADA) consensus report “Diabetes in amination (MMSE) and the Montreal must take this heterogeneity into con- Older Adults” for details (3). Cognitive Assessment (MoCA), which sideration when setting and prioritizing may help to identify patients requiring treatment goals (Table 10.1). NEUROCOGNITIVE FUNCTION neuropsychological evaluation, particu- Older adults with diabetes are at higher larly those in whom dementia is sus- Healthy Patients With Good risk of cognitive decline and institution- pected (i.e., experiencing memory loss Functional Status alization (4,5). The presentation of cog- and decline in their basic and instrumen- There are few long-term studies in nitive impairment ranges from subtle tal activities of daily living). older adults demonstrating the bene- fi executive dysfunction to memory loss ts of intensive glycemic, blood pres- and overt dementia. Diabetes increases HYPOGLYCEMIA sure, and lipid control. Patients who the incidence of all-cause dementia, It is important to prevent hypoglycemia can be expected to live long enough fi Alzheimer disease, and vascular demen- to reduce the risk of cognitive decline to reap the bene ts of long-term inten- tia when compared with rates in people and to carefully assess and reassess pa- sive diabetes management, who have with normal glucose tolerance (6). The tients’ risk for worsening of glycemic good cognitive and physical function, effects of hyperglycemia and hyperinsu- control and functional decline. Older and who choose to do so via shared de- linemia on the brain are areas of intense adults are at higher risk of hypoglycemia cision making may be treated using research interest. Clinical trials of spe- for many reasons, including insulin de- therapeutic interventions and goals cific interventionsdincluding cholines- ficiency and progressive renal insuffi- similar to those for younger adults terase inhibitors and glutamatergic ciency. In addition, older adults tend to with diabetes. As with all patients antagonistsdhave not shown positive have higher rates of unidentified cogni- with diabetes, diabetes self-management therapeutic benefit in maintaining or tive deficits, causing difficulty in com- education and ongoing diabetes self- significantly improving cognitive func- plex self-care activities (e.g., glucose management support are vital compo- tion or in preventing cognitive decline monitoring, adjusting insulin doses, nents of diabetes care for older adults (7). Recent pilot studies in patients etc.). These deficits have been associ- and their caregivers. with mild cognitive impairment evaluat- ated with increased risk of hypoglyce- Patients With Complications and fi ing the potential bene ts of intranasal mia and with severe hypoglycemia Reduced Functionality insulin therapy or metformin therapy linked to increased dementia. There- For patients with advanced diabetes com- provide insights for future clinical trials fore, it is important to routinely screen plications, life-limiting comorbid illness, or – and mechanistic studies (8 10). older adults for cognitive dysfunction substantial cognitive or functional impair- fi The presence of cognitive impairment and discuss ndings with the caregivers. ment, it is reasonable to set less intensive can make it challenging for clinicians to Hypoglycemic events should be dili- glycemic target goals. These patients are help their patients to reach individual- gently monitored and avoided, whereas less likely to benefit from reducing the risk ized glycemic, blood pressure, and lipid glycemic targets and pharmacological of microvascular complications and more targets. Cognitive dysfunction makes it interventions may need to be adjusted likely to suffer serious adverse effects fi dif cult for patients to perform complex to accommodate for the changing needs from hypoglycemia. However, patients self-care tasks, such as glucose monitor- of the older adult (3). with poorly controlled diabetes may be ing and adjusting insulin doses. It also TREATMENT GOALS subject to acute complications of diabe- hinders their ability to appropriately tes, including dehydration, poor wound Rationale maintain the timing and content of diet. healing, and hyperglycemic hyperosmolar When clinicians are managing these The care of older adults with diabetes is coma. Glycemic goals at a minimum types of patients, it is critical to simplify complicated by their clinical and func- should avoid these consequences. drug regimens and to involve caregivers tional heterogeneity. Some older indi- in all aspects of care. viduals may have developed diabetes Vulnerable Patients at the End of Life Poor glycemic control is associated years earlier and have significant com- For patients receiving palliative care and with a decline in cognitive function (11), plications, others are newly diagnosed end-of-life care, the focus should be to and longer duration of diabetes worsens and may have had years of undiagnosed avoid symptoms and complications from cognitive function. There are ongoing diabetes with resultant complications, glycemic management. Thus, when organ studies evaluating whether preventing and still other older adults may have failure develops, several agents will have or delaying diabetes onset may help to truly recent-onset disease with few or to be titrated or discontinued. For the care.diabetesjournals.org Older Adults S83

Table 10.1—Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes Patient Fasting or characteristics/ Reasonable A1C preprandial health status Rationale goal‡ glucose Bedtime glucose Blood pressure Lipids Healthy (few coexisting Longer remaining ,7.5% 90–130 mg/dL 90–150 mg/dL ,140/90 mmHg Statin unless chronic illnesses, intact life expectancy (58 mmol/mol) (5.0–7.2 mmol/L) (5.0–8.3 mmol/L) contraindicated cognitive and functional or not tolerated status) Complex/intermediate Intermediate ,8.0% 90–150 mg/dL 100–180 mg/dL ,140/90 mmHg Statin unless (multiple coexisting remaining life (64 mmol/mol) (5.0–8.3 mmol/L) (5.6–10.0 mmol/L) contraindicated chronic illnesses* or expectancy, high or not tolerated 21 instrumental ADL treatment burden, impairments or mild-to- hypoglycemia moderate cognitive vulnerability, impairment) fall risk Very complex/poor health Limited remaining ,8.5%† 100–180 mg/dL 110–200 mg/dL ,150/90 mmHg Consider (LTC or end-stage chronic life expectancy (69 mmol/mol) (5.6–10.0 mmol/L) (6.1–11.1 mmol/L) likelihood of illnesses** or moderate- makes benefit benefitwith to-severe cognitive uncertain statin (secondary impairment or 21 ADL prevention more dependencies) so than primary) This represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes. The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient’s health status and preferences may change over time. ADL, activities of daily living. ‡A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarction, and stroke. By “multiple,” we mean at least three, but many patients may have five or more (27). **The presence of a single end-stage chronic illness, such as stage 3–4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status and significantly reduce life expectancy. †A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of ;200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing. dying patient most agents for type 2 di- Insulin Sensitizers hypoglycemia, and its use requires that abetes may be removed. There is, how- Metformin is the first-line agent in older patients or caregivers have good visual ever, no consensus for the management adults with type 2 diabetes. However, it and motor skills and cognitive ability. of type 1 diabetes in this scenario (13,14). is contraindicated in patients with renal insufficiency or significant heart failure. Incretin-Based Therapies Beyond Glycemic Control Since serum creatinine levels do not ad- Glucagon-like peptide 1 receptor ago- Although hyperglycemia control may be equately reflect renal function in older nists and dipeptidyl peptidase 4 inhibi- important in older individuals with dia- people (muscle mass losses are associ- tors have few side effects, but their betes, greater reductions in morbidity ated with chronic conditions and func- costs may be a barrier to some older and mortality are likely to result from tional decline), a timed urine collection patients. A systematic review concluded control of other cardiovascular risk fac- to assess creatinine clearance has been that incretin-based agents do not in- tors rather than from tight glycemic con- recommended, particularly in those crease major adverse cardiovascular trol alone. There is strong evidence from aged $80 years. Metformin may be events (19). Glucagon-like peptide 1 clinical trials of the value of treating hy- temporarily discontinued before proce- receptor agonists are injectable agents, pertension in the elderly (15,16). There is dures, during hospitalizations, and which require visual, motor, and cogni- less evidence for lipid-lowering and aspirin when acute illness may compromise re- tive skills. therapy, although the benefits of these in- nal or liver function. Thiazolidinediones, Sodium–Glucose Cotransporter 2 terventions for primary and secondary if used at all, should be used very cau- Inhibitors prevention are likely to apply to older tiously in those with, or at risk for, con- Sodium–glucose cotransporter 2 inhibi- adults whose life expectancies equal or ex- gestive heart failure and have been tors offer an oral route, which may be ceed the time frames seen in clinical trials. associated with fractures. convenient for older adults with diabe- PHARMACOLOGICAL THERAPY tes; however, long-term experience is Insulin Secretagogues limited despite the initial efficacy and Special care is required in prescribing Sulfonylureas and other insulin secre- safety data reported with these agents. and monitoring pharmacological ther- tagogues are associated with hypo- apy in older adults (17). Cost may be a glycemia and should be used with Other Factors to Consider significant factor, especially as older caution. Glyburide is contraindicated The needs of older adults with diabetes adults tend to be on many medications. in older adults (18). Insulin can also cause and their caregivers should be evaluated S84 Older Adults Diabetes Care Volume 39, Supplement 1, January 2016

to construct a tailored care plan. Social intake and contribute to unintentional END-OF-LIFE CARE difficulties may impair their quality of weight loss and undernutrition. Diets tai- The management of the older adult at life and increase the risk of functional lored to a patient’s culture, preferences, the end of life receiving palliative medi- dependency. The patient’s living situa- and personal goals might increase qual- cine or hospice is a unique situation. tion must be considered, as it may affect ity of life, satisfaction with meals, and Overall, palliative medicine promotes diabetes management and support. nutrition status (22). comfort, symptom control, and preven- Older adults in assisted living facilities tion (pain, hypoglycemia and hyperglyce- may not have support to administer Hypoglycemia mia, dehydration) and preservation of their own medications, whereas those Older adults with diabetes in LTC are dignity and quality of life in patients living in a nursing home (community liv- especially vulnerable to hypoglycemia. with limited life expectancy (21,24). A pa- ing centers) may rely completely on the They have a disproportionately high tient has the right to refuse testing and care plan and nursing support. Those re- number of clinical complications and co- treatment, whereas providers may con- ceiving palliative care (with or without morbidities that can increase hypogly- sider withdrawing treatment and limiting hospice) may require an approach that cemia risk: impaired renal function, diagnostic testing, including a reduction emphasizes comfort and symptom man- slowed hormonal regulation and coun- in the frequency of finger-stick testing agement, while deemphasizing strict terregulation, and suboptimal hydra- (25). Glucose targets should aim to pre- metabolic and blood pressure control. tion, variable appetite and nutritional vent hypoglycemia and hyperglycemia. intake, polypharmacy, and slowed intes- TREATMENT IN SKILLED NURSING Treatment interventions need to be tinal absorption (23). FACILITIES AND NURSING HOMES mindful of quality of life. Careful monitor- Another consideration for the LTC set- ing of oral intake is warranted. The de- Management of diabetes in the long- ting is that unlike the hospital setting, cision process may need to involve the term care (LTC) setting (i.e., nursing medical providers are not required to patient, family, and caregivers, leading homes and skilled nursing facilities) is evaluate the patients daily. According to a care plan that is both convenient unique. Individualization of health care to federal guidelines, assessments and effective for the goals of care (26). is important in all patients; however, should be done at least every 30 days The pharmacological therapy may in- practical guidance is needed for medical for the first 90 days after admission clude oral agents as first line, followed providersaswellastheLTCstaffand and then at least once every 60 days. by a simplified insulin regimen. If needed, caregivers. The American Medical Di- Although in practice the patients may basal insulin can be implemented, ac- rectors Association (AMDA) guidelines actually be seen more frequently, the offer a 12-step program for staff (20). concern is that patients may have uncon- companied by oral agents and without This training includes diabetes detection trolled glucose levels or wide excursions rapid-acting insulin. Agents that can and institutional quality assessment. It without the practitioner being notified. cause gastrointestinal symptoms such is also recommended that LTC facilities Providers may make adjustments to as nausea or excess weight loss may not develop their own policies and proce- treatment regimens by telephone, be good choices in this setting. As symp- dures for prevention and management fax, or order directly at the LTC facili- toms progress, some agents may be of hypoglycemia. ties provided they are given timely no- slowly tapered down and discontinued. fi Strata have been proposed for diabe- Resources ti cation from a standardized alert system. tes management in those with advanced Staff of LTC facilities should receive ap- disease (14). propriate diabetes education to improve The following alert strategy could be considered: the management of older adults with di- 1. A stable patient:continuewiththe abetes. Major organizations such as the ’ 1. Call provider immediately:incase patient s previous regimen, with a ADA, the American Geriatrics Society of hypoglycemia (,70 mg/dL focus on the prevention of hypogly- (AGS), the International Association of [3.9 mmol/L]). Low finger-stick blood cemia and the management of hy- Gerontology and Geriatrics (IAGG), and glucose values should be confirmed perglycemia, keeping levels below the European Diabetes Working Party by laboratory glucose measurement. the renal threshold of glucose. There for Older People (EDWPOP) concur with 2. Call as soon as possible:a)glucose is very little role for A1C monitoring the AMDA on the need to individualize values between 70 and 100 mg/dL and lowering. treatments for each patient, the need to (between 3.9 and 5.6 mmol/L) 2. A patient with organ failure: pre- avoid both hypoglycemia and the meta- (regimen may need to be adjusted), venting hypoglycemia is of greater bolic complications of diabetes, and the b) glucose values greater than significance. Dehydration must be pre- need to provide adequate diabetes train- 250 mg/dL (13.9 mmol/L) within a vented and handled. In people with ing to LTC staff (3,21). 24-h period, c) glucose values greater type 1 diabetes, insulin administration Nutrition Considerations than 300 mg/dL (16.7 mmol/L) within may be reduced as the oral intake of An older adult residing in an LTC facility 2 consecutive days, d) or when any food decreases. For those with type 2 may have irregular and unpredictable reading is too high, e) or the patient diabetes, agents that may cause hypo- meal consumption, undernutrition, an- is sick, with vomiting or other malady glycemia should be titrated. The main orexia, and impaired swallowing. Fur- that can reflect hyperglycemic crisis, goal is to avoid hypoglycemia, allow- thermore, therapeutic diets may may lead to poor oral intake, and thus ing for glucose values in the upper inadvertently lead to decreased food requires regimen adjustment. level of the desired target range. care.diabetesjournals.org Older Adults S85

3. A dying patient: for patients with amnestic mild cognitive impairment: a pilot clin- 19. Rotz ME, Ganetsky VS, Sen S, Thomas TF. type 2 diabetes, the discontinuation ical trial. Arch Neurol 2012;69:29–38 Implications of incretin-basedtherapies on cardio- – of all medications may be a pertinent 9. Freiherr J, Hallschmid M, Frey WH 2nd, et al. vascular disease. Int J Clin Pract 2015;69:531 549 Intranasal insulin as a treatment for Alzheimer’s 20. American Medical Directors Association. approach, as they are unlikely to have disease: a review of basic research and clinical Diabetes management in the long-term care any oral intake. In patients with type 1 evidence. CNS Drugs 2013;27:505–514 setting [Internet]. Available from http://www diabetes, there is no consensus, but a 10. Alagiakrishnan K, Sankaralingam S, Ghosh .amda.com/tools/guidelines.cfm#diabetes. Ac- small amount of basal insulin may M, Mereu L, Senior P. Antidiabetic drugs and cessed 5 October 2015 ~ maintain glucose levels and prevent their potential role in treating mild cognitive 21. Sinclair A, Morley JE, Rodriguez-Manas L, impairment and Alzheimer’s disease. Discov et al. Diabetes mellitus in older people: position acute hyperglycemic complications. Med 2013;16:277–286 statement on behalf of the International Asso- 11. Yaffe K, Falvey C, Hamilton N, et al. Diabe- ciation of Gerontology and Geriatrics (IAGG), References tes, glucose control, and 9-year cognitive de- the European Diabetes Working Party for Older 1. Centers for Disease Control and Prevention. cline among older adults without dementia. People (EDWPOP), and the International Task – National diabetes statistics report: estimates of Arch Neurol 2012;69:1170 1175 Force of Experts in Diabetes. J Am Med Dir Assoc – diabetes and its burden in the United States, 12. Launer LJ, Miller ME, Williamson JD, et al.; 2012;13:497 502 2014 [Internet]. Available from http://www.cdc ACCORD MIND Investigators. Effects of inten- 22. Dorner B, Friedrich EK, Posthauer ME. Prac- .gov/diabetes/data/statistics/2014statisticsreport sive glucose lowering on brain structure and tice paper of the American Dietetic Association: .html. Accessed 1 October 2015 function in people with type 2 diabetes individualized nutrition approaches for older 2. Kimbro LB, Mangione CM, Steers WN, et al. (ACCORD MIND): a randomised open-label sub- adults in health care communities. J Am Diet – – Depression and all-cause mortality in persons study. Lancet Neurol 2011;10:969 977 Assoc 2010;110:1554 1563 with diabetes mellitus: are older adults at 13. Sinclair A, Dunning T, Colagiuri S. Managing 23. Migdal A, Yarandi SS, Smiley D, Umpierrez higher risk? Results from the Translating older people with type 2 diabetes: global guide- GE. Update on diabetes in the elderly and in Research Into Action for Diabetes Study. J Am line. International Diabetes Federation, 2013 nursing home residents. J Am Med Dir Assoc Geriatr Soc 2014;62:1017–1022 14. Angelo M, Ruchalski C, Sproge BJ. An ap- 2011;12:627–632.e2 3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabe- proach to diabetes mellitus in hospice and pal- 24. Quinn K, Hudson P, Dunning T. Diabetes man- tes in older adults. Diabetes Care 2012;35: liative medicine. J Palliat Med 2011;14:83–87 agement in patients receiving palliative care. 2650–2664 15. Beckett NS, Peters R, Fletcher AE, et al.; J Pain Symptom Manage 2006;32:275–286 4. Cukierman T, Gerstein HC, Williamson JD. HYVET Study Group. Treatment of hypertension 25. Ford-Dunn S, Smith A, Quin J. Management Cognitive decline and dementia in diabetes: sys- in patients 80 years of age or older. N Engl J Med of diabetes during the last days of life: attitudes tematic overview of prospective observational 2008;358:1887–1898 of consultant diabetologists and consultant pal- studies. Diabetologia 2005;48:2460–2469 16. James PA, Oparil S, Carter BL, et al. 2014 liative care physicians in the UK. Palliat Med 5. Roberts RO, Knopman DS, Przybelski SA, evidence-based guideline for the management 2006;20:197–203 et al. Association of type 2 diabetes with brain of high blood pressure in adults: report from 26. Mallery LH, Ransom T, Steeves B, Cook B, atrophy and cognitive impairment. Neurology the panel members appointed to the Eighth Dunbar P, Moorhouse P. Evidence-informed 2014;82:1132–1141 Joint National Committee (JNC 8). JAMA 2014; guidelines for treating frail older adults with 6. Xu WL, von Strauss E, Qiu CX, Winblad B, 311:507–520 type 2 diabetes: from the Diabetes Care Pro- Fratiglioni L. Uncontrolled diabetes increases the 17. Valencia WM, Florez H. Pharmacological gram of Nova Scotia (DCPNS) and the Palliative risk of Alzheimer’s disease: a population-based treatment of diabetes in older people. Diabetes and Therapeutic Harmonization (PATH) pro- cohort study. Diabetologia 2009;52:1031–1039 Obes Metab 2014;16:1192–1203 gram. J Am Med Dir Assoc 2013;14:801–808 7. Ghezzi L, Scarpini E, Galimberti D. Disease- 18. Campanelli CM; American Geriatrics Society 27. Laiteerapong N, Iveniuk J, John PM, modifying drugs in Alzheimer’sdisease.Drug 2012 Beers Criteria Update Expert Panel. Ameri- Laumann EO, Huang ES. Classiﬁcation of older Des Devel Ther 2013;7:1471–1478 can Geriatrics Society updated Beers Criteria for adults who have diabetes by comorbid condi- 8. Craft S, Baker LD, Montine TJ, et al. Intranasal potentially inappropriate medication use in older tions, United States, 2005-2006. Prev Chronic insulin therapy for Alzheimer disease and adults. J Am Geriatr Soc 2012;60:616–631 Dis 2012;9:E100 S86 Diabetes Care Volume 39, Supplement 1, January 2016

11. Children and Adolescents American Diabetes Association Diabetes Care 2016;39(Suppl. 1):S86–S93 | DOI: 10.2337/dc16-S014

TYPE 1 DIABETES Three-quarters of all cases of type 1 diabetes are diagnosed in individuals ,18 years of age. The provider must consider the unique aspects of care and management of children and adolescents with type 1 diabetes, such as changes in insulin sensitivity related to physical growth and sexual maturation, ability to provide self-care, supervision in the child care and school environment, and neurological vulnerability to hypoglycemia and hyperglycemia in young children, as well as possible adverse neurocognitive effects of diabetic ketoacidosis (1,2). Attention to family dynamics, developmental stages, and physiological differences related to sexual maturity are all essential in developing and implementing an optimal diabetes regimen (3). Due to the paucity of clinical research in children, the recommendations for children and adolescents are less likely to be based on clinical trial evidence. However, expert opinion and a review of available and relevant experimental data are summarized in the American Diabetes Association (ADA) position statement “Care of Children and Adolescents With Type 1 Diabetes” (4) and have been updated in the ADA position statement “Type 1 Diabetes Through the Life Span” (5). A multidisciplinary team of specialists trained in pediatric diabetes management and sensitive to the challenges of children and adolescents with type 1 diabetes and their families should provide care for this population. It is essential that diabetes 11. CHILDREN AND ADOLESCENTS self-management education (DSME) and support (DSMS), medical nutrition therapy, and psychosocial support be provided at diagnosis and regularly thereafter by individuals experienced with the educational, nutritional, behavioral, and emotional needs of the growing child and family. The appropriate balance between adult supervision and independent self-care should be deﬁned at the ﬁrst interaction and reevaluated at subsequent clinic visits. The balance between adult supervision and independent self-care will evolve as the adolescent gradually becomes an emerging young adult. Diabetes Self-management Education and Support

Recommendation c Youth with type 1 diabetes and parents/caregivers (for patients aged ,18 years) should receive culturally sensitive and developmentally appropriate individualized diabetes self-management education and support according to national standards at diagnosis and routinely thereafter. B

No matter how sound the medical regimen, it can only be effective if the family and/ or affected individuals are able to implement it. Family involvement is a vital component of optimal diabetes management throughout childhood and adolescence. Health care providers (the diabetes care team) who care for children and adolescents must be capable of evaluating the educational, behavioral, emotional, and psychosocial factors that impact implementation of a treatment plan and must work with the individual and family to overcome barriers or redeﬁne goals as appropriate. DSME and DSMS require periodic reassessment, especially as the youth grows, develops, and acquires the need for greater independent self-care skills. In addition, Suggested citation: American Diabetes Associa- it is necessary to assess the educational needs and skills of day care providers, school tion. Children and adolescents. Sec. 11. In Stan- nurses, or other school personnel who participate in the care of the young child with dards of Medical Care in Diabetesd2016. diabetes (6). Diabetes Care 2016;39(Suppl. 1):S86–S93 © 2016 by the American Diabetes Association. School and Child Care Readers may use this article as long as the work As a large portion of a child’s day is spent in school, close communication with and is properly cited, the use is educational and not the cooperation of school or day care personnel are essential for optimal diabetes for proﬁt, and the work is not altered. care.diabetesjournals.org Children and Adolescents S87

management, safety, and maximal aca- Screening impairmentafter episodes of severe hypo- demic opportunities. Refer to the ADA Screening for psychosocial distress and glycemia, current data have not confirmed position statements “Diabetes Care in mental health problems is an important this notion (18–20). Furthermore, new the School Setting” (7) and “Care of Young component of ongoing care. It is impor- therapeutic modalities, such as rapid- Children With Diabetes in the Child Care tant to consider the impact of diabetes and long-acting insulin analogs, techno- Setting” (8) for additional details. on quality of life as well as the develop- logical advances (e.g., continuous glucose Psychosocial Issues ment of mental health problems related monitors, low glucose suspend insulin to diabetes distress, fear of hypoglyce- pumps), and education may mitigate the Recommendations mia (and hyperglycemia), symptoms of incidence of severe hypoglycemia (21). c At diagnosis and during routine anxiety, disordered eating behaviors as The Diabetes Control and Complica- follow-up care, assess psychosocial well as eating disorders, and symptoms tions Trial (DCCT) demonstrated that issues and family stresses that could of depression (15). Consider screening near-normalization of blood glucose levels impact adherence to diabetes man- for depression and disordered eating was more difficult to achieve in adoles- agement and provide appropriate behaviors using available screening cents than in adults. Nevertheless, the in- referrals to trained mental health tools (9,16), and, with respect to disor- creased use of basal–bolus regimens, professionals, preferably experi- dered eating, it is important to recognize insulin pumps, frequent blood glucose enced in childhood diabetes. E the unique and dangerous disordered monitoring, goal setting, and improved c Encourage developmentally appro- eating behavior of insulin omission for patient education in youth from infancy priate family involvement in diabetes weight control in type 1 diabetes (17). through adolescence have been associ- management tasks for children and The presence of a mental health profes- ated with more children reaching the adolescents, recognizing that prema- sional on pediatric multidisciplinary blood glucose targets set by the ADA ture transfer of diabetes care to the teams highlights the importance of at- (7,22–25) in those families in which both child can result in nonadherence and tending to the psychosocial issues of di- the parents and the child with diabetes deterioration in glycemic control. B abetes. These psychosocial factors are participate jointly to perform the required c Consider mental health professionals significantly related to nonadherence, diabetes-related tasks. Furthermore, as integral members of the pediatric suboptimal glycemic control, reduced studies documenting neurocognitive imag- diabetes multidisciplinary team. E quality of life, and higher rates of acute ing differences related to hyperglycemia and chronic diabetes complications. in children provide another compelling Diabetes management throughout child- Glycemic Control motivation for lowering glycemic targets (1). hood and adolescence places substantial In selecting glycemic goals, the long- burdens on the youth and family, neces- Recommendation term health benefits of achieving a lower sitating ongoing assessment of psychoso- c An A1C goal of ,7.5% (58 mmol/mol) A1C should be balanced against the risks cial issues and distress during routine is recommended across all pediatric of hypoglycemia and the developmental diabetes visits (9–11). Further, the com- age-groups. E burdens of intensive regimens in children plexities of diabetes management require and youth. In addition, achieving lower ongoing parental involvement in care Current standards for diabetes manage- A1C levels is more likely to be related to throughout childhood with developmen- ment reflect the need to lower glucose as setting lower A1C targets (26,27). A1C tally appropriate family teamwork be- safely as possible. This should be done goals are presented in Table 11.1. tween the growing child/teen and with stepwise goals. Special consideration Autoimmune Conditions parent in order to maintain adherence should be given to the risk of hypoglyce- and to prevent deterioration in glycemic mia in young children (aged ,6 years) Recommendation control (12,13). As diabetes-specificfam- who are often unable to recognize, artic- c Assess for the presence of additional ily conflict is related to poorer adherence ulate, and/or manage their hypoglycemic autoimmune conditions soon after the and glycemic control, it is appropriate to symptoms. This “hypoglycemia unaware- diagnosis and if symptoms develop. E inquire about such conflict during visits ness” should be considered when estab- and to either help to negotiate a plan lishing individualized glycemic targets. Because of the increased frequency of for resolution or refer to an appropriate Although it was previously thought that other autoimmune diseases in type 1 mental health specialist (14). young children were at risk for cognitive diabetes, screening for thyroid dysfunction

Table 11.1—Blood glucose and A1C goals for type 1 diabetes across all pediatric age-groups Blood glucose goal range Before meals Bedtime/overnight A1C Rationale 90–130 mg/dL 90–150 mg/dL ,7.5% A lower goal (,7.0% [53 mmol/mol]) is reasonable if it can be (5.0–7.2 mmol/L) (5.0–8.3 mmol/L) (58 mmol/mol) achieved without excessive hypoglycemia Key concepts in setting glycemic goals: c Goals should be individualized, and lower goals may be reasonable based on a beneﬁt–risk assessment. c Blood glucose goals should be modiﬁed in children with frequent hypoglycemia or hypoglycemia unawareness. c Postprandial blood glucose values should be measured when there is a discrepancy between preprandial blood glucose values and A1C levels and to assess preprandial insulin doses in those on basal–bolus regimens. S88 Children and Adolescents Diabetes Care Volume 39, Supplement 1, January 2016

and celiac disease should be considered. Celiac Disease antibody positivity on a separate blood Periodic screening in asymptomatic indi- sample). It is also advisable to check for Recommendations viduals has been recommended, but the HLA types in patients who are diagnosed c Consider screening children with fi optimal frequency and bene t of screen- type 1 diabetes for celiac disease without a small intestinal biopsy. Asymp- ing are unclear. by measuring either tissue transglu- tomaticat-riskchildrenshouldhaveanin- Although much less common than ce- taminase or deamidated gliadin an- testinal biopsy (37). liac disease and thyroid dysfunction, tibodies, with documentation of In symptomatic children with type 1 di- fi other autoimmune conditions, such as normal total serum IgA levels, soon abetes and con rmed celiac disease, Addison disease (primary adrenal insuf- after the diagnosis of diabetes. E gluten-free diets reduce symptoms and ficiency), autoimmune hepatitis, auto- rates of hypoglycemia (38). The challeng- c Consider screening in children who immune gastritis, dermatomyositis, have a first-degree relative with celiac ing dietary restrictions associated with and myasthenia gravis, occur more com- disease, growth failure, weight loss, having both type 1 diabetes and celiac dis- fi monly in the population with type 1 dia- failure to gain weight, diarrhea, flatu- ease place a signi cant burden on individ- betes than in the general pediatric lence, abdominal pain, or signs of uals. Therefore, we recommend a biopsy fi population and should be assessed and malabsorption or in children with fre- to con rm the diagnosis of celiac disease, monitored as clinically indicated. quent unexplained hypoglycemia or especially in asymptomatic children, before endorsing significant dietary changes. Thyroid Disease deterioration in glycemic control. E fi c Children with biopsy-con rmed celiac Management of Cardiovascular Risk Recommendations diseaseshouldbeplacedonagluten- Factors c Consider testing children with free diet and have a consultation Hypertension type 1 diabetes for antithyroid per- with a dietitian experienced in manag- oxidase and antithyroglobulin anti- ing both diabetes and celiac disease. B Recommendations bodies soon after the diagnosis. E Screening c Measure thyroid-stimulating hor- Celiac disease is an immune-mediated dis- c Blood pressure should be measured mone concentrations soon after the order that occurs with increased fre- diagnosis of type 1 diabetes and after at each routine visit. Children found quency in patients with type 1 diabetes to have high-normal blood pressure glucose control has been estab- (1.6–16.4% of individuals compared with lished. If normal, consider rechecking (systolic blood pressure or diastolic 0.3–1% in the general population) (33–35). $ every 1–2 years or sooner if the pa- blood pressure 90th percentile tient develops symptoms suggestive Testing. Testing for celiac disease in- for age, sex, and height) or hyper- of thyroid dysfunction, thyromegaly, cludes measuring serum levels of IgA tension (systolic blood pressure or $ an abnormal growth rate, or an un- and antitissue transglutaminase anti- diastolic blood pressure 95th per- fi explained glycemic variation. E bodies, or, with IgA de ciency, screening centile for age, sex, and height) can include measuring IgG tissue transglu- should have blood pressure con- fi B Autoimmune thyroid disease is the taminase antibodies or IgG deamidated rmed on 3 separate days. most common autoimmune disorder gliadin peptide antibodies. Because most Treatment associated with diabetes, occurring in cases of celiac disease are diagnosed c Initial treatment of high-normal 17–30% of patients with type 1 diabe- within the first 5 years after the diagnosis blood pressure (systolic blood prestes (28). At the time of diagnosis, about of type 1 diabetes, screening should be sure or diastolic blood pressure con- 25% of children with type 1 diabetes considered at the time of diagnosis and sistently $90th percentile for age, have thyroid autoantibodies (29); repeated within 2 and 5 years thereafter. sex, and height) includes dietary their presence is predictive of thyroid Although celiac disease can be diag- modification and increased exercise, dysfunctiondmost commonly hypothy- nosed more than 10 years after diabe- if appropriate, aimed at weight con- roidism, although hyperthyroidism tes diagnosis, there are insufficient data trol. If target blood pressure is not occurs in ;0.5% of cases (30,31). Thy- after 5 years to determine the optimal reached with 3–6 months of initiating roid function tests may be misleading screening frequency. Testing for antitis- lifestyle intervention, pharmacologi- (euthyroid sick syndrome) if performed sue transglutaminase antibody should cal treatment should be considered. E at time of diagnosis owing to the effect be considered at other times in patients c In addition to lifestyle modification, of previous hyperglycemia, ketosis or with symptoms suggestive of celiac disease pharmacological treatment of hyper- ketoacidosis, weight loss, etc. There- (35). A small-bowel biopsy in antibody- tension (systolic blood pressure or fore, thyroid function tests should be positive children is recommended to diastolic blood pressure consistently performed soon after a period of meta- confirm the diagnosis (36). European $95th percentile for age, sex, and bolic stability and good glycemic con- guidelines on screening for celiac dis- height) should be considered as trol. Subclinical hypothyroidism may ease in children (not specific to children soon as hypertension is confirmed. E be associated with increased risk of with type 1 diabetes) suggest that bi- c ACE inhibitors or angiotensin recep- symptomatic hypoglycemia (32) and re- opsy may not be necessary in symptom- tor blockers should be considered duced linear growth rate. Hyperthyroid- atic children with high antibody titers for the initial pharmacological treat- ism alters glucose metabolism and (i.e., greater than 10 times the upper limit ment of hypertension, following re- usually causes deterioration of meta- of normal) provided that further testing is productive counseling due to the bolic control. performed (verification of endomysial care.diabetesjournals.org Children and Adolescents S89

potential teratogenic effects of have two or more cardiovascular disease however, studies have shown short- both drug classes. E (CVD) risk factors (40–42), and the preva- term safety equivalent to that seen in c The goal of treatment is blood lence of CVD risk factors increases with adults and efficacy in lowering LDL cho- pressure consistently ,90th per- age (42), with girls having a higher risk lesterol levels in familial hypercholes- centile for age, sex, and height. E burden than boys (41). terolemia or severe hyperlipidemia, improving endothelial function, and Pathophysiology. The atherosclerotic Blood pressure measurements should process begins in childhood, and al- causing regression of carotid intimal be determined using the appropriate though CVD events are not expected thickening (54,55). Statins are not ap- size cuff with the child seated and re- , to occur during childhood, observations proved for patients aged 10 years, laxed. Hypertension should be con- using a variety of methodologies show andstatintreatmentshouldgenerally firmed on at least 3 separate days. that youth with type 1 diabetes may have notbeusedinchildrenwithtype1 Evaluation should proceed as clinically subclinical CVD abnormalities within the diabetes before this age. Statins are indicated. Treatment is generally initi- first decade of diagnosis (43–45). Studies category X in pregnancy; therefore, ated with an ACE inhibitor, but an angio- of carotid intima-media thickness have pregnancy prevention is of paramount tensin receptor blocker can be used if importance for postpubertal girls (see yielded inconsistent results (39). the ACE inhibitor is not tolerated (e.g., Section 12 “Management of Diabetes in due to cough). Normal blood pressure Treatment. Pediatric lipid guidelines pro- Pregnancy” for more information). levels for age, sex, and height and ap- vide some guidance relevant to children Smoking propriate methods for measurement with type 1 diabetes (46–48); however, are available online at www.nhlbi.nih there are few studies on modifying lipid Recommendation .gov/health/prof/heart/hbp/hbp_ped levels in children with type 1 diabetes. A c Elicit a smoking history at initial .pdf (39). 6-month trial of dietary counseling and follow-up diabetes visits and produced a significant improvement in discourage smoking in youth who Dyslipidemia lipid levels (49); likewise, a lifestyle do not smoke and encourage Recommendations intervention trial with 6 months of ex- smoking cessation in those who ercise in adolescents demonstrated im- do smoke. B Testing provement in lipid levels (50). c Obtain a fasting lipid profile in chil- Although intervention data are sparse, The adverse health effects of smoking dren $10 years of age soon after the American Heart Association (AHA) cat- are well recognized with respect to fu- the diagnosis (after glucose con- egorizes children with type 1 diabetes in ture cancer and CVD risk. In youth with trol has been established). E the highest tier for cardiovascular risk and diabetes, it is important to avoid addi- c If lipids are abnormal, annual recommends both lifestyle and pharmaco- tional CVD risk factors. Smoking increases monitoring is reasonable. If LDL logical treatment for those with elevated the risk of onset of albuminuria; there- cholesterol values are within the LDL cholesterol levels (48,51). Initial ther- fore, smoking avoidance is important accepted risk level (,100 mg/dL apy should be with a Step 2 AHA diet, to prevent both microvascular and mac- [2.6 mmol/L]), a lipid profile re- which restricts saturated fat to 7% of total rovascular complications (46,56). Dis- peated every 3–5 years is rea- calories and restricts dietary cholesterol to couraging cigarette smoking, including sonable. E 200 mg/day. Data from randomized clini- e-cigarettes, is an important part of rou- Treatment cal trials in children as young as 7 months tine diabetes care. In younger children, it c Initial therapy should consist of of age indicate that this diet is safe and is important to assess exposure to ciga- optimizing glucose control and does not interfere with normal growth rette smoke in the home due to the ad- medical nutrition therapy using a and development (52). verse effects of secondhand smoke and Step 2 American Heart Association For children with a significant family to discourage youth from ever smoking diet to decrease the amount of history of CVD, the National Heart, Lung, if exposed to smokers in childhood. saturated fat in the diet. B and Blood Institute recommends ob- Microvascular Complications c After the age of 10 years, addition taining a fasting lipid panel beginning of a statin is suggested in patients at 2 years of age (46). Abnormal results Nephropathy who, despite medical nutrition ther- from a random lipid panel should be Recommendations confirmed with a fasting lipid panel. apy and lifestyle changes, continue Screening to have LDL cholesterol .160 mg/dL Data from the SEARCH for Diabetes in c Annual screening for albuminuria (4.1 mmol/L) or LDL cholesterol Youth (SEARCH) study show that im- with a random spot urine sample .130 mg/dL (3.4 mmol/L) and one proved glucose control over a 2-year pe- for albumin–to–creatinine ra- or more cardiovascular disease risk riod is associated with a more favorable tio should be considered once factors. E lipid profile; however, improved glyce- the child has had diabetes for c The goal of therapy is an LDL mic control alone will not normalize lip- 5years.B cholesterol value ,100 mg/dL ids in youth with type 1 diabetes and c Estimate glomerular filtration rate (2.6 mmol/L). E dyslipidemia (53). at initial evaluation and then Neither long-term safety nor cardio- based on age, diabetes duration, Population-based studies estimate that vascular outcome efficacy of statin ther- and treatment. E 14–45% of children with type 1 diabetes apy has been established for children; S90 Children and Adolescents Diabetes Care Volume 39, Supplement 1, January 2016

Treatment duration of only 1–2 years. Referrals team, including a physician, diabetes c Treatment with an ACE inhibitor, should be made to eye care professionals nurse educator, registered dietitian, titrated to normalization of albumin with expertise in diabetic retinopathy and behavioral specialist or social excretion, should be considered and experience in counseling the pedi- worker, is essential. In addition to blood when elevated urinary albumin– atric patient and family on the importance glucose control, treatment must in- to–creatinine ratio (.30 mg/g) is of early prevention and intervention. clude management of comorbidities documented with at least two of Neuropathy such as obesity, dyslipidemia, hyperten- three urine samples. These should sion, and albumin levels from the outset. Recommendation be obtained over a 6-month inter- Presentation with ketosis or ketoacidosis c Consider an annual comprehensive val following efforts to improve requires a period of insulin therapy un- foot exam for the child at the start glycemic control and normalize til fasting and postprandial glycemia of puberty or at age $10 years, blood pressure. B have been restored to normal or near- whichever is earlier, once the youth normal. Metformin therapy may be has had type 1 diabetes for 5 years. E Data from 7,549 participants ,20 years used as an adjunct after resolution of of age in the T1D Exchange clinic registry ketosis/ketoacidosis. Initial treatment Neuropathy rarely occurs in prepubertal emphasize the importance of good gly- should also be with insulin when the children or after only 1–2 years of diabe- cemic and blood pressure control, par- distinction between type 1 diabetes tes (60). A comprehensive foot exam, in- ticularly as diabetes duration increases, and type 2 diabetes is unclear and cluding inspection, palpation of dorsalis in order to reduce the risk of nephropa- in patients who have random blood pedis and posterior tibial pulses, assess- $ thy. The data also underscore the impor- glucose concentrations 250 mg/dL ment of the patellar and Achilles reflexes, . tance of routine screening to ensure (13.9 mmol/L) and/or A1C 9% and determination of proprioception, vi- (75 mmol/mol) (65). early diagnosis and timely treatment of bration, and monofilament sensation, albuminuria (57). An estimation of glo- Patients and their families must prior- should be performed annually along fi merular filtration rate (GFR), calculated itize lifestyle modi cations such as with assessment of symptoms of neuro- eating a balanced diet, maintaining a using GFR estimating equations from pathic pain. Foot inspection can be per- healthy weight, and exercising regu- the serum creatinine, height, age, and formed at each visit to educate youth larly. A family-centered approach to nu- sex (58), should be determined at base- regarding the importance of foot care. trition and lifestyle modification is line and repeated as indicated based on essential in children with type 2 diabe- clinical status, age, diabetes duration, TYPE 2 DIABETES tes. Nutrition recommendations should and therapies. Estimated GFR is calcu- For information on testing for type 2 be culturally appropriate and sensitive lated from a serum creatinine measure- diabetes and prediabetes in children to family resources (see Section 3 ment using an estimating equation. This and adolescents, please refer to Sec- “Foundations of Care and Comprehen- is not a recommendation to perform a tion 2 “Classification and Diagnosis of sive Medical Evaluation”). measurement of creatinine clearance (in- Diabetes.” When insulin treatment is not re- volves timed urine collection) every year. The Centers for Disease Control and quired, initiation of metformin, currently There are ongoing clinical trials assessing Prevention recently published projections the only oral hypoglycemic agent specifi- the efficacy of early treatment of persis- for type 2 diabetes prevalence using the cally approved for use in children with tent albuminuria with ACE inhibitors (59). SEARCH database. Assuming a 2.3% an- type 2 diabetes, is recommended. How- ever, the Treatment Options for type 2 Di- Retinopathy nual increase, the prevalence of type 2 diabetes in those under 20 years of age abetes in Adolescents and Youth (TODAY) Recommendations will quadruple in 40 years (61,62). Given study found that metformin alone pro- c An initial dilated and comprehen- the current obesity epidemic, distinguish- vided durable glycemic control (A1C sive eye examination is recom- ing between type 1 and type 2 diabetes in #8% [64 mmol/mol] for 6 months) in ap- mended at age $10 years or children can be difficult. For example, ex- proximately half of the subjects (66), sug- after puberty has started, which- cessive weight is common in children with gesting that many youth with type 2 ever is earlier, once the youth type 1 diabetes (63). Furthermore, diabetes- diabetes are likely to require combination has had diabetes for 3–5years.B associated autoantibodies and ketosis treatment within a few years of diagnosis. c After the initial examination, an- may be present in patients with features nual routine follow-up is generally of type 2 diabetes (including obesity and Comorbidities recommended. Less frequent ex- acanthosis nigricans) (64). Nevertheless, Comorbidities may already be present at aminations, every 2 years, may accurate diagnosis is critical as treatment the time of diagnosis in youth with be acceptable on the advice of an regimens, educational approaches, die- type 2 diabetes (67). Therefore, blood eye care professional. E tary advice, and outcomes differ mark- pressure measurement, a fasting lipid edly between the two diagnoses. panel, assessment for albumin excre- Although retinopathy (like albuminuria) tion, and a dilated eye examination most commonly occurs after the onset Treatment should be performed at diagnosis. of puberty and after 5–10 years of dia- The general treatment goals for type 2 Thereafter, screening guidelines and betes duration (60), it has been reported diabetes are the same as those for type treatment recommendations for hyper- in prepubertal children and with diabetes 1 diabetes. A multidisciplinary diabetes tension, dyslipidemia, albumin excretion, care.diabetesjournals.org Children and Adolescents S91

and retinopathy are similar to those for Although scientific evidence is limited, with type 1 diabetes. Pediatrics 2013;132: youth with type 1 diabetes. Additional it is clear that comprehensive and coordi- e1395–e1402 problems that may need to be addressed nated planning that begins in early ado- 10. Hood KK, Beavers DP, Yi-Frazier J, et al. Psy- chosocial burden and glycemic control during include polycystic ovary disease and lescence, or at least 1 year before the the first 6 years of diabetes: results from the other comorbidities associated with pe- date of transition, is necessary to facilitate SEARCH for Diabetes in Youth study. J Adolesc diatric obesity, such as sleep apnea, a seamless transition from pediatric to Health 2014;55:498–504 hepatic steatosis, orthopedic complica- adult health care (71,72). A comprehen- 11. Ducat L, Philipson LH, Anderson BJ. The mental health comorbidities of diabetes. JAMA tions, and psychosocial concerns. The sive discussion regarding the challenges – “ fi 2014;312:691 692 ADA consensus report Type 2 Diabetes faced during this period, including speci c 12. Katz ML, Volkening LK, Butler DA, Anderson in Children and Adolescents” (68) and a recommendations, is found in the ADA BJ, Laffel LM. Family-based psychoeducation more recent American Academy of Pe- position statement “Diabetes Care for and care ambassador intervention to improve diatrics clinical practice guideline (69) Emerging Adults: Recommendations for glycemic control in youth with type 1 diabetes: a provide guidance on the prevention, Transition From Pediatric to Adult Diabe- randomized trial. Pediatr Diabetes 2014;15: 142–150 screening, and treatment of type 2 di- tes Care Systems” (72). 13. Laffel LM, Vangsness L, Connell A, Goebel- abetes and its comorbidities in children The National Diabetes Education Pro- Fabbri A, Butler D, Anderson BJ. Impact of and adolescents. gram (NDEP) has materials available to ambulatory, family-focused teamwork inter- facilitate the transition process (http:// vention on glycemic control in youth with TRANSITION FROM PEDIATRIC TO – ndep.nih.gov/transitions), and the En- type 1 diabetes. J Pediatr 2003;142:409 416 ADULT CARE 14. Anderson BJ, Vangsness L, Connell A, Butler docrine Society in collaboration with D, Goebel-Fabbri A, Laffel LM. Family conflict, Recommendations the ADA and other organizations has de- adherence, and glycaemic control in youth with c Health care providers and families veloped transition tools for clinicians short duration type 1 diabetes. Diabet Med – should begin to prepare youth in and youth and families (http://www 2002;19:635 642 15. Lawrence JM, Yi-Frazier JP, Black MH, et al.; .endo-society.org/clinicalpractice/ early to mid-adolescence and, at SEARCH for Diabetes in Youth Study Group. De- the latest, at least 1 year before transition_of_care.cfm). mographic and clinical correlates of diabetes- the transition to adult health care. E related quality of life among youth with type 1 c Both pediatricians and adult References diabetes. J Pediatr 2012;161:201–207.e2 health care providers should assist 1. Barnea-Goraly N, Raman M, Mazaika P, et al.; 16. Markowitz JT, Butler DA, Volkening LK, Diabetes Research in Children Network (DirecNet). Antisdel JE, Anderson BJ, Laffel LM. Brief screening in providing support and links to tool for disordered eating in diabetes: internal con- resources for the teen and emerg- Alterations in white matter structure in young children with type 1 diabetes. Diabetes Care 2014;37: sistency and external validity in a contemporary ing adult. B 332–340 sample of pediatric patients with type 1 diabetes. 2. Cameron FJ, Scratch SE, Nadebaum C, et al.; Diabetes Care 2010;33:495–500 Care and close supervision of diabetes DKA Brain Injury Study Group. Neurological conse- 17. Wisting L, Frøisland DH, Skrivarhaug T, quences of diabetic ketoacidosis at initial presenta- Dahl-Jørgensen K, Rø O. Disturbed eating be- management are increasingly shifted havior and omission of insulin in adolescents from parents and other adults to the tion of type 1 diabetes in a prospective cohort study of children. Diabetes Care 2014;37:1554–1562 receiving intensified insulin treatment: a na- youth with diabetes throughout child- 3. Markowitz JT, Garvey KC, Laffel LM. Devel- tionwide population-based study. Diabetes hood and adolescence. The shift from opmental changes in the roles of patients and Care 2013;36:3382–3387 pediatrics to adult health care providers, families in type 1 diabetes management. Curr 18. Seaquist ER, Anderson J, Childs B, et al. Hy- poglycemia and diabetes: a report of a work- however, often occurs abruptly as the Diabetes Rev 2015;11:231–238 4. Silverstein J, Klingensmith G, Copeland K, group of the American Diabetes Association older teen enters the next developmen- et al.; American Diabetes Association. Care of and the Endocrine Society. Diabetes Care tal stage referred to as emerging adult- children and adolescents with type 1 diabetes: 2013;36:1384–1395 hood (70), which is a critical period for a statement of the American Diabetes Associa- 19. Wysocki T, Harris MA, Mauras N, et al. Ab- young people who have diabetes. During tion. Diabetes Care 2005;28:186–212 sence of adverse effects of severe hypoglycemia 5. Chiang JL, Kirkman MS, Laffel LM, Peters AL; on cognitive function in school-aged children this period of major life transitions, youth Type 1 Diabetes Sourcebook with diabetes over 18 months. Diabetes Care ’ Authors. Type 1 di- begin to move out of their parents home abetes through the life span: a position state- 2003;26:1100–1105 and must become fully responsible for ment of the American Diabetes Association. 20. Blasetti A, Chiuri RM, Tocco AM, et al. The their diabetes care. Their new responsi- Diabetes Care 2014;37:2034–2054 effect of recurrent severe hypoglycemia on cog- bilities include self-management of 6. Driscoll KA, Volkening LK, Haro H, et al. Are nitive performance in children with type 1 di- children with type 1 diabetes safe at school? abetes: a meta-analysis. J Child Neurol 2011;26: their diabetes, making medical appoint- 1383–1391 fi Examining parent perceptions. Pediatr Diabe- ments, and nancing health care, once tes. 30 September 2014 [Epub ahead of print]. 21. Cooper MN, O’Connell SM, Davis EA, Jones they are no longer covered by their par- DOI: 10.1111/pedi.12204 TW. A population-based study of risk factors for ents’ health insurance plan (ongoing 7. Jackson CC, Albanese-O’Neill A, Butler KL, severe hypoglycaemia in a contemporary cohort coverage until age 26 years is possible et al. Diabetes care in the school setting: a po- of childhood-onset type 1 diabetes. Diabetolo- gia 2013;56:2164–2170 with recent U.S. health care reform). In sition statement of the American Diabetes As- sociation. Diabetes Care 2015;38:1958–1963 22. Rosenbauer J, Dost A, Karges B, et al.; DPV addition to lapses in health care, this is 8. Siminerio LM, Albanese-O’Neill A, Chiang JL, Initiative and the German BMBF Competence also a period associated with deteriora- et al.; American Diabetes Association. Care of Network Diabetes Mellitus. Improved metabolic tion in glycemic control; increased occur- young children with diabetes in the child care control in children and adolescents with type 1 rence of acute complications; psychosocial, setting: a position statement of the American diabetes: a trend analysis using prospective Diabetes Association. Diabetes Care 2014;37: multicenter data from Germany and Austria. emotional, and behavioral challenges; and 2834–2842 Diabetes Care 2012;35:80–86 the emergence of chronic complications 9. Corathers SD, Kichler J, Jones NH, et al. Im- 23. Cameron FJ, de Beaufort C, Aanstoot HJ, (71–74). proving depression screening for adolescents et al.; Hvidoere International Study Group. S92 Children and Adolescents Diabetes Care Volume 39, Supplement 1, January 2016

Lessons from the Hvidoere International Study Gastroenterology, Hepatology, and Nutrition. structured dietician training to a Mediterranean- Group on childhood diabetes: be dogmatic European Society for Pediatric Gastroenterol- style diet. J Endocrinol Invest 2012;35:160–168 about outcome and flexible in approach. Pediatr ogy, Hepatology, and Nutrition guidelines for 50. Salem MA, Aboelasrar MA, Elbarbary NS, Diabetes 2013;14:473–480 the diagnosis of coeliac disease. J Pediatr Gas- Elhilaly RA, Refaat YM. Is exercise a therapeutic 24. Nimri R, Weintrob N, Benzaquen H, Ofan R, troenterol Nutr 2012;54:136–160 tool for improvement of cardiovascular risk fac- Fayman G, Phillip M. Insulin pump therapy in 38. Abid N, McGlone O, Cardwell C, McCallion W, tors in adolescents with type 1 diabetes melli- youth with type 1 diabetes: a retrospective Carson D. Clinical and metabolic effects of gluten tus? A randomised controlled trial. Diabetol paired study. 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Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, Disease in the Young, with the Council on Car- Hvidoere Study Group on Childhood Diabetes. et al. Prevalence of cardiovascular disease risk diovascular Nursing. Circulation 2007;115: Target setting in intensive insulin management factors in U.S. children and adolescents with di- 1948–1967 is associated with metabolic control: the Hvi- abetes: the SEARCH for Diabetes in Youth study. 52. Salo P, Viikari J, Ham¨ al¨ ainen¨ M, et al. Serum doere childhood diabetes study group centre Diabetes Care 2006;29:1891–1896 cholesterol ester fatty acids in 7- and 13-month- differences study 2005. Pediatr Diabetes 2010; 41. Margeirsdottir HD, Larsen JR, Brunborg C, old children in a prospective randomized trial 11:271–278 Overby NC, Dahl-Jørgensen K; Norwegian Study of a low-saturated fat, low-cholesterol diet: 27. Maahs DM, Hermann JM, DuBose SN, et al.; Group for Childhood Diabetes. High prevalence the STRIP baby project. 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Thyroid au- atherogenic risk factors in 27,358 children, ado- 162:101–107.e1 toimmunity in children and adolescents with lescents, and young adults with type 1 diabetes: 54. McCrindle BW, Ose L, Marais AD. Efficacy Type 1 diabetes mellitus. Diabetes Nutr Metab cross-sectional data from the German diabetes and safety of atorvastatin in children and ado- 1999;12:27–31 documentation and quality management system lescents with familial hypercholesterolemia or 29. Triolo TM, Armstrong TK, McFann K, et al. (DPV). Diabetes Care 2006;29:218–225 severe hyperlipidemia: a multicenter, random- Additional autoimmune disease found in 33% of 43.SinghTP,GroehnH,KazmersA.Vascular ized, placebo-controlled trial. J Pediatr 2003; patients at type 1 diabetes onset. Diabetes Care function and carotid intimal-medial thickness 143:74–80 2011;34:1211–1213 in children with insulin-dependent diabetes 55. Wiegman A, Hutten BA, de Groot E, et al. 30. Kordonouri O, Deiss D, Danne T, Dorow A, mellitus. J Am Coll Cardiol 2003;41:661–665 Efficacy and safety of statin therapy in chil- Bassir C, Gruters-Kieslich¨ A. Predictivity of thy- 44. Haller MJ, Stein J, Shuster J, et al. Peripheral dren with familial hypercholesterolemia: a roid autoantibodies for the development of thy- artery tonometry demonstrates altered endo- randomized controlled trial. JAMA 2004;292: roid disorders in children and adolescents with thelial function in children with type 1 diabetes. 331–337 type 1 diabetes. Diabet Med 2002;19:518–521 Pediatr Diabetes 2007;8:193–198 56. Scott LJ, Warram JH, Hanna LS, Laffel LM, 31. Dost A, Rohrer TR, Frohlich-Reiterer¨ E, 45. Urbina EM, Wadwa RP, Davis C, et al. Prev- Ryan L, Krolewski AS. A nonlinear effect of hy- et al.; DPV Initiative and the German Compe- alence of increased arterial stiffness in children perglycemia and current cigarette smoking are tence Network Diabetes Mellitus. Hyperthy- with type 1 diabetes mellitus differs by mea- major determinants of the onset of microalbu- roidism in 276 children and adolescents with surement site and sex: the SEARCH for Diabetes minuria in type 1 diabetes. Diabetes 2001;50: type 1 diabetes from Germany and Austria. in Youth study. J Pediatr 2010;156:731–737.e1 2842–2849 Horm Res Paediatr 2015;84:190–198 46. Expert Panel on Integrated Guidelines for 57. Daniels M, DuBose SN, Maahs DM, et al.; 32. Mohn A, Di Michele S, Di Luzio R, Tumini S, Cardiovascular Health and Risk Reduction in Chil- T1D Exchange Clinic Network. Factors associ- Chiarelli F. The effect of subclinical hypothyroid- dren and Adolescents; National Heart, Lung, and ated with microalbuminuria in 7,549 children ism on metabolic control in children and adoles- Blood Institute. Expert panel on integrated guide- and adolescents with type 1 diabetes in the cents with type 1 diabetes mellitus. 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Rubio-Tapia A, Hill ID, Kelly CP, Calderwood High Blood Pressure Research, Cardiovascular 2- to 5-yr duration of type 1 diabetes from 1990 AH, Murray JA; American College of Gastroen- Nursing, and the Kidney in Heart Disease; and to 2006. Pediatr Diabetes 2011;12:682–689 terology. ACG clinical guidelines: diagnosis and the Interdisciplinary Working Group on Quality 61. Imperatore G, Boyle JP, Thompson TJ, et al.; management of celiac disease. Am J Gastroen- of Care and Outcomes Research: endorsed by SEARCH for Diabetes in Youth Study Group. Pro- terol 2013;108:656–676 the American Academy of Pediatrics. Circulation jections of type 1 and type 2 diabetes burden in 37. Husby S, Koletzko S, Korponay-SzaboIR,´ 2006;114:2710–2738 the U.S. population aged ,20 years through et al.; ESPGHAN Working Group on Coeliac Dis- 49. 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62. Pettitt DJ, Talton J, Dabelea D, et al.; 67. Eppens MC, Craig ME, Cusumano J, et al. a position statement of the American Diabetes SEARCH for Diabetes in Youth Study Group. Prevalence of diabetes complications in adoles- Association, with representation by the American Prevalence of diabetes in U.S. youth in 2009: cents with type 2 compared with type 1 diabe- College of Osteopathic Family Physicians, the the SEARCH for Diabetes in Youth study. Diabe- tes. Diabetes Care 2006;29:1300–1306 American Academy of Pediatrics, the American tes Care 2014;37:402–408 68. American Diabetes Association. Type 2 di- Association of Clinical Endocrinologists, the Amer- 63. DuBose SN, Hermann JM, Tamborlane WV, abetes in children and adolescents. Diabetes ican Osteopathic Association, the Centers for Dis- et al.; Type 1 Diabetes Exchange Clinic Network Care 2000;23:381–389 ease Control and Prevention, Children with and Diabetes Prospective Follow-up Registry. 69. Copeland KC, Silverstein J, Moore KR, et al.; Diabetes, The Endocrine Society, the International Obesity in youth with type 1 diabetes in Ger- American Academy of Pediatrics. Management Society for Pediatric and Adolescent Diabetes, many, Austria, and the United States. J Pediatr of newly diagnosed type 2 diabetes mellitus Juvenile Diabetes Research Foundation Interna- 2015;167:627–632.e4 (T2DM) in children and adolescents. Pediatrics tional, the National Diabetes Education Program, 64. Klingensmith GJ, Pyle L, Arslanian S, et al.; 2013;131:364–382 and the Pediatric Endocrine Society (formerly TODAY Study Group. The presence of GAD and 70. Arnett JJ. Emerging adulthood. A theory of Lawson Wilkins Pediatric Endocrine Society). Di- IA-2 antibodies in youth with a type 2 diabetes development from the late teens through the abetes Care 2011;34:2477–2485 phenotype: results from the TODAY study. Di- twenties. Am Psychol 2000;55:469–480 73. Bryden KS, Peveler RC, Stein A, Neil A, abetes Care 2010;33:1970–1975 71. Weissberg-Benchell J, Wolpert H, Anderson BJ. Mayou RA, Dunger DB. Clinical and psychologi- 65. Copeland KC, Silverstein J, Moore KR, et al. Transitioning from pediatric to adult care: a new ap- cal course of diabetes from adolescence to Management of newly diagnosed type 2 diabe- proach to the post-adolescent young person with young adulthood: a longitudinal cohort study. tes mellitus (T2DM) in children and adolescents. type 1 diabetes. Diabetes Care 2007;30:2441–2446 Diabetes Care 2001;24:1536–1540 Pediatrics 2013;131:364–382 72. Peters A, Laffel L; American Diabetes Associ- 74. Laing SP, Jones ME, Swerdlow AJ, Burden AC, 66. TODAY Study Group. A clinical trial to main- ation Transitions Working Group. Diabetes care Gatling W. Psychosocial and socioeconomic risk fac- tain glycemic control in youth with type 2 di- for emerging adults: recommendations for transi- tors for premature death in young people with abetes. N Engl J Med 2012;366:2247–2256 tion from pediatric to adult diabetes care systems: type 1 diabetes. Diabetes Care 2005;28:1618–1623 S94 Diabetes Care Volume 39, Supplement 1, January 2016

12. Management of Diabetes in American Diabetes Association Pregnancy

Diabetes Care 2016;39(Suppl. 1):S94–S98 | DOI: 10.2337/dc16-S015

For guidelines related to the diagnosis of gestational diabetes mellitus, please refer to Section 2 “Classiﬁcation and Diagnosis of Diabetes.”

Recommendations Pregestational Diabetes c Provide preconception counseling that addresses the importance of glycemic control as close to normal as is safely possible, ideally A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies. B c Family planning should be discussed and effective contraception should be prescribed and used until a woman is prepared and ready to become pregnant. A c Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. Eye examinations should occur before pregnancy or in the first trimester and then be monitored every trimester and for 1 year postpartum as indicated by degree of retinopathy. B Gestational Diabetes Mellitus c Lifestyle change is an essential component of management of gestational diabetes mellitus and may suffice for treatment for many women. Medications should be added if needed to achieve glycemic targets. A 12. MANAGEMENT OF DIABETES IN PREGNANCY c Preferred medications in gestational diabetes mellitus are insulin and metformin; glyburide may be used but may have a higher rate of neonatal hypoglycemia and macrosomia than insulin or metformin. Other agents have not been adequately studied. Most oral agents cross the placenta, and all lack long-term safety data. A General Principles for Management of Diabetes in Pregnancy c Potentially teratogenic medications (ACE inhibitors, statins, etc.) should be avoided in sexually active women of childbearing age who are not using reliable contraception. B c Fasting, preprandial, and postprandial self-monitoring of blood glucose are recommended in both gestational diabetes mellitus and pregestational diabetes in pregnancy to achieve glycemic control. B c Due to increased red blood cell turnover, A1C is lower in normal pregnancy than in normal nonpregnant women. The A1C target in pregnancy is 6–6.5% (42–48 mmol/mol); ,6% (42 mmol/mol) may be optimal if this can be achieved without significant hypoglycemia, but the target may be relaxed to ,7% (53 mmol/mol) if necessary to prevent hypoglycemia. B

DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. The majority is gestational diabetes mellitus (GDM) with the remainder primarily pregestational type 1 diabetes and type 2 diabetes. The rise in GDM and pregestational type 2 diabetes in parallel with obesity both in the U.S. and worldwide is of particular concern. Both pre- Suggested citation: American Diabetes Associa- gestational type 1 diabetes and type 2 diabetes confer significantly greater maternal and tion. Management of diabetes in pregnancy. Sec. 12. In Standards of Medical Care in Diabetesd2016. fetal risk than GDM, with some differences according to type as outlined below. In general, Diabetes Care 2016;39(Suppl. 1):S94–S98 specific risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal © 2016 by the American Diabetes Association. anomalies, preeclampsia, intrauterine fetal demise, macrosomia, neonatal hypoglyce- Readers may use this article as long as the work mia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in preg- is properly cited, the use is educational and not nancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2). for profit, and the work is not altered. care.diabetesjournals.org Management of Diabetes in Pregnancy S95

PRECONCEPTION COUNSELING Insulin Physiology early in gestation (4,9–11). Clinical tri- All women of childbearing age with di- Early pregnancy is a time of insulin sen- als have not evaluated the risks and abetes should be counseled about the sitivity, lower glucose levels, and lower benefits of achieving these targets, and importance of near-normal glycemic con- insulin requirements in women with type 1 treatment goals should account for the trol prior to conception. Observational diabetes. The situation rapidly reverses risk of maternal hypoglycemia in set- studies show an increased risk of diabetic as insulin resistance increases exponen- ting an individualized target of ,6% embryopathy, especially anencephaly, tially during the second and early third (42 mmol/mol) to ,7% (53 mmol/mol). microcephaly, congenital heart disease, trimesters and levels off toward the end Due to physiological increases in red and caudal regression directly propor- of the third trimester. In women with blood cell turnover, A1C levels fall during tional to elevations in A1C during the first normal pancreatic function, insulin pro- normal pregnancy (12). Additionally, as fi 10 weeks of pregnancy. Although obser- duction is suf cient to meet the challenge A1C represents an integrated measure of vational studies are confounded by the of this physiological insulin resistance glucose, it may not fully capture post- association between elevated periconcep- and to maintain normal glucose levels. prandial hyperglycemia, which drives tional A1C and other poor self-care behav- However, in women with GDM and pre- macrosomia. Thus, while A1C may be iors, the quantity and consistency of data gestational type 2 diabetes, hyperglyce- useful, it should be used as a secondary are convincing and support the rec- mia occurs if treatment is not adjusted measure, after self-monitoring of blood ommendation to optimize glycemic con- appropriately. glucose. trol prior to conception, with A1C ,6.5% In the second and third trimester, A1C Glucose Monitoring (48 mmol/mol) associated with the low- ,6% (42 mmol/mol) has the lowest risk fl est risk of congenital anomalies (3,4). Re ecting this physiology, preprandial of large-for-gestational-age infants, There are opportunities to educate all and postprandial monitoring of blood glu- whereas other adverse outcomes in- women and adolescents of reproductive cose is recommended to achieve meta- crease with A1C $6.5% (48 mmol/mol). age with diabetes about the risks of un- bolic control in pregnant women with Taking all of this into account, a target of planned pregnancies and the opportu- diabetes. Postprandial monitoring is as- 6–6.5% (42–48 mmol/mol) is recom- nities for improved maternal and fetal sociated with better glycemic control mended but ,6% (42 mmol/mol) may outcomes with pregnancy planning (5). and lower risk of preeclampsia (7). There be optimal as pregnancy progresses. Effective preconception counseling are no adequately powered randomized These levels should be achieved without could avert substantial health and asso- trials comparing different fasting and hypoglycemia, which, in addition to the ciated cost burden in offspring (6). Fam- postmeal glycemic targets in diabetes usual adverse sequelae, may increase ily planning should be discussed, and in pregnancy. the risk of low birth weight. Given the effective contraception should be pre- Nevertheless, the American College of alteration in red blood cell kinetics dur- scribed and used, until a woman is pre- Obstetricians and Gynecologists (ACOG) ing pregnancy and physiological pared and ready to become pregnant. (8) recommends the following targets changes in glycemic parameters, A1C for women with pregestational type 1 or levels may need to be monitored Preconception Testing type 2 diabetes: more frequently than usual (e.g., Preconception counseling visits should monthly). address rubella, rapid plasma reagin, hep- ○ Fasting #90 mg/dL (5.0 mmol/L) atitis B virus, and HIV testing as well as ○ One-hour postprandial #130–140 MANAGEMENT OF GESTATIONAL Pap smear, cervical cultures, blood typ- mg/dL (7.2–7.8 mmol/L) DIABETES MELLITUS ○ Two-hour postprandial #120 mg/dL ing, prescription of prenatal vitamins GDM is characterized by increased risk m (6.7 mmol/L) (with at least 400 g of folic acid), and of macrosomia and birth complications smoking cessation counseling, if indi- and an increased risk of maternal diabe- fi These values represent optimal control cated. Diabetes-speci c testing should tes after pregnancy. The association of if they can be achieved safely. In practice, include A1C, thyroid-stimulating hor- macrosomia and birth complications – it may be challenging for women with mone, creatinine, and urinary albumin with oral glucose tolerance test (OGTT) – type 1 diabetes to achieve these targets to creatinine ratio testing; review of the results is continuous, with no clear in- without hypoglycemia, particularly women medication list for potentially teratogenic flection points (13). In other words, risks with a history of severe hypoglycemia or drugs (i.e., ACE inhibitors, statins); and increase with progressive hyperglyce- referral for a comprehensive eye exam. hypoglycemia unawareness. If women cannot achieve these tar- mia. Therefore, all women should be screened as outlined in Section 2 “Clas- GLYCEMIC TARGETS IN gets without significant hypoglycemia, fi ” PREGNANCY the American Diabetes Association si cation and Diagnosis of Diabetes. Al- though there is some heterogeneity, Pregnancy in women with normal glucose (ADA) suggests less stringent targets based on clinical experience and individ- many randomized controlled trials sug- metabolism is characterized by fasting lev- gestthattheriskofGDMmaybere- ualization of care. els of blood glucose that are lower than in duced by diet, exercise, and lifestyle the nonpregnant state due to insulin- counseling (14,15). independent glucose uptake by the pla- A1C in Pregnancy centa and by postprandial hyperglycemia Observational studies show the lowest Lifestyle Management and carbohydrate intolerance as a result rates of adverse fetal outcomes in associa- After diagnosis, treatment starts with of diabetogenic placental hormones. tion with A1C ,6–6.5% (42–48 mmol/mol) medical nutrition therapy, physical S96 Management of Diabetes in Pregnancy Diabetes Care Volume 39, Supplement 1, January 2016

activity, and weight management de- insulin for maternal health if it suffices to pregnancy that may decrease hypoglyce- pending on pregestational weight, as control hyperglycemia (23–25); how- mia awareness. Hypoglycemia education outlined in the section on pregestational ever, metformin may slightly increase for patients and family members is impor- type 2 diabetes below, and glucose mon- the risk of prematurity. None of these tant before and during early pregnancy itoring aiming for the targets recom- studies or meta-analyses evaluated and throughout pregnancy to help to pre- mended by the Fifth International long-term outcomes in the offspring. vent and manage the risks of hypoglyce- Workshop-Conference on Gestational Thus, patients treated with oral agents mia. Insulin resistance drops rapidly with Diabetes Mellitus (16): should be informed that they cross the delivery of the placenta. Women become placenta and, while no adverse effects very insulin sensitive immediately follow- ○ Fasting #95 mg/dL (5.3 mmol/L) and on the fetus have been demonstrated, ing delivery and may initially require either long-term studies are lacking. much less insulin than in the prepartum ○ One-hour postprandial #140 mg/dL Insulin period. (7.8 mmol/L) or Insulin may be required to treat hyper- Pregnancy is a ketogenic state, and ○ # Two-hour postprandial 120 mg/dL glycemia, and its use should follow the women with type 1 diabetes, and to a (6.7 mmol/L) guidelines below. lesser extent those with type 2 diabetes, are at risk for diabetic ketoacidosis at Depending on the population, studies MANAGEMENT OF lower blood glucose levels than in the suggestthat70–85% of women diag- PREGESTATIONAL TYPE 1 nonpregnant state. All insulin-deficient nosed with GDM under Carpenter- DIABETES AND TYPE 2 DIABETES women need ketone strips at home and Coustan or National Diabetes Data IN PREGNANCY education on diabetic ketoacidosis pre- Group (NDDG) criteria can control Insulin Use vention and detection. In addition, rapid GDM with lifestyle modification alone; Insulin is the preferred agent for man- implementation of tight glycemic control it is anticipated that this proportion agement of pregestational type 1 diabe- in the setting of retinopathy is associated will increase using the lower Interna- tes and type 2 diabetes that are not with worsening of retinopathy (26). tional Association of the Diabetes and adequately controlled with diet, exer- Type 2 Diabetes Pregnancy Study Groups (IADPSG) (17) cise, and metformin. Pregestational type 2 diabetes is often diagnostic thresholds. The physiology of pregnancy requires associated with obesity. Recommended frequent titration of insulin to match Pharmacological Therapy weight gain during pregnancy for over- changing requirements. In the first tri- Women with greater initial degrees of weight women is 15–25 lb and for obese mester, there is often a decrease in total hyperglycemia may require early initia- women is 10–20 lb. Glycemic control is daily insulin requirements, and women, tion of pharmacological therapy. Treat- often easier to achieve in type 2 diabe- particularly those with type 1 diabetes, ment has been demonstrated to tes than in type 1 diabetes but can re- may experience increased hypoglyce- improve perinatal outcomes in two quire much higher doses of insulin, mia. In the second trimester, rapidly large randomized studies as summa- sometimes necessitating concentrated increasing insulin resistance requires rized in a U.S. Preventive Services Task insulin formulations. As in type 1 diabetes, weekly or biweekly increases in insulin Force review (18). Insulin is the first-line insulin requirements drop dramatically af- dose to achieve glycemic targets. In agent recommended for treatment of ter delivery. Associated hypertension and general, a smaller proportion of the total GDM in the U.S. Individual randomized other comorbidities often render preges- daily dose should be given as basal in- controlled trials support the efficacy tational type 2 diabetes as high or higher sulin (,50%) and a greater proportion and short-term safety of metformin risk than pregestational type 1 diabetes, (.50%) as prandial insulin. In the late (19,20) (pregnancy category B) and gly- even if the diabetes is better controlled third trimester, there is often a leveling buride (21) (pregnancy category B) for and of shorter duration, with pregnancy off or small decrease in insulin require- the treatment of GDM. However, both loss appearing to be more prevalent in ments. Due to the complexity of insulin agents cross the placenta, and long- the third trimester in type 2 diabetes management in pregnancy, referral to a term safety data are not available for compared with the first trimester in specialized center offering team-based either agent (22). type 1 diabetes (27,28). care (with team members including Sulfonylureas high-risk obstetrician, endocrinologist, POSTPARTUM CARE More recently, several meta-analyses dietitian, nurse, and social worker, as Postpartum care should include psychoso- and large observational studies examin- needed) is recommended if this resource cial assessment and support for self-care. ing maternal and fetal outcomes have is available. suggested that sulfonylureas, such as gly- All insulins are pregnancy category B Lactation buride, may be inferior to insulin and except for glargine, glulisine, and de- In light of the immediate nutritional and metformin due to increased risk of neo- gludec, which are labeled category C. immunological benefits of breastfeed- natal hypoglycemia and macrosomia with ing for the baby, all women including this class. Type 1 Diabetes those with diabetes should be sup- Metformin Women with type 1 diabetes have an ported in attempts to breastfeed. Metformin, which is associated with a increased risk of hypoglycemia in the Breastfeeding may also confer longer- lower risk of hypoglycemia and potential first trimester and, like all women, have term metabolic benefits to both mother lower weight gain, may be preferable to altered counterregulatory response in (29) and offspring (30). care.diabetesjournals.org Management of Diabetes in Pregnancy S97

Gestational Diabetes Mellitus by 35% and 40%, respectively, over 10 years restriction. Antihypertensive drugs Initial Testing compared with placebo (35). known to be effective and safe in preg- Because GDM may represent preexist- nancy include methyldopa, labetalol, ing undiagnosed type 2 or even type 1 Pregestational Type 1 and Type 2 diltiazem, clonidine, and prazosin. diabetes, women with GDM should be Diabetes Chronic diuretic use during pregnancy tested for persistent diabetes or predia- Insulin sensitivity increases with delivery is not recommended as it has been as- betes at 6–12 weeks postpartum with a of the placenta and then returns to pre- sociated with restricted maternal plasma – 75-g OGTT using nonpregnancy criteria pregnancy levels over the following 1 2 volume, which may reduce uteroplacental as outlined in Section 2 “Classification weeks. In women taking insulin, particu- perfusion (37). and Diagnosis of Diabetes.” lar attention is needed to hypoglycemia prevention in the setting of erratic sleep References Postpartum Follow-up and eating schedules. If the pregnancy 1. Holmes VA, Young IS, Patterson CC, et al.; The OGTT is recommended over A1C has motivated the adoption of a healthier Diabetes and Pre-eclampsia Intervention Trial at the 6- to 12-week postpartum visit diet, building on these gains to support Study Group. Optimal glycemic control, pre- because A1C may be persistently im- weight loss is recommended in the post- eclampsia, and gestational hypertension in womenwithtype1diabetesinthediabetes pacted (lowered) by the increased red partum period. and pre-eclampsia intervention trial. Diabetes blood cell turnover related to pregnancy – Contraception Care 2011;34:1683 1688 or blood loss at delivery. Because GDM 2. Dabelea D, Hanson RL, Lindsay RS, et al. In- is associated with increased maternal A major barrier to effective preconcep- trauterine exposure to diabetes conveys risks risk for diabetes, women should also tion care is the fact that the majority of for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208–2211 be tested every 1–3 years thereafter if pregnancies are unplanned. Planning pregnancy is critical in women with pre- 3. Guerin A, Nisenbaum R, Ray JG. Use of ma- 6- to 12-week 75-g OGTT is normal, with ternal GHb concentration to estimate the risk of gestational diabetes due to the need for frequency of screening depending on congenital anomalies in the offspring of women other risk factors including family his- preconception glycemic control and with prepregnancy diabetes. Diabetes Care – tory, prepregnancy BMI, and need for preventive health services. Therefore, 2007;30:1920 1925 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- insulin or oral glucose-lowering medica- all women with diabetes of childbearing age should have family planning options conceptional A1C and risk of serious adverse tion during pregnancy. Ongoing screening pregnancy outcome in 933 women with type 1 may be performed with any recommended reviewed at regular intervals. This ap- diabetes. Diabetes Care 2009;32:1046–1048 glycemic test (e.g., hemoglobin A1C, fast- plies to women in the immediate post- 5. Charron-Prochownik D, Sereika SM, Becker D, ing plasma glucose, or 75-g OGTT using partum period. Women with diabetes et al. Long-term effects of the booster-enhanced READY-Girls preconception counseling program nonpregnant thresholds). have the same contraception options and recommendations as those without on intentions and behaviors for family planning in teens with diabetes. Diabetes Care 2013;36: Gestational Diabetes Mellitus and Type 2 diabetes. The risk of an unplanned preg- 3870–3874 Diabetes nancy outweighs the risk of any given 6. Peterson C, Grosse SD, Li R, et al. Preventable Women with a history of GDM have a contraception option. health and cost burden of adverse birth out- greatly increased risk of conversion to comes associated with pregestational diabetes type 2 diabetes over time and not solely PREGNANCY AND in the United States. Am J Obstet Gynecol 2015; – within the 6- to 12-week postpartum ANTIHYPERTENSIVE DRUGS 212:74.e1 74.e9 7. Manderson JG, Patterson CC, Hadden DR, time frame (31). In the prospective In normal pregnancy, blood pressure is Traub AI, Ennis C, McCance DR. Preprandial ver- Nurses’ Health Study II, subsequent di- lower than in the nonpregnant state. sus postprandial blood glucose monitoring in abetes risk after a history of GDM was In a pregnancy complicated by diabetes type 1 diabetic pregnancy: a randomized con- significantly lower in women who fol- and chronic hypertension, target goals trolled clinical trial. Am J Obstet Gynecol 2003; – 189:507–512 lowed healthy eating patterns (32). Ad- of systolic blood pressure 110 129 mmHg – – 8. Committee on Practice Bulletins Obstetrics. justing for BMI moderately, but not and diastolic blood pressure 65 79 mmHg Practice Bulletin No. 137: gestational diabetes completely, attenuated this association. are reasonable. Lower blood pressure mellitus. Obstet Gynecol 2013;122:406–416 Interpregnancy or postpartum weight levels may be associated with im- 9. Nielsen GL, Møller M, Sørensen HT. HbA1c in gain is associated with increased risk of paired fetal growth. In a 2015 study early diabetic pregnancy and pregnancy out- adverse pregnancy outcomes in subse- targeting diastolic blood pressure of comes: a Danish population-based cohort study of 573 pregnancies in women with type 1 dia- quent pregnancies (33) and earlier pro- 100 mmHg versus 85 mmHg in preg- betes. Diabetes Care 2006;29:2612–2616 gression to type 2 diabetes. nant women, only 6% of whom had 10. Suhonen L, Hiilesmaa V, Teramo K. Glycae- Both metformin and intensive life- GDM at enrollment, there was no differ- mic control during early pregnancy and fetal style intervention prevent or delay pro- ence in pregnancy loss, neonatal care, or malformations in women with type I diabetes – gression to diabetes in women with other neonatal outcomes, although mellitus. Diabetologia 2000;43:79 82 11. Maresh MJA, Holmes VA, Patterson CC, et al.; prediabetes and a history of GDM. Of women in the less intensive treatment Diabetes and Pre-eclampsia Intervention Trial women with a history of GDM and im- group had a higher rate of uncontrolled Study Group. Glycemic targets in the second and paired glucose tolerance, only 5–6indi- hypertension (36). third trimester of pregnancy for women with viduals need to be treated with either During pregnancy, treatment with type 1 diabetes. Diabetes Care 2015;38:34–42 intervention to prevent one case of di- ACE inhibitors and angiotensin receptor 12. Nielsen LR, Ekbom P, Damm P, et al. HbA1c levels are significantly lower in early and late abetes over 3 years (34). In these blockers is contraindicated, because they pregnancy. Diabetes Care 2004;27:1200–1201 women, lifestyle intervention and met- may cause fetal renal dysplasia, oligo- 13. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO formin reduced progression to diabetes hydramnios, and intrauterine growth Study Cooperative Research Group. Hyperglycemia S98 Management of Diabetes in Pregnancy Diabetes Care Volume 39, Supplement 1, January 2016

and adverse pregnancy outcomes. N Engl J Med and insulin in women with gestational diabetes 30. Pereira PF, Alfenas RdeCG, Araujo´ RM. Does 2008;358:1991–2002 mellitus. N Engl J Med 2000;343:1134–1138 breastfeeding influence the risk of developing 14. Bain E, Crane M, Tieu J, Han S, Crowther CA, 22. Coustan DR. Pharmacological management diabetes mellitus in children? A review of cur- Middleton P. Diet and exercise interventions for of gestational diabetes: an overview. Diabetes rent evidence. J Pediatr (Rio J) 2014;90:7–15 preventing gestational diabetes mellitus. Co- Care 2007;30(Suppl. 2):S206–S208 31. Kim C, Newton KM, Knopp RH. Gestational chrane Database Syst Rev 2015;4:CD010443 23. Balsells M, Garc´ıa-Patterson A, Sola` I, Roque´ diabetes and the incidence of type 2 diabetes: a 15. Koivusalo SB, Ron¨ o¨ K, Klemetti MM, et al. M, Gich I, Corcoy R. Glibenclamide, metformin, systematic review. Diabetes Care 2002;25: Gestational diabetes mellitus can be prevented and insulin for the treatment of gestational dia- 1862–1868 by lifestyle intervention: the Finnish Gestational betes: a systematic review and meta-analysis. 32. Tobias DK, Hu FB, Chavarro J, Rosner B, Diabetes Prevention Study (RADIEL): a random- BMJ 2015;350:h102 Mozaffarian D, Zhang C. Healthful dietary pat- ized controlled trial. Diabetes Care 2016;39:24–30 24. JiangY-F,ChenX-Y,DingT,WangX-F,Zhu terns and type 2 diabetes mellitus risk among fi 16. Metzger BE, Buchanan TA, Coustan DR, Z-N, Su S-W. Comparative ef cacy and safety women with a history of gestational diabetes et al. Summary and recommendations of the of OADs in management of GDM: network mellitus. Arch Intern Med 2012;172:1566– Fifth International Workshop-Conference on meta-analysis of randomized controlled tri- 1572 – Gestational Diabetes Mellitus. Diabetes Care als. J Clin Endocrinol Metab 2015;100:2071 33. Villamor E, Cnattingius S. Interpregnancy – 2007;30(Suppl. 2):S251 S260 2080 weight change and risk of adverse pregnancy 25. Camelo Castillo W, Boggess K, Sturmer¨ T, 17. Mayo K, Melamed N, Vandenberghe H, Berger outcomes: a population-based study. Lancet Brookhart MA, Benjamin DK Jr, Jonsson Funk H. The impact of adoption of the International 2006;368:1164–1170 M. Association of adverse pregnancy outcomes Association of Diabetes in Pregnancy Study Group 34. Ratner RE, Christophi CA, Metzger BE, et al.; with glyburide vs insulin in women with gesta- criteria for the screening and diagnosis of gesta- Diabetes Prevention Program Research Group. tional diabetes. Am J Obstet Gynecol 2015;212: tional diabetes. JAMA Pediatr 2015;169:452– Prevention of diabetes in women with a history 224.e1–224.e9 458 of gestational diabetes: effects of metformin 18. Hartling L, Dryden DM, Guthrie A, Muise M, 26. Chew EY, Mills JL, Metzger BE, et al.; Na- and lifestyle interventions. J Clin Endocrinol Vandermeer B, Donovan L. Benefits and harms tional Institute of Child Health and Human De- Metab 2008;93:4774–4779 of treating gestational diabetes mellitus: a sys- velopment Diabetes in Early Pregnancy Study. 35. Aroda VR, Christophi CA, Edelstein SL, et al.; tematic review and meta-analysis for the U.S. Metabolic control and progression of retinopa- Preventive Services Task Force and the National thy: the Diabetes in Early Pregnancy Study. Di- Diabetes Prevention Program Research Group. Institutes of Health Office of Medical Applica- abetes Care 1995;18:631–637 The effect of lifestyle intervention and metfor- tions of Research. Ann Intern Med 2013;159: 27. Clausen TD, Mathiesen E, Ekbom P, Hellmuth min on preventing or delaying diabetes among 123–129 E, Mandrup-Poulsen T, Damm P. Poor pregnancy women with and without gestational diabetes: 19. Rowan JA, Hague WM, Gao W, Battin MR, outcome in women with type 2 diabetes. Diabe- the Diabetes Prevention Program Outcomes Moore MP; MiG Trial Investigators. Metformin tes Care 2005;28:323–328 Study 10-year follow-up. J Clin Endocrinol versus insulin for the treatment of gestational 28. Cundy T, Gamble G, Neale L, et al. Differing Metab 2015;100:1646–1653 diabetes. N Engl J Med 2008;358:2003–2015 causes of pregnancy loss in type 1 and type 2 36. Magee LA, von Dadelszen P, Rey E, et al. 20. Gui J, Liu Q, Feng L. Metformin vs insulin in diabetes. Diabetes Care 2007;30:2603–2607 Less-tight versus tight control of hypertension the management of gestational diabetes: a 29. Stuebe AM, Rich-Edwards JW, Willett WC, in pregnancy. N Engl J Med 2015;372:407–417 meta-analysis. PLoS One 2013;8:e64585 Manson JE, Michels KB. Duration of lactation 37. Sibai BM. Treatment of hypertension in 21. Langer O, Conway DL, Berkus MD, Xenakis and incidence of type 2 diabetes. JAMA 2005; pregnant women. N Engl J Med 1996;335: EM-J, Gonzales O. A comparison of glyburide 294:2601–2610 257–265 Diabetes Care Volume 39, Supplement 1, January 2016 S99

13. Diabetes Care in the Hospital American Diabetes Association Diabetes Care 2016;39(Suppl. 1):S99–S104 | DOI: 10.2337/dc16-S016

Recommendations c Consider performing an A1C on all patients with diabetes or hyperglycemia admitted to the hospital if not performed in the prior 3 months. C c Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold $180 mg/dL (10.0 mmol/L). Once insulin therapy is started, a target glucose range of 140–180 mg/dL (7.8–10.0 mmol/L) is recommended for the majority of critically ill patients A and noncritically ill patients. C c More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L) may be appropriate for selected critically ill patients, as long as this can be achieved without significant hypoglycemia. C HOSPITAL THE IN CARE DIABETES 13. c Intravenous insulin infusions should be administered using validated written or computerized protocols that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose. E c A basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who are taking nothing by mouth. An insulin regimen with basal, nutritional, and correction components is the preferred treatment for patients with good nutritional intake. A c The sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged. A c A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system. A plan for preventing and treating hypoglycemia should be established for each patient. Episodes of hypoglycemia in the hospital should be documented in the medical record and tracked. E c The treatment regimen should be reviewed and changed if necessary to prevent further hypoglycemia when a blood glucose value is ,70 mg/dL (3.9 mmol/L). C c There should be a structured discharge plan tailored to the individual patient. B

Both hyperglycemia and hypoglycemia are associated with adverse outcomes, including death (1,2). Therefore, hospital goals for the patient with diabetes include preventing both hyperglycemia and hypoglycemia, promoting the shortest safe hospital stay, and providing an effective transition out of the hospital that prevents complications and readmission. High-quality hospital care requires both hospital care delivery standards, often assured by structured order sets, and quality assurance standards for process improvement.

HOSPITAL CARE DELIVERY STANDARDS “Best practice” protocols, reviews, and guidelines (2) are inconsistently implemented within hospitals. To correct this, hospitals have established protocols for structured patient care and structured order sets, which include computerized physician order entry (CPOE).

Computerized Physician Order Entry In 2009, the federal Health Information Technology for Economic and Clinical Health (HITECH) Act was enacted. A core requirement for stage 1 of the HITECH Act’s Suggested citation: American Diabetes Associa- “meaningful use” included CPOE. The Institute of Medicine also recommends tion. Diabetes care in the hospital. Sec. 13. In fi Standards of Medical Care in Diabetesd2016. CPOE to prevent medication-related errors and increase ef ciency in medication Diabetes Care 2016;39(Suppl. 1):S99–S104 administration (3). A Cochrane review of randomized controlled trials using com- fi © 2016 by the American Diabetes Association. puterized advice to improve glucose control in the hospital found signi cant im- Readers may use this article as long as the work provement in percentage of time in target glucose range, lower mean blood glucose, is properly cited, the use is educational and not and no increase in hypoglycemia (4). As hospitals move to comply with “meaningful for profit, and the work is not altered. S100 Diabetes Care in the Hospital Diabetes Care Volume 39, Supplement 1, January 2016

use,” efforts should be made to ensure insulin therapy is initiated, a glucose target for glycemic fluctuations and insulin dose that all components of structured insu- of 140–180 mg/dL (7.8–10.0 mmol/L) is rec- (2,12). lin order sets are incorporated in the ommended for most critically ill patients Noncritical Care Setting orders (5). Thus, where feasible, there (2). More stringent goals, such as 110–140 Outside of critical care units, scheduled should be routine structured order sets – mg/dL (6.1 7.8 mmol/L) may be appropri- subcutaneous insulin injections should that produce computerized advice for ate for select patients, such as cardiac sur- align with meals and bedtime or every glucose control. gery patients (7), and patients with acute 4–6 h if no meals or if continuous enteral/ ischemic cardiac (9) or neurological events CONSIDERATIONS ON ADMISSION parenteral therapy is used (2). A basal provided the targets can be achieved plus correction insulin regimen is the fi Initial orders should state that the pa- without signi cant hypoglycemia. preferred treatment for patients with tient has type 1 diabetes or type 2 diabe- A glucose target between 140 and 180 poor oral intake or those who are taking tes or no previous history of diabetes. If mg/dL (between 7.8 and 10.0 mmol/L) is nothing by mouth (NPO) (13). An insulin the patient has diabetes, an order for an recommended for most patients in non- regimen with basal, nutritional, and A1C should be placed if none is available critical care units (2). Patients with a prior correction components (basal–bolus) is within the prior 3 months (2). In addition, history of successful tight glycemic con- the preferred treatment for patients diabetes self-management education trol in the outpatient setting who are clin- with good nutritional intake (10). In should be ordered and should include ically stable may be maintained with a such instances, point-of-care (POC) glu- appropriate skills needed after dis- glucose target below 140 mg/dL cose testing should be performed imme- charge, such as taking glycemic medica- (7.8 mmol/L). Conversely, higher glucose diately before meals. tion, glucose monitoring, and coping with ranges may be acceptable in terminally ill If oral intake is poor, a safer procedure hypoglycemia (2). patients, in patients with severe comor- is to administer the short-acting insulin bidities, and in in-patient care settings after the patient eats or to count the car- GLYCEMIC TARGETS IN where frequent glucose monitoring or bohydrates and cover the amount in- HOSPITALIZED PATIENTS close nursing supervision is not feasible. gested. A randomized controlled trial Standard Definition of Glucose Clinical judgment combined with ongo- has shown that basal–bolus treatment Abnormalities ing assessment of the patient’s clinical improved glycemic control and reduced Hyperglycemia in hospitalized patients status, including changes in the trajectory hospital complications compared with has been defined as blood glucose of glucose measures, illness severity, nu- sliding scale insulin in general surgery .140 mg/dL (7.8 mmol/L). Blood glu- tritional status, or concomitant medica- patients with type 2 diabetes (14). cose levels that are significantly and tions that might affect glucose levels persistently above this level require re- (e.g., glucocorticoids), should be incorpo- Type 1 Diabetes For patients with type 1 diabetes, dosing assessing treatment. An admission A1C rated into the day-to-day decisions re- insulin based solely on premeal glucose value $6.5% (48 mmol/mol) suggests garding insulin doses (2). levels does not account for basal insulin that diabetes preceded hospitalization requirements or calorie intake, increas- (see Section 2 “Classification and Diag- ANTIHYPERGLYCEMIC AGENTS IN ing both hypoglycemia and hyperglyce- nosis of Diabetes”). Hypoglycemia in HOSPITALIZED PATIENTS mia risks and potentially leading to hospitalized patients has been defined In most instances in the hospital setting, diabetic ketoacidosis (DKA). Typically as blood glucose ,70 mg/dL (3.9 mmol/L) insulin is the preferred treatment for basal insulin dosing schemes are based and severe hypoglycemia as ,40 mg/dL glycemic control (2). However, in certain on body weight, with some evidence (2.2 mmol/L) (6). circumstances, it may be appropriate to that patients with renal insufficiency Moderate Versus Tight Glycemic continue home regimens including oral should be treated with lower doses (15). antihyperglycemic medications (10). If Control Transitioning Intravenous to Glycemic goals within the hospital set- oral medications are held in the hospi- Subcutaneous Insulin ting have changed in the last 14 years. tal, there should be a protocol for re- When discontinuing intravenous insulin, a – The initial target of 80–110 mg/dL (4.4– suming them 1 2 days before discharge. transition protocol is associated with 6.1 mmol/L) was based on a 42% relative less morbidity and lower costs of care Insulin Therapy reduction in intensive care unit mortal- The sole use of sliding scale insulin in the (16) and is therefore recommended. A ity in critically ill surgical patients (7). inpatient hospital setting is strongly dis- patient with type 1 or type 2 diabetes However, a meta-analysis of over 26 stud- being transitioned to outpatient subcu- couraged (2,11). ies, including the largest, Normoglycemia taneous insulin should receive sub- in Intensive Care Evaluation–Survival Critical Care Setting cutaneous insulin 1–2hbeforethe Using Glucose Algorithm Regulation In the critical care setting, continuous intravenous insulin is discontinued. (NICE-SUGAR), showed increased rates intravenous insulin infusion has been Converting to basal insulin at 60–80% of severe hypoglycemia and mortality shown to be the best method for achiev- of the daily infusion dose has been in tightly versus moderately controlled ing glycemic targets. Intravenous insulin showntobeeffective(2,16,17). cohorts (8). This evidence established infusions should be administered based new standards: initiate insulin therapy on validated written or computerized Noninsulin Therapies for persistent hyperglycemia greater protocols that allow for predefined ad- The safety and efficacy of noninsulin than 180 mg/dL (10.0 mmol/L). Once justments in the infusion rate, accounting antihyperglycemic therapies in the hospital care.diabetesjournals.org Diabetes Care in the Hospital S101

setting is an area of active research. A re- 2. Preoperative risk assessment for pa- any correctable underlying cause of cent randomized pilot trial in general tients at high risk for ischemic heart DKA, such as sepsis. Low-dose insulin, medicine and surgery patients reported disease and those with autonomic given intravenously, intramuscularly, or that a dipeptidyl peptidase 4 inhibitor neuropathy or renal failure. subcutaneously, is safe and effective in alone or in combination with basal insulin 3. The morning of surgery or proce- treating DKA (23). was well tolerated and resulted in similar dure, hold any oral hypoglycemic Several studies have shown that in glucose control and frequency of hypogly- agents and give half of NPH dose or uncomplicated mild-to-moderate DKA, cemia compared with a basal–bolus regi- full doses of a long-acting analog or subcutaneous lispro (24) or aspart insu- men (18). A report suggested that given pump basal insulin. lin (25) dosed every 1–2 h is as effective the serious consequences of hypoglyce- 4. Monitor blood glucose every 4–6h and safe as intravenous regular insulin mia, incretin agents, which do not cause while NPO and dose with short- when used in conjunction with standard hypoglycemia, may substitute for insulin, acting insulin as needed. intravenous fluid and potassium replace- sulfonylureas, or metformin (19). A re- ment protocols (23). If subcutaneous ad- view of several studies concluded that in- A review found that tight peri- ministration is used, it is important, for cretins show promise; however, proof of operative glycemic control did not im- safety reasons, to provide adequate nurs- safety and efficacy compared with stan- prove outcomes and was associated ing training and care and frequent bed- dard therapies await the results of further with more hypoglycemia (22); there- side testing. However, in critically ill and randomized controlled trials (20). fore, in general, tighter glycemic targets mentally obtunded patients, continuous than mentioned above are not advised. intravenous insulin infusion is required. Several studies have shown that the use STANDARDS FOR SPECIAL Moderate Versus Tight Glycemic SITUATIONS of bicarbonate in patients with DKA made Control Targets no difference in resolution of acidosis or Enteral/Parenteral Feedings In general surgery (noncardiac) patients, time to discharge, and its use is generally For full enteral/parenteral feeding guid- basal insulin plus premeal regular or not recommended (26). ance, the reader is encouraged to consult short-acting insulin (basal–bolus) cover- review articles (2,21) and see Table 13.1. age has been associated with improved Continuous Glucose Monitoring glycemic control and lower rates of peri- Continuous glucose monitoring (CGM) Glucocorticoid Therapy operative complications compared with provides continuous estimates, direction, The duration of glucocorticoid action the traditional sliding scale regimen and magnitude of glucose trends, which must be considered to prevent hyper- (regular or short-acting insulin coverage may have an advantage over POC glucose glycemia. Once-a-day short-acting ste- only with no basal dosing) (13,14). testing in detecting and reducing the in- roids such as prednisone peak in about cidence of hypoglycemia. Several studies 8 h, so coverage with intermediate- Diabetic Ketoacidosis and have shown that CGM use did not im- acting insulin (NPH) may be sufficient. For Hyperosmolar Hyperglycemic State prove glucose control, but detected a long-acting steroids such as dexametha- There is considerable variability in the greater number of hypoglycemic events sone or multidose or continuous steroid presentation of DKA and hyperosmolar than POC testing. A recent review has rec- use, long-acting insulin may be used hyperglycemic state, ranging from eu- ommended against using CGM in adults (10,21). Whatever orders are started, glycemia or mild hyperglycemia and in a hospital setting until more safety and adjustments based on POC glucose test acidosis to severe hyperglycemia, efficacy data become available (27). results are critical. dehydration, and coma; therefore, treatment individualization based on a TREATING AND PREVENTING Perioperative Care careful clinical and laboratory assess- HYPOGLYCEMIA Standards for perioperative care include ment is needed (23). Patients with or without diabetes may the following: Management goals include restora- experience hypoglycemia in the hospital tion of circulatory volume and tissue setting. While increased mortality is as- 1. Target glucose range for the peri- perfusion, resolution of hyperglycemia, sociated with hypoglycemia, it may be a operative period should be 80–180 and correction of electrolyte imbalance marker of underlying disease rather mg/dL (4.4–10.0 mmol/L). and ketosis. It is also important to treat than the cause of increased mortality. However, until it is proven not to be Table 13.1—Insulin dosing for enteral/parenteral feedings causal, it is prudent to avoid hypoglyce- Situation Basal Bolus mia. Despite the preventable nature of Continuous enteral feedings Glargine q.d. or SQ rapid-acting correction many inpatient episodes of hypoglyce- NPH/detemir b.i.d. every 4 h mia, institutions are more likely to have Bolus enteral feedings Continue prior basal; SQ rapid-acting insulin with nursing protocols for hypoglycemia if none, consider each bolus feeding to cover treatment than for its prevention when 10 units NPH or the bolus feeding and to both are needed. glargine insulin correct for hyperglycemia Triggering Events Parenteral feedings Regular insulin to Rapid-acting insulin SQ every TPN IV bottle 4 h to correct for hyperglycemia Iatrogenic hypoglycemia triggers may include sudden reduction of corticosteroid IV, intravenous; SQ, subcutaneous; TPN, total parenteral nutrition. dose, altered ability of the patient to S102 Diabetes Care in the Hospital Diabetes Care Volume 39, Supplement 1, January 2016

report symptoms, reduced oral intake, hypoglycemia protocol be adopted and Orders should also reflect that the meal emesis, new NPO status, inappropriate implemented in each hospital system, delivery and nutritional insulin coverage timing of short-acting insulin in relation and all episodes should be tracked in be matched, as their variability often to meals, reduced infusion rate of intrave- the medical records (2). creates the possibility of hyperglycemic nous dextrose, and unexpected interrup- and hypoglycemic events. tion of oral, enteral, or parenteral feedings. SELF-MANAGEMENT IN THE HOSPITAL Predictors of Hypoglycemia TRANSITION FROM THE ACUTE Diabetes self-management in the hos- In one study, 84% of patients with an CARE SETTING pital may be appropriate for select episode of severe hypoglycemia (,40 A Cochrane systematic review noted youth and adult patients. Candidates mg/dL [2.2 mmol/L]) had a prior episode that a structured discharge plan tailored include patients who successfully con- of hypoglycemia (,70 mg/dL [3.9 to the individual patient may reduce duct self-management of diabetes at mmol/L]) during the same admission length of hospital stay, readmission rates, home, have the cognitive and physical (28). In another study of hypoglycemic and increase patient satisfaction (33). skills needed to successfully self- episodes (,50 mg/dL [2.8 mmol/L]), Therefore, there should be a structured administer insulin, and perform self- 78% of patients were using basal insulin, discharge plan tailored to each patient. monitoring of blood glucose. In addition, with the incidence of hypoglycemia peak- Discharge planning should begin at ad- they should have adequate oral intake, ing between midnight and 6 A.M. Despite mission and be updated as patient needs be proficient in carbohydrate estima- recognition of hypoglycemia, 75% of pa- change. tion, use multiple daily insulin injec- tients did not have their dose of basal in- Transition from the acute care setting tions or continuous subcutaneous sulin changed before the next insulin is a risky time for all patients. Inpatients insulin infusion (CSII) pump therapy, administration (29). may be discharged to varied settings, have stable insulin requirements, and including home (with or without visiting Hypoglycemia Treatment understand sick-day management. If nurse services), assisted living, rehabili- self-management is to be used, a pro- There should be a standardized hospital- tation, or skilled nursing facilities. For wide, nurse-initiated hypoglycemia tocol should include a requirement that the patient, nursing staff, and phy- the patient who is discharged to assisted treatment protocol to immediately ad- living or to home, the optimal program dress hypoglycemia (,70 mg/dL [3.9 sician agree that patient self-management is appropriate. If CSII is to be used, hospital will need to consider diabetes type and mmol/L]) (2). ’ policy and procedures delineating guide- severity, effects of the patient sillness ’ Prevention lines for CSII therapy are advised (31). on blood glucose levels, and the patient s Common preventable sources of iatro- capacities and desires. MEDICAL NUTRITION THERAPY IN genic hypoglycemia are improper pre- An outpatient follow-up visit with THE HOSPITAL scribing of hypoglycemic medications, the primary care provider, endocrinol- inappropriate management of the first The goals of medical nutrition therapy are ogist, or diabetes educator within 1 episode of hypoglycemia, and nutrition– to optimize glycemic control, provide month of discharge is advised for all insulin mismatch, often related to an adequate calories to meet metabolic patients having hyperglycemia in the unexpected interruption of nutrition. A demands, address personal food pre- hospital. If glycemic medications are study of “bundled” preventative thera- ferences, and create a discharge plan. changed or glucose control is not opti- pies including proactive surveillance of The ADA does not endorse any single mal at discharge, continuing contact glycemic outliers and an interdisciplinary meal plan or specified percentages of may be needed to avoid hyperglycemia data-driven approach to glycemic man- macronutrients, and the term “ADA and hypoglycemia. A recent discharge agement showed that hypoglycemic diet” should no longer be used. Current algorithm for glycemic medication ad- episodes in the hospital could be pre- nutrition recommendations advise indi- justment based on admission A1C vented. Compared with baseline, the vidualization based on treatment goals, found that the average A1C in patients study found that the relative risk of a se- physiological parameters, and medication with diabetes decreased from 8.7% (72 vere hypoglycemic event was 0.44 (95% use. Consistent carbohydrate meal plans mmol/mol) on admission to 7.3% (56 CI 0.34–0.58) in the postintervention pe- are preferred by many hospitals as they mmol/mol) 3 months after discharge riod (30). facilitate matching the prandial insulin (34). Therefore, if an A1C from the prior dose to the amount of carbohydrate con- 3 months is unavailable, measuring the Hospital Hypoglycemia Prevention sumed (32). A1C in all patients with diabetes or hy- and Treatment When the nutritional issues in the perglycemia admitted to the hospital is The Joint Commission recommends that hospital are complex, a registered dieti- recommended. all hypoglycemic episodes be evaluated tian, knowledgeable and skilled in med- Clear communication with outpatient for a root cause and the episodes be ical nutrition therapy, can serve as an providers either directly or via hospital aggregated and reviewed to address individual inpatient team member. discharge summaries facilitates safe systemic issues. An American Diabetes That person should be responsible for transitions to outpatient care. Providing Association (ADA) hypoglycemia con- integrating information about the pa- information regarding the cause of hy- sensus report suggested that the treat- tient’s clinical condition, meal planning, perglycemia (or the plan for determin- ment regimen be reviewed when a blood and lifestyle habits and for establishing ing the cause), related complications glucose value is ,70 mg/dL (3.9 mmol/L), a realistic treatment goals after discharge. and comorbidities, and recommended care.diabetesjournals.org Diabetes Care in the Hospital S103

treatments can assist outpatient pro- with appropriate education at the time status should be confirmed through con- viders as they assume ongoing care. of discharge in order to avoid a poten- ventional laboratory glucose tests. The The Agency for Healthcare Research tially dangerous hiatus in care. FDA established a separate category for and Quality (AHRQ) recommends that POC glucose meters for use in health care Quality Assurance Standards at a minimum, discharge plans include settings and has released a draft on in- Even the best orders may not be carried the following (35): hospital use with stricter standards. Before out in a way that improves quality, nor are choosing a device, consider the device’s they automatically updated when new approval status and accuracy. Medication Reconciliation evidence arises. To this end, the Joint ○ The patient’s medications must be Commission has an accreditation program References cross-checked to ensure that no for the hospital care of diabetes, and the chronic medications were stopped 1. Clement S, Braithwaite SS, Magee MF, et al.; Society of Hospital Medicine has a work- American Diabetes Association Diabetes in Hos- and to ensure the safety of new book for program development (36). pitals Writing Committee. Management of dia- prescriptions. betes and hyperglycemia in hospitals. Diabetes ○ Prescriptions for new or changed DIABETES CARE PROVIDERS Care 2004;27:553–591 medication should be filled and re- IN THE HOSPITAL 2. Moghissi ES, Korytkowski MT, DiNardo M, viewed with the patient and family et al.; American Association of Clinical Endocri- Appropriately trained specialists or spe- nologists; American Diabetes Association. at or before discharge. cialty teams may reduce length of stay, American Association of Clinical Endocrinolo- improve glycemic control, and improve gists and American Diabetes Association con- Structured Discharge Communication outcomes, but the studies are few. A sensus statement on inpatient glycemic ○ – Information on medication changes, call to action outlined the studies needed control. Diabetes Care 2009;32:1119 1131 pending tests and studies, and 3. Institute of Medicine. Preventing Medication to evaluate these outcomes (11). Details Errors follow-up needs must be accurately . Aspden P, Wolcott J, Bootman JL, of team formation are available from the Cronenwett LR, Eds. Washington, DC, The and promptly communicated to Society of Hospital Medicine and the Joint National Academies Press, 2007 outpatient physicians. Commission standards for programs. 4. Gillaizeau F, Chan E, Trinquart L, et al. Com- ○ Discharge summaries should be puterized advice on drug dosage to improve transmitted to the primary physician BEDSIDE BLOOD GLUCOSE prescribing practice. Cochrane Database Syst as soon as possible after discharge. MONITORING Rev 2013;11:CD002894 5. Wexler DJ, Shrader P, Burns SM, Cagliero E. ○ Appointment-keeping behavior is Indications Effectiveness of a computerized insulin order enhanced when the inpatient Bedside POC blood glucose monitoring template in general medical inpatients with team schedules outpatient medi- guides insulin dosing. In the patient re- type 2 diabetes: a cluster randomized trial. Di- cal follow-up prior to discharge. abetes Care 2010;33:2181–2183 ceiving nutrition, glucose monitoring 6. Seaquist ER, Anderson J, Childs B, et al. Hy- should be performed before meals to poglycemia and diabetes: a report of a work- It is recommended that the following match food ingestion. In the patient group of the American Diabetes Association areas of knowledge be reviewed and ad- not receiving nutrition, glucose moni- and the Endocrine Society. Diabetes Care – dressed prior to hospital discharge: toring is advised every 4–6h(2).More 2013;36:1384 1395 7. van den Berghe G, Wouters P, Weekers F, frequent blood glucose testing ranging et al. Intensive insulin therapy in critically ill ○ Identifythehealthcareprovider from every 30 min to every 2 h is re- patients. N Engl J Med 2001;345:1359–1367 who will provide diabetes care quired for patients receiving intrave- 8. Finfer S, Chittock DR, Su SY-S, et al.; NICE- after discharge. nous insulin. Safety standards should SUGAR Study Investigators. Intensive versus ○ Level of understanding related to the conventional glucose control in critically ill pa- be established for blood glucose moni- tients. N Engl J Med 2009;360:1283–1297 diabetes diagnosis, self-monitoring toring that prohibit the sharing of finger- of blood glucose, and explanation 9. Steg PG, James SK, Atar D, et al.; Task Force stick lancing devices, lancets, needles, onthemanagementofST-segmentelevation of home blood glucose goals. and pens to reduce the risk of transmis- acute myocardial infarction of the European So- ○ fi De nition, recognition, treatment, sion of blood-borne diseases. ciety of Cardiology (ESC). ESC Guidelines for the and prevention of hyperglycemia management of acute myocardial infarction in and hypoglycemia. Limitations in the Hospital Setting patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–2619 ○ Information on consistent nutri- POC meters have limitations for measur- ’ ing blood glucose. Although the U.S. Food 10. Maynard G, Wesorick DH, O Malley C, tion habits. Inzucchi SE; Society of Hospital Medicine Glyce- ○ If relevant, when and how to take and Drug Administration (FDA) has stan- mic Control Task Force. Subcutaneous insulin blood glucose–lowering medica- dards for blood glucose meters used by order sets and protocols: effective design and tions, including insulin administra- lay persons, there have been questions implementation strategies. J Hosp Med 2008;3 – tion. about the appropriateness of these crite- (Suppl.):29 41 11. Draznin B, Gilden J, Golden SH, et al.; PRIDE ○ ria, especially in the hospital and for lower Sick-day management. Investigators. Pathways to quality inpatient man- ○ Proper use and disposal of needles blood glucose readings (37). Significant agement of hyperglycemia and diabetes: a call to and syringes. discrepancies between capillary, venous, action. Diabetes Care 2013;36:1807–1814 and arterial plasma samples have been 12. Umpierrez G, Cardona S, Pasquel F, et al. It is important that patients be pro- observed in patients with low or high he- Randomized controlled trial of intensive versus conservative glucose control in patients under- vided with appropriate durable medical moglobin concentrations and with hypo- going coronary artery bypass graft surgery: equipment, medications, supplies (e.g., perfusion. Any glucose result that does GLUCO-CABG trial. Diabetes Care 2015;38: insulin pens), and prescriptions along not correlate with the patient’s clinical 1665–1672 S104 Diabetes Care in the Hospital Diabetes Care Volume 39, Supplement 1, January 2016

13. Umpierrez GE, Smiley D, Hermayer K, et al. proven itself and is considered the mainstay of during hospitalization. Endocr Pract 2015;21: Randomized study comparing a basal-bolus treatment. Diabetes Care 2013;36:2112–2117 501–507 with a basal plus correction insulin regimen 21. Corsino L, Dhatariya K, Umpierrez G. 30. Maynard G, Kulasa K, Ramos P, et al. Impact for the hospital management of medical and Management of Diabetes and Hyperglycemia of a hypoglycemia reduction bundle and a sys- surgical patients with type 2 diabetes: basal in Hospitalized Patients, 2000 [Internet]. tems approach to inpatient glycemic manage- plus trial. Diabetes Care 2013;36:2169–2174 Available from http://www.ncbi.nlm.nih ment. Endocr Pract 2015;21:355–367 14. Umpierrez GE, Smiley D, Jacobs S, et al. Ran- .gov/books/NBK279093/. Accessed 6 October 31. Houlden RL, Moore S. In-hospital manage- domized study of basal-bolus insulin therapy in 2015 ment of adults using insulin pump therapy. Can J the inpatient management of patients with 22. Buchleitner AM, Mart´ınez-Alonso M, Diabetes 2014;38:126–133 type 2 diabetes undergoing general surgery Hernandez´ M, Sola` I, Mauricio D. Perioperative 32. Curll M, Dinardo M, Noschese M, (RABBIT 2 surgery). Diabetes Care 2011;34: glycaemic control for diabetic patients undergo- Korytkowski MT. Menu selection, glycaemic 256–261 ing surgery. Cochrane Database Syst Rev 2012; control and satisfaction with standard and patient- 15. Baldwin D, Zander J, Munoz C, et al. A ran- 9:CD007315 controlled consistent carbohydrate meal plans domized trial of two weight-based doses of in- 23.KitabchiAE,UmpierrezGE,MilesJM, in hospitalised patients with diabetes. Qual Saf sulin glargine and glulisine in hospitalized Fisher JN. Hyperglycemic crises in adult pa- Health Care 2010;19:355–359 subjects with type 2 diabetes and renal insuffi- tients with diabetes. Diabetes Care 2009;32: 33. Shepperd S, Lannin NA, Clemson LM, ciency. Diabetes Care 2012;35:1970–1974 1335–1343 McCluskey A, Cameron ID, Barras SL. Discharge 16. Schmeltz LR, DeSantis AJ, Thiyagarajan V, 24. Umpierrez GE, Latif K, Stoever J, et al. Effi- planning from hospital to home. Cochrane et al. Reduction of surgical mortality and mor- cacy of subcutaneous insulin lispro versus con- Database Syst Rev 2013;1:CD000313 bidity in diabetic patients undergoing cardiac tinuous intravenous regular insulin for the 34. Umpierrez GE, Reyes D, Smiley D, et al. Hos- surgery with a combined intravenous and sub- treatment of patients with diabetic ketoacidosis. pital discharge algorithm based on admission cutaneous insulin glucose management strat- Am J Med 2004;117:291–296 HbA1c for the management of patients with egy. Diabetes Care 2007;30:823–828 25. Umpierrez GE, Cuervo R, Karabell A, Latif K, type 2 diabetes. Diabetes Care 2014;37:2934– 17. Shomali ME, Herr DL, Hill PC, Pehlivanova Freire AX, Kitabchi AE. Treatment of diabetic 2939 M, Sharretts JM, Magee MF. Conversion from ketoacidosis with subcutaneous insulin aspart. 35. Agency for Healthcare Research and Qual- intravenous insulin to subcutaneous insulin af- Diabetes Care 2004;27:1873–1878 ity. Adverse events after hospital discharge [In- ter cardiovascular surgery: transition to target 26. Duhon B, Attridge RL, Franco-Martinez AC, ternet], 2014. Available from http://psnet.ahrq study. Diabetes Technol Ther 2011;13:121–126 Maxwell PR, Hughes DW. Intravenous sodium .gov/primer.aspx?primerID511. Accessed 1 18. Umpierrez GE, Gianchandani R, Smiley D, bicarbonate therapy in severely acidotic dia- October 2015 et al. Safety and efficacy of sitagliptin therapy betic ketoacidosis. Ann Pharmacother 2013; 36. Society of Hospital Medicine. Clinical for the inpatient management of general med- 47:970–975 Tools: Glycemic Control Implementation Tool- icine and surgery patients with type 2 diabetes: 27. Gomez AM, Umpierrez GE. Continuous glu- kit [Internet]. Available from http://www a pilot, randomized, controlled study. Diabetes cose monitoring in insulin-treated patients in .hospitalmedicine.org/Web/Quality_Innovation/ Care 2013;36:3430–3435 non-ICU settings. J Diabetes Sci Technol 2014; Implementation_Toolkits/Glycemic_Control/Web/ 19. Schwartz SS, DeFronzo RA, Umpierrez GE. 8:930–936 Quality___Innovation/Implementation_ Practical implementation of incretin-based 28. Dendy JA, Chockalingam V, Tirumalasetty Toolkit/Glycemic/Clinical_Tools/Clinical_Tools.aspx. therapy in hospitalized patients with type 2 di- NN, et al. Identifying risk factors for severe hy- Accessed 25 August 2015 abetes. Postgrad Med 2015;127:251–257 poglycemia in hospitalized patients with diabe- 37. Boyd JC, Bruns DE. Quality specifications for 20. Umpierrez GE, Korytkowski M. Is incretin- tes. Endocr Pract 2014;20:1051–1056 glucose meters: assessment by simulation mod- based therapy ready for the care of hospitalized 29. Ulmer BJ, Kara A, Mariash CN. Temporal oc- eling of errors in insulin dose. Clin Chem 2001; patients with type 2 diabetes? Insulin therapy has currences and recurrence patterns of hypoglycemia 47:209–214 Diabetes Care Volume 39, Supplement 1, January 2016 S105

14. Diabetes Advocacy American Diabetes Association

Diabetes Care 2016;39(Suppl. 1):S105–S106 | DOI: 10.2337/dc16-S017

Managing the daily health demands of diabetes can be challenging. People living with diabetes should not have to face additional discrimination due to diabetes. By advocating for the rights of those with diabetes at all levels, the American Diabetes Association (ADA) can help to ensure that they live a healthy and productive life. A strategic goal of the ADA is that more children and adults with diabetes live free from the burden of discrimination. One tactic for achieving this goal is to implement the ADA’sStandardsof Medical Care through advocacy-oriented position statements. The ADA publishes evidence-based, peer-reviewed statements on topics such as diabetes and employment, diabetes and driving, and diabetes management in certain settings such as schools, child care programs, and correctional institutions. In addition to ADA’s clinical position statements, these advocacy position statements are im- ADVOCACY DIABETES 14. portant tools in educating schools, employers, licensing agencies, policymakers, and others about the intersection of diabetes medicine and the law.

ADVOCACY POSITION STATEMENTS Partial list, with most recent publications appearing ﬁrst

Diabetes Care in the School Setting (1) First publication: 1998 (revised 2015) A sizeable portion of a child’s day is spent in school, so close communication with and cooperation of school personnel are essential to optimize diabetes management, safety, and academic opportunities. See the ADA position statement “Diabe- tes Care in the School Setting” (http://care.diabetesjournals.org/content/38/10/ 1958.full.pdf1html).

Care of Young Children With Diabetes in the Child Care Setting (2) First publication: 2014 Very young children (aged ,6 years) with diabetes have legal protections and can be safely cared for by child care providers with appropriate training, access to resources, and a system of communication with parents and the child’s diabetes provider. See the ADA position statement “Care of Young Children With Diabetes in the Child Care Setting” (http://care.diabetesjournals.org/content/37/10/2834).

Diabetes and Driving (3) First publication: 2012 Peoplewithdiabeteswhowishtooperatemotorvehiclesaresubjecttoagreatvarietyof licensing requirements applied by both state and federal jurisdictions, which may lead to loss of employment or significant restrictions on a person’s license. Presence of a medical condition that can lead to significantly impaired consciousness or cognition may lead to drivers being evaluated for fitness to drive. People with diabetes should be individually assessed by a health care professional knowledgeable in diabetes if license restrictions are being considered, and patients should be counseled about detecting and avoiding hypoglycemia while driving. See the ADA position statement “Diabetes and Driving” (http://care.diabetesjournals.org/content/37/Supplement_1/S97).

Diabetes and Employment (4) Suggested citation: American Diabetes Associa- First publication: 1984 (revised 2009) tion. Diabetes advocacy. Sec. 14. In Standards of Medical Care in Diabetesd2016. Diabetes Care Any person with diabetes, whether insulin treated or noninsulin treated, should be eligible 2016;39(Suppl. 1):S105–S106 for any employment for which he or she is otherwise qualified. Employment decisions © 2016 by the American Diabetes Association. should never be based on generalizations or stereotypes regarding the effects of diabetes. Readers may use this article as long as the work When questions arise about the medical fitness of a person with diabetes for a particular is properly cited, the use is educational and not job, a health care professional with expertise in treating diabetes should perform for profit, and the work is not altered. S106 Diabetes Advocacy Diabetes Care Volume 39, Supplement 1, January 2016

an individualized assessment. See the have written policies and procedures Association. Diabetes Care 2015;38:1958– ADA position statement “Diabetes and Em- for the management of diabetes and 1963 ’ ployment” (http://care.diabetesjournals for training of medical and correctional 2. Siminerio LM, Albanese-O Neill A, Chiang JL, et al. Care of young children with diabetes in the .org/content/37/Supplement_1/S112). staff in diabetes care practices. See the child care setting: a position statement of the ADA position statement “Diabetes Man- American Diabetes Association. Diabetes Care Diabetes Management in Correctional agement in Correctional Institutions” 2014;37:2834–2842 Institutions (5) (http://care.diabetesjournals.org/content/ 3. American Diabetes Association. Diabetes and First publication: 1989 (revised 2008) – 37/Supplement_1/S104). driving. Diabetes Care 2014;37:(Suppl. 1):S97 S103 People with diabetes in correctional fa- 4. American Diabetes Association. Diabetes and employment. Diabetes Care 2014;37(Suppl. 1): cilities should receive care that meets References S112–S117 national standards. Because it is estimated 1. Jackson CC, Albanese-O’Neill A, Butler KL, 5. American Diabetes Association. Diabetes that nearly 80,000 inmates have diabe- et al. Diabetes care in the school setting: a management in correctional institutions. Diabe- tes, correctional institutions should position statement of the American Diabetes tes Care 2014;37(Suppl. 1):S104–S111 RFSINLPATC COMMITTEE PRACTICE PROFESSIONAL Diabetes Care Volume 39, Supplement 1, January 2016 S107

Professional Practice Committee for the Standards of Medical Care in Diabetesd2016 Diabetes Care 2016;39(Suppl. 1):S107–S108 | DOI: 10.2337/dc16-S018

Committee members disclosed the following ﬁnancial or other conﬂicts of interest covering the period of 12 months before December 2015 Industry-sponsored Other research Member Employment research grant support William H. Herman, MD, MPH (Chair) University of Michigan, Ann Arbor, MI None None Thomas W. Donner, MD Johns Hopkins University School of Medicine, Novo Nordisk*# None Baltimore, MD R. James Dudl, MD Kaiser Permanente, Bonita, CA None None Hermes J. Florez, MD, PhD, MPH University of Miami and GRECC-Miami VA None None Healthcare System, Miami, FL Judith E. Fradkin, MD National Institutes of Health, Bethesda, MD None None Charlotte A. Hayes, MMSc, MS, Private practices: (NF)2 Nutrition and Fitness None None RD, CDE, ACSM CCEP Consulting, Atlanta, GA Rita Rastogi Kalyani, MD, MHS, FACP Johns Hopkins University, Baltimore, MD None None Suneil Koliwad, MD, PhD University of California, San Francisco, San None None Francisco, CA Joseph A. Stankaitis, MD, MPH Monroe Plan for Medical Care, Pittsford, NY; None None YourCare Health Plan, Buffalo, NY Tracey H. Taveira, PharmD, University of RhodeIslandCollegeof Pharmacy, None None CDOE, CVDOE Kingston, RI; Providence VA Medical Center, Warren Alpert Medical School of Brown University, Providence, RI Deborah J. Wexler, MD, MSc Massachusetts General Hospital, Boston, MA U01DK098246dGRADE None R18DK102737dREAL HEALTH-Diabetes Joseph Wolfsdorf, MB, BCh Boston Children’s Hospital, Boston, MA None None Jane L. Chiang, MD (Staff) American Diabetes Association, Alexandria, VA None None Erika Gebel Berg, PhD (Staff) American Diabetes Association, Alexandria, VA None None Allison T. McElvaine, PhD (Staff) American Diabetes Association, Alexandria, VA None None DSMB, Data and Safety Monitoring Board; GRECC, Geriatric Research Education and Clinical Center; MEDCAC, Medicare Evidence Development & Coverage Advisory Committee. *$$10,000 per year from company to individual. #Grant or contract is to university or other employer. S108 Professional Practice Committee Diabetes Care Volume 39, Supplement 1, January 2016

Speakers’ bureau/ Member honoraria Ownership interest Consultant/advisory board Other W.H.H. None None Merck Sharp & Dohme National Committee for Quality Assurance (Chair, DSMB),* Lexicon (Chair, Diabetes Panel), Centers for Medicare Pharmaceuticals & Medicaid Services (member, MEDCAC), (Chair, DSMB) Diabetic Medicine (Editor for the Americas), Diabetes Care (ad hoc Editor in Chief) T.W.D. None None None None R.J.D. None None None None H.J.F. None None None None J.E.F. None None None None C.A.H. Scherer Clinical None Emory University: Emory at Receives royalties from the American Communications Grady Diabetes Course Diabetes Association, Academy of Nutrition and Dietetics (Chair, Legislative and Public Policy Committee) R.R.K. None None AstraZeneca (Advisory Diabetes Care (Editorial Board) Group member) S.K. None Yes Health None None J.A.S. None None None National Committee for Quality Assurance (physician surveyor and member of the Reconsideration Committee), New York State Department of Health Medicaid Redesign Team’s Evidence-Based Beneﬁt Review Workgroup, Board member for St. Ann’s Community, Rochester, NY, a nonproﬁt senior living/long-term care organization T.H.T. None None None None D.J.W. None None None Diabetes Care (Editorial Board), PracticeUpdate: Diabetes (Editorial Board) J.W. None None None Diabetes Care, Hormone Research in Paediatrics,andPediatric Diabetes (Editorial Board); UpToDate (Section Editor) J.L.C. None None None None E.G.B. None None None None A.T.M. None None None None Diabetes Care Volume 39, Supplement 1, January 2016 S109

Index

A1C body mass index (BMI), S17 smoking in, S29, S89 age in diagnosis, S14 bromocriptine, S55 statins in, S89 CGM effects on, S39, S40, S101 thyroid disease in, S88 in children, S18, S41 calcium channel blockers, S74 type 1 diabetes in, S86–S90 in children, adolescents, S87 canagliflozin, S53, S54, S56, S58 type 2 diabetes in, S90–S91 CVD outcomes and, S42–S43 cancer, S31 vaccination schedule, S29 diagnostic criteria, S13–S14 capsaicin, S77 chlorthalidone, S63 epidemiology, S7 carbamazepine, S77 Chronic Care Model, S7, S23 goals, S41 carbohydrates, S27, S37 chronic kidney disease, S27, S72–S74 hyperglycemia and, S9–S10 cardiac autonomic neuropathy, S77 Chronic Kidney Disease Epidemiology limitations, S41 cardiac testing, S67 Collaboration (CKD-EPI) equation, S73 mean glucose levels for specified A1C level, cardiovascular disease classification, S13 S41 antiplatelet agents, S4–S5, S66–S67, S75 clinical evaluation, S23, S24 microvascular complications, S42 in children, adolescents, S88–S89 clopidogrel, S66 older adults, S83 heart failure, S68 clozapine, S49 pregnancy levels, S95 hypertension/blood pressure cognitive dysfunction, S9–S10, S26, S31–S32, race/ethnicity differences, S14, S41 control, S60–S63, S81, S88–S89 S44, S82 recommendations, S40, S41 insulin regimens, S43 cognitive function, statin use and, S66 testing, S40–S41 LDL cholesterol, S64, S65, S68 colesevelam, S55 acarbose, S55 lifestyle modification, S7, S36–S37, S47, complications access to health care, S8–S9 S48, S62–S64, S68 A1C, microvascular, S42 ACCORD trial, S10, S31–S32, S42–S44, S61, S62 lipid management, S63–S66 epidemiology, S8 ACE inhibitors, S61–S63, S68, S72–S74, S89, outcomes, S42–S43, S73 prevention of, S7, S27 S97 overview, S4, S60 risk factors, S14, S29 ADAG study, S41, S44 pharmacological interventions, S62–S63 consensus reports, S1 adherence, S8 prevention, S26, S27, S37 continuous glucose monitoring (CGM), S39, S40, ADVANCE trial, S42–S44, S61 risk calculator tool, S64 S101 advocacy, S6, S105–S106 as risk factor, S16, S60 Contrave (naltrexone/bupropion), S50 African Americans, S14, S15, S27 risk factors for, S15, S17, S29, S31, S60, coronary artery calcium screening, S67–S68 AIM-HIGH trial, S65–S66 S64, S74 coronary heart disease, S8, S67–S68 albiglutide, S50, S53, S54, S56, S58 smoking and, S29, S89 correctional facilities, S106 albuminuria, S29, S72–S74, S90 care improvement strategies cultural differences, S8 alcohol, S26, S65 adherence, S8 cystic fibrosis, S18 alogliptin, S53–S55, S68 advocacy, S6, S105–S106 cystic fibrosis–related diabetes, S20 amlodipine, S63 Chronic Care Model, S7 amputation, S78 delivery systems, S7 dapagliflozin, S53, S54, S56, S58 amylin mimetics, S53, S56 demographics, S6 dementia, S9, S31–S32, S82 anemia, S14 institutional changes, S7–S8 depression, S10, S30 angiotensin receptor blockers, S61, S62, S68, intermediate outcomes, S8 Diabetes Control and Complications Trial S72–S74, S89, S97 objectives, S7–S8 (DCCT), S42, S44, S52, S87 antidepressants, S49 outcomes, S8 diabetes distress, S30 antihyperglycemic agents, S100–S101 patient-centered, S6 Diabetes Prevention Program (DPP), S36, S37 antihypertensive agents, S63, S97 processes of care, S8 Diabetes Prevention Program Outcomes Study antiplatelet agents, S4–S5, S66–S67, S75 recommendations, S6, S9, S10 (DPPOS), S36 antipsychotics, S49 team building, S7 Diabetes Prevention Recognition Program antiretroviral agents, S10 treatment intensification, S8 (DPRP), S37 Antithrombotic Trialists’ (ATT) metanalysis, S66 child care, school, S86–S87, S105 diabetes self-management education, support antivascular endothelial growth factor, S75, S76 children, adolescents (DSME, DSMS), S7, S8–S9, S24–S25, S36, Asian Americans, S8, S15, S17, S47 A1C levels in, S18, S41 S37, S86, S102 ASPIRE trial, S40 autoimmune diseases in, S87–S88 diabetic ketoacidosis (DKA), S13, S16–S17, S45, aspirin resistance, S67 celiac disease in, S88 S58, S90, S101 aspirin therapy, S4–S5, S66–S67, S75 diabetes management, S87 diabetic kidney disease, S27, S29, S72–S74 atherosclerotic cardiovascular disease. see DSME, DSMS, S7, S8–S9, S24–S25, S36, Diabetic Retinopathy Study, S76 cardiovascular disease S37, S86 diagnosis atorvastatin, S64 dyslipidemia management, S89 A1C (see A1C) autonomic neuropathy, S29, S76–S78 exercise for, S28 anemia, S14 a-glucosidase inhibitors, S37, S55 glycemic control, S87, S89 community screening, S17–S18 hypertension, S88–S89 comorbidities, S31–S32 bariatric surgery, S49–S51, S58 hypoglycemia in, S44, S87 confirmation of, S14 b-blockers, S74 nephropathy, S27, S29, S72–S74, S89–S90 fasting test, S13, S14 INDEX Belviq (lorcaserin), S50 neuropathy, S28–S29, S76–S78, S90 hemoglobinopathies, S14 benazepril, S63 pediatric to adult care transition, S91 monogenic syndromes, S19–S20 bile acid sequestrants, S55 psychosocial issues, S87 one-step strategy, S18–S20 bipolar disorder, S10 retinopathy, S28, S73–S76, S90 plasma glucose criteria, S13 blood glucose control. see glycemic control school, child care, S86–S87, S105 prediabetes, S14–S17, S36 blood pressure control, S60–S63, S81, S88–S89 screening, S87 red blood cell turnover, S14 S110 Index Diabetes Care Volume 39, Supplement 1, January 2016

referrals, S30 intercurrent illness, S45 treatment, S9, S44, S101–S102 2-hour plasma glucose, S13, S14 kidney disease treatment, S73–S74 type 1 diabetes, S44–S45 two-step strategy, S19, S20 neurocognitive function, S82 hypoglycemia unawareness, S44 type 1 diabetes (see type 1 neuropathy treatment, S77 diabetes) older adults, S82, S83 immune-mediated type 1 diabetes, S15 type 2 diabetes (see type 2 omega-3 fatty acids, S27 immunizations, S29–S30 diabetes) physical activity in, S28 IMPROVE-IT trial, S65 diastolic blood pressure, S62 pregnancy, S95 incident diabetes, statin use and, S66 diuretics, S61–S63, S74, S97 recommendations, S39, S43, S44 incretin-based therapies, S53 dopamine-2 agonists, S55 self-monitoring of blood glucose (SMBG), indapamide–perindopril, S62–S63 DPP-4 inhibitors, S53–S55, S58, S68, S101 S39–S40 infections, S79 driving, S105 targets, S43–S44 influenza, S29 dulaglutide, S50, S53, S54, S56, S58 GRADE study, S54 insulin, insulin secretagogues duloxetine, S77 grading system, S1–S2 basal, S40, S54, S57–S58 dyslipidemia, S65, S83, S89 bolus, S58 health care access, S8–S9 carbohydrate counting, S27 Early Treatment Diabetic Retinopathy health disparities, S8 characterization, S56 Study, S76 hearing impairment, S31 in children, adolescents, S90 eating patterns, S26 heart failure, S68 continuous subcutaneous infusion, S58 e-cigarettes, S29 hemoglobinopathies, S14 CVD targeting, S43 empagliflozin, S53, S54, S56, S58, S68 hepatitis B, S30 hospital care, S99, S100 EMPA-REG OUTCOME study, S56, S68 herbal supplements, S26 hypoglycemia unawareness, S44 employment, S105–S106 HITECH Act, S99–S100 inhaled, S58 end-of-life treatment, S82–S85 HIV patients, diabetes care in, S10 neurocognitive function, S82 energy balance, S26 homelessness, S9 older adults, S83 erectile dysfunction, S77–S78 hospital care oral agents, S40, S57–S58 ethnic differences, S8, S14, S17, S41 admission considerations, S100 physical activity, S28 euthyroid sick syndrome, S88 antihyperglycemic therapies, physiology in pregnancy, S95, S96 evaluation, S23, S24, S31 S100–S101 self-monitoring of blood glucose (SMBG), EXAMINE trial, S68 bedside glucose monitoring, S103 S39–S40 exenatide, S50, S53, S54, S56, S58 CGM, S39, S40, S101 type 1 diabetes, S52–S53 exercise, S27–S29, S37, S48 computerized physician order entry, insurance, S9 ezetimibe, S64, S65 S99–S100 islet cell transplantation, S53 critical care setting, S100 fasting test, S13, S14 diabetes self-management, S102 Japanese Americans, S17 fats, S26, S27. see also lipid management diabetic ketoacidosis (DKA), S13, S16–S17, fatty liver disease, S31 S45, S58, S90, S101 Kumamoto Study, S42 fibrate/statin therapy, S65 discharge plan, S102–S103 5-HT2C receptor agonists, S50 enteral/parenteral feeding, S101 fluvastatin, S64 glucocorticoids, S101 laser photocoagulation therapy, S75, S76 food insecurity, S9 glycemic control, S100, S101 LDL cholesterol, S64, S65, S68 foot care, S78–S79 hyperglycemia in, S100 lifestyle modification, S7, S36–S37, S47, S48, foundations of care, S23 hyperosmolar hyperglycemic state, S62–S64, S68 fractures, S31 S101 linagliptin, S53–S55 hypoglycemia, S99–S102 lipase inhibitors, S37, S50 – see also gabapentin, S77 insulin therapy, S99, S100 lipid management, S63 S66. fats fi gastrointestinal neuropathies, S77 medical nutrition therapy, lipid pro les, S65 gastroparesis, S77 S25–S27, S102 liraglutide, S50, S53, S54, S56, S58 genitourinary neuropathies, S77 perioperative care, S101 liraglutide (Saxenda), S50 fi gestational diabetes mellitus, S18–S20, S37, recommendations, S99 literacy de ciencies, S9 S94–S97 target glucose ranges, S99–S101 lixisenatide, S50, S53, S54, S56, S58 glibenclamide, S55 type 1 diabetes, S100 Look AHEAD, S47, S68 gliclazide, S55 HOT trial, S62 lorcaserin (Belviq), S50 glimepiride, S55 hydrochlorothiazide, S63 loss of protective sensation, S78 glipizide, S55 hyperglycemia, S9–S10, S42, S45, S96, lovastatin, S64 glomerular filtration rate estimation, S73 S99–S101 GLP-1 receptor agonists, S50, S53, S54, S56, S58, Hyperglycemia and Adverse Pregnancy macular edema, S75, S76 S83 Outcome (HAPO) study, S18 MAO inhibitors, S49 glucagon, S44 hypertension, S60–S63, S81, S88–S89 maturity-onset diabetes of the young (MODY), glucocorticoids, S101 hypertriglyceridemia, S65 S13, S19–S20 glucose, S44. see also glycemic control hypoglycemia medical evaluation, S31 glyburide, S55, S83, S96 in children, adolescents, S44, S87 medical nutrition therapy, S25–S27, S102. see glycemic control glycemic control, S27, S28, S40 also nutrition A1C (see A1C) hospital care, S99–S102 Medicare, S8, S25 carbohydrate counting, S27 maternal, S95 medications, S10, S17, S49, S103. see also under children, adolescents, S87, S89 nutrition in control of, S27 specific conditions continuous glucose monitoring (CGM), in older adults, S82, S84 Mediterranean diet, S10, S27, S37 S39, S40, S101 physical activity in control of, S28 meglitinides, S54, S55 hospital care, S100, S101 predictors of, S102 mental illness, S10 hyperglycemia, S9–S10, S42, S45, S96, prevention, S9, S27, S28, metformin S99–S101 S101–S102 cardiovascular disease, S67, S68 hypoglycemia (see hypoglycemia) symptoms, S10 children, adolescents, S90 care.diabetesjournals.org Index S111

effectiveness of, S36, S37 pancreatic transplantation, S53 scientific evidence grading, S1–S2 hospital care, S101 Patient-Centered Medical Home, S7 scientific statements, S1 older adults, S83 PCSK9 inhibitors, S65 SEARCH study, S89 in pregnancy, S96 percent of days covered (PDC), S8 self-monitoring of blood glucose (SMBG), therapy generally, S53–S55 perindopril–indapamide, S62–S63 S39–S40 metoclopramide, S77 periodontal disease, S31 sex differences, S8, S66–S67 miglitol, S55 peripheral arterial disease (PAD), S78 SGLT2 inhibitors, S53, S54, S56, S58, S83 mineralocorticoid receptor blockers, S74 peripheral neuropathy, S28–S29, S76–S78 simvastatin, S64 Modification of Diet in Renal Disease (MDRD) phentermine/topiramate combination, S50 sitagliptin, S53–S55, S68 study, S73 photocoagulation therapy, S75 smoking cessation, S29, S89 physical activity, S27–S29, S37, S48 socioeconomic differences, S8 naltrexone/bupropion (Contrave), S50 pioglitazone, S37, S54, S55 sodium, S26, S27 nateglinide, S54, S55 pitavastatin, S64 spironolactone, S74 neonatal diabetes, S19 plasma glucose criteria, S13 SPRINT trial, S61–S62 nephrologist, referrals to, S74 pneumococcal pneumonia, S29–S30 SSRIs, S49 nephropathy, S27, S29, S72–S74, S89–S90 pneumococcal polysaccharide vaccine 23 (PPSV23), Standards of Care, S1 neuropathy, S28–S29, S76–S78, S90 S29–S30 statins NHANES, S7, S14, S31 POC meters, S103 in CHD management, S68 niacin/statin therapy, S65–S66 position statements, S1 children, adolescents, S89 NICE-SUGAR study, S100 pramlintide, S53, S56 cognitive function and, S66 nonketotic hyperosmolar state, S45 pravastatin, S64 dementia and, S10 nucleoside reverse transcriptase inhibitors (NRTIs), S10 prediabetes, S14–S17, S36 in lipid management, S64–S66 numeracy deficiencies, S9 pregabalin, S77 type 1 diabetes, S64–S65 nutrition pregestational diabetes, S94–S96 type 2 diabetes, S63–S66 alcohol, S26, S65 pregnancy sulfonylureas, S54, S55, S58, S83, S96, S101 carbohydrates, S27, S37 A1C levels, S95 sympathomimetic amine anorectic/antiepileptic cognitive dysfunction and, S10 antihypertensive medications in, combination, S50 in diabetes prevention, S37 S63, S97 systolic blood pressure, S62 eating patterns, S26 blood pressure targets, S61 energy balance, S26 contraception, S97 tapentadol, S77 fats, S26, S27 gestational diabetes mellitus, TECOS trial, S68 – – herbal supplements, S26 S18 S20, S37, S94 S97 testosterone levels, S31 kidney disease treatment, S73 glucose monitoring, S95 thiazolidinediones, S37, S54, S55, S67, S83 macronutrient distribution, S26 glycemic control, S95 thyroid disease, S88 micronutrients, S26 hyperglycemia, S96 tobacco, S29, S89 older adults, S84 insulin physiology, S95, S96 TODAY study, S90 – protein, S26, S27 lactation, S96 S97 tramadol, S77 sodium, S26, S27 pharmacological therapy, S96, S97 Translating Research Into Action for Diabetes – postpartum care, S96 S97 (TRIAD) study, S8 preconception counseling, testing, S95 obesity treatment. see also specific therapies pregestational diabetes, S94–S96 assessment, S47 adherence, S8 recommendations, S94 bariatric surgery, S49–S51, S58 DSME, DSMS, S7, S8–S9, S24–S25 retinopathy, S75–S76 concomitant medications, S49 exercise, S27–S29, S37, S48 type 1 diabetes, S96–S97 diet, S48 (see also nutrition) foundations of care, S23 type 2 diabetes, S96–S97 lifestyle modification, S7, S36–S37, S47, glucose, S44 Professional Practice Committee, S3, S107–S108 S48, S62–S64, S68 hypoglycemia, S44 proliferative diabetic retinopathy, S75, S76 pharmacotherapy, S48–S50 immunizations, S29–S30 protease inhibitors, S10 physical activity, S27–S29, S37, S48 initial care basis, S23–S24 protein, S26, S27 recommendations, S48 intensification, S8 psychosocial issues, S30, S87 treatment, S47, S48 lifestyle modification, S7, S36–S37, S47, P2Y12 receptor antagonists, S67 weight management, S25–S27, S68 S48, S62–S64, S68 obstructive sleep apnea, S31 medical nutrition therapy, S25–S27, S102 olanzapine, S49 red blood cell turnover test, S14 ongoing care, S24 older adults referrals, S24, S30, S74, S75 patient engagement, S23 end-of-life treatment, S82–S85 reimbursement, DSME/DSMS, S25 pharmacological, S36, S37 geriatric syndromes screening, S81 renal function assessment, S72–S73 psychosocial issues, S30 hypertension, S81 repaglinide, S54, S55 referrals, S24 hypoglycemia, S82, S84 resistance training, S27 smoking cessation, S29, S89 long-term care facilities, S81, S84 retinal photography, S75 tailoring, S8–S9 neurocognitive function, S82 retinopathy, S28, S73–S76, S90 technology in, S37 nutrition, S84 revisions summary, S4–S5 type 1 diabetes, S52–S53 overview, S81–S82 Reye syndrome, S67 type 2 diabetes, S53–S58 palliative care, S60–S63, S81 risperidone, S49 weight management, S25–S27, S68 pharmacological therapy, S83–S84 rosiglitazone, S37, S54, S55 tricyclic antidepressants, S49, S77 recommendations, S81 rosuvastatin, S64 2-hour plasma glucose, S13, S14 treatment, S82–S83 type 1 diabetes omega-3 fatty acids, S27 SAVOR-TIMI 53 trial, S68 A1C microvascular complications, S42 ophthalmologist, referrals to, S75 saxagliptin, S53–S55, S68 carbohydrate counting, S27 opioid antagonist/aminoketone antidepressant Saxenda (liraglutide), S50 in children, adolescents, S86–S90 combination, S50 schizoaffective disorder, S10 classification, S13 orlistat, S37, S50 schizophrenia, S10 CVD outcomes and, S42 orthostatic hypotension, S77 school, child care, S86–S87, S105 demographics, S6 S112 Index Diabetes Care Volume 39, Supplement 1, January 2016

diagnosis, S15–S16 BMI, ethnicity factors, S17 pharmacological therapy, S53–S58 differential diagnosis, S18 carbohydrate counting, S27 pregnancy, S96–S97 epidemiology, S8 children, adolescents, S18, S19 prevention, delay, S36–S37 glycemic control, S39 in children, adolescents, S90–S91 resistance training, S27 hospital care, S100 classiﬁcation, S13 retinopathy, S75 hypoglycemia, S9, S44–S45 combination therapy, S53–S57 risk factors, S17 idiopathic, S15–S16 CVD outcomes and, S42–S43 statin therapy, S63–S66 immune-mediated, S15 demographics, S6, S8 pharmacological therapy, S52–S53 diagnosis, S16–S19 UK Prospective Diabetes Study (UKPDS), S42, – physical activity, S27 S29 differential diagnosis, S18, S19 S67, S74 pregnancy, S96–S97 exercise, S27–S29 retinopathy, S75 glycemic control, S40 risk factors, S16 hyperglycemia in, S9–S10 venlafaxine, S77 statin therapy, S64–S65 hypoglycemia, S9 Veterans Affairs Diabetes Trial (VADT), S42–S43 type 2 diabetes hypoglycemia in, S10 vildagliptin, S53–S55 A1C microvascular complications, S42 mental illness in, S10 bariatric surgery, S49–S51, S58 obesity in, S48 weight management, S25–S27, S68