Standards of Medical Care in Diabetes—2017

THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION VOLUME 40 | SUPPLEMENT 1

WWW.DIABETES.ORG/DIABETESCARE JANUARY 2017

PLE M E P N U T S 1 AMERICAN DIABETES ASSOCIATION STANDARDS OF MEDICAL CARE IN DIABETES—2017

ISSN 0149-5992 American Diabetes Association Standards of Medical Care in Diabetesd2017

January 2017 Volume 40, 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 Maureen Monaghan, PhD, CDE Lawrence Blonde, MD, FACP Vanita R. Aroda, MD Kristen J. Nadeau, MD, MS Andrew J.M. Boulton, MD Geremia Bolli, MD Kwame Osei, MD David D’Alessio, MD John B. Buse, MD, PhD Kevin A. Peterson, MD, MPH, FRCS(Ed), Mary de Groot, PhD Robert J. Chilton, DO, FACC, FAHA FAAFP Eddie L. Greene, MD Kenneth Cusi, MD, FACP, FACE Jonathan Q. Purnell, MD Frank B. Hu, MD, MPH, PhD Paresh Dandona, MD, PhD Peter Reaven, MD Steven E. Kahn, MB, ChB J. Hans DeVries, MD, PhD Ravi Retnakaran, MD, MSc, FRCPC Derek LeRoith, MD, PhD Ele Ferrannini, MD Helena Wachslicht Rodbard, MD Robert G. Moses, MD Franco Folli, MD, PhD Elizabeth Seaquist, MD Stephen Rich, PhD Meredith A. Hawkins, MD, MS Guntram Schernthaner, MD Matthew C. Riddle, MD Richard Hellman, MD David J. Schneider, MD Julio Rosenstock, MD Norbett Hermanns, PhD, MSc Norbert Stefan, MD William V. Tamborlane, MD George S. Jeha, MD Jan S. Ulbrecht, MB, BS Katie Weinger, EdD, RN Irl B. Hirsch, MD, MACP Joseph Wolfsdorf, MD, BCh Judith Wylie-Rosett, EdD, RD Lee M. Kaplan, MD, PhD Tien Yin Wong, MBBS, FRCSE, FRANZCO, M. Sue Kirkman, MD MPH, PhD Ildiko Lingvay, MD, MPH, MSCS Bernard Zinman, CM, MD, FRCPC, FACP Harold David McIntyre, MD, FRACP

AMERICAN DIABETES ASSOCIATION OFFICERS CHAIR OF THE BOARD David A. DeMarco, PhD PRESIDENT, MEDICINE & SCIENCE Alvin C. Powers, MD PRESIDENT, HEALTH CARE & EDUCATION Brenda Montgomery, RN, MSHS, CDE SECRETARY/TREASURER Umesh Verma CHIEF EXECUTIVE OFFICER Kevin L. Hagan

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 © 2017 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 more information about submitting manuscripts, publication charges, ordering reprints, PRINT ISSN 0149-5992 subscribing to the journal, becoming an ADA member, advertising, permission to reuse ’ ONLINE ISSN 1935-5548 content, and the journal s publication policies. PRINTED IN THE USA Periodicals postage paid at Alexandria, VA, and additional mailing ofﬁces.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS

VICE PRESIDENT, PUBLISHER EDITORIAL CONTENT MANAGER ADVERTISING SALES Michael Eisenstein Nancy C. Baldino

ASSOCIATE PUBLISHER, PHARMACEUTICAL/DEVICE DIGITAL ADVERTISING SCHOLARLY JOURNALS TECHNICAL EDITORS e-Healthcare Solutions Christian S. Kohler Oedipa Rice John Burke Theresa Cooper Chief Revenue Ofﬁcer EDITORIAL OFFICE DIRECTOR [email protected] Lyn Reynolds ASSOCIATE DIRECTOR, BILLING & COLLECTIONS (609) 882-8887, ext. 149 PEER REVIEW MANAGER Laurie Ann Hall Shannon Potts PHARMACEUTICAL/DEVICE PRINT ADVERTISING DIRECTOR, MEMBERSHIP/SUBSCRIPTION The Jackson-Gaeta Group, Inc. EDITORIAL ASSISTANT SERVICES B. Joseph Jackson Joan Garrett Donald Crowl [email protected] DIRECTOR, SCHOLARLY JOURNALS Paul Nalbandian SENIOR ADVERTISING MANAGER Heather Norton Blackburn [email protected] Julie DeVoss Graff Tina Auletta CONTENT PRODUCTION MANAGER [email protected] [email protected] Kelly Newton (703) 299-5511 (973) 403-7677 January 2017 Volume 40, Supplement 1

Standards of Medical Care in Diabetes—2017

S1 Introduction S75 9. Cardiovascular Disease and Risk S3 Professional Practice Committee Management S4 Standards of Medical Care in Diabetes—2017: Hypertension/Blood Pressure Control Summary of Revisions Lipid Management S6 1. Promoting Health and Reducing Disparities in Antiplatelet Agents Populations Coronary Heart Disease Diabetes and Population Health S88 10. Microvascular Complications and Tailoring Treatment to Reduce Disparities Foot Care S11 2. Classiﬁcation and Diagnosis of Diabetes Diabetic Kidney Disease Diabetic Retinopathy Classiﬁcation Neuropathy Diagnostic Tests for Diabetes Foot Care Categories of Increased Risk for Diabetes (Prediabetes) Type 1 Diabetes S99 11. Older Adults Type 2 Diabetes Gestational Diabetes Mellitus Neurocognitive Function Monogenic Diabetes Syndromes Hypoglycemia Cystic Fibrosis–Related Diabetes Treatment Goals Posttransplantation Diabetes Mellitus Pharmacologic Therapy Treatment in Skilled Nursing Facilities S25 3. Comprehensive Medical Evaluation and and Nursing Homes Assessment of Comorbidities End-of-Life Care

Patient-Centered Collaborative Care S105 12. Children and Adolescents Comprehensive Medical Evaluation Assessment of Comorbidities Type 1 Diabetes Type 2 Diabetes S33 4. Lifestyle Management Transition From Pediatric to Adult Care Diabetes Self-management Education and Support Nutrition Therapy S114 13. Management of Diabetes in Pregnancy Physical Activity Diabetes in Pregnancy Smoking Cessation: Tobacco and e-Cigarettes Preconception Counseling Psychosocial Issues Glycemic Targets in Pregnancy Management of Gestational Diabetes Mellitus S44 5. Prevention or Delay of Type 2 Diabetes Management of Preexisting Type 1 Diabetes Lifestyle Interventions and Type 2 Diabetes in Pregnancy Pharmacologic Interventions Postpartum Care Prevention of Cardiovascular Disease Pregnancy and Drug Considerations Diabetes Self-management Education and Support S120 14. Diabetes Care in the Hospital S48 6. Glycemic Targets Hospital Care Delivery Standards Assessment of Glycemic Control Glycemic Targets in Hospitalized Patients A1C Testing Bedside Blood Glucose Monitoring A1C Goals Antihyperglycemic Agents in Hospitalized Hypoglycemia Patients Intercurrent Illness Hypoglycemia S57 7. Obesity Management for the Treatment of Type 2 Medical Nutrition Therapy in the Hospital Diabetes Self-management in the Hospital Standards for Special Situations Assessment Transition From the Acute Care Setting Diet, Physical Activity, and Behavioral Therapy Preventing Admissions and Readmissions Pharmacotherapy Metabolic Surgery S128 15. Diabetes Advocacy S64 8. Pharmacologic Approaches to Glycemic Advocacy Position Statements Treatment S130 Professional Practice Committee Disclosures Pharmacologic Therapy for Type 1 Diabetes Pharmacologic Therapy for Type 2 Diabetes S132 Index

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Diabetes Care Volume 40, Supplement 1, January 2017 S1 INTRODUCTION

Introduction Diabetes Care 2017;40(Suppl. 1):S1–S2 | DOI: 10.2337/dc17-S001

Diabetes is a complex, chronic illness re- ADA’s clinical practice recommendations Consensus Report quiring continuous medical care with are viewed as important resources for A consensus report contains a compre- multifactorial risk-reduction strategies health care professionals who care for hensive examination by an expert panel beyond glycemic control. Ongoing patient people with diabetes. ADA’s Standards (i.e., consensus panel) of a scientificor self-management education and support of Care, position statements, and scien- medical issue related to diabetes. A con- are critical to preventing acute complica- tific statements undergo a formal review sensus report is not an ADA position and tions and reducing the risk of long-term process by ADA’s Professional Prac- represents expert opinion only. The cat- complications. Significant evidence exists tice Committee (PPC) and the Board of egory may also include task force and that supports a range of interventions to Directors. Readers who wish to comment expert committee reports. The need improve diabetes outcomes. on the 2017 Standards of Care are invited for a consensus report arises when clini- The American Diabetes Association’s to do so at http://professional.diabetes cians or scientists desire guidance on a (ADA’s) “Standards of Medical Care in Di- .org/SOC. subject for which the evidence is contra- abetes,” referred to as the “Standards of dictory or incomplete. A consensus re- Care,” is intended to provide clinicians, pa- Standards of Care port is developed following a consensus tients, researchers, payers, and other in- Standards of Care: ADA position state- conference where the controversial issue terested individuals with the components ment that provides key clinical practice is extensively discussed. The report of diabetes care, general treatment goals, recommendations. The PPC performs an represents the panel’s collective anal- and tools to evaluate the quality of care. extensive literature search and updates ysis, evaluation, and opinion at that The Standards of Care recommendations the Standards of Care annually based point in time based in part on the con- are not intended to preclude clinical judg- on the quality of new evidence. ference proceedings. A consensus re- ment and must be applied in the context port does not undergo a formal ADA ADA Position Statement review process. of excellent clinical care, with adjustments A position statement is an official ADA for individual preferences, comorbidities, point of view or belief that contains clin- GRADING OF SCIENTIFIC EVIDENCE and other patient factors. For more de- ical or research recommendations. Posi- fi tailed information about management of tion statements are issued on scientific Since the ADA rst began publishing diabetes, please refer to Medical Manage- or medical issues related to diabetes. practice guidelines, there has been con- ment of Type 1 Diabetes (1) and Medical They are published in the ADA journals siderable evolution in the evaluation of fi Management of Type 2 Diabetes (2). and other scientific/medical publica- scienti c evidence and in the develop- The recommendations include screen- tions. ADA position statements are typ- ment of evidence-based guidelines. In fi ing, diagnostic, and therapeutic actions ically based on a systematic review or 2002, the ADA developed a classi cation fi that are known or believed to favorably other review of published literature. system to grade the quality of scienti c affect health outcomes of patients with di- Position statements undergo a formal evidence supporting ADA recommenda- abetes. Many of these interventions have review process. They are updated every tions for all new and revised ADA posi- also been shown to be cost-effective (3). 5 years or as needed. tion statements. A recent analysis of the The ADA strives to improve and up- evidence cited in the Standards of Care date the Standards of Care to ensure ADA Scientific Statement found steady improvement in quality that clinicians, health plans, and policy- Ascientific statement is an official ADA over the past 10 years, with the 2014 makers can continue to rely on them as point of view or belief that may or may Standards of Care for the first time the most authoritative and current not contain clinical or research recom- having the majority of bulleted recom- guidelines for diabetes care. mendations. Scientific statements con- mendations supported by A-orB-level tain scholarly synopsis of a topic related evidence (4). A grading system (Table ADA STANDARDS, STATEMENTS, to diabetes. Workgroup reports fall into 1) developed by the ADA and modeled AND REPORTS this category. Scientific statements are after existing methods was used to clar- The ADA has been actively involved in published in the ADA journals and other ify and codify the evidence that forms the development and dissemination of scientific/medical publications, as ap- the basis for the recommendations. ADA diabetes care standards, guidelines, and propriate. Scientificstatementsalso recommendations are assigned ratings related documents for over 25 years. undergo a formal review process. of A, B,orC, depending on the quality

“Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: December 2015. © 2017 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. More information is available at http://www.diabetesjournals.org/content/license. S2 Introduction Diabetes Care Volume 40, Supplement 1, January 2017

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” clinical decision making. Clinicians care Level of for patients, not populations; guidelines evidence Description must always be interpreted with the individual patient in mind. Individual A Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered, including circumstances, such as comorbid and c Evidence from a well-conducted multicenter trial coexisting diseases, age, education, dis- c Evidence from a meta-analysis that incorporated quality ratings in the ability, and, above all, patients’ values analysis and preferences, must be considered Compelling nonexperimental evidence, i.e., “all or none” rule developed by the and may lead to different treatment tar- Centre for Evidence-Based Medicine at the University of Oxford gets and strategies. Furthermore, con- Supportive evidence from well-conducted randomized controlled trials that are ventional evidence hierarchies, such as adequately powered, including c Evidence from a well-conducted trial at one or more institutions the one adapted by the ADA, may miss c Evidence from a meta-analysis that incorporated quality ratings in the nuances important in diabetes care. For analysis example, although there is excellent ev- B Supportive evidence from well-conducted cohort studies idence from clinical trials supporting c Evidence from a well-conducted prospective cohort study or registry the importance of achieving multiple c Evidence from a well-conducted meta-analysis of cohort studies risk factor control, the optimal way to Supportive evidence from a well-conducted case-control study achievethisresultislessclear.Itisdif- C Supportive evidence from poorly controlled or uncontrolled studies ficult to assess each component of c Evidence from randomized clinical trials with one or more major or three or such a complex intervention. more minor methodological flaws that could invalidate the results c Evidence from observational studies with high potential for bias (such as References case series with comparison with historical controls) c Evidence from case series or case reports 1. American Diabetes Association. Medical Management of Type 1 Diabetes.6thed. Conflicting evidence with the weight of evidence supporting the Kaufman FR, Ed. Alexandria, VA, American Di- recommendation abetes Association, 2012 E Expert consensus or clinical experience 2. American Diabetes Association. Medical Management of Type 2 Diabetes.7thed. Burant CF, Young LA, Eds. Alexandria, VA, Amer- of evidence. Expert opinion E is a sepa- Generally, these recommendations ican Diabetes Association, 2012 3. Li R, Zhang P, Barker LE, Chowdhury FM, rate category for recommendations in have the best chance of improving out- Zhang X. Cost-effectiveness of interventions to which there is no evidence from clinical comes when applied to the population prevent and control diabetes mellitus: a sys- trials, in which clinical trials may be im- to which they are appropriate. Recom- tematic review. Diabetes Care 2010;33:1872– practical, or in which there is conflicting mendations with lower levels of evi- 1894 4. Grant RW, Kirkman MS. Trends in the evi- evidence. Recommendations with an A dence may be equally important but dence level for the American Diabetes Associa- rating are based on large well-designed are not as well supported. Of course, tion’s “Standards of Medical Care in Diabetes” clinical trials or well-done meta-analyses. evidence is only one component of from 2005 to 2014. Diabetes Care 2015;38:6–8 RFSINLPATC COMMITTEE PRACTICE PROFESSIONAL Diabetes Care Volume 40, Supplement 1, January 2017 S3

Professional Practice Committee Diabetes Care 2017;40(Suppl. 1):S3 | DOI: 10.2337/dc17-S002

The Professional Practice Committee human studies related to each section Matt Petersen; Sean Petrie; Louis H. (PPC) of the American Diabetes Asso- and published since 1 January 2016. Rec- Philipson, MD, PhD; Margaret A. ciation (ADA) is responsible for the ommendations were revised based on Powers, PhD, RD, CDE; Desmond “Standards of Medical Care in Diabetes” new evidence or, in some cases, to clar- Schatz, MD; Philip R. Schauer, MD; position statement, referred to as the ify the prior recommendation or match Sonali N. Thosani, MD; and Guillermo “Standards of Care.” The PPC is a multi- the strength of the wording to the strength E. Umpierrez, MD. disciplinary expert committee com- of the evidence. A table linking the changes prised of physicians, diabetes educators, in recommendations to new evidence Members of the PPC registered dietitians, and others who can be reviewed at http://professional have expertise in a range of areas, in- .diabetes.org/SOC. As for all position William H. Herman, MD, MPH (Co-Chair) cluding adult and pediatric endocrinol- statements, the Standards of Care posi- RitaR.Kalyani,MD,MHS,FACP(Co-Chair)* ogy, epidemiology, public health, lipid tion statement was approved by the Andrea L. Cherrington, MD, MPH research, hypertension, preconception Executive Committee of ADA’sBoard Donald R. Coustan, MD planning, and pregnancy care. Appoint- of Directors, which includes health ment to the PPC is based on excellence care professionals, scientists, and lay Ian de Boer, MD, MS in clinical practice and research. Although people. Robert James Dudl, MD the primary role of the PPC is to review Feedback from the larger clinical Hope Feldman, CRNP, FNP-BC and update the Standards of Care, it is community was valuable for the 2017 re- also responsible for overseeing the review vision of the Standards of Care. Readers Hermes J. Florez, MD, PhD, MPH* and revision of ADA’s position statements who wish to comment on the 2017 Suneil Koliwad, MD, PhD* fi and scienti c statements. Standards of Care are invited to do so at Melinda Maryniuk, MEd, RD, CDE The ADA adheres to the Institute of http://professional.diabetes.org/SOC. Medicine Standards for Developing Trust- The ADA funds development of the Joshua J. Neumiller, PharmD, CDE, FASCP* worthy Clinical Practice Guidelines. All Standards of Care and all ADA position Joseph Wolfsdorf, MB, BCh members of the PPC are required to dis- statements out of its general revenues *Subgroup leaders close potential conflicts of interest with and does not use industry support for industry and/or other relevant organiza- these purposes. The PPC would like ADA Staff tions. These disclosures are discussed to thank the following individuals at the onset of each Standards of Care re- whoprovidedtheirexpertiseinre- Erika Gebel Berg, PhD vision meeting. Members of the commit- viewing and/or consulting with the (Corresponding author: tee, their employer, and their disclosed committee: Conor J. Best, MD; William [email protected]) conflicts of interest are listed in the T. Cefalu, MD; Mary de Groot, PhD; Sheri Colberg-Ochs, PhD “ Professional Practice Committee Disclo- Gary D. Hack, DDS; Silvio E. Inzucchi, Alicia H. McAuliffe-Fogarty, PhD, CPsychol sures” table (see p. S130). MD; Meghan Jardine, MS, MBA, RD, For the current revision, PPC members LD, CDE; Victor R. Lavis, MD; Mark E. Sacha Uelmen, RDN, CDE systematically searched MEDLINE for Molitch, MD; Antoinette Moran, MD; Robert E. Ratner, MD, FACP, FACE

© 2017 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. More information is available at http://www.diabetesjournals.org/content/license. S4 Diabetes Care Volume 40, Supplement 1, January 2017

Standards of Medical Care in Diabetesd2017: SUMMARY OF REVISIONS Summary of Revisions Diabetes Care 2017;40(Suppl. 1):S4–S5 | DOI: 10.2337/dc17-S003

GENERAL CHANGES approaches were described, and Fig. 2.1 medical evaluation based on emerging ev- In light of the American Diabetes Associa- was included to provide an example of a idence suggesting a relationship between tion’s(ADA’s) new position statement on validated tool to screen for prediabetes and sleep quality and glycemic control. psychosocial care in the treatment of di- previously undiagnosed type 2 diabetes. An expanded list of diabetes comorbid- abetes, the “Standards of Medical Care in Due to recent data, delivering a baby ities now includes autoimmune diseases, Diabetes,” referred to as the “Standards of weighing 9 lb or more is no longer listed HIV, anxiety disorders, depression, disor- Care,” has been updated to address psy- as an independent risk factor for the dered eating behavior, and serious mental chosocial issues in all aspects of care in- development of prediabetes and type 2 illness. diabetes. cluding self-management, mental health, Section 4. Lifestyle Management communication, complications, comorbid- A section was added that discusses This section, previously entitled “Foun- ities, and life-stage considerations. recent evidence on screening for diabe- dations of Care and Comprehensive Although levels of evidence for several tes in dental practices. Medical Evaluation,” was refocused on recommendations have been updated, The recommendation to test women lifestyle management. these changes are not addressed below with gestational diabetes mellitus for The recommendation for nutrition as the clinical recommendations have re- persistent diabetes was changed from therapy in people prescribed flexible in- – ’ – ’ mained the same. Changes in evidence 6 12 weeks postpartum to 4 12 weeks sulin therapy was updated to include fat level from, for example, E to C are not postpartum to allow the test to be sched- and protein counting in addition to car- noted below. The 2017 Standards of uled just before the standard 6-week post- bohydrate counting for some patients to Care contains, in addition to many minor partum obstetrical checkup so that the reflect evidence that these dietary fac- changes that clarify recommendations or results can be discussed with the patient tors influence insulin dosing and blood reflect new evidence, the following more at that time of the visit or to allow the test glucose levels. substantive revisions. to be rescheduled at the visit if the patient Based on new evidence of glycemic did not get the test. benefits, the Standards of Care now SECTION CHANGES Additional detail was added to the recommends that prolonged sitting be Section 1. Promoting Health and section on monogenic diabetes syn- interrupted every 30 min with short Reducing Disparities in Populations dromes, and a new table was added (Ta- bouts of physical activity. Thissectionwasrenamedandnowfo- ble 2.7) describing the most common A recommendation was added to cuses on improving outcomes and re- forms of monogenic diabetes. highlight the importance of balance ducing disparities in populations with Anewsectionwasaddedonpost- and flexibility training in older adults. diabetes. transplantation diabetes mellitus. A new section and table provide infor- Recommendations were added to as- mation on situations that might warrant Section 3. Comprehensive Medical sess patients’ social context as well as referral to a mental health provider. refer to local community resources and Evaluation and Assessment of provide self-management support. Comorbidities Section 5. Prevention or Delay of This new section, including components Type 2 Diabetes Section 2. Classification and Diagnosis of the 2016 section “Foundations of To help providers identify those patients of Diabetes Care and Comprehensive Medical Eval- who would benefit from prevention ef- The section was updated to include a uation,” highlights the importance of forts, new text was added emphasizing new consensus on the staging of type 1 assessing comorbidities in the context the importance of screening for prediabe- diabetes (Table 2.1) and a discussion of a of a patient-centered comprehensive tes using an assessment tool or informal proposed unifying diabetes classification medical evaluation. assessment of risk factors and performing scheme that focuses on b-cell dysfunc- A new discussion of the goals of provider- a diagnostic test when appropriate. tion and disease stage as indicated by patient communication is included. To reflect new evidence showing an glucose status. The Standards of Care now recom- association between B12 deficiency and Language was added to clarify screen- mends the assessment of sleep pattern long-term metformin use, a recommen- ing and testing for diabetes. Screening and duration as part of the comprehensive dation was added to consider periodic

measurement of B12 levels and supple- The algorithm for the use of combina- footwear for patients at high risk for mentation as needed. tion injectable therapy in patients with foot problems. type 2 diabetes (Fig. 8.2) has been changed Section 6. Glycemic Targets to reflect studies demonstrating the non- Section 12. Children and Adolescents Based on recommendations from the In- inferiority of basal insulin plus glucagon- Additional recommendations highlight ternational Hypoglycaemia Study Group, the importance of assessment and re- fi like peptide 1 receptor agonist versus basal serious, clinically signi cant hypoglycemia ferral for psychosocial issues in youth. is now defined as glucose ,54 mg/dL insulin plus rapid-acting insulin versus two daily injections of premixed insulin, as well Due to the risk of malformations asso- (3.0 mmol/L), while the glucose alert value ciated with unplanned pregnancies and fi # as studies demonstrating the noninferior- is de ned as 70 mg/dL (3.9 mmol/L) (Ta- poor metabolic control, a new recom- ble 6.3). Clinical implications are discussed. ity of multiple dose premixed insulin regimens versus basal-bolus therapy. mendation was added encouraging pre- Section 7. Obesity Management for Due to concerns about the affordability conception counseling starting at puberty the Treatment of Type 2 Diabetes of antihyperglycemic agents, new tables for all girls of childbearing potential. To be consistent with other ADA position were added showing the median costs of To address diagnostic challenges asso- statements and to reinforce the role of noninsulin agents (Table 8.2) and insulins ciated with the current obesity epidemic, a discussion was added about distinguish- surgery in the treatment of type 2 diabe- (Table 8.3). tes, bariatric surgery is now referred to as ing between type 1 and type 2 diabetes in youth. metabolic surgery. Section 9. Cardiovascular Disease and fl A section was added describing recent To re ect the results of an international Risk Management workgroup report endorsed by the ADA To better align with existing data, the hy- nonrandomized studies of metabolic sur- and many other organizations, recommen- pertension treatment recommendation gery for the treatment of obese adoles- dations regarding metabolic surgery for diabetes now suggests that, for pa- cents with type 2 diabetes. have been substantially changed, in- tients without albuminuria, any of the Section 13. Management of Diabetes cluding those related to BMI thresholds four classes of blood pressure medications for surgical candidacy (Table 7.1), men- in Pregnancy (ACE inhibitors, angiotensin receptor Insulin was emphasized as the treatment tal health assessment, and appropriate blockers, thiazide-like diuretics, or dihy- surgical venues. of choice in pregnancy based on concerns dropyridine calcium channel blockers) about the concentration of metformin on fi Section 8. Pharmacologic Approaches that have shown bene cial cardiovascular the fetal side of the placenta and glyburide to Glycemic Treatment outcomes may be used. levels in cord blood. The title of this section was changed from To optimize maternal health without Based on available data, preprandial “Approaches to Glycemic Treatment” to risking fetal harm, the recommendation self-monitoring of blood glucose was “Pharmacologic Approaches to Glycemic for the treatment of pregnant patients deemphasized in the management of Treatment” to reinforce that the section with diabetes and chronic hypertension diabetes in pregnancy. focuses on pharmacologic therapy alone. was changed to suggest a blood pressure In the interest of simplicity, fasting and Lifestyle management and obesity manage- target of 120–160/80–105 mmHg. postprandial targets for pregnant women ment are discussed in separate chapters. A section was added describing the cardio- with gestational diabetes mellitus and To reflect new evidence showing an as- vascular outcome trials that demonstrated preexisting diabetes were unified. sociation between B12 deficiency and long- benefits of empagliflozin and liraglutide in term metformin use, a recommendation certain high-risk patients with diabetes. Section 14. Diabetes Care in the was added to consider periodic measure- Hospital ment of B12 levels and supplementation Section 10. Microvascular This section was reorganized for clarity. as needed. Complications and Foot Care A treatment recommendation was up- A section was added describing the A recommendation was added to high- dated to clarify that either basal insulin or role of newly available biosimilar insu- light the importance of provider commu- basal plus bolus correctional insulin lins in diabetes care. nication regarding the increased risk of may be used in the treatment of non- Based on the results of two large clin- retinopathy in women with preexisting critically ill patients with diabetes in a ical trials, a recommendation was added type 1 or type 2 diabetes who are plan- hospital setting, but not sliding scale to consider empagliflozin or liraglutide in ning pregnancy or who are pregnant. alone. patients with established cardiovascular The section now includes specificrec- The recommendations for insulin dos- disease to reduce the risk of mortality. ommendations for the treatment of ing for enteral/parenteral feedings were Figure 8.1, antihyperglycemic ther- neuropathic pain. expanded to provide greater detail on in- apy in type 2 diabetes, was updated to A new recommendation highlights sulin type, timing, dosage, correctional, and acknowledge the high cost of insulin. the benefits of specialized therapeutic nutritional considerations. S6 Diabetes Care Volume 40, Supplement 1, January 2017

1. Promoting Health and Reducing American Diabetes Association Disparities in Populations Diabetes Care 2017;40(Suppl. 1):S6–S10 | DOI: 10.2337/dc17-S004

Recommendations c Treatment decisions should be timely, rely on evidence-based guidelines, and be made collaboratively with patients based on individual preferences, prog- noses, and comorbidities. B c Providers should consider the burden of treatment and self-efﬁcacy of patients when recommending treatments. E c Treatment plans should align with the Chronic Care Model, emphasizing 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 AND POPULATION HEALTH Clinical practice guidelines are key to improving population health; however, for optimal outcomes, diabetes care must be individualized for each patient. Thus, efforts to improve population health will require a combination of system-level and patient-level approaches. With such an integrated approach in mind, the American Diabetes Asso- ciation (ADA) highlights the importance of patient-centered care,deﬁned as care that is respectful of and responsive to individual patient preferences, needs, and values and 1. PROMOTING HEALTH AND REDUCING DISPARITIES ensuring that patient values guide all clinical decisions (1). 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 faced with making treatment recommendations for a patient who may not meet the eligibility criteria used in the studies on which guidelines are based. Recognizing that one size does not ﬁt all, the standards presented here provide guidance for when and how to adapt recommendations for an individual.

Care Delivery Systems Over the last 10 years, there has been steady improvement in the proportion of patients with diabetes who are treated with statins and who achieve recommended hemoglobin A1C (A1C), blood pressure, and LDL cholesterol levels (2). The mean A1C nationally among people with diabetes has declined from 7.6% (60 mmol/mol) in 1999–2002 to 7.2% (55 mmol/mol) in 2007–2010 based on the National Health and Nutrition Exam- ination Survey (NHANES), with younger adults less likely to meet treatment targets than older adults (2). This has been accompanied by improvements in cardiovascular outcomes and has led to substantial reductions in end-stage microvascular complications. Nevertheless, 33–49% of patients still do not meet targets for glycemic, blood pressure, or cholesterol control, and only 14% meet targets for all three measures while also avoiding smoking (2). Evidence suggests that progress in cardiovascular risk factor control (particularly tobacco use) may be slowing (2,3). Certain segments Suggested citation: American Diabetes Associa- of the population, such as young adults and patients with complex comorbidities, tion. Promoting health and reducing disparities financial or other social hardships, and/or limited English proficiency, face particular in populations. Sec. 1. In Standards of Medical d challenges to goal-based care (4–6). Even after adjusting for these patient factors, Care in Diabetes 2017. Diabetes Care 2017; 40(Suppl. 1):S6–S10 the persistent variability in the quality of diabetes care across providers and practice settings indicates that substantial system-level improvements are still needed. © 2017 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 Chronic Care Model profit, and the work is not altered. More informa- Numerous interventions to improve adherence to the recommended standards tion is available at http://www.diabetesjournals have been implemented. However, a major barrier to optimal care is a delivery .org/content/license. care.diabetesjournals.org Promoting Health and Reducing Disparities in Populations S7

system that is often fragmented, lacks and/or pharmacological therapy for pa- satisfaction, and glucose outcomes. clinical information capabilities, dupli- tients who have not achieved the rec- National DSME standards call for an in- cates services, and is poorly designed ommended metabolic targets (12–14). tegrated approach that includes clinical for the coordinated delivery of chronic To inform this process, providers should content and skills, behavioral strategies care. The Chronic Care Model (CCM) routinely assess medication adherence. (goal setting, problem solving), and en- takes these factors into consideration, At a system level, “adequate” adher- gagement with psychosocial concerns andisaneffectiveframeworkforim- ence is defined as 80% (calculated as (26). proving the quality of diabetes care (7). the number of pills taken by the patient In devising approaches to support dis- Six Core Elements. The CCM includes six in a given time period divided by the ease self-management, it is notable that core elements to optimize the care of number of pills prescribed by the physi- in 23% of cases, uncontrolled A1C, blood patients with chronic disease: cian in that same time period) (15). If pressure, or lipids were associated with adherence is 80% or above, then treat- poor medication adherence (15). Barriers 1. Delivery system design (moving ment intensification should be con- to adherence may include patient factors from a reactive to a proactive care sidered (e.g., up-titration). Additional (remembering to obtain or take medica- delivery system where planned visits strategies shown to improve care team tions, fear, depression, or health beliefs), are coordinated through a team- behavior and thereby catalyze reductions medication factors (complexity, multiple based approach) in A1C, blood pressure, and/or LDL cho- daily dosing, cost, or side effects), and 2. Self-management support lesterol include explicit and collaborative system factors (inadequate follow-up or 3. Decision support (basing care on goal setting with patients (16,17); identi- support). A patient-centered, nonjudg- evidence-based, effective care guidelines) fying and addressing language, numeracy, mental communication style can help 4. Clinical information systems (using or cultural barriers to care (18–20); inte- providers to identify barriers to adher- registries that can provide patient- grating evidence-based guidelines and ence as well as motivation for self-care specific and population-based sup- clinical information tools into the process (17). Nurse-directed interventions, home port to the care team) of care (21–23); soliciting performance aides, diabetes education, and pharmacy- 5. Community resources and policies feedback, setting reminders, and provid- derived interventions improved adher- (identifying or developing resources ing structured care (e.g., guidelines, ence but had a very small effect on to support healthy lifestyles) formal case management, and patient outcomes, including metabolic control 6. Health systems (to create a quality- education resources) (6); and incorpo- (27). Success in overcoming barriers to oriented culture) rating care management teams including adherence may be achieved if the patient nurses, dietitians, pharmacists, and other and provider agree on a targeted ap- Redefining the roles of the health care providers (24,25). proach for a specific barrier (10). For ex- delivery team and empowering patient ample, simplifying a complex treatment self-management are fundamental to Objective 2: Support Patient Self-management. Successful diabetes care requires a sys- regimen may improve adherence in those the successful implementation of the tematic approach to supporting patients’ who identify complexity as a barrier. CCM (8). Collaborative, multidisciplinary teams are best suited to provide care for behavior change efforts, including the Objective3:ChangetheCareSystem. people with chronic conditions such as following: A characteristic of most successful care diabetes and to facilitate patients’ self- systems is making high-quality care an 1. Healthy lifestyle choices (healthy management (9–11). institutional priority (28). Changes that eating, physical activity, tobacco ces- increase the quality of diabetes care in- Strategies for System-Level Improvement sation, weight management, and ef- clude providing care on evidence-based Optimal diabetes management requires fective strategies for coping with guidelines (21); expanding the role of an organized, systematic approach and stress) teams to implement more intensive dis- the involvement of a coordinated team of 2. Disease self-management (taking ease management strategies (6,24,29); dedicated health care professionals work- and managing medications and, when tracking medication adherence at a sys- ing in an environment where patient- clinically appropriate, self-monitoring tem level (15); redesigning the care pro- centered high-quality care is a priority of glucose and blood pressure) cess (30); implementing electronic (6). The National Diabetes Education Pro- 3. Prevention of diabetes complica- health record tools (31,32); empower- gram (NDEP) maintains an online resource tions (self-monitoring of foot health; ing and educating patients (33,34); re- (www.betterdiabetescare.nih.gov) to active participation in screening for moving financial barriers and reducing help health care professionals to design eye, foot, and renal complications; patient out-of-pocket costs for diabetes and implement more effective health and immunizations) education, eye exams, self-monitoring of care delivery systems for those with dia- 4. Identification of self-management blood glucose, and necessary medica- fi betes. Three speci c objectives, with ref- problems and development of strate- tions (6); assessing and addressing erences to literature outlining practical gies to solve those problems, including psychosocial issues (26,35); and identify- strategies to achieve each, are as follows. self-selected behavioral goal setting ing/developing/engaging community re- Objective 1: Optimize Provider and Team sources and public policy that support Behavior. The care team, which includes High-quality diabetes self-management healthy lifestyles (36). the patient, should prioritize timely and education (DSME) has been shown to Initiatives such as the Patient-Centered appropriate intensification of lifestyle improve patient self-management, Medical Home show promise for improving S8 Promoting Health and Reducing Disparities in Populations Diabetes Care Volume 40, Supplement 1, January 2017

outcomes by coordinating primary care around diabetes management, racial care community linkages are receiving and offering new opportunities for and ethnic minorities remain at higher increasing attention from the American team-based chronic disease manage- risk for microvascular complications Medical Association, the Agency for ment (37). Additional strategies to than nonminorities. Type 2 diabetes de- Healthcare Research and Quality, and improve diabetes care include reimburse- velops more frequently in women with others as a means of promoting trans- ment structures that, in contrast to visit- prior gestational diabetes mellitus (43) lation of clinical recommendations based billing, reward the provision of and in certain racial/ethnic groups (African for lifestyle modification in real-world appropriate and high-quality care to American, Native American, Hispanic/ settings (53). To overcome disparities, achieve metabolic goals (38), and incen- Latino, and Asian American) (44). Women community health workers (54), peers tives that accommodate personalized with diabetes are also at greater risk of (55,56), and lay leaders (57) may assist care goals (6,39). coronary heart disease than men with di- in the delivery of DSME and diabetes abetes (45). self-management support services (58), TAILORING TREATMENT TO particularly in underserved communi- REDUCE DISPARITIES Access to Health Care ties. Strong social support leads to im- Socioeconomic and ethnic inequalities Recommendations proved clinical outcomes, a reduction in exist in the provision of health care to c Providers should assess social con- psychosocial issues, and adoption of individuals with diabetes (46). For exam- text, including potential food in- healthier lifestyles (59). ple, children with type 1 diabetes from security, housing stability, and racial/ethnic minority populations with financial barriers, and apply that in- Food Insecurity lower socioeconomic status are at risk Food insecurity (FI) is the unreliable avail- formation to treatment decisions. A for poor metabolic control and poor ability of nutritious food and the inability c Patients should be referred to lo- emotional functioning (47). Significant to consistently obtain food without re- cal community resources when racial differences and barriers exist in sorting to socially unacceptable practices. available. B self-monitoring and outcomes (48). Over 14% (or one of every seven people c Patients should be provided with self- in the U.S.) are food insecure. The rate is management support from lay health Lack of Health Insurance higher in some racial/ethnic minority coaches, navigators, or community Not having health insurance affects the groups including African American and health workers when available. A processes and outcomes of diabetes care. Individuals without insurance cov- Latino populations, in low-income house- holds,andinhomesheadedbyasin- The causes of health disparities are com- erage for blood glucose monitoring sup- gle mother. FI may involve a tradeoff plex and include societal issues such as in- plies have a 0.5% higher A1C than those between purchasing more expensive nu- stitutional racism, discrimination, with coverage (49). In a recent study of tritious food and less expensive energy- socioeconomic status, poor access to predominantly African American or His- and carbohydrate-dense processed foods, health care, education, and lack of health panic uninsured patients with diabetes, which may contribute to obesity. insurance. Social determinants of health 50–60% had hypertension, but only 22– The risk for type 2 diabetes is increased can be defined as the economic, environ- 37% had systolic blood pressure controlled twofold in those with FI (42). Therefore, in mental, political, and social conditions in by treatments to under 130 mmHg (50). people with FI, interventions should focus which people live, and are responsible The Affordable Care Act has improved ac- on preventing diabetes. In those with di- for a major part of health inequality world- cess to health care; however, many remain abetes and FI, the priority is mitigating the wide (40). Given the tremendous burden without coverage (www.cdc.gov/nchs/ increased risk for uncontrolled hypergly- that obesity, unhealthy eating, physical in- fastats/health-insurance.htm). cemia and severe hypoglycemia. Reasons activity, and smoking place on the health for the increased risk of hyperglycemia in- of patients with diabetes, efforts are System-Level Interventions Eliminating disparities will require indi- clude the steady consumption of inexpen- needed to address and change the societal vidualized, patient-centered, and cultur- sive carbohydrate-rich processed foods, determinants of these problems (41). ally appropriate strategies as well as binge eating, financial constraints to the TheADArecognizestheassociationbe- system-level interventions. Structured filling of diabetes medication prescrip- tween social and environmental factors interventions that are developed for di- tions, and anxiety/depression leading to and the development of obesity and verse populations and that integrate poor diabetes self-care behaviors. Hypo- type 2 diabetes and has issued a call for culture, language, finance, religion, and glycemia can occur as a result of inade- research that seeks to better understand literacy and numeracy skills positively quate or erratic carbohydrate consumption how these social determinants influence influence patient outcomes (51). All following administration of sulfonylureas behaviors and how the relationships be- providers and health care systems are or insulin. Providers should recognize that tween these variables might be modified encouraged to use the National Quality FI complicates diabetes management and for the prevention and management of di- Forum’s National Voluntary Consensus seek local resources that can help pa- abetes (42). Standards for Ambulatory CaredMeasuring tients and the parents of patients with Healthcare Disparities (52). diabetes to more regularly obtain nutri- Ethnic/Cultural/Sex Differences tious food (60). Ethnic, cultural, and sex differences may Community Support affect diabetes prevalence and out- Identification or development of re- Treatment Options comes. Despite advances over the last sources to support healthy lifestyles If using a sulfonylurea in patients with several decades in medical knowledge is a core element of the CCM (7). Health FI, glipizide may be considered due to its care.diabetesjournals.org Promoting Health and Reducing Disparities in Populations S9

relatively short half-life. It can be taken 3. Wang J, Geiss LS, Cheng YJ, et al. Long-term tailored diabetes self-management interven- immediately before meals, thus obviating and recent progress in blood pressure levels tion for low-income Latinos: Latinos en Control. – the need to plan meals to an extent that among U.S. adults with diagnosed diabetes, Diabetes Care 2011;34:838 844 1988-2008. Diabetes Care 2011;34:1579–1581 20. Osborn CY, Cavanaugh K, Wallston KA, et al. may be unreachable for those with FI. 4. Kerr EA, Heisler M, Krein SL, et al. Beyond Health literacy explains racial disparities in di- For those needing insulin, short-acting comorbidity counts: how do comorbidity type abetes medication adherence. J Health Com- insulin analogs, preferably delivered by a and severity influence diabetes patients’ treat- mun 2011;16(Suppl. 3):268–278 pen, may be used immediately after meal ment priorities and self-management? J Gen In- 21. O’Connor PJ, Bodkin NL, Fradkin J, et al. 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N Engl J Med 2010;363:2611–2620 ment of the American Diabetes Association, the 11. Parchman ML, Zeber JE, Romero RR, Pugh American Association of Diabetes Educators, goal of preventing diabetes and building JA. Risk of coronary artery disease in type 2 di- and the Academy of Nutrition and Dietetics. Di- diabetes awareness in people who can- abetes and the delivery of care consistent with abetes Care 2015;38:1372–1382 not easily read or write in English. the chronic care model in primary care settings: 27. Vermeire E, Wens J, Van Royen P, Biot Y, a STARNet study. Med Care 2007;45:1129–1134 Hearnshaw H, Lindenmeyer A. Interventions for Homelessness 12. Davidson MB. How our current medical improving adherence to treatment recommenda- Homelessness often accompanies many care system fails people with diabetes: lack of tions in people with type 2 diabetes mellitus. Co- barriers to diabetes self-management, timely, appropriate clinical decisions. Diabetes chrane Database Syst Rev 2005;2:CD003638 Care 2009;32:370–372 28. Tricco AC, Ivers NM, Grimshaw JM, et al. including FI, literacy and numeracy defi- 13. Selby JV, Uratsu CS, Fireman B, et al. Treat- Effectiveness of quality improvement strategies ciencies, lack of insurance, cognitive ment intensification and risk factor control: to- on the management of diabetes: a systematic dysfunction, and mental health issues. ward more clinically relevant quality measures. review and meta-analysis. Lancet 2012;379: Therefore, providers who care for Med Care 2009;47:395–402 2252–2261 14. Raebel MA, Ellis JL, Schroeder EB, et al. In- 29. Peikes D, Chen A, Schore J, Brown R. Effects homeless individuals should be well tensification of antihyperglycemic therapy of care coordination on hospitalization, quality versed or have access to social workers among patients with incident diabetes: a Surveil- of care, and health care expenditures among to facilitate temporary housing for their lance Prevention and Management of Diabetes Medicare beneficiaries: 15 randomized trials. patients as a means to prevent and con- Mellitus (SUPREME-DM) study. Pharmacoepide- JAMA 2009;301:603–618 trol diabetes. Additionally, patients with miol Drug Saf 2014;23:699–710 30. Feifer C, Nemeth L, Nietert PJ, et al. Differ- 15.RaebelMA,SchmittdielJ,KarterAJ, ent paths to high-quality care: three archetypes diabetes who are homeless need secure Konieczny JL, Steiner JF. Standardizing terminol- of top-performing practice sites. Ann Fam Med places to keep their diabetes supplies ogy and definitions of medication adherence and 2007;5:233–241 and refrigerator access to properly store persistence in research employing electronic da- 31. Reed M, Huang J, Graetz I, et al. Outpatient their insulin and have access to take it tabases. Med Care 2013;51(Suppl. 3):S11–S21 electronic health records and the clinical care on a regular schedule. 16. Grant RW, Pabon-Nau L, Ross KM, Youatt EJ, and outcomes of patients with diabetes melli- Pandiscio JC, Park ER. Diabetes oral medication tus. Ann Intern Med 2012;157:482–489 initiation and intensification: patient views 32. Cebul RD, Love TE, Jain AK, Hebert CJ. Elec- References compared with current treatment guidelines. tronic health records and quality of diabetes 1. Institute of Medicine. Committee on Quality Diabetes Educ 2011;37:78–84 care. N Engl J Med 2011;365:825–833 of Health Care in America. Crossing the quality 17. Tamhane S, Rodriguez-Gutierrez R, 33. Battersby M, Von Korff M, Schaefer J, et al. chasm: a new health system for the 21st century Hargraves I, Montori VM. Shared decision-making Twelve evidence-based principles for implement- [Internet], 2001. Washington, DC, The National in diabetes care. Curr Diab Rep 2015;15:112 ing self-management support in primary care. Jt Academies Press. Available from http://www.nap 18. Schillinger D, Piette J, Grumbach K, et al. Comm J Qual Patient Saf 2010;36:561–570 .edu/catalog/10027. Accessed 8 September 2016 Closing the loop: physician communication 34. Grant RW, Wald JS, Schnipper JL, et al. 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, with diabetic patients who have low health lit- Practice-linked online personal health records Imperatore G, Gregg EW. Achievement of goals eracy. Arch Intern Med 2003;163:83–90 for type 2 diabetes mellitus: a randomized con- in U.S. diabetes care, 1999–2010. N Engl J Med 19. Rosal MC, Ockene IS, Restrepo A, et al. Ran- trolled trial. 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35. Young-Hyman D, de Groot M, Hill-Briggs F, 44. Hutchinson RN, Shin S. Systematic review of measuring healthcare disparities [Internet], Gonzalez JS, Hood K, Peyrot M. Psychosocial health disparities for cardiovascular diseases 2008. Available from https://www.qualityforum care for people with diabetes: a position state- and associated factors among American Indian .org/Publications/2008/03/National_Voluntary_ ment of the American Diabetes Association. Di- and Alaska Native populations. PLoS One 2014; Consensus_Standards_for_Ambulatory_Care% abetes Care 2016;39:2126–2140 9:e80973 E2%80%94Measuring_Healthcare_Disparities 36. Pullen-Smith B, Carter-Edwards L, Leathers 45. Peters SAE, Huxley RR, Woodward M. Dia- .aspx. Accessed 18 November 2016 KH. Community health ambassadors: a model betes as risk factor for incident coronary heart 53. Agency for Healthcare Research and Quality. for engaging community leaders to promote disease in women compared with men: a sys- Clinical-community linkages [Internet]. Avai- better health in North Carolina. J Public Health tematic review and meta-analysis of 64 cohorts lable from http://www.ahrq.gov/professionals/ Manag Pract 2008;14(Suppl.):S73–S81 including 858,507 individuals and 28,203 coro- prevention-chronic-care/improve/community/ – 37. Bojadzievski T, Gabbay RA. Patient-centered nary events. Diabetologia 2014;57:1542 1551 index.html. Accessed 10 October 2016 medical home and diabetes. Diabetes Care 2011; 46. Ricci-Cabello I, Ruiz-Perez´ I, Olry de Labry- 54. Shah M, Kaselitz E, Heisler M. The role of 34:1047–1053 Lima A, Marquez-Calder´ on´ S. Do social inequal- community health workers in diabetes: update 38. Rosenthal MB, Cutler DM, Feder J. The ACO rulesd ities exist in terms of the prevention, diagnosis, on current literature. Curr Diab Rep 2013;13: striking the balance between participation and treatment, control and monitoring of diabetes? 163–171 transformative potential. N Engl J Med 2011;365:e6 A systematic review. Health Soc Care Commu- 55. Heisler M, Vijan S, Makki F, Piette JD. Di- – 39. Washington AE, Lipstein SH. The Patient- nity 2010;18:572 587 abetes control with reciprocal peer support ver- 47. Borschuk AP, Everhart RS. Health disparities Centered Outcomes Research Institutedpromoting sus nurse care management: a randomized trial. among youth with type 1 diabetes: a systematic better information, decisions, and health. N Engl J Ann Intern Med 2010;153:507–515 review of the current literature. Fam Syst Health Med 2011;365:e31 56. Long JA, Jahnle EC, Richardson DM, 2015;33:297–313 40. Commission on Social Determinants of Health. Loewenstein G, Volpp KG. Peer mentoring and 48. Campbell JA, Walker RJ, Smalls BL, Egede Closing the gap in a generation: health equity financial incentives to improve glucose control LE. Glucose control in diabetes: the impact of through action on the social determinants of racial differences on monitoring and outcomes. in African American veterans: a randomized tri- – health. Final report of the Commission on Social Endocrine 2012;42:471–482 al. Ann Intern Med 2012;156:416 424 Determinants of Health. Geneva, World Health 49. Bowker SL, Mitchell CG, Majumdar SR, Toth 57. Foster G, Taylor SJ, Eldridge SE, Ramsay J, fi Organization. Available from http://apps.who.int/ EL, Johnson JA. Lack of insurance coverage for Grif ths CJ. Self-management education pro- iris/bitstream/10665/43943/1/9789241563703_eng testing supplies is associated with poorer glyce- grammes by lay leaders for people with chronic .pdf. Accessed 18 November 2016 mic control in patients with type 2 diabetes. conditions. Cochrane Database Syst Rev 2007;4: 41. Jack L, Jack NH, Hayes SC. Social determi- CMAJ 2004;171:39–43 CD005108 nants of health in minority populations: a call 50. Baumann LC, Chang M-W, Hoebeke R. Clin- 58. Siminerio L, Ruppert KM, Gabbay RA. Who for multidisciplinary approaches to eliminate ical outcomes for low-income adults with can provide diabetes self-management support in diabetes-related health disparities. Diabetes hypertension and diabetes. Nurs Res 2002;51: primary care? Findings from a randomized con- Spectr 2012;25:9–13 191–198 trolled trial. Diabetes Educ 2013;39:705–713 42. Hill JO, Galloway JM, Goley A, et al. Scien- 51. Zeh P, Sandhu HK, Cannaby AM, Sturt JA. 59. Strom JL, Egede LE. The impact of social tific statement: socioecological determinants of The impact of culturally competent diabetes care support on outcomes in adult patients with prediabetes and type 2 diabetes. Diabetes Care interventions for improving diabetes-related out- type 2 diabetes: a systematic review. Curr Diab 2013;36:2430–2439 comes in ethnic minority groups: a systematic re- Rep 2012;12:769–781 43. Kim C, Newton KM, Knopp RH. Gestational di- view. Diabet Med 2012;29:1237–1252 60. Seligman HK, Schillinger D. Hunger and so- abetes and the incidence of type 2 diabetes: a sys- 52. National Quality Forum. National voluntary cioeconomic disparities in chronic disease. N tematic review. Diabetes Care 2002;25:1862–1868 consensus standards for ambulatory cared Engl J Med 2010;363:6–9 Diabetes Care Volume 40, Supplement 1, January 2017 S11

2. Classification and Diagnosis American Diabetes Association of Diabetes Diabetes Care 2017;40(Suppl. 1):S11–S24 | DOI: 10.2337/dc17-S005

CLASSIFICATION Diabetes can be classiﬁed into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to ab- DIABETES OF DIAGNOSIS AND CLASSIFICATION 2. solute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 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), particularly ethnic minorities (2). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with DKA (3). 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 distin- guishing diabetes type may occur in all age-groups at onset, the true diagnosis becomes more obvious over time. In October 2015, the ADA, JDRF, the European Association for the Study of Di- abetes, and the American Association of Clinical Endocrinologists convened the Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Re- search Symposium (4). The goals of the symposium were to discuss the genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, to determine appropriate therapeutic approaches based on disease pathophysiology and stage, and to define research gaps hindering a personalized approach to treatment. The experts agreed that in both type 1 and type 2 diabetes, various genetic and environmental factors can result in the progressive loss of b-cell mass and/or Suggested citation: American Diabetes Associa- function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, tion. Classification and diagnosis of diabetes. patients with all forms of diabetes are at risk for developing the same complications, Sec. 2. In Standards of Medical Care in Diabetesd although rates of progression may differ. They concluded that the identification of 2017. Diabetes Care 2017;40(Suppl. 1):S11–S24 individualized therapies for diabetes in the future will require better characteriza- © 2017 by the American Diabetes Association. tion of the many paths to b-cell demise or dysfunction. Readers may use this article as long as the work is properly cited, the use is educational and not Characterization of the underlying pathophysiology is much more developed in for profit, and the work is not altered. More infor- type 1 diabetes than in type 2 diabetes. It is now clear from studies of first-degree mation is available at http://www.diabetesjournals relatives of patients with type 1 diabetes that the persistent presence of two or .org/content/license. S12 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

more autoantibodies is an almost cer- interventions for primary prevention of advantages may be offset by the lower tain predictor of clinical hyperglycemia type 2 diabetes (7,8) has primarily been sensitivity of A1C at the designated cut and diabetes. The rate of progression is demonstrated among individuals with point, greater cost, limited availability dependent on the age at first detection impaired glucose tolerance (IGT), not of A1C testing in certain regions of the of antibody, number of antibodies, anti- for individuals with isolated impaired developing world, and the imperfect body specificity, and antibody titer. Glu- fasting glucose (IFG) or for those with correlation between A1C and average cose and A1C levels rise well before the prediabetes defined by A1C criteria. glucose in certain individuals. National clinical onset of diabetes, making diag- The same tests may be used to screen Health and Nutrition Examination Survey nosis feasible well before the onset of for and diagnose diabetes and to detect (NHANES) data indicate that an A1C cut DKA. Three distinct stages of type 1 di- individuals with prediabetes. Diabetes point of $6.5% (48 mmol/mol) identifies abetes can be identified (Table 2.1) and maybeidentified anywhere along the one-third fewer cases of undiagnosed di- serve as a framework for future research spectrum of clinical scenarios: in seem- abetes than a fasting glucose cut point and regulatory decision making (4,5). ingly low-risk individuals who happen of $126 mg/dL (7.0 mmol/L) (9). The paths to b-cell demise and dys- to have glucose testing, in individuals When using A1C to diagnose diabetes, function are less well definedintype2 tested based on diabetes risk assess- it is important to recognize that A1C is diabetes, but deficient b-cell insulin se- ment, and in symptomatic patients. an indirect measure of average blood glu- cretion frequently in the setting of insu- cose levels and to take other factors into lin resistance appears to be the common Fasting and 2-Hour Plasma Glucose The FPG and 2-h PG may be used to di- considerationthatmayimpact hemoglobin denominator. Characterization of sub- agnose diabetes (Table 2.2). The concor- glycation independently of glycemia in- types of this heterogeneous disorder dance between the FPG and 2-h PG tests cluding age, race/ethnicity, and anemia/ have been developed and validated in is imperfect, as is the concordance be- hemoglobinopathies. Scandinavian and Northern European tween A1C and either glucose-based Age populations, but have not been con- test. Numerous studies have confirmed The epidemiological studies that formed firmed in other ethnic and racial groups. that,comparedwithFPGandA1Ccut the basis for recommending A1C to di- Type 2 diabetes is primarily associated points, the 2-h PG value diagnoses agnose diabetes included only adult pop- with insulin secretory defects related more people with diabetes. ulations. Therefore, it remains unclear if to inflammation and metabolic stress among other contributors including A1C and the same A1C cut point should A1C be used to diagnose diabetes in children genetic factors. Future classification The A1C test should be performed and adolescents (9,10). schemes for diabetes will likely focus usingamethodthatiscertified by the on the pathophysiology of the under- NGSP (www.ngsp.org) and standardized Race/Ethnicity lying b-cell dysfunction and the stage or traceable to the Diabetes Control and A1C levels may vary with race/ethnicity of disease as indicated by glucose status Complications Trial (DCCT) reference as- independently of glycemia (11,12). For (normal, impaired, or diabetes) (4). say. Although point-of-care A1C assays example, African Americans may have may be NGSP certified, proficiency test- higher A1C levels than non-Hispanic DIAGNOSTIC TESTS FOR DIABETES ing is not mandated for performing the whites despite similar fasting and post- Diabetes may be diagnosed based on test, so use of point-of-care assays for glucose load glucose levels (13). Though plasma glucose criteria, either the fast- diagnostic purposes is not recommen- thereissomeconflicting data, African ing plasma glucose (FPG) or the 2-h ded but may be considered in the future Americans may also have higher levels plasma glucose (2-h PG) value after a if proficiency testing is performed and of fructosamine and glycated albumin 75-g oral glucose tolerance test (OGTT) documented. and lower levels of 1,5-anhydroglucitol, or A1C criteria (1,6) (Table 2.2). The A1C has several advantages com- suggesting that their glycemic burden FPG, 2-h PG after 75-g OGTT, and A1C pared with the FPG and OGTT, including (particularly postprandially) may be are equally appropriate for diagnostic greater convenience (fasting not re- higher (14,15). The association of A1C testing. It should be noted that the tests quired), greater preanalytical stability, with risk for complications appears to do not necessarily detect diabetes in and less day-to-day perturbations dur- be similar in African Americans and the same individuals. The efficacy of ing stress and illness. However, these non-Hispanic whites (16).

Table 2.1—Staging of type 1 diabetes (4,5) Stage 1 Stage 2 Stage 3 Stage c Autoimmunity c Autoimmunity c New-onset hyperglycemia c Normoglycemia c Dysglycemia c Symptomatic c Presymptomatic c Presymptomatic Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptoms c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria c FPG 100–125 mg/dL (5.6–6.9 mmol/L) c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L) c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C care.diabetesjournals.org Classiﬁcation and Diagnosis of Diabetes S13

Table 2.2—Criteria for the diagnosis of diabetes c To test for prediabetes, fasting FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* plasma glucose, 2-h plasma glucose OR after 75-g oral glucose tolerance 2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described test, and A1C are equally appropri- by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose ate. B dissolved in water.* c In patients with prediabetes, OR identify and, if appropriate, treat $ A1C 6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that other cardiovascular disease risk is NGSP certified and standardized to the DCCT assay.* factors. B OR c Testing for prediabetes should be In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma considered in children and ado- glucose $200 mg/dL (11.1 mmol/L). lescents who are overweight or *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. obeseandwhohavetwoormore additional risk factors for diabetes. E Hemoglobinopathies/Red Blood Cell FPG (,126 mg/dL [7.0 mmol/L]), that Turnover person should nevertheless be consid- Interpreting A1C levels in the presence ered to have diabetes. Description of certain hemoglobinopathies may be Since all the tests have preanalytic In 1997 and 2003, the Expert Committee fi problematic. For patients with an abnor- and analytic variability, it is possible on the Diagnosis and Classi cation of mal hemoglobin but normal red blood that an abnormal result (i.e., above the Diabetes Mellitus (17,18) recognized a cell turnover, such as those with the diagnostic threshold), when repeated, group of individuals whose glucose lev- sickle cell trait, an A1C assay without will produce a value below the diagnos- els did not meet the criteria for diabetes interference from abnormal hemoglo- tic cut point. This scenario is likely for but were too high to be considered nor- “ ” bins should be used. An updated list of FPG and 2-h PG if the glucose samples mal. Prediabetes is the term used for interferences is available at www.ngsp remain at room temperature and are individuals with IFG and/or IGT and/or – – .org/interf.asp. not centrifuged promptly. Because of A1C 5.7 6.4% (39 47 mmol/mol). Pre- In conditions associated with in- the potential for preanalytic variability, diabetes should not be viewed as a clin- creased red blood cell turnover, such it is critical that samples for plasma glu- ical entity in its own right but rather as as pregnancy (second and third trimes- cose be spun and separated immedi- an increased risk for diabetes (Table 2.3) ters), hemodialysis, recent blood loss or ately after they are drawn. If patients and cardiovascular disease (CVD). transfusion, or erythropoietin therapy, have test results near the margins of Prediabetes is associated with obe- only blood glucose criteria should be the diagnostic threshold, the health sity (especially abdominal or visceral used to diagnose diabetes. care professional should follow the pa- obesity), dyslipidemia with high triglyc- tient closely and repeat the test in erides and/or low HDL cholesterol, and fi Con rming the Diagnosis 3–6months. hypertension. Unless there is a clear clinical diagnosis (e.g., patient in a hyperglycemic crisis or CATEGORIES OF INCREASED RISK Diagnosis with classic symptoms of hyperglycemia FOR DIABETES (PREDIABETES) The Expert Committee on the Diagnosis and a random plasma glucose $200 and Classification of Diabetes Mellitus Recommendations mg/dL [11.1 mmol/L]), a second test is re- (17,18) defined IFG as FPG levels be- c Screening for prediabetes and risk quired for confirmation. It is recom- tween 100 and 125 mg/dL (between for future diabetes with an infor- mended that the same test be repeated 5.6 and 6.9 mmol/L) and IGT as 2-h PG mal assessment of risk factors or without delay using a new blood sample after 75-g OGTT levels between 140 and validated tools should be consid- for confirmation because there will be a 199 mg/dL (between 7.8 and 11.0 mmol/L). ered in asymptomatic adults. B greater likelihood of concurrence. For ex- It should be noted that the World Health c Testing for prediabetes and risk ample, if the A1C is 7.0% (53 mmol/mol) Organization (WHO) and numerous other for future diabetes in asymptom- and a repeat result is 6.8% (51 mmol/mol), diabetes organizations define the IFG atic people should be considered the diagnosis of diabetes is confirmed. If cutoff at 110 mg/dL (6.1 mmol/L). in adults of any age who are over- two different tests (such as A1C and FPG) As with the glucose measures, several weight or obese (BMI $25 kg/m2 are both above the diagnostic threshold, prospective studies that used A1C to or $23 kg/m2 in Asian Ameri- this also confirms the diagnosis. On the predict the progression to diabetes as cans) and who have one or more other hand, if a patient has discordant defined by A1C criteria demonstrated a additional risk factors for diabe- results from two different tests, then the strong, continuous association between tes. B test result that is above the diagnostic cut A1C and subsequent diabetes. In a sys- c For all people, testing should be- point should be repeated. The diagnosis tematic review of 44,203 individuals gin at age 45 years. B is made on the basis of the confirmed from 16 cohort studies with a follow-up c If tests are normal, repeat testing test. For example, if a patient meets interval averaging 5.6 years (range 2.8– carried out at a minimum of 3-year the diabetes criterion of the A1C (two 12 years), those with A1C between 5.5 intervals is reasonable. C results $6.5% [48 mmol/mol]) but not and 6.0% (between 37 and 42 mmol/mol) S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults andmayserveasanindicationfor 2 2 1. Testing should be considered in overweight or obese (BMI $25 kg/m or $23 kg/m in Asian intervention in the setting of a clini- Americans) adults who have one or more of the following risk factors: cal trial. Outcomes may include re- c A1C $5.7% (39 mmol/mol), IGT, or IFG on previous testing c first-degree relative with diabetes version of autoantibody status, c high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, prevention of glycemic progression Pacific Islander) within the normal or prediabetes c women who were diagnosed with GDM range, prevention of clinical diabe- c history of CVD tes, or preservation of residual $ c hypertension ( 140/90 mmHg or on therapy for hypertension) C-peptide secretion. A c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL (2.82 mmol/L) c women with polycystic ovary syndrome Diagnosis c physical inactivity In a patient with classic symptoms, mea- c other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis surement of blood glucose is sufficient nigricans). to diagnose diabetes (symptoms of hy- 2. For all patients, testing should begin at age 45 years. perglycemia or hyperglycemic crisis 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with plus a random plasma glucose $200 consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status. mg/dL [11.1 mmol/L]). In these cases, knowing the blood glucose level is critical because, in addition to confirming that symptoms are due to diabetes, it had a substantially increased risk of diabe- Table 2.4 summarizes the categories will inform management decisions. tes (5-year incidence from 9 to 25%). An of prediabetes and Table 2.3 the criteria Some providers may also want to know A1C range of 6.0–6.5% (42–48 mmol/mol) for prediabetes testing. The ADA diabe- the A1C to determine how long a patient had a 5-year risk of developing diabetes tes risk test is an additional option for has had hyperglycemia. between 25 and 50% and a relative risk screening (Fig. 2.1). For recommenda- 20 times higher compared with A1C of tions regarding risk factors and screen- Immune-Mediated Diabetes 5.0% (31 mmol/mol) (19). In a community- ing for prediabetes, see pp. S17–S18 This form, previously called “insulin- based study of African American and (“Screening and Testing for Type 2 Di- dependent diabetes” or “juvenile-onset non-Hispanic white adults without diabe- abetes and Prediabetes in Asymptom- diabetes,” accounts for 5–10% of diabetes, baseline A1C was a stronger predictor atic Adults” and “Screening and Testing tes and is due to cellular-mediated au- of subsequent diabetes and cardiovascu- for Type 2 Diabetes and Prediabetes in toimmune destruction of the pancreatic lar events than fasting glucose (20). Children and Adolescents”). b-cells. Autoimmune markers include is- Other analyses suggest that A1C of let cell autoantibodies and autoanti- 5.7% (39 mmol/mol) or higher is associ- bodies to GAD (GAD65), insulin, the ated with a diabetes risk similar to that TYPE 1 DIABETES tyrosine phosphatases IA-2 and IA-2b, and ZnT8. Type 1 diabetes is defined of the high-risk participants in the Di- Recommendations by the presence of one or more of these abetes Prevention Program (DPP) (21), c Blood glucose rather than A1C should autoimmune markers. The disease has and A1C at baseline was a strong pre- be used to diagnose the acute onset strong HLA associations, with linkage dictor of the development of glucose- of type 1 diabetes in individuals with fi to the DQA and DQB genes. These de ned diabetes during the DPP and its symptoms of hyperglycemia. E HLA-DR/DQ alleles can be either predis- follow-up (22). c Screening for type 1 diabetes with a posing or protective. Hence, it is reasonable to consider an panel of autoantibodies is currently – – Therateofb-cell destruction is quite A1C range of 5.7 6.4% (39 47 mmol/mol) recommended only in the setting variable, being rapid in some individuals as identifying individuals with prediabe- of a research trial or in first-degree (mainly infants and children) and slow in tes. Similar to those with IFG and/or IGT, family members of a proband with – – others (mainly adults). Children and ado- individuals with A1C of 5.7 6.4% (39 type 1 diabetes. B lescents may present with ketoacidosis as 47 mmol/mol) should be informed of c Persistence of two or more autoan- the first manifestation of the disease. their increased risk for diabetes and tibodies predicts clinical diabetes CVD and counseled about effective strat- Others have modest fasting hyperglycemia egies to lower their risks (see Section “ 5 Prevention or Delay of Type 2 Diabe- Table 2.4—Categories of increased risk for diabetes (prediabetes)* tes”). Similar to glucose measurements, FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) the continuum of risk is curvilinear, so as OR A1C rises, the diabetes risk rises dispro- 2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) portionately (19). Aggressive interven- OR tions and vigilant follow-up should be A1C 5.726.4% (39247 mmol/mol) pursued for those considered at very high risk (e.g., those with A1C .6.0% *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range. [42 mmol/mol]). care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

Figure 2.1—ADA risk test. that can rapidly change to severe hyper- ketoacidosis for many years; such indi- disease, there is little or no insulin secre- glycemia and/or ketoacidosis with infec- viduals eventually become dependent tion, as manifested by low or undetectable tion or other stress. Adults may retain on insulin for survival and are at risk for levels of plasma C-peptide. Immune-mediated sufﬁcient b-cellfunctiontoprevent ketoacidosis. At this latter stage of the diabetes commonly occurs in childhood S16 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

and adolescence, but it can occur at any 70% developed type 1 diabetes within c Testing for type 2 diabetes should age, even in the 8th and 9th decades of life. 10 years and 84% within 15 years (24). be considered in children and ado- Autoimmune destruction of b-cells These findings are highly significant lescents who are overweight or has multiple genetic predispositions because, while the German group was obese and who have two or more ad- and is also related to environmental fac- recruited from offspring of parents with ditional risk factors for diabetes. E tors that are still poorly defined. Al- type 1 diabetes, the Finnish and American though patients are not typically obese groups were recruited from the general when they present with type 1 diabetes, population. Remarkably, the findings in Description obesity should not preclude the diag- all three groups were the same, suggesting Type 2 diabetes, previously referred to nosis. Patients with type 1 diabetes are that the same sequence of events led to as “noninsulin-dependent diabetes” or also prone to other autoimmune disor- clinical disease in both “sporadic” and fa- “adult-onset diabetes,” accounts for ders such as Hashimoto thyroiditis, milial cases of type 1 diabetes. Indeed, the 90–95% of all diabetes. This form en- Graves disease, Addison disease, celiac risk of type 1 diabetes increases as the compasses individuals who have relative disease, vitiligo, autoimmune hepatitis, number of relevant autoantibodies de- (rather than absolute) insulin deficiency myasthenia gravis, and pernicious ane- tected increases (25–27). and have peripheral insulin resistance. At mia (see Section 3 “Comprehensive Although there is currently a lack of least initially, and often throughout their Medical Evaluation and Assessment of accepted screening programs, one should lifetime, these individuals may not need Comorbidities”). consider referring relatives of those with insulin treatment to survive. type 1 diabetes for antibody testing for There are various causes of type 2 di- Idiopathic Type 1 Diabetes risk assessment in the setting of a clinical abetes. Although the specific etiologies Some forms of type 1 diabetes have no research study (http://www.diabetestrialnet are not known, autoimmune destruc- known etiologies. These patients have .org). Widespread clinical testing of tion of b-cells does not occur, and pa- permanent insulinopenia and are prone asymptomatic low-risk individuals is not tients do not have any of the other to ketoacidosis, but have no evidence of currently recommended due to lack of known causes of diabetes. Most, but b-cell autoimmunity. Although only a approved therapeutic interventions. In- not all, patients with type 2 diabetes minority of patients with type 1 diabetes dividuals who test positive will be coun- are overweight or obese. Excess weight fall into this category, of those who do, seled about the risk of developing itself causes some degree of insulin re- most are of African or Asian ancestry. diabetes, diabetes symptoms, and DKA sistance. Patients who are not obese or Individuals with this form of diabetes prevention. Numerous clinical studies overweight by traditional weight criteria suffer from episodic ketoacidosis and are being conducted to test various may have an increased percentage of exhibit varying degrees of insulin defi- methods of preventing type 1 diabetes body fat distributed predominantly in ciency between episodes. This form of in those with evidence of autoimmunity the abdominal region. diabetes is strongly inherited and is not (www.clinicaltrials.gov). Ketoacidosis seldom occurs sponta- HLA associated. An absolute requirement neously in type 2 diabetes; when seen, for insulin replacement therapy in affected TYPE 2 DIABETES it usually arises in association with the patients may be intermittent. stress of another illness such as infec- Recommendations tion. Type 2 diabetes frequently goes c Screening for type 2 diabetes with undiagnosed for many years because Testing for Type 1 Diabetes Risk an informal assessment of risk fac- The incidence and prevalence of type 1 hyperglycemia develops gradually and, tors or validated tools should be con- diabetes is increasing (23). Patients with at earlier stages, is often not severe sideredinasymptomaticadults.B type 1 diabetes often present with acute enough for the patient to notice the c Testing for type 2 diabetes in asymp- symptoms of diabetes and markedly el- classic diabetes symptoms. Neverthe- tomatic people should be considered evated blood glucose levels, and ap- less, even undiagnosed patients are at in adults of any age who are over- proximately one-third are diagnosed increased risk of developing macrovas- weight or obese (BMI $25 kg/m2 with life-threatening ketoacidosis (3). cular and microvascular complications. or $23 kg/m2 in Asian Americans) Several studies indicate that measuring Whereas patients with type 2 diabe- and who have one or more additional islet autoantibodies in relatives of those tes may have insulin levels that appear risk factors for diabetes. B with type 1 diabetes may identify indi- normal or elevated, the higher blood c For all people, testing should be- viduals who are at risk for developing glucose levels in these patients would gin at age 45 years. B type 1 diabetes (5). Such testing, cou- be expected to result in even higher in- c If tests are normal, repeat testing pled with education about diabetes sulin values had their b-cell function carried out at a minimum of 3-year symptoms and close follow-up, may en- been normal. Thus, insulin secretion is intervals is reasonable. C able earlier identification of type 1 di- defective in these patients and insuffi- c To test for type 2 diabetes, fasting abetes onset. A study reported the risk cient to compensate for insulin resis- plasma glucose, 2-h plasma glucose of progression to type 1 diabetes from tance. Insulin resistance may improve with after 75-g oral glucose tolerance test, the time of seroconversion to autoanti- weight reduction and/or pharmacological and A1C are equally appropriate. B body positivity in three pediatric co- treatment of hyperglycemia but is seldom c In patients with diabetes, identify and horts from Finland, Germany, and the restored to normal. treat other cardiovascular disease U.S. Of the 585 children who developed The risk of developing type 2 diabetes risk factors. B more than two autoantibodies, nearly increases with age, obesity, and lack of care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

physical activity. It occurs more fre- 40 and 69 years were screened for di- numerous false positives. An argument quently in women with prior GDM, in abetes and randomly assigned by prac- can be made to push the BMI cut point those with hypertension or dyslipide- tice to intensive treatment of multiple to lower than 23 kg/m2 in favor of in- mia, and in certain racial/ethnic sub- risk factors or routine diabetes care. Af- creased sensitivity; however, this would groups (African American, American ter 5.3 years of follow-up, CVD risk fac- lead to an unacceptably low specificity Indian, Hispanic/Latino, and Asian American). tors were modestly but significantly (13.1%). Data from the WHO also suggest It is often associated with a strong improved with intensive treatment that a BMI of $23 kg/m2 should be used genetic predisposition, more so than compared with routine care, but the in- to define increased risk in Asian Ameri- type 1 diabetes. However, the genetics cidence of first CVD events or mortality cans (34). The finding that half of diabe- of type 2 diabetes is poorly understood. was not significantly different between tes in Asian Americans is undiagnosed In adults without traditional risk factors the groups (29). The excellent care pro- suggests that testing is not occurring at for type 2 diabetes and/or younger age, vided to patients in the routine care lower BMI thresholds (28). consider antibody testing for type 1 di- group and the lack of an unscreened Evidence also suggests that other abetes (i.e., GAD). control arm limited the authors’ ability populations may benefitfromlower to determine whether screening and BMI cut points. For example, in a large Screening and Testing for Type 2 early treatment improved outcomes multiethnic cohort study, for an equiva- Diabetes and Prediabetes in compared with no screening and later lent incidence rate of diabetes, a BMI of Asymptomatic Adults treatment after clinical diagnoses. Com- 30 kg/m2 in non-Hispanic whites was Screening for prediabetes and type 2 di- puter simulation modeling studies sug- equivalent to a BMI of 26 kg/m2 in Afri- abetes through an informal assessment gest that major benefits are likely to can Americans (35). of risk factors (Table 2.3)orwithanas- accrue from the early diagnosis and treat- Medications sessment tool, such as the ADA risk test ment of hyperglycemia and cardiovas- Certain medications, such as glucocorti- (Fig. 2.1), is recommended to guide pro- cular risk factors in type 2 diabetes coids, thiazide diuretics, and atypical an- viders on whether performing a diag- (30); moreover, screening, beginning tipsychotics (36), are known to increase nostic test (Table 2.2) is appropriate. at age 30 or 45 years and independent the risk of diabetes and should be consid- Prediabetes and type 2 diabetes meet of risk factors, may be cost-effective ered when deciding whether to screen. criteria for conditions in which early de- (,$11,000 per quality-adjusted life-year tection is appropriate. Both conditions gained) (31). Testing Interval fi are common and impose signi cant clin- Additional considerations regarding The appropriate interval between ical and public health burdens. There is testing for type 2 diabetes and predia- screening tests is not known (37). The often a long presymptomatic phase be- betes in asymptomatic patients include rationale for the 3-year interval is that fore the diagnosis of type 2 diabetes. the following. with this interval, the number of false- Simple tests to detect preclinical disease positive tests that require confirmatory Age are readily available. The duration of testing will be reduced and individuals Screening recommendations for diabe- glycemic burden is a strong predictor with false-negative tests will be retested tes in asymptomatic adults are listed in of adverse outcomes. There are effec- before substantial time elapses and Table 2.3. Age is a major risk factor for tive interventions that prevent progres- complications develop (37). sion from prediabetes to diabetes (see diabetes. Testing should begin at age Community Screening Section 5 “Prevention or Delay of Type 2 45 years for all patients. Screening Ideally, testing should be carried out Diabetes”) and reduce the risk of diabe- should be considered in overweight or within a health care setting because of tes complications (see Section 9 “Cardio- obese adults of any age with one or the need for follow-up and treatment. vascular Disease and Risk Management” more risk factors for diabetes. Community screening outside a health and Section 10 “Microvascular Complica- BMI and Ethnicity care setting is not recommended be- tions and Foot Care”). In general, BMI $25 kg/m2 is a risk fac- cause people with positive tests may Approximately one-quarter of people tor for diabetes. Data and recommenda- not seek, or have access to, appropriate with diabetes in the U.S. and nearly half tions from the ADA position statement follow-up testing and care. Community of Asian and Hispanic Americans with “BMI Cut Points to Identify At-Risk testing may also be poorly targeted; i.e., diabetes are undiagnosed (28). Although Asian Americans for Type 2 Diabetes it may fail to reach the groups most at screening of asymptomatic individuals to Screening” (32,33) suggest that the identify those with prediabetes or diabetes BMI cut point should be lower for the risk and inappropriately test those at might seem reasonable, rigorous clinical Asian American population. The BMI cut very low risk or even those who have trials to prove the effectiveness of such points fall consistently between 23 and already been diagnosed (38). screening have not been conducted and 24 kg/m2 (sensitivity of 80%) for nearly Screening in Dental Practices are unlikely to occur. all Asian American subgroups (with levels Because periodontal disease is associ- A large European randomized con- slightly lower for Japanese Americans). ated with diabetes, the utility of chair- trolled trial compared the impact of This makes a rounded cut point of side screening and referral to primary screening for diabetes and intensive 23 kg/m2 practical. In determining a sin- care as a means to improve the diagno- multifactorial intervention with that of gle BMI cut point, it is important to bal- sis of prediabetes and diabetes has been screening and routine care (29). General ance sensitivity and specificity so as to explored (39–41), with one study esti- practice patients between the ages of provide a valuable screening tool without mating that 30% of patients $30 years S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

of age seen in general dental practices Table 2.5—Testing for type 2 diabetes or prediabetes in asymptomatic children* (46) had dysglycemia (41). Further research Criteria is needed to demonstrate the feasibility, c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or effectiveness, and cost-effectiveness of weight .120% of ideal for height) screening in this setting. Plus any two of the following risk factors: c Family history of type 2 diabetes in first- or second-degree relative Screening and Testing for Type 2 c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Diabetes and Prediabetes in Children Islander) and Adolescents c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis In the last decade, the incidence and nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for- prevalence of type 2 diabetes in ado- gestational-age birth weight) ’ lescents has increased dramatically, c Maternal history of diabetes or GDM during the child s gestation especially in racial and ethnic minority Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age populations (23). Recent studies ques- Frequency: every 3 years tion the validity of A1C in the pediatric *Persons aged #18 years. population, especially among certain ethnicities, and suggest OGTT or FPG OGTT were not derived from data in as more suitable diagnostic tests (42). have lifelong screening for the de- the first half of pregnancy, so the diag- However, many of these studies do not velopment of diabetes or predia- nosis of GDM in early pregnancy by ei- recognize that diabetes diagnostic crite- betes at least every 3 years. B ther FPG or OGTT values is not evidence ria are based on long-term health out- c Women with a history of gestational based (48). comes, and validations are not currently diabetes mellitus found to have pre- available in the pediatric population diabetes should receive intensive Diagnosis (43). The ADA acknowledges the limited lifestyle interventions or metformin GDM carries risks for the mother and data supporting A1C for diagnosing to prevent diabetes. A neonate. Not all adverse outcomes are type 2 diabetes in children and adoles- of equal clinical importance. The Hyper- cents. Although A1C is not recom- fi glycemia and Adverse Pregnancy Out- mended for diagnosis of diabetes in De nition For many years, GDM was defined as come (HAPO) study (49), a large-scale children with cystic fibrosis or symptoms any degree of glucose intolerance that multinational cohort study completed suggestive of acute onset of type 1 di- was first recognized during pregnancy by more than 23,000 pregnant women, abetes and only A1C assays without (17), regardless of whether the condi- demonstrated that risk of adverse ma- interference are appropriate for children tion may have predated the pregnancy ternal, fetal, and neonatal outcomes with hemoglobinopathies, the ADA con- or persisted after the pregnancy. This continuously increased as a function of tinues to recommend A1C for diagnosis definition facilitated a uniform strategy maternal glycemia at 24–28 weeks, even of type 2 diabetes in this cohort (44,45). for detection and classification of GDM, within ranges previously considered The modified recommendations of the but it was limited by imprecision. normal for pregnancy. For most compli- ADA consensus report “Type 2 Diabetes The ongoing epidemic of obesity and cations, there was no threshold for risk. in Children and Adolescents” are sum- diabetes has led to more type 2 diabetes These results have led to careful recon- marized in Table 2.5 (46). in women of childbearing age, with an sideration of the diagnostic criteria for GESTATIONAL DIABETES increase in the number of pregnant GDM. GDM diagnosis (Table 2.6)can MELLITUS women with undiagnosed type 2 diabe- be accomplished with either of two tes (47). Because of the number of preg- strategies: Recommendations nant women with undiagnosed type 2 c Test for undiagnosed diabetes at diabetes, it is reasonable to test women 1. “One-step” 75-g OGTT or the first prenatal visit in those with risk factors for type 2 diabetes 2. “Two-step” approach with a 50-g with risk factors, using standard (Table 2.3) at their initial prenatal visit, (nonfasting) screen followed by a diagnostic criteria. B using standard diagnostic criteria (Table 100-g OGTT for those who screen c Test for gestational diabetes mel- 2.2). Women diagnosed with diabetes in positive litus at 24–28 weeks of gestation the first trimester should be classified as in pregnant women not previously having preexisting pregestational diabe- Different diagnostic criteria will identify known to have diabetes. A tes (type 2 diabetes or, very rarely, different degrees of maternal hypergly- c Test women with gestational dia- type 1 diabetes). GDM is diabetes that cemia and maternal/fetal risk, leading betes mellitus for persistent dia- is first diagnosed in the second or third some experts to debate, and disagree betes at 4–12 weeks’ postpartum, trimester of pregnancy that is not clearly on, optimal strategies for the diagnosis using the oral glucose tolerance either preexisting type 1 or type 2 dia- of GDM. test and clinically appropriate betes (see Section 13 “Management of One-Step Strategy nonpregnancy diagnostic crite- Diabetes in Pregnancy”). The Interna- In the 2011 Standards of Care (50), the ria. E tional Association of the Diabetes and ADA for the first time recommended c Women with a history of gesta- Pregnancy Study Groups (IADPSG) that all pregnant women not known to tional diabetes mellitus should GDM diagnostic criteria for the 75-g have prior diabetes undergo a 75-g care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Table 2.6—Screening for and diagnosis of GDM criteria for diagnosing GDM (54). The One-step strategy 15-member panel had representatives Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and from obstetrics/gynecology, maternal- 2h,at24228 weeks of gestation in women not previously diagnosed with overt diabetes. fetal medicine, pediatrics, diabetes re- The OGTT should be performed in the morning after an overnight fast of at least 8 h. search, biostatistics, and other related The diagnosis of GDM is made when any of the following plasma glucose values are met or fields. The panel recommended a two- exceeded: step approach to screening that used a c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) 1-h 50-g glucose load test (GLT) fol- c 2 h: 153 mg/dL (8.5 mmol/L) lowedbya3-h100-gOGTTforthose Two-step strategy who screened positive. Commonly Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 used cutoffs for the 1-h 50-g GLT include weeks of gestation in women not previously diagnosed with overt diabetes. 130, 135, and 140 mg/dL (7.2, 7.5, and If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 7.8 mmol/L). The American College of 140 mg/dL* (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT. Obstetricians and Gynecologists (ACOG) Step 2: The 100-g OGTT should be performed when the patient is fasting. recommends either 135 or 140 mg/dL The diagnosis of GDM is made if at least two of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded: (45). A systematic review for the U.S. Pre- ventive Services Task Force compared Carpenter/Coustan (59) or NDDG (60) GLT cutoffs of 130 mg/dL (7.2 mmol/L) c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) and 140 mg/dL (7.8 mmol/L) (55). The c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) higher cutoff yielded sensitivity of c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) – fi – c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) 70 88% and speci city of 69 89%, while the lower cutoff was 88–99% NDDG, National Diabetes Data Group. *The ACOG recommends either 135 mg/dL (7.5 mmol/L) – fi or 140 mg/dL (7.8 mmol/L). A systematic review determined that a cutoff of 130 mg/dL sensitive and 66 77% speci c. Data (7.2 mmol/L) was more sensitive but less specific than 140 mg/dL (7.8 mmol/L) (55). regarding a cutoff of 135 mg/dL are limited. As for other screening tests, choice of a cutoff is based upon the tradeoff between sensitivity and specificity. The use – OGTT at 24 28 weeks of gestation, older GDM diagnostic criteria. Those tri- of A1C at 24–28 weeks as a screening test fi based on a recommendation of the als found modest bene ts including re- for GDM does not function as well as the fi IADPSG (51). The IADPSG de ned diag- duced rates of large-for-gestational-age GLT (56). nostic cut points for GDM as the average births and preeclampsia (52,53). It is im- Key factors cited by the NIH panel in – fasting, 1-h, and 2-h plasma glucose val- portant to note that 80 90% of women their decision-making process were ues in the HAPO study at which odds for being treated for mild GDM in two ran- the lack of clinical trial data demon- adverse outcomes reached 1.75 times domized controlled trials could be man- strating the benefits of the one-step the estimated odds of these outcomes aged with lifestyle therapy alone. The strategy and the potential negative con- at the mean fasting, 1-h, and 2-h PG levels OGTT glucose cutoffs in these two trials sequences of identifying a large group of of the study population. This one-step overlapped with the thresholds recom- women with GDM, including medicaliza- strategy was anticipated to signifi- mended by the IADPSG, and in one trial tion of pregnancy with increased health cantly increase the incidence of GDM (53), the 2-h PG threshold (140 mg/dL care utilization and costs. Moreover, (from 5–6% to 15–20%), primarily be- [7.8 mmol/L]) was lower than the cutoff screening with a 50-g GLT does not re- cause only one abnormal value, not recommended by the IADPSG (153 mg/dL quire fasting and is therefore easier to two, became sufficient to make the di- [8.5 mmol/L]). No randomized con- accomplish for many women. Treatment agnosis. The ADA recognized that the trolled trials of identifying and treating of higher threshold maternal hypergly- anticipated increase in the incidence of GDM using the IADPSG criteria versus cemia, as identified by the two-step GDM would have a substantial impact older criteria have been published to approach, reduces rates of neonatal on costs and medical infrastructure date. Data are also lacking on how the macrosomia, large-for-gestational-age needs and had the potential to “medi- treatment of lower levels of hyperglyce- births (57), and shoulder dystocia, with- ’ calize” pregnancies previously catego- mia affects a mother s future risk for the out increasing small-for-gestational-age rized as normal. Nevertheless, the ADA development of type 2 diabetes and her births. ACOG updated its guidelines in ’ recommended these changes in diag- offspring s risk for obesity, diabetes, and 2013 and supported the two-step ap- nostic criteria with the intent of optimiz- other metabolic disorders. Additional proach (58). The ACOG recommends ei- ing gestational outcomes because these well-designed clinical studies are needed ther of two sets of diagnostic thresholds criteria were the only ones based on to determine the optimal intensity of for the 3-h 100-g OGTT (59,60). Each is pregnancy outcomes rather than end monitoring and treatment of women based on different mathematical con- points such as prediction of subsequent with GDM diagnosed by the one-step versions of the original recommended maternal diabetes. strategy. thresholds, which used whole blood The expected benefits to the offspring Two-Step Strategy and nonenzymatic methods for glucose are inferred from intervention trials that In 2013, the National Institutes of Health determination. A recent secondary anal- focused on women with lower levels of (NIH) convened a consensus develop- ysis of data from a randomized clinical hyperglycemia than identified using ment conference to consider diagnostic trial of identification and treatment of S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

mild GDM (61) demonstrated that treat- ages). MODY is characterized by impaired inheritance) should have genetic ment was similarly beneficial in patients insulin secretion with minimal or no de- testing for maturity-onset diabe- meeting only the lower thresholds (59) fects in insulin action (in the absence of tes of the young. A and in those meeting only the higher coexistent obesity). It is inherited in an au- c In both instances, consultation thresholds (60). If the two-step approach tosomal dominant pattern with abnormal- with a center specializing in diabetes is used, it would appear advantageous to ities in at least 13 genes on different genetics is recommended to under- use the lower diagnostic thresholds as chromosomes identified to date. The stand the significance of these mu- shown in Step 2 in Table 2.6. most commonly reported forms are GCK- tations and how best to approach MODY (MODY2), HNF1A-MODY (MODY3), Future Considerations further evaluation, treatment, and and HNF4A-MODY (MODY1). The conflicting recommendations from genetic counseling. E expert groups underscore the fact that Clinically, patients with GCK-MODY there are data to support each strategy. exhibit mild, stable, fasting hyperglyce- A cost-benefit estimation comparing the Monogenic defects that cause b-cell mia and do not require antihyperglyce- two strategies concluded that the one- dysfunction, such as neonatal diabetes mic therapy except sometimes during step approach is cost-effective only if and MODY, represent a small fraction of pregnancy. Patients with HNF1A- or patients with GDM receive postdelivery patients with diabetes (,5%). Table 2.7 HNF4A-MODY usually respond well to counseling and care to prevent type 2 describes the most common causes of low doses of sulfonylureas, which are fi diabetes (62). The decision of which monogenic diabetes. For a comprehen- considered rst-line therapy. Mutations strategy to implement must therefore sive list of causes, see Genetic Diagnosis or deletions in HNF1B are associated be made based on the relative values of Endocrine Disorders (68). with renal cysts and uterine malforma- placed on factors that have yet to be tions (renal cysts and diabetes [RCAD] measured (e.g., willingness to change Neonatal Diabetes syndrome). Other extremely rare forms practice based on correlation studies Diabetes occurring under 6 months of of MODY have been reported to involve rather than intervention trial results, age is termed “neonatal” or “congeni- other transcription factor genes includ- available infrastructure, and importance tal” diabetes, and about 80–85% of ing PDX1 (IPF1)andNEUROD1. of cost considerations). cases can be found to have an underly- As the IADPSG criteria (“one-step strating monogenic cause (69). Neonatal Diagnosis egy”) have been adopted internationally, diabetes occurs much less often after A diagnosis of one of the three most further evidence has emerged to support 6 months of age, whereas autoimmune common forms of MODY including GCK- improved pregnancy outcomes with cost type 1 diabetes rarely occurs before MODY, HNF1A-MODY, and HNF4A-MODY savings (63) and may be the preferred ap- 6 months of age. Neonatal diabetes allows for more cost-effective therapy (no proach. Data comparing population-wide can either be transient or permanent. therapy for GCK-MODY; sulfonylureas as fi outcomes with one-step versus two-step Transient diabetes is most often due to rst-line therapy for HNF1A-MODY and approaches have been inconsistent to overexpression of genes on chromo- HNF4A-MODY). Additionally, diagnosis fi date (64,65). In addition, pregnancies com- some 6q24, is recurrent in about half canleadtoidenti cation of other affected plicated by GDM per the IADPSG criteria, of cases, and may be treatable with med- family members. but not recognized as such, have compa- ications other than insulin. Permanent A diagnosis of MODY should be con- rable outcomes to pregnancies diag- neonatal diabetes is most commonly sidered in individuals who have atypical nosed as GDM by the more stringent due to autosomal dominant mutations diabetes and multiple family members two-step criteria (66,67). There remains in the genes encoding the Kir6.2 subunit with diabetes not characteristic of strong consensus that establishing a uni- (KCNJ11) and SUR1 subunit (ABCC8)of type 1 or type 2 diabetes, although ad- mittedly “atypical diabetes” is becoming form approach to diagnosing GDM will the b-cell KATP channel. Correct diagnosis fi fi benefit patients, caregivers, and policy- has critical implications because most pa- increasingly dif cult to precisely de ne in the absence of a definitive set of tests makers. Longer-term outcome studies tients with KATP-related neonatal diabetes are currently under way. will exhibit improved glycemic control for either type of diabetes. In most when treated with high-dose oral sulfo- cases, the presence of autoantibodies MONOGENIC DIABETES nylureas instead of insulin. Insulin gene for type 1 diabetes precludes further SYNDROMES (INS) mutations are the second most testing for monogenic diabetes, but the common cause of permanent neonatal presence of autoantibodies in patients Recommendations diabetes, and, while treatment presently with monogenic diabetes has been re- c All children diagnosed with diabe- ported (70). Individuals in whom mono- tes in the first 6 months of life is intensive insulin management, there genic diabetes is suspected should be should have immediate genetic are important genetic considerations as referred to a specialist for further eva- testing for neonatal diabetes. A most of the mutations that cause diabetes are dominantly inherited. luation if available, and consultation is c Children and adults, diagnosed in available from several centers. Readily early adulthood, who have diabe- available commercial genetic testing tes not characteristic of type 1 or Maturity-Onset Diabetes of the Young MODY is frequently characterized by following the criteria listed below now type 2 diabetes that occurs in suc- onset of hyperglycemia at an early enables a cost-effective (71), often cessive generations (suggestive of age (classically before age 25 years, al- cost-saving, genetic diagnosis that is in- an autosomal dominant pattern of though diagnosis may occur at older creasingly supported by health insurance. It care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

Table 2.7—Most common causes of monogenic diabetes (68) Gene Inheritance Clinical features MODY GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does not require treatment; microvascular complications are rare; small rise in 2-h PG level on OGTT (,54 mg/dL [3 mmol/L]) HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive to sulfonylureas HNF1B AD HNF1B-MODY:developmentalrenaldisease(typicallycystic);genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout Neonatal diabetes KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures; responsive to sulfonylureas INS AD Permanent: IUGR; insulin requiring ABCC8 AD Transient or permanent: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 AD for paternal Transient:IUGR;macroglossia;umbilical hernia;mechanismsincludeUPD6, (PLAGL1, HYMA1) duplications paternal duplication or maternal methylation defect; may be treatable with medications other than insulin GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine insufficiency; insulin requiring EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine insufficiency; insulin requiring FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome: autoimmune diabetes; autoimmune thyroid disease; exfoliative dermatitis; insulin requiring AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction. is critical to correctly diagnose one of the features, especially with strong family Cystic fibrosis–related diabetes (CFRD) is monogenic forms of diabetes because history of diabetes) the most common comorbidity in people these patients may be incorrectly diag- ○ Stable, mild fasting hyperglycemia with cystic fibrosis, occurring in about 20% nosed with type 1 or type 2 diabetes, lead- (100–150 mg/dL [5.5–8.5 mmol/L]), of adolescents and 40–50% of adults. Di- ing to suboptimal, even potentially harmful, stable A1C between 5.6 and 7.6% abetes in this population, compared with treatment regimens and delays in diagnos- (between 38 and 60 mmol/mol), espe- individuals with type 1 or type 2 diabetes, ing other family members (72). The infor- cially if nonobese is associated with worse nutritional status, mation is especially critical for GCK-MODY more severe inflammatory lung disease, CYSTIC FIBROSIS–RELATED mutations where multiple studies have and greater mortality. Insulin insufficiency DIABETES shown that no complications ensue in is the primary defect in CFRD. Genetically the absence of glucose-lowering therapy Recommendations determined b-cell function and insulin re- fi – (73). Genetic counseling is recommen- c Annual screening for cystic brosis sistance associated with infection and in- fl ded to ensure that affected individuals related diabetes with oral glucose ammation may also contribute to the understand the patterns of inheritance tolerance test should begin by age development of CFRD. Milder abnormali- 10 years in all patients with cystic fi- and the importance of a correct diagnosis. ties of glucose tolerance are even more brosis not previously diagnosed with The diagnosis of monogenic diabetes common and occur at earlier ages than cystic fibrosis–related diabetes. B should be considered in children and CFRD. Whether individuals with IGT should c A1C as a screening test for cystic adults diagnosed with diabetes in early be treated with insulin replacement has not fibrosis–related diabetes is not adulthood with the following findings: currently been determined. Although recommended. B screening for diabetes before the age of c Patients with cystic fibrosis–related ○ Diabetes diagnosed within the first 10 years can identify risk for progression diabetes should be treated with in- 6 months of life (with occasional to CFRD in those with abnormal glucose sulin to attain individualized glyce- cases presenting later, mostly INS tolerance, no benefit has been established mic goals. A and ABCC8 mutations) (69,74) with respect to weight, height, BMI, or c Beginning 5 years after the diagnosis ○ Diabetes without typical features of lung function. Continuous glucose monitor- of cystic fibrosis–related diabetes, type 1 or type 2 diabetes (negative ing may be more sensitive than OGTT to annual monitoring for complications diabetes–associated autoantibodies; detect risk for progression to CFRD; how- of diabetes is recommended. E nonobese, lacking other metabolic ever, evidence linking continuous glucose S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

monitoring results to long-term outcomes describes individuals who develop diabetes diagnosis: the Search for Diabetes in is lacking, and its use is not recommended new-onset diabetes following trans- Youth Study. Pediatrics 2014;133:e938–e945 for screening (75). plant. NODAT excludes patients with 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differen- fi tiation of diabetes by pathophysiology, natural his- CFRD mortality has signi cantly de- pretransplant diabetes that was undiag- tory, and prognosis. Diabetes. 15 December 2016 creased over time, and the gap in mor- nosed as well as posttransplant hyper- [Epub ahead of print]. DOI: 10.2337/db16-0806 tality between cystic fibrosis patients glycemia that resolves by the time of 5. Insel RA, Dunne JL, Atkinson MA, et al. Stag- with and without diabetes has consider- discharge (80). Another term, “posttrans- ing presymptomatic type 1 diabetes: a scientific ably narrowed (76). There are limited plantation diabetes mellitus” (PTDM) statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes clinical trial data on therapy for CFRD. (80), describes the presence of diabetes Care 2015;38:1964–1974 The largest study compared three regi- in the posttransplant setting irrespective 6. International Expert Committee. Interna- mens: premeal insulin aspart, repagli- of the timing of diabetes onset. tional Expert Committee report on the role of nide, or oral placebo in cystic fibrosis Hyperglycemia is very common dur- the A1C assay in the diagnosis of diabetes. – patients with diabetes or abnormal glu- ing the early posttransplant period, Diabetes Care 2009;32:1327 1334 7. Knowler WC, Barrett-Connor E, Fowler SE, cose tolerance. Participants all had weight with ;90% of kidney allograft recipients et al.; Diabetes Prevention Program Research loss in the year preceding treatment; how- exhibiting hyperglycemia in the first Group. Reduction in the incidence of type 2 di- ever, in the insulin-treated group, this pat- few weeks following transplant (80,81). abetes with lifestyle intervention or metformin. tern was reversed, and patients gained In most cases, such stress or steroid- N Engl J Med 2002;346:393–403 ¨ 0.39 (6 0.21) BMI units (P 5 0.02). The induced hyperglycemia resolves by the 8. Tuomilehto J, Lindstrom J, Eriksson JG, et al.; Finnish Diabetes Prevention Study Group. Pre- repaglinide-treated group had initial time of discharge. Risk factors for PTDM vention of type 2 diabetes mellitus by changes in weight gain, but this was not sustained include both general diabetes risks (such lifestyle among subjects with impaired glucose by 6 months. The placebo group continued as age, family history of diabetes, etc.) tolerance. N Engl J Med 2001;344:1343–1350 to lose weight (77). Insulin remains the as well as transplant-specificfactors, 9. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prev- alence of diabetes and high risk for diabetes most widely used therapy for CFRD (78). such as use of immunosuppressant using A1C criteria in the U.S. population in Recommendations for the clinical agents. Whereas posttransplantation 1988–2006. Diabetes Care 2010;33:562–568 management of CFRD can be found in hyperglycemia is an important risk factor 10. Nowicka P, Santoro N, Liu H, et al. Utility of the ADA position statement “Clinical for subsequent PTDM, a formal diagnosis hemoglobin A1c for diagnosing prediabetes and Care Guidelines for Cystic Fibrosis–Related of PTDM is optimally made once the pa- diabetes in obese children and adolescents. Di- abetes Care 2011;34:1306–1311 Diabetes: A Position Statement of the tient is stable on maintenance immuno- 11. Ziemer DC, Kolm P, Weintraub WS, et al. American Diabetes Association and a suppression and in the absence of acute Glucose-independent, black-white differences in Clinical Practice Guideline of the Cystic infection. hemoglobin A1c levels: a cross-sectional analysis Fibrosis Foundation, Endorsed by the The OGTT is considered the gold stan- of 2 studies. Ann Intern Med 2010;152:770–777 Pediatric Endocrine Society” (79). dard test for the diagnosis of PTDM 12. Kumar PR, Bhansali A, Ravikiran M, et al. Utility – of glycated hemoglobin in diagnosing type 2 diabe- (80,82 84). However, screening patients tes mellitus: a community-based study. J Clin Endo- POSTTRANSPLANTATION using fasting glucose and/or A1C can crinol Metab 2010;95:2832–2835 DIABETES MELLITUS identify high-risk patients requiring fur- 13. Herman WH, Ma Y, Uwaifo G, et al.; Diabe- ther assessment and may reduce the tes Prevention Program Research Group. Differ- Recommendations number of overall OGTTs required (85). ences in A1C by race and ethnicity among c Patients should be screened after patients with impaired glucose tolerance in There is currently a lack of clinical data organ transplantation for hyper- the Diabetes Prevention Program. Diabetes glycemia, with a formal diagnosis examining the use of antidiabetes agents Care 2007;30:2453–2457 fi of posttransplantation diabetes in the setting of PTDM to inform speci c 14. Carson AP, Munter P, Selvin E, et al. Do glycemic marker levels vary by race? Differing mellitus being best made once a recommendations for use in this population. Although the use of immunosup- results from a cross-sectional analysis of individ- patient is stable on an immuno- uals with and without diagnosed diabetes. BMJ pressive therapies is a major contributor suppressive regimen and in the ab- Open Diabetes Res Care 2016;4:e000213 sence of an acute infection. E to the development of PTDM, the risks of 15. Herman WH, Dungan KM, Wolffenbuttel BH, transplant rejection outweigh the risks of et al. Racial and ethnic differences in mean plasma c The oral glucose tolerance test is glucose, hemoglobin A1c, and 1,5-anhydroglucitol the preferred test to make a diag- PTDM and the role of the diabetes care provider is to treat hyperglycemia appro- in over 2000 patients with type 2 diabetes. J Clin nosis of posttransplantation dia- Endocrinol Metab 2009;94:1689–1694 priately regardless of the type of immuno- betes mellitus. B 16. Selvin E, Rawlings AM, Bergenstal RM, suppression (80). c Immunosuppressive regimens Coresh J, Brancati FL. No racial differences in shown to provide the best outcomes the association of glycated hemoglobin with kidney disease and cardiovascular outcomes. for patient and graft survival should References Diabetes Care 2013;36:2995–3001 be used, irrespective of posttrans- 1. American Diabetes Association. Diagnosis 17. 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N Engl J Med 2005;352:2477–2486 conversion to multiple islet autoantibodies and Community-based screening for diabetes in 54. Vandorsten JP, Dodson WC, Espeland MA, risk of progression to diabetes in children. JAMA Michigan. Diabetes Care 2003;26:668–670 et al. NIH consensus development conference: 2013;309:2473–2479 39. Lalla E, Kunzel C, Burkett S, Cheng B, diagnosing gestational diabetes mellitus. NIH 25. Sosenko JM, Skyler JS, Palmer JP, et al.; Lamster IB. Identification of unrecognized dia- Consens State Sci Statements 2013;29:1–31 Type 1 Diabetes TrialNet Study Group; Diabetes betes and pre-diabetes in a dental setting. 55. Donovan L, Hartling L, Muise M, Guthrie A, Prevention Trial–Type 1 Study Group. The pre- J Dent Res 2011;90:855–860 Vandermeer B, Dryden DM. Screening tests for diction of type 1 diabetes by multiple autoanti- 40. Lalla E, Cheng B, Kunzel C, Burkett S, gestational diabetes: a systematic review for body levels and their incorporation into an Lamster IB. Dental findings and identification the U.S. Preventive Services Task Force. Ann In- autoantibody risk score in relatives of type 1 of undiagnosed hyperglycemia. J Dent Res tern Med 2013;159:115–122 diabetic patients. Diabetes Care 2013;36: 2013;92:888–892 56. Khalafallah A, Phuah E, Al-Barazan AM, 2615–2620 41. Herman WH, Taylor GW, Jacobson JJ, Burke et al. Glycosylated haemoglobin for screening 26. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY R, Brown MB. Screening for prediabetes and and diagnosis of gestational diabetes mellitus. Study Group. Predictors of progression from the type 2 diabetes in dental offices. J Public Health BMJ Open 2016;6:e011059 appearance of islet autoantibodies to early Dent 2015;75:175–182 57. Horvath K, Koch K, Jeitler K, et al. Effects of childhood diabetes: The Environmental Deter- 42. Buse JB, Kaufman FR, Linder B, Hirst K, El treatment in women with gestational diabetes minants of Diabetes in the Young (TEDDY). 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Int J Pediatr En- Obstet Gynecol 1982;144:768–773 Prevalence of and trends in diabetes among docrinol 2012;2012:31 60. National Diabetes Data Group. Classifica- adults in the United States, 1988–2012. JAMA 44. Kester LM, Hey H, Hannon TS. Using hemo- tion and diagnosis of diabetes mellitus and 2015;314:1021–1029 globin A1c for prediabetes and diabetes diagno- other categories of glucose intolerance. Diabe- 29. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. sis in adolescents: can adult recommendations tes 1979;28:1039–1057 Effect of early intensive multifactorial therapy be upheld for pediatric use? J Adolesc Health 61. Harper LM, Mele L, Landon MB, et al.; Eu- on 5-year cardiovascular outcomes in individu- 2012;50:321–323 nice Kennedy Shriver National Institute of Child als with type 2 diabetes detected by screening 45. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness Health and Human Development (NICHD) (ADDITION-Europe): a cluster-randomised trial. of screening strategies for identifying pediatric Maternal-Fetal Medicine Units (MFMU) Network. Lancet 2011;378:156–167 diabetes mellitus and dysglycemia. JAMA Pediatr Carpenter-Coustan compared with National 30. Herman WH, Ye W, GriffinSJ,etal.Early 2013;167:32–39 Diabetes Data Group criteria for diagnosing ges- detection and treatment of type 2 diabetes re- 46. American Diabetes Association. Type 2 dia- tational diabetes. Obstet Gynecol 2016;127: duce cardiovascular morbidity and mortality: a betes in children and adolescents. Diabetes 893–898 simulation of the results of the Anglo-Danish- Care 2000;23:381–389 62. Werner EF, Pettker CM, Zuckerwise L, et al. Dutch study of intensive treatment in people 47. Lawrence JM, Contreras R, Chen W, Sacks Screening for gestational diabetes mellitus: are with screen-detected diabetes in primary care DA. Trends in the prevalence of preexisting the criteria proposed by the International Asso- (ADDITION-Europe). Diabetes Care 2015;38: diabetes and gestational diabetes mellitus ciation of the Diabetes and Pregnancy Study 1449–1455 among a racially/ethnically diverse population Groups cost-effective? Diabetes Care 2012;35: 31. Kahn R, Alperin P, Eddy D, et al. Age at ini- of pregnant women, 1999–2005. Diabetes Care 529–535 tiation and frequency of screening to detect 2008;31:899–904 63. Duran A, Saenz´ S, Torrejon´ MJ, et al. Intro- type 2 diabetes: a cost-effectiveness analysis. 48. McIntyre HD, Sacks DA, Barbour LA, et al. duction of IADPSG criteria for the screening and Lancet 2010;375:1365–1374 Issues with the diagnosis and classification of diagnosis of gestational diabetes mellitus re- 32. Araneta MR, Kanaya A, Hsu WC, et al. Op- hyperglycemia in early pregnancy. Diabetes sults in improved pregnancy outcomes at a timum BMI cut points to screen Asian Ameri- Care 2016;39:53–54 lower cost in a large cohort of pregnant women: cans for type 2 diabetes. Diabetes Care 2015; 49. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO the St. Carlos Gestational Diabetes Study. Dia- 38:814–820 Study Cooperative Research Group. Hyperglycemia betes Care 2014;37:2442–2450 S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

64. Wei Y, Yang H, Zhu W, et al. International with later diabetes onset and higher HbA1c 78. Onady GM, Stolfi A. Insulin and oral agents Association of Diabetes and Pregnancy Study level. Diabet Med 2014;31:466–471 for managing cystic fibrosis-related diabetes. Group criteria is suitable for gestational diabetes 71. Naylor RN, John PM, Winn AN, et al. Cost- Cochrane Database Syst Rev 2016;4:CD004730 mellitus diagnosis: further evidence from China. effectiveness of MODY genetic testing: translat- 79. Moran A, Brunzell C, Cohen RC, et al.; CFRD Chin Med J (Engl) 2014;127:3553–3556 ing genomic advances into practical health Guidelines Committee. Clinical care guidelines 65. Feldman RK, Tieu RS, Yasumura L. Gestational applications. Diabetes Care 2014;37:202–209 for cystic fibrosis–related diabetes: a position diabetes screening: the International Association 72. Hattersley A, Bruining J, Shield J, Njolstad P, statement of the American Diabetes Association of the Diabetes and Pregnancy Study Groups Donaghue KC. The diagnosis and management and a clinical practice guideline of the Cystic Fibrosis compared with Carpenter-Coustan screening. of monogenic diabetes in children and adolescents. Foundation, endorsed by the Pediatric Endocrine – Obstet Gynecol 2016;127:10–17 Pediatr Diabetes 2009;10(Suppl. 12):33–42 Society. Diabetes Care 2010;33:2697 2708 66. Ethridge JK Jr, Catalano PM, Waters TP. 73. Rubio-Cabezas O, Hattersley AT, Njølstad 80. Sharif A, Hecking M, de Vries APJ, et al. Pro- Perinatal outcomes associated with the diagno- PR, et al.; International Society for Pediatric ceedings from an international consensus meet- sis of gestational diabetes made by the Interna- and Adolescent Diabetes. ISPAD Clinical Practice ing on posttransplantation diabetes mellitus: tional Association of the Diabetes and Pregnancy Consensus Guidelines 2014. The diagnosis and recommendations and future directions. Am J Transplant 2014;14:1992–2000 Study Groups criteria. Obstet Gynecol 2014;124: management of monogenic diabetes in children 81. Ramirez SC, Maaske J, Kim Y, et al. The as- 571–578 and adolescents. Pediatr Diabetes 2014;15 sociation between glycemic control and clinical 67. Mayo K, Melamed N, Vandenberghe H, (Suppl. 20):47–64 outcomes after kidney transplantation. Endocr Berger H. The impact of adoption of the Inter- 74. Greeley SAW, Naylor RN, Philipson LH, Bell Pract 2014;20:894–900 national Association of Diabetes in Pregnancy GI. Neonatal diabetes: an expanding list of 82. Sharif A, Moore RH, Baboolal K. The use of Study Group criteria for the screening and di- genes allows for improved diagnosis and treat- oral glucose tolerance tests to risk stratify for – agnosis of gestational diabetes. Am J Obstet Gy- ment. Curr Diab Rep 2011;11:519 532 new-onset diabetes after transplantation: an – necol 2015;212:224.e1 224.e9 75. Ode KL, Moran A. New insights into cystic underdiagnosed phenomenon. Transplantation fi 68. Carmody D, Støy J, Greeley SA, Bell GI, brosis-related diabetes in children. Lancet Di- 2006;82:1667–1672 – Philipson LH. A clinical guide to monogenic diabetes Endocrinol 2013;1:52 58 83. Hecking M, Werzowa J, Haidinger M, et al. abetes. In Genetic Diagnosis of Endocrine Disor- 76.MoranA,DunitzJ,NathanB,SaeedA,Holme Novel views on new-onset diabetes after transplan- fi ders. 2nd ed. Weiss RE, Refetoff S, Eds. Philadelphia, B, Thomas W. Cystic brosis-related diabetes: cur- tation: development, prevention and treatment. PA, Elsevier, 2016 rent trends in prevalence, incidence, and mortality. Nephrol Dial Transplant 2013;28:550–566 69. De Franco E, Flanagan SE, Houghton JAL, Diabetes Care 2009;32:1626–1631 84. Hecking M, Kainz A, Werzowa J, et al. Glu- et al. The effect of early, comprehensive geno- 77. Moran A, Pekow P, Grover P, et al.; Cystic cose metabolism after renal transplantation. Di- mic testing on clinical care in neonatal diabetes: Fibrosis Related Diabetes Therapy Study Group. abetes Care 2013;36:2763–2771 an international cohort study. Lancet 2015;386: Insulin therapy to improve BMI in cystic fibrosis- 85. Valderhaug TG, Jenssen T, Hartmann A, 957–963 related diabetes without fasting hyperglycemia: et al. Fasting plasma glucose and glycosylated 70. UrbanovaJ,Ryp´ aćkovˇ aB,Proch´ azkov´ aZ,´ results of the Cystic Fibrosis Related Diabetes hemoglobin in the screening for diabetes melli- et al. Positivity for islet cell autoantibodies in Therapy Trial. Diabetes Care 2009;32:1783– tus after renal transplantation. Transplantation patients with monogenic diabetes is associated 1788 2009;88:429–434 Diabetes Care Volume 40, Supplement 1, January 2017 S25

3. Comprehensive Medical American Diabetes Association Evaluation and Assessment of Comorbidities Diabetes Care 2017;40(Suppl. 1):S25–S32 | DOI: 10.2337/dc17-S006

PATIENT-CENTERED COLLABORATIVE CARE

Recommendation

c A patient-centered communication style that uses active listening, elicits pa- COMORBIDITIES AND EVALUATION MEDICAL tient preferences and beliefs, and assesses literacy, numeracy, and potential barriers to care should be used to optimize patient health outcomes and health-related quality of life. B

A successful medical evaluation depends on beneficial interactions between the patient and the care team. The Chronic Care Model (1–3) (see Section 1 “Promoting Health and Reducing Disparities in Populations”) is a patient-centered approach to care that requires a close working relationship between the patient and clinicians involved in treatment planning. People with diabetes should receive health care from a team that may include physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals. Individuals with diabetes must assume an active role in their care. The patient, family or support persons, physician, and health care team should formulate the management plan, which includes lifestyle management (see Section 4 “Lifestyle Management”). Treatment goals and plans should be created with the patients based on their individual preferences, values, and goals. The management plan should take into account the patient’s age, cognitive abilities, school/work schedule and conditions, health beliefs, support systems, eating patterns, physical activity, social situation, financial concerns, cultural factors, literacy and numeracy (mathematical literacy) skills, diabetes complications, comorbidities, health priorities, other medical conditions, preferences for care, and life expectancy. Various strategies and techniques should be used to support patients’ self-management efforts, including providing education on problem-solving skills for all aspects of diabetes management. Provider communications with patients/families should acknowledge that multiple factors impact glycemic management, but also emphasize that collaboratively developed treatment plans and a healthy lifestyle can significantly improve disease outcomes and well-being (4–7). Thus, the goal of provider-patient communication is to establish a collaborative relationship and to assess and address self-management barriers without blaming patients for “noncompliance” or “nonadherence” when the outcomes of self-management are not optimal (8). The familiar terms “noncompliance” and “nonadherence” denote a passive, obedient role for a person with diabetes in “following doctor’sorders” that is at odds with the active role people Suggested citation: American Diabetes Associa- with diabetes take in directing the day-to-day decision making, planning, monitor- tion. Comprehensive medical evaluation and as- ing, evaluation, and problem-solving involved in diabetes self-management. Using sessment of comorbidities. Sec. 3. In Standards of a nonjudgmental approach that normalizes periodic lapses in self-management Medical Care in Diabetesd2017. Diabetes Care may help minimize patients’ resistance to reporting problems with self-management. 2017;40(Suppl. 1):S25–S32 Empathizing and using active listening techniques, such as open-ended ques- © 2017 by the American Diabetes Association. tions, reflective statements, and summarizing what the patient said can help Readers may use this article as long as the work ’ is properly cited, the use is educational and not facilitate communication. Patients perceptions about their own ability, or self- for profit, and the work is not altered. More infor- efficacy, to self-manage diabetes are one important psychosocial factor related mation is available at http://www.diabetesjournals to improved diabetes self-management and treatment outcomes in diabetes .org/content/license. S26 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 40, Supplement 1, January 2017

(9–13) and should be a target of ongo- and implementing an approach to glycemic Pneumococcal Pneumonia ing assessment, patient education, control with the patient is a part, not the Like influenza, pneumococcal pneumonia and treatment planning. sole goal, of care. is a common, preventable disease. People with diabetes may be at increased risk for Immunization the bacteremic form of pneumococcal in- COMPREHENSIVE MEDICAL Recommendations fection and have been reported to have a EVALUATION c Provide routine vaccinations for chil- high risk of nosocomial bacteremia, with a Recommendations dren and adults with diabetes accord- mortalityrateashighas50%(18).Allpa- A complete medical evaluation should ing to age-related recommendations. C tients with diabetes 2 years of age and be performed at the initial visit to c Annual vaccination against influenza older should receive the pneumococcal is recommended for all persons with polysaccharide vaccine (PPSV23). There c Confirm the diagnosis and classify diabetes $6monthsofage.C is sufficient evidence to support that diabetes. B c Vaccination against pneumonia is adults with diabetes ,65 years of age c Detect diabetes complications and recommended for all people with have appropriate serologic and clinical re- potential comorbid conditions. E diabetes 2 through 64 years of age sponses to these vaccinations (19). The c Review previous treatment and risk with pneumococcal polysaccharide American Diabetes Association (ADA) en- factor control in patients with estab- vaccine (PPSV23). At age $65 years, dorses recommendations from the CDC lished diabetes. E administer the pneumococcal conju- ACIP that all adults 65 years of age or older c Begin patient engagement in the gate vaccine (PCV13) at least 1 year receive a dose of pneumococcal conjugate formulation of a care management after vaccination with PPSV23, fol- vaccine (PCV13) followed by a dose of plan. B lowed by another dose of vaccine PPSV23 at least 1 year later (and at least c Develop a plan for continuing care. B PPSV23 at least 1 year after PCV13 5 years after their previous PPSV23 dose). and at least 5 years after the last Hepatitis B The comprehensive medical evaluation dose of PPSV23. C Compared with the general population, (Table 3.1) includes the initial and ongo- c Administer 3-dose series of hepa- people with type 1 or type 2 diabetes ing evaluations, assessment of com- titis B vaccine to unvaccinated adults have higher rates of hepatitis B. This may plications, psychosocial assessment, with diabetes who are age 19–59 be due to contact with infected blood or management of comorbid conditions, years. C through improper equipment use (glucose and engagement of the patient through- c Consider administering 3-dose se- monitoring devices or infected needles). out the process. The goal is to provide ries of hepatitis B vaccine to un- Because of the higher likelihood of trans- the health care team information to opti- vaccinated adults with diabetes mission, hepatitis B vaccine is recom- mally support a patient. In addition to the who are age $60 years. C mended for adults with diabetes. medical history, physical examination, and laboratory tests, providers should assess di- As for the general population, all children ASSESSMENT OF COMORBIDITIES abetes self-management behaviors, nutri- and adults with diabetes should receive Besides assessing diabetes-related compli- tion, and psychosocial health (see Section vaccinations (15,16) according to age- cations, clinicians and their patients need 4 “Lifestyle Management”) and give guid- specific recommendations. The child and to be aware of common comorbidities ance on routine immunizations. Consider adolescent vaccination schedule is avail- that affect people with diabetes and may the assessment of sleep pattern and dura- able at http://www.cdc.gov/vaccines/ complicate management (20–24). Diabetes tion; a recent meta-analysis found that schedules/hcp/imz/child-adolescent.html, comorbidities are conditions that affect peo- poor sleep quality, short sleep, and long and the adult vaccination schedule is avail- ple with diabetes more often than age- sleep were associated with higher A1C in able at http://www.cdc.gov/vaccines/ matched people without diabetes. The people with type 2 diabetes (14). schedules/hcp/imz/adult.html. list below includes many of the common Lifestyle management and psychosocial The Centers for Disease Control and comorbidities observed in patients with care are the cornerstones of diabetes Prevention (CDC) Advisory Committee on diabetes but is not necessarily inclusive of management. Patients should be referred Immunization Practices (ACIP) recom- all the conditions that have been reported. for diabetes self-management education mends influenza and pneumococcal vac- (DSME), diabetes self-management sup- cines for individuals with diabetes (http:// Autoimmune Diseases port (DSMS), medical nutrition therapy www.cdc.gov/vaccines/schedules). Recommendation (MNT), and psychosocial/emotional health c Consider screening patients with concerns if indicated. Patients should receive Influenza type 1 diabetes for autoimmune recommended preventive care services Influenza is a common, preventable in- thyroid disease and celiac disease (e.g., immunizations, cancer screening, etc.); fectious disease associated with high soon after diagnosis. E smoking cessation counseling; and oph- mortality and morbidity in vulnera- thalmological, dental, and podiatric re- ble populations including the young and People with type 1 diabetes are at in- ferrals. Additional referrals should be the elderly and people with chronic dis- creased risk for other autoimmune dis- arranged as necessary (Table 3.2). Clini- eases. In a case-control study, the influ- eases including thyroid disease, primary cians should ensure that individuals with enza vaccine was found to reduce adrenal insufficiency, celiac disease, auto- diabetes are appropriately screened for diabetes-related hospital admission by immune gastritis, autoimmune hepatitis, complications and comorbidities. Discussing as much as 79% during fluepidemics(17). dermatomyositis, and myasthenia gravis care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S27

Table 3.1—Components of the comprehensive diabetes medical evaluation* Medical history c Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic laboratory finding) c Eating patterns, nutritional status, weight history, sleep behaviors (pattern and duration), and physical activity habits; nutrition education and behavioral support history and needs c Complementary and alternative medicine use c Presence of common comorbidities and dental disease c Screen for depression, anxiety, and disordered eating using validated and appropriate measures** c Screen for diabetes distress using validated and appropriate measures** c Screen for psychosocial problems and other barriers to diabetes self-management, such as limited financial, logistical, and support resources c History of tobacco use, alcohol consumption, and substance use c Diabetes education, self-management, and support history and needs c Review of previous treatment regimens and response to therapy (A1C records) c Assess medication-taking behaviors and barriers to medication adherence c Results of glucose monitoring and patient’s use of data c Diabetic ketoacidosis frequency, severity, and cause c Hypoglycemia episodes, awareness, and frequency and causes c History of increased blood pressure, abnormal lipids c Microvascular complications: retinopathy, nephropathy, and neuropathy (sensory, including history of foot lesions; autonomic, including sexual dysfunction and gastroparesis) c Macrovascular complications: coronary heart disease, cerebrovascular disease, and peripheral arterial disease c For women with childbearing capacity, review contraception and preconception planning Physical examination c Height, weight, and BMI; growth and pubertal development in children and adolescents c Blood pressure determination, including orthostatic measurements when indicated c Fundoscopic examination c Thyroid palpation c Skin examination (e.g., for acanthosis nigricans, insulin injection or infusion set insertion sites) c Comprehensive foot examination ○ Inspection ○ Palpation of dorsalis pedis and posterior tibial pulses ○ Presence/absence of patellar and Achilles reflexes ○ Determination of proprioception, vibration, and monofilament sensation Laboratory evaluation c A1C, if the results are not available within the past 3 months c If not performed/available within the past year ○ Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides, as needed ○ Liver function tests ○ Spot urinary albumin–to–creatinine ratio ○ Serum creatinine and estimated glomerular filtration rate ○ Thyroid-stimulating hormone in patients with type 1 diabetes *The comprehensive medical evaluation should ideally be done on the initial visit, although different components can be done as appropriate on follow-up visits. **Refer to the ADA position statement “Psychosocial Care for People With Diabetes” for additional details on diabetes-specific screening measures (65).

(25,26). Type 1 diabetes may also occur shared risk factors between type 2 diabetes be tailored to avoid significant hy- with other autoimmune diseases in the and cancer (older age, obesity, and physical poglycemia. B context of specific genetic disorders or pol- inactivity) but may also be due to diabetes- yglandular autoimmune syndromes (27). related factors (29), such as underlying dis- Diabetes is associated with a signifi- In autoimmune diseases, the immune sys- ease physiology or diabetes treatments, cantly increased risk and rate of cogni- tem fails to maintain self-tolerance to spe- although evidence for these links is scarce. tive decline and an increased risk of cific peptides within target organs. It is Patients with diabetes should be encour- likely that many factors trigger autoim- agedtoundergorecommendedage- mune disease; however, common trigger- and sex-appropriate cancer screenings and — ing factors are known for only some to reduce their modifiable cancer risk factors Table 3.2 Referrals for initial care management autoimmune conditions (i.e., gliadin pep- (obesity, physical inactivity, and smoking). c Eye care professional for annual dilated tides in celiac disease) (see Section 12 eye exam “Children and Adolescents”). Cognitive Impairment/Dementia c Family planning for women of reproductive age Recommendation c Cancer Registered dietitian for MNT c In people with cognitive impairment/ c Diabetes is associated with increased DSME/DSMS dementia, intensive glucose con- c Dentist for comprehensive dental and risk of cancers of the liver, pancreas, en- trol cannot be expected to reme- periodontal examination dometrium, colon/rectum, breast, and blad- diate deficits. Treatment should c Mental health professional, if indicated der (28). The association may result from S28 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 40, Supplement 1, January 2017

dementia (30,31). A recent meta-analysis Cochrane review found insufficient evi- general population and include vitamin of prospective observational studies in dence to recommend any dietary change D supplementation. For patients with people with diabetes showed a 73% infor the prevention or treatment of cogni- type 2 diabetes with fracture risk factors, creased risk of all types of dementia, a tive dysfunction (40). thiazolidinediones (48) and sodium– 56% increased risk of Alzheimer demen- glucose cotransporter 2 inhibitors (49) tia, and 127% increased risk of vascular Statins should be used with caution. A systematic review has reported that dementia compared with individuals data do not support an adverse effect of Hearing Impairment without diabetes (32). The reverse is statins on cognition (41). The U.S. Food Hearing impairment, both in high-frequency also true: people with Alzheimer demen- and Drug Administration (FDA) postmar- and low/mid-frequency ranges, is more tia are more likely to develop diabetes keting surveillance databases have also commoninpeoplewithdiabetesthanin than people without Alzheimer demen- revealed a low reporting rate for cogni- those without, perhaps due to neuropathy tia. In a 15-year prospective study of com- tive-related adverse events, including and/or vascular disease. In a National munity-dwelling people .60 years of age, cognitive dysfunction or dementia, with Health and Nutrition Examination Survey the presence of diabetes at baseline sig- statin therapy, similar to rates seen with (NHANES) analysis, hearing impairment nificantly increased the age- and sex- other commonly prescribed cardiovascu- was about twice as prevalent in people adjusted incidence of all-cause dementia, lar medications (41). Therefore fear of with diabetes compared with those with- Alzheimer disease, and vascular dementia cognitive decline should not be a barrier out, after adjusting for age and other risk compared with rates in those with normal to statin use in individuals with diabetes factors for hearing impairment (50). glucose tolerance (33). and a high risk for cardiovascular disease. HIV Hyperglycemia Fatty Liver Disease In those with type 2 diabetes, the degree Elevations of hepatic transaminase con- Recommendation c Patients with HIV should be screened and duration of hyperglycemia are re- centrations are associated with higher for diabetes and prediabetes with lated to dementia. More rapid cognitive BMI, waist circumference, and triglycer- a fasting glucose level every 6– decline is associated with both increased ide levels and lower HDL cholesterol 12 months before starting antire- A1C and longer duration of diabetes (34). levels. In a prospective analysis, diabe- troviral therapy and 3 months after The Action to Control Cardiovascular Risk tes was significantly associated with in- starting or changing antiretroviral in Diabetes (ACCORD) study found that cident nonalcoholic chronic liver disease therapy. If initial screening results each 1% higher A1C level was associated and with hepatocellular carcinoma (42). are normal, checking fasting glu- with lower cognitive function in individu- Interventions that improve metabolic cose every year is advised. If predi- als with type 2 diabetes (35). However, abnormalities in patients with diabetes abetes is detected, continue to the ACCORD study found no difference (weight loss, glycemic control, and treat- measure fasting glucose levels ev- in cognitive outcomes in participants ran- ment with specific drugs for hyperglyce- ery 3–6 months to monitor for pro- domly assigned to intensive and standard mia or dyslipidemia) are also beneficial gression to diabetes. E glycemic control, supporting the recom- for fatty liver disease (43,44). mendation that intensive glucose control should not be advised for the improve- Fractures Diabetes risk is increased with certain pro- ment of cognitive function in individuals Age-specific hip fracture risk is signifi- tease inhibitors (PIs) and nucleoside re- with type 2 diabetes (36). cantly increased in people with both verse transcriptase inhibitors (NRTIs). type 1 (relative risk 6.3) and type 2 (rel- New-onset diabetes is estimated to occur Hypoglycemia ative risk 1.7) diabetes in both sexes in more than 5% of patients infected with In type 2 diabetes, severe hypoglycemia (45). Type 1 diabetes is associated with HIV on PIs, whereas more than 15% may is associated with reduced cognitive osteoporosis, but in type 2 diabetes, an have prediabetes (51). PIs are associated function, and those with poor cognitive increased risk of hip fracture is seen de- with insulin resistance and may also lead function have more severe hypoglyce- spite higher bone mineral density (BMD) to apoptosis of pancreatic b-cells. NRTIs mia. In a long-term study of older pa- (46). In three large observational studies also affect fat distribution (both lipohy- tients with type 2 diabetes, individuals of older adults, femoral neck BMD T score pertrophy and lipoatrophy), which is asso- with one or more recorded episode of and the World Health Organization Frac- ciated with insulin resistance. severe hypoglycemia had a stepwise in- ture Risk Assessment Tool (FRAX) score Individuals with HIV are at higher risk crease in risk of dementia (37). Likewise, were associated with hip and nonspine for developing prediabetes and diabetes the ACCORD trial found that as cognitive fractures. Fracture risk was higher in par- on antiretroviral (ARV) therapies, so a function decreased, the risk of severe ticipants with diabetes compared with screening protocol is recommended hypoglycemia increased (38). Tailoring those without diabetes for a given T score (52). The A1C test underestimates glyce- glycemic therapy may help to prevent and age for a given FRAX score (47). Pro- mia in people with HIV and is not recom- hypoglycemia in individuals with cogni- viders should assess fracture history and mended for diagnosis and may present tive dysfunction. risk factors in older patients with diabetes challenges for monitoring (53). In those Nutrition and recommend measurement of BMD if with prediabetes, weight loss through In one study, adherence to the Mediter- appropriate for the patient’s age and sex. healthy nutrition and physical activity may ranean diet correlated with improved Fracture prevention strategies for people reduce the progression toward diabetes. cognitive function (39). However, a recent with diabetes are the same as for the Among patients with HIV and diabetes, care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S29

preventive health care using an approach diagnoses are considerably more com- General anxiety is a predictor of injection- similar to that used in patients without HIV mon in people with diabetes than for related anxiety and associated with fear is critical to reduce the risks of microvascu- those without the disease (64). Symp- of hypoglycemia (69,73). Fear of hypo- lar and macrovascular complications. toms, both clinical and subclinical, that glycemia and hypoglycemia unawareness For patients with HIV and ARV-associated interfere with the person’s ability to carry often co-occur, and interventions aimed hyperglycemia, it may be appropriate to out diabetes self-management must be at treating one often benefit both (74). consider discontinuing the problematic addressed. Diabetes distress is addressed Fear of hypoglycemia may explain avoid- ARV agents if safe and effective alterna- in Section 4 “Lifestyle Management,” as ance of behaviors associated with lowering tives are available (54). Before making this state is very common and distinct glucose such as increasing insulin doses or ARV substitutions, carefully consider the from a psychological disorder (65). frequency of monitoring. If fear of hypogly- possible effect on HIV virological control cemia is identified and a person does not and the potential adverse effects of new Anxiety Disorders have symptoms of hypoglycemia, a struc- ARV agents. In some cases, antihypergly- Recommendations tured program, blood glucose awareness cemic agents may still be necessary. c Consider screening for anxiety in training, delivered in routine clinical prac- people exhibiting anxiety or worries tice, can improve A1C, reduce the rate of Low Testosterone in Men regarding diabetes complications, severe hypoglycemia, and restore hypogly- Mean levels of testosterone are lower in insulin injections or infusion, taking cemia awareness (75,76). menwithdiabetescomparedwithage- medications, and/or hypoglycemia matched men without diabetes, but obe- that interfere with self-management Depression sity is a major confounder (55). Treatment behaviors and those who express Recommendations in asymptomatic men is controversial. The fear, dread, or irrational thoughts c Providers should consider annual evidence that testosterone replacement and/or show anxiety symptoms screening of all patients with dia- affects outcomes is mixed, and recent such as avoidance behaviors, exces- betes, especially those with a self- guidelines do not recommend testing or sive repetitive behaviors, or social reported history of depression, for treating men without symptoms (56). withdrawal. Refer for treatment if depressive symptoms with age- anxiety is present. B appropriate depression screening Obstructive Sleep Apnea c Persons with hypoglycemic un- Age-adjusted rates of obstructive sleep measures, recognizing that further awareness, which can co-occur apnea, a risk factor for cardiovascular evaluation will be necessary for with fear of hypoglycemia, should disease, are significantly higher (4- to individuals who have a positive be treated using blood glucose 10-fold) with obesity, especially with screen. B awareness training (or other c central obesity (57). The prevalence of Beginning at diagnosis of complica- evidence-based similar intervention) fi obstructive sleep apnea in the populations or when there are signi cant to help re-establish awareness of tion with type 2 diabetes may be as high changes in medical status, consider hypoglycemia and reduce fear of as 23%, and the prevalence of any sleep assessment for depression. B hyperglycemia. A c disordered breathing may be as high as Referrals for treatment of depres- 58% (58,59). In obese participants en- sion should be made to mental rolled in the Action for Health in Diabetes health providers with experience Anxiety symptoms and diagnosable disor- using cognitive behavioral ther- (Look AHEAD) trial, it exceeded 80% (60). ders (e.g., generalized anxiety disorder, Sleep apnea treatment (lifestyle modifi- apy, interpersonal therapy, or body dysmorphic disorder, obsessive- other evidence-based treatment cation, continuous positive airway pres- fi compulsive disorder, speci c phobias, approaches in conjunction with sure, oral appliances, and surgery) and posttraumatic stress disorder) are significantly improves quality of life and collaborative care with the pa- common in people with diabetes (66). tient’s diabetes treatment team. A blood pressure control. The evidence The Behavioral Risk Factor Surveillance for a treatment effect on glycemic con- System (BRFSS) estimated the lifetime trol is mixed (61). prevalence of generalized anxiety disor- History of depression, current depres- der to be 19.5% in people with either sion, and antidepressant medication Periodontal Disease Periodontal disease is more severe, and type 1 or type 2 diabetes (67). Common use are risk factors for the development fi maybemoreprevalent,inpatients diabetes-speci c concerns include fears of type 2 diabetes, especially if the indi- with diabetes than in those without related to hyperglycemia (68,69), not vidual has other risk factors such as obe- (62,63). Current evidence suggests meeting blood glucose targets (66), and sity and family history of type 2 diabetes – that periodontal disease adversely af- insulin injections or infusion (70). Onset (77 79). Elevated depressive symptoms fects diabetes outcomes, although ev- of complications presents another critical and depressive disorders affect one in idence for treatment benefits remains point when anxiety can occur (71). People four patients with type 1 or type 2 di- controversial (24). with diabetes who exhibit excessive diabetes (80). Thus, routine screening for abetes self-management behaviors well depressive symptoms is indicated in this Psychosocial/Emotional Disorders beyond what is prescribed or needed to high-risk population including people Prevalence of clinically significant psycho- achieve glycemic targets may be experi- with prediabetes (particularly those who pathology in people with diabetes ranges encing symptoms of obsessive-compulsive are overweight), type 1 or type 2 diabe- across diagnostic categories, and some disorder (72). tes, gestational diabetes mellitus and S30 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 40, Supplement 1, January 2017

postpartum diabetes. Regardless of diabe- When evaluating symptoms of disor- 3. Gabbay RA, Bailit MH, Mauger DT, Wagner tes type, women have significantly higher dered or disrupted eating in people with EH, Siminerio L. Multipayer patient-centered rates of depression than men (81). diabetes, etiology and motivation for the medical home implementation guided by the Chronic Care Model. Jt Comm J Qual Patient Routine monitoring with patient- behavior should be considered (85,91). Ad- Saf 2011;37:265–273 appropriate validated measures can junctive medication such as glucagon-like 4. UK Prospective Diabetes Study (UKPDS) help to identify if referral is warranted. peptide 1 receptor agonists (92) may help Group. Intensive blood-glucose control with sulpho- Remission of depressive symptoms or individuals to not only meet glycemic tar- nylureas or insulin compared with conventional disorder in adult patients suggests the gets but also to regulate hunger and food treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; need for ongoing monitoring of depression intake, thus having the potential to re- 352:837–853 recurrence within the context of routine duce uncontrollable hunger and bulimic 5. The Diabetes Control and Complications Trial care (77). Integrating mental and physical symptoms. Research Group. The effect of intensive health care can improve outcomes. Serious Mental Illness treatment of diabetes on the development and progression of long-term complications in insulin- When a patient is in psychological ther- Recommendations dependent diabetes mellitus. N Engl J Med 1993; apy (talk therapy), the mental health pro- c Annually screen people who are 329:977–986 vider should be incorporated into the prescribed atypical antipsychotic 6. Lachin JM, Genuth S, Nathan DM, Zinman B, diabetes treatment team (82). medications for prediabetes or Rutledge BN; DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascu- diabetes. B Disordered Eating Behavior lar complications in the Diabetes Control and c If a second-generation antipsy- Complications Trialdrevisited. Diabetes 2008; Recommendations chotic medication is prescribed for 57:995–1001 c Providers should consider reevalu- adolescents or adults with diabetes, 7. White NH, Cleary PA, Dahms W, Goldstein D, changes in weight, glycemic con- Malone J, Tamborlane WV; Diabetes Control ating the treatment regimen of and Complications Trial (DCCT)/Epidemiology people with diabetes who present trol, and cholesterol levels should of Diabetes Interventions and Complications with symptoms of disordered eat- be carefully monitored and the (EDIC) Research Group. Beneficial effects of in- ing behavior, an eating disorder, treatment regimen should be reas- tensive therapy of diabetes during adolescence: or disrupted patterns of eating. B sessed. C outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pe- c c Consider screening for disor- Incorporate monitoring of diabetes diatr 2001;139:804–812 dered or disrupted eating using self-care activities into treatment 8. Anderson RM, Funnell MM. Compliance and validated screening measures goals in people with diabetes and adherence are dysfunctional concepts in diabe- when hyperglycemia and weight serious mental illness. B tes care. Diabetes Educ 2000;26:597–604 loss are unexplained based on 9. Sarkar U, Fisher L, Schillinger D. Is self-efficacy associated with diabetes self-management across self-reported behaviors related Studies of individuals with serious men- race/ethnicity and health literacy? Diabetes Care to medication dosing, meal plan, – tal illness, particularly schizophrenia 2006;29:823 829 and physical activity. In addition, a 10. King DK, Glasgow RE, Toobert DJ, et al. and other thought disorders, show sig- review of the medical regimen is Self-efficacy, problem solving, and social- nificantly increased rates of type 2 dia- recommended to identify poten- environmental support are associated with di- betes (93). People with schizophrenia abetes self-management behaviors. Diabetes tial treatment-related effects on should be monitored for type 2 diabetes Care 2010;33:751–753 hunger/caloric intake. B because of the known comorbidity. Dis- 11. Nouwen A, Urquhart Law G, Hussain S, McGovern S, Napier H. Comparison of the role ordered thinking and judgment can be of self-efficacy and illness representations in re- Estimated prevalence of disordered expected to make it difficult to engage lation to dietary self-care and diabetes distress eating behaviors and diagnosable eat- in behaviors that reduce risk factors for in adolescents with type 1 diabetes. Psychol – ing disorders in people with diabetes type 2 diabetes, such as restrained eat- Health 2009;24:1071 1084 – ing for weight management. Coordinated 12. Beckerle CM, Lavin MA. Association of self- varies (83 85). For people with type 1 efficacy and self-care with glycemic control in diabetes, insulin omission causing gly- management of diabetes or prediabetes diabetes. Diabetes Spectr 2013;26:172–178 cosuria in order to lose weight is the and serious mental illness is recommended 13. Iannotti RJ, Schneider S, Nansel TR, et al. most commonly reported disordered to achieve diabetes treatment targets. In Self-efficacy, outcome expectations, and diabe- eating behavior (86,87); in people with addition, those taking second-generation tes self-management in adolescents with type 1 – (atypical) antipsychotics such as olanza- diabetes. J Dev Behav Pediatr 2006;27:98 105 type 2 diabetes, bingeing (excessive 14. Lee SWH, Ng KY, Chin WK. The impact of food intake with an accompanying pine require greater monitoring because sleep amount and sleep quality on glycemic con- sense of loss of control) is most com- of an increase in risk of type 2 diabetes trol in type 2 diabetes: a systematic review and monly reported. For people with type associated with this medication (94). meta-analysis. 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64. de Groot M, Golden SH, Wagner J. Psycho- of hypoglycemia in adults with type 1 diabetes: clinical sample of type 2 diabetes mellitus pa- logical conditions in adults with diabetes. Am a systematic review and meta-analysis. Diabe- tients. Rev Bras Psiquiatr 2005;27:135–138 Psychol 2016;71:552–562 tes Care 2015;38:1592–1609 85. Young-Hyman DL, Davis CL. Disordered eat- 65. Young-Hyman D, de Groot M, Hill-Briggs F, 75. Cox DJ, Gonder-Frederick L, Polonsky W, ing behavior in individuals with diabetes: impor- Gonzalez JS, Hood K, Peyrot M. Psychosocial Schlundt D, Kovatchev B, Clarke W. Blood tance of context, evaluation, and classification. care for people with diabetes: a position state- glucose awareness training (BGAT-2): long- Diabetes Care 2010;33:683–689 ment of the American Diabetes Association. Di- term benefits. Diabetes Care 2001;24:637– 86. Pinhas-Hamiel O, Hamiel U, Greenfield Y, abetes Care 2016;39:2126–2140 642 et al. Detecting intentional insulin omission for 66. 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Martyn-Nemeth P, Quinn L, Hacker E, Park H, poglycemia in diabetes: implications for diabe- during the Diabetes Prevention Program. Diabe- Kujath AS. Diabetes distress may adversely affect tes management and patient education. Patient tes Care 2008;31:420–426 the eating styles of women with type 1 diabetes. Educ Couns 2007;68:10–15 80. Anderson RJ, Freedland KE, Clouse RE, Acta Diabetol 2014;51:683–686 70. Zambanini A, Newson RB, Maisey M, Feher Lustman PJ. The prevalence of comorbid de- 91. Peterson CM, Fischer S, Young-Hyman D. MD. Injection related anxiety in insulin-treated di- pression in adults with diabetes: a meta-analysis. Topical review: a comprehensive risk model abetes. Diabetes Res Clin Pract 1999;46:239–246 Diabetes Care 2001;24:1069–1078 for disordered eating in youth with type 1 di- 71. Young-Hyman D, Peyrot M. Psychosocial 81. Clouse RE, Lustman PJ, Freedland KE, abetes. J Pediatr Psychol 2015;40:385–390 Care for People with Diabetes. 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4. Lifestyle Management American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S33–S43 | DOI: 10.2337/dc17-S007

Lifestyle management is a fundamental aspect of diabetes care and includes diabetes self-management education (DSME), diabetes self-management support (DSMS), nutrition therapy, physical activity, smoking cessation counseling, and psychosocial care. Patients and care providers should focus together on how to optimize lifestyle from the time of the initial comprehensive medical evaluation, throughout all subsequent evaluations and follow-up, and during the assessment of complications and management of comorbid conditions in order to enhance diabetes care.

DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT .LFSYEMANAGEMENT LIFESTYLE 4. Recommendations c In accordance with the national standards for diabetes self-management education and support, all people with diabetes should participate in diabetes self-management education to facilitate the knowledge, skills, and ability necessary for diabetes self-care and in diabetes self-management support to assist with implementing and sustaining skills and behaviors needed for ongoing self-management, both at diagnosis and as needed thereafter. B c Effective self-management and improved clinical outcomes, health status, and quality of life are key goals of diabetes self-management education and support that should be measured and monitored as part of routine care. C c Diabetes self-management education and support should be patient centered, respectful, and responsive to individual patient preferences, needs, and values and should help guide clinical decisions. A c Diabetes self-management education and support programs have the necessary elements in their curricula to delay or prevent the development of type 2 diabetes. Diabetes self-management education and support programs should therefore be able to tailor their content when prevention of diabetes is the desired goal. B c Because diabetes self-management education and support can improve outcomes and reduce costs B, diabetes self-management education and support should be adequately reimbursed by third-party payers. E

DSME and DSMS programs facilitate the knowledge, skills, and abilities necessary for optimal diabetes self-care and incorporate the needs, goals, and life experi- ences of the person with diabetes. The overall objectives of DSME and DSMS are to support informed decision making, self-care behaviors, problem solving, and active collaboration with the health care team to improve clinical outcomes, health status, and quality of life in a cost-effective manner (1). Providers should consider the burden of treatment and the patient’s level of confidence/self- efficacy for management behaviors as well as the level of social and family support when providing DSME or DSMS. Monitor patient performance of self- ’ management behaviors as well as psychosocial factors impacting the person s Suggested citation: American Diabetes Associa- self-management. tion. Lifestyle management. Sec. 4. In Standards DSME and DSMS, and the current national standards guiding them (1,2), are of Medical Care in Diabetesd2017. Diabetes based on evidence of their benefits. Specifically, DSME helps people with diabetes Care 2017;40(Suppl. 1):S33–S43 to identify and implement effective self-management strategies and cope with di- © 2017 by the American Diabetes Association. abetes at the four critical time points (described below) (1). Ongoing DSMS helps Readers may use this article as long as the work is properly cited, the use is educational and not people with diabetes to maintain effective self-management throughout a lifetime for profit, and the work is not altered. More infor- of diabetes as they face new challenges and as advances in treatment become mation is available at http://www.diabetesjournals available (3). .org/content/license. S34 Lifestyle Management Diabetes Care Volume 40, Supplement 1, January 2017

Four critical time points have been de- and have lower Medicare and insurance patterns containing nutrient-dense, high- fined when the need for DSME and DSMS claim costs (16,31). Despite these bene- quality foods with less focus on specific should be evaluated by the medical care fits, reports indicate that only 5–7% of nutrients. The Mediterranean (45), Die- provider and/or multidisciplinary team, individuals eligible for DSME through tary Approaches to Stop Hypertension with referrals made as needed (1): Medicare or a private insurance plan ac- (DASH) (46,47), and plant-based diets tually receive it (33,34). This low partic- (48) are all examples of healthful eating 1. At diagnosis ipation may be due to lack of referral or patterns. See Table 4.1 for specific nutri- 2. Annually for assessment of education, other identified barriers such as logistical tion recommendations. nutrition, and emotional needs issues (timing, costs) and the lack of a For complete discussion and refer- 3.When new complicating factors (health perceived benefit (35). Thus, alternative ences, see the ADA position statement conditions, physical limitations, emo- and innovative models of DSME delivery “Nutrition Therapy Recommendations tional factors, or basic living needs) arise need to be explored and evaluated. for the Management of Adults With Di- that influence self-management abetes” (37). 4. When transitions in care occur Reimbursement Medicare reimburses DSME and DSMS, Goals of Nutrition Therapy for Adults DSME focuses on supporting patient empow- when provided by a program that meets With Diabetes erment by providing people with diabetes the national standards (2) and is recog- 1. To promote and support healthful eat- the tools to make informed self-management nized by the American Diabetes Associa- ing patterns, emphasizing a variety of decisions (4). Diabetes care has shifted to an tion (ADA) or other approval bodies. nutrient-dense foods in appropriate approach that is more patient centered and DSME is also covered by most health in- portion sizes, in order to improve over- places the person with diabetes and his or surance plans. DSMS has been shown to all health and specifically to: her family at the center of the care model, be instrumental for improving outcomes ○ Achieve and maintain body weight workingincollaborationwithhealthcarepro- when it follows the completion of a DSME goals fessionals. Patient-centered care is respectful program. DSME and DSMS are frequently ○ Attain individualized glycemic, of and responsive to individual patient pref- reimbursed when performed in person. blood pressure, and lipid goals erences, needs, and values. It ensures that However, although DSME and DSMS can ○ Delay or prevent the complications patient values guide all decision making (5). also be provided via phone calls and tele- of diabetes health, these remote versions may not 2. To address individual nutrition needs Evidence for the Benefits always be reimbursed. based on personal and cultural prefer- Studies have found that DSME is associ- ences, health literacy and numeracy, ac- ated with improved diabetes knowledge NUTRITION THERAPY cess to healthful foods, willingness and and self-care behaviors (2), lower A1C For many individuals with diabetes, the ability to make behavioral changes, and (6–9), lower self-reported weight (10,11), most challenging part of the treatment barriers to change improved quality of life (8,12), healthy plan is determining what to eat and 3. To maintain the pleasure of eating by coping (13,14), and reduced health care following a food plan. There is not a providing nonjudgmental messages costs (15,16). Better outcomes were re- one-size-fits-all eating pattern for indi- about food choices ported for DSME interventions that were viduals with diabetes. Nutrition therapy 4. To provide an individual with diabe- over 10 h in total duration, included follow- has an integral role in overall diabetes tes the practical tools for developing up with DSMS (3,17), were culturally management, and each person with healthy eating patterns rather than (18,19) and age appropriate (20,21), diabetes should be actively engaged in focusing on individual macronutri- were tailored to individual needs and education, self-management, and treat- ents, micronutrients, or single foods preferences, and addressed psychosocial ment planning with his or her health issues and incorporated behavioral strat- care team, including the collaborative Weight Management egies (4,13,22,23). Individual and group development of an individualized eating Body weight management is important approaches are effective (11,24). Emerg- plan (36,37). All individuals with diabe- for overweight and obese people with ing evidence is pointing to the benefitof tes should receive individualized medi- type 1 and type 2 diabetes. Lifestyle in- Internet-based DSME programs for diabe- cal nutrition therapy (MNT), preferably tervention programs should be intensive tes prevention and the management of provided by a registered dietitian who is and have frequent follow-up to achieve type 2 diabetes (25,26). There is growing knowledgeable and skilled in providing significant reductions in excess body evidence for the role of community health diabetes-specific MNT. MNT delivered weight and improve clinical indicators. workers (27), as well as peer (27–29) and lay by a registered dietitian is associated with There is strong and consistent evidence (30) leaders, in providing ongoing support. A1C decreases of 0.3–1% for people with that modest persistent weight loss can de- DSME is associated with an increased type 1 diabetes (38–40) and 0.5–2% for peo- lay the progression from prediabetes to use of primary care and preventive ser- ple with type 2 diabetes (41–44). type 2 diabetes (49,50) and is beneficial vices (15,31,32) and less frequent use of It is important that each member of to the management of type 2 diabetes acute care and inpatient hospital ser- thehealthcareteambeknowledgeable (see Section 7 “Obesity Management for vices (10). Patients who participate in about nutrition therapy principles for the Treatment of Type 2 Diabetes”). DSMEaremorelikelytofollowbest people with all types of diabetes and In overweight and obese patients practice treatment recommendations, par- be supportive of their implementation. with type 2 diabetes, modest weight ticularly among the Medicare population, Emphasis should be on healthful eating loss, defined as sustained reduction of care.diabetesjournals.org Lifestyle Management S35

Table 4.1—MNT recommendations Evidence Topic Recommendations 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 and those with type 2 diabetes who are prescribed a A flexible insulin therapy program, education on how to use carbohydrate counting and in some cases fat and protein gram 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 emphasizing B portion control and healthy food choices 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 reduction of calorie intake and A lifestyle modification benefits overweight or obese adults with type 2 diabetes and also those with prediabetes. Intervention programs to facilitate this process are recommended. Eating patterns and macronutrient c As there is no single ideal dietary distribution of calories among carbohydrates, fats, E distribution and proteins for people with diabetes, macronutrient distribution should be individualized while keeping total calorie and metabolic goals in mind. c A variety of eating patterns are acceptable for the management of type 2 diabetes B and prediabetes including Mediterranean, DASH, and plant-based diets. 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 in B, A order to control weight and reduce their risk for CVD and fatty liver B and should minimize the consumption of foods with added sugar 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 v-3 fatty acids, such as fatty fish (EPA and DHA) and B, A nuts and seeds (ALA) is recommended to prevent or treat CVD B; however, evidence does not support a beneficial role for v-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 outcomes in people with diabetes who do not have underlying deficiencies, 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 than C 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 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. Nonnutritive sweeteners c The use of nonnutritive sweeteners has the potential to reduce overall calorie and B carbohydrate intake if substituted for caloric sweeteners and without compensation by intake of additional calories from other food sources. Nonnutritive sweeteners are generally safe to use within the defined acceptable daily intake levels. S36 Lifestyle Management Diabetes Care Volume 40, Supplement 1, January 2017

5% of initial body weight, has been shown Individuals with type 1 or type 2 di- the recommended daily allowance of to improve glycemic control and to reduce abetes taking insulin at mealtimes 0.8 g/kg body weight/day. Reducing the need for glucose-lowering medications should be offered intensive education the amount of dietary protein below (51–53). Sustaining weight loss can be chal- on the need to couple insulin administra- the recommended daily allowance is lenging (54). Weight loss can be attained tion with carbohydrate intake. For people not recommended because it does not with lifestyle programs that achieve a whose meal schedules or carbohydrate alter glycemic measures, cardiovascular 500–750 kcal/day energy deficit or pro- consumption is variable, regular counsel- risk measures, or the rate at which glo- vide ;1,200–1,500 kcal/day for women ing to help them understand the com- merular filtration rate declines (71,72). and 1,500–1,800 kcal/day for men, ad- plex relationship between carbohydrate In individuals with type 2 diabetes, in- justed for the individual’s baseline body intake and insulin needs is important. gested protein may enhance the insulin weight. For many obese individuals with In addition, education regarding the response to dietary carbohydrates (73). type 2 diabetes, weight loss .5% is needed carbohydrate-counting approach to Therefore, carbohydrate sources high in to produce beneficial outcomes in glyce- meal planning can assist them with effec- protein should not be used to treat or mic control, lipids, and blood pressure, tively modifying insulin dosing from meal prevent hypoglycemia. and sustained weight loss of $7% is op- to meal and improving glycemic control Fats timal (54). (39,59,65–67). Individuals who consume The ideal amount of dietary fat for indi- The diets used in intensive lifestyle meals containing more protein and viduals with diabetes is controversial. The management for weight loss may differ fat than usual may also need to make Institute of Medicine has definedanac- in the types of foods they restrict (e.g., mealtime insulin dose adjustments to ceptable macronutrient distribution for high-fat vs. high-carbohydrate foods), compensate for delayed postprandial total fat for all adults to be 20–35% of but their emphasis should be on nutrient- glycemic excursions (68,69). For individ- energy (74). The type of fats consumed dense foods, such as whole grains, vegeta- uals on a fixed daily insulin schedule, is more important than total amount of bles, fruits, legumes, low-fat dairy, lean meal planning should emphasize a rela- fat when looking at metabolic goals and meats, nuts, and seeds, as well as on achiev- tively fixed carbohydrate consumption CVD risk (64,75–78). Multiple random- ing the desired energy deficit (55–58). The pattern with respect to both time and ized controlled trials including patients diet choice should be based on the patients’ amount (37). By contrast, a simpler di- with type 2 diabetes have reported that health status and preferences. abetes meal planning approach empha- a Mediterranean-style eating pattern sizing portion control and healthful food (75,79–82), rich in monounsaturated Carbohydrates choices may be better suited for some fats, can improve both glycemic control Studies examining the ideal amount of elderly individuals, those with cognitive and blood lipids. However, supplements carbohydrate intake for people with dia- dysfunction, and those for whom there do not seem to have the same effects. A betes are inconclusive, although monitor- are concerns over health literacy and nu- systematic review concluded that dietary ing carbohydrate intake and considering meracy (37–39,41,59,65). The modified supplements with v-3 fatty acids did not the blood glucose response to dietary car- plate method (which uses measuring improve glycemic control in individuals bohydrate are key for improving post- cups to assist with portion measure- with type 2 diabetes (61). Randomized prandial glucose control (59,60). The ment) may be an effective alternative controlled trials also do not support rec- literature concerning glycemic index and to carbohydrate counting for some pa- ommending v-3 supplements for primary glycemic load in individuals with diabetes tients in improving glycemia (70). or secondary prevention of CVD (83–87). is complex, though in some studies low- People with diabetes should be advised to ering the glycemic load of consumed Protein follow the guidelines for the general pop- carbohydrates has demonstrated A1C There is no evidence that adjusting the ulation for the recommended intakes of reductions of –0.2% to –0.5% (61,62). A daily level of protein ingestion (typically saturated fat, dietary cholesterol, and systematic review (61) found that whole- 1–1.5 g/kg body weight/day or 15–20% trans fat (64). In general, trans fats should grain consumption was not associated total calories) will improve health in be avoided. with improvements in glycemic control individuals without diabetic kidney dis- in type 2 diabetes. One study did find a ease, and research is inconclusive re- Sodium potential benefit of whole-grain intake in garding the ideal amount of dietary As for the general population, people reducing mortality and cardiovascular dis- protein to optimize either glycemic con- with diabetes should limit their sodium ease (CVD) among individuals with type 2 trol or CVD risk (61). Therefore, protein consumption to ,2,300 mg/day. Lower- diabetes (63). intake goals should be individualized ing sodium intake (i.e., 1,500 mg/day) As for all Americans, individuals with based on current eating patterns. Some may benefit blood pressure in certain cir- diabetes should be encouraged to replace research has found successful manage- cumstances (88). However, other studies refined carbohydrates and added sugars ment of type 2 diabetes with meal plans (89,90) have recommended caution for with whole grains, legumes, vegetables, including slightly higher levels of pro- universal sodium restriction to 1,500 mg and fruits. The consumption of sugar- tein (20–30%), which may contribute to in people with diabetes. Sodium intake sweetened beverages and processed increased satiety (47). recommendations should take into ac- “low-fat” or “nonfat” food products For those with diabetic kidney disease count palatability, availability, affordability, with high amounts of refined grains (with albuminuria and/or reduced esti- and the difficulty of achieving low-sodium and added sugars should be strongly mated glomerular filtration rate), die- recommendations in a nutritionally ade- discouraged (64). tary protein should be maintained at quate diet (91). care.diabetesjournals.org Lifestyle Management S37

Micronutrients and Supplements greater improvements in A1C and in fit- vigorous intensity physical activity There continues to be no clear evidence ness (99). Other benefits include slowing per week, spread over at least of benefit from herbal or nonherbal (i.e., the decline in mobility among overweight 3days/week,withnomorethan vitamin or mineral) supplementation for patients with diabetes (100). The ADA 2 consecutive days without activ- people with diabetes without under- position statement “Physical Activity/ ity. Shorter durations (minimum lying deficiencies (37). Metformin is as- Exercise and Diabetes: A Position State- 75 min/week) of vigorous-intensity sociated with vitamin B12 deficiency, ment of the American Diabetes Asso- or interval training may be suffi- with a recent report from the Diabetes ciation” reviews the evidence for the cient for younger and more physi- Prevention Program Outcomes Study benefits of exercise in people with di- cally fit individuals. (DPPOS) suggesting that periodic testing abetes (101). c Adults with type 1 C and type 2 B of vitamin B12 levels should be con- diabetes should engage in 2–3 sidered in metformin-treated patients, Exercise and Children sessions/week of resistance exer- particularly in those with anemia or peri- All children, including children with di- cise on nonconsecutive days. pheral neuropathy (92). Routine supple- abetes or prediabetes, should be en- c All adults, and particularly those mentation with antioxidants, such as couraged to engage in at least 60 min with type 2 diabetes, should de- vitamins E and C and carotene, is not ad- of physical activity each day. Chil- crease the amount of time spent vised because of lack of evidence of effi- dren should engage in at least 60 min in daily sedentary behavior. B Pro- cacy and concern related to long-term of moderate-to-vigorous aerobic activ- longed sitting should be interrup- safety. In addition, there is insufficient evi- ity every day with muscle- and bone- ted every 30 min for blood glucose dence to support the routine use of herbals strengthening activities at least 3 days benefits, particularly in adults with and micronutrients, such as cinnamon (93) per week (102). In general, youth with type 2 diabetes. C and vitamin D (94), to improve glycemic type 1 diabetes benefit from being phys- c Flexibility training and balance control in people with diabetes (37,95). ically active, and an active lifestyle training are recommended 2–3 should be recommended to all. Alcohol times/week for older adults with Moderate alcohol consumption does diabetes. Yoga and tai chi may be Frequency and Type of Physical not have major detrimental effects on included based on individual pref- Activity long-term blood glucose control in people erences to increase flexibility, The U.S. Department of Health and Hu- with diabetes. Risks associated with alco- muscular strength, and balance. C man Services’ physical activity guide- hol consumption include hypoglycemia lines for Americans (103) suggest that (particularly for those using insulin or in- adults over age 18 years engage in Physical activity is a general term that sulin secretagogue therapies), weight 150 min/week of moderate-intensity includes all movement that increases gain, and hyperglycemia (for those con- or 75 min/week of vigorous-intensity energy use and is an important part of suming excessive amounts) (37,95). aerobic physical activity, or an equiva- the diabetes management plan. Exercise lent combination of the two. In addition, fi Nonnutritive Sweeteners is a more speci c form of physical activity the guidelines suggest that adults do For people who are accustomed to sugar- that is structured and designed to im- muscle-strengthening activities that in- fi sweetened products, nonnutritive sweet- prove physical tness. Both physical activ- volve all major muscle groups 2 or more eners have the potential to reduce overall ity and exercise are important. Exercise days/week. The guidelines suggest that calorie and carbohydrate intake and may has been shown to improve blood glucose adults over age 65 years and those with be preferred to sugar when consumed in control, reduce cardiovascular risk fac- disabilities follow the adult guidelines if moderation. Regulatory agencies set ac- tors, contribute to weight loss, and im- possible or, if not possible, be as physi- ceptable daily intake levels for each non- prove well-being. Physical activity is as cally active as they are able. fi nutritive sweetener, de ned as the amount important for those with type 1 diabetes Recent evidence supports that all in- ’ thatcanbesafelyconsumedoverapersons as it is for the general population, but its dividuals, including those with diabetes, fi lifetime (37,96). speci c role in the prevention of diabetes should be encouraged to reduce the complications and the management of amount of time spent being sedentary PHYSICAL ACTIVITY blood glucose is not as clear as it is for (e.g., working at a computer, watching those with type 2 diabetes. Recommendations TV), by breaking up bouts of sedentary Structured exercise interventions of c Children and adolescents with activity (.30 min) by brieflystanding, at least 8 weeks’ duration have been type 1 or type 2 diabetes or predi- walking, or performing at other light showntolowerA1Cbyanaverageof abetes should engage in 60 min/day physical activities (104,105). Avoiding 0.66%inpeoplewithtype2diabetes, or more of moderate- or vigorous- extended sedentary periods may help even without a significant change in intensity aerobic activity, with vig- prevent type 2 diabetes for those at BMI (97). There are also considerable orous muscle-strengthening and risk and may also aid in glycemic control data for the health benefits (e.g., in- bone-strengthening activities at for those with diabetes. creased cardiovascular fitness, greater least 3 days/week. C muscle strength, improved insulin sensi- Physical Activity and Glycemic c Most adults with with type 1 C and tivity, etc.) of regular exercise for those type 2 B diabetes should engage in Control with type 1 diabetes (98). Higher levels Clinical trials have provided strong evi- 150 min or more of moderate-to- of exercise intensity are associated with dence for the A1C-lowering value of S38 Lifestyle Management Diabetes Care Volume 40, Supplement 1, January 2017

resistance training in older adults with provider should customize the exercise neuropathy who use proper footwear type 2 diabetes (106) and for an additive regimen to the individual’s needs. Those (111). In addition, 150 min/week of mod- benefit of combined aerobic and resis- with complications may require a more erate exercise was reported to improve tance exercise in adults with type 2 diabe- thorough evaluation (98). outcomes in patients with prediabetic neu- tes (107). If not contraindicated, patients ropathy (112). All individuals with periph- with type 2 diabetes should be encour- Hypoglycemia eral neuropathy should wear proper aged to do at least two weekly sessions In individuals taking insulin and/or insu- footwear and examine their feet daily to of resistance exercise (exercise with free lin secretagogues, physical activity may detect lesions early. Anyone with a foot weights or weight machines), with each cause hypoglycemia if the medication injury or open sore should be restricted session consisting of at least one set dose or carbohydrate consumption is to non–weight-bearing activities. not altered. Individuals on these thera- (group of consecutive repetitive exercise Autonomic Neuropathy fi pies may need to ingest some added motions) of ve or more different resis- Autonomic neuropathy can increase the carbohydrate if pre-exercise glucose tance exercises involving the large muscle risk of exercise-induced injury or ad- , groups (106). levels are 100 mg/dL (5.6 mmol/L), de- verse events through decreased cardiac For type 1 diabetes, although exercise pending on whether they can lower responsiveness to exercise, postural hy- in general is associated with improve- insulin levels during the workout (such potension, impaired thermoregulation, ment in disease status, care needs to as with an insulin pump or reduced pre- impaired night vision due to impaired be taken in titrating exercise with re- exercise insulin dosage), the time of day papillary reaction, and greater suscepti- spect to glycemic management. Each in- exercise is done, and the intensity and bility to hypoglycemia (113). Cardiovascu- dividual with type 1 diabetes has a duration of the activity (98,101). Hypo- lar autonomic neuropathy is also an variable glycemic response to exercise. glycemia is less common in patients independent risk factor for cardiovascular This variability should be taken into con- with diabetes who are not treated with death and silent myocardial ischemia sideration when recommending the insulin or insulin secretagogues, and no (114). Therefore, individuals with diabetic type and duration of exercise for a given routine preventive measures for hypo- autonomic neuropathy should undergo individual (98). glycemia are usually advised in these cardiac investigation before beginning Women with preexisting diabetes, cases. In some patients, hypoglycemia physical activity more intense than that particularly type 2 diabetes, and those after exercise may occur and last for sev- to which they are accustomed. at risk for or presenting with gestational eral hours due to increased insulin sensi- diabetes mellitus should be advised to tivity. Intense activities may actually raise Diabetic Kidney Disease Physical activity can acutely increase uri- engage in regular moderate physical ac- blood glucose levels instead of lowering nary albumin excretion. However, there tivity prior to and during their pregnan- them, especially if pre-exercise glucose is no evidence that vigorous-intensity cies as tolerated (101). levels are elevated (109). exercise increases the rate of progres- fi Pre-exercise Evaluation Exercise in the Presence of Speci c sion of diabetic kidney disease, and fi As discussed more fully in Section 9 “Car- Long-term Complications of Diabetes there appears to be no need for speci c diovascular Disease and Risk Manage- Retinopathy exercise restrictions for people with di- ment,” the best protocol for assessing If proliferative diabetic retinopathy or abetic kidney disease (110). asymptomatic patients with diabetes for severe nonproliferative diabetic retinop- coronary artery disease remains unclear. athy is present, then vigorous-intensity SMOKING CESSATION: TOBACCO The ADA consensus report “Screening for aerobic or resistance exercise may be AND e-CIGARETTES Coronary Artery Disease in Patients With contraindicated because of the risk of Recommendations Diabetes” (108) concluded that routine triggering vitreous hemorrhage or retinal c Advise all patients not to use ciga- testing is not recommended. However, detachment (110). Consultation with an rettes and other tobacco products providers should perform a careful his- ophthalmologist prior to engaging in A or e-cigarettes. E tory, assess cardiovascular risk factors, an intense exercise regimen may be c Include smoking cessation coun- and be aware of the atypical presentation appropriate. seling and other forms of treat- of coronary artery disease in patients with Peripheral Neuropathy ment as a routine component of diabetes. Certainly, high-risk patients Decreasedpainsensationandahigherpain diabetes care. B should be encouraged to start with short threshold in the extremities result in an periods of low-intensity exercise and increased risk of skin breakdown, infection, Results from epidemiological, case-control, slowly increase the intensity and dura- and Charcot joint destruction with some and cohort studies provide convincing tion. Providers should assess patients for forms of exercise. Therefore, a thorough evidence to support the causal link be- conditions that might contraindicate cer- assessment should be done to ensure tween cigarette smoking and health risks tain types of exercise or predispose to in- that neuropathy does not alter kinesthetic (115). Recent data show tobacco use is jury, such as uncontrolled hypertension, or proprioceptive sensation during physical higher among adults with chronic condi- untreated proliferative retinopathy, auto- activity, particularly in those with more se- tions (116). Other studies of individuals nomic neuropathy, peripheral neuropathy, vere neuropathy. Studies have shown that with diabetes consistently demonstrate and a history of foot ulcers or Charcot foot. moderate-intensity walking may not lead that smokers (and people exposed to sec- The patient’s age and previous physical to an increased risk of foot ulcers or ondhand smoke) have a heightened risk of activity level should be considered. The reulceration in those with peripheral CVD, premature death, and microvascular care.diabetesjournals.org Lifestyle Management S39

complications. Smoking may have a role in interventions modestly but significantly centered approach and provided to the development of type 2 diabetes (117). improved A1C (standardized mean differ- all people with diabetes, with the One study in smokers with newly diag- ence –0.29%) and mental health outcomes goals of optimizing health outcomes nosed type 2 diabetes found that smoking (129). However, there was a limited as- and health-related quality of life. A cessation was associated with amelioration sociation between the effects on A1C c Psychosocial screening and follow- of metabolic parameters and reduced andmentalhealth,andnointervention up may include, but are not lim- blood pressure and albuminuria at 1 year characteristics predicted benefiton ited to, attitudes about the illness, (118). both outcomes. expectations for medical manage- The routine and thorough assessment ment and outcomes, affect or mood, of tobacco use is essential to prevent Screening general and diabetes-related qual- smoking or encourage cessation. Nu- Key opportunities for psychosocial screen- ity of life, available resources (fi- merous large randomized clinical trials ing occur at diabetes diagnosis, during reg- nancial, social, and emotional), and have demonstrated the efficacy and ularly scheduled management visits, during psychiatric history. E cost-effectiveness of brief counseling in hospitalizations, with new onset of compli- c Providers should consider assess- smoking cessation, including the use of cations, or when problems with glucose ment for symptoms of diabetes telephone quit lines, in reducing tobacco control, quality of life, or self-management distress, depression, anxiety, dis- use. For the patient motivated to quit, the are identified (1). Patients are likely to ordered eating, and cognitive ca- addition of pharmacological therapy to exhibit psychological vulnerability at diag- pacities using patient-appropriate counseling is more effective than either nosis, when their medical status changes standardized and validated tools treatment alone. Special considerations (e.g., end of the honeymoon period), when at the initial visit, at periodic inter- should include assessment of level of nic- the need for intensified treatment is evident, vals, and when there is a change in otine dependence, which is associated and when complications are discovered. disease, treatment, or life circum- with difficulty in quitting and relapse Providers can start with informal ver- stance. Including caregivers and (119). Although some patients may gain bal inquires, for example, by asking if family members in this assessment weight in the period shortly after smoking there have been changes in mood dur- is recommended. B cessation, recent research has demon- ing the past 2 weeks or since their last c Consider screening older adults strated that this weight gain does not di- visit. Providers should consider asking (aged $65 years) with diabetes minish the substantial CVD benefitrealized if there are new or different barriers to for cognitive impairment and de- from smoking cessation (120). treatment and self-management, such pression. B Nonsmokers should be advised not to as feeling overwhelmed or stressed by use e-cigarettes. There are no rigorous diabetes or other life stressors. Stan- studies that have demonstrated that Please refer to the ADA position state- dardized and validated tools for psycho- e-cigarettes are a healthier alternative ment “Psychosocial Care for People with social monitoring and assessment can to smoking or that e-cigarettes can facil- Diabetes” for a list of assessment tools also be used by providers, with positive itate smoking cessation. More extensive and additional details (124). findings leading to referral to a mental research of their short- and long-term Emotional well-being is an important health provider specializing in diabetes effects is needed to determine their part of diabetes care and self-management. for comprehensive evaluation, diagno- safety and their cardiopulmonary effects Psychological and social problems can sis, and treatment. in comparison with smoking and stan- impair the individual’s (125–127) or fam- dard approaches to smoking cessation ily’s (128) ability to carry out diabetes Diabetes Distress – care tasks and therefore potentially com- (121 123). Recommendation promise health status. There are oppor- c Routinely monitor people with di- PSYCHOSOCIAL ISSUES tunities for the clinician to routinely abetes for diabetes distress, par- assess psychosocial status in a timely Recommendations ticularly when treatment targets and efficient manner for referral to appro- c Psychosocial care should be inte- are not met and/or at the onset priate services. A systematic review and grated with a collaborative, patient- of diabetes complications. B meta-analysis showed that psychosocial

Table 4.2—Situations that warrant referral of a person with diabetes to a mental health provider for evaluation and treatment c If self-care remains impaired in a person with diabetes distress after tailored diabetes education c If a person has a positive screen on a validated screening tool for depressive symptoms c In the presence of symptoms or suspicions of disordered eating behavior, an eating disorder, or disrupted patterns of eating c If intentional omission of insulin or oral medication to cause weight loss is identified c If a person has a positive screen for anxiety or fear of hypoglycemia c If a serious mental illness is suspected c In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress c If a person screens positive for cognitive impairment c Declining or impaired ability to perform diabetes self-care behaviors c Before undergoing bariatric or metabolic surgery and after surgery if assessment reveals an ongoing need for adjustment support S40 Lifestyle Management Diabetes Care Volume 40, Supplement 1, January 2017

Diabetes distress (DD) is very common Referral to a Mental Health Specialist 7. Frosch DL, Uy V, Ochoa S, Mangione CM. and is distinct from other psychological Indications for referral to a mental health Evaluation of a behavior support intervention disorders (130–132). DD refers to signifi- specialist familiar with diabetes manage- for patients with poorly controlled diabetes. Arch Intern Med 2011;171:2011–2017 cant negative psychological reactions re- ment may include positive screening for 8. Cooke D, Bond R, Lawton J, et al.; U.K. NIHR lated to emotional burdens and worries overall stress related to work-life balance, DAFNE Study Group. Structured type 1 diabetes specific to an individual’s experience in DD, diabetes management difficulties, education delivered within routine care: impact having to manage a severe, complicated, depression, anxiety, disordered eating, on glycemic control and diabetes-specificqual- – and demanding chronic disease such as di- and cognitive functioning difficulties (see ity of life. Diabetes Care 2013;36:270 272 – 9. Chrvala CA, Sherr D, Lipman RD. Diabetes abetes (131 133). The constant behavioral Table 4.2 for a complete list). It is prefer- self-management education for adults with demands (medication dosing, frequency, able to incorporate psychosocial assess- type 2 diabetes mellitus: a systematic review and titration; monitoring blood glucose, ment and treatment into routine care of the effect on glycemic control. Patient Educ food intake, eating patterns, and physical rather than waiting for a specificproblem Couns 2016;99:926–943 activity)ofdiabetesself-management or deterioration in metabolic or psycho- 10. Steinsbekk A, Rygg LØ, Lisulo M, Rise MB, Fretheim A. Group based diabetes self-management and the potential or actuality of disease logical status to occur (22,130). Providers education compared to routine treatment for peo- progression are directly associated with should identify behavioral and mental ple with type 2 diabetes mellitus. A systematic re- reports of DD (131). The prevalence of health providers, ideally those who are view with meta-analysis. BMC Health Serv Res DD is reported to be 18–45%withanin- knowledgeable about diabetes treatment 2012;12:213 cidence of 38–48% over 18 months (133). and the psychosocial aspects of diabetes, 11. Deakin T, McShane CE, Cade JE, Williams RDRR. Group based training for self-management In the second Diabetes Attitudes, Wishes to whom they can refer patients. Ideally, strategies in people with type 2 diabetes and Needs (DAWN2) study, significant psychosocial care providers should be mellitus. Cochrane Database Syst Rev 2005;2: DD was reported by 45% of the partici- embedded in diabetes care settings. Al- CD003417 pants, but only 24% reported that their though the clinician may not feel qualified 12. Cochran J, Conn VS. Meta-analysis of quality of life outcomes following diabetes self-management health care teams asked them how to treat psychological problems (137), – – training. Diabetes Educ 2008;34:815 823 diabetes affected their lives (130). optimizing the patient provider relation- 13. Thorpe CT, Fahey LE, Johnson H, Deshpande High levels of DD significantly impact ship as a foundation may increase the M, Thorpe JM, Fisher EB. Facilitating healthy medication-taking behaviors and are likelihood of the patient accepting re- coping in patients with diabetes: a systematic linked to higher A1C, lower self-efficacy, ferral for other services. Collaborative review. Diabetes Educ 2013;39:33–52 and poorer dietary and exercise behav- care interventions and a team approach 14. Fisher L, Hessler D, Glasgow RE, et al. REDEEM: fi a pragmatic trial to reduce diabetes distress. Dia- iors (14,131,133). DSME has been shown have demonstrated ef cacy in diabe- betes Care 2013;36:2551–2558 to reduce DD (14). It may be helpful to tes self-management and psychosocial 15. Robbins JM, Thatcher GE, Webb DA, provide counseling regarding expected functioning (14). Valdmanis VG. Nutritionist visits, diabetes classes, diabetes-related versus generalized and hospitalization rates and charges: the Urban – psychological distress at diagnosis Diabetes Study. Diabetes Care 2008;31:655 660 References 16. Duncan I, Ahmed T, Li QE, et al. Assessing and when disease state or treatment 1. Powers MA, Bardsley J, Cypress M, et al. Di- the value of the diabetes educator. Diabetes changes (134). abetes self-management education and support Educ 2011;37:638–657 DD should be routinely monitored in type 2 diabetes: a joint position statement of 17. Piatt GA, Anderson RM, Brooks MM, et al. the American Diabetes Association, the Ameri- 3-year follow-up of clinical and behavioral im- (135) using patient-appropriate vali- can Association of Diabetes Educators, and the fi provements following a multifaceted diabetes dated measures. If DD is identi ed, the Academy of Nutrition and Dietetics. Diabetes care intervention: results of a randomized con- person should be referred for specific Care 2015;38:1372–1382 trolled trial. Diabetes Educ 2010;36:301–309 diabetes education to address areas of 2. Haas L, Maryniuk M, Beck J, et al.; 2012 Stan- 18. Glazier RH, Bajcar J, Kennie NR, Willson K. A diabetes self-care that are most relevant dards Revision Task Force. National standards for systematic review of interventions to improve to the patient and impact clinical man- diabetes self-management education and support. diabetes care in socially disadvantaged popula- Diabetes Care 2014;37(Suppl. 1):S144–S153 tions. Diabetes Care 2006;29:1675–1688 agement. People whose self-care re- 3. Tang TS, Funnell MM, Brown MB, Kurlander 19. Hawthorne K, Robles Y, Cannings-John R, mains impaired after tailored diabetes JE. Self-management support in “real-world” Edwards AG. Culturally appropriate health education education should be referred by their settings: an empowerment-based intervention. for type 2 diabetes mellitus in ethnic minority groups. care team to a behavioral health pro- Patient Educ Couns 2010;79:178–184 Cochrane Database Syst Rev 2008;3:CD006424 vider for evaluation and treatment. 4. Marrero DG, Ard J, Delamater AM, et al. 20. Chodosh J, Morton SC, Mojica W, et al. Twenty-first century behavioral medicine: a Meta-analysis: chronic disease self-management Other psychosocial issues known to context for empowering clinicians and patients programs for older adults. Ann Intern Med 2005; affect self-management and health with diabetes: a consensus report. Diabetes 143:427–438 outcomes include attitudes about the Care 2013;36:463–470 21. Sarkisian CA, Brown AF, Norris KC, Wintz RL, illness, expectations for medical manage- 5. Committee on Quailty of Health Care in Mangione CM. A systematic review of diabetes ment and outcomes, available resources America; Institute of Medicine. Crossing the self-care interventions for older, African American, – fi Quality Chasm. A New Health System for the or Latino adults. Diabetes Educ 2003;29:467 479 ( nancial, social, and emotional) (136), 21st Century [Internet]. Washington, DC, Na- 22. Peyrot M, Rubin RR. Behavioral and psycho- and psychiatric history. For additional tional Academies Press, 2001. Available from social interventions in diabetes: a conceptual information on psychiatric comorbid- http://www.nap.edu/catalog/10027. Accessed review. Diabetes Care 2007;30:2433–2440 ities (depression, anxiety, disordered 8 September 2016 23. Naik AD, Palmer N, Petersen NJ, et al. Com- eating, and serious mental illness), 6. Norris SL, Lau J, Smith SJ, Schmid CH, parative effectiveness of goal setting in diabetes “ Engelgau MM. Self-management education for mellitus group clinics: randomized clinical trial. please refer to Section 3 Comprehen- adults with type 2 diabetes: a meta-analysis of Arch Intern Med 2011;171:453–459 sive Medical Evaluation and Assess- the effect on glycemic control. Diabetes Care 24. Duke S-AS, Colagiuri S, Colagiuri R. Individ- ment of Comorbidities.” 2002;25:1159–1171 ual patient education for people with type 2 care.diabetesjournals.org Lifestyle Management S41

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Nu- type 2 diabetes among persons at increased risk: a and the risks of all-cause and cardiovascular dis- trition therapy recommendations for the man- systematic review for the Community Preventive ease-specific mortality among women with type 2 agement of adults with diabetes. Diabetes Care. Services Task Force. Ann Intern Med 2015;164: diabetes mellitus. Circulation 2010;121:2162–2168 2014;37(Suppl. 1):S120–S143 164–175 64. Office of Disease Prevention and Health 38. Kulkarni K, Castle G, Gregory R, et al. Nutri- 51. UK Prospective Diabetes Study 7. UK Pro- Promotion, U.S. Department of Health and Hu- tion practice guidelines for type 1 diabetes mel- spective Diabetes Study 7: response of fasting man Services. Dietary Guidelines for Americans: litus positively affect dietitian practices and plasma glucose to diet therapy in newly pre- 2015–2020. 8th ed. Available from https:// patient outcomes. The Diabetes Care and Edu- senting type II diabetic patients, UKPDS Group. health.gov/dietaryguidelines/2015/guidelines/. cation Dietetic Practice Group. J Am Diet Assoc Metabolism 1990;39:905–912 Accessed 17 October 2016 1998;98:62–70; quiz 71–72 52. Goldstein DJ. Beneficial health effects of 65. Laurenzi A, Bolla AM, Panigoni G, et al. Ef- 39. Rossi MCE, Nicolucci A, Di Bartolo P, et al. modest weight loss. Int J Obes Relat Metab Dis- fects of carbohydrate counting on glucose con- Diabetes Interactive Diary: a new telemedicine ord 1992;16:397–415 trol and quality of life over 24 weeks in adult system enabling flexible diet and insulin therapy 53. Pastors JG, Warshaw H, Daly A, Franz M, patients with type 1 diabetes on continuous while improving quality of life: an open-label, Kulkarni K. The evidence for the effectiveness subcutaneous insulin infusion: a randomized, S42 Lifestyle Management Diabetes Care Volume 40, Supplement 1, January 2017

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107. Church TS, Blair SN, Cocreham S, et al. Ef- 118. Voulgari C, Katsilambros N, Tentolouris N. 128. Kovacs Burns K, Nicolucci A, Holt RIG, fects of aerobic and resistance training on he- Smoking cessation predicts amelioration of mi- et al.; DAWN2 Study Group. Diabetes Attitudes, moglobin A1c levels in patients with type 2 croalbuminuria in newly diagnosed type 2 dia- Wishes and Needs second study (DAWN2Ô): diabetes: a randomized controlled trial. JAMA betes mellitus: a 1-year prospective study. cross-national benchmarking indicators for fam- 2010;304:2253–2262 Metabolism 2011;60:1456–1464 ily members living with people with diabetes. 108. Bax JJ, Young LH, Frye RL, Bonow RO, 119. Ranney L, Melvin C, Lux L, McClain E, Lohr Diabet Med 2013;30:778–788 Steinberg HO, Barrett EJ; American Diabetes As- KN. Systematic review: smoking cessation inter- 129. Harkness E, Macdonald W, Valderas J, sociation. Screening for coronary artery disease vention strategies for adults and adults in spe- Coventry P, Gask L, Bower P. Identifying psycho- in patients with diabetes. Diabetes Care 2007; cial populations. Ann Intern Med 2006;145: social interventions that improve both physical 30:2729–2736 845–856 and mental health in patients with diabetes: a 109. Peters AL, Laffel L; American Diabetes As- 120. Clair C, Rigotti NA, Porneala B, et al. Associa- systematic review and meta-analysis. Diabetes sociation; JDRF. American Diabetes Association/ tion of smoking cessation and weight change with Care 2010;33:926–930 JDRF Type 1 Diabetes Sourcebook.PetersA, cardiovascular disease among adults with and 130. Nicolucci A, Kovacs Burns K, Holt RIG, Laffel L, Eds. Alexandria, VA, American Diabetes without diabetes. JAMA 2013;309:1014–1021 et al.; DAWN2 Study Group. Diabetes Attitudes, Association, 2013 121. Schraufnagel DE, Blasi F, Drummond MB, Wishes and Needs second study (DAWN2Ô): 110. Colberg SR. Exercise and Diabetes: A Clinician’s et al.; Forum of International Respiratory Socie- cross-national benchmarking of diabetes- Guide to Prescribing Physical Activity.1sted. ties. Electronic cigarettes. A position statement of related psychosocial outcomes for people with Alexandria, VA, American Diabetes Association, 2013 the Forum of International Respiratory Societies. diabetes. Diabet Med 2013;30:767–777 111. Lemaster JW, Reiber GE, Smith DG, Am J Respir Crit Care Med 2014;190:611–618 131. Fisher L, Hessler DM, Polonsky WH, Heagerty PJ, Wallace C. Daily weight-bearing ac- 122. Bam TS, Bellew W, Berezhnova I, et al.; Mullan J. When is diabetes distress clinically tivity does not increase the risk of diabetic foot Tobacco Control Department International meaningful?: Establishing cut points for the Di- ulcers. Med Sci Sports Exerc 2003;35:1093–1099 Union Against Tuberculosis and Lung Disease. abetes Distress Scale. Diabetes Care 2012;35: 112. Smith AG, Russell J, Feldman EL, et al. Life- Position statement on electronic cigarettes or 259–264 style intervention for pre-diabetic neuropathy. electronic nicotine delivery systems. Int J Tu- 132. Fisher L, Glasgow RE, Strycker LA. The re- Diabetes Care 2006;29:1294–1299 berc Lung Dis 2014;18:5–7 lationship between diabetes distress and clini- 113. Spallone V, Ziegler D, Freeman R, et al.; 123. Bhatnagar A, Whitsel LP, Ribisl KM, et al.; cal depression with glycemic control among Toronto Consensus Panel on Diabetic Neuropa- American Heart Association Advocacy Coordi- patients with type 2 diabetes. Diabetes Care thy. Cardiovascular autonomic neuropathy in nating Committee, Council on Cardiovascular 2010;33:1034–1036 diabetes: clinical impact, assessment, diagnosis, and Stroke Nursing, Council on Clinical Cardiol- 133. Aikens JE. Prospective associations between and management. Diabetes Metab Res Rev ogy, and Council on Quality of Care and Out- emotional distress and poor outcomes in type 2 2011;27:639–653 comes Research. Electronic cigarettes: a policy diabetes. Diabetes Care 2012;35:2472–2478 114. Pop-Busui R, Evans GW, Gerstein HC, et al.; statement from the American Heart Associa- 134. Fisher L, Skaff MM, Mullan JT, et al. Clinical Action to Control Cardiovascular Risk in Diabetes tion. Circulation 2014;130:1418–1436 depression versus distress among patients with Study Group. Effects of cardiac autonomic dys- 124. Young-Hyman D, de Groot M, Hill-Briggs F, type 2 diabetes: not just a question of seman- function on mortality risk in the Action to Control Gonzalez JS, Hood K, Peyrot M. Psychosocial tics. Diabetes Care 2007;30:542–548 Cardiovascular Risk in Diabetes (ACCORD) trial. care for people with diabetes: a position state- 135. Snoek FJ, Bremmer MA, Hermanns N. Con- Diabetes Care 2010;33:1578–1584 ment of the American Diabetes Association. Di- structs of depression and distress in diabetes: 115. Suarez L, Barrett-Connor E. Interaction be- abetes Care 2016;39:2126–2140 time for an appraisal. Lancet Diabetes Endocri- tween cigarette smoking and diabetes mellitus 125. Anderson RJ, Grigsby AB, Freedland KE, nol 2015;3:450–460 in the prediction of death attributed to cardio- et al. Anxiety and poor glycemic control: a 136. Gary TL, Safford MM, Gerzoff RB, et al. vascular disease. Am J Epidemiol 1984;120:670– meta-analytic review of the literature. Int J Psy- Perception of neighborhood problems, health 675 chiatry Med 2002;32:235–247 behaviors, and diabetes outcomes among 116. Stanton CA, Keith DR, Gaalema DE, et al. 126. Delahanty LM, Grant RW, Wittenberg E, adults with diabetes in managed care: the Trends in tobacco use among US adults with et al. Association of diabetes-related emotional Translating Research Into Action for Diabetes chronic health conditions: National Survey on distress with diabetes treatment in primary care (TRIAD) study. Diabetes Care 2008;31:273–278 Drug Use and Health 2005-2013. Prev Med patients with type 2 diabetes. Diabet Med 2007; 137. Beverly EA, Hultgren BA, Brooks KM, 2016;92:160–168 24:48–54 Ritholz MD, Abrahamson MJ, Weinger K. Under- 117. Jankowich M, Choudhary G, Taveira TH, Wu 127. Anderson RJ, Freedland KE, Clouse RE, standing physicians’ challenges when treating W-C. Age-, race-, and gender-speciﬁcprevalenceof Lustman PJ. The prevalence of comorbid depres- type 2 diabetic patients’ social and emotional diabetes among smokers. Diabetes Res Clin Pract sion in adults with diabetes: a meta-analysis. difﬁculties: a qualitative study. Diabetes Care 2011;93:e101–e105 Diabetes Care 2001;24:1069–1078 2011;34:1086–1088 S44 Diabetes Care Volume 40, Supplement 1, January 2017

5. Prevention or Delay of Type 2 American Diabetes Association Diabetes Diabetes Care 2017;40(Suppl. 1):S44–S47 | DOI: 10.2337/dc17-S008

For guidelines related to screening for increased risk for type 2 diabetes (prediabetes), please refer to Section 2 “Classiﬁcation and Diagnosis of Diabetes.”

Recommendations c At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E c Patients with prediabetes should be referred to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program to achieve and maintain 7% loss of initial body weight and increase moderate- intensity physical activity (such as brisk walking) to at least 150 min/week. A c Technology-assisted tools including Internet-based social networks, distance learning, DVD-based content, and mobile applications may be useful elements of effective lifestyle modiﬁcation to prevent diabetes. B c Given the cost-effectiveness of diabetes prevention, such intervention programs should be covered by third-party payers. B

Screening for prediabetes and type 2 diabetes through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes

5. PREVENTION OR DELAY OF TYPE 2 DIABETES Association risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test for prediabetes (Table 2.4) and previously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classiﬁcation and Diagnosis of Diabetes”). Those determined to be at high risk for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. At least annual monitoring for the development of diabetes in those with prediabetes is suggested.

LIFESTYLE INTERVENTIONS The Diabetes Prevention Program The strongest evidence for diabetes prevention comes from the Diabetes Preven- tion Program (DPP) (1). The DPP demonstrated that an intensive lifestyle intervention could reduce the incidence of type 2 diabetes by 58% over 3 years. Follow-up of three large studies of lifestyle intervention for diabetes prevention has shown sustained reduction in the rate of conversion to type 2 diabetes: 43% reduction at 20 years in the Da Qing study (2), 43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS) (1), and 34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS) (3). The two major goals of the DPP intensive, behavioral, lifestyle intervention were to achieve and maintain a minimum of 7% weight loss and 150 min of physical activity per week similar in intensity to brisk walking. The DPP lifestyle intervention was a goal-based intervention: all participants were given the same weight loss and Suggested citation: American Diabetes Associa- physical activity goals, but individualization was permitted in the specific methods tion. Prevention or delay of type 2 diabetes. Sec. 5. used to achieve the goals (4). In Standards of Medical Care in Diabetesd2017. The 7% weight loss goal was selected because it was feasible to achieve and Diabetes Care 2017;40(Suppl. 1):S44–S47 maintain and likely to lessen the risk of developing diabetes. Participants were © 2017 by the American Diabetes Association. encouraged to achieve the 7% weight loss during the first 6 months of the inter- Readers may use this article as long as the work – is properly cited, the use is educational and not vention. The recommended pace of weight loss was 1 2 lb/week. Calorie goals were for profit, and the work is not altered. More infor- calculated by estimating the daily calories needed to maintain the participant’s mation is available at http://www.diabetesjournals initial weight and subtracting 500–1,000 calories/day (depending on initial body .org/content/license. care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S45

weight). The initial focus was on reduc- grains may help to prevent type 2 dia- begun to certify electronic and mobile ing total dietary fat. After several weeks, betes(11).Higherintakesofnuts(12), health-based modalities as effective vehi- the concept of calorie balance and the berries (13), yogurt (14), coffee, and cles for DPP-based interventions that may need to restrict calories as well as fat tea (15) are associated with reduced di- be considered alongside more traditional was introduced (4). abetes risk. Conversely, red meats and face-to-face and coach-driven programs. The goal for physical activity was sugar-sweetened beverages are associ- A recent study showed that an all-mobile selected to approximate at least 700 ated with an increased risk of type 2 approach to administering DPP content kcal/week expenditure from physical ac- diabetes (6). can be effective as a prevention tool, at tivity. For ease of translation, this goal was As is the case for those with diabetes, least over the short term, in overweight described as at least 150 min of moderate- individualized medical nutrition therapy and obese individuals at high risk for dia- intensity physical activity per week similar (see Section 4 “Lifestyle Management” betes (32). in intensity to brisk walking. Partici- for more detailed information) is effec- pants were encouraged to distribute tive in lowering A1C in individuals diag- Cost-effectiveness A cost-effectiveness model suggested their activity throughout the week with a nosed with prediabetes (16). that the lifestyle intervention used in minimum frequency of three times per the DPP was cost-effective (33). Actual week with at least 10 min per session. A Physical Activity cost data from the DPP and DPPOS con- maximum of 75 min of strength train- Just as 150 min/week of moderate- firmed this (34). Group delivery of DPP ing could be applied toward the total intensity physical activity, such as brisk content in community settings has the po- 150 min/week physical activity goal (4). walking, showed beneficial effects in tential to reduce overall program costs To implement the weight loss and those with prediabetes (17), moderate- while still producing weight loss and diabe- physical activity goals, the DPP used an intensity physical activity has been tes risk reduction (35,36). The CDC helps to individual model of treatment rather showntoimproveinsulinsensitivity coordinate the National Diabetes Preven- than a group-based approach. This choice and reduce abdominal fat in children tion Program, a resource designed to bring was based on a desire to intervene before and young adults (18,19). On the basis evidence-based lifestyle change programs participants had the possibility of devel- of these findings, providers are encour- for preventing type 2 diabetes to com- oping diabetes or losing interest in the aged to promote a DPP-style program, munities (http://www.cdc.gov/diabetes/ program. The individual approach also al- including its focus on physical activity, prevention/index.htm). On 7 July 2016, lowed for tailoring of interventions to re- to all individuals who have been identi- the Centers for Medicare and Medicaid flect the diversity of the population (4). fied to be at an increased risk of type 2 Services (CMS) proposed expanded Medi- The DPP intervention was adminis- diabetes. In addition to aerobic activity, care reimbursement coverage for DPP tered as a structured core curriculum an exercise regimen designed to prevent programs in an effort to expand preven- followed by a more flexible mainte- diabetes may include resistance training tive services using a cost-effective model nance program of individual sessions, (1,20). Breaking up prolonged sedentary (https://www.cms.gov/site-search/search- group classes, motivational campaigns, time may also be encouraged, as it is results.html?q5diabetes%20prevention). and restart opportunities. The 16-session associated with moderately lower post- core curriculum was completed within prandial glucose levels (21,22). The pre- the first 24 weeks of the program and in- ventative effects of exercise appear to PHARMACOLOGIC INTERVENTIONS cluded sections on lowering calories, in- extend to the prevention of gestational creasing physical activity, self-monitoring, diabetes mellitus (GDM) (23). Recommendations maintaining healthy lifestyle behaviors, c Metformin therapy for preven- and psychological, social, and motivational Technology Assistance to Deliver tion of type 2 diabetes should be challenges. For further details on the core Lifestyle Interventions considered in those with predia- curriculum sessions, refer to ref. 4. New information technology platforms betes, especially for those with may effectively deliver the core compo- BMI $35 kg/m2, those aged ,60 Nutrition nents of the DPP (24–26). Initial studies years, women with prior gestational Reducing caloric intake is of paramount have validated DVD-based content deliv- diabetes mellitus, and/or those importance for those at high risk for de- ery (27). This has been corroborated in a with rising A1C despite lifestyle veloping type 2 diabetes, though recent primary care patient population (28). Re- intervention. A evidence suggests that the quality of cent studies support content delivery c Long-term use of metformin may fats consumed in the diet is more impor- through virtual small groups (29), Inter- be associated with biochemical tant than the total quantity of dietary fat net-driven social networks (30,31), cellu- vitamin B12 deficiency, and peri- (5–7). For example, the Mediterranean lar phones, and other mobile devices. odic measurement of vitamin diet, which is relatively high in monoun- Mobile applications for weight loss and B12 levels should be considered saturated fats, may help to prevent type diabetes prevention have been validated in metformin-treated patients, es- 2 diabetes (8–10). for their ability to reduce A1C in the set- pecially in those with anemia or Whereas overall healthy low-calorie ting of prediabetes (31). The Centers for peripheral neuropathy. B eating patterns should be encouraged, Disease Control and Prevention (CDC) Di- thereisalsosomeevidencethatpar- abetes Prevention Recognition Program Pharmacologic agents including metfor- ticular dietary components impact di- (DPRP) (http://www.cdc.gov/diabetes/ min, a-glucosidase inhibitors, orlistat, abetes risk. Data suggest that whole prevention/recognition/index.htm) has glucagon-like peptide 1 (GLP-1) receptor S46 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

agonists, and thiazolidinediones have 9. Salas-Salvado´ J, Guasch-FerreM,LeeCH,´ appropriate venues for people each been shown to decrease incident Estruch R, Clish CB, Ros E. Protective effects of with prediabetes to receive educa- diabetes to various degrees in those with the Mediterranean diet on type 2 diabetes and tion and support to develop and metabolic syndrome. J Nutr 2016;jn218487 prediabetes. Metformin has the strongest maintain behaviors that can pre- 10. Bloomfield HE, Koeller E, Greer N, evidence base and demonstrated long- vent or delay the development of MacDonald R, Kane R, Wilt TJ. Effects on health term safety as pharmacologic therapy for outcomes of a Mediterranean diet with no re- diabetes. B diabetes prevention (37). For other drugs, striction on fat intake: a systematic review and – cost, side effects, and durable efficacy meta-analysis. Ann Intern Med 2016;165:491 As for those with established diabetes, the 500 require consideration. standards for diabetes self-management 11. Montonen J, Knekt P, Jarvinen¨ R, Aromaa A, Metformin was less effective than fi educationand support (see Section 4 “Life- Reunanen A. Whole-grain and ber intake and lifestyle modification in the DPP and the incidence of type 2 diabetes. Am J Clin Nutr style Management”) can also apply to DPPOS but may be cost-saving over a 2003;77:622–629 people with prediabetes. Currently, there 10-year period (34). It was as effective 12. Afshin A, Micha R, Khatibzadeh S, are significant barriers to the provision of Mozaffarian D. Consumption of nuts and le- as lifestyle modification in participants education and support to those with pre- gumes and risk of incident ischemic heart dis- with BMI $35 kg/m2 but not signifi- diabetes. However, the strategies for sup- ease, stroke, and diabetes: a systematic review cantly better than placebo in those and meta-analysis. Am J Clin Nutr 2014;100: porting successful behavior change, and over 60 years of age (17). In the DPP, 278–288 the healthy behaviors recommended for for women with history of GDM, metfor- 13. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi people with prediabetes are comparable T, Voutilainen S. Intake of fruit, berries, and min and intensive lifestyle modification to those for diabetes. Although reim- vegetables and risk of type 2 diabetes in Finnish ledtoanequivalent50%reductionin bursement remains a barrier, studies men: the Kuopio Ischaemic Heart Disease Risk diabetes risk (38), and both interven- Factor Study. Am J Clin Nutr 2014;99:328–333 show that providers of diabetes self- tions remained highly effective dur- 14. Chen M, Sun Q, Giovannucci E, et al. Dairy management education and support are ing a 10-year follow-up period (39). consumption and risk of type 2 diabetes: 3 particularly well equipped to assist people cohorts of US adults and an updated meta- Metformin should be recommended as with prediabetes in developing and main- analysis. BMC Med 2014;12:215 an option for high-risk individuals (e.g., taining behaviors that can prevent or de- 15. Mozaffarian D. Dietary and policy priorities those with a history of GDM, those who for cardiovascular disease, diabetes, and obe- lay the development of diabetes (16,41). are very obese, and/or those with rel- sity: a comprehensive review. Circulation 2016; – atively more hyperglycemia) and/or 133:187 225 16. Parker AR, Byham-Gray L, Denmark R, those with rising A1C despite lifestyle References Winkle PJ. The effect of medical nutrition ther- intervention. Consider monitoring B12 1. Lindstrom¨ J, Ilanne-Parikka P, Peltonen M, apy by a registered dietitian nutritionist in levels in those taking metformin chroni- et al.; Finnish Diabetes Prevention Study Group. patients with prediabetes participating in a cally to check for possible deficiency (see Sustained reduction in the incidence of type 2 randomized controlled clinical research trial. – Section 8 “Pharmacologic Approaches to diabetes by lifestyle intervention: follow-up of J Acad Nutr Diet 2014;114:1739 1748 17. Knowler WC, Barrett-Connor E, Fowler SE, Glycemic Treatment” for more details). the Finnish Diabetes Prevention Study. Lancet 2006;368:1673–1679 et al.; Diabetes Prevention Program Research 2. Li G, Zhang P, Wang J, et al. The long-term Group. Reduction in the incidence of type 2 di- PREVENTION OF CARDIOVASCULAR effect of lifestyle interventions to prevent dia- abetes with lifestyle intervention or metformin. DISEASE betes in the China Da Qing Diabetes Prevention N Engl J Med 2002;346:393–403 Study: a 20-year follow-up study. Lancet 2008; 18. Fedewa MV, Gist NH, Evans EM, Dishman Recommendation 371:1783–1789 RK. Exercise and insulin resistance in youth: a c Screening for and treatment of 3. Knowler WC, Fowler SE, Hamman RF, et al.; meta-analysis. Pediatrics 2014;133:e163–e174 modifiable risk factors for cardio- Diabetes Prevention Program Research Group. 19. Davis CL, Pollock NK, Waller JL, et al. Exer- vascular disease is suggested for 10-year follow-up of diabetes incidence and cise dose and diabetes risk in overweight and obese children: a randomized controlled trial. those with prediabetes. B weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–1686 JAMA 2012;308:1103–1112 4. Diabetes Prevention Program (DPP) Research 20. Sigal RJ, Alberga AS, Goldfield GS, et al. Ef- People with prediabetes often have Group. The Diabetes Prevention Program (DPP): fects of aerobic training, resistance training, or other cardiovascular risk factors, includ- description of lifestyle intervention. Diabetes Care both on percentage body fat and cardiometa- ing hypertension and dyslipidemia, and 2002;25:2165–2171 bolic risk markers in obese adolescents: the healthy eating aerobic and resistance training are at increased risk for cardiovascular 5. Jacobs S, Harmon BE, Boushey CJ, et al. A priori-defined diet quality indexes and risk of in youth randomized clinical trial. JAMA Pediatr disease (40). Although treatment goals type 2 diabetes: the Multiethnic Cohort. Diabe- 2014;168:1006–1014 for people with prediabetes are the tologia 2015;58:98–112 21. Thorp AA, Kingwell BA, Sethi P, Hammond L, same as for the general population, in- 6. Ley SH, Hamdy O, Mohan V, Hu FB. Preven- Owen N, Dunstan DW. Alternating bouts of sit- creased vigilance is warranted to identify tion and management of type 2 diabetes: die- ting and standing attenuate postprandial glu- tary components and nutritional strategies. cose responses. Med Sci Sports Exerc 2014;46: and treat these and other cardiovascular Lancet 2014;383:1999–2007 2053–2061 risk factors (e.g., smoking). 7. Chiuve SE, Fung TT, Rimm EB, et al. Alterna- 22. Healy GN, Dunstan DW, Salmon J, et al. tive dietary indices both strongly predict risk of Breaks in sedentary time: beneficial associa- DIABETES SELF-MANAGEMENT chronic disease. J Nutr 2012;142:1009–1018 tions with metabolic risk. Diabetes Care 2008; EDUCATION AND SUPPORT 8. Salas-SalvadoJ,Bull´ o´ M, Babio N, et al.; 31:661–666 PREDIMED Study Investigators. Reduction in 23. Russo LM, Nobles C, Ertel KA, Chasan-Taber Recommendation the incidence of type 2 diabetes with the Med- L, Whitcomb BW. Physical activity interventions c Diabetes self-management educa- iterranean diet: results of the PREDIMED-Reus in pregnancy and risk of gestational diabetes tion and support programs may be nutrition intervention randomized trial. Diabe- mellitus: a systematic review and meta-analysis. tes Care 2011;34:14–19 Obstet Gynecol 2015;125:576–582 care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S47

24. Levine DM, Savarimuthu S, Squires A, social network: validation against CDC stan- systematic review for the Community Preventive Nicholson J, Jay M. Technology-assisted weight dards. Diabetes Educ 2014;40:435–443 Services Task. Ann Intern Med 2015;163:437–451 loss interventions in primary care: a systematic 31. Sepah SC, Jiang L, Peters AL. Long-term out- 37. Diabetes Prevention Program Research review. J Gen Intern Med 2015;30:107–117 comes of a Web-based diabetes prevention pro- Group. Long-term safety, tolerability, and 25. Allen JK, Stephens J, Patel A. Technology- gram: 2-year results of a single-arm longitudinal weight loss associated with metformin in the assisted weight management interventions: study. J Med Internet Res 2015;17:e92 Diabetes Prevention Program Outcomes Study. systematic review of clinical trials. Telemed J E 32. Michaelides A, Raby C, Wood M, Farr K, Diabetes Care 2012;35:731–737 Health 2014;20:1103–1120 Toro-Ramos T. Weight loss efﬁcacy of a novel 38. Ratner RE, Christophi CA, Metzger BE, et al.; 26. Oldenburg B, Taylor CB, O’Neil A, Cocker F, mobile Diabetes Prevention Program delivery Diabetes Prevention Program Research Group. Cameron LD. Using new technologies to im- platform with human coaching. BMJ Open Di- Prevention of diabetes in women with a history prove the prevention and management of abetes Res Care 2016;4:e000264 of gestational diabetes: effects of metformin chronic conditions in populations. Annu Rev 33. Herman WH, Hoerger TJ, Brandle M, et al.; and lifestyle interventions. J Clin Endocrinol Public Health 2015;36:483–505 Diabetes Prevention Program Research Group. Metab 2008;93:4774–4779 27. Kramer MK, Kriska AM, Venditti EM, et al. A The cost-effectiveness of lifestyle modiﬁcation 39. Aroda VR, Christophi CA, Edelstein SL, et al.; novel approach to diabetes prevention: evalua- or metformin in preventing type 2 diabetes in Diabetes Prevention Program Research Group. tion of the Group Lifestyle Balance program de- adults with impaired glucose tolerance. Ann The effect of lifestyle intervention and metfor- livered via DVD. Diabetes Res Clin Pract 2010; Intern Med 2005;142:323–332 min on preventing or delaying diabetes among 90:e60–e63 34. Diabetes Prevention Program Research women with and without gestational diabetes: 28. Ma J, Yank V, Xiao L, et al. Translating the Group. The 10-year cost-effectiveness of life- the Diabetes Prevention Program Outcomes Diabetes Prevention Program lifestyle inter- style intervention or metformin for diabetes Study 10-year follow-up. J Clin Endocrinol vention for weight loss into primary care: a prevention: an intent-to-treat analysis of the Metab 2015;100:1646–1653 randomized trial. JAMA Intern Med 2013;173: DPP/DPPOS. Diabetes Care 2012;35:723–730 40. Ford ES, Zhao G, Li C. Pre-diabetes and the 113–121 35. Ackermann RT, Finch EA, Brizendine E, Zhou risk for cardiovascular disease: a systematic re- 29. Azar KM, Aurora M, Wang EJ, Muzaffar A, H, Marrero DG. Translating the Diabetes Pre- view of the evidence. J Am Coll Cardiol 2010; Pressman A, Palaniappan LP. Virtual small vention Program into the community: the 55:1310–1317 groups for weight management: an innovative DEPLOY pilot study. Am J Prev Med 2008;35: 41. Butcher MK, Vanderwood KK, Hall TO, delivery mechanism for evidence-based lifestyle 357–363 Gohdes D, Helgerson SD, Harwell TS. Capacity interventions among obese men. Transl Behav 36. Balk EM, Earley A, Raman G, Avendano EA, of diabetes education programs to provide both Med 2015;5:37–44 Pittas AG, Remington PL. Combined diet and diabetes self-management education and to im- 30. Sepah SC, Jiang L, Peters AL. Translating the physical activity promotion programs to prevent plement diabetes prevention services. J Public Diabetes Prevention Program into an online type 2 diabetes among persons at increased risk: a Health Manag Pract 2011;17:242–247 S48 Diabetes Care Volume 40, Supplement 1, January 2017

6. Glycemic Targets American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S48–S56 | DOI: 10.2337/dc17-S009

ASSESSMENT OF GLYCEMIC CONTROL Patient self-monitoring of blood glucose (SMBG) and A1C are available to health care providers and patients to assess the effectiveness and safety of the management plan on glycemic control. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in subgroups of patients with type 1 diabetes and in selected patients with type 2 diabetes.

Recommendations c Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform self-monitoring of blood glucose (SMBG) prior to meals and snacks, at bedtime, occasionally postprandially, 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 prescribed as part of a broad educational program, SMBG may help to guide treatment decisions and/or self-management for patients taking less frequent insulin injections B or noninsulin therapies. E 6. GLYCEMIC TARGETS c When prescribing SMBG, ensure that patients receive ongoing instruction and regular evaluation of SMBG technique, SMBG results, and their ability to use SMBG data to adjust therapy. E 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 useful tool in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. C c Given the 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 Suggested citation: American Diabetes Associa- ’ tion. Glycemic targets. Sec. 6. In Standards of correlation between greater SMBG frequency and lower A1C (2). The patient s Medical Care in Diabetesd2017. Diabetes Care specific needs and goals should dictate SMBG frequency and timing. 2017;40(Suppl. 1):S48–S56 Optimization © 2017 by the American Diabetes Association. SMBG accuracy is dependent on the instrument and user, so it is important to Readers may use this article as long as the work ’ is properly cited, the use is educational and not evaluate each patient s monitoring technique, both initially and at regular intervals for profit, and the work is not altered. More infor- thereafter. Optimal use of SMBG requires proper review and interpretation of the mation is available at http://www.diabetesjournals data, by both the patient and the provider. Among patients who check their blood .org/content/license. care.diabetesjournals.org Glycemic Targets S49

glucose at least once daily, many report by 0.25–0.3% at 6 months (10,13), but the A meta-analysis suggests that com- taking no action when results are high or effect was attenuated at 12 months in one paredwithSMBG,CGMisassociatedwith low. In a yearlong study of insulin-naive analysis (13). A key consideration is that per- short-term A1C lowering of ;0.26% in inpatients with suboptimal initial glycemic forming SMBG alone does not lower blood sulin-treated patients (22). The long-term control, a group trained in structured glucose levels. To be useful, the information effectiveness of CGM needs to be deter- SMBG (a paper tool was used at least quar- must be integrated into clinical and self- mined. This technology may be particularly terly to collect and interpret 7-point SMBG management plans. useful in insulin-treated patients with hypo- profiles taken on 3 consecutive days) re- glycemia unawareness and/or frequent duced their A1C by 0.3 percentage points Continuous Glucose Monitoring hypoglycemic episodes, although studies more than the control group (3). Patients CGM measures interstitial glucose (which have not shown consistent reductions in se- should be taught how to use SMBG data to correlates well with plasma glucose) and in- vere hypoglycemia (22–24). A CGM device adjust food intake, exercise, or pharmaco- cludes sophisticated alarms for hypo- and equipped with an automatic low glucose logical therapy to achieve specific goals. hyperglycemic excursions. The U.S. Food suspend feature has been approved by The ongoing need for and frequency of and Drug Administration (FDA) has not yet the FDA. The Automation to Simulate Pan- SMBG should be reevaluated at each rou- approvedthesedevicesasasoledeviceto creatic Insulin Response (ASPIRE) trial of tine visit to avoid overuse (4–6). SMBG is monitor glucose. CGMs require calibration 247 patients with type 1 diabetes and docu- especially important for insulin-treated pa- with SMBG, and SMBG is still required to mented nocturnal hypoglycemia showed tients to monitor for and prevent asymp- make treatment decisions. An FDA advisory that sensor-augmented insulin pump ther- tomatic hypoglycemia and hyperglycemia. panel recently recommended approval for apy with a low glucose suspend function use of one CGM device alone (without significantly reduced nocturnal hypoglyce- For Patients on Intensive Insulin Regimens SMBG) to make treatment decisions, but mia over 3 months without increasing A1C Most patients using intensive insulin regi- the final FDA decision is still pending. levels (25). These devices may offer the op- mens (multiple-dose insulin or insulin A 26-week randomized trial of 322 pa- portunity to reduce hypoglycemia for those pump therapy) should perform SMBG prior tients with type 1 diabetes showed that with a history of nocturnal hypoglycemia. In to meals and snacks, at bedtime, occasion- adults aged $25 years using intensive September 2016, the FDA approved the ally postprandially, prior to exercise, when insulin therapy and CGM experienced a first hybrid closed-loop system, which they suspect low blood glucose, after treat- 0.5% reduction in A1C (from ;7.6% to may be considered as an option in those ing low blood glucose until they are nor- 7.1% [;60 mmol/mol to 54 mmol/mol]) already on an insulin pump when it is avail- moglycemic, and prior to critical tasks such compared with those using intensive insulin able on the market. The safety of hybrid as driving. For many patients, this will re- therapy with SMBG (14). CGM use in those closed-loop systems has been supported quire testing 6–10 (or more) times daily, aged ,25 years (children, teens, and in the literature (26). although individual needs may vary. A da- adults) did not result in significant A1C Due to variable adherence, optimal tabase study of almost 27,000 children and lowering, and there was no significant dif- CGM use requires an assessment of in- adolescents with type 1 diabetes showed ference in hypoglycemia in any group. The dividual readiness for the technology as that, after adjustment for multiple con- greatest predictor of A1C lowering for all well as initial and ongoing education and founders, increased daily frequency of age-groups was frequency of sensor use, support (17,27). Additionally, providers SMBG was significantly associated with which was highest in those aged $25 years need to provide robust diabetes educa- lower A1C (–0.2% per additional test per and lower in younger age-groups. Other tion, training, and support for optimal day) and with fewer acute complications. small, short-term studies have demon- CGM implementation and ongoing use. For Patients Using Basal Insulin or Oral Agents strated similar A1C reductions using CGM As people with type 1 or type 2 diabetes The evidence is insufficient regarding compared with SMBG in adults with A1C are living longer healthier lives, individu- when to prescribe SMBG and how often levels $7% (53 mmol/mol) (15,16). als who have been successfully using testing is needed for patients who do not A registry study of 17,317 participants CGM should have continued access to use intensive insulin regimens, such as confirmed that more frequent CGM use these devices after they turn 65 years of those with type 2 diabetes using oral agents is associated with lower A1C (17), whereas age (28). or basal insulin. For patients using basal in- another study showed that children sulin, lowering of A1C has been demon- with .70% sensor use (i.e., $5daysper A1C TESTING strated for those who adjust their dose to week) missed fewer school days (18). Small Recommendations attain a fasting glucose as determined by randomized controlled trials in adults and c Perform the A1C test at least two SMBG within a targeted range (7,8). children with baseline A1C ,7.0–7.5% (53– times a year in patients who are For individuals with type 2 diabetes on 58 mmol/mol) have confirmed favorable meeting treatment goals (and who less intensive insulin therapy, more frequent outcomes including a reduced frequency have stable glycemic control). E SMBG (e.g., fasting, before/after meals) of hypoglycemia (defined as a blood glu- c Perform the A1C test quarterly in may be helpful, as increased frequency is cose level ,70 mg/dL [3.9 mmol/L]) and patients whose therapy has changed associated with meeting A1C targets (9). maintaining A1C ,7% (53 mmol/mol) dur- or who are not meeting glycemic Several randomized trials have called ing the study period in groups using CGM, goals. E into question the clinical utility and cost- suggesting that CGM may provide further c Point-of-care testing for A1C provides effectiveness of routine SMBG in noninsulin- benefit for individuals with type 1 diabetes the opportunity for more timely treated patients (10–12). Meta-analyses who already have good glycemic control treatment changes. E have suggested that SMBG can reduce A1C (19–21). S50 Glycemic Targets Diabetes Care Volume 40, Supplement 1, January 2017

A1C reflects average glycemia over ap- SMBG results) and the adequacy of the available, it seems prudent to establish proximately 3 months and has strong SMBG testing schedule. A1C goals in these populations with predictive value for diabetes complica- consideration of both individualized A1C and Mean Glucose tions (29,30). Thus, A1C testing should SMBG and A1C results. Table 6.1 shows the correlation be- be performed routinely in all patients tweenA1Clevelsandmeanglucose with diabetesdat initial assessment levels based on two studies: the inter- A1C GOALS and as part of continuing care. Measure- national A1C-Derived Average Glucose For glycemic goals in children, please re- ment approximately every 3 months de- (ADAG) study, which assessed the fer to Section 12 “Children and Adoles- termines whether patients’ glycemic correlation between A1C and fre- cents.” For glycemic goals in pregnant targets have been reached and main- quent SMBG and CGM in 507 adults women, please refer to Section 13 “Man- tained. The frequency of A1C testing (83% non-Hispanic whites) with type 1, agement of Diabetes in Pregnancy.” should depend on the clinical situation, type 2, and no diabetes (32), and an em- the treatment regimen, and the clinician’s Recommendations pirical study of the average blood glu- judgment. The use of point-of-care A1C c A reasonable A1C goal for many cose levels at premeal, postmeal, and testing may provide an opportunity for nonpregnant adults is ,7% (53 bedtime associated with specified A1C more timely treatment changes during mmol/mol). A levels using data from the ADAG trial encounters between patients and c Providers might reasonably sug- (27). The American Diabetes Associ- providers. Patients with type 2 diabe- gest more stringent A1C goals ation (ADA) and the American Asso- tes with stable glycemia well within (such as ,6.5% [48 mmol/mol]) ciation for Clinical Chemistry have target may do well with A1C testing for selected individual patients determined that the correlation (r 5 only twice per year. Unstable or inten- if this can be achieved without sig- 0.92) in the ADAG trial is strong enough sively managed patients (e.g., pregnant nificant hypoglycemia or other ad- to justify reporting both the A1C result women with type 1 diabetes) may reverse effects of treatment (i.e., and the eAG result when a clinician or- quire testing more frequently than ev- polypharmacy). Appropriate pa- ders the A1C test (Table 6.1). Clinicians ery 3 months (31). tients might include those with should note that the mean plasma glu- short duration of diabetes, type 2 cose numbers in the table are based diabetes treated with lifestyle or A1C Limitations on ;2,700 readings per A1C in the The A1C test is an indirect measure of metformin only, long life expec- ADAG trial. average glycemia and, as such, is subject tancy, or no significant cardiovas- to limitations. Conditions that affect red A1C Differences in Ethnic Populations cular disease. C blood cell turnover (hemolysis, blood and Children c Less stringent A1C goals (such loss) and hemoglobin variants must be In the ADAG study, there were no signif- as ,8% [64 mmol/mol]) may be considered, particularly when the A1C icant differences among racial and ethnic appropriate for patients with a his- result does not correlate with the pa- groups in the regression lines between tory of severe hypoglycemia, lim- tient’s SMBG levels. For patients in A1C and mean glucose, although the ited life expectancy, advanced whom A1C/estimated average glucose study was underpowered to detect a dif- microvascular or macrovascular (eAG) and measured blood glucose ap- ference and there was a trend toward a complications, extensive comor- pear discrepant, clinicians should con- difference between the African/African bid conditions, or long-standing sider the possibilities of altered red American and non-Hispanic white co- diabetes in whom the goal is diffi- blood cell turnover. Options for moni- horts, with higher values observed in cult to achieve despite diabetes toring include more frequent and/or Africans/African Americans compared self-management education, ap- different timing of SMBG or CGM with non-Hispanic whites. Other studies propriate glucose monitoring, use. Other measures of average gly- have also demonstrated higher A1C levels and effective doses of multiple cemia such as fructosamine and 1,5- in African Amercans than in whites (33). A glucose-lowering agents including anhydroglucitol (1,5-AG) are available, small study comparing A1C to CGM data insulin. B but their translation into average glu- in children with type 1 diabetes found a cose levels and their prognostic signifi- highly statistically significant correlation A1C and Microvascular Complications cance are not as clear as for A1C (see between A1C and mean blood glucose, Hyperglycemia defines diabetes, and Section 2 “Classification and Diagnosis although the correlation (r 5 0.7) was sig- glycemic control is fundamental to dia- of Diabetes”). nificantly lower than in the ADAG trial betes management. The Diabetes Con- A1C does not provide a measure of (34). Whether there are clinically mean- trol and Complications Trial (DCCT) (1), a glycemic variability or hypoglycemia. ingful differences in how A1C relates prospective randomized controlled trial For patients prone to glycemic variabil- to average glucose in children or in dif- of intensive versus standard glycemic ity, especially patients with type 1 dia- ferent ethnicities is an area for further control in patients with type 1 diabetes, betes or type 2 diabetes with severe study (35,36). For the time being, the showed definitively that better glycemic insulin deficiency, glycemic control is question has not led to different recom- control is associated with significantly de- best evaluated by the combination of mendations about testing A1C or to dif- creased rates of development and pro- results from SMBG and A1C. A1C may ferent interpretations of the clinical gression of microvascular (retinopathy also confirm the accuracy of the pa- meaning of given levels of A1C in those [37] and diabetic kidney disease) and neu- tient’s meter (or the patient’s reported populations. Until further evidence is ropathic complications. Follow-up of the care.diabetesjournals.org Glycemic Targets S51

Table 6.1—Mean glucose levels for speciﬁed A1C levels (27,32) A1C Mean plasma glucose* Mean fasting glucose Mean premeal glucose Mean postmeal glucose Mean bedtime glucose % (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 (100–152) (5.5–8.5) 5.5–6.49 122 6.8 118 6.5 144 8.0 136 7.5 (37–47) (117–127) (6.5–7.0) (115–121) (6.4–6.7) (139–148) (7.7–8.2) (131–141) (7.3–7.8) 6.5–6.99 142 7.9 139 7.7 164 9.1 153 8.5 (47–53) (135–150) (7.5–8.3) (134–144) (7.4–8.0) (159–169) (8.8–9.4) (145–161) (8.0–8.9) 7 (53) 154 8.6 (123–185) (6.8–10.3) 7.0–7.49 152 8.4 152 8.4 176 9.8 177 9.8 (53–58) (143–162) (7.9–9.0) (147–157) (8.2–8.7) (170–183) (9.4–10.2) (166–188) (9.2–10.4) 7.5–7.99 167 9.3 155 8.6 189 10.5 175 9.7 (58–64) (157–177) (8.7–9.8) (148–161) (8.2–8.9) (180–197) (10.0–10.9) (163–188) (9.0–10.4) 8 (64) 183 10.2 (147–217) (8.1–12.1) 8.0–8.5 178 9.9 179 9.9 206 11.4 222 12.3 (64–69) (164–192) (9.1–10.7) (167–191) (9.3–10.6) (195–217) (10.8–12.0) (197–248) (10.9–13.8) 9 (75) 212 11.8 (170–249) (9.4–13.9) 10 (86) 240 13.4 (193–282) (10.7–15.7) 11 (97) 269 14.9 (217–314) (12.0–17.5) 12 (108) 298 16.5 (240–347) (13.3–19.3) Data in parentheses represent 95% CI, unless otherwise noted. 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 (32).

DCCT cohorts in the Epidemiology of Di- suggest that further lowering of A1C from and patient preferences, select patients, es- abetes Interventions and Complications 7% to 6% [53 mmol/mol to 42 mmol/mol] pecially those with little comorbidity and (EDIC) study (38) demonstrated persis- is associated with further reduction in the long life expectancy, may benefit from tence of these microvascular benefits de- risk of microvascular complications, al- adopting more intensive glycemic targets spite the fact that the glycemic separation though the absolute risk reductions become (e.g., A1C target ,6.5% [48 mmol/mol]) as between the treatment groups dimin- much smaller. Given the substantially in- long as significant hypoglycemia does ished and disappeared during follow-up. creased risk of hypoglycemia in type 1 di- not become a barrier. The Kumamoto Study (39) and UK abetes trials and with polypharmacy in Prospective Diabetes Study (UKPDS) type 2 diabetes, the risks of lower glyce- A1C and Cardiovascular Disease (40,41) confirmed that intensive glycemic targets outweigh the potential bene- Outcomes mic control significantly decreased rates fits on microvascular complications. Cardiovascular Disease and Type 1 of microvascular and neuropathic com- Diabetes plications in patients with type 2 diabe- ACCORD, ADVANCE, and VADT Cardiovascular disease (CVD) is a more tes. Long-term follow-up of the UKPDS Three landmark trials (Action to Control common cause of death than microvas- cohorts showed enduring effects of Cardiovascular Risk in Diabetes [ACCORD], cular complications in populations with early glycemic control on most micro- Action in Diabetes and Vascular Disease: diabetes. There is evidence for a cardiovascular complications (42). Preterax and Diamicron MR Controlled vascular benefit of intensive glycemic Therefore, achieving A1C targets Evaluation [ADVANCE], and Veterans Af- control after long-term follow-up of cohorts of ,7% (53 mmol/mol) has been shown fairs Diabetes Trial [VADT]) showed that treated early in the course of type 1 and to reduce microvascular complications of lower A1C levels were associated with re- type 2 diabetes. In the DCCT, there was a diabetes. Epidemiological analyses of the duced onset or progression of microvascu- trend toward lower risk of CVD events with DCCT (1) and UKPDS (43) demonstrate a cur- lar complications (44–46). intensive control. In the 9-year post-DCCT vilinear relationship between A1C and mi- The concerning mortality findings in follow-up of the EDIC cohort, participants crovascular complications. Such analyses the ACCORD trial (47), discussed below, previously randomized to the intensive arm suggest that, on a population level, the great- and the relatively intense efforts required had a significant 57% reduction in the risk est number of complications will be averted to achieve near-euglycemia should also be of nonfatal myocardial infarction (MI), by taking patients from very poor control considered when setting glycemic targets. stroke, or cardiovascular death compared to fair/good control. These analyses also However, on the basis of physician judgment with those previously randomized to the S52 Glycemic Targets Diabetes Care Volume 40, Supplement 1, January 2017

standard arm (48). The benefitofintensive increased mortality rate in the intensive Many factors, including patient prefer- glycemic control in this cohort with type 1 compared with the standard treatment ences, should be taken into account when diabetes has been shown to persist for arm (1.41% vs. 1.14% per year; hazard ra- developing a patient’s individualized goals several decades (49) and to be associ- tio 1.22 [95% CI 1.01–1.46]), with a similar (Table 6.2) ated with a modest reduction in all-cause increase in cardiovascular deaths. Analysis mortality (50). of the ACCORD data did not identify a A1C and Glycemic Targets clear explanation for the excess mortal- Numerous aspects must be considered Cardiovascular Disease and Type 2 ity in the intensive treatment arm (47). when setting glycemic targets. The Diabetes Longer-term follow-up has shown no ev- ADA proposes optimal targets, but In type 2 diabetes, there is evidence that idence of cardiovascular benefitorharmin each target must be individualized to more intensive treatment of glycemia in the ADVANCE trial (52). The end-stage re- the needs of each patient and his or her newly diagnosed patients may reduce nal disease rate was lower in the intensive disease factors. long-term CVD rates. During the UKPDS, treatment group over follow-up. However, When possible, such decisions should there was a 16% reduction in CVD events fl 10-year follow-up of the VADT cohort (53) be made with the patient, re ecting his (combined fatal or nonfatal MI and sud- or her preferences, needs, and values. showed a reduction in the risk of cardiovas- den death) in the intensive glycemic Figure 6.1 is not designed to be applied cular events (52.7 [control group] vs. 44.1 control arm that did not reach statistical rigidly but to be used as a broad con- [intervention group] events per 1,000 per- significance (P 5 0.052), and there was struct to guide clinical decision making son-years) with no benefit in cardiovascular no suggestion of benefit on other CVD (58), both in type 1 and type 2 diabetes. or overall mortality. Heterogeneity of mor- outcomes (e.g., stroke). However, after Recommended glycemic targets for 10 years of observational follow-up, those tality effects across studies was noted, many nonpregnant adults are shown in fl originally randomized to intensive glyce- which may re ect differences in glycemic Table 6.2. The recommendations in- mic control had significant long-term re- targets, therapeutic approaches, and pop- clude blood glucose levels that appear ductions in MI (15% with sulfonylurea or ulation characteristics (54). to correlate with achievement of an fi insulin as initial pharmacotherapy, 33% Mortality ndings in ACCORD (47) A1C of ,7% (53 mmol/mol). The issue with metformin as initial pharmacother- and subgroup analyses of VADT (55) sug- of preprandial versus postprandial SMBG apy) and in all-cause mortality (13% and gest that the potential risks of intensive targets is complex (59). Elevated post- 27%, respectively) (42). glycemic control may outweigh its bene- challenge (2-h oral glucose tolerance The ACCORD, ADVANCE, and VADT fits in higher-risk patients. In all three tri- test) glucose values have been associ- suggestednosignificant reduction in als, severe hypoglycemia was significantly ated with increased cardiovascular risk CVD outcomes with intensive glycemic more likely in participants who were ran- independent of fasting plasma glucose control in participants followed for 3.5– domly assigned to the intensive glycemic in some epidemiological studies, but in- 5.6 years who had more advanced type 2 control arm. Those patients with long tervention trials have not shown post- diabetes than UKPDS participants. All three duration of diabetes, a known history of prandial glucose to be a cardiovascular trials were conducted in relatively older hypoglycemia, advanced atherosclerosis, risk factor independent of A1C. In sub- participants with longer known duration or advanced age/frailty may benefitfrom jects with diabetes, surrogate measures of diabetes (mean duration 8–11 years) less aggressive targets (56,57). of vascular pathology, such as endothelial and either CVD or multiple cardiovascular Providers should be vigilant in pre- dysfunction, are negatively affected by risk factors. The target A1C among intensive venting hypoglycemia in patients with postprandial hyperglycemia. It is clear control subjects was ,6% (42 mmol/mol) advanced disease and should not aggres- that postprandial hyperglycemia, like in ACCORD, ,6.5% (48 mmol/mol) in sively attempt to achieve near-normal preprandial hyperglycemia, contributes ADVANCE, and a 1.5% reduction in A1C A1C levels in patients in whom such tar- to elevated A1C levels, with its relative compared with control subjects in VADT, gets cannot be safely and reasonably contribution being greater at A1C levels with achieved A1C of 6.4% versus 7.5% achieved. Severe or frequent hypoglyce- that are closer to 7% (53 mmol/mol). (46 mmol/mol vs. 58 mmol/mol) in mia is an absolute indication for the However, outcome studies have clearly ACCORD, 6.5% versus 7.3% (48 mmol/ modification of treatment regimens, in- shown A1C to be the primary predictor mol vs. 56 mmol/mol) in ADVANCE, and cluding setting higher glycemic goals. of complications, and landmark trials 6.9% versus 8.4% (52 mmol/mol vs. 68 mmol/mol) in VADT. Details of these studies are reviewed extensively in the Table 6.2—Summary of glycemic recommendations for many nonpregnant adults ADA position statement “Intensive Glycemic with diabetes A1C ,7.0% (53 mmol/mol)* Control and the Prevention of Cardiovascu- Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) lar Events: Implications of the ACCORD, Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L) ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Asso- *More or less stringent glycemic goals may be appropriate for individual patients. Goals should fi be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, ciation and a Scienti c Statement of the known CVD or advanced microvascular complications, hypoglycemia unawareness, and American College of Cardiology Foundation individual patient considerations. †Postprandial glucose may be targeted if A1C goals are and the American Heart Association” (51). not met despite reaching preprandial glucose goals. Postprandial glucose measurements The glycemic control comparison in should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes. ACCORD was halted early due to an care.diabetesjournals.org Glycemic Targets S53

c Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger reevalua- tion of the treatment regimen. E c Insulin-treated patients with hypoglycemia unawareness or an episode of clinically signiﬁcant hypoglycemia should be advised to raise their glycemic targets to strictly avoid hypoglycemia for at least several weeks in order to partially reverse hypoglycemia unawareness and reduce risk of future episodes. A c Ongoing assessment of cognitive function is suggested with increased vigilance for hypoglycemia by the clinician, patient, and caregivers if low cognition or declining cognition is found. B

Hypoglycemia is the major limiting factor in the glycemic management of type 1 and type 2 diabetes. Recommen- Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets. Char- dations from the International Hypogly- acteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward caemia Study Group regarding the the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (58). classification of hypoglycemia are outlined in Table 6.3 (61). Of note, this clas- of glycemic control such as the DCCT and HYPOGLYCEMIA sification scheme considers a blood UKPDS relied overwhelmingly on pre- glucose ,54 mg/dL (3.0 mmol/L) de- Recommendations prandial SMBG. Additionally, a random- tected by SMBG, CGM (for at least c Individuals at risk for hypoglyce- ized controlled trial in patients with 20 min), or laboratory measurement of mia should be asked about symptom- known CVD found no CVD benefitofin- plasma glucose as sufficiently low to in- atic and asymptomatic hypoglycemia sulin regimens targeting postprandial glu- dicate serious, clinically significant hypo- at each encounter. C cose compared with those targeting glycemia that should be included in c Glucose (15–20 g) is the preferred preprandial glucose (60). Therefore, it is reports of clinical trials of glucose-lowering treatment for the conscious individu- reasonable for postprandial testing to be drugs for the treatment of diabetes al with hypoglycemia (glucose alert recommended for individuals who have (61). However, a glucose alert value of value of #70 mg/dL [3.9 mmol/L]), premeal glucose values within target but $70 mg/dL (3.9 mmol/L) can be impor- although any form of carbohydrate have A1C values above target. Measuring tant for therapeutic dose adjustment of that contains glucose may be used. postprandial plasma glucose 1–2 h after glucose-lowering drugs in clinical care Fifteen minutes after treatment, if the start of a meal and using treat- and is often related to symptomatic hy- SMBG shows continued hypoglyce- ments aimed at reducing postprandial poglycemia. Severe hypoglycemia is de- mia, the treatment should be re- plasma glucose values to ,180 mg/dL fined as severe cognitive impairment peated. Once SMBG returns to (10.0 mmol/L) may help to lower A1C. requiring assistance from another person normal, the individual should con- An analysis of data from 470 participants for recovery (62). sume a meal or snack to prevent re- in the ADAG study (237 with type 1 diabe- Symptoms of hypoglycemia include, currence of hypoglycemia. E tes and 147 with type 2 diabetes) found but are not limited to, shakiness, irritabil- c Glucagon should be prescribed for that actual average glucose levels associ- ity, confusion, tachycardia, and hunger. all individuals at increased risk of clin- ated with conventional A1C targets were Hypoglycemia may be inconvenient or ically significant hypoglycemia, de- higher than older DCCT and ADA targets frightening to patients with diabetes. Se- fined as blood glucose ,54 mg/dL (Table 6.1) (27,29). These findings support vere hypoglycemia may be recognized or (3.0 mmol/L), so it is available should that premeal glucose targets may be re- unrecognized and can progress to loss of it be needed. Caregivers, school per- laxed without undermining overall glycemic consciousness, seizure, coma, or death. It is sonnel, or family members of these control as measured by A1C. These data reversed by administration of rapid-acting individuals should know where it is prompted the revision in the ADA- glucose or glucagon. Clinically signifi- and when and how to administer it. recommended premeal glucose target cant hypoglycemia can cause acute harm Glucagon administration is not lim- to 80–130 mg/dL (4.4–7.2 mmol/L) but did to the person with diabetes or others, es- ited to health care professionals. E not affect the definition of hypoglycemia. pecially if it causes falls, motor vehicle S54 Glycemic Targets Diabetes Care Volume 40, Supplement 1, January 2017

Table 6.3—Classification of hypoglycemia (61) Level Glycemic criteria Description Glucose alert value (level 1) #70 mg/dL (3.9 mmol/L) Sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy Clinically significant hypoglycemia (level 2) ,54 mg/dL (3.0 mmol/L) Sufficiently low to indicate serious, clinically important hypoglycemia Severe hypoglycemia (level 3) No specific glucose threshold Hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery

accidents, or other injury. A large cohort additional goal of raising the lower range SMBG and, for some patients, CGM are study suggested that among older adults of the glycemic target was to limit over- essential tools to assess therapy and de- with type 2 diabetes, a history of severe treatment and provide a safety margin in tect incipient hypoglycemia. Patients hypoglycemia was associated with greater patients titrating glucose-lowering drugs should understand situations that in- risk of dementia (63). Conversely, in a sub- such as insulin to glycemic targets. crease their risk of hypoglycemia, such study of the ACCORD trial, cognitive as fasting for tests or procedures, de- impairment at baseline or decline in Hypoglycemia Treatment layed meals, during or after intense ex- cognitive function during the trial was Providers should continue to counsel ercise, and during sleep. Hypoglycemia significantly associated with subsequent patients to treat hypoglycemia with may increase the risk of harm to self or episodes of severe hypoglycemia (64). fast-acting carbohydrates at the blood others, such as with driving. Teaching Evidence from DCCT/EDIC, which in- glucose alert value of 70 mg/dL (3.9 people with diabetes to balance insulin volved adolescents and younger adults mmol/L) or less. Hypoglycemia treat- use and carbohydrate intake and exer- with type 1 diabetes, found no associa- ment requires ingestion of glucose- or car- cise are necessary, but these strategies fi tion between frequency of severe hypo- bohydrate-containing foods. The acute are not always suf cient for prevention. glycemia and cognitive decline (65), as glycemic response correlates better with In type 1 diabetes and severely insulin- fi discussed in Section 12 “Children and the glucose content of food than with the de cient type 2 diabetes, hypoglycemia un- Adolescents.” carbohydrate content of food. Pure glucose awareness (or hypoglycemia-associated Severe hypoglycemia was associated is the preferred treatment, but any form of autonomic failure) can severely compro- withmortalityinparticipantsinboththe carbohydrate that contains glucose will mise stringent diabetes control and qual- standard and the intensive glycemia arms raise blood glucose. Added fat may retard ity of life. This syndrome is characterized fi of the ACCORD trial, but the relationships and then prolong the acute glycemic re- by de cient counterregulatory hormone between hypoglycemia, achieved A1C, and sponse. Ongoing insulin activity or insulin release, especially in older adults, and a treatment intensity were not straightfor- secretagogues may lead to recurrent hypo- diminished autonomic response, which ward. An association of severe hypoglyce- glycemia unless further food is ingested af- both are risk factors for, and caused by, “ mia with mortality was also found in the ter recovery. Once the glucose returns to hypoglycemia. A corollary to this vicious ” ADVANCE trial (66). An association be- normal, the individual should be counseled cycle is that several weeks of avoidance tween self-reported severe hypoglycemia to eat a meal or snack to prevent recurrent of hypoglycemia has been demonstrated and 5-year mortality has also been report- hypoglycemia. to improve counterregulation and hypo- ed in clinical practice (67). glycemia awareness in many patients Glucagon Young children with type 1 diabetes (68). Hence, patients with one or more The use of glucagon is indicated for the episodes of clinically significant hypogly- and the elderly are noted as particularly treatment of hypoglycemia in people un- vulnerable to clinically significant hypo- cemia may benefit from at least short- able or unwilling to consume carbohy- term relaxation of glycemic targets. glycemia because of their reduced ability drates by mouth. Those in close contact to recognize hypoglycemic symptoms and with, or having custodial care of, people effectively communicate their needs. In- with hypoglycemia-prone diabetes (fam- INTERCURRENT ILLNESS dividualized glucose targets, patient edu- ily members, roommates, school person- For further information on management cation, dietary intervention (e.g., bedtime nel, child care providers, correctional of patients with hyperglycemia in the snack to prevent overnight hypoglycemia), institution staff, or coworkers) should hospital, please refer to Section 14 “Di- exercise management, medication ad- be instructed on the use of glucagon abetes Care in the Hospital.” justment, glucose monitoring, and rou- kits including where the kit is and when Stressful events (e.g., illness, trauma, tine clinical surveillance may improve and how to administer glucagon. An indi- surgery, etc.) may worsen glycemic con- patient outcomes (62). vidual does not need to be a health care trol and precipitate diabetic ketoacidosis In 2015, the ADA changed its prepran- professional to safely administer glucagon. or nonketotic hyperosmolar state, life- – dial glycemic target from 70 130 mg/dL Care should be taken to ensure that gluca- threatening conditions that require imme- (3.9–7.2 mmol/L) to 80–130 mg/dL gon kits are not expired. diate medical care to prevent complications (4.4–7.2 mmol/L). This change reflects and death. Any condition leading to deteri- the results of the ADAG study, which Hypoglycemia Prevention oration in glycemic control necessitates demonstrated that higher glycemic tar- Hypoglycemia prevention is a critical more frequent monitoring of blood glu- gets corresponded to A1C goals (27). An component of diabetes management. cose; ketosis-prone patients also require care.diabetesjournals.org Glycemic Targets S55

urine or blood ketone monitoring. If accom- 10. Farmer A, Wade A, Goyder E, et al. Impact reduces severe hypoglycemia in hypoglycemia- panied by ketosis, vomiting, or alteration in of self monitoring of blood glucose in the man- unaware patients with type 1 diabetes. Diabetes – the level of consciousness, marked hyper- agement of patients with non-insulin treated Care 2013;36:4160 4162 diabetes: open parallel group randomised trial. 24. Choudhary P, Rickels MR, Senior PA, et al. glycemia requires temporary adjustment of BMJ 2007;335:132 Evidence-informed clinical practice recommen- the treatment regimen and immediate in- 11. O’Kane MJ, Bunting B, Copeland M, Coates dations for treatment of type 1 diabetes com- teraction with the diabetes care team. The VE; ESMON study group. Efficacy of self moni- plicated by problematic hypoglycemia. Diabetes patient treated with noninsulin therapies or toring of blood glucose in patients with newly Care 2015;38:1016–1029 medical nutrition therapy alone may tem- diagnosed type 2 diabetes (ESMON study): 25. Bergenstal RM, Klonoff DC, Garg SK, et al.; randomised controlled trial. BMJ 2008;336: fl ASPIRE In-Home Study Group. Threshold-based porarily require insulin. Adequate uid and 1174–1177 insulin-pump interruption for reduction of hy- caloric intake must be ensured. Infection or 12. Simon J, Gray A, Clarke P, Wade A, Neil A, poglycemia. N Engl J Med 2013;369:224–232 dehydration is more likely to necessitate Farmer A; Diabetes Glycaemic Education and 26. Bergenstal RM, Garg S, Weinzimer SA, et al. hospitalization of the person with diabetes Monitoring Trial Group. Cost effectiveness of Safety of a hybrid closed-loop insulin delivery than the person without diabetes. self monitoring of blood glucose in patients system in patients with type 1 diabetes. JAMA with non-insulin treated type 2 diabetes: eco- 2016;316:1407–1408 A physician with expertise in diabetes nomic evaluation of data from the DiGEM trial. 27. Wei N, Zheng H, Nathan DM. Empirically management should treat the hospital- BMJ 2008;336:1177–1180 establishing blood glucose targets to achieve ized patient. For further information on 13. Malanda UL, Welschen LM, Riphagen II, HbA1c goals. Diabetes Care 2014;37:1048–1051 the management of diabetic ketoacidosis Dekker JM, Nijpels G, Bot SD. Self-monitoring 28. Herman WH, Ilag LL, Johnson SL, et al. A and the hyperglycemic nonketotic hyper- of blood glucose in patients with type 2 diabetes clinical trial of continuous subcutaneous insulin mellitus who are not using insulin. Cochrane infusion versus multiple daily injections in older osmolar state, please refer to the ADA Database Syst Rev 2012;1:CD005060 adults with type 2 diabetes. Diabetes Care 2005; consensus report “Hyperglycemic Crises 14. Juvenile Diabetes Research Foundation Con- 28:1568–1573 in Adult Patients With Diabetes” (69). tinuous Glucose Monitoring Study Group, 29. Albers JW, Herman WH, Pop-Busui R, et al.; Tamborlane WV, Beck RW, et al. Continuous glu- Diabetes Control and Complications Trial/ cose monitoring and intensive treatment of type 1 Epidemiology of Diabetes Interventions and References diabetes. N Engl J Med 2008;359:1464–1476 Complications Research Group. Effect of prior 1. The Diabetes Control and Complications Trial 15. Deiss D, Bolinder J, Riveline J-P, et al. Im- intensive insulin treatment during the Diabetes Research Group. The effect of intensive treatment proved glycemic control in poorly controlled Control and Complications Trial (DCCT) on pe- of diabetes on the development and progression patients with type 1 diabetes using real-time ripheral neuropathy in type 1 diabetes during of long-term complications in insulin-dependent continuous glucose monitoring. 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Real-time continuous 31. Jovanovicˇ L, Savas H, Mehta M, Trujillo A, Structured self-monitoring of blood glucose sig- glucose monitoring among participants in the Pettitt DJ. Frequent monitoring of A1C during nificantly reduces A1C levels in poorly con- T1D Exchange clinic registry. Diabetes Care pregnancy as a treatment tool to guide therapy. trolled, noninsulin-treated type 2 diabetes: 2014;37:2702–2709 Diabetes Care 2011;34:53–54 results from the Structured Testing Program 18. Hommel E, Olsen B, Battelino T, et al.; 32. Nathan DM, Kuenen J, Borg R, Zheng H, study. Diabetes Care 2011;34:262–267 SWITCH Study Group. Impact of continuous glu- Schoenfeld D, Heine RJ; A1c-Derived Average 4. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good cose monitoring on quality of life, treatment Glucose (ADAG) Study Group. Translating the CB,FineMJ.DualuseofDepartmentofVet- satisfaction, and use of medical care resources: A1C assay into estimated average glucose val- erans Affairs and Medicare benefits and use of analyses from the SWITCH study. Acta Diabetol ues. Diabetes Care 2008;31:1473–1478 test strips in veterans with type 2 diabetes mel- 2014;51:845–851 33. Selvin E. Are there clinical implications of litus. JAMA Intern Med 2015;175:26–34 19. Battelino T, Phillip M, Bratina N, Nimri R, racial differences in HbA1c? A difference, to 5. Grant RW, Huang ES, Wexler DJ, et al. Pa- Oskarsson P, Bolinder J. Effect of continuous be a difference, must make a difference. Diabe- tients who self-monitor blood glucose and their glucose monitoring on hypoglycemia in type 1 tes Care 2016;39:1462–1467 unused testing results. Am J Manag Care 2015; diabetes. Diabetes Care 2011;34:795–800 34. Diabetes Research in Children Network 21:e119–e129 20. Juvenile Diabetes Research Foundation (DirecNet) Study Group. 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Elgart JF, Gonzalez´ L, Prestes M, Rucci E, meta-analysis. Ann Intern Med 2012;157: Trial (DCCT)/Epidemiology of Diabetes Interven- Gagliardino JJ. Frequency of self-monitoring 336–347 tions and Complications (EDIC) Research Group. blood glucose and attainment of HbA1c target 23. Choudhary P, Ramasamy S, Green L, et al. Real- Effect of intensive diabetes therapy on the pro- values. Acta Diabetol 2016;53:57–62 time continuous glucose monitoring significantly gression of diabetic retinopathy in patients with S56 Glycemic Targets Diabetes Care Volume 40, Supplement 1, January 2017

type 1 diabetes: 18 years of follow-up in the cardiovascular disease in patients with type 1 58. Inzucchi SE, Bergenstal RM, Buse JB, et al. DCCT/EDIC. Diabetes 2015;64:631–642. diabetes. N Engl J Med 2005;353:2643–2653 Management of hyperglycemia in type 2 diabe- 38. The Diabetes Control and Complications 49. Diabetes Control and Complications Trial/ tes, 2015: a patient-centered approach: update Trial/Epidemiology of Diabetes Interventions Epidemiology of Diabetes Interventions and to a position statement of the American Diabe- and Complications Research Group. Retinopa- Complications (DCCT/EDIC) Research Group, tes Association and the European Association thy and nephropathy in patients with type 1 di- Nathan DM, Zinman B, et al. Modern-day clinical for the Study of Diabetes. 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Diabetes Care 2009;32:381–386 40. UK Prospective Diabetes Study (UKPDS) Group, Orchard TJ, Nathan DM, et al. Associa- 61. International Hypoglycaemia Study Group. Group. Effect of intensive blood-glucose control tion between 7 years of intensive treatment of Glucose concentrations of less than 3.0 mmol/L with metformin on complications in overweight type 1 diabetes and long-term mortality. JAMA (54 mg/dL) should be reported in clinical trials: a patients with type 2 diabetes (UKPDS 34). Lan- 2015;313:45–53 joint position statement of the American Diabe- cet 1998;352:854–865 51. Skyler JS, Bergenstal R, Bonow RO, et al. tes Association and the European Association 41. UK Prospective Diabetes Study (UKPDS) Intensive glycemic control and the prevention for the Study of Diabetes. Diabetes Care 2017; Group. Intensive blood-glucose control with sul- of cardiovascular events: implications of the 40:155–157 phonylureas or insulin compared with conven- ACCORD, ADVANCE, and VA Diabetes Trials: a 62. Seaquist ER, Anderson J, Childs B, et al. Hy- tional treatment and risk of complications in position statement of the American Diabetes poglycemia and diabetes: a report of a work- patients with type 2 diabetes (UKPDS 33). Lan- Association and a scientiﬁc statement of the group of the American Diabetes Association cet 1998;352:837–853 American College of Cardiology Foundation and the Endocrine Society. Diabetes Care 42. Holman RR, Paul SK, Bethel MA, Matthews and the American Heart Association [published 2013;36:1384–1395 DR, Neil HAW. 10-year follow-up of intensive correction appears in Diabetes Care 2009;32: 63. Whitmer RA, Karter AJ, Yaffe K, Quesenberry glucose control in type 2 diabetes. N Engl J 754]. Diabetes Care 2009;32:187–192 CP Jr, Selby JV. Hypoglycemic episodes and risk of Med 2008;359:1577–1589 52. Zoungas S, Chalmers J, Neal B, et al.; dementia in older patients with type 2 diabetes 43. Adler AI, Stratton IM, Neil HAW, et al. As- ADVANCE-ON Collaborative Group. Follow-up mellitus. JAMA 2009;301:1565–1572 sociation of systolic blood pressure with macro- of blood-pressure lowering and glucose control 64. Punthakee Z, Miller ME, Launer LJ, et al.; vascular and microvascular complications of in type 2 diabetes. N Engl J Med 2014;371:1392– ACCORD Group of Investigators; ACCORD- type 2 diabetes (UKPDS 36): prospective obser- 1406 MIND Investigators. Poor cognitive function vational study. BMJ 2000;321:412–419 53. Hayward RA, Reaven PD, Wiitala WL, et al.; and risk of severe hypoglycemia in type 2 dia- 44. Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Follow-up of glycemic betes: post hoc epidemiologic analysis of the VADT Investigators. Glucose control and vascu- control and cardiovascular outcomes in type 2 ACCORD trial. Diabetes Care 2012;35:787–793 lar complications in veterans with type 2 diabe- diabetes. N Engl J Med 2015;372:2197–2206 65. Diabetes Control and Complications Trial/ tes. N Engl J Med 2009;360:129–139 54. Control Group, Turnbull FM, Abraira C, Epidemiology of Diabetes Interventions and Com- 45. ADVANCE Collaborative Group, Patel A, et al. Intensive glucose control and macrovas- plications Study Research Group, Jacobson AM, MacMahon S, et al. Intensive blood glucose con- cular outcomes in type 2 diabetes [published Musen G, et al. Long-term effect of diabetes and trol and vascular outcomes in patients with type 2 correction appears in Diabetologia 2009;52: its treatment on cognitive function. N Engl J Med diabetes. N Engl J Med 2008;358:2560–2572 2470]. Diabetologia 2009;52:2288–2298 2007;356:1842–1852 46. Ismail-Beigi F, Craven T, Banerji MA, et al.; 55. Duckworth WC, Abraira C, Moritz TE, et al.; 66. Zoungas S, Patel A, Chalmers J, et al.; ACCORD trial group. Effect of intensive treatment Investigators of the VADT. The duration of di- ADVANCE Collaborative Group. Severe hypogly- of hyperglycaemia on microvascular outcomes abetes affects the response to intensive glucose cemia and risks of vascular events and death. in type 2 diabetes: an analysis of the ACCORD control in type 2 subjects: the VA Diabetes Trial. N Engl J Med 2010;363:1410–1418 randomised trial. Lancet 2010;376:419–430 J Diabetes Complications 2011;25:355–361 67. McCoy RG, Van Houten HK, Ziegenfuss JY, 47. Action to Control Cardiovascular Risk in Di- 56. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Shah ND, Wermers RA, Smith SA. Increased mor- abetes Study Group, Gerstein HC, Miller ME, et al. Steinman MA. Potential overtreatment of dia- tality of patients with diabetes reporting severe Effects of intensive glucose lowering in type 2 betes mellitus in older adults with tight glycemic hypoglycemia. Diabetes Care 2012;35:1897–1901 diabetes. N Engl J Med 2008;358:2545–2559 control. JAMA Intern Med 2015;175:356–362 68. Cryer PE. Diverse causes of hypoglycemia- 48. Nathan DM, Cleary PA, Backlund J-YC, et al.; 57. Vijan S, Sussman JB, Yudkin JS, Hayward RA. associated autonomic failure in diabetes. N Engl Diabetes Control and Complications Trial/ Effect of patients’ risks and preferences on J Med 2004;350:2272–2279 Epidemiology of Diabetes Interventions and health gains with plasma glucose level lowering 69. Kitabchi AE, Umpierrez GE, Miles JM, Fisher Complications (DCCT/EDIC) Study Research in type 2 diabetes mellitus. JAMA Intern Med JN. Hyperglycemic crises in adult patients with Group. Intensive diabetes treatment and 2014;174:1227–1234 diabetes. 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7. Obesity Management for the American Diabetes Association Treatment of Type 2 Diabetes Diabetes Care 2017;40(Suppl. 1):S57–S63 | DOI: 10.2337/dc17-S010

There is strong and consistent evidence that obesity management can delay the progression from prediabetes to type 2 diabetes (1,2) and may be beneﬁcial in the treatment of type 2 diabetes (3–8). 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 demon-

strated that in obese patients with type 2 diabetes more extreme dietary energy DIABETES 2 TYPE OF TREATMENT THE FOR MANAGEMENT OBESITY 7. 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 (7,9,10). 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 (5,8,10). 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, discussed with the patient, and documented in the patient record. In Asian Americans, the BMI cutoff points to deﬁne overweight and obesity are lower than in other populations (Table 7.1) (11,12). Providers should advise overweight and obese patients that higher BMIs increase the risk of cardiovascular disease and all- cause mortality. Providers should assess each patient’s readiness to achieve weight loss and jointly determine weight loss goals and intervention strategies. Strategies include diet, physical activity, behavioral therapy, pharmacological therapy, and metabolic surgery (Table 7.1). The latter two strategies may be prescribed for carefully selected patients as adjuncts to diet, physical activity, and behavioral therapy.

DIET, PHYSICAL ACTIVITY, AND BEHAVIORAL THERAPY

Recommendations c Diet, physical activity, and behavioral therapy designed to achieve .5% weight loss should be prescribed for overweight and obese patients with type 2 diabetes ready to achieve weight loss. A c Such interventions should be high intensity ($16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500–750 Suggested citation: American Diabetes Associa- kcal/day energy deﬁcit. A tion. Obesity management for the treatment of c Diets should be individualized, as those that provide the same caloric restric- type 2 diabetes. Sec. 7. In Standards of Medi- cal Care in Diabetesd2017. Diabetes Care 2017; tion but differ in protein, carbohydrate, and fat content are equally effective in 40(Suppl. 1):S57–S63 achieving weight loss. A © 2017 by the American Diabetes Association. c For patients who achieve short-term weight loss goals, long-term ($1-year) Readers may use this article as long as the work comprehensive weight maintenance programs should be prescribed. Such is properly cited, the use is educational and not programs should provide at least monthly contact and encourage ongo- for proﬁt, and the work is not altered. More infor- ing monitoring of body weight (weekly or more frequently), continued mation is available at http://www.diabetesjournals .org/content/license. S58 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

fi Table 7.1—Treatment for overweight and obesity in type 2 diabetes de cit. Interventions should be pro- BMI category (kg/m2) vided by trained interventionists in either individual or group sessions (21). 23.0* or 27.5* or Overweight and obese patients with Treatment 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40 type 2 diabetes who have lost weight Diet, physical activity, during the 6-month intensive behavioral ┼┼┼┼┼ and behavioral therapy lifestyle intervention should be enrolled Pharmacotherapy ┼┼┼┼in long-term ($1-year) comprehensive Metabolic surgery ┼┼┼weight loss maintenance programs *Cutoff points for Asian American individuals. that provide at least monthly contact ┼Treatment may be indicated for selected motivated patients. with a trained interventionist and focus on ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced calorie diet, 27% lost $10% of their initial body consumption of a reduced calorie and participation in high levels of phys- weight at 8 years (14). Participants ran- diet, and participation in high ical activity (200–300 min/week). Some domly assigned to the intensive lifestyle levels of physical activity (200– commercial and proprietary weight loss group achieved equivalent risk factor 300 min/week). A programs have shown promising weight control but required fewer glucose-, c To achieve weight loss of .5%, loss results (22). blood pressure–, and lipid-lowering short-term (3-month) interven- When provided by trained practi- medications than those randomly as- tions that use very low-calorie di- tioners in medical care settings with signed to standard care. Secondary ets (#800 kcal/day) and total meal close medical monitoring, short-term analyses of the Look AHEAD trial and replacements may be prescribed (3-month) interventions that use very other large cardiovascular outcome for carefully selected patients by low-calorie diets (defined as #800 kcal/ studies document other benefits of trained practitioners in medical day) and total meal replacements may weight loss in patients with type 2 di- care settings with close medical achieve greater short-term weight loss abetes, including improvements in mo- monitoring. To maintain weight (10–15%) than intensive behavioral life- bility, physical and sexual functioning, loss, such programs must incorpo- style interventions that typically achieve and health-related quality of life (15). rate long-term comprehensive 5% weight loss. Weight regain follow- weight maintenance counseling. B Lifestyle Interventions ing the cessation of very low-calorie Weightlosscanbeattainedwithlife- diets is greater than following inten- Among overweight or obese patients with style programs that achieve a 500–750 sive behavioral lifestyle interventions type 2 diabetes and inadequate glycemic, kcal/day energy deficit or provide ap- unless a long-term comprehensive blood pressure, and lipid control and/or proximately 1,200–1,500 kcal/day for weight loss maintenance program is other obesity-related medical conditions, women and 1,500–1,800 kcal/day for provided (23,24). lifestyle changes that result in modest men, adjusted for the individual’sbase- and sustained weight loss produce clini- line body weight. Although benefits PHARMACOTHERAPY cally meaningful reductions in blood glu- may be seen with as little as 5% weight Recommendations cose, A1C, and triglycerides (3–5). Greater loss, sustained weight loss of $7% is c When choosing glucose-lowering weight loss produces even greater bene- optimal. medications for overweight or fits, including reductions in blood pressure, These diets may differ in the types of obese patients with type 2 di- improvements in LDL and HDL cholesterol, foods they restrict (such as high-fat or abetes, consider their effect on and reductions in the need for medications high-carbohydrate foods) but are effec- weight. E to control blood glucose, blood pressure, tive if they create the necessary energy c Whenever possible, minimize the and lipids (13,14). deficit (16–19). Use of meal replace- medications for comorbid condi- ment plans prescribed by trained prac- tions that are associated with titioners, with close patient monitoring, Look AHEAD Trial weight gain. E Although the Action for Health in Diabe- can be beneficial. Within the intensive c Weight loss medications may be tes (Look AHEAD) trial did not show that lifestyle intervention group of the Look effective as adjuncts to diet, physi- an intensive lifestyle intervention re- AHEAD trial, for example, use of a cal activity, and behavioral counsel- duced cardiovascular events in over- partial meal replacement plan was as- ing for selected patients with type weight or obese adults with type 2 sociated with improvements in diet 2 diabetes and BMI $27 kg/m2. diabetes (13), it did show the feasibility quality (20). The diet choice should be Potential benefits must be weighed of achieving and maintaining long-term based on the patient’s health status against the potential risks of the weight loss in patients with type 2 and preferences. medications. A diabetes. In the Look AHEAD intensive Intensive behavioral lifestyle inter- c If a patient’s response to weight lifestyle intervention group, mean ventions should include $16 sessions loss medications is ,5% weight weight loss was 4.7% at 8 years (14). in 6 months and focus on diet, physical loss after 3 months or if there are Approximately 50% of intensive lifestyle activity, and behavioral strategies to anysafetyortolerabilityissuesat intervention participants lost $5% and achieve an ;500–750 kcal/day energy care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S59

low-calorie diets and to reinforce life- any time, the medication should and nutritional status must be pro- style changes including physical activity. be discontinued and alternative vided to patients after surgery, Providers should be knowledgeable medications or treatment ap- according to guidelines for postop- about the product label and should bal- proaches should be considered. A erative management of metabolic ance the potential benefits of successful surgerybynationalandinterna- weight loss against the potential risks of tional professional societies. C Antihyperglycemic Therapy the medication for each patient. These When evaluating pharmacological treat- c People presenting for metabolic medications are contraindicated in ments for overweight or obese patients surgery should receive a compre- women who are or may become preg- with type 2 diabetes, providers should first hensive mental health assessment. nant. Women in their reproductive years consider their choice of glucose-lowering B Surgery should be postponed in must be cautioned to use a reliable medications. Whenever possible, medica- patients with histories of alcohol or method of contraception. tions should be chosen to promote weight substance abuse, significant de- loss or to be weight neutral. Agents asso- Assessing Efficacy and Safety pression, suicidal ideation, or other fi ciated with weight loss include metformin, Ef cacy and safety should be assessed at mental health conditions until fi a-glucosidase inhibitors, sodium–glucose least monthly for the rst 3 months of treat- these conditions have been fully cotransporter 2 inhibitors, glucagon-like ment. If a patient’s response is deemed addressed. E fi , peptide 1 agonists, and amylin mimetics. insuf cient (weight loss 5%) or if there c People who undergo metabolic Dipeptidyl peptidase 4 inhibitors ap- are any safety or tolerability issues at any surgery should be evaluated to as- pear to be weight neutral. Unlike these time, the medication should be discontin- sess the need for ongoing mental agents, insulin secretagogues, thiazolidin- ued and alternative medications or treat- health services to help them ad- ediones, and insulin have often been ment approaches should be considered. just to medical and psychosocial associated with weight gain (see Section In general, pharmacological treat- changes after surgery. C 8 “Pharmacologic Approaches to Glyce- ment of obesity has been limited by fi mic Treatment”). low adherence, modest ef cacy, adverse effects, and weight regain after medica- Several gastrointestinal (GI) operations Concomitant Medications tion cessation (25). promote dramatic and durable improve- Providers should carefully review the pa- ment of type 2 diabetes. Given the mag- tient’s concomitant medications and, METABOLIC SURGERY nitude and rapidity of the effect of GI surgery on hyperglycemia, and experi- whenever possible, minimize or provide Recommendations mental evidence that rearrangements of alternatives for medications that promote c Metabolic surgery should be recom- GI anatomy similar to those in some met- weight gain. Medications associated with mended to treat type 2 diabetes in abolic procedures directly affect glucose weight gain include atypical antipsychotics appropriate surgical candidates with homeostasis (28), GI interventions have (e.g., clozapine, olanzapine, risperidone, BMI $40 kg/m2 (BMI $37.5 kg/m2 been suggested as treatments for type 2 etc.) and antidepressants (e.g., tricyclic in Asian Americans), regardless of diabetes, and in that context are termed antidepressants, selective serotonin re- the level of glycemic control or com- “metabolic surgery.” uptake inhibitors, and monoamine oxi- plexity of glucose-lowering regi- A substantial body of evidence has now dase inhibitors), glucocorticoids, oral mens, and in adults with BMI 35.0– accumulated, including data from numer- contraceptives that contain progestins, 39.9 kg/m2 (32.5–37.4 kg/m2 in ous randomized controlled clinical trials, anticonvulsants including gabapentin, Asian Americans) when hypergly- demonstrating that metabolic surgery and a number of antihistamines and cemia is inadequately controlled achieves superior glycemic control and anticholinergics. despite lifestyle and optimal medical reduction of cardiovascular risk factors therapy. A Approved Weight Loss Medications in obese patients with type 2 diabetes c Metabolic surgery should be con- The U.S. Food and Drug Administration compared with various lifestyle/medical sidered for adults with type 2 di- (FDA) has approved five weight loss interventions (29). Improvements in abetes and BMI 30.0–34.9 kg/m2 medications (or combination medica- micro- and macrovascular complications (27.5–32.4 kg/m2 in Asian Ameri- tions) for long-term use (more than a of diabetes, cardiovascular disease, and cans) if hyperglycemia is in- few weeks) by patients with BMI cancer have been observed only in adequately controlled despite $27 kg/m2 with one or more obesity- nonrandomized observational studies optimal medical control by either associated comorbid conditions (e.g., (30–37). Cohort studies attempting to oral or injectable medications (in- type 2 diabetes. hypertension, and match surgical and nonsurgical subjects cluding insulin). B dyslipidemia) and by patients with suggest that the procedure may reduce c Metabolic surgery should be per- BMI $30 kg/m2 who are motivated to longer-term mortality (31). formed in high-volume centers lose weight (25–27). Medications ap- On the basis of this mounting evi- with multidisciplinary teams that proved for long-term weight loss and dence, several organizations and gov- understand and are experienced weight loss maintenance and their ernment agencies have recommended in the management of diabetes advantages and disadvantages are sum- expanding the indications for metabolic and gastrointestinal surgery. C marized in Table 7.2. The rationale for surgery to include patients with inade- c Long-term lifestyle support and rou- weight loss medications is to help pa- quately controlled type 2 diabetes and tine monitoring of micronutrient tients to more consistently adhere to BMI as low as 30 kg/m2 (27.5 kg/m2 for 6 bst aaeetfrteTeteto ye2Diabetes 2 Type of Treatment the for Management Obesity S60

Table 7.2—Medications approved by the FDA for the long-term (more than a few weeks) treatment of obesity – 1-Year weight change status2 5 – Generic drug name Adverse effects2,6 12 (proprietary name[s]) and Average wholesale Average weight loss % Patients with $5% dosage strength and form Adult dosing frequency price (per month)1 relative to placebo loss of baseline weight Common7 Serious7 Lipase inhibitor Orlistat (Alli) 60 mg caps or 60mgor 120mgt.i.d.(duringor $43–86 (60 mg); 2.5 kg (60 mg); 35–73% Abdominal pain/discomfort, oily Liver failure and oxalate orlistat (Xenical) 120 mg caps up to 1 h after a low-fat meal) $670 (120 mg) 3.4 kg (120 mg) spotting/stool, fecal urgency, nephropathy ﬂatulence, malabsorption of fat- soluble vitamins (A, D, E, K) and medications (e.g., cyclosporine, thyroid hormone replacement, oranticonvulsants),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, Serotonin syndrome or NMS-like fatigue reactions, suicidal ideation, heart valve disorder (,2.4%),bradycardia Sympathomimetic amine anorectic/antiepileptic combination Phentermine/topiramate ER (Qsymia) Recommended dose: 3.75 $239 (maximum 6.7 kg (7.5 mg/46 mg); 45–70% Paresthesia, xerostomia, Topiramate is teratogenic and 3.75 mg/23 mg caps, mg/23 mg q.d. for 14 days, dose using the 8.9 kg (15 mg/92 mg) constipation, headache has been associated with 7.5 mg/46 mg caps, then increase to 7.5 mg/46 mg highest strength) cleft lip/palate 11.25 mg/69 mg caps, q.d. Maximum dose: 15 mg/92 mg caps 15 mg/92 mg q.d. Opioid antagonist/aminoketone antidepressant combination Naltrexone/bupropion (Contrave) Maximum dose: twotabletsof $251 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, Depression,precipitationofmania, 8 mg/90 mg tabs Contrave b.i.d. for a total (32 mg/360 mg) headache, vomiting contraindicated in patients with a daily dosage of naltrexone seizure disorder 32 mg/bupropion 360 mg Acylated human glucagon-like peptide 1 receptor agonist Liraglutide (Saxenda) Maintenance dose: 3 mg s.c. q.d. $1,385 5.8–5.9 kg 51–73% Hypoglycemia, nausea, Pancreatitis, thyroid C-cell tumors 6 mg/mL prefilled pen vomiting, diarrhea, in rodents, contraindicated in Care Diabetes constipation, headache patients with personal/family history of MTC or MEN2, acute renal failure All medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method 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. 2017 January 1, Supplement 40, Volume 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 S61

Asian Americans) (38–41). Please refer suggest that proficiency of the operating References to the American Diabetes Association con- surgeon is an important factor for deter- 1. Tuomilehto J. The emerging global epidemic of sensus report “Metabolic Surgery in the mining mortality, complications, reopera- type 1 diabetes. Curr Diab Rep 2013;13:795–804 Treatment Algorithm for Type 2 Diabe- tions, and readmissions (60). 2. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research tes: A Joint Statement by International Although metabolic surgery has been Group. Reduction in the incidence of type 2 di- Diabetes Organizations” for a thorough shown to improve the metabolic profiles abetes with lifestyle intervention or metformin. review (29). of morbidly obese patients with type 1 N Engl J Med 2002;346:393–403 Randomized controlled trials with diabetes, establishing the role of meta- 3. UK Prospective Diabetes Study 7. UK Pro- postoperative follow-up ranging from bolic surgery in such patients will re- spective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly pre- 1 to 5 years have documented sustained quire larger and longer studies (61). senting type II diabetic patients, UKPDS Group. diabetes remission in 30–63% of pa- Retrospective analyses and modeling Metabolism 1990;39:905–912 tients (29). Available data suggest an studies suggest that metabolic surgery 4. Goldstein DJ. Beneficial health effects of erosion of diabetes remission over may be cost-effective or even cost-saving modest weight loss. Int J Obes Relat Metab Dis- – time: 35–50% or more of patients who for patients with type 2 diabetes, but the ord 1992;16:397 415 5.PastorsJG,WarshawH,DalyA,FranzM, initially achieve remission of diabetes results are largely dependent on assump- Kulkarni K. The evidence for the effectiveness eventually experience recurrence. How- tions about the long-term effectiveness of medical nutrition therapy in diabetes man- ever, the median disease-free period and safety of the procedures (62,63). agement. Diabetes Care 2002;25:608–613 among such individuals following 6. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 di- Roux-en-Y gastric bypass (RYGB) is 8.3 Adverse Effects abetes: normalisation of beta cell function in as- years (42,43). With or without diabetes Metabolic surgery is costly and has association with decreased pancreas and liver relapse, the majority of patients who sociated risks. Longer-term concerns in- triacylglycerol. Diabetologia 2011;54:2506–2514 undergo surgery maintain substan- clude dumping syndrome (nausea, colic, 7. Jackness C, Karmally W, Febres G, et al. Very tial improvement of glycemic control diarrhea), vitamin and mineral deficien- low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sen- from baseline for at least 5 (44) to 15 cies, anemia, osteoporosis, and, rarely sitivity and b-cell Function in type 2 diabetic (31,32,43,45–47) years. (64), severe hypoglycemia from insulin patients. Diabetes 2013;62:3027–3032 Younger age, shorter duration of diabe- hypersecretion. Long-term nutritional 8. Rothberg AE, McEwen LN, Kraftson AT, tes (e.g., ,8 years) (48), nonuse of insulin, and micronutrient deficiencies and re- Fowler CE, Herman WH. Very-low-energy diet and better glycemic control are consis- lated complications occur with variable for type 2 diabetes: an underutilized therapy? J Diabetes Complications 2014;28:506–510 tently associated with higher rates of di- frequency depending on the type of pro- 9. Day JW, Ottaway N, Patterson JT, et al. A new abetes remission and/or lower risk of cedure and require lifelong vitamin/ glucagon and GLP-1 co-agonist eliminates obe- recidivism (31,46,48). Greater baseline nutritional supplementation (65,66). sity in rodents. Nat Chem Biol 2009;5:749–757 visceral fat area may also help to predict Postprandial hypoglycemia is most 10. Steven S, Hollingsworth KG, Al-Mrabeh A, better postoperative outcomes, espe- likely to occur with RYGB (66,67). The et al. Very low-calorie diet and 6 months of cially among Asian American patients exact prevalence of symptomatic hy- weight stability in type 2 diabetes: pathophysi- ological changes in responders and nonre- with type 2 diabetes, who typically have poglycemia is unknown. In one study, sponders. Diabetes Care 2016;39:808–815 more visceral fat compared with Cauca- it affected 11% of 450 patients who 11. WHO Expert Consultation. Appropriate sians with diabetes of the same BMI (49). had undergone RYGB or vertical sleeve body-mass index for Asian populations and its Beyond improving glycemia, metabolic gastrectomy (67). Patients who un- implications for policy and intervention strate- – surgery has been shown to confer addi- dergo metabolic surgery may be at in- gies. Lancet 2004;363:157 163 fi 12. Araneta MRG, Kanaya A, Fujimoto W, et al. tional health bene ts in randomized creased risk for substance use, including Optimum BMI cut-points to screen Asian Amer- controlled trials, including greater re- drug and alcohol use and cigarette icans for type 2 diabetes: The UCSD Filipino ductions in cardiovascular disease risk smoking (68). Health Study and the North Kohala Study [Ab- factors (29) and enhancements in qual- People with diabetes presenting for stract]. Diabetes 2014;63(Suppl. 1):A20 13. Wing RR, Bolin P, Brancati FL, et al.; Look ity of life (44,48,50). metabolic surgery also have increased AHEAD Research Group. Cardiovascular effects Thesafetyofmetabolicsurgeryhas rates of depression and other major psy- of intensive lifestyle intervention in type 2 di- improved significantly over the past chiatric disorders (69). Candidates for met- abetes. N Engl J Med 2013;369:145–154 two decades, with continued refine- abolic surgery with histories of alcohol 14. Look AHEAD Research Group. Eight-year ment of minimally invasive approaches or substance abuse, significant depres- weight losses with an intensive lifestyle intervention: the Look AHEAD study. Obesity (Silver (laparoscopic surgery), enhanced train- sion, suicidal ideation, or other mental Spring) 2014;22:5–13 ing and credentialing, and involvement health conditions should therefore first 15. Wilding JPH. The importance of weight of multidisciplinary teams. Mortality rates be assessed by a mental health profes- management in type 2 diabetes mellitus. Int J with metabolic operations are typically sional with expertise in obesity manage- Clin Pract 2014;68:682–691 0.1–0.5%, similar to cholecystectomy or ment prior to consideration for surgery 16. Sacks FM, Bray GA, Carey VJ, et al. Compar- ison of weight-loss diets with different compo- hysterectomy (51–55). Morbidity has (70). Individuals with preoperative psy- sitions of fat, protein, and carbohydrates. N Engl also dramatically declined with laparo- chopathology should be assessed regu- J Med 2009;360:859–873 scopic approaches. Major complications larly following metabolic surgery to 17. de Souza RJ, Bray GA, Carey VJ, et al. Effects rates are 2–6%, with minor complications optimize mental health management of 4 weight-loss diets differing in fat, protein, – and carbohydrate on fat mass, lean mass, vis- in up to 15% (51 59), comparing favor- and to ensure psychiatric symptoms do ceral adipose tissue, and hepatic fat: results ably with other commonly performed not interfere with weight loss and lifestyle from the POUNDS LOST trial. Am J Clin Nutr elective operations (55). Empirical data changes. 2012;95:614–625 S62 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

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Brethauer SA, Aminian A, Romero-Talamas´ H, cal skill and complication rates after bariatric for type 2 diabetes: a joint statement by inter- et al. Can diabetes be surgically cured? Long-term surgery. N Engl J Med 2013;369:1434–1442 national diabetes organizations. Diabetes Care metabolic effects of bariatric surgery in obese 61. Kirwan JP, Aminian A, Kashyap SR, Burguera 2016;39:861–877 patients with type 2 diabetes mellitus. Ann Surg B, Brethauer SA, Schauer PR. Bariatric surgery in 30. Sjostr¨ om¨ L, Lindroos A-K, Peltonen M, et al.; 2013;258:628–636; discussion 636–637 obese patients with type 1 diabetes. Diabetes Swedish Obese Subjects Study Scientific Group. 47. Hsu C-C, Almulaifi A, Chen J-C, et al. Effect of Care 2016;39:941–948 Lifestyle, diabetes, and cardiovascular risk fac- bariatric surgery vs medical treatment on type 2 62. Rubin JK, Hinrichs-Krapels S, Hesketh R, tors 10 years after bariatric surgery. N Engl J diabetes in patients with body mass index lower Martin A, Herman WH, Rubino F. Identifying Med 2004;351:2683–2693 than 35: five-year outcomes. JAMA Surg 2015; barriers to appropriate use of metabolic/ 31. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. 150:1117–1124 bariatric surgery for type 2 diabetes treat- Association of bariatric surgery with long-term 48. Schauer PR, Bhatt DL, Kirwan JP, et al.; ment: Policy Lab results. Diabetes Care 2016; remission of type 2 diabetes and with microvascular STAMPEDE Investigators. Bariatric surgery versus 39:954–963 care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S63

63. Fouse T, Schauer P. The socioeconomic im- practice for the perioperative nutritional, met- 67. Lee CJ, Clark JM, Schweitzer M, et al. Prev- pact of morbid obesity and factors affecting ac- abolic, and nonsurgical support of the bariatric alence of and risk factors for hypoglycemic cess to obesity surgery. Surg Clin North Am surgery patient. Obesity (Silver Spring) 2009;17 symptoms after gastric bypass and sleeve gas- 2016;96:669–679 (Suppl. 1):S1–S70 trectomy. Obesity (Silver Spring) 2015;23:1079– 64. Service GJ, Thompson GB, Service FJ, 66. Mechanick JI, Youdim A, Jones DB, et al.; 1084 Andrews JC, Collazo-Clavell ML, Lloyd RV. Hy- American Association of Clinical Endocrinolo- 68. Conason A, Teixeira J, Hsu C-H, Puma L, perinsulinemic hypoglycemia with nesidioblas- gists; Obesity Society; American Society for Knafo D, Geliebter A. Substance use following tosis after gastric-bypass surgery. N Engl J Med Metabolic & Bariatric Surgery. Clinical practice bariatric weight loss surgery. JAMA Surg 2013; 2005;353:249–254 guidelines for the perioperative nutritional, 148:145–150 65. Mechanick JI, Kushner RF, Sugerman HJ, metabolic, and nonsurgical support of the bari- 69. Young-Hyman D, Peyrot M. Psychosocial et al.; American Association of Clinical Endocri- atric surgery patient–2013 update: cospon- Care for People with Diabetes.1sted.Alexandria, nologists; Obesity Society; American Society for sored by American Association of Clinical VA, American Diabetes Association, 2012 Metabolic & Bariatric Surgery. American Asso- Endocrinologists, The Obesity Society, and 70. Greenberg I, Sogg S, M Perna F. Behavioral ciation of Clinical Endocrinologists, The Obesity American Society for Metabolic & Bariatric Sur- and psychological care in weight loss surgery: Society, and American Society for Metabolic & gery. Obesity (Silver Spring) 2013;21(Suppl. 1): best practice update. Obesity (Silver Spring) Bariatric Surgery medical guidelines for clinical S1–S27 2009;17:880–884 S64 Diabetes Care Volume 40, Supplement 1, January 2017

8. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment Diabetes Care 2017;40(Suppl. 1):S64–S74 | DOI: 10.2337/dc17-S011

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations c Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion. A c Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A c Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E c Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin Therapy Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/ day of total insulin with higher amounts required during puberty. The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients who are metabolically stable, with higher weight-based dosing required immediately following presentation with ketoacidosis (1), and provides detailed information on intensiﬁcation of therapy to meet individualized needs. The American Diabetes 8. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT Association (ADA) position statement “Type 1 Diabetes Management Through the Life Span” additionally provides a thorough overview of type 1 diabetes treatment and associated recommendations (2). Education regarding matching prandial insulin dosing to carbohydrate intake, premeal glucose levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation (3–5). Although most studies of multiple daily injections (MDI) versus continuous subcutaneous insulin infusion (CSII) 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 (6). A 3-month 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 levels (7). In- tensive management using CSII and continuous glucose monitoring (CGM) should be encouraged in selected patients when there is active patient/family participation (8–10). The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive Suggested citation: American Diabetes Associa- therapy with MDI or CSII delivered by multidisciplinary teams of physicians, nurses, dieti- tion. Pharmacologic approaches to glycemic tians, and behavioral scientists improved glycemia and resulted in better long-term out- treatment.Sec.8.InStandards of Medical comes (11–13). The study was carried out with short-acting and intermediate-acting Care in Diabetesd2017. Diabetes Care 2017; human insulins. Despite better microvascular, macrovascular, and all-cause mortality 40(Suppl. 1):S64–S74 outcomes, intensive therapy was associated with a high rate of severe hypoglycemia © 2017 by the American Diabetes Association. (61 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid- Readers may use this article as long as the work is properly cited, the use is educational and not acting and long-acting insulin analogs have been developed. These analogs are as- for proﬁt, and the work is not altered. More infor- sociated with less hypoglycemia in type 1 diabetes, while matching the A1C lowering mation is available at http://www.diabetesjournals of human insulins (14,15). .org/content/license. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S65

Rapid-acting inhaled insulin used be- total pancreatectomy for medically refrac- c Long-term use of metformin may fore meals in type 1 diabetes was shown tory chronic pancreatitis. be associated with biochemical to be noninferior when compared with vitamin B12 deficiency, and peri- aspart insulin for A1C lowering, with less Investigational Agents odic measurement of vitamin B12 hypoglycemia observed with inhaled in- Metformin levels should be considered in sulin therapy (16). However, the mean Adding metformin to insulin therapy may metformin-treated patients, es- reduction in A1C was greater with aspart reduce insulin requirements and improve pecially in those with anemia or (20.21% vs. 20.40%, satisfying the non- metabolic control in overweight/obese pa- peripheral neuropathy. B inferiority margin of 0.4%), and more patients with poorly controlled type 1 diabe- c Consider initiating insulin therapy tients in the insulin aspart group tes. In a meta-analysis, metformin in type 1 (with or without additional agents) achieved A1C goals of #7.0% (53 diabetes was found to reduce insulin re- , in patients with newly diagnosed mmol/mol) and #6.5% (48 mmol/mol). quirements (6.6 units/day, P 0.001) and type 2 diabetes who are symptom- Because inhaled insulin cartridges are led to small reductions in weight and total atic and/or have A1C $10% (86 only available in 4, 8, and 12 unit doses, and LDL cholesterol but not to improved mmol/mol) and/or blood glucose people with type 1 diabetes may have glycemic control (absolute A1C reduction 5 levels $300 mg/dL (16.7 mmol/L). E limited dosing increments to fine-tune 0.11%, P 0.42) (18). Metformin is not c If noninsulin monotherapy at prandial insulin doses when using this FDA-approved for use in patients with maximum tolerated dose does not therapy. type 1 diabetes. achieve or maintain the A1C target Postprandial glucose excursions may be Incretin-Based Therapies after 3 months, add a second oral better controlled by adjusting the timing Due to their potential protection of b-cell agent, a glucagon-like peptide 1 re- of prandial (bolus) insulin dose adminis- mass and suppression of glucagon release, ceptor agonist, or basal insulin. A tration. The optimal time to administer glucagon-like peptide 1 (GLP-1) receptor c A patient-centered approach should prandial insulin varies, based on the agonists and dipeptidyl peptidase 4 (DPP-4) be used to guide the choice of phar- type of insulin used (regular, rapid-acting inhibitors are being studied in patients with macologic agents. Considerations in- analog, inhaled, etc.), the measured type 1 diabetes but are not currently FDA- clude efficacy, hypoglycemia risk, blood glucose level, timing of meals, approved for use in patients with type 1 impact on weight, potential side ef- and carbohydrate consumption. Rec- diabetes. fects, cost, and patient preferences. E ommendations for prandial insulin Sodium–Glucose Cotransporter c For patients with type 2 diabetes dose administration should therefore 2 Inhibitors who are not achieving glycemic be individualized. – Sodium glucose cotransporter 2 (SGLT2) goals, insulin therapy should not inhibitors provide insulin-independent glu- Pramlintide be delayed. B Pramlintide, an amylin analog, is an cose lowering by blocking glucose reab- c In patients with long-standing agent that delays gastric emptying, sorption in the proximal renal tubule by suboptimally controlled type 2 di- blunts pancreatic secretion of glucagon, inhibiting SGLT2. These agents provide abetes and established athero- and enhances satiety. It is U.S. Food and modest weight loss and blood pressure sclerotic cardiovascular disease, Drug Administration (FDA)–approved reduction in type 2 diabetes. There are empagliflozin or liraglutide should for use in adults with type 1 diabetes. It three FDA-approved agents for patients be considered as they have been has been shown to induce weight loss with type 2 diabetes, but none are FDA- shown to reduce cardiovascular and lower insulin doses. Concurrent re- approved for the treatment of patients and all-cause mortality when duction of prandial insulin dosing is re- with type 1 diabetes (2). The FDA issued a added to standard care. Ongoing quired to reduce the risk of severe warning about the risk of ketoacidosis oc- studies are investigating the cardio- fi hypoglycemia. curring in the absence of signi cant hyper- vascular benefits of other agents in glycemia (euglycemic diabetic ketoacidosis) these drug classes. B Pancreas and Islet Transplantation in patients with type 1 and type 2 diabetes Pancreas and islet transplantation have treated with SGLT2 inhibitors. Symptoms of been shown to normalize glucose levels ketoacidosis include dyspnea, nausea, vom- The use of metformin as first-line ther- but require lifelong immunosuppression iting, and abdominal pain. Patients should apy was supported by findings from to prevent graft rejection and recurrence be instructed to stop taking SGLT2 inhibi- a large meta-analysis, with selection of autoimmune islet destruction. Given tors and seek medical attention immedi- of second-line therapies based on the potential adverse effects of immuno- atelyiftheyhavesymptomsorsignsof patient-specific considerations (20). suppressive therapy, pancreas transplan- ketoacidosis (19). An ADA/European Association for the tation should be reserved for patients Study of Diabetes position statement with type 1 diabetes undergoing simulta- PHARMACOLOGIC THERAPY FOR (21) recommended a patient-centered neous renal transplantation, following TYPE 2 DIABETES approach, including assessment of ef- renal transplantation, or for those with ficacy, hypoglycemia risk, impact on Recommendations recurrent ketoacidosis or severe hypogly- weight, side effects, costs, and patient c Metformin, if not contraindicated cemia despite intensive glycemic manage- preferences. Renal effects may also be con- and if tolerated, is the preferred ini- ment (17). Islet transplantation remains sidered when selecting glucose-lowering tial pharmacologic agent for the investigational. Autoislet transplantation medications for individual patients. Life- treatment of type 2 diabetes. A may be considered for patients requiring style modifications that improve health S66 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

(see Section 4 “Lifestyle Management”) medication in cases of nausea, vomiting, effective where other agents may not be should be emphasized along with any or dehydration. Metformin is associated and should be considered as part of any pharmacologic therapy. with vitamin B12 deficiency, with a recent combination regimen when hyperglycemia report from the Diabetes Prevention Pro- is severe, especially if symptoms are pre- Initial Therapy gram Outcomes Study (DPPOS) suggesting sent or any catabolic features (weight Metformin monotherapy should be started that periodic testing of vitamin B12 levels loss, ketosis) are present. Consider ini- at diagnosis of type 2 diabetes unless should be considered in metformin-treated tiating combination insulin injectable there are contraindications. Metformin patients, especially in those with anemia or therapy (Fig. 8.2) when blood glucose is effective and safe, is inexpensive, and peripheral neuropathy (25). is $300 mg/dL (16.7 mmol/L) or A1C may reduce risk of cardiovascular events In patients with metformin contrain- is $10% (86 mmol/mol) or if the patient and death (22). Metformin may be safely dications or intolerance, consider an ini- has symptoms of hyperglycemia (i.e., used in patients with estimated glo- tial drug from another class depicted in polyuria or polydipsia). As the patient’s merular filtration rate (eGFR) as low as Fig. 8.1 under “Dual Therapy” and pro- glucose toxicity resolves, the regimen 30 mL/min/1.73 m2 (23), and the U.S. ceed accordingly. When A1C is $9% may, potentially, be simplified. label for metformin was recently re- (75 mmol/mol), consider initiating dual visedtoreflect its safety in patients combination therapy (Fig. 8.1)tomore Combination Therapy with eGFR $30 mL/min/1.73 m2 (24). expeditiously achieve the target A1C Although there are numerous trials com- Patients should be advised to stop the level. Insulin has the advantage of being paring dual therapy with metformin alone,

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. 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.*Seeref.21for description of efﬁcacy and cost categorization. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (21). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S67

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; GLP-1 RA, GLP-1 receptor agonist; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. (21). few directly compare drugs as add-on ther- the six available treatment options: sul- ;3 months of triple therapy, proceed apy. A comparative effectiveness meta- fonylurea, thiazolidinedione, DPP-4 in- to combination injectable therapy analysis (23) suggests that each new class hibitor, SGLT2 inhibitor, GLP-1 receptor (Fig. 8.2). of noninsulin agents added to initial ther- agonist, or basal insulin (Fig. 8.1). If A1C Drug choice is based on patient pref- apy generally lowers A1C approximately target is still not achieved after ;3 erences (26), as well as various patient, 0.9–1.1%. If the A1C target is not achieved months of dual therapy, proceed to disease, and drug characteristics, with after approximately 3 months, consider a three-drug combination (Fig. 8.1). Again, the goal of reducing blood glucose levels combination of metformin and one of if A1C target is not achieved after while minimizing side effects, especially 6 hraooi prahst lcmcTreatment Glycemic to Approaches Pharmacologic S68

Table 8.1—Properties of available glucose-lowering agents in the U.S. that may guide individualized treatment choices in patients with type 2 diabetes (21) Primary physiological Class Compound(s) Cellular mechanism(s) action(s) Advantages Disadvantages Cost* Biguanides c Metformin Activates AMP-kinase c ↓ Hepatic glucose c Extensive experience c Gastrointestinal side effects Low (? other) production c Rare hypoglycemia (diarrhea, abdominal cramping, nausea) c ↓ CVD events (UKPDS) c Vitamin B12 deﬁciency c Relatively higher A1C c Contraindications: eGFR ,30 efﬁcacy mL/min/1.73 m2, 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 (UKPDS) c ↑ Weight c Glipizide c Relatively higher A1C c Glimepiride efﬁcacy

Meglitinides c Repaglinide Closes KATP channels on b-cell c ↑ Insulin secretion c ↓ Postprandial glucose c Hypoglycemia Moderate (glinides) c Nateglinide plasma membranes excursions c ↑ Weight c Dosing flexibility c Frequent dosing schedule TZDs c Pioglitazone‡ Activates the nuclear c ↑ Insulin sensitivity c Rare hypoglycemia c ↑ Weight Low c Rosiglitazone§ transcription factor PPAR-g c Relatively higher A1C c Edema/heart failure efficacy c Bone fractures c Durability c ↑ LDL-C (rosiglitazone) c ↓ Triglycerides (pioglitazone) c ? ↓ CVD events (PROactive, pioglitazone) c ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA (IRIS study [42], pioglitazone) a-Glucosidase c Acarbose Inhibits intestinal c Slows intestinal carbohydrate c Rare hypoglycemia c Generally modest A1C efficacy Low to Care Diabetes inhibitors c Miglitol a-glucosidase digestion/absorption c ↓ Postprandial glucose c Gastrointestinal side effects moderate excursions (flatulence, diarrhea) c ? ↓ CVD events in prediabetes c Frequent dosing schedule (STOP-NIDDM) c Nonsystemic 2017 January 1, Supplement 40, Volume DPP-4 c Sitagliptin Inhibits DPP-4 activity, increasing c ↑ Insulin secretion c Rare hypoglycemia c Angioedema/urticaria and other High inhibitors c Saxagliptin postprandial incretin (GLP-1, GIP) (glucose dependent) c Well tolerated immune-mediated dermatological effects c Linagliptin concentrations c ↓ Glucagon secretion c ?Acutepancreatitis c Alogliptin (glucose dependent) c ↑ Heart failure hospitalizations (saxagliptin; ? alogliptin) Bile acid c Colesevelam Binds bile acids in intestinal tract, c ? ↓ Hepatic glucose c Rare hypoglycemia c Modest A1C efficacy High sequestrants increasing hepatic bile acid production c ↓ LDL-C c Constipation production c ? ↑ Incretin levels c ↑ Triglycerides c May ↓ absorption of other medications Continued on p. S69 Table 8.1—Continued aedaeejunl.r hraooi prahst lcmcTetetS69 Treatment Glycemic to Approaches Pharmacologic care.diabetesjournals.org Primary physiological Class Compound(s) Cellular mechanism(s) action(s) Advantages Disadvantages Cost* Dopamine-2 c Bromocriptine Activates dopaminergic c Modulates hypothalamic c Rare hypoglycemia c Modest A1C efficacy High agonists (quick release)§ receptors regulation of metabolism c ? ↓ CVD events c Dizziness/syncope c ↑ Insulin sensitivity (Cycloset Safety Trial) c Nausea c Fatigue c Rhinitis SGLT2 c Canagliflozin Inhibits SGLT2 in the c Blocks glucose reabsorption c Rare hypoglycemia c Genitourinary infections High inhibitors c Dapagliflozin‡ proximal nephron by the kidney, increasing c ↓ Weight c Polyuria c Empagliflozin glucosuria c ↓ Blood pressure c Volume depletion/hypotension/dizziness c Associated with lower CVD event c ↑ LDL-C rate and mortality in patients with c ↑ Creatinine (transient) CVD (empagliflozin EMPA-REG c DKA, urinary tract infections leading OUTCOME) to urosepsis, pyelonephritis GLP-1 receptor c Exenatide Activates GLP-1 receptors c ↑ Insulin secretion c Rare hypoglycemia c Gastrointestinal side effects High agonists c Exenatide extended (glucose dependent) c ↓ Weight (nausea/vomiting/diarrhea) release c ↓ Glucagon secretion c ↓ Postprandial glucose excursions c ↑ Heart rate c Liraglutide (glucose dependent) c ↓ Some cardiovascular risk factors c ? Acute pancreatitis c Albiglutide c Slows gastric emptying c Associated with lower CVD event c C-cell hyperplasia/medullary thyroid c Lixisenatide c ↑ Satiety rate and mortality in patients with tumors in animals c Dulaglutide CVD (liraglutide LEADER) (30) c Injectable c Training requirements Amylin mimetics c Pramlintide§ Activates amylin receptors c ↓ Glucagon secretion c ↓ Postprandial glucose excursions c Modest A1C efficacy High c Slows gastric emptying c ↓ Weight c Gastrointestinal side effects c ↑ Satiety (nausea/vomiting) c Hypoglycemia unless insulin dose is simultaneously reduced c Injectable c Frequent dosing schedule c Training requirements Insulins c Rapid-acting analogs Activates insulin receptors c ↑ Glucose disposal c Nearly universal response c Hypoglycemia High# - Lispro c ↓ Hepatic glucose c Theoretically unlimited efficacy c Weight gain - Aspart production c ↓ Microvascular risk (UKPDS) c Training requirements - Glulisine c Suppresses ketogenesis c Patient and provider reluctance - Inhaled insulin c Injectable (except inhaled insulin) c Short-acting c Pulmonary toxicity (inhaled insulin) - Human Regular c Intermediate-acting - Human NPH

Continued on p. S70 S70 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

hypoglycemia. Table 8.1 lists drugs commonly used in the U.S. Cost-effectiveness models have suggested that some of the newer agents may be of relatively lower clinical utility based on high cost and moderate glycemic effect (27). Table 8.2 provides cost information for currently approved noninsulin therapies. Of note, prices listed are average wholesale prices (AWP) and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. While there are alternative means to estimate medication prices, AWP was utilized ; PROactive, Prospective Pioglitazone Clinical Trial in

g to provide a comparison of list prices with the primary goal of highlighting the importance of cost considerations when pre- zolidinedione; UKPDS, UK Prospective Diabetes Study (45,46). scribing antihyperglycemic treatments.The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness activated receptor – Study (GRADE) will compare four drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin) when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes (28). , peroxisome proliferator lnitial concerns regarding bladder cancer risk are decreasing after subsequent study. §Not licensed in g Rapid-acting secretagogues (megliti- ‡ nides) may be used instead of sulfonylureas in patients with sulfa allergies, irregular meal schedules, or those who develop late postprandial hypoglycemia when taking a sulfonylurea. Other drugs

action(s) Advantages Disadvantagesnot Cost* shown in Fig. 8.1 (e.g., inhaled insulin, a-glucosidase inhibitors, colesevelam, bro- human insulins) and dosage. Adapted with permission from Inzucchi et al. (21).

Primary physiological mocriptine, and pramlintide) may be tried . in speciﬁc situations but are not often used ﬁ

ozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (29); GIP, glucose-dependent insulinotropic peptide; due to modest ef cacy in type 2 diabetes, ﬂ the frequency of administration, the potential for drug interactions, and/or side effects.

Cardiovascular Outcome Trials Several recently published cardiovascular outcome trials (CVOTs) have provided data on patients with type 2 diabetes with cardiovascular disease or at high riskforcardiovasculardisease.TheBI 10773 (Empagliﬂozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was a randomized, double-blind trial that 70/30 aspart mix 75/25 lispro mix 50/50 lispro mix - Glargine - Degludec - NPH/Regular 70/30 2 2 2 - Detemir ﬂ Premixed insulin products

Basal insulin analogs assessed the effect of empagli ozin, a c c SGLT2 inhibitor, versus placebo and stan-

Continued dard care, on cardiovascular outcomes in — patients with type 2 diabetes and existing cardiovascular disease. Study participants had a mean age of 63 years, 57% had di- Class Compound(s) Cellular mechanism(s) Table 8.1 CVD, cardiovascular disease; EMPA-REG OUTCOME, BI 10773 (Empagli HDL-C, HDL cholesterol; IRIS, Insulin Resistance Intervention After Stroke Trial; LDL-C, LDL cholesterol; PPAR- Macrovascular Events (43); STOP-NIDDM, StudyCycloset to trial Prevent of quick-release Non-Insulin-Dependent bromocriptine Diabetes (47). Mellitus *Cost (44); is TIA, based on transient lowest-priced ischemic member attack; of TZD, the thia class (21). Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs abetes for more than 10 years, and 99% care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S71

Table 8.2—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. (48) Dosage strength/product Median AWP Maximum approved Class Compound(s) (if applicable) (min, max)† daily dose* Biguanides c Metformin 500 mg (IR) $84 ($5, $94) 2,000 mg 850 mg (IR) $108 ($5, $108) 2,550 mg 1,000 mg (IR) $86 ($4, $87) 2,000 mg 500 mg (ER) $90 ($82, $6,672) 2,000 mg 750 mg (ER) $72 ($65, $92) 1,500 mg 1,000 mg (ER) $1,028 ($1,010, $7,213) 2,000 mg Sulfonylureas (2nd Gen) c Glyburide 5 mg $94 ($64, $103) 20 mg 6 mg (micronized) $50 ($48, $71) 12 mg (micronized) c Glipizide 10 mg (IR) $74 ($67, $97) 40 mg (IR) 10 mg (XL) $97 20 mg (XL) c Glimepiride 4 mg $74 ($71, $198) 8 mg Meglitinides (glinides) c Repaglinide 2 mg $799 ($163, $878) 16 mg c Nateglinide 120 mg $156 360 mg TZDs c Pioglitazone 45 mg $349 ($348, $349) 45 mg c Rosiglitazone 4 mg $355 8 mg a-Glucosidase inhibitors c Acarbose 100 mg $104 ($104, 105) 300 mg c Miglitol 100 mg $241 300 mg DPP-4 inhibitors c Sitagliptin 100 mg $436 100 mg c Saxagliptin 5 mg $436 5 mg c Linagliptin 5 mg $428 5 mg c Alogliptin 25 mg $436 25 mg Bile acid sequestrant c Colesevelam 625 mg tabs $679 3.75 g 1.875 g suspension $1,357 3.75 g Dopamine-2 agonists c Bromocriptine 0.8 mg $719 4.8 mg SGLT2 inhibitors c Canagliflozin 300 mg $470 300 mg c Dapagliflozin 10mg $470 10mg c Empagliflozin 25 mg $470 25 mg GLP-1 receptor agonists c Exenatide 10 mg pen $729 20 mg c Exenatide 2 mg powder for suspension or pen $692 2 mg** (extended-release) c Liraglutide 18 mg/3 mL pen $831 1.8 mg c Albiglutide 50 mg pen $527 50 mg** c Dulaglutide 1.5/0.5 mL pen $690 1.5 mg** Amylin mimetics c Pramlintide 120 mg pen $2,124 120 mg/injection†† ER and XL, extended release; IR, immediate release; TZD, thiazolidinedione. †Calculated for 30 day supply (AWP unit price 3 number of doses required to provide maximum approved daily dose 3 30 days); median AWP listed alone when only one product and/or price. *Utilized to calculate median AWP (min, max); generic prices used, if available commercially. **Administered once weekly. ††AWP calculated based on 120 mg three times daily. had established cardiovascular disease. (LEADER) trial was a randomized double- the placebo group (14.9%) after a median EMPA-REG OUTCOME showed that over a blind trial that assessed the effect of follow-up of 3.8 years (30). Whether other median follow-up of 3.1 years, treatment liraglutide, a GLP-1 receptor agonist, ver- GLP-1 receptor agonists will have the same reduced the composite outcome of MI, sus placebo and standard care, on cardio- effect in high-risk patients or if this drug class stroke, and cardiovascular death by 14% vascular outcomes in patients with type 2 will have similar effects in lower-risk patients (absolute rate 10.5% vs. 12.1% in the pla- diabetes at high risk for cardiovascular dis- with diabetes remains unknown. cebo group) and cardiovascular death by ease or with cardiovascular disease. Study CVOT data for the DPP-4 inhibitors 38% (absolute rate 3.7% vs. 5.9%) (29). The participants had a mean age of 64 years sitagliptin (31), saxagliptin (32), and FDA recently added a new indication for and a mean duration of diabetes of nearly alogliptin (33) have also been reported, empagliflozin, to reduce the risk of cardio- 13 years. Over 80% of study participants with no significant difference in rates of vascular death in adults with type 2 diabe- had established cardiovascular disease major cardiovascular events noted between tes and cardiovascular disease. Whether inclusive of a prior myocardial infarction treatment and placebo groups in any of other SGLT2 inhibitors will have the same (MI), prior stroke or transient ischemic these trials. effect in high-risk patients and whether attack, prior revascularization procedure, empagliflozin or other SGLT2 inhibitors or $50% stenosis of coronary, carotid, Insulin Therapy will have a similar effect in lower-risk pa- or lower-extremity arteries. LEADER Many patients with type 2 diabetes even- tients with diabetes remains unknown. showed that the composite primary out- tually require and benefit from insulin The Liraglutide Effect and Action in Di- come (MI, stroke, or cardiovascular death) therapy. The progressive nature of type abetes: Evaluation of Cardiovascular Out- occurred in fewer participants in the treat- 2 diabetes should be regularly and objec- come Results: A Long Term Evaluation ment group (13.0%) when compared with tively explained to patients. Providers S72 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

should avoid using insulin as a threat or without a history of hypoglycemia may recommended starting dose of mealtime describing it as a sign of personal failure use NPH insulin safely and at much lower insulin is 4 units, 0.1 U/kg, or 10% of the or punishment. cost (27,35). Table 8.3 provides average basal dose. If A1C is ,8% (64 mmol/mol) Equipping patients with an algorithm for wholesale price information (cost per when starting mealtime bolus insulin, con- self-titration of insulin doses based on self- 1,000 units) for currently available insulin sideration should be given to decreasing monitoring of blood glucose (SMBG) im- products in the U.S. There have been sub- the basal insulin dose. proves glycemic control in patients with stantial increases in the price of insulin over Premixed Insulin type 2 diabetes initiating insulin (34). Com- the past decade and the cost-effectiveness Premixed insulin products contain both a prehensive education regarding SMBG, of different antihyperglycemic agents is an basal and prandial component, allowing diet, and the avoidance of and appropriate important consideration when selecting coverage of both basal and prandial needs treatment of hypoglycemia are critically therapies (36). A follow-on U-100 (100 with a single injection. NPH/Regular 70/30 important in any patient using insulin. units/mL) glargine product (basaglar) is insulin, for example, is composed of Basal Insulin now available in the U.S. This product was 70% NPH insulin and 30% regular insulin. Basal insulin alone is the most convenient approved through an abbreviated FDA ap- The use of premixed insulin products has ’ initial insulin regimen, beginning at 10 units proval pathway based, in part, on the FDA s its advantages and disadvantages, as fi per day or 0.1–0.2 units/kg/day, depending nding of safety and effectiveness for the discussed below in COMBINATION INJECTABLE on the degree of hyperglycemia. Basal in- reference U-100 glargine product. THERAPY. sulin is usually prescribed in conjunction Bolus Insulin Concentrated Insulin Products with metformin and sometimes one addi- Many individuals with type 2 diabetes may Several concentrated insulin preparations tional noninsulin agent. While there is evi- require mealtime bolus insulin dosing in are currently available. U-500 regular insu- dence for reduced risk of hypoglycemia addition to basal insulin. Rapid-acting lin, by definition, is fivetimesasconcen- with newer, longer-acting basal insulin analogs are preferred due to their trated as U-100 regular insulin and has a analogs, people with type 2 diabetes prompt onset of action after dosing. The delayed onset and longer duration of

Table 8.3—Median cost of insulins in the U.S. calculated as average wholesale price per 1,000 units of specified dosage form/product (48) Median AWP package Insulins Compounds Dosage form/product price (min, max)* Rapid-acting analogs c Lispro U-100 vial $306 U-100 3 mL cartridges $306 ($306, $379) U-100 prefilled pen; U-200 prefilled pen $394 c Aspart U-100 vial $306 U-100 3 mL cartridges $380 U-100 prefilled pen $395 c Glulisine U-100 vial $283 U-100 prefilled pen $365 c Inhaled insulin Inhalation cartridges $557 ($453, $754) Short-acting c Human Regular U-100 vial $165 Intermediate-acting c Human NPH U-100 vial $165 U-100 prefilled pen $350 Concentrated Human Regular insulin c U-500 Human Regular insulin U-500 vial $165 U-500 prefilled pen $213 Basal analogs c Glargine U-100 vial; U-100 prefilled pen; U-300 prefilled pen $298 c Detemir U-100 vial; U-100 prefilled pen $323 c Degludec U-100 prefilled pen; U-200 prefilled pen $355 Premixed products c NPH/Regular 70/30 U-100 vial $165 U-100 prefilled pen $350 c Lispro 50/50 U-100 vial $317 U-100 prefilled pen $394 c Lispro 75/25 U-100 vial $317 U-100 prefilled pen $394 c Aspart 70/30 U-100 vial $318 U-100 prefilled pen $395 AWP listed alone when only one product and/or price. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S73

action than U-100 regular, posessing both important with adjustments made in both similar rates of hypoglycemia (41). If a prandial and basal properties. U-300 mealtime and basal insulins based on the patient is still above the A1C target on glargine and U-200 degludec are three blood glucose levels and an understanding basal insulin 1 single injection of rapid- and two times as concentrated as their of the pharmacodynamic profile of each acting insulin before the largest meal, ad- U-100 formulations, have longer dura- formulation (pattern control). vance to a basal-bolus regimen with $2 tions of action, and allow higher doses Studies have demonstrated the non- injections of rapid-acting insulin before of basal insulin administration per volume inferiority of basal insulin plus a single meals. Consider switching patients from used. The FDA has also approved a concen- injection of rapid-acting insulin at the one regimen to another (i.e., premixed trated formulation of rapid-acting insulin largest meal relative to basal insulin analog insulin three times daily to basal- lispro, U-200 (200 units/mL). These concen- plus a GLP-1 receptor agonist relative bolus regimen or vice-versa) if A1C targets trated preparations may be more comfort- to two daily injections of premixed insulins are not being met and/or depending on able for the patient and may improve (Fig. 8.2). Basal insulin plus GLP-1 receptor other patient considerations (39,40). adherence for patients with insulin resis- agonists are associated with less hypogly- tance who require large doses of insulin. cemia and with weight loss instead of References While U-500 regular insulin is available in weight gain but may be less tolerable 1. American Diabetes Association, JDRF. American both prefilled pens and vials (a dedicated and have a greater cost (37,38). In No- Diabetes Association/JDRF Type 1 Diabetes syringe was FDA approved in July 2016), vember 2016, the FDA approved two Sourcebook. Peters AL, Laffel L, Eds. Alexandria, other concentrated insulins are available different once-daily combination products VA, American Diabetes Association, 2013 only in prefilled pens to minimize the risk containing basal insulin plus a GLP-1 recep- 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL. Type 1 diabetes through the life span: a position of dosing errors. tor agonist: insulin glargine plus lixisenatide statement of the American Diabetes Associa- and insulin degludec plus liraglutide. Other Inhaled Insulin tion. Diabetes Care 2014;37:2034–2054 fi Inhaled insulin is available for prandial options for treatment intensi cation include 3. Wolpert HA, Atakov-Castillo A, Smith SA, Steil GM. Dietary fat acutely increases glucose use with a more limited dosing range. adding a single injection of rapid-acting insulin analog (lispro, aspart, or glulisine) be- concentrations and insulin requirements in It is contraindicated in patients with patients with type 1 diabetes: implications for chronic lung disease such as asthma fore the largest meal or stopping the basal carbohydrate-based bolus dose calculation and and chronic obstructive pulmonary insulin and initiating a premixed (or bi- intensive diabetes management. Diabetes Care – disease and is not recommended in phasic) insulin (NPH/Regular 70/30, 70/30 2013;36:810 816 4.BellKJ,ToschiE,SteilGM,WolpertHA. patients who smoke or who recently aspart mix, 75/25 or 50/50 lispro mix) twice daily, usually before breakfast and before Optimized mealtime insulin dosing for fat and stopped smoking. It requires spirometry protein in type 1 diabetes: application of a dinner. Each approach has its advantages (FEV1) testing to identify potential lung model-based approach to derive insulin doses disease in all patients prior to and after and disadvantages. For example, providers for open-loop diabetes management. Diabetes fl – starting therapy. maywishtoconsiderregimen exibility Care 2016;39:1631 1634 when devising a plan for the initiation and 5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, adjustment of insulin therapy in people King B, Wolpert HA. Impact of fat, protein, and Combination Injectable Therapy glycemic index on postprandial glucose control If basal insulin has been titrated to an with type 2 diabetes, with rapid-acting in- in type 1 diabetes: implications for intensive diabe- acceptable fasting blood glucose level sulin offering greater flexibility in terms tes management in the continuous glucose moni- (or if the dose is .0.5 units/kg/day) of meal planning than premixed insulin. If toring era. Diabetes Care 2015;38:1008–1015 and A1C remains above target, consider one regimen is not effective (i.e., basal in- 6. Yeh H-C, Brown TT, Maruthur N, et al. Compar- 1 ative effectiveness and safety of methods of in- advancing to combination injectable sulin GLP-1 receptor agonist), consider sulin delivery and glucose monitoring for diabetes therapy (Fig. 8.2). When initiating com- switching to another regimen to achieve mellitus: a systematic review and meta-analysis. bination injectable therapy, metformin A1C targets (i.e., basal insulin 1 single in- Ann Intern Med 2012;157:336–347 therapy should be maintained while jection of rapid-acting insulin or premixed 7. Bergenstal RM, Klonoff DC, Garg SK, et al.; other oral agents may be discontinued insulin twice daily) (39,40). Regular human ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypo- on an individual basis to avoid unneces- insulin and human NPH/Regular premixed glycemia. N Engl J Med 2013;369:224–232 sarily complex or costly regimens (i.e., formulations (70/30) are less costly alter- 8. Wood JR, Miller KM, Maahs DM, et al.; T1D adding a fourth antihyperglycemic natives to rapid-acting insulin analogs and Exchange Clinic Network. Most youth with agent). In general, GLP-1 receptor ago- premixed insulin analogs, respectively, type 1 diabetes in the T1D Exchange Clinic Reg- nists should not be discontinued with the but their pharmacodynamic profiles may istry do not meet American Diabetes Associa- tion or International Society for Pediatric and initiation of basal insulin. Sulfonylureas, make them less optimal. Adolescent Diabetes clinical guidelines. Diabe- DPP-4 inhibitors, and GLP-1 receptor ago- Figure 8.2 outlines these options, as tes Care 2013;36:2035–2037 nists are typically stopped once more com- well as recommendations for further in- 9. Kmietowicz Z Insulin pumps improve control plex insulin regimens beyond basal are tensification, if needed, to achieve gly- and reduce complications in children with used. In patients with suboptimal blood cemic goals. If a patient is still above the type 1 diabetes. BMJ 2013;347:f5154 10. Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control, especially those requiring A1Ctargetonpremixedinsulintwice glucose control with an artificial pancreas at a di- large insulin doses, adjunctive use of a thia- daily, consider switching to premixed abetes camp. N Engl J Med 2013;368:824–833 zolidinedione or SGLT2 inhibitor may help analog insulin three times daily (70/30 11. The Diabetes Control and Complications to improve control and reduce the amount aspart mix, 75/25 or 50/50 lispro mix). In Trial Research Group. The effect of intensive treatment of diabetes on the development of insulin needed, though potential side general, three times daily premixed an- and progression of long-term complications in effects should be considered. Once an in- alog insulins have been found to be noninsulin-dependent diabetes mellitus. N Engl J sulin regimen is initiated, dose titration is inferior to basal-bolus regimens with Med 1993;329:977–986 S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

12. Nathan DM, Cleary PA, Backlund J-YC, et al.; SafetyInformation/SafetyAlertsforHumanMedical 37. Diamant M, Nauck MA, Shaginian R, et al.; 4B Diabetes Control and Complications Trial/ Products/ucm494829.htm?source5govdelivery& Study Group. Glucagon-like peptide 1 receptor Epidemiology of Diabetes Interventions and utm_medium5email&utm_source5govdelivery. agonist or bolus insulin with optimized basal in- Complications (DCCT/EDIC) Study Research Accessed 3 October 2016 sulin in type 2 diabetes. Diabetes Care 2014;37: Group. Intensive diabetes treatment and car- 25. Aroda VR, Edelstein SL, Goldberg RB, et al.; 2763–2773 diovascular disease in patients with type 1 di- Diabetes Prevention Program Research Group. 38. Eng C, Kramer CK, Zinman B, Retnakaran R. abetes. N Engl J Med 2005;353:2643–2653 Long-term metformin use and vitamin B12 defi- Glucagon-like peptide-1 receptor agonist and 13. Diabetes Control and Complications Trial ciency in the Diabetes Prevention Program Out- basal insulin combination treatment for the (DCCT)/Epidemiology of Diabetes Interventions comes Study. J Clin Endocrinol Metab 2016;101: management of type 2 diabetes: a systematic and Complications (EDIC) Study Research 1754–1761 review and meta-analysis. Lancet 2014;384: Group. Mortality in type 1 diabetes in the 26. Vijan S, Sussman JB, Yudkin JS, Hayward RA. 2228–2234 DCCT/EDIC versus the general population. Dia- Effect of patients’ risks and preferences on 39. Dieuzeide G, Chuang L-M, Almaghamsi A, betes Care 2016;39:1378–1383 health gains with plasma glucose level lowering Zilov A, Chen J-W, Lavalle-Gonzalez´ FJ. Safety 14. DeWitt DE, Hirsch IB. Outpatient insulin in type 2 diabetes mellitus. JAMA Intern Med and effectiveness of biphasic insulin aspart therapy in type 1 and type 2 diabetes mellitus: 2014;174:1227–1234 30 in people with type 2 diabetes switching from scientific review. JAMA 2003;289:2254–2264 27. Institute for Clinical and Economic Review. basal-bolus insulin regimens in the A1chieve study. 15. Rosenstock J, Dailey G, Massi-Benedetti M, Controversies in the Management of Patients Prim Care Diabetes 2014;8:111–117 Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia with Type 2 Diabetes [Internet]. Available from 40. Mathieu C, Storms F, Tits J, Veneman TF, risk with insulin glargine: a meta-analysis compar- http://icer-review.org/wp-content/uploads/2015/ Colin IM. Switching from premixed insulin to ing insulin glargine with human NPH insulin in 03/CEPAC-T2D-Final-Report-December-22.pdf. basal-bolus insulin glargine plus rapid-acting in- type 2 diabetes. Diabetes Care 2005;28:950–955 Accessed 17 November 2016 sulin: the ATLANTIC study. Acta Clin Belg 2013; 16. Bode BW, McGill JB, Lorber DL, Gross JL, Chang 28. Nathan DM, Buse JB, Kahn SE, et al.; GRADE 68:28–33 PC, Bregman DB; Affinity 1 Study Group. Inhaled Study Research Group. Rationale and design of 41. Giugliano D, Chiodini P, Maiorino MI, technosphere insulin compared with injected pran- the Glycemia Reduction Approaches in Diabetes: A Bellastella G, Esposito K. Intensification of insu- dial insulin in type 1 diabetes: a randomized Comparative Effectiveness Study (GRADE). Diabe- lin therapy with basal-bolus or premixed insulin 24-week trial. Diabetes Care 2015;38:2266–2273 tes Care 2013;36:2254–2261 regimens in type 2 diabetes: a systematic review 17. American Diabetes Association. Pancreas 29. Zinman B, Wanner C, Lachin JM, et al.; and meta-analysis of randomized controlled and islet transplantation in type 1 diabetes. Di- EMPA-REG OUTCOME Investigators. Empagli- trials. Endocrine 2016;51:417–428 abetes Care 2006;29:935 flozin, cardiovascular outcomes, and mortality 42. Kernan WN, Viscoli CM, Furie KL, et al.; IRIS 18. Vella S, Buetow L, Royle P, Livingstone S, in type 2 diabetes. N Engl J Med 2015;373:2117– Trial Investigators. Pioglitazone after ischemic Colhoun HM, Petrie JR. The use of metformin 2128 stroke or transient ischemic attack. N Engl J in type 1 diabetes: a systematic review of effi- 30. Marso SP, Daniels GH, Brown-Frandsen K, Med 2016;374:1321–1331 cacy. Diabetologia 2010;53:809–820 et al.; LEADER Steering Committee; LEADER Trial 43. Dormandy JA, Charbonnel B, Eckland DJA, 19. –U.S. Food and Drug Administration. SGLT2 Investigators. Liraglutide and cardiovascular et al.; PROactive Investigators. Secondary pre- Inhibitors: Drug Safety Communication - Labels outcomes in type 2 diabetes. N Engl J Med vention of macrovascular events in patients to Include Warnings About Too Much Acid in 2016;375:311–322 with type 2 diabetes in the PROactive Study the Blood and Serious Urinary Tract Infections 31. Green JB, Bethel MA, Armstrong PW, et al.; (PROspective pioglitAzone Clinical Trial In [Internet]. Available from http://www.fda TECOS Study Group. Effect of sitagliptin on car- macroVascular Events): a randomised controlled .gov/safety/medwatch/safetyinformation/ diovascular outcomes in type 2 diabetes. N Engl trial. Lancet 2005;366:1279–1289 safetyalertsforhumanmedicalproducts/ucm475553 J Med 2015;373:232–242 44. Chiasson J-L, Josse RG, Gomis R, Hanefeld .htm. Accessed 3 October 2016 32. Scirica BM, Bhatt DL, Braunwald E, et al.; M, Karasik A, Laakso M; STOP-NIDDM Trial Re- 20. Palmer SC, Mavridis D, Nicolucci A, et al. SAVOR-TIMI 53 Steering Committee and Investiga- search Group. Acarbose for prevention of type 2 Comparison of clinical outcomes and adverse tors. Saxagliptin and cardiovascular outcomes in diabetes mellitus: the STOP-NIDDM randomised events associated with glucose-lowering drugs patients with type 2 diabetes mellitus. N Engl J trial. Lancet 2002;359:2072–2077 in patients with type 2 diabetes: a meta-analysis. Med 2013;369:1317–1326 45. UK Prospective Diabetes Study (UKPDS) JAMA 2016;316:313–324 33. White WB, Cannon CP, Heller SR, et al.; Group. Intensive blood-glucose control with sul- 21. Inzucchi SE, Bergenstal RM, Buse JB, et al. EXAMINE Investigators. Alogliptin after acute phonylureas or insulin compared with conven- Management of hyperglycemia in type 2 diabetes, coronary syndrome in patients with type 2 ditional treatment and risk of complications in 2015: a patient-centered approach: update to a abetes. N Engl J Med 2013;369:1327–1335 patients with type 2 diabetes (UKPDS 33). Lan- position statement of the American Diabetes Asso- 34. Blonde L, Merilainen M, Karwe V, Raskin P; cet 1998;352:837–853 ciation and the European Association for the Study TITRATE Study Group. Patient-directed titration 46. UK Prospective Diabetes Study (UKPDS) of Diabetes. Diabetes Care 2015;38:140–149 for achieving glycaemic goals using a once-daily Group. Effect of intensive blood-glucose control 22. Holman RR, Paul SK, Bethel MA, Matthews DR, basal insulin analogue: an assessment of two with metformin on complications in overweight Neil HAW. 10-year follow-up of intensive glucose different fasting plasma glucose targets - the patients with type 2 diabetes (UKPDS 34). Lan- control in type 2 diabetes. N Engl J Med 2008;359: TITRATE study. Diabetes Obes Metab 2009;11: cet 1998;352:854–865 1577–1589 623–631 47. Gaziano JM, Cincotta AH, O’Connor CM, 23. Bennett WL, Maruthur NM, Singh S, et al. 35. Tricco AC, Ashoor HM, Soobiah C, et al. et al. Randomized clinical trial of quick-release Comparative effectiveness and safety of medi- Safety, effectiveness, and cost of long-acting bromocriptine among patients with type 2 cations for type 2 diabetes: an update including versus intermediate-acting insulin for type 1 di- diabetes on overall safety and cardiovascu- new drugs and 2-drug combinations. Ann Intern abetes: protocol for a systematic review and lar outcomes. Diabetes Care 2010;33:1503– Med 2011;154:602–613 network meta-analysis. Syst Rev 2013;2:73 1508 24. U.S. Food and Drug Administration. Metformin- 36. Hua X, Carvalho N, Tew M, Huang ES, 48. Truven Health Analytics. Red Book: A Com- containing Drugs: Drug Safety Communication - Herman WH, Clarke P. Expenditures and prices prehensive, Consistent Drug Pricing Resource Revised Warnings for Certain Patients With of antihyperglycemic medications in the [Internet], 2016. Available from http://micromedix Reduced Kidney Function [Internet]. Available United States: 2002-2013. JAMA 2016;315: .com/products/product-suites/clinical-knowledge/ from http://www.fda.gov/Safety/MedWatch/ 1400–1402 redbook. Accessed 29 July 2016 Diabetes Care Volume 40, Supplement 1, January 2017 S75

9. Cardiovascular Disease and Risk American Diabetes Association Management Diabetes Care 2017;40(Suppl. 1):S75–S87 | DOI: 10.2337/dc17-S012

For prevention and management of diabetes complications in children and adolescents, please refer to Section 12 “Children and Adolescents.” 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 MANAGEMENT RISK AND DISEASE CARDIOVASCULAR 9. 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 clear risk factors for ASCVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy 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). In all patients with diabetes, cardiovascular risk factors should be systematically assessed at least annually. These risk factors include hypertension, dyslipidemia, smoking, a family history of premature coronary disease, and the presence of albuminuria. Abnormal risk factors should be treated as described in these guidelines.

HYPERTENSION/BLOOD PRESSURE CONTROL

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 c Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of ,140 mmHg and a diastolic blood pressure goal of ,90 mmHg. A c Lower systolic and diastolic blood pressure targets, such as 130/80 mmHg, may be appropriate for individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden. C c In pregnant patients with diabetes and chronic hypertension, blood pressure targets of 120–160/80–105 mmHg are suggested in the interest of optimizing long-term maternal health and minimizing impaired fetal growth. E Suggested citation: American Diabetes Associa- Treatment tion. Cardiovascular disease and risk manage- c Patients with confirmed office-based blood pressure .140/90 mmHg should, ment. Sec. 9. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1): in addition to lifestyle therapy, have prompt initiation and timely titration of S75–S87 pharmacologic therapy to achieve blood pressure goals. A fi fi . © 2017 by the American Diabetes Association. c Patients with con rmed of ce-based blood pressure 160/100 mmHg should, Readers may use this article as long as the work in addition to lifestyle therapy, have prompt initiation and timely titration of is properly cited, the use is educational and not two drugs or a single pill combination of drugs demonstrated to reduce car- for profit, and the work is not altered. More infor- diovascular events in patients with diabetes. A mation is available at http://www.diabetesjournals .org/content/license. S76 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

population: measurement in the seated landmark trials, Action to Control Cardio- c Treatment for hypertension should position, with feet on the floor and arm vascular Risk in Diabetes (ACCORD) and include drug classes demonstrated supported at heart level, after 5 min of Action in Diabetes and Vascular Disease: to reduce cardiovascular events in pa- rest. Cuff size should be appropriate for Preterax and Diamicron MR Controlled tients with diabetes (ACE inhibitors, the upper-arm circumference. Elevated Evaluation–Blood Pressure (ADVANCE- angiotensin receptor blockers, thia- values should be confirmed on a separate BP), examined the benefit of tighter blood zide-like diuretics, or dihydropyridine day. Postural changes in blood pressure pressure control in patients with type 2 calcium channel blockers). Multiple- and pulse may be evidence of autonomic diabetes. Additional studies, such as the drug therapy is generally required to neuropathy and therefore require adjust- Systolic Blood Pressure Intervention Trial achieve blood pressure targets (but ment of blood pressure targets. (SPRINT) and the Hypertension Optimal not a combination of ACE inhibitors Home blood pressure self-monitoring Treatment (HOT) trial, also examined the and angiotensin receptor blockers). A and 24-h ambulatory blood pressure potential benefits of intensive versus stan- c An ACE inhibitor or angiotensin re- monitoring may provide evidence of ceptor blocker, at the maximum dard control, though the relevance of their white-coat hypertension, masked hyper- tolerated dose indicated for blood resultstopeoplewithdiabetesislessclear. tension, or other discrepancies between pressure treatment, is the recom- ACCORD. The ACCORD trial examined office and “true” blood pressure. Studies mended first-line treatment for whether an SBP of ,120 mmHg in pain individuals without diabetes found that hypertension in patients with dia- tients with type 2 diabetes at high risk home measurements may better correlate betes and urinary albumin–to– for ASCVD provided greater cardio- with ASCVD risk than office measurements creatinine ratio $300 mg/g creati- vascular protection than an SBP of (6,7). However, most of the evidence of nine (A)or30–299 mg/g creatinine 130–140 mmHg (13). The study did not benefits of hypertension treatment in (B). If one class is not tolerated, the find a benefit in the primary end point people with diabetes is based on office other should be substituted. B (nonfatal MI, nonfatal stroke, and car- measurements. c For patients treated with an ACE diovascular death) comparing intensive inhibitor, angiotensin receptor Treatment Goals blood pressure treatment (intensive BP; , blocker, or diuretic, serum creatinine/ Epidemiological analyses show that goal 120 mmHg, average blood pres- estimated glomerular filtration rate blood pressure .115/75 mmHg is asso- sure achieved 119/64 mmHg on 3.4 and serum potassium levels should ciated with increased cardiovascular medications) with standard treatment be monitored. B event rates and mortality in individuals (standard BP; average blood pressure c For patients with blood pres- with diabetes (8). Randomized clinical achieved 143/70 mmHg on 2.1 medica- sure .120/80 mmHg, lifestyle in- trials have demonstrated the benefit tions). However, a follow-up analysis found tervention consists of weight loss (reduction of CHD events, stroke, and a strong interaction between glycemic con- if overweight or obese; a Dietary diabetic kidney disease) of lowering trol and blood pressure control. Compared Approaches to Stop Hypertension– blood pressure to ,140 mmHg systolic with the standard glycemia/standard BP style dietary pattern including and ,90 mmHg diastolic in individuals control group in the blood pressure trial, reducing sodium and increasing with diabetes (9,10). There is limited the intensive BP/intensive glycemia, inten- potassium intake; moderation of prespecified clinical trial evidence for sive BP/standard glycemia, and standard alcohol intake; and increased phys- the benefits of lower systolic blood pres- BP/intensive glycemia groups all showed ical activity. B sure (SBP) or diastolic blood pressure benefit for reducing the risk of major (DBP) targets (11). A meta-analysis of cardiovascular disease (14). Stroke was fi Hypertension, de ned as a sustained randomized trials of adults with type 2 significantly reduced in the intensive BP $ blood pressure 140/90 mmHg, is a diabetes comparing intensive blood treatment groups, but the intensive BP/ common comorbidity of type 1 and pressure targets (upper limit of 130 intensive glycemia group showed no ev- type 2 diabetes. The prevalence of hy- mmHg systolic and 80 mmHg diastolic) idence of incremental benefit compared pertension depends on type of diabetes, with standard targets (upper limit of with either single intensive intervention age, sex, BMI, and race/ethnicity. Hyper- 140–160 mmHg systolic and 85–100 (14). Thus, more intensive blood pres- tension is a major risk factor for both mmHg diastolic) found no significant sure control may be reasonable in cer- ASCVD and microvascular complica- reduction in mortality or nonfatal MI. tain motivated, ACCORD-like patients tions. In type 1 diabetes, hypertension There was a statistically significant 35% (40–79 years of age with prior evidence is often the result of underlying diabetic relative risk (RR) reduction in stroke of cardiovascular disease or multiple car- kidney disease, while in type 2 diabetes, with intensive targets, but the absolute diovascular risk factors) who have been it usually coexists with other cardiome- risk reduction was only 1%, and inten- educated about the added treatment tabolic risk factors. Please refer to the sive targets were associated with an in- burden, side effects, and costs of more American Diabetes Association (ADA) creased risk for adverse events such as intensive blood pressure control and for “ position statement Diabetes and Hy- hypotension and syncope (12). patients who prefer to lower their risk of pertension” for a detailed review (5). stroke beyond what can be achieved Randomized Controlled Trials of Intensive Screening and Diagnosis Versus Standard Blood Pressure Control through standard care. Blood pressure should be measured by a Given the epidemiological relationship ADVANCE. In ADVANCE, the active blood trained individual and should follow the between lower blood pressure and bet- pressure intervention arm (a single-pill, guidelines established for the general ter long-term clinical outcomes, two fixed-dose combination of perindopril care.diabetesjournals.org Cardiovascular Disease and Risk Management S77

and indapamide) showed a significant Systolic Blood Pressure without diabetes and has shown antihy- reduction in the risk of the primary com- The evidence that SBP .140 mmHg is pertensive effects similar to those of phar- posite end point (major macrovascular harmful is irrefutable, suggesting that macologic monotherapy. or microvascular event) and significant clinicians promptly initiate and ti- Lifestyle therapy consists of reduc- reductions in the risk of death from any trate therapy to achieve and maintain ing excess body weight through caloric cause and of death from cardiovascular SBP ,140 mmHg in most patients. For restriction, restricting sodium intake causes (15). The baseline blood pres- some patients, lower SBP targets closer (,2,300 mg/day), increasing consump- sure among the study subjects was to 130 mmHg are appropriate. A recent tion of fruits and vegetables (8–10 serv- 145/81 mmHg. Compared with the pla- systematic review and meta-analysis ings per day) and low-fat dairy products cebo group, the patients treated with a evaluating SBP lowering in adults with (2–3 servings per day), avoiding exces- single-pill, fixed-dose combination of type 2 diabetes showed that each sive alcohol consumption (no more than perindopril and indapamide experienced 10 mmHg reduction of SBP was associ- 2servingsperdayinmenandnomore an average reduction of 5.6 mmHg in ated with significantly lower risk of than 1 serving per day in women) (21), SBPand2.2mmHginDBP.Thefinal mortality, cardiovascular events, CHD, and increasing activity levels (11). blood pressure in the treated group was stroke, albuminuria, and retinopathy. These lifestyle (nonpharmacologic) 136/73 mmHg, not quite the intensive or However, when trials were stratified by strategies may also positively affect gly- $ tight control achieved in ACCORD. The mean baseline SBP 140 mmHg or cemia and lipid control and should be , – recently published 6-year follow-up of 140 mmHg, blood pressure lowering encouraged in those with even mildly the ADVANCE trial, the ADVANCE–Post- treatment was associated with lower elevated blood pressure, although the Trial Observational Study (ADVANCE-ON), risks of stroke and albuminuria, regard- impact of lifestyle therapy on cardiovas- reported that the reductions in the risk of less of initial SBP (9). Therefore, indivi- cular events has not been established. death from any cause and of death from duals in whom cardiovascular disease Nonpharmacologic therapy is reasonable cardiovascular causes in the intervention risk, particularly stroke, is a concern in individuals with diabetes and mildly el- group were attenuated but remained sig- may, as part of shared decision making, evated blood pressure (SBP .120 mmHg nificant (16). have lower systolic targets than 140 or DBP .80 mmHg). If the blood pressure mmHg. This is especially true if lower is confirmed to be $140 mmHg systolic HOT. The Hypertension Optimal Treat- blood pressure can be achieved with and/or $90 mmHg diastolic, pharma- ment (HOT) trial included patients with few drugs and without side effects of cologic therapy should be initiated and without diabetes and compared therapy. For older adults, treating to # # # along with nonpharmacologic therapy DBP targets of 90, 85, and 80 an SBP of ,130 mmHg has not been (11). A lifestyle therapy plan should be mmHg. Post hoc analyses found cardio- showntoimprovecardiovascularout- fi developed in collaboration with the pa- vascular bene t with more intensive comes (19). targets in the subpopulation with dia- tient and discussed as part of diabetes betes (17). The HOT trial results, taken Diastolic Blood Pressure management. Similarly, strong evidence from random- together with the higher quality data Pharmacologic Interventions ized clinical trials supports DBP targets from ACCORD and ADVANCE, support Lowering of blood pressure with regimens of ,90 mmHg. These targets are in har- the current recommendation to achieve based on a variety of antihypertensive mony with the Eighth Joint National blood pressure levels ,140/90 mmHg, agents, including ACE inhibitors, angioten- Committee (JNC 8) recommendation with lower targets in selected patients. sin receptor blockers (ARBs), diuretics, and of a DBP threshold of ,90 mmHg for calcium channel blockers has been shown SPRINT. The Systolic Blood Pressure In- individuals over 18 years of age with di- to be effective in reducing cardiovascular tervention Trial (SPRINT) was a multi- abetes (11). A DBP of ,80 mmHg may events (9,22). center, randomized controlled trial still be appropriate for patients with In people with diabetes and albumin- that compared two strategies for treat- long life expectancy, chronic kidney dis- uria, ACE inhibitors or ARBs may have ing SBP with either the standard target ease, elevated urinary albumin excretion, , of 140 mmHg or an intensive target evidence of cardiovascular disease, or unique advantages for initial or early , of 120 mmHg; primary outcomes additional risk factors such as dyslipidemia, treatment of hypertension. In a trial of wereMI,ACS,stroke,heartfailure, smoking, or obesity (17). In older adults, individuals at high risk for ASCVD, and death due to cardiovascular dis- treating to a DBP of ,70 mmHg has been including a large subset with diabetes, ease. Patients assigned to the intensive associated with a greater risk of mortality an ACE inhibitor reduced ASCVD out- SBP target of ,120 mmHg, compared (20). comes and the development of albumin- with a target SBP of 140 mmHg, had uria when compared with placebo, even reduced RR of cardiovascular events Treatment Strategies after adjustment for differences in by almost a third and of death by almost Lifestyle Intervention blood pressure, an effect that has been a quarter, though risks of electrolyte ab- Although there are no well-controlled termed a “blood pressure independent normalities and acute kidney injury were studies of diet and exercise in the treat- effect” (23). In patients with congestive increased (18). Of note, patients with di- ment of elevated blood pressure or hy- heart failure, including subgroups with abetes were excluded from participating pertension in individuals with diabetes, diabetes, ARBs have been shown to re- in this trial, so the results have no direct the Dietary Approaches to Stop Hyperten- duce major ASCVD outcomes (24–26). implications for blood pressure manage- sion (DASH) study evaluated the impact of Among patients with type 2 diabetes, ment in patients with diabetes. healthy dietary patterns in individuals urine albumin–to–creatinine ratio (UACR) S78 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

$300 mg/g creatinine, and elevated se- significantly reduced combined micro- recommendations for the management rum creatinine concentration, an ARB sig- vascular and macrovascular outcomes, of hypertension in pregnant women nificantly reduced progression of kidney as well as death from cardiovascular with diabetes should be similar to those disease compared with placebo (27). A causes and total mortality. The improved for all pregnant women. The American meta-analysis confirmed that treatment outcomes could also have been due to College of Obstetricians and Gynecolo- of patients with diabetic kidney disease lower achieved blood pressure in the gists (ACOG) has recommended that with an ACE inhibitor or ARB reduces the perindopril–indapamide arm (15). Another women with mild gestational hyperten- risk of progressing to end-stage renal dis- trial showed a decrease in morbidity and sion (SBP ,160 mmHg or DBP ,110 ease, though strong evidence of benefit mortality in those receiving ACE inhibi- mmHg) do not need to be treated with was limited to participants with baseline tor benazepril and calcium channel antihypertensive medications as there is UACR $300 mg/g creatinine (28). Smaller blocker amlodipine versus benazepril no benefitidentified that clearly out- trials also suggest reduction in composite and thiazide-like diuretic hydrochloro- weighs potential risks of therapy (40). cardiovascular events and reduced pro- thiazide (36,37). If needed to achieve A 2014 Cochrane systematic review of gression of advanced nephropathy blood pressure targets, amlodipine antihypertensive therapy for mild to (29–31). and indapamide or hydrochlorothia- moderate chronic hypertension that However, the superiority of ACE in- zide or thiazide-like diuretic chlorthalidone included 49 trials and over 4,700 hibitors or ARBs over other antihyper- can be added. If estimated glomerular women did not find any conclusive ev- 2 tensive agents for prevention of filtration rate is ,30 mL/min/1.73 m , idence for or against blood pressure cardiovascular outcomes has not been a loop diuretic should be prescribed. treatment to reduce the risk of pre- consistently shown for all patients with Titration of and/or addition of further eclampsia for the mother or effects diabetes (22,28,32,33). In particular, a recent blood pressure medications should be on perinatal outcomes such as preterm meta-analysis suggests that thiazide- made in a timely fashion to overcome birth, small-for-gestational-age in- type diuretics or dihydropyridine calcium clinical inertia in achieving blood pres- fants, or fetal death (41). For pregnant channel blockers have cardiovascular sure targets. women who require antihypertensive – benefit similar to that of ACE inhibitors therapy, SBP levels of 120 160 mmHg Bedtime Dosing – or ARBs (22). Therefore, among patients Growing evidence suggests that there is and DBP levels of 80 105 mmHg are without albuminuria for whom cardio- an association between absence of noc- suggested to optimize maternal health vascular disease prevention is the pri- turnal blood pressure dipping and the without risking fetal harm. Lower tar- – – mary goal of blood pressure control, a incidence of ASCVD. A randomized con- gets (SBP 110 119mmHgandDBP65 thiazide-like diuretic or dihydropyridine trolled trial of 448 participants with 79 mmHg) may contribute to improved calcium channel blocker may be consid- type 2 diabetes and hypertension dem- long-term maternal health; however, ered instead of or in addition to an ACE onstrated reduced cardiovascular events they may be associated with impaired fetal growth. Pregnant women with inhibitor or ARB. and mortality with median follow-up of There are no adequate head-to-head 5.4 years if at least one antihyperten- hypertension and evidence of end-organ comparisons of ACE inhibitors and ARBs, sive medication was given at bedtime damage from cardiovascular and/or renal disease may be considered for but there is clinical trial support for each (38). Consider administering one or lower blood pressure targets to avoid of the following statements: In patients more antihypertensive medications at progression of these conditions during with type 1 diabetes with hypertension bedtime (39). pregnancy. and any degree of albuminuria, ACE in- Other Considerations During pregnancy, treatment with hibitors have been shown to reduce loss An important caveat is that most pa- ACE inhibitors, ARBs, and spironolac- of glomerular filtration rate and delay tients with diabetes and hypertension tone are contraindicated as they may the progression of nephropathy. In require multiple-drug therapy to reach cause fetal damage. Antihypertensive patients with type 2 diabetes, hyper- blood pressure treatment goals (21). drugs known to be effective and safe tension, and UACR 30–299 mg/g cre- Identifying and addressing barriers to in pregnancy include methyldopa, labe- atinine, ACE inhibitors and ARBs have medication adherence (such as cost talol, hydralazine, carvedilol, clonidine, been shown to delay the progression to and side effects) should routinely be and long-acting nifedipine (40). Di- UACR $300 mg/g creatinine. The use of done. If blood pressure remains uncon- uretics are not recommended for blood fi both ACE inhibitors and ARBs in combina- trolled despite con rmed adherence pressure control in pregnancy but may tion is not recommended given the lack of to optimal doses of at least three be used during late-stage pregnancy if fi added ASCVD bene tandincreasedrate antihypertensive agents of different needed for volume control (40,42). d of adverse events namely, hyperkale- classes, one of which should be a di- ACOG also recommends that postpar- mia, syncope, and acute kidney injury uretic, clinicians should consider an tum patients with gestational hyperten- (34,35). evaluation for secondary causes of sion, preeclampsia, and superimposed Combination Drug Therapy hypertension. preeclampsia have their blood pres- The blood pressure arm of the ADVANCE Pregnancy and Antihypertensive sures observed for 72 h in hospital and trial demonstrated that routine admin- Medications for 7–10 days postpartum. Long-term istration of a fixed-dose combination Since there is a lack of randomized con- follow-up is recommended for these of the ACE inhibitor perindopril and trolled trials of antihypertensive ther- women as they have increased lifetime the thiazide-like diuretic indapamide apy in pregnant women with diabetes, cardiovascular risk (43). care.diabetesjournals.org Cardiovascular Disease and Risk Management S79

LIPID MANAGEMENT Recommendations should focus on re- c For patients with diabetes aged ducing saturated fat, cholesterol, and Recommendations .75 years without additional ath- trans fat intake and increasing plant c In adults not taking statins, it is erosclerotic cardiovascular dis- stanols/sterols, v-3 fatty acids, and vis- reasonable to obtain a lipid profile ease risk factors, consider using cous fiber (such as in oats, legumes, and at the time of diabetes diagnosis, moderate-intensity statin therapy citrus). Glycemic control may also benefi- at an initial medical evaluation, and and lifestyle therapy. B cially modify plasma lipid levels, particularly every 5 years thereafter, or more c For patients with diabetes aged in patients with very high triglycerides and frequently if indicated. E .75 years with additional athero- poor glycemic control. c Obtain a lipid profile at initiation sclerotic cardiovascular disease risk of statin therapy and periodically factors, consider using moderate- Statin Treatment thereafter as it may help to monitor intensity or high-intensity statin Initiating Statin Therapy Based on Risk the response to therapy and inform therapy and lifestyle therapy. B Patients with type 2 diabetes have an adherence. E c In clinical practice, providers may increased prevalence of lipid abnormal- c Lifestyle modification focusing on need to adjust intensity of statin ities, contributing to their high risk of weight loss (if indicated); the reduc- therapy based on individual patient ASCVD. Multiple clinical trials have dem- tion of saturated fat, trans fat, and response to medication (e.g., side onstrated the beneficial effects of phar- cholesterol intake; increase of di- effects, tolerability, LDL cholesterol macologic (statin) therapy on ASCVD etary v-3 fatty acids, viscous fiber, levels). E outcomes in subjects with and without and plant stanols/sterols intake; c The addition of ezetimibe to CHD (44,45). Subgroup analyses of pa- and increased physical activity moderate-intensity statin therapy tients with diabetes in larger trials should be recommended to im- has been shown to provide addi- (46–50) and trials in patients with dia- prove the lipid profile in patients tional cardiovascular benefit com- betes (51,52) showed significant pri- with diabetes. A pared with moderate-intensity mary and secondary prevention of c Intensify lifestyle therapy and opti- statin therapy alone for patients with ASCVD events and CHD death in patients mize glycemic control for patients recent acute coronary syndrome with diabetes. Meta-analyses, including with elevated triglyceride levels and LDL cholesterol $50 mg/dL data from over 18,000 patients with di- ($150 mg/dL [1.7 mmol/L]) and/or (1.3 mmol/L) and should be consid- abetes from 14 randomized trials of low HDL cholesterol (,40 mg/dL ered for these patients A and also statin therapy (mean follow-up 4.3 years), [1.0 mmol/L] for men, ,50 mg/dL in patients with diabetes and his- demonstrate a 9% proportional reduc- [1.3 mmol/L] for women). C tory of ASCVD who cannot tolerate tion in all-cause mortality and 13% re- c For patients with fasting triglyceride high-intensity statin therapy. E duction in vascular mortality for each levels $500 mg/dL (5.7 mmol/L), c Combination therapy (statin/fibrate) mmol/L (39 mg/dL) reduction in LDL evaluate for secondary causes of has not been shown to improve ath- cholesterol (53). hypertriglyceridemia and consider erosclerotic cardiovascular disease As in those without diabetes, abso- medical therapy to reduce the risk outcomes and is generally not rec- lute reductions in ASCVD outcomes of pancreatitis. C ommended. A However, therapy (CHD death and nonfatal MI) are great- c For patients of all ages with diabe- with statin and fenofibrate may est in people with high baseline ASCVD tes and atherosclerotic cardiovas- be considered for men with both risk (known ASCVD and/or very high LDL cular disease, high-intensity statin triglyceride level $204 mg/dL cholesterol levels), but the overall ben- therapy should be added to life- (2.3 mmol/L) and HDL cholesterol efits of statin therapy in people with di- style therapy. A level #34 mg/dL (0.9 mmol/L). B abetes at moderate or even low risk for c For patients with diabetes aged c Combination therapy (statin/niacin) ASCVD are convincing (54,55). Statins ,40 years with additional athero- has not been shown to provide ad- are the drugs of choice for LDL choles- sclerotic cardiovascular disease risk ditional cardiovascular benefit above terol lowering and cardioprotection. factors, consider using moderate- statin therapy alone and may in- Most trials of statins and ASCVD out- intensity or high-intensity statin creasetheriskofstrokeandisnot comes tested specificdosesofstatins and lifestyle therapy. C generally recommended. A against placebo or other statins rather c For patients with diabetes aged c Statin therapy is contraindicated than aiming for specific LDL cholesterol 40–75 years without additional in pregnancy. B goals (56), suggesting that the initiation atherosclerotic cardiovascular dis- and intensification of statin therapy ease risk factors, consider using be based on risk profile (Table 9.1 and moderate-intensity statin and life- Lifestyle Intervention Lifestyle intervention, including weight Table 9.2). style therapy. A loss, increased physical activity, and The Risk Calculator. The American College c For patients with diabetes aged medical nutrition therapy, allows some of Cardiology/American Heart Associa- 40–75 years with additional ath- patients to reduce ASCVD risk factors. tion ASCVD risk calculator may be a use- erosclerotic cardiovascular dis- Nutrition intervention should be tai- ful tool to estimate 10-year ASCVD risk ease risk factors, consider using lored according to each patient’sage, (http://my.americanheart.org). As dia- high-intensity statin and lifestyle diabetes type, pharmacologic treatment, betes itself confers increased risk for therapy. B lipid levels, and medical conditions. ASCVD, the risk calculator has limited S80 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

fi Table 9.1—Recommendations for statin and combination treatment in people signi cant, reduction in risk as patients with diabetes with type 2 diabetes (47). Even though Recommended the data are not definitive, similar statin Age Risk factors statin intensity* treatment approaches should be consid- ,40 years None None ered for patients with type 1 or type 2 ASCVD risk factor(s)** Moderate or high diabetes, particularly in the presence of ASCVD High other cardiovascular risk factors. Please 40–75 years None Moderate refer to “Type 1 Diabetes Mellitus and ASCVD risk factors High Cardiovascular Disease: A Scientific ASCVD High Statement From the American Heart As- ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) Moderate plus sociation and American Diabetes Associ- or in patients with a history of ASCVD who ezetimibe ation” (60) for additional discussion. cannot tolerate high-dose statins High-intensity statin therapy is rec- .75 years None Moderate ommended for all patients with diabe- ASCVD risk factors Moderate or high tes and ASCVD. Treatment with a ASCVD High moderate dose of statin should be con- ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) Moderate plus sidered if the patient does not have or in patients with a history of ASCVD who ezetimibe cannot tolerate high-dose statins ASCVD but has additional ASCVD risk factors. *In addition to lifestyle therapy. **ASCVD risk factors include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD. Ongoing Therapy and Monitoring With Lipid Panel In adults with diabetes, it is reasonable use for assessing cardiovascular risk in based on risk profile. High-intensity sta- to obtain a lipid profile (total choles- individuals with diabetes. tins, if well tolerated, are still appropri- terol, LDL cholesterol, HDL cholesterol, Age 40–75 Years ate and recommended for older adults and triglycerides) at the time of diagno- In low-risk patients with diabetes aged with ASCVD. High-intensity statin ther- sis, at the initial medical evaluation, and 40–75 years, moderate-intensity statin apy may also be appropriate in adults at least every 5 years thereafter. A lipid treatment should be considered in addi- with diabetes .75 years of age with ad- panel should also be obtained immedi- tion to lifestyle therapy. Clinical trials in ditional ASCVD risk factors. However, ately before initiating statin therapy. high-risk patients with increased cardio- the risk–benefitprofile should be rou- Once a patient is taking a statin, testing vascular risk (e.g., LDL cholesterol $100 tinely evaluated in this population, for LDL cholesterol may be considered mg/dL [2.6 mmol/L], high blood pres- with downward titration (e.g., high to on an individual basis (e.g., to monitor sure, smoking, albuminuria, and family moderate intensity) performed as for adherence and efficacy). In cases history of premature ASCVD) and with needed. See Section 11 “Older Adults” where patients are adherent but the ASCVD (57–59) have demonstrated that for more details on clinical consider- LDL cholesterol level is not responding, more aggressive therapy with high ations for this population. clinical judgment is recommended to fi doses of statins led to a signi cant re- Age <40 Years and/or Type 1 Diabetes determine the need for and timing of duction in cardiovascular events. High- Very little clinical trial evidence exists lipid panels. In individual patients, the intensity statins are recommended in all for patients with type 2 diabetes under highly variable LDL cholesterol–lowering such patients. the age of 40 years or for patients with response seen with statins is poorly un- Age >75 Years type 1 diabetes of any age. In the Heart derstood (61). When maximally tolerated For adults with diabetes .75 years of Protection Study (lower age limit 40 doses of statins fail to substantially lower age, there are limited data regarding years), the subgroup of ;600 patients LDL cholesterol (,30% reduction from the benefits and risks of statin therapy. with type 1 diabetes had a proportion- the patient’s baseline), there is no strong Statin therapy should be individualized ately similar, although not statistically evidence that combination therapy should be used. Clinicians should attempt to find a dose or alternative statin that is tol- Table 9.2—High-intensity and moderate-intensity statin therapy* erable, if side effects occur. There is evi- High-intensity statin therapy Moderate-intensity statin therapy fi (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30% to ,50%) dence for bene t from even extremely low, less than daily, statin doses (62). – – Atorvastatin 40 80 mg Atorvastatin 10 20 mg Increased frequency of LDL choles- – – Rosuvastatin 20 40 mg Rosuvastatin 5 10 mg terol monitoring should be considered Simvastatin 20–40 mg for patients with new-onset ACS. In- Pravastatin 40–80 mg Lovastatin 40 mg creased frequency of LDL cholesterol Fluvastatin XL 80 mg monitoring may also be considered in Pitavastatin 2–4mg adults with heterozygous familial hypercholesterolemia who require additional *Once-daily dosing. XL, extended release. lowering of LDL cholesterol. care.diabetesjournals.org Cardiovascular Disease and Risk Management S81

Combination Therapy for LDL Low levels of HDL cholesterol, often niacin is not recommended given the Cholesterol Lowering associated with elevated triglyceride lack of efficacy on major ASCVD out- Statins and Ezetimibe levels, are the most prevalent pattern comes, possible increase in risk of ische- The IMProved Reduction of Outcomes: of dyslipidemia in individuals with mic stroke, and side effects. Vytorin Efficacy International Trial type 2 diabetes. However, the evidence (IMPROVE-IT) was a randomized con- for the use of drugs that target these Diabetes With Statin Use trolled trial comparing the addition of eze- lipid fractions is substantially less robust Several studies have reported an in- timibe to simvastatin therapy versus than that for statin therapy (67). In a creased risk of incident diabetes with simvastatin alone. Individuals were $50 large trial in patients with diabetes, fe- statin use (72,73), which may be limited years of age, had experienced an ACS nofibrate failed to reduce overall cardio- to those with diabetes risk factors. within the preceding 10 days, and had vascular outcomes (68). An analysis of one of the initial studies an LDL cholesterol level $50 mg/dL suggested that although statins were (1.3 mmol/L). In those with diabetes Combination Therapy linked to diabetes risk, the cardiovascu- (27%), the combination of moderate- Statin and Fibrate lar event rate reduction with statins far fi intensity simvastatin (40 mg) and ezetimibe Combination therapy (statin and - outweighed the risk of incident diabetes (10 mg) showed a significant reduction of brate) is associated with an increased even for patients at highest risk for di- major adverse cardiovascular events with risk for abnormal transaminase levels, abetes (74). The absolute risk increase an absolute risk reduction of 5% (40% vs. myositis, and rhabdomyolysis. The risk was small (over 5 years of follow-up, 45%) and RR reduction of 14% (RR 0.86 of rhabdomyolysis is more common 1.2% of participants on placebo devel- [95% CI 0.78–0.94]) over moderate-intensity with higher doses of statins and renal oped diabetes and 1.5% on rosuvastatin fi simvastatin (40 mg) alone (63). Therefore, insuf ciency and appears to be higher developed diabetes) (74). A meta-analysis fi for people meeting IMPROVE-IT eligibil- when statins are combined with gem - of 13 randomized statin trials with fi ity criteria, ezetimibe should be added brozil (compared with feno brate) (69). 91,140 participants showed an odds ratio to moderate-intensity statin therapy. In the ACCORD study, in patients with of 1.09 for a new diagnosis of diabetes, so Though not explicitly studied, these re- type 2 diabetes who were at high risk for that (on average) treatment of 255 patients fi sults may also suggest that the addition ASCVD, the combination of feno brate with statins for 4 years resulted in one of ezetimibe should be considered for and simvastatin did not reduce the rate additional case of diabetes while simulta- any patient with diabetes and history of of fatal cardiovascular events, nonfatal neously preventing 5.4 vascular events ASCVD who cannot tolerate high-intensity MI, or nonfatal stroke as compared with among those 255 patients (73). fi statin therapy. simvastatin alone. Prespeci ed subgroup analyses suggested heterogeneity Statins and Cognitive Function A recent systematic review of the U.S. Statins and PCSK9 Inhibitors in treatment effects with possible ben- Food and Drug Administration’spost- Placebo-controlled trials evaluating efit for men with both a triglyceride marketing surveillance databases, ran- the addition of the PCSK9 inhibitors level $204 mg/dL (2.3 mmol/L) and domized controlled trials, and cohort, evolocumab and alirocumab to maxi- an HDL cholesterol level #34 mg/dL case-control, and cross-sectional stud- mally tolerated doses of statin therapy (0.9 mmol/L) (70). in participants who were at high risk for ies evaluating cognition in patients re- ASCVD demonstrated an average reduc- Statin and Niacin ceiving statins found that published tion in LDL cholesterol ranging from 36% The Atherothrombosis Intervention in data do not reveal an adverse effect of to 59%. These agents may therefore be Metabolic Syndrome With Low HDL/High statins on cognition. Therefore, a concern considered as adjunctive therapy for Triglycerides: Impact on Global Health that statins might cause cognitive dys- patients with diabetes at high risk for Outcomes (AIM-HIGH) trial randomized function or dementia should not deter ASCVD events who require additional over 3,000 patients (about one-third their use in individuals with diabetes at lowering of LDL cholesterol or who re- with diabetes) with established ASCVD, high risk for ASCVD (75). , quire but are intolerant to high-intensity low LDL cholesterol levels ( 180 mg/dL statin therapy (64,65). It is important to [4.7 mmol/L]), low HDL cholesterol lev- ANTIPLATELET AGENTS els (men ,40 mg/dL [1.0 mmol/L] and note that the effects of this novel class Recommendations women ,50 mg/dL [1.3 mmol/L]), and of agents on ASCVD outcomes are un- c Use aspirin therapy (75–162 mg/day) triglyceride levels of 150–400 mg/dL known as phase 4 studies are currently as a secondary prevention strat- (1.7–4.5 mmol/L) to statin therapy under way. egy in those with diabetes and a plus extended-release niacin or pla- history of atherosclerotic cardio- cebo. The trial was halted early due to Treatment of Other Lipoprotein vascular disease. A Fractions or Targets lack of efficacy on the primary ASCVD c For patients with atherosclerotic Hypertriglyceridemia should be ad- outcome (first event of the composite cardiovascular disease and docu- dressed with dietary and lifestyle of death from CHD, nonfatal MI, ische- mented aspirin allergy, clopidogrel changes including abstinence from alco- mic stroke, hospitalization for an ACS, (75 mg/day) should be used. B hol (66). Severe hypertriglyceridemia or symptom-driven coronary or cere- c Dual antiplatelet therapy is reason- (.1,000 mg/dL) may warrant pharma- bral revascularization) and a possible ableforuptoayearafteranacute cologic therapy (fibric acid derivatives increase in ischemic stroke in those on coronary syndrome and may have and/or fish oil) to reduce the risk of combination therapy (71). Therefore, benefits beyond this period. B acute pancreatitis. combination therapy with a statin and S82 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

vascular events by 12% (RR 0.88 [95% recommendations for using aspirin as c Consider aspirin therapy (75–162 CI 0.82–0.94]). The largest reduction primary prevention include both men mg/day) as a primary prevention was for nonfatal MI, with little effect and women aged $50 years with diabe- strategy in those with type 1 or on CHD death (RR 0.95 [95% CI 0.78– tes and at least one additional major type 2 diabetes who are at in- 1.15]) or total stroke. There was some risk factor (family history of premature creased cardiovascular risk. This evidence of a difference in aspirin effect ASCVD, hypertension, dyslipidemia, includes most men and women by sex: aspirin significantly reduced smoking, or chronic kidney disease/ with diabetes aged $50 years ASCVD events in men but not in women. albuminuria) who are not at increased who have at least one additional Conversely, aspirin had no effect on risk of bleeding (83–86). While risk calcu- major risk factor (family history stroke in men but significantly reduced lators such as those from the American of premature atherosclerotic car- stroke in women. However, there was College of Cardiology/American Heart As- diovascular disease, hypertension, no heterogeneity of effect by sex in the sociation (http://my.americanheart.org) dyslipidemia, smoking, or albu- risk of serious vascular events (P 5 0.9). may be a useful tool to estimate 10-year minuria) and are not at increased Sex differences in aspirin’seffects ASCVD risk, diabetes itself confers in- risk of bleeding. C have not been observed in studies of creased risk for ASCVD. As a result, such c Aspirin should not be recommended secondary prevention (76). In the six tri- for atherosclerotic cardiovascular risk calculators have limited utility in help- als examined by the ATT collaborators, fi disease prevention for adults with ing to assess the potential bene ts of as- the effects of aspirin on major vascular diabetes at low atherosclerotic car- pirin therapy in individuals with diabetes. events were similar for patients with or diovascular disease risk, such as Noninvasive imaging techniques such as without diabetes: RR 0.88 (95% CI 0.67– in men or women with diabetes coronary computed tomography angiog- 1.15) and RR 0.87 (95% CI 0.79–0.96), aged ,50 years with no other major raphy may potentially help further tailor respectively. The confidence interval atherosclerotic cardiovascular dis- aspirin therapy, particularly in those at was wider for those with diabetes be- ease risk factors, as the potential ad- low risk (87), but are not generally recom- cause of smaller numbers. verse effects from bleeding likely mended. Sex differences in the antiplate- Aspirin appears to have a modest ef- offset the potential benefits. C let effect of aspirin have been suggested fect on ischemic vascular events, with c When considering aspirin therapy in the general population (88); however, the absolute decrease in events depend- in patients with diabetes ,50 further studies are needed to investigate ing on the underlying ASCVD risk. The years of age with multiple other the presence of such differences in indi- main adverse effects appear to be an atherosclerotic cardiovascular dis- viduals with diabetes. increased risk of gastrointestinal bleed- ease risk factors, clinical judgment ing. The excess risk may be as high as Aspirin Use in People <50 Years of Age is required. E 1–5 per 1,000 per year in real-world Aspirin is not recommended for those at settings. In adults with ASCVD risk .1% low risk of ASCVD (such as men and Risk Reduction per year, the number of ASCVD events pre- women aged ,50 years with diabetes Aspirin has been shown to be effective vented will be similar to or greater than the with no other major ASCVD risk factors) in reducing cardiovascular morbidity number of episodes of bleeding induced, as the low benefit is likely to be out- and mortality in high-risk patients with although these complications do not have weighed by the risks of bleeding. Clinical previous MI or stroke (secondary preven- equal effects on long-term health (81). judgment should be used for those at tion). Its net benefit in primary prevention intermediate risk (younger patients among patients with no previous cardio- Treatment Considerations with one or more risk factors or older vascular events is more controversial both In 2010, a position statement of the patients with no risk factors) until fur- for patients with diabetes and for patients ADA, the American Heart Association, ther research is available. Patients’ will- without diabetes (76,77). Previous ran- and the American College of Cardiol- ingness to undergo long-term aspirin domized controlled trials of aspirin specif- ogy Foundation recommended that therapy should also be considered ically in patients with diabetes failed to low-dose (75–162 mg/day) aspirin for (89). Aspirin use in patients aged ,21 consistently show a significant reduction primary prevention is reasonable for years is generally contraindicated due in overall ASCVD end points, raising ques- adults with diabetes and no previous to the associated risk of Reye syndrome. tions about the efficacy of aspirin for pri- history of vascular disease who are at mary prevention in people with diabetes, increased ASCVD risk and who are not Aspirin Dosing although some sex differences were sug- at increased risk for bleeding (82). This Average daily dosages used in most gested (78–80). previous statement included sex-specific clinical trials involving patients with di- The Antithrombotic Trialists’ (ATT) recommendations for use of aspirin ther- abetes ranged from 50 mg to 650 mg collaborators published an individual apy as primary prevention persons with but were mostly in the range of 100– patient-level meta-analysis of the six diabetes. However, since that time, 325 mg/day. There is little evidence to large trials of aspirin for primary pre- multiple recent well-conducted studies support any specific dose, but using the vention in the general population. These and meta-analyses have reported a risk lowest possible dose may help to re- trials collectively enrolled over 95,000 of heart disease and stroke that is duce side effects (90). In the U.S., the participants, including almost 4,000 equivalent if not higher in women com- most common low-dose tablet is 81 mg. with diabetes. Overall, they found that pared with men with diabetes, including Although platelets from patients with aspirin reduced the risk of serious among nonelderly adults. Thus, current diabetes have altered function, it is care.diabetesjournals.org Cardiovascular Disease and Risk Management S83

unclear what, if any, effect that finding MI may reverse over time, adding to or symptoms of associated vascular has on the required dose of aspirin for the controversy concerning aggressive disease including carotid bruits, tran- cardioprotective effects in the patient screening strategies (99). In prospective sient ischemic attack, stroke, claudi- with diabetes. Many alternate pathways trials, coronary artery calcium has been cation, or peripheral arterial disease; for platelet activation exist that are in- established as an independent predictor or electrocardiogram abnormalities dependent of thromboxane A and thus of future ASCVD events in patients with 2 (e.g., Q waves). E not sensitive to the effects of aspirin diabetes and is superior to both the UK (91). “Aspirin resistance” has been de- Treatment Prospective Diabetes Study (UKPDS) risk scribed in patients with diabetes when c In patients with known atheroscle- engine and the Framingham Risk Score measured by a variety of ex vivo and rotic cardiovascular disease, use in predicting risk in this population in vitro methods (platelet aggregometry, aspirin and statin therapy (if not (100–102). However, a randomized ob- measurement of thromboxane B2) (88), contraindicated) A and consider servational trial demonstrated no clini- but other studies suggest no impairment ACE inhibitor therapy C to reduce cal benefit to routine screening of in aspirin response among patients with the risk of cardiovascular events. asymptomatic patients with type 2 dia- diabetes (92). A recent trial suggested c In patients with prior myocardial betes and normal ECGs (103). Despite that more frequent dosing regimens of infarction, b-blockers should be abnormal myocardial perfusion imaging aspirin may reduce platelet reactivity in continued for at least 2 years after in more than one in five patients, cardiac individuals with diabetes (93); however, the event. B outcomes were essentially equal (and these observations alone are insuffi- c In patients with symptomatic very low) in screened versus unscreened cient to empirically recommend that heart failure, thiazolidinedione patients. Accordingly, indiscriminate higher doses of aspirin be used in this treatment should not be used. A screening is not considered cost-effective. group at this time. It appears that 75– c In patients with type 2 diabetes Studies have found that a risk factor– 162 mg/day is optimal. with stable congestive heart failure, based approach to the initial diagnostic metformin may be used if estimated evaluation and subsequent follow-up for Indications for P2Y12 Use glomerular filtration remains .30 coronary artery disease fails to identify A P2Y12 receptor antagonist in combi- mL/min but should be avoided in un- which patients with type 2 diabetes will nation with aspirin should be used for at stable or hospitalized patients with have silent ischemia on screening tests least 1 year in patients following an ACS congestive heart failure. B (104,105). Any benefit of newer noninva- and may have benefits beyond this sive coronary artery disease screening period. Evidence supports use of either methods, such as computed tomography ticagrelor or clopidogrel if no percuta- Cardiac Testing and computed tomography angiography, neous coronary intervention was per- Candidates for advanced or invasive car- to identify patient subgroups for different formed and clopidogrel, ticagrelor, or diac testing include those with 1)typical treatment strategies remains unproven. prasugrel if a percutaneous coronary or atypical cardiac symptoms and 2)an Although asymptomatic patients with intervention was performed (94). In pa- abnormal resting electrocardiogram diabetes with higher coronary disease tients with diabetes and prior MI (1–3 (ECG). Exercise ECG testing without or burden have more future cardiac events years before), adding ticagrelor to as- with echocardiography may be used as (100,106,107), the role of these tests be- pirin significantly reduces the risk of the initial test. In adults with diabetes yond risk stratification is not clear. Their recurrent ischemic events including car- $40 years of age, measurement of cor- routine use leads to radiation exposure diovascular and coronary heart disease onaryarterycalciumisalsoreason- and may result in unnecessary invasive death (95). More studies are needed to able for cardiovascular risk assessment. testing such as coronary angiography investigate the longer-term benefits of Pharmacologic stress echocardiography and revascularization procedures. The ul- these therapies after ACS among pa- or nuclear imaging should be considered timate balance of benefit, cost, and risks tients with diabetes. in individuals with diabetes in whom resting ECG abnormalities preclude ex- of such an approach in asymptomatic patients remains controversial, particularly CORONARY HEART DISEASE ercise stress testing (e.g., left bundle branch block or ST-T abnormalities). In in the modern setting of aggressive Recommendations addition, individuals who require stress ASCVD risk factor control. Screening testing and are unable to exercise Lifestyle and Pharmacologic c In asymptomatic patients, routine should undergo pharmacologic stress screening for coronary artery dis- echocardiography or nuclear imaging. Interventions Intensive lifestyle intervention focusing ease is not recommended as it on weight loss through decreased calo- does not improve outcomes as Screening Asymptomatic Patients The screening of asymptomatic pa- ric intake and increased physical activity long as atherosclerotic cardiovascu- tients with high ASCVD risk is not rec- as performed in the Action for Health in lar disease risk factors are treated. A ommended (96), in part because these Diabetes (Look AHEAD) trial may be con- c Consider investigations for coro- high-risk patients should already be re- sidered for improving glucose control, nary artery disease in the presence ceiving intensive medical therapydan fitness, and some ASCVD risk factors of any of the following: atypical approach that provides similar benefit (108). Patients at increased ASCVD risk cardiac symptoms (e.g., unexplained as invasive revascularization (97,98). should receive aspirin and a statin and dyspnea, chest discomfort); signs There is also some evidence that silent ACE inhibitor or ARB therapy if the S84 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

patient has hypertension, unless there with the placebo group (3.1%; 1.09 per primary outcome (MI, stroke, or cardiovas- are contraindications to a particular 100 person-years) (118). cular death) occurred in fewer participants drug class. While clear benefitexists in the treatment group (13.0%) when com- for ACE inhibitor and ARB therapy in pa- Antihyperglycemic Therapies and paredwiththeplacebogroup(14.9%)after tients with nephropathy or hyperten- Cardiovascular Outcomes a median follow-up of 3.8 years (120). sion, the benefits in patients with Recently published cardiovascular out- Whether other glucagon-like peptide 1 re- ASCVD in the absence of these condi- come trials have provided additional ceptor agonists will have the same effect tions are less clear, especially when data on cardiovascular outcomes in inhigh-riskpatientsorifthisdrugclass LDL cholesterol is concomitantly con- patients with type 2 diabetes with car- will have similar effects in lower-risk pa- trolled (109,110). In patients with prior diovascular disease or at high risk for tients with diabetes remains unknown. MI, b-blockers should be continued for cardiovascular disease. The BI 10773 fl at least 2 years after the event (111). (Empagli ozin) Cardiovascular Outcome References Event Trial in Type 2 Diabetes Mellitus 1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Patients (EMPA-REG OUTCOME) was a Imperatore G, Gregg EW. Achievement of goals Diabetes and Heart Failure in U.S. diabetes care, 1999-2010. N Engl J Med As many as 50% of patients with type 2 randomized, double-blind trial that – fl 2013;368:1613 1624 diabetes may develop heart failure (112). assessed the effect of empagli ozin, a 2. 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EXAMINE re- blind trial that assessed the effect of Collins R; Prospective Studies Collaboration. ported that the hospital admission rate liraglutide, a glucagon-like peptide 1 recep- Age-specific relevance of usual blood pressure for heart failure was 3.1% for patients tor agonist, versus placebo and standard to vascular mortality: a meta-analysis of individ- randomly assigned to alogliptin com- ual data for one million adults in 61 prospective care on cardiovascular outcomes in patients studies. Lancet 2002;360:1903–1913 pared with 2.9% for those randomly as- with type 2 diabetes at high risk for cardio- 9. Emdin CA, Rahimi K, Neal B, Callender T, signed to placebo (hazard ratio 1.07 vascular disease or with cardiovascular dis- Perkovic V, Patel A. Blood pressure lowering in [95% CI 0.79–1.46]) (117). Alogliptin had ease. 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Diabetes Care 2012;35: ALLHAT Collaborative Research Group. Clinical prognosis of diabetic patients with coronary 2650–2664 outcomes in antihypertensive treatment of heart disease. A subgroup analysis of the Scan- 20. Anderson RJ, Bahn GD, Moritz TE, Kaufman type 2 diabetes, impaired fasting glucose con- dinavian Simvastatin Survival Study (4S). Diabe- D, Abraira C, Duckworth W; VADT Study Group. centration, and normoglycemia: Antihyperten- tes Care 1997;20:614–620 Blood pressure and cardiovascular disease risk sive and Lipid-Lowering Treatment to Prevent 47. Collins R, Armitage J, Parish S, Sleigh P, Peto in the Veterans Affairs Diabetes Trial. Diabetes Heart Attack Trial (ALLHAT). Arch Intern Med R; Heart Protection Study Collaborative Group. Care 2011;34:34–38 2005;165:1401–1409 MRC/BHF Heart Protection Study of cholesterol- 21. Sacks FM, Svetkey LP, Vollmer WM, et al.; 33. Remonti LR, Dias S, Leitão CB, et al. 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Endpoints in Non-Insulin-Dependent Diabetes of 25 randomized, controlled trials. BMC Med 80. De Berardis G, Sacco M, Strippoli GFM, et al. Mellitus (ASPEN). Diabetes Care 2006;29: 2015;13:123 Aspirin for primary prevention of cardiovascular 1478–1485 66. Berglund L, Brunzell JD, Goldberg AC, et al.; events in people with diabetes: meta-analysis of 52. Colhoun HM, Betteridge DJ, Durrington PN, Endocrine Society. Evaluation and treatment of randomised controlled trials. BMJ 2009;339: et al.; CARDS investigators. Primary prevention of hypertriglyceridemia: an Endocrine Society clin- b4531 cardiovascular disease with atorvastatin in type 2 ical practice guideline. J Clin Endocrinol Metab 81. Pignone M, Earnshaw S, Tice JA, Pletcher diabetes in the Collaborative Atorvastatin Diabetes 2012;97:2969–2989 MJ. Aspirin, statins, or both drugs for the primary Study (CARDS): multicentre randomised placebo- 67. Singh IM, Shishehbor MH, Ansell BJ. 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Zaccardi F, Rizzi A, Petrucci G, et al. In vivo design and rationale of ODYSSEY ALTERNATIVE, a 2008;337:a1840 platelet activation and aspirin responsiveness in randomized phase 3 trial. J Clin Lipidol 2014;8: 79. Zhang C, Sun A, Zhang P, et al. Aspirin for type 1 diabetes. Diabetes 2016;65:503–509 554–561 primary prevention of cardiovascular events in 93. Bethel MA, Harrison P, Sourij H, et al. Ran- 65. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and patients with diabetes: a meta-analysis. Diabe- domized controlled trial comparing impact on efficacy of anti-PCSK9 antibodies: a meta-analysis tes Res Clin Pract 2010;87:211–218 platelet reactivity of twice-daily with once-daily care.diabetesjournals.org Cardiovascular Disease and Risk Management S87

aspirin in people with type 2 diabetes. Diabet myocardial perfusion scintigraphy. Eur Heart J 111. Kezerashvili A, Marzo K, De Leon J. Beta Med 2016;33:224–230 2006;27:713–721 blocker use after acute myocardial infarction in 94. Vandvik PO, Lincoff AM, Gore JM, et al.; 103. Young LH, Wackers FJT, Chyun DA, et al.; the patient with normal systolic function: when American College of Chest Physicians. Primary DIAD Investigators. Cardiac outcomes after is it “ok” to discontinue? Curr Cardiol Rev 2012; and secondary prevention of cardiovascular dis- screening for asymptomatic coronary artery dis- 8:77–84 ease: Antithrombotic Therapy and Prevention ease in patients with type 2 diabetes: the DIAD 112. Kannel WB, Hjortland M, Castelli WP. Role of Thrombosis, 9th ed: American College of study: a randomized controlled trial. JAMA of diabetes in congestive heart failure: the Fra- Chest Physicians Evidence-Based Clinical Prac- 2009;301:1547–1555 mingham study. 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Singh S, Loke YK, Furberg CD. Long-term 96. Bax JJ, Young LH, Frye RL, Bonow RO, tery disease in asymptomatic patients with risk of cardiovascular events with rosiglitazone: Steinberg HO, Barrett EJ; ADA. Screening for type 2 diabetes mellitus. J Am Coll Cardiol a meta-analysis. JAMA 2007;298:1189–1195 coronary artery disease in patients with diabe- 2006;47:65–71 115. Lincoff AM, Wolski K, Nicholls SJ, Nissen – tes. Diabetes Care 2007;30:2729 2736 106. Hadamitzky M, Hein F, Meyer T, et al. SE. Pioglitazone and risk of cardiovascular ’ 97. Boden WE, O Rourke RA, Teo KK, et al.; Prognostic value of coronary computed tomo- events in patients with type 2 diabetes mellitus: COURAGE Trial Research Group. Optimal medi- graphic angiography in diabetic patients with- a meta-analysis of randomized trials. JAMA cal therapy with or without PCI for stable coro- out known coronary artery disease. Diabetes 2007;298:1180–1188 nary disease. N Engl J Med 2007;356:1503–1516 Care 2010;33:1358–1363 116. Scirica BM, Bhatt DL, Braunwald E, et al.; 98. BARI 2D Study Group, Frye RL, August P, 107. Choi E-K, Chun EJ, Choi S-I, et al. Assess- SAVOR-TIMI 53 Steering Committee and Inves- et al. A randomized trial of therapies for ment of subclinical coronary atherosclerosis in tigators. Saxagliptin and cardiovascular out- type 2 diabetes and coronary artery disease. asymptomatic patients with type 2 diabetes comes in patients with type 2 diabetes mellitus. N Engl J Med 2009;360:2503–2015 mellitus with single photon emission computed – 99. Wackers FJT, Chyun DA, Young LH, et al.; N Engl J Med 2013;369:1317 1326 Detection of Ischemia in Asymptomatic Dia- tomography and coronary computed tomog- 117. Zannad F, Cannon CP, Cushman WC, et al.; betics (DIAD) Investigators. Resolution of asymp- raphy angiography. Am J Cardiol 2009;104: EXAMINE Investigators. Heart failure and mor- – tomatic myocardial ischemia in patients with 890 896 tality outcomes in patients with type 2 diabetes type 2 diabetes in the Detection of Ischemia in 108. Look AHEAD Research Group, Wing RR, taking alogliptin versus placebo in EXAMINE: a Asymptomatic Diabetics (DIAD) study. Diabetes Bolin P, et al. Cardiovascular effects of intensive multicentre, randomised, double-blind trial. – Care 2007;30:2892–2898 lifestyle intervention in type 2 diabetes. N Engl J Lancet 2015;385:2067 2076 – 100. Elkeles RS, Godsland IF, Feher MD, et al.; Med 2013;369:145 154 118. Green JB, Bethel MA, Armstrong PW, PREDICT Study Group. Coronary calcium mea- 109. Braunwald E, Domanski MJ, Fowler SE, et al.; TECOS Study Group. Effect of sitagliptin surement improves prediction of cardiovascular et al.; PEACE Trial Investigators. Angiotensin- on cardiovascular outcomes in type 2 diabetes. events in asymptomatic patients with type 2 di- converting-enzyme inhibition in stable coronary N Engl J Med 2015;373:232–242 abetes: the PREDICT study. Eur Heart J 2008;29: artery disease. N Engl J Med 2004;351:2058– 119. Zinman B, Wanner C, Lachin JM, et al.; 2244–2251 2068 EMPA-REG OUTCOME Investigators. Empagli- 101. Raggi P, Shaw LJ, Berman DS, Callister TQ. 110. Telmisartan Randomised AssessmeNt ﬂozin, cardiovascular outcomes, and mortality Prognostic value of coronary artery calcium Study in ACE iNtolerant subjects with cardiovas- in type 2 diabetes. N Engl J Med 2015;373:2117– screening in subjects with and without diabetes. cular Disease (TRANSCEND) Investigators, Yusuf S, 2128 J Am Coll Cardiol 2004;43:1663–1669 Teo K, et al. Effects of the angiotensin-receptor 120. Marso SP, Daniels GH, Brown-Frandsen K, 102.AnandDV,LimE,HopkinsD,etal.Risk blocker telmisartan on cardiovascular events et al.; LEADER Steering Committee; LEADER Trial stratiﬁcation in uncomplicated type 2 diabetes: in high-risk patients intolerant to angiotensin- Investigators. Liraglutide and cardiovascular prospective evaluation of the combined use of converting enzyme inhibitors: a randomised con- outcomes in type 2 diabetes. N Engl J Med coronary artery calcium imaging and selective trolled trial. Lancet 2008;372:1174–1183 2016;375:311–322 S88 Diabetes Care Volume 40, Supplement 1, January 2017

10. Microvascular Complications American Diabetes Association and Foot Care Diabetes Care 2017;40(Suppl. 1):S88–S98 | DOI: 10.2337/dc17-S013

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 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 approximately 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. B c In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an angiotensin receptor blocker is recommended for those with modestly elevated urinary albumin–to–creatinine ratio (30–299 mg/g creatinine) B and is strongly recommended for those with urinary albumin– to–creatinine ratio $300 mg/g creatinine and/or estimated glomerular filtration rate ,60 mL/min/1.73 m2. A 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 10. MICROVASCULAR COMPLICATIONS AND FOOT CARE 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 creatinine), 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 an 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 Suggested citation: American Diabetes Associa- uncertainty about the etiology of kidney disease, difficult management issues, tion. Microvascular complications and foot and rapidly progressing kidney disease. B care. Sec. 10. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1): S88–S98 Assessment of Albuminuria and Estimated Glomerular Filtration Rate © 2017 by the American Diabetes Association. Chronic kidney disease (CKD) is diagnosed by the presence of elevated urinary Readers may use this article as long as the work fi is properly cited, the use is educational and not albumin excretion (albuminuria), low estimated glomerular ltration rate (eGFR), for profit, and the work is not altered. More infor- or other manifestations of kidney damage (1,2). Diabetic kidney disease, or CKD mation is available at http://www.diabetesjournals attributed to diabetes, occurs in 20–40% of patients with diabetes and is the leading .org/content/license. care.diabetesjournals.org Microvascular Complications and Foot Care S89

cause of end-stage renal disease (ESRD) Table 10.1—Stages of CKD (1). Diabetic kidney disease typically Stage Description eGFR (mL/min/1.73 m2) develops after a diabetes duration of 10 $ years, or at least 5 years in type 1 diabe- 1 Kidney damage* with normal or increased eGFR 90 – tes, but may be present at diagnosis of 2 Kidney damage* with mildly decreased eGFR 60 89 type 2 diabetes. 3 Moderately decreased eGFR 30–59 Screening for albuminuria can be most 4 Severely decreased eGFR 15–29 easily performed by urinary albumin–to– 5 Kidney failure ,15 or dialysis creatinine ratio (UACR) in a random spot *Kidney damage is defined as UACR persistently $30 mg/g Cr or other abnormalities on urine collection (1,2). Timed or 24-h collec- pathological, urine, blood, or imaging tests. Adapted from Levey et al. (4). tions are more burdensome and add little to prediction or accuracy. Measurement of a spot urine sample for albumin alone CKD staging that incorporates albuminuria of diabetic kidney disease, monitor pro- (whether by immunoassay or by using a and is more closely associated with risks gression of diabetic kidney disease, assess sensitive dipstick test specific for albumin- of cardiovascular disease (CVD) and CKD risk of CKD complications, dose drugs ap- uria) without simultaneously measuring progression (2). It has not been deter- propriately, and determine whether ne- urine creatinine (Cr) is less expensive but mined whether application of the more phrology referral is needed (Table 10.2). susceptible to false-negative and false- complex system aids clinical care or im- Albuminuria and eGFR may change due positive determinations as a result of varia- proves health outcomes. to progression of diabetic kidney disease, tion in urine concentration due to hydration. development of superimposed kidney dis- Diagnosis of Diabetic Kidney Disease fi Normal UACR is generally de ned as Diabetic kidney disease is usually a clin- ease, or the effects of medication, includ- , 30 mg/g Cr, and increased urinary albu- ical diagnosis made based on the pres- ing many antihypertensive medications fi $ min excretion is de ned as 30 mg/g Cr. ence of albuminuria and/or reduced (e.g., ACE inhibitors, angiotensin receptor However, UACR is a continuous measure- eGFR in the absence of signs or symp- blockers [ARBs], and diuretics) and some ment, and differences within the normal toms of other primary causes of kidney glucose-lowering medications (e.g., – and abnormal ranges are associated with damage. The typical presentation of di- sodium glucose cotransporter 2 [SGLT2] renal and cardiovascular outcomes. Fur- abetic kidney disease is considered inhibitors). For patients with eGFR thermore, because of biological variability ,60 mL/min/1.73 m2, appropriate medi- to include a long-standing duration of in urinary albumin excretion, two of three cation dosing should be verified, exposure diabetes, retinopathy, albuminuria specimens of UACR collected within a 3- to to nephrotoxins (e.g., nonsteroidal anti- without hematuria, and gradually pro- 6-month period should be abnormal be- inflammatory drugs and iodinated con- gressive kidney disease. However, signs fore considering a patient to have albumin- trast) should be minimized, and potential of CKD may be present at diagnosis or uria. Exercise within 24 h, infection, fever, CKD complications should be evaluated. without retinopathy in type 2 diabetes, congestive heart failure, marked hypergly- The need for annual quantitative as- and reduced eGFR without albuminuria cemia, menstruation, and marked hyper- sessment of albumin excretion after di- has been frequently reported in type 1 tension may elevate UACR independently agnosis of albuminuria, institution of and type 2 diabetes and is becoming of kidney damage. ACE inhibitors or ARB therapy, and more common over time as the preva- eGFR should be calculated from serum achieving blood pressure control is a lence of diabetes increases in the U.S. Cr using a validated formula. The Chronic subject of debate. Continued surveil- (5–8). Kidney Disease Epidemiology Collabora- lance can assess both response to ther- An active urinary sediment (contain- tion (CKD-EPI) equation is generally pre- apy and disease progression and may ing red or white blood cells or cellular ferred (2). eGFR is routinely reported by aid in assessing adherence to ACE inhib- casts), rapidly increasing albuminuria or laboratories with serum Cr, and eGFR cal- itor or ARB therapy. In addition, in clin- nephrotic syndrome, rapidly decreasing culators are available from http://www ical trials of ACE inhibitors or ARB eGFR, or the absence of retinopathy (in .nkdep.nih.gov. An eGFR ,60 mL/min/ therapy in type 2 diabetes, reducing al- type 1 diabetes) may suggest alternative 1.73 m2 is generally considered abnormal, buminuria from levels $300 mg/g Cr has though optimal thresholds for clinical di- or additional causes of kidney disease. been associated with improved renal agnosis are debated (3). For patients with these features, referral and cardiovascular outcomes, leading Urinary albumin excretion and eGFR to a nephrologist for further diagnosis, some to suggest that medications each vary within people over time, and including the possibility of kidney bi- should be titrated to minimize UACR. abnormal results should be confirmed opsy, should be considered. It is rare However, this approach has not been to stage CKD (1,2). Since 2003, stage for patients with type 1 diabetes to de- formally evaluated in prospective trials, 1–2 CKD has been defined by evidence velop kidney disease without retinopa- and in type 1 diabetes, remission of al- of kidney damage (usually albuminuria) thy. In type 2 diabetes, retinopathy is buminuria may occur spontaneously and fi with eGFR $60 mL/min/1.73 m2,while only moderately sensitive and speci c is not associated with improved clinical fi stages 3–5 CKD have been defined by for CKD caused by diabetes, as con rmed outcomes (10). The prevalence of CKD progressively lower ranges of eGFR (4) by kidney biopsy (9). complications correlates with eGFR. 2 (Table 10.1). More recently, Kidney Dis- Surveillance When eGFR is ,60 mL/min/1.73 m , ease: Improving Global Outcomes (KDIGO) Albuminuria and eGFR should be moni- screening for complications of CKD is in- recommended a more comprehensive tored regularly to enable timely diagnosis dicated (Table 10.2). Early vaccination S90 Microvascular Complications and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017

Table 10.2—Management of CKD in diabetes of at least 2 years in type 2 diabetes to eGFR over 10 years in type 1 diabetes for the (mL/min/1.73 m2) Recommended management effects of intensive glucose control to manifest as improved eGFR outcomes All patients Yearly measurement of UACR, serum Cr, potassium (17,25,26). Therefore, in some patients 45–60 Referral to a nephrologist if possibility for nondiabetic kidney disease exists (duration of type 1 diabetes ,10 years, persistent albuminuria, with prevalent diabetic kidney disease and abnormal findings on renal ultrasound, resistant hypertension, rapid substantial comorbidity, target A1C levels fall in eGFR, or active urinary sediment on urine microscopic should be .7% (53 mmol/mol) (1,27). examination) The glucose-lowering effects of SGLT2 in- Consider the need for dose adjustment of medications hibitors are blunted with reduced eGFR, Monitor eGFR every 6 months but the renal and cardiovascular benefits Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, fl and parathyroid hormone at least yearly of empagli ozin, compared with placebo, Assure vitamin D sufficiency were not reduced among trial participants Vaccinate against Hep B virus with baseline eGFR 30–59 mL/min/1.73 m2, Consider bone density testing compared with participants with baseline Referral for dietary counseling eGFR $60 mL/min/1.73 m2 (19,28). 30–44 Monitor eGFR every 3 months With reduced eGFR, drug dosing may Monitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid require modification (1). The U.S. Food hormone, hemoglobin, albumin, and weight every 3–6 months and Drug Administration (FDA) revised Consider the need for dose adjustment of medications guidance for the use metformin in dia- ,30 Referral to a nephrologist betic kidney disease in 2016 (29), recommending use of eGFR instead of serum Cr to guide treatment and expand- against hepatitis B virus is indicated in pa- whileavarietyofagentswereusedinclin- ing the pool of patients with kidney disease tients likely to progress to ESRD. ical trials of type 2 diabetes, supporting the for whom metformin treatment should be conclusion that glycemic control itself considered. Revised FDA guidance states Interventions helps prevent diabetic kidney disease Nutrition that metformin is contraindicated in and its progression. The effects of glucose- , For people with nondialysis-dependent patients with an eGFR 30 mL/min/ lowering therapies on diabetic kidney dis- 1.73 m2, eGFR should be monitored while diabetic kidney disease, dietary protein fi ease have helped de ne hemoglobin A1C taking metformin, the benefits and risks of intake should be approximately 0.8 g/kg targets (Table 6.2). continuing treatment should be reassessed body weight per day (the recommended Some glucose-lowering medications when eGFR falls ,45 mL/min/1.73 m2, daily allowance) (1). Compared with also have effects on the kidney that are metformin should not be initiated for pa- higher levels of dietary protein intake, direct, i.e., not mediated through glycemia. tients with an eGFR ,45 mL/min/1.73 m2, this level slowed GFR decline with evi- For example, SGLT2 inhibitors reduce and metformin should be temporarily dis- dence of a greater effect over time. renal tubular glucose reabsorption, intra- continued at the time of or before iodin- Higher levels of dietary protein intake glomerular pressure, and albuminuria and . ated contrast imaging procedures in ( 20% of daily calories from protein slow GFR loss through mechanisms that . patients with eGFR 30–60 mL/min/ or 1.3 g/kg/day) have been associated appear independent of glycemia (18–20). 1.73 m2. Other glucose-lowering medica- with increased albuminuria, more rapid kid- Glucagon-like peptide 1 receptor agonists tions also require dose adjustment or dis- ney function loss, and CVD mortality and and dipeptidyl peptidase 4 inhibitors also continuation at low eGFR (1). therefore should be avoided. Reducing the have direct effects on the kidney and have amount of dietary protein below the rec- been reported to improve renal outcomes Cardiovascular Disease and Blood Pressure ommended daily allowance of 0.8 g/kg/day compared with placebo (21,22). Renal ef- Patients with diabetic kidney disease are is not recommended because it does not fects may be considered among other fac- at high risk of CVD. To reduce cardiovas- alter glycemic measures, cardiovascular risk tors when selecting glucose-lowering cular risk, statin therapy and blood pres- measures, or the course of GFR decline. medications for individual patients (see sure treatment should be considered in Glycemia Section 8 “Pharmacologic Approaches to patients with diabetic kidney disease. Intensive glycemic control with the goal Glycemic Treatment”). Blood pressure control reduces risk of of achieving near-normoglycemia has The presence of diabetic kidney dis- cardiovascular events (30). been shown in large prospective ran- ease affects the risks and benefits of in- Hypertension is a strong risk factor for domized studies to delay the onset and tensive glycemic control and a number the development and progression of di- progression of albuminuria and reduced of specific glucose-lowering medica- abetic kidney disease. Antihypertensive eGFR in patients with type 1 diabetes tions. In the Action to Control Cardio- therapy reduces the risk of albuminuria (11,12) and type 2 diabetes (1,13–17). vascular Risk in Diabetes (ACCORD) trial (30–32), and among patients with type 1 Insulin alone was used to lower blood of type 2 diabetes, adverse effects of in- or 2 diabetes with established diabetic glucose in the Diabetes Control and tensive glycemic control (hypoglycemia kidney disease (eGFR ,60 mL/min/1.73 m2 Complications Trial (DCCT)/Epidemiology and mortality) were increased among pa- and UACR $300 mg/g Cr), ACE inhibitor or of Diabetes Interventions and Complica- tients with kidney disease at baseline ARB therapy reduce the risk of progression tions (EDIC) study of type 1 diabetes, (23,24). Moreover, there is a lag time to ESRD (33–35). care.diabetesjournals.org Microvascular Complications and Foot Care S91

Blood pressure levels ,140/90 mmHg acute kidney injury) (43). Therefore, the slow the progression of diabetic ret- in diabetes are recommended to reduce combined use of ACE inhibitors and ARBs inopathy. A CVD mortality and slow CKD progression. should be avoided. In individuals with albuminuria, who are at Mineralocorticoid receptor antagonists Screening increasedriskofCVDandCKDprogression, (spironolactone, eplerenone, and finere- c Adults with type 1 diabetes should lower blood pressure targets (e.g., ,130/80 none) in combination with ACE inhibitors have an initial dilated and compre- mmHg) may be considered (36). Of note, or ARBs remain an area of great interest. hensive eye examination by an there is an adverse safety signal in clini- Mineralocorticoid receptor antagonists ophthalmologist or optometrist cal trials of diabetic kidney disease when areeffectiveformanagementofresistant within 5 years after the onset of diastolic blood pressure is treated to hypertension, have been shown to reduce diabetes. B ,70 mmHg and especially ,60 mmHg in albuminuria in short-term studies of dia- c Patients with type 2 diabetes older populations. As a result, clinical betic kidney disease, and may have addi- should have an initial dilated and judgment should be used when attempt- tional cardiovascular benefits (44–46). comprehensive eye examination ing to achieve systolic blood pressure There has been, however, an increase in by an ophthalmologist or optome- targets ,130 mmHg to avoid diastolic hyperkalemic episodes in those on dual tristatthetimeofthediabetes blood pressure levels ,60–70 mmHg. therapy, and larger, longer trials with clin- diagnosis. B ACE inhibitors or ARBs are the pre- ical outcomes are needed before recom- c If there is no evidence of retinop- ferred first-line agent for blood pressure mending such therapy. athy for one or more annual eye treatment among patients with diabetes, Diuretics, calcium channel blockers, exams and glycemia is well con- hypertension, eGFR ,60 mL/min/1.73 m2, and b-blockers can be used as add-on ther- trolled, then exams every 2 years and UACR $300 mg/g Cr because of apy to achieve blood pressure goals in pa- may be considered. If any level of their proven benefits for prevention of tients treated with maximum doses of ACE diabetic retinopathy is present, CKD progression and major CVD events inhibitors or ARBs (47) or as alternate subsequent dilated retinal exami- (37). In general, ACE inhibitors and ARBs therapy in the rare individual unable to nations should be repeated at are considered to have similar benefits tolerate ACE inhibitors and ARBs. least annually by an ophthalmologist or optometrist. If retinopathy is pro- (38)andrisks.Inthesettingoflower Referral to a Nephrologist – levels of albuminuria (30 299 mg/g Cr), Consider referral to a physician experi- gressing or sight-threatening, then ACE inhibitor or ARB therapy has been enced in the care of kidney disease when examinations will be required more demonstrated to reduce progression to there is uncertainty about the etiology frequently. B $ c more advanced albuminuria ( 300 mg/g of kidney disease, difficult management While retinal photography may Cr) and cardiovascular events but not pro- issues (anemia, secondary hyperparathy- serve as a screening tool for reti- gression to ESRD (37,39). While ACE inhib- roidism, metabolic bone disease, resistant nopathy, it is not a substitute for a itors or ARB are often prescribed for hypertension, or electrolyte disturbances), comprehensive eye exam. E albuminuria without hypertension, clinical or advanced kidney disease (eGFR ,30 c Women with preexisting type 1 or trials have not been performed in this set- mL/min/1.73 m2) requiring discussion of type 2 diabetes who are planning ting to determine whether this improves renal replacement therapy for ESRD. The pregnancy or who are pregnant renal outcomes. threshold for referral may vary depending should be counseled on the risk of Absent kidney disease, ACE inhibitors on the frequency with which a provider development and/or progression of or ARBs are useful to control blood pres- encounters patients with diabetes and diabetic retinopathy. B sure but may not be superior to alterna- kidney disease. Consultation with a ne- c Eye examinations should occur be- fi tive classes of antihypertensive therapy phrologist when stage 4 CKD develops fore pregnancy or in the rst trimes- (40). In a trial of people with type 2 di- (eGFR #30 mL/min/1.73 m2) has been ter in patients with preexisting abetes and normal urine albumin excre- found to reduce cost, improve quality of type 1 or type 2 diabetes, and then tion, an ARB reduced or suppressed the care, and delay dialysis (48). However, patients should be monitored every development of albuminuria but in- other specialists and providers should trimester and for 1 year postpartum creased the rate of cardiovascular events also educate their patients about the pro- as indicated by the degree of reti- (41). In a trial of people with type 1 di- gressive nature of diabetic kidney disease, nopathy. B abetes exhibiting neither albuminuria nor fi the kidney preservation bene ts of proac- Treatment hypertension, ACE inhibitors or ARBs did tive treatment of blood pressure and c Promptly refer patients with any not prevent the development of diabetic blood glucose, and the potential need for level of macular edema, severe non- glomerulopathy assessed by kidney biopsy renal replacement therapy. proliferative diabetic retinopathy (a (42). Therefore, ACE inhibitors or ARBs are precursor of proliferative diabetic not recommended for patients without hy- DIABETIC RETINOPATHY retinopathy), or any proliferative di- pertension to prevent the development of Recommendations abetic retinopathy to an ophthal- diabetic kidney disease. c Optimize glycemic control to reduce mologist who is knowledgeable and Two clinical trials studied the combina- the risk or slow the progression of experienced in the management of tions of ACE inhibitors and ARBs and found diabetic retinopathy. A diabetic retinopathy. A no benefits on CVD or diabetic kidney dis- c Optimize blood pressure and serum c Laser photocoagulation therapy is ease, and the drug combination had higher lipid control to reduce the risk or indicated to reduce the risk of vision adverse event rates (hyperkalemia and/or S92 Microvascular Complications and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017

Screening Type 2 Diabetes loss in patients with high-risk prolif- The preventive effects of therapy and Patients with type 2 diabetes who may erative diabetic retinopathy and, in the fact that patients with proliferative have had years of undiagnosed diabetes some cases, severe nonproliferative diabetic retinopathy (PDR) or macular and have a significant risk of prevalent diabetic retinopathy. A edema may be asymptomatic provide diabetic retinopathy at the time of di- c Intravitreal injections of anti–vascular strong support for screening to detect agnosis should have an initial dilated endothelial growth factor are indi- diabetic retinopathy. and comprehensive eye examination at cated for central-involved diabetic An ophthalmologist or optometrist the time of diagnosis. macular edema, which occurs be- who is knowledgeable and experienced neath the foveal center and may Pregnancy in diagnosing diabetic retinopathy should threaten reading vision. A Pregnancy is associated with a rapid perform the examinations. If diabetic reti- c The presence of retinopathy is progression of diabetic retinopathy nopathy is present, prompt referral to an not a contraindication to aspirin (64,65). Women with preexisting type 1 ophthalmologist is recommended. Subse- therapy for cardioprotection, as or type 2 diabetes who are planning preg- quent examinations for patients with aspirin does not increase the risk nancy or who have become pregnant type 1 or type 2 diabetes are generally re- of retinal hemorrhage. A should be counseled on the risk of devel- peated annually for patients with minimal opment and/or progression of diabetic Diabetic retinopathy is a highly specific to no retinopathy. Exams every 2 years retinopathy. In addition, rapid implemen- vascular complication of both type 1 maybecost-effectiveafteroneormore tation of intensive glycemic management and type 2 diabetes, with prevalence normal eye exams, and in a population in the setting of retinopathy is associated stronglyrelatedtoboththeduration with well-controlled type 2 diabetes, there with early worsening of retinopathy (58). of diabetes and the level of glycemic con- was essentially no risk of development of Women who develop gestational diabetes fi trol. Diabetic retinopathy is the most signi cant retinopathy with a 3-year inter- mellitus do not require eye examinations frequent cause of new cases of blind- val after a normal examination (59). More during pregnancy and do not appear to be ness among adults aged 20–74 years in frequent examinations by the ophthal- at increased risk of developing diabetic ret- developed countries. Glaucoma, cata- mologist will be required if retinopathy inopathy during pregnancy (66). racts, and other disorders of the eye oc- is progressing. cur earlier and more frequently in people Retinal photography with remote Treatment with diabetes. reading by experts has great potential Two of the main motivations for screen- In addition to diabetes duration, factors to provide screening services in areas ing for diabetic retinopathy are to pre- fi that increase the risk of, or are associated where quali ed eye care professionals vent loss of vision and to intervene with with, retinopathy include chronic hypergly- are not readily available (60,61). High- treatment when vision loss can be pre- cemia (49), nephropathy (50), hyperten- quality fundus photographs can detect vented or reversed. fi sion (51), and dyslipidemia (52). Intensive most clinically signi cant diabetic reti- Photocoagulation Surgery diabetes management with the goal of nopathy. Interpretation of the images Two large trials, the Diabetic Retinopa- achieving near-normoglycemia has been should be performed by a trained eye thy Study (DRS) in patients with PDR and shown in large prospective randomized care provider. Retinal photography may the Early Treatment Diabetic Retinopathy fi studies to prevent and/or delay the onset also enhance ef ciency and reduce costs Study (ETDRS) in patients with macular and progression of diabetic retinopathy when the expertise of ophthalmologists edema, provide the strongest support for and potentially improve patient-reported can be used for more complex examina- the therapeutic benefits of photocoagula- visual function (14,53–55). tions and for therapy (62). In-person ex- tion surgery. The DRS (67) showed that Lowering blood pressure has been ams are still necessary when the retinal panretinal photocoagulation surgery re- showntodecreaseretinopathyprogres- photos are of unacceptable quality and duced the risk of severe vision loss from sion, although tight targets (systolic blood for follow-up if abnormalities are de- PDR from 15.9% in untreated eyes to 6.4% pressure ,120 mmHg) do not impart ad- tected. Retinal photos are not a substitute in treated eyes with the greatest benefit ditional benefit (54). ACE inhibitors and for comprehensive eye exams, which ratiointhosewithmoreadvancedbase- ARBsarebotheffectivetreatmentsindi- should be performed at least initially line disease (disc neovascularization or abetic retinopathy (56). In patients with and at intervals thereafter as recom- vitreous hemorrhage). The ETDRS also dyslipidemia, retinopathy progression mended by an eye care professional. Re- verified the benefits of panretinal photo- may be slowed by the addition of fenofi- sults of eye examinations should be coagulation for high-risk PDR and in brate, particularly with very mild nonpro- documented and transmitted to the re- older-onset patients with severe NPDR liferative diabetic retinopathy (NPDR) at ferring health care professional. or less-than-high-risk PDR. Panretinal la- baseline (52). Several case series and a Type 1 Diabetes ser photocoagulation is still commonly controlled prospective study suggest that Because retinopathy is estimated to take used to manage complications of diabetic pregnancy in patients with type 1 diabetes at least 5 years to develop after the onset retinopathy that involve retinal neovascu- may aggravate retinopathy and threaten of hyperglycemia, patients with type 1 di- larization and its complications. vision, especially when glycemic control is abetes should have an initial dilated and Anti–Vascular Endothelial Growth Factor poor at the time of conception (57,58). comprehensive eye examination within Treatment Laser photocoagulation surgery can mini- 5 years after the diagnosis of diabetes While the ETDRS (68) established the mize the risk of vision loss (58). (63). benefit of focal laser photocoagulation care.diabetesjournals.org Microvascular Complications and Foot Care S93

surgery in eyes with clinically significant Diagnosis c Symptoms and signs of autonomic macular edema (defined as retinal Diabetic Peripheral Neuropathy neuropathy should be assessed in edema located at or within 500 mmof Patients with type 1 diabetes for 5 or patients with microvascular and the center of the macula), current data more years and all patients with type 2 neuropathic complications. E from well-designed clinical trials dem- diabetes should be assessed annually onstrate that intravitreal anti–vascular Treatment for DPN using the medical history and endothelial growth factor (anti-VEGF) c Optimize glucose control to pre- simple clinical tests. Symptoms vary agents provide a more effective treat- vent or delay the development of according to the class of sensory fibers ment regimen for central-involved dia- neuropathy in patients with type 1 involved. The most common early symp- betic macular edema than monotherapy diabetes A andtoslowthepro- toms are induced by the involvement of or even combination therapy with laser gression of neuropathy in patients small fibers and include pain and dyses- (69–71). with type 2 diabetes. B thesias (unpleasant sensations of burning In both trials, laser photocoagula- c Assess and treat patients to reduce and tingling). The involvement of large tion surgery was beneficial in reducing pain related to diabetic peripheral fibers may cause numbness and loss of the risk of further visual loss in af- neuropathy B and symptoms of au- protective sensation (LOPS). LOPS indi- fected patients but generally not ben- tonomic neuropathy and to improve cates the presence of distal sensorimotor eficial in reversing already diminished quality of life. E polyneuropathy and is a risk factor for acuity. Now, anti-VEGF improves vi- c Either pregabalin or duloxetine are diabetic foot ulceration. The following sion and has replaced the need for recommended as initial pharmaco- clinical tests may be used to assess small- laser photocoagulation in the vast ma- logic treatments for neuropathic and large-fiber function and protective jority of patients with diabetic macular pain in diabetes. A sensation: edema in most cases (72). Most patients require near-monthly adminis- The diabetic neuropathies are a hetero- 1. Small-fiber function: pinprick and tration of intravitreal therapy with geneous group of disorders with diverse temperature sensation fi anti-VEGF agents during the rst clinical manifestations. The early recog- 2. Large-fiber function: vibration per- 12 months of treatment with fewer in- nition and appropriate management of ception, 10-g monofilament, and an- jections needed in subsequent years neuropathy in the patient with diabetes kle reflexes to maintain remission from central- is important. 3. Protective sensation: 10-g monofilament involved diabetic macular edema. In- travitreous anti-VEGF therapy is also a 1. Diabetic neuropathy is a diagnosis of These tests not only screen for the pres- potentially viable alternative treat- exclusion. Nondiabetic neuropathies ence of dysfunction but also predict ment for PDR (73). Other emerging may be present in patients with di- future risk of complications. Electrophysi- therapies for retinopathy that may abetes and may be treatable. ological testing or referral to a neurologist use sustained intravitreal delivery of 2. Numerous treatment options exist is rarely needed, except in situations pharmacologic agents are currently for symptomatic diabetic neuropathy. where the clinical features are atypical or under investigation. 3. Up to 50% of diabetic peripheral neu- the diagnosis is unclear. ropathy (DPN) may be asymptomatic. If In all patients with diabetes and DPN, not recognized and if preventive foot causes of neuropathy other than diabetes NEUROPATHY care is not implemented, patients are should be considered, including toxins Recommendations at risk for injuries to their insensate (alcohol), neurotoxic medications (chemo- feet. Screening therapy), vitamin B12 deficiency, hypo- 4. Recognition and treatment of auto- c All patients should be assessed thyroidism, renal disease, malignancies for diabetic peripheral neu- nomic neuropathy may improve symp- (multiple myeloma, bronchogenic carci- ropathy starting at diagnosis of toms, reduce sequelae, and improve noma), infections (HIV), chronic inflamma- quality of life. type 2 diabetes and 5 years af- tory demyelinating neuropathy, inherited ter the diagnosis of type 1 dia- neuropathies, and vasculitis (77). Specific treatment for the underlying betes and at least annually nerve damage, other than improved gly- Diabetic Autonomic Neuropathy thereafter. B cemic control, is currently not available. The symptoms and signs of autonomic c Assessment for distal symmetric Glycemic control can effectively prevent neuropathy should be elicited carefully polyneuropathy should include DPN and cardiac autonomic neuropathy during the history and physical examina- a careful history and assessment (CAN) in type 1 diabetes (74,75) and may tion. Major clinical manifestations of di- of either temperature or pinprick modestly slow their progression in abetic autonomic neuropathy include sensation (small-fiber function) type 2 diabetes (16) but does not hypoglycemia unawareness, resting and vibration sensation using a reverse neuronal loss. Therapeutic strat- tachycardia, orthostatic hypotension, 128-Hz tuning fork (for large-fiber egies (pharmacologic and nonpharma- gastroparesis, constipation, diarrhea, function). All patients should have cologic) for the relief of painful DPN fecal incontinence, erectile dysfunction, annual 10-g monofilament testing and symptoms of autonomic neuropa- neurogenic bladder, and sudomotor dys- to identify feet at risk for ulcera- thy can potentially reduce pain (76) function with either increased or de- tion and amputation. B and improve quality of life. creased sweating. S94 Microvascular Complications and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017

Cardiac Autonomic Neuropathy Treatment 50% improvement in pain (88,90,92–95). CAN is associated with mortality inde- Glycemic Control However, not all trials with pregabalin pendently of other cardiovascular risk Near-normal glycemic control, imple- have been positive (88,90,96,97), es- factors (78,79). In its early stages, CAN mented early in the course of diabetes, pecially when treating patients with may be completely asymptomatic and has been shown to effectively delay or advanced refractory DPN (94). Adverse detected only by decreased heart rate prevent the development of DPN and effects may be more severe in older pa- variability with deep breathing. Ad- CAN in patients with type 1 diabetes tients (98) and may be attenuated by vanced disease may be associated with (81–84). Although the evidence for the lower starting doses and more gradual resting tachycardia (.100 bpm) and or- benefit of near-normal glycemic control titration. thostatic hypotension (a fall in systolic is not as strong for type 2 diabetes, some Duloxetine is a selective norepineph- or diastolic blood pressure by .20 mmHg studies have demonstrated a modest rine and serotonin reuptake inhibitor. . or 10 mmHg, respectively, upon stand- slowing of progression without reversal Doses of 60 and 120 mg/day showed ing without an appropriate increase in of neuronal loss (16,85). Specificglucose- efficacy in the treatment of pain associ- heart rate). CAN treatment is generally lowering strategies may have different ated with DPN in multicenter random- focused on alleviating symptoms. effects. In a post hoc analysis, partici- ized trials, although some of these had Gastrointestinal Neuropathies pants, particularly men, in the Bypass An- high drop-out rates (88,90,95,97). Duloxe- Gastrointestinal neuropathies may in- gioplasty Revascularization Investigation tine also appeared to improve neuropathy- volve any portion of the gastrointestinal in Type 2 Diabetes (BARI 2D) trial treated related quality of life (99). In longer-term tract with manifestations including with insulin sensitizers had a lower inci- studies, a small increase in A1C was esophageal dysmotility, gastroparesis, dence of distal symmetric polyneurop- reported in people with diabetes treat- constipation, diarrhea, and fecal inconti- athy over 4 years than those treated ed with duloxetine compared with pla- nence. Gastroparesis should be suspected with insulin/sulfonylurea (86). cebo (100). Adverse events may be more in individuals with erratic glycemic control Neuropathic Pain severe in older people, but may be at- or with upper gastrointestinal symptoms Neuropathic pain can be severe and can tenuated with lower doses and slower without another identified cause. Exclu- impact quality of life, limit mobility, and titrations of duloxetine. sion of organic causes of gastric outlet ob- contribute to depression and social dys- Tapentadol is a centrally acting opioid struction or peptic ulcer disease (with function (87). No compelling evidence analgesic that exerts its analgesic effects esophagogastroduodenoscopy or a bar- exists in support of glycemic control or through both m-opioid receptor ago- ium study of the stomach) is needed lifestyle management as therapies for nism and noradrenaline reuptake inhibi- before considering a diagnosis of or spe- neuropathic pain in diabetes or predia- tion. Extended-release tapentadol was cialized testing for gastroparesis. The di- betes, which leaves only pharmaceutical approved by the FDA for the treatment agnostic gold standard for gastroparesis interventions. of neuropathic pain associated with is the measurement of gastric emptying Pregabalin and duloxetine have re- diabetes based on data from two mul- with scintigraphy of digestible solids at ceived regulatory approval by the FDA, ticenter clinical trials in which partici- 15-min intervals for 4 h after food intake. Health Canada, and the European Med- pants titrated to an optimal dose of 13 The use of Coctanoicacidbreathtest icines Agency for the treatment of neu- tapentadol were randomly assigned to is emerging as a viable alternative. ropathic pain in diabetes. The opioid continue that dose or switch to placebo (101,102). However, both used a design Genitourinary Disturbances tapentadol has regulatory approval in Diabetic autonomic neuropathy may the U.S. and Canada, but the evidence enriched for patients who responded to also cause genitourinary disturbances, of its use is weaker (88). Comparative tapentadol and therefore their results including sexual dysfunction and blad- effectiveness studies and trials that in- are not generalizable. A recent system- der dysfunction. In men, diabetic auto- clude quality-of-life outcomes are rare, atic review and meta-analysis by the nomic neuropathy may cause erectile so treatment decisions must consider Special Interest Group on Neuropathic dysfunction and/or retrograde ejacula- each patient’s presentation and comor- Pain of the International Association tion (76). Female sexual dysfunction bidities and often follow a trial-and-error for the Study of Pain found the evidence occurs more frequently in those with approach. Given the range of partially ef- supporting the effectiveness of tapenta- diabetes and presents as decreased sex- fective treatment options, a tailored and dol in reducing neuropathic pain to be ual desire, increased pain during inter- stepwise pharmacologic strategy with inconclusive (88). Therefore, given the course, decreased sexual arousal, and careful attention to relative symptom im- high risk for addiction and safety concerns inadequate lubrication (80). Lower uri- provement, medication adherence, and compared with the relatively modest nary tract symptoms manifest as urinary medication side effects is recommended pain reduction, the use of tapentadol ER incontinence and bladder dysfunction to achieve pain reduction and improve is not generally recommended as a first- (nocturia, frequent urination, urination quality of life (89–91). or second-line therapy. urgency, and weak urinary stream). Pregabalin, a calcium channel a2-d Tricyclic antidepressants, gabapentin, Evaluation of bladder function should subunit ligand, is the most extensively venlafaxine, carbamazepine, tramadol, be performed for individuals with diabe- studied drug for DPN. The majority and topical capsaicin, although not ap- tes who have recurrent urinary tract in- of studies testing pregabalin have proved for the treatment of painful DPN, fections, pyelonephritis, incontinence, reported favorable effects on the pro- may be effective and considered for the or a palpable bladder. portion of participants with at least 30– treatment of painful DPN (76,88,90). care.diabetesjournals.org Microvascular Complications and Foot Care S95

Orthostatic Hypotension and treatment of patients with diabe- risk factors for ulcers and amputa- Treating orthostatic hypotension is chal- tes and feet at risk for ulcers and am- tions. B lenging. The therapeutic goal is to minimize putations can delay or prevent adverse c All patients with diabetes should postural symptoms rather than to restore outcomes. have their feet inspected at every normotension. Most patients require both The risk of ulcers or amputations is visit. C nonpharmacologic measures (e.g., ensuring increasedinpeoplewhohavethefol- c Obtain a prior history of ulcera- adequate salt intake, avoiding medications lowing risk factors: that aggravate hypotension, or using com- tion, amputation, Charcot foot, angioplasty or vascular surgery, pressive garments over the legs and ab- ○ Poor glycemic control cigarette smoking, retinopathy, domen) and pharmacologic measures. ○ Peripheral neuropathy with LOPS and renal disease and assess cur- Physical activity and exercise should be en- ○ Cigarette smoking rent symptoms of neuropathy couraged to avoid deconditioning, which is ○ Foot deformities (pain, burning, numbness) and known to exacerbate orthostatic intoler- ○ Preulcerative callus or corn vascular disease (leg fatigue, ance, and volume repletion with fluids ○ PAD and salt is critical. Midodrine and droxidopa claudication). B ○ History of foot ulcer c are approved by the FDA for the treatment The examination should include in- ○ Amputation of orthostatic hypotension. spection of the skin, assessment of ○ Visual impairment foot deformities, neurological assess- ○ Diabetic nephropathy (especially pa- Gastroparesis ment (10-g monofilament testing Treatment for diabetic gastroparesis may be tients on dialysis) with at least one other assessment: very challenging. Dietary changes may be pinprick, temperature, vibration, or useful, such as eating multiple small meals Clinicians are encouraged to review ankle reflexes), and vascular assess- and decreasing dietary fat and fiber intake. American Diabetes Association screen- ment including pulses in the legs Withdrawing drugs with adverse effects on ing recommendations for further details and feet. B gastrointestinal motility including opioids, and practical descriptions of how to per- c Patients who are 50 years or older anticholinergics, tricyclic antidepressants, form components of the comprehensive and any patients with symptoms glucagon-like peptide 1 receptor agonists, foot examination (105). of claudication or decreased and/or pramlintide, and possibly dipeptidyl pepti- absent pedal pulses should be re- dase 4 inhibitors, may also improve intestinal Evaluation for Loss of Protective motility (103,104). In cases of severe gastro- ferred for further vascular assess- Sensation paresis, pharmacologic interventions are ment as appropriate. C All adults with diabetes should undergo c needed. Only metoclopramide, a prokinetic A multidisciplinary approach is rec- a comprehensive foot evaluation at agent, is approved by the FDA for the treat- ommended for individuals with least annually. Detailed foot assessment of gastroparesis. However, the level of foot ulcers and high-risk feet ments may occur more frequently in evidence regarding the benefits of metoclo- (e.g., dialysis patients and those patientswithhistoriesofulcersoram- pramide for the management of gastro- with Charcot foot, prior ulcers, or putations, foot deformities, insensate paresisisweak,andgiventheriskforserious amputation). B feet, and PAD (106). Foot inspections c adverse effects (extrapyramidal signs such as Refer patients who smoke or should occur at every visit in all patients acute dystonic reactions, drug-induced par- who have histories of prior lower- with diabetes. To assess risk, clinicians kinsonism, akathisia, and tardive dyskinesia), extremity complications, loss of should ask about history of foot ulcers its use in the treatment of gastroparesis be- protective sensation, structural ab- or amputation, neuropathic and periph- yond 5 days is no longer recommended by normalities, or peripheral arterial eral vascular symptoms, impaired vision, the FDA or the European Medicines Agency. disease to foot care specialists for renal disease, tobacco use, and foot care It should be reserved for severe cases that ongoing preventive care and life- practices. A general inspection of skin in- are unresponsive to other therapies (104). long surveillance. C tegrity and musculoskeletal deformities c Provide general preventive foot should be performed. Vascular assess- Erectile Dysfunction self-care education to all patients ment should include inspection and pal- Treatments for erectile dysfunction may with diabetes. B pation of pedal pulses. include phosphodiesterase type 5 inhibitors, c The use specialized therapeutic foot- The neurological exam performed as intracorporeal or intraurethral prostaglan- wear is recommended for high-risk part of the foot examination is designed dins, vacuum devices, or penile prostheses. patients with diabetes including to identify LOPS rather than early neu- As with DPN treatments, these interventions those with severe neuropathy, foot ropathy. The 10-g monofilament is the do not change the underlying pathology and deformities, or history of amputa- most useful test to diagnose LOPS. Ide- natural history of the disease process but tion. B ally, the 10-g monofilament test should ’ may improve the patient s quality of life. be performed with at least one other Foot ulcers and amputation, which are assessment (pinprick, temperature or vi- FOOT CARE consequences of diabetic neuropathy bration sensation using a 128-Hz tuning and/or peripheral arterial disease fork, or ankle reflexes). Absent monofila- Recommendations (PAD), are common and represent major ment sensation suggests LOPS, while at c Perform a comprehensive foot eval- causes of morbidity and mortality in least two normal tests (and no abnormal uation at least annually to identify people with diabetes. Early recognition test) rules out LOPS. S96 Microvascular Complications and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017

Evaluation for Peripheral Arterial neuroarthropathy is the best way to pre- 8. Molitch ME, Steffes M, Sun W, et al. Devel- Disease vent deformities that increase the risk of opment and progression of renal insufficiency Initial screening for PAD should include a ulceration and amputation. The routine with and without albuminuria in adults with type 1 diabetes in the Diabetes Control and history of decreased walking speed, leg prescription of therapeutic footwear is Complications Trial and the Epidemiology of Di- fatigue, claudication, and an assessment not generally recommended. However, abetes Interventions and Complications study. of the pedal pulses. Ankle-brachial index patients should be provided adequate in- Diabetes Care 2010;33:1536–1543 testing should be performed in patients formation to aid in selection of appropriate 9. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic with symptoms or signs of PAD. footwear. General footwear recommenda- retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal dis- tions include a broad and square toe box, Patient Education ease: a meta-analysis. Diabetologia 2013;56: laces with three or four eyes per side, pad- – All patients with diabetes and particu- 457 466 ded tongue, quality lightweight materials, 10. de Boer IH, Gao X, Cleary PA, Bebu I, Lachin larly those with high-risk foot conditions and sufficient size to accommodate a cush- JM, Molitch ME, et al. Albuminuria changes and (history of ulcer or amputation, defor- ioned insole. Use of custom therapeutic cardiovascular and renal outcomes in type 1 di- mity, LOPS, or PAD) and their families abetes: the DCCT/EDIC study. Clin J Am Soc footwear can help reduce the risk of future should be provided general education Nephrol 2016;11:1969–1977 foot ulcers in high-risk patients (106,108). about risk factors and appropriate man- 11. DCCT/EDIC Research Group. Effect of inten- Most diabetic foot infections are poly- sive diabetes treatment on albuminuria in agement (107). Patients at risk should microbial, with aerobic gram-positive type 1 diabetes: long-term follow-up of the Di- understand the implications of foot de- cocci. Staphylococci and Streptococci abetes Control and Complications Trial and formities, LOPS, and PAD; the proper Epidemiology of Diabetes Interventions and are the most common causative organ- care of the foot, including nail and skin Complications study. Lancet Diabetes Endocri- isms. Wounds without evidence of soft- – care; and the importance of foot moni- nol 2014;2:793 800 tissue or bone infection do not require 12. DCCT/EDIC Research Group, de Boer IH, Sun toring on a daily basis. Patients with antibiotic therapy. Empiric antibiotic W, et al. Intensive diabetes therapy and glomer- LOPS should be educated on ways to fi therapy can be narrowly targeted at ular ltration rate in type 1 diabetes. N Engl J substitute other sensory modalities Med 2011;365:2366–2376 gram-positive cocci in many patients (palpation or visual inspection using an 13. UK Prospective Diabetes Study (UKPDS) with acute infections, but those at risk unbreakable mirror) for surveillance of Group. Effect of intensive blood-glucose control for infection with antibiotic-resistant with metformin on complications in overweight early foot problems. organisms or with chronic, previously patients with type 2 diabetes (UKPDS 34). Lan- The selection of appropriate footwear – treated, or severe infections require cet 1998;352:854 865 and footwear behaviors at home should 14. UK Prospective Diabetes Study (UKPDS) broader-spectrum regimens and should also be discussed. Patients’ understand- Group. Intensive blood-glucose control with sul- be referred to specialized care centers ing of these issues and their physical phonylureas or insulin compared with conven- (109). Foot ulcers and wound care may tional treatment and risk of complications in ability to conduct proper foot surveillance require care by a podiatrist, orthopedic patients with type 2 diabetes (UKPDS 33). Lan- and care should be assessed. Patients with – or vascular surgeon, or rehabilitation spe- cet 1998;352:837 853 visual difficulties, physical constraints pre- 15. ADVANCE Collaborative Group, Patel A, cialist experienced in the management venting movement, or cognitive problems MacMahon S, et al. Intensive blood glucose con- of individuals with diabetes (109). that impair their ability to assess the control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560– dition of the foot and to institute appro- References 2572 priate responses will need other people, 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic 16. 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Re- glycemia, blood pressure, and the 9-year inci- nary Artery Risk Development in Young Adults noprotective effect of the angiotensin-receptor dence of diabetic retinopathy: the Barbados Eye (CARDIA) Study. Diabetes 2007;56:2990–2996 antagonist irbesartan in patients with nephropa- Studies. Ophthalmology 2005;112:799–805 67. The Diabetic Retinopathy Study Research thy due to type 2 diabetes. N Engl J Med 2001; 52. Chew EY, Davis MD, Danis RP, et al. The Group. Preliminary report on effects of photo- 345:851–860 effects of medical management on the progres- coagulation therapy. Am J Ophthalmol 1976;81: 36. National Kidney Foundation. KDIGO clinical sion of diabetic retinopathy in persons with 383–396 practice guideline for the management of blood type 2 diabetes: the Action to Control Cardio- 68. Early Treatment Diabetic Retinopathy pressure in chronic kidney disease. Kidney Int vascular Risk in Diabetes (ACCORD) Eye Study. Study Research Group. 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diabetic macular edema. Ophthalmology 2010; diabetes during the Epidemiology of Diabetes and active-controlled study of T-type calcium 117:1064–1077.e35 Interventions and Complications (EDIC) Study. channel blocker ABT-639 in patients with diabetic 70. Mitchell P, Bandello F, Schmidt-Erfurth U, Diabetes Care 2010;33:1090–1096 peripheral neuropathic pain. Pain 2015;156: et al. The RESTORE study: ranibizumab mono- 84. Pop-Busui R, Low PA, Waberski BH, et al. 2013–2020 therapy or combined with laser versus laser Effects of prior intensive insulin therapy on car- 97. Quilici S, Chancellor J, Lothgren¨ M, et al. monotherapy for diabetic macular edema. Oph- diac autonomic nervous system function in Meta-analysis of duloxetine vs. pregabalin and thalmology 2011;118:615–625 type 1 diabetes mellitus: The Diabetes Control gabapentin in the treatment of diabetic periph- 71. Elman MJ, Bressler NM, Qin H, et al. Ex- and Complications Trial/Epidemiology of Dia- eral neuropathic pain. BMC Neurol 2009;9:6 panded 2-year follow-up of ranibizumab plus betes Interventions and Complications Study 98. Dworkin RH, Jensen MP, Gammaitoni AR, prompt or deferred laser or triamcinolone plus (DCCT/EDIC). Circulation 2009;119:2886–2893 Olaleye DO, Galer BS. Symptom profiles differ in prompt laser for diabetic macular edema. Oph- 85. Callaghan BC, Little AA, Feldman EL, Hughes patients with neuropathic versus non-neuropathic thalmology 2011;118:609–614 RAC. Enhanced glucose control for preventing pain. J Pain 2007;8:118–126 72. Nguyen QD, Brown DM, Marcus DM, et al. and treating diabetic neuropathy. Cochrane 99. Wernicke JF, Pritchett YL, D’Souza DN, et al. Ranibizumab for diabetic macular edema: re- Database Syst Rev 2012;6:CD007543 A randomized controlled trial of duloxetine in sults from 2 phase III randomized trials: RISE 86. Pop-Busui R, Lu J, Brooks MM, et al. Impact diabetic peripheral neuropathic pain. Neurol- and RIDE. 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Neuropathy and related Pharmacotherapy for neuropathic pain in randomized withdrawal, placebo-controlled findings in the Diabetes Control and Complica- adults: a systematic review and meta-analysis. study evaluating the efficacy and tolerability tions Trial/Epidemiology of Diabetes Interven- Lancet Neurol 2015;14:162–173 of tapentadol extended release in patients tions and Complications study. Diabetes Care 89. Bril V, England J, Franklin GM, et al. Evidence- with chronic painful diabetic peripheral neurop- 2014;37:31–38 based guideline: treatment of painful diabetic athy. Diabetes Care 2014;37:2302–2309 76. Pop-Busui R, Boulton AJM, Feldman EL, neuropathy: report of the American Academy of 103. Camilleri M, Parkman HP, Shafi MA, Abell et al. Diabetic neuropathy: a position statement Neurology, the American Association of Neuro- TL, Gerson L; American College of Gastroenter- by the American Diabetes Association. Diabetes muscular and Electrodiagnostic Medicine, and ology. Clinical guideline: management of gastro- Care 2017;40:136–154 the American Academy of Physical Medicine and paresis. Am J Gastroenterol 2013;108:18–37; 77. Freeman R. Not all neuropathy in diabetes is of Rehabilitation. Neurology 2011;76:1758–1765 quiz 38 diabetic etiology: differential diagnosis of diabetic 90. Griebeler ML, Morey-Vargas OL, Brito JP, 104. McCall AL. Hypoglycemia in diabetes. In neuropathy. Curr Diab Rep 2009;9:423–431 et al. Pharmacologic interventions for painful Therapy for Diabetes Mellitus and Related Dis- 78. Pop-Busui R, Evans GW, Gerstein HC, et al. diabetic neuropathy: an umbrella systematic re- orders. 6th ed. Umpierrez GE, Ed. Alexandria, Effects of cardiac autonomic dysfunction on view and comparative effectiveness network VA, American Diabetes Association, 2014, p. 704 mortality risk in the Action to Control Cardio- meta-analysis. Ann Intern Med 2014;161:639– 105. Boulton AJM, Armstrong DG, Albert SF, vascular Risk in Diabetes (ACCORD) trial. 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11. Older Adults American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S99–S104 | DOI: 10.2337/dc17-S014

Recommendations c Consider the assessment of medical, mental, functional, and social geriatric domains in older adults to provide a framework to determine targets and therapeutic approaches for diabetes management. C 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 and be related to health-related quality of life. C c Annual screening for early detection of mild cognitive impairment or dementia is indicated for adults 65 years of age or older. B c Older adults ($65 years of age) with diabetes should be considered a high- 1 LE ADULTS OLDER 11. priority population for depression screening and treatment. B c Hypoglycemia should be avoided in older adults with diabetes. It should be assessed and managed by adjusting glycemic targets and pharmacologic interventions. B c Older adults who are cognitively and functionally intact and have significant life expectancy may receive diabetes care with goals similar to those developed for younger adults. C 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. C c Screening for diabetes complications should be individualized in older adults. Particular attention should be paid to complications that would lead to functional impairment. C c Treatment of hypertension to individualized target levels is indicated in most older adults. C c Treatment of other cardiovascular risk factors should be individualized in older adults considering the time frame of benefit. Lipid-lowering therapy and aspirin therapy may benefit those with life expectancies at least equal to the time frame of primary prevention or secondary intervention 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 glycemic goals 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 Suggested citation: American Diabetes Asso- Diabetes is an important health condition for the aging population; approximately ciation. Older adults. Sec. 11. In Standards of one-quarter of people over the age of 65 years have diabetes (1), and this pro- Medical Care in Diabetesd2017. Diabetes Care portion is expected to increase rapidly in the coming decades. Older individuals with 2017;40(Suppl. 1):S99–S104 diabetes have higher rates of premature death, functional disability, and coexisting © 2017 by the American Diabetes Association. illnesses, such as hypertension, coronary heart disease, and stroke, than those Readers may use this article as long as the work is properly cited, the use is educational and not without diabetes. Older adults with diabetes also are at greater risk than other for profit, and the work is not altered. More infor- older adults for several common geriatric syndromes, such as polypharmacy, cog- mation is available at http://www.diabetesjournals nitive impairment, urinary incontinence, injurious falls, and persistent pain. .org/content/license. S100 Older Adults Diabetes Care Volume 40, Supplement 1, January 2017

Screening for diabetes complications in simplify drug regimens and to involve older adults for cognitive dysfunction older adults should be individualized and caregivers in all aspects of care. and discuss findings with the patients periodically revisited, as the results of Poor glycemic control is associated and their caregivers. Hypoglycemic screening tests may impact therapeutic with a decline in cognitive function events should be diligently monitored approaches and targets. Older adults are (11), and longer duration of diabetes and avoided, whereas glycemic targets at increased risk for depression and worsens cognitive function. There are and pharmacologic interventions may should therefore be screened and treat- ongoing studies evaluating whether pre- need to be adjusted to accommodate ed accordingly (2). Diabetes manage- venting or delaying diabetes onset may for the changing needs of the older ment may require assessment of help to maintain cognitive function in adult (3). medical, mental, functional, and social older adults. However, studies examining domains. This may provide a framework the effects of intensive glycemic and TREATMENT GOALS fi to determine targets and therapeutic blood pressure control to achieve speci c Rationale approaches. Particular attention should targets have not demonstrated a reduc- The care of older adults with diabetes is be paid to complications that can de- tion in brain function decline (12). complicated by their clinical, mental, velop over short periods of time and/or Older adults with diabetes should be and functional heterogeneity. Some that would significantly impair functional carefully screened and monitored for older individuals may have developed status, such as visual and lower-extremity cognitive impairment (3). Several orga- diabetes years earlier and have signifi- complications. Please refer to the Amer- nizations have released simple assess- cant complications, others are newly di- ican Diabetes Association (ADA) con- ment tools, such as the Mini-Mental agnosed and may have had years of sensus report “Diabetes in Older Adults” State Examination (13) and the Mon- undiagnosed diabetes with resultant for details (3). treal Cognitive Assessment (14), which complications, and still other older may help to identify patients requiring adults may have truly recent-onset dis- neuropsychological evaluation, particu- ease with few or no complications (18). NEUROCOGNITIVE FUNCTION larly those in whom dementia is sus- Some older adults with diabetes have Older adults with diabetes are at higher pected (i.e., experiencing memory loss other underlying chronic conditions, risk of cognitive decline and institution- and decline in their basic and instru- substantial diabetes-related comorbid- alization (4,5). The presentation of cog- mental activities of daily living). Annual ity, limited cognitive or physical func- nitive impairment ranges from subtle screening for cognitive impairment is tioning, or frailty (19,20). Other older executive dysfunction to memory loss indicated for adults 65 years of age or individuals with diabetes have little co- and overt dementia. People with diabe- older for early detection of mild cogni- morbidity and are active. Life expectan- tes have higher incidences of all-cause tive impairment or dementia (15). Peo- ciesarehighlyvariablebutareoften dementia, Alzheimer disease, and vas- ple who screen positive for cognitive longer than clinicians realize. Providers cular dementia than people with normal impairment should receive diagnostic caring for older adults with diabetes glucose tolerance (6). The effects of hy- assessment as appropriate, including must take this heterogeneity into consid- perglycemia and hyperinsulinemia on referral to a behavioral health provider eration when setting and prioritizing the brain are areas of intense research. for formal cognitive/neuropsychological treatment goals (21) (Table 11.1). In ad- Clinical trials of specific interventionsd evaluation (16). dition, older adults with diabetes should including cholinesterase inhibitors and be assessed for disease treatment and glutamatergic antagonistsdhave not HYPOGLYCEMIA self-management knowledge, health lit- shown positive therapeutic benefitin It is important to prevent hypoglycemia eracy, and mathematical literacy (nu- maintaining or significantly improving to reduce the risk of cognitive decline meracy) at the onset of treatment. cognitive function or in preventing cog- (17) and other major adverse outcomes. nitive decline (7). Recent pilot studies in It is also important to carefully assess Healthy Patients With Good patients with mild cognitive impairment and reassess patients’ risk for worsening Functional Status evaluating the potential benefits of in- of glycemic control and functional de- There are few long-term studies in older tranasal insulin therapy and metformin cline. Older adults are at higher risk of adults demonstrating the benefits of in- therapy provide insights for future clini- hypoglycemia for many reasons, includ- tensive glycemic, blood pressure, and cal trials and mechanistic studies (8–10). ing insulin deficiency necessitating in- lipid control. Patients who can be ex- The presence of cognitive impairment sulin therapy and progressive renal pected to live long enough to reap the can make it challenging for clinicians to insufficiency. In addition, older adults benefits of long-term intensive diabetes help their patients to reach individual- tend to have higher rates of unidentified management, who have good cognitive ized glycemic, blood pressure, and lipid cognitive deficits, causing difficulty in and physical function, and who choose targets. Cognitive dysfunction makes it complex self-care activities (e.g., glu- to do so via shared decision making may difficult for patients to perform complex cose monitoring, adjusting insulin be treated using therapeutic interven- self-care tasks, such as glucose monitor- doses, etc.). These cognitive deficits tions and goals similar to those for ing and adjusting insulin doses. It also have been associated with increased younger adults with diabetes. As with hinders their ability to appropriately risk of hypoglycemia, and, conversely, all patients with diabetes, diabetes self- maintain the timing and content of severe hypoglycemia has been linked management education and ongoing diet. When clinicians are managing to increased risk of dementia. There- diabetes self-management support are these types of patients, it is critical to fore, it is important to routinely screen vital components of diabetes care care.diabetesjournals.org Older Adults S101 .%(9mo/o)aentrcmedda hymyeps ainst oefeun ihrguoevle n h ct ik rmgyoui,dehydra glycosuria, from risks acute the and values glucose higher frequent more to patients expose may they healing. as wound recommended poor not and are mmol/mol) signi (69 and 8.5% status functional of impairment hoi lns,sc ssae3 stage as such illness, chronic ttsRtoaeRaoal 1 goal A1C Reasonable Rationale status characteristics/health Patient 11.1 Table elh fwceitn chronic coexisting (few Healthy ope/nemdae(multiple Complex/intermediate eycmlxpo elh(T or (LTC health complex/poor Very hoi lnse r odtossroseog orqiemdctoso ietl aaeetadmyicueatrts acr ogsiehear congestive cancer, arthritis, include i may By treatment and stroke. of management and aspect infarction, lifestyle myocardial important or disease, an medications kidney is chronic require worse preferences to or 3 caregiver enough stage and serious incontinence, living. patient conditions daily of of are Consideration activities diabetes illnesses with ADL, category. chronic adults time. older particular over in a change dyslipidemia and into may pressure, fall preferences blood clearly glycemia, for will goals patient treatment considering every for framework consensus a represents This for older adults and their caregivers. ucinlstatus) functional and cognitive intact illnesses, impairment) cognitive moderate mild-to- or impairments r2 or illnesses* chronic coexisting 2 or impairment cognitive moderate-to-severe or illnesses** chronic end-stage

1 Self-management knowledge and skills D dependencies) ADL 1 should be reassessed when regimen changes ntuetlADL instrumental aremadeoranindividual’s functional —

rmwr o osdrn ramn ol o lcma lo rsue n ylpdmai le dlswt diabetes with adults older in dyslipidemia and pressure, blood glycemia, for goals treatment considering for Framework abilities diminish. In addition, declining or impaired ability to perform diabetes self-care behaviors may be an indication for referral of older adults with diabetes for cognitive and physical functional as- –

ogsiehatfiueo xgndpnetln ies,crnckde ies eurn ilss rucnrle eattccne,myca may cancer, metastatic uncontrolled or dialysis, requiring disease kidney chronic disease, lung oxygen-dependent or failure heart congestive 4 sessment using age-normalized evaluation tools (16,22). ogrrmiiglife remaining Longer nemdaeremaining Intermediate iie eann life remaining Limited expectancy unrblt,fl risk fall vulnerability, hypoglycemia burden, treatment high expectancy, life bene makes expectancy

ﬁ Patients With Complications and atyrdc ieexpectancy. life reduce cantly

ﬁ Reduced Functionality uncertain t Forpatientswithadvanceddiabetes complications, life-limiting comorbid illnesses, or substantial cognitive or functional impairments, it is reasonable to set less intensive glycemic goals. These ‡

oe 1 olmyb e o nidvda faheal ihu eurn rsvr yolcmao nu ramn udn *Coexisting burden. treatment undue or hypoglycemia severe or recurrent without achievable if individual an for set be may goal A1C lower A ﬁ

, patients are less likely to bene tfrom , , 8.5% .%(8mo/o)90 mmol/mol) (58 7.5% .%(4mo/o)90 mmol/mol) (64 8.0% reducing the risk of microvascular com- †

† plications and more likely to suffer seri- 1 f85 6 mlml qae oa siae vrg lcs of glucose average estimated an to equates mmol/mol) (69 8.5% of A1C 6 mlml 100 mmol/mol) (69 ous adverse effects from hypoglycemia. However, patients with poorly controlled diabetes may be subject to acute complications of diabetes, including de- ‡ “

multiple, hydration, poor wound healing, and hyperglycemic hyperosmolar coma. atn rpreprandial or Fasting

(5.6 Glycemic goals at a minimum should (5.0 (5.0 ” ema tlattre u ayptet a have may patients many but three, least at mean we

– avoid these consequences. – – – – 00mmol/L) 10.0 – lcs etm lcs lo rsueLipids pressure Blood glucose Bedtime glucose . mmol/L) 8.3 . mmol/L) 7.2 3 mg/dL 130 5 mg/dL 150 8 mg/dL 180 Vulnerable Patients at the End of Life For patients receiving palliative care and end-of-life care, the focus should be to avoid symptoms and complications from glycemic management. Thus, when organ failure develops, several (5.6 (6.1 (5.0 100 110 agents will have to be titrated or discon- 90 – – – – 00mmol/L) 10.0 11mmol/L) 11.1 tinued. For the dying patient, most – – . mmol/L) 8.3 5 mg/dL 150 8 mg/dL 180 0 mg/dL 200 agents for type 2 diabetes may be re- moved. There is, however, no consensus for the management of type 1 diabetes h ain hrceitcctgre r eea ocps Not concepts. general are categories characteristic patient The . dvdaiain diinly patient a Additionally, ndividualization.

alr,dpeso,epyea al,hypertension, falls, emphysema, depression, failure, t in this scenario (23,24). ; 0 gd 1. mlL.Loe 1 agt above targets A1C Looser mmol/L). (11.1 mg/dL 200 Beyond Glycemic Control ﬁ , , , eo oe(0.*Tepeec fasnl end-stage single a of presence **The (40). more or ve Although hyperglycemia control may be 4/0mH ttnuls contraindicated unless Statin mmHg 140/90 4/0mH ttnuls contraindicated unless Statin mmHg 140/90 5/0mH osdrlklho fbene of likelihood Consider mmHg 150/90

in yegyei yeomlrsyndrome, hyperosmolar hyperglycemic tion, important in older individuals with diabetes, greater reductions in morbidity and mortality are likely to result from control of other cardiovascular risk factors rather than from tight glycemic control alone. There is strong evidence from clin- s signi use rnttolerated not or rnttolerated not or primary) than so more prevention (secondary statin with ical trials of the value of treating hyperten-

’ sion in older adults (25,26). There is less elhsau and status health s ﬁ

atsmtm or symptoms cant evidence for lipid-lowering therapy and aspirin therapy, although the beneﬁts of these interventions for primary prevention and secondary intervention are likely to apply to older adults whose ﬁ t life expectancies equal or exceed the time frames of the clinical trials. S102 Older Adults Diabetes Care Volume 40, Supplement 1, January 2017

PHARMACOLOGIC THERAPY Insulin Therapy training includes diabetes detection Special care is required in prescribing The use of insulin therapy requires that and institutional quality assessment. and monitoring pharmacologic thera- patients or their caregivers have good The guidelines also recommend that pies in older adults (27). Cost may be visual and motor skills and cognitive LTC facilities develop their own policies an important consideration, espe- ability. Insulin therapy relies on the abil- and procedures for prevention and cially as older adults tend to be on ity of the older patient to administer in- management of hypoglycemia. many medications. sulin on their own or with the assistance of a caregiver. Insulin doses should be Resources Metformin titrated to meet individualized glycemic Staff of LTC facilities should receive ap- Metformin is the first-line agent for older targets and to avoid hypoglycemia. propriate diabetes education to im- adults with type 2 diabetes. Recent stud- Once-daily basal insulin injection ther- prove the management of older adults ies have indicated that it may be used apy is associated with minimal side ef- with diabetes. Treatments for each pa- safely in patients with estimated glomer- fects and may be a reasonable option in tient should be individualized. Special 2 ular filtration rate $30 mL/min/1.73 m many older patients. Multiple daily in- management considerations include (28). However, it is contraindicated in pa- jections of insulin may be too complex theneedtoavoidbothhypoglycemia tients with advanced renal insufficiency or for the older patient with advanced di- and the metabolic complications of di- significant heart failure. Metformin may abetes complications, life-limiting co- abetes and the need to provide ade- be temporarily discontinued before pro- morbid illnesses, or limited functional quate diabetes training to LTC staff cedures, during hospitalizations, and status. (3,34). For more information, see the when acute illness may compromise renal ADA position statement “Management or liver function. Other Factors to Consider of Diabetes in Long-term Care and The needs of older adults with diabetes Skilled Nursing Facilities: A Position Thiazolidinediones and their caregivers should be evaluated Statement of the American Diabetes Thiazolidinediones, if used at all, should to construct a tailored care plan. Social Association” (32). be used very cautiously in those with, difficulties may impair their quality of or at risk for, congestive heart failure and life and increase the risk of functional Nutritional Considerations those at risk for falls or fractures. An older adult residing in an LTC facility dependency (31). The patient’s living sit- may have irregular and unpredictable meal uation must be considered, as it may Insulin Secretagogues consumption, undernutrition, anorexia, Sulfonylureas and other insulin secreta- affect diabetes management and sup- and impaired swallowing. Furthermore, gogues are associated with hypoglyce- port. Social and instrumental support therapeutic diets may inadvertently mia and should be used with caution. networks (e.g., adult children, care- lead to decreased food intake and con- If used, shorter-duration sulfonylureas takers) that provide instrumental or tribute to unintentional weight loss and such as glipizide are preferred. Glybur- emotional support for older adults undernutrition. Diets tailored to a pa- ide is a longer-duration sulfonylurea and with diabetes should be included in di- tient’s culture, preferences, and per- contraindicated in older adults (29). abetes management discussions and sonal goals might increase quality of shared decision making. life, satisfaction with meals, and nutri- Incretin-Based Therapies Older adults in assisted living facilities tion status (35). Oral dipeptidyl peptidase 4 inhibitors may not have support to administer have few side effects and minimal hypo- their own medications, whereas those glycemia, but their costs may be a bar- Hypoglycemia living in a nursing home (community liv- Older adults with diabetes in LTC are rier to some older patients. A systematic ing centers) may rely completely on the especially vulnerable to hypoglycemia. review concluded that incretin-based care plan and nursing support. Those re- They have a disproportionately high agents do not increase major adverse ceiving palliative care (with or without number of clinical complications and co- cardiovascular events (30). hospice) may require an approach that morbidities that can increase hypogly- Glucagon-like peptide 1 receptor ag- emphasizes comfort and symptom man- cemia risk: impaired cognitive and onists are injectable agents, which re- agement, while deemphasizing strict renal function, slowed hormonal regula- quire visual, motor, and cognitive skills. metabolic and blood pressure control. tion and counterregulation, suboptimal They may be associated with nausea, hydration, variable appetite and nutri- vomiting, and diarrhea. Also, weight TREATMENT IN SKILLED NURSING tional intake, polypharmacy, and slowed loss with GLP-1 receptor agonists may FACILITIES AND NURSING HOMES intestinal absorption (36). not be desirable in some older patients, Management of diabetes in the long- Another consideration for the LTC particularly those with cachexia. term care (LTC) setting (i.e., nursing setting is that unlike the hospital setting, Sodium–Glucose Cotransporter 2 homes and skilled nursing facilities) is medical providers are not required to Inhibitors unique. Individualization of health care evaluate the patients daily. According Sodium–glucose cotransporter 2 inhibi- is important in all patients; however, to federal guidelines, assessments tors offer an oral route, which may be practical guidance is needed for medical should be done at least every 30 days convenient for older adults with diabe- providersaswellastheLTCstaffand for the first 90 days after admission tes; however, long-term experience is caregivers (32). The American Medical and then at least once every 60 days. limited despite the initial efficacy and Directors Association guidelines offer Although in practice the patients may safety data reported with these agents. a 12-step program for staff (33). This actually be seen more frequently, the care.diabetesjournals.org Older Adults S103

concern is that patients may have uncon- basal insulin can be implemented, ac- 4. Cukierman T, Gerstein HC, Williamson JD. trolled glucose levels or wide excursions companied by oral agents and without Cognitive decline and dementia in diabetes– without the practitioner being notified. rapid-acting insulin. Agents that can systematic overview of prospective observational studies. Diabetologia 2005;48:2460–2469 Providers may make adjustments to cause gastrointestinal symptoms such 5. Roberts RO, Knopman DS, Przybelski SA, treatment regimens by telephone, fax, as nausea or excess weight loss may et al. Association of type 2 diabetes with brain or order directly at the LTC facilities pro- not be good choices in this setting. As atrophy and cognitive impairment. Neurology vided they are given timely notification symptoms progress, some agents may 2014;82:1132–1141 from a standardized alert system. be slowly tapered and discontinued. 6.XuWL,vonStraussE,QiuCX,WinbladB, Fratiglioni L. Uncontrolled diabetes increases The following alert strategy could be Strata have been proposed for diabe- the risk of Alzheimer’s disease: a population- considered: tes management in those with advanced based cohort study. Diabetologia 2009;52: disease (24). 1031–1039 1. Call provider immediately:incaseof 7. Ghezzi L, Scarpini E, Galimberti D. Disease- , modifying drugs in Alzheimer’sdisease.Drug low blood glucose levels ( 70 mg/dL 1. Astablepatient: continue with the – fi ’ Des Devel Ther 2013;7:1471 1478 [3.9 mmol/L]). Low nger-stick blood patient spreviousregimen,witha 8. Craft S, Baker LD, Montine TJ, et al. Intranasal glucose values should be confirmed focus on the prevention of hypogly- insulin therapy for Alzheimer disease and am- by laboratory glucose measurement. cemia and the management of hy- nestic mild cognitive impairment: a pilot clinical 2. Call as soon as possible:a)glucose perglycemia using blood glucose trial. Arch Neurol 2012;69:29–38 values between 70 and 100 mg/dL testing, keeping levels below the re- 9. Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer’s (between 3.9 and 5.6 mmol/L) (regi- nal threshold of glucose. There is disease: a review of basic research and clinical men may need to be adjusted), b) glu- very little role for A1C monitoring evidence. CNS Drugs 2013;27:505–514 cose values greater than 250 mg/dL and lowering. 10. Alagiakrishnan K, Sankaralingam S, Ghosh (13.9 mmol/L) within a 24-h period, c) 2. A patient with organ failure:pre- M, Mereu L, Senior P. Antidiabetic drugs and their potential role in treating mild cognitive glucose values greater than 300 mg/dL venting hypoglycemia is of greater ’ fi impairment and Alzheimer sdisease.Discov (16.7 mmol/L) within 2 consecutive signi cance. Dehydration must be Med 2013;16:277–286 days, d) when any reading is too high, prevented and treated. In people 11. Yaffe K, Falvey C, Hamilton N, et al. Diabe- or e) the patient is sick, with vomit- with type 1 diabetes, insulin admin- tes, glucose control, and 9-year cognitive de- ing or other malady that can reflect istration may be reduced as the oral cline among older adults without dementia. – hyperglycemic crisis and may lead to intake of food decreases but should Arch Neurol 2012;69:1170 1175 12. Launer LJ, Miller ME, Williamson JD, et al.; poor oral intake, thus requiring regi- not be stopped. For those with type 2 ACCORD MIND Investigators. Effects of inten- men adjustment. diabetes, agents that may cause hy- sive glucose lowering on brain structure and poglycemia should be titrated. The function in people with type 2 diabetes (ACCORD main goal is to avoid hypoglycemia, MIND): a randomised open-label substudy. – END-OF-LIFE CARE allowing for glucose values in the Lancet Neurol 2011;10:969 977 13. Cummings JL, Frank JC, Cherry D, et al. The management of the older adult at upper level of the desired target Guidelines for managing Alzheimer’sdisease: the end of life receiving palliative range. part I. Assessment. Am Fam Physician 2002;65: medicine or hospice care is a unique 3. A dying patient: for patients with 2263–2272 situation. Overall, palliative medicine type 2 diabetes, the discontinuation 14. Nasreddine ZS, Phillips NA, Bedirian´ V, et al. of all medications may be a reason- The Montreal Cognitive Assessment, MoCA: a promotes comfort, symptom control brief screening tool for mild cognitive impair- and prevention (pain, hypoglycemia, able approach, as patients are un- ment. J Am Geriatr Soc 2005;53:695–699 hyperglycemia, and dehydration) and likely to have any oral intake. In 15. Institute of Medicine. Cognitive aging: preservation of dignity and quality-of- patients with type 1 diabetes, there progress in understanding and opportunities life in patients with limited life ex- is no consensus, but a small amount for action [Internet]. Available from http:// of basal insulin may maintain glucose nationalacademies.org/hmd/Reports/2015/ pectancy (34,37). A patient has the Cognitive-Aging.aspx. Accessed 3 October 2016 right to refuse testing and treatment, levels and prevent acute hyperglyce- 16. American Psychological Association. Guide- whereas providers may consider with- mic complications. lines for the evaluation of dementia and age- drawing treatment and limiting diagnos- related cognitive change [Internet]. Available tic testing, including a reduction in the References from http://www.apa.org/practice/guidelines/ fi 1. Centers for Disease Control and Prevention. dementia.aspx. Accessed 3 October 2016 frequency of nger-stick testing (38). 17. Feinkohl I, Aung PP, Keller M, et al.; Edin- National diabetes statistics report: estimates Glucose targets should aim to prevent burgh Type 2 Diabetes Study (ET2DS) Investiga- of diabetes and its burden in the United States, hypoglycemia and hyperglycemia. tors. Severe hypoglycemia and cognitive decline 2014 [Internet]. Available from http://www.cdc in older people with type 2 diabetes: the Treatment interventions need to be .gov/diabetes/data/statistics/2014statisticsreport mindful of quality of life. Careful moni- Edinburgh type 2 diabetes study. Diabetes Care .html. Accessed 21 November 2016 2014;37:507–515 toring of oral intake is warranted. The 2. Kimbro LB, Mangione CM, Steers WN, et al. 18. Selvin E, Coresh J, Brancati FL. The burden decision process may need to involve Depression and all-cause mortality in persons and treatment of diabetes in elderly individuals the patient, family, and caregivers, lead- with diabetes mellitus: are older adults at in the U.S. Diabetes Care 2006;29:2415–2419 ing to a care plan that is both convenient higher risk? Results from the Translating Re- 19. Bandeen-Roche K, Seplaki CL, Huang J, et al. search Into Action for Diabetes Study. J Am Ger- and effective for the goals of care (39). Frailty in older adults: a nationally representa- iatr Soc 2014;62:1017–1022 tive profile in the United States. J Gerontol A The pharmacologic therapy may include 3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabe- Biol Sci Med Sci 2015;70:1427–1434 oral agents as first line, followed by a tes in older adults. Diabetes Care 2012;35: 20. Kalyani RR, Tian J, Xue Q-L, et al. Hypergly- simplified insulin regimen. If needed, 2650–2664 cemia and incidence of frailty and lower S104 Older Adults Diabetes Care Volume 40, Supplement 1, January 2017

extremity mobility limitations in older women. type 2 diabetes and kidney disease: a systematic Force of Experts in Diabetes. J Am Med Dir Assoc J Am Geriatr Soc 2012;60:1701–1707 review. JAMA 2014;312:2668–2675 2012;13:497–502 21. Blaum C, Cigolle CT, Boyd C, et al. Clinical 29. Campanelli CM; American Geriatrics Soci- 35. Dorner B, Friedrich EK, Posthauer ME. Prac- complexity in middle-aged and older adults with ety 2012 Beers Criteria Update Expert Panel. tice paper of the American Dietetic Association: diabetes: the Health and Retirement Study. American Geriatrics Society updated Beers Cri- individualized nutrition approaches for older Med Care 2010;48:327–334 teria for potentially inappropriate medication adults in health care communities. J Am Diet 22. Young-Hyman D, de Groot M, Hill-Briggs F, use in older adults. J Am Geriatr Soc 2012;60: Assoc 2010;110:1554–1563 Gonzalez JS, Hood K, Peyrot M. Psychosocial 616–631 36. Migdal A, Yarandi SS, Smiley D, Umpierrez care for people with diabetes: a position state- 30. Rotz ME, Ganetsky VS, Sen S, Thomas TF. GE. Update on diabetes in the elderly and in ment of the American Diabetes Association. Implications of incretin-based therapies on car- nursing home residents. J Am Med Dir Assoc Diabetes Care 2016;39:2126–2140 diovascular disease. Int J Clin Pract 2015;69: 2011;12:627–632.e2 23. Sinclair A, Dunning T, Colagiuri S. IDF Global 531–549 37. Quinn K, Hudson P, Dunning T. Diabetes Guideline for Managing Older People With 31. Laiteerapong N, Karter AJ, Liu JY, et al. Cor- management in patients receiving palliative Type 2 Diabetes.Brussels,Belgium,Interna- relates of quality of life in older adults with di- care. J Pain Symptom Manage 2006;32:275–286 tional Diabetes Federation, 2013 abetes: the Diabetes & Aging Study. Diabetes 38. Ford-Dunn S, Smith A, Quin J. Management 24. Angelo M, Ruchalski C, Sproge BJ. An ap- Care 2011;34:1749–1753 of diabetes during the last days of life: attitudes proach to diabetes mellitus in hospice and pal- 32. Munshi MN, Florez H, Huang ES, et al. Man- of consultant diabetologists and consultant palliative medicine. J Palliat Med 2011;14:83–87 agement of diabetes in long-term care and liative care physicians in the UK. Palliat Med 25. Beckett NS, Peters R, Fletcher AE, et al.; skilled nursing facilities: a position statement 2006;20:197–203 HYVET Study Group. Treatment of hypertension of the American Diabetes Association. Diabetes 39. Mallery LH, Ransom T, Steeves B, Cook B, in patients 80 years of age or older. N Engl J Med Care 2016;39:308–318 Dunbar P, Moorhouse P. Evidence-informed 2008;358:1887–1898 33. American Medical Directors Association. guidelines for treating frail older adults with 26. James PA, Oparil S, Carter BL, et al. 2014 Diabetes management in the long-term care type 2 diabetes: from the Diabetes Care Pro- evidence-based guideline for the management setting [Internet]. Available from http://www gram of Nova Scotia (DCPNS) and the Pallia- of high blood pressure in adults: report from the .amda.com/tools/guidelines.cfm#diabetes. Ac- tive and Therapeutic Harmonization (PATH) panel members appointed to the Eighth Joint Na- cessed 5 October 2015 program. J Am Med Dir Assoc 2013;14:801– tional Committee (JNC 8). JAMA 2014;311:507–520 34. Sinclair A, Morley JE, Rodriguez-Manas~ L, 808 27. Valencia WM, Florez H. Pharmacological et al. Diabetes mellitus in older people: position 40. Laiteerapong N, Iveniuk J, John PM, treatment of diabetes in older people. Diabetes statement on behalf of the International Asso- Laumann EO, Huang ES. Classiﬁcation of older Obes Metab 2014;16:1192–1203 ciation of Gerontology and Geriatrics (IAGG), adults who have diabetes by comorbid condi- 28. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, the European Diabetes Working Party for Older tions, United States, 2005-2006. Prev Chronic McGuire DK. Metformin in patients with People (EDWPOP), and the International Task Dis 2012;9:E100 Diabetes Care Volume 40, Supplement 1, January 2017 S105

12. Children and Adolescents American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S105–S113 | DOI: 10.2337/dc17-S015

TYPE 1 DIABETES Three-quarters of all cases of type 1 diabetes are diagnosed in individuals ,18 years of age (although recent data using genetic risk scoring would suggest that over 40% of patients with autoimmune diabetes are diagnosed over the age of 30 years) (1). 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 ADOLESCENTS AND CHILDREN 12. possible adverse neurocognitive effects of diabetic ketoacidosis (DKA) (2,3). Atten- tion to family dynamics, developmental stages, and physiological differences related to sexual maturity are all essential in developing and implementing an optimal diabetes treatment plan (4). 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 Associ- ation (ADA) position statement “Care of Children and Adolescents With Type 1 Diabetes” (5) and have been updated in the ADA position statement “Type 1 Di- abetes Through the Life Span” (6). 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 self-management education (DSME) and support (DSMS), medical nutrition therapy, and psychosocial support be provided at diagnosis and regularly thereafter in a developmentally appropriate format that builds on prior knowledge 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 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 Suggested citation: American Diabetes Association. providers (the diabetes care team) who care for children and adolescents must be Children and adolescents. Sec. 12. In Standards of capable of evaluating the educational, behavioral, emotional, and psychosocial factors Medical Care in Diabetesd2017.DiabetesCare that impact implementation of a treatment plan and must work with the individual 2017;40(Suppl. 1):S105–S113 and family to overcome barriers or redeﬁne goals as appropriate. DSME and DSMS © 2017 by the American Diabetes Association. require periodic reassessment, especially as the youth grows, develops, and acquires Readers may use this article as long as the work is properly cited, the use is educational and not the need for greater independent self-care skills. In addition, it is necessary to assess for proﬁt, and the work is not altered. More infor- the educational needs and skills of day care providers, school nurses, or other school mation is available at http://www.diabetesjournals personnel who participate in the care of the young child with diabetes (7). .org/content/license. S106 Children and Adolescents Diabetes Care Volume 40, Supplement 1, January 2017

School and Child Care adulthood. Diabetes management during Screening As a large portion of a child’s day is spent childhood and adolescence places sub- Screening for psychosocial distress and in school, close communication with and stantial burdens on the youth and family, mental health problems is an important the cooperation of school or day care necessitating ongoing assessment of psy- component of ongoing care. It is important personnel are essential for optimal dia- chosocial status and diabetes distress dur- to consider the impact of diabetes on qual- betes management, safety, and maximal ing routine diabetes visits (10–12). Early ity of life as well as the development of academic opportunities. Refer to the detection of depression, anxiety, eating mental health problems related to dia- ADA position statements “Diabetes disorders, and learning disabilities can fa- betes distress, fear of hypoglycemia (and Care in the School Setting” (8) and cilitate effective treatment options and hyperglycemia), symptoms of anxiety, dis- “Care of Young Children With Diabetes help minimize adverse effects on diabetes ordered eating behaviors as well as eating in the Child Care Setting” (9) for addi- management and disease outcomes (13). disorders, and symptoms of depression tional details. Furthermore, the complexities of diabe- (22). Consider assessing youth for diabetes tes management require ongoing pa- distress, generally starting at 7 or 8 years of Psychosocial Issues rental involvement in care throughout age (13). Consider screening for depres- Recommendations childhood with developmentally appro- sion and disordered eating behaviors us- c At diagnosis and during routine priate family teamwork between the ing available screening tools (10,23). With follow-up care, assess psychoso- growing child/teen and parent in order respect to disordered eating, it is impor- cial issues and family stresses to maintain adherence and to prevent de- tant to recognize the unique and dan- that could impact adherence to di- terioration in glycemic control (14,15). As gerous disordered eating behavior of abetes management and provide diabetes-specific family conflict is related insulin omission for weight control in appropriate referrals to trained to poorer adherence and glycemic con- type 1 diabetes (24). The presence of a mental health professionals, pref- trol, it is appropriate to inquire about mental health professional on pediatric erably experienced in childhood such conflict during visits and to either multidisciplinary teams highlights the diabetes. E help to negotiate a plan for resolution or importance of attending to the psycho- c Mental health professionals should refertoanappropriatementalhealth social issues of diabetes. These psycho- be considered integral members of specialist (16). Monitoring of social ad- social factors are significantly related to the pediatric diabetes multidisci- justment (peer relationships) and school nonadherence, suboptimal glycemic plinary team. E performance can facilitate both well- control, reduced quality of life, and c Encourage developmentally appro- being and academic achievement. Sub- higher rates of acute and chronic diabe- priate family involvement in diabe- optimal glycemic control is a risk factor tes complications. tes management tasks for children for below average school performance Glycemic Control and adolescents, recognizing that and increased absenteeism (17). premature transfer of diabetes Shared decision-making with youth re- Recommendation care to the child can result in non- garding the adoption of regimen compo- c An A1C goal of ,7.5% (58 mmol/mol) adherence and deterioration in gly- nents and self-management behaviors can is recommended across all pediat- cemic control. B improve diabetes self-efficacy, adherence, ric age-groups. E c Providers should assess children’s and metabolic outcomes (18). Although and adolescents’ diabetes distress, cognitive abilities vary, the ethical position Current standards for diabetes manage- social adjustment (peer relation- often adopted is the “mature minor rule,” ment reflect the need to lower glucose as ships), and school performance to whereby children after age 12 or 13 years safely as possible. This should be done determine whether further inter- whoappeartobe“mature” have the right with stepwise goals. When establishing vention is needed. B to consent or withhold consent to general individualized glycemic targets, special c In youth and families with behav- medical treatment, except in cases in consideration should be given to the ioral self-care difficulties, repeated which refusal would significantly endanger risk of hypoglycemia in young children hospitalizations for diabetic keto- health (19). (aged ,6 years) who are often unable acidosis, or significant distress, Beginning at the onset of puberty or at to recognize, articulate, and/or manage consider referral to a mental diagnosis of diabetes, all adolescent girls hypoglycemia. health provider for evaluation and and women with childbearing potential Type 1 diabetes can be associated treatment. E should receive education about the risks with adverse effects on cognition during c Adolescents should have time by of malformations associated with un- childhood and adolescence. Factors that themselves with their care pro- planned pregnancies and poor metabolic contribute to adverse effects on brain vider(s) starting at age 12 years. E control and the use of effective contra- development and function include c Starting at puberty, preconception ception to prevent unplanned pregnancy. young age or DKA at onset of type 1 di- counseling should be incorporated Preconception counseling using develop- abetes, severe hypoglycemia ,6 years of into routine diabetes care for all mentally appropriate educational tools age, and chronic hyperglycemia (25,26). girls of childbearing potential. A enables adolescent girls to make well- However, meticulous use of new therapeu- informed decisions (20). Preconception tic modalities, such as rapid- and long-acting Rapid and dynamic cognitive, develop- counseling resources tailored for adoles- insulin analogs, technological advances mental, and emotional changes occur dur- cents are available at no cost through the (e.g., continuous glucose monitors, low ing childhood, adolescence, and emerging ADA (21). glucose suspend insulin pumps), and care.diabetesjournals.org Children and Adolescents S107

intensive self-management education Because of the increased frequency (36); their presence is predictive of now make it more feasible to achieve ex- of other autoimmune diseases in type 1 thyroid dysfunctiondmost commonly cellent glycemic control while reducing diabetes, screening for thyroid dysfunc- hypothyroidism, although hyperthy- the incidence of severe hypoglycemia tion and celiac disease should be consid- roidism occurs in ;0.5% of patients (27,28). ered. Periodic screening in asymptomatic with type 1 diabetes (37,38). Thyroid The Diabetes Control and Complica- individuals has been recommended, but function tests may be misleading (eu- tions Trial (DCCT), which did not enroll the optimal frequency and benefitof thyroid sick syndrome) if performed at children ,13 years of age, demonstrated screening are unclear. time of diagnosis owing to the effect of that near normalization of blood glucose Although much less common than previous hyperglycemia, ketosis or keto- levels was more difficult to achieve in ado- thyroid dysfunction and celiac disease, acidosis, weight loss, etc. Therefore, thy- lescents than in adults. Nevertheless, the other autoimmune conditions, such as roid function tests should be performed increased use of basal-bolus regimens, in- Addison disease (primary adrenal insuf- soon after a period of metabolic stability sulin pumps, frequent blood glucose mon- ficiency), autoimmune hepatitis, auto- and good glycemic control. Subclinical itoring, goal setting, and improved patient immune gastritis, dermatomyositis, and hypothyroidism may be associated with education in youth from infancy through myasthenia gravis, occur more com- increased risk of symptomatic hypogly- adolescence have been associated with monly in the population with type 1 di- cemia (39) and reduced linear growth more children reaching the blood glu- abetes than in the general pediatric rate. Hyperthyroidism alters glucose cose targets recommended by the ADA population and should be assessed and metabolism and usually causes deterio- (29–32), particularly in those families in monitored as clinically indicated. ration of glycemic control. which both the parents and the child Thyroid Disease with diabetes participate jointly to Celiac Disease perform the required diabetes-related Recommendations Recommendations tasks. Furthermore, studies documenting c Consider testing individuals with c Consider screening individuals with neurocognitive imaging differences re- type 1 diabetes for antithyroid per- type 1 diabetes for celiac disease lated to hyperglycemia in children pro- oxidase and antithyroglobulin anti- by measuring either tissue transglu- vide another motivation for lowering bodies soon after the diagnosis. E taminase or deamidated gliadin an- glycemic targets (2). c Measure thyroid-stimulating hor- tibodies, with documentation of In selecting glycemic goals, the long- mone concentrations soon after fi normal total serum IgA levels, soon term health bene ts of achieving a lower the diagnosis of type 1 diabetes after the diagnosis of diabetes. E A1C should be balanced against the risks and after glucose control has been c Consider screening individuals of hypoglycemia and the developmental established. If normal, consider re- who have a first-degree relative burdens of intensive regimens in children checking every 1–2 years or sooner with celiac disease, growth failure, and youth. In addition, achieving lower if the patient develops symptoms weight loss, failure to gain weight, A1C levels is more likely to be related to suggestive of thyroid dysfunction, diarrhea, flatulence, abdominal setting lower A1C targets (33,34). A1C thyromegaly, an abnormal growth pain, or signs of malabsorption or goals are presented in Table 12.1. rate, or an unexplained glycemic in individuals with frequent unex- variation. E plained hypoglycemia or deterio- Autoimmune Conditions ration in glycemic control. E Autoimmune thyroid disease is the Recommendation c Individuals with biopsy-confirmed most common autoimmune disorder c Assess for the presence of auto- celiac disease should be placed associated with diabetes, occurring in immune conditions associated on a gluten-free diet and have 17–30% of patients with type 1 di- with type 1 diabetes soon after a consultation with a dietitian ex- abetes (35). At the time of diagnosis, the diagnosis and if symptoms periencedinmanagingbothdia- about 25% of children with type 1 di- develop. E betes and celiac disease. B abetes have thyroid autoantibodies

Table 12.1—Blood glucose and A1C goals for children and adolescents with type 1 diabetes 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 or pump regimens. S108 Children and Adolescents Diabetes Care Volume 40, Supplement 1, January 2017

Celiac disease is an immune-mediated Management of Cardiovascular Risk Normal blood pressure levels for age, sex, disorder that occurs with increased Factors and height and appropriate methods for frequency in patients with type 1 dia- Hypertension measurement are available online at betes (1.6–16.4% of individuals com- www.nhlbi.nih.gov/health/prof/heart/ pared with 0.3–1% in the general Recommendations hbp/hbp_ped.pdf. population) (40–42). Screening Screening. Screening for celiac disease c Blood pressure should be measured Dyslipidemia at each routine visit. Children found includes measuring serum levels of Recommendations IgA and anti–tissue transglutaminase to have high-normal blood pressure antibodies, or, with IgA deficiency, (systolic blood pressure or diastolic Testing c Obtain a fasting lipid profile in screening can include measuring IgG blood pressure $90th percentile for children $10 years of age soon af- tissue transglutaminase antibodies age, sex, and height) or hypertension ter the diagnosis (after glucose or IgG deamidated gliadin peptide (systolic blood pressure or diastolic control has been established). E antibodies. Because most cases of blood pressure $95th percentile c If lipids are abnormal, annual moni- celiac disease are diagnosed within for age, sex, and height) should toring is reasonable. If LDL cholesterol the first 5 years after the diagnosis have elevated blood pressure con- values are within the accepted risk of type 1 diabetes, screening should firmed on 3 separate days. B level (,100 mg/dL [2.6 mmol/L]), a be considered at the time of di- Treatment lipid profile repeated every 3–5years agnosis and repeated 2 and 5 years c Initial treatment of high-normal is reasonable. E thereafter. blood pressure (systolic blood pres- Although celiac disease can be diag- sure or diastolic blood pressure Treatment nosed more than 10 years after diabe- consistently $90th percentile for c Initial therapy should consist of op- fi tes diagnosis, there are insuf cient data age, sex, and height) includes di- timizing glucose control and medi- after 5 years to determine the optimal etary modification and increased cal nutrition therapy using a Step screening frequency. Measurement of exercise, if appropriate, aimed at 2 American Heart Association diet – anti tissue transglutaminase antibody weight control. If target blood to decrease the amount of satu- should be considered at other times pressure is not reached within rated fat in the diet. B in patients with symptoms suggestive 3–6 months of initiating lifestyle in- c After the age of 10 years, addition of celiac disease (42). A small-bowel tervention, pharmacologic treat- of a statin is suggested in patients biopsy in antibody-positive children ment should be considered. E who, despite medical nutrition fi isrecommendedtocon rm the diag- c In addition to lifestyle modification, therapy and lifestyle changes, nosis (43). European guidelines on pharmacologic treatment of hy- continue to have LDL cholesterol . screening for celiac disease in children pertension (systolic blood pressure 160 mg/dL (4.1 mmol/L) or LDL fi . (not speci ctochildrenwithtype1 or diastolic blood pressure consis- cholesterol 130 mg/dL (3.4 mmol/L) diabetes) suggest that biopsy may tently $95th percentile for age, sex, and one or more cardiovascular not be necessary in symptomatic chil- and height) should be considered as disease risk factors, following re- dren with high antibody titers (i.e., soon as hypertension is confirmed. E productive counseling and imple- greater than 10 times the upper limit c ACE inhibitors or angiotensin recep- mentationofeffectivebirthcontrol of normal) provided that further testing tor blockers should be considered due to the potential teratogenic effi is performed (veri cation of endomy- for the initial pharmacologic treat- fects of statins. E sial antibody positivity on a separate ment of hypertension, following c The goal of therapy is an LDL blood sample). It is also advisable to reproductive counseling and imple- cholesterol value ,100 mg/dL check for HLA types in patients who mentation of effective birth control (2.6 mmol/L). E are diagnosed without a small intesti- due to the potential teratogenic ef- nal biopsy. Asymptomatic at-risk chil- fects of both drug classes. E Population-based studies estimate that – dren should have an intestinal biopsy c The goal of treatment is blood 14 45% of children with type 1 diabetes (44). pressure consistently ,90th per- have two or more cardiovascular disease – In symptomatic children with type 1 centile for age, sex, and height. E (CVD) risk factors (47 49), and the prev- diabetes and confirmed celiac dis- alence of CVD risk factors increases with ease, gluten-free diets reduce symp- age (49), with girls having a higher risk toms and rates of hypoglycemia (45). Blood pressure measurements should burden than boys (48). The challenging dietary restrictions be performed using the appropriate size Pathophysiology. The atherosclerotic associated with having both type 1 cuff with the child seated and relaxed. process begins in childhood, and although diabetes and celiac disease place a Hypertension should be confirmed on at CVD events are not expected to occur dur- significant burden on individuals. least 3 separate days. Evaluation should ing childhood, observations using a variety Therefore, a biopsy to confirm the di- proceed as clinically indicated. Treat- of methodologies show that youth with agnosis of celiac disease is recom- ment is generally initiated with an ACE type 1 diabetes may have subclinical CVD mended, especially in asymptomatic inhibitor, but an angiotensin receptor within the first decade of diagnosis (50–52). children, before endorsing significant blocker can be used if the ACE inhibitor Studies of carotid intima-media thickness dietary changes. is not tolerated (e.g., due to cough) (46). have yielded inconsistent results (46). care.diabetesjournals.org Children and Adolescents S109

Treatment. Pediatric lipid guidelines Smoking Data from 7,549 participants ,20 years provide some guidance relevant to chil- of age in the T1D Exchange clinic regis- Recommendation dren with type 1 diabetes (53–55); how- try emphasize the importance of good c Elicit a smoking history at initial ever, there are few studies on modifying and follow-up diabetes visits. Dis- glycemic and blood pressure control, lipid levels in children with type 1 diabe- courage smoking in youth who do particularly as diabetes duration in- tes. A 6-month trial of dietary counsel- not smoke and encourage smoking creases, in order to reduce the risk of fi ing produced a signi cant improvement cessation in those who do smoke. B nephropathy. The data also underscore in lipid levels (56); likewise, a lifestyle the importance of routine screening intervention trial with 6 months of exer- The adverse health effects of smoking to ensure early diagnosis and timely cise in adolescents demonstrated im- are well recognized with respect to fu- treatment of albuminuria (66). An estima- fi provement in lipid levels (57). ture cancer and CVD risk. Despite this, tion of glomerular ltration rate (GFR), cal- Although intervention data are sparse, smoking rates are significantly higher culated using GFR estimating equations the American Heart Association (AHA) among youth with diabetes than among from the serum creatinine, height, age, categorizes children with type 1 diabetes youth without diabetes (63,64). In youth and sex (67), should be determined at in the highest tier for cardiovascular risk with diabetes, it is important to avoid ad- baseline and repeated as indicated based and recommends both lifestyle and ditional CVD risk factors. Smoking in- on clinical status, age, diabetes duration, pharmacologic treatment for those creases the risk of onset of albuminuria; and therapies. Estimated GFR is calcu- with elevated LDL cholesterol levels therefore, smoking avoidance is impor- lated from a serum creatinine measure- (55,58). Initial therapy should be with tant to prevent both microvascular and ment using an estimating equation. There a Step 2 AHA diet, which restricts satu- macrovascular complications (53,65). are ongoing clinical trials assessing the fi rated fat to 7% of total calories and re- Discouraging cigarette smoking, includ- ef cacy of early treatment of persistent stricts dietary cholesterol to 200 mg/day. ing e-cigarettes, is an important part of albuminuria with ACE inhibitors (68). Data from randomized clinical trials in routine diabetes care. In younger chil- Retinopathy children as young as 7 months of age dren, it is important to assess exposure indicate that this diet is safe and does to cigarette smoke in the home due to Recommendations not interfere with normal growth and the adverse effects of secondhand c An initial dilated and comprehen- development (59). smoke and to discourage youth from sive eye examination is recom- fi $ For children with a signi cant family ever smoking if exposed to smokers in mended at age 10 years or after history of CVD, the National Heart, childhood. puberty has started, whichever is Lung, and Blood Institute recommends earlier, once the youth has had obtaining a fasting lipid panel beginning type 1 diabetes for 3–5 years. B Microvascular Complications at 2 years of age (53). Abnormal results c After the initial examination, an- Nephropathy from a random lipid panel should be con- nual routine follow-up is generally firmed with a fasting lipid panel. Data Recommendations recommended. Less frequent ex- from the SEARCH for Diabetes in Youth Screening aminations, every 2 years, may (SEARCH) study show that improved glu- c Annual screening for albuminuria be acceptable on the advice of an cose control over a 2-year period is asso- with a random spot urine sample eye care professional. E ciated with a more favorable lipid profile; for albumin-to-creatinine ratio however, improved glycemic control alone should be considered once the Retinopathy (like albuminuria) most com- will not normalize lipids in youth with child has had type 1 diabetes for monly occurs after the onset of puberty type 1 diabetes and dyslipidemia (60). 5 years. B and after 5–10 years of diabetes duration Neither long-term safety nor cardiovas- c Estimate glomerular filtration rate (69). Referrals should be made to eye cular outcome efficacy of statin therapy at initial evaluation and then care professionals with expertise in dia- has been established for children; how- based on age, diabetes duration, betic retinopathy and experience in ever, studies have shown short-term safety and treatment. E counseling the pediatric patient and fam- equivalent to that seen in adults and effi- ily on the importance of early prevention Treatment cacy in lowering LDL cholesterol levels in and intervention. c When persistently elevated uri- familial hypercholesterolemia or severe hy- nary albumin-to-creatinine ratio perlipidemia, improving endothelial func- Neuropathy (.30 mg/g) is documented with tion and causing regression of carotid at least two of three urine sam- Recommendation intimal thickening (61,62). Statins are not c Consider an annual comprehensive ples, treatment with an ACE inhib- approved for patients aged ,10 years, and foot exam for the child at the start itor should be considered and the statin treatment should generally not of puberty or at age $10 years, dose titrated to maintain blood be used in children with type 1 diabetes whichever is earlier, once the pressure within the age-appropriate before this age. Statins are category X in youth has had type 1 diabetes for normal range. The urine samples pregnancy; therefore, prevention of un- 5 years. E should be obtained over a 6-month planned pregnancies is of paramount im- interval following efforts to improve portance for postpubertal girls (see Diabetic neuropathy rarely occurs in pre- glycemic control and normalize Section 13 “Management of Diabetes in pubertal children or after only 1–2years blood pressure. C Pregnancy” for more information). of diabetes (69). A comprehensive foot S110 Children and Adolescents Diabetes Care Volume 40, Supplement 1, January 2017

exam, including inspection, palpation diabetes in children can be difficult. dynamics, mental health, community of dorsalis pedis and posterior tibial Overweight and obesity are common readiness, and the broader environmen- pulses, assessment of the patellar and in children with type 1 diabetes (75), tal system (73). Achilles reflexes, and determination of and diabetes-associated autoantibodies When insulin treatment is not re- proprioception, vibration, and monofil- and ketosis may be present in pediatric quired, initiation of metformin is rec- ament sensation, should be performed patients with features of type 2 diabetes ommended. The Treatment Options for annually along with an assessment of (including obesity and acanthosis nigri- type 2 Diabetes in Adolescents and Youth symptoms of neuropathic pain. Foot in- cans) (76). At onset, DKA occurs in ;6% (TODAY) study found that metformin spection can be performed at each of youth aged 10–19 years with type 2 alone provided durable glycemic control visit to educate youth regarding the im- diabetes (77). Accurate diagnosis is criti- (A1C #8% [64 mmol/mol] for 6 months) portance of foot care (see Section cal as treatment regimens, educational in approximately half of the subjects (79). 10 “Microvascular Complications and approaches, dietary advice, and out- To date, the TODAY study is the only trial Foot Care”). comes differ markedly between patients combining lifestyle and metformin ther- with the two diagnoses. apy in youth with type 2 diabetes; the TYPE 2 DIABETES combination did not perform better For information on testing for type 2 di- Treatment than metformin alone in achieving dura- abetes and prediabetes in children The general treatment goals for youth ble glycemic control (79). and adolescents, please refer to Sec- with type 2 diabetes are the same as Small retrospective analyses and a tion 2 “Classification and Diagnosis of those for youth with type 1 diabetes. A recent prospective multicenter non- Diabetes.” multidisciplinary diabetes team, includ- randomized study suggest that bariatric Type 2 diabetes in youth has in- ing a physician, diabetes nurse educator, or metabolic surgery may have similar creased over the past 20 years and re- registered dietitian, and psychologist or benefits in obese adolescents with cent estimates suggest an incidence of social worker, is essential. In addition to type 2 diabetes compared with those ;5,000 new cases per year in the U.S. blood glucose control, initial treatment observed in adults. Teenagers experi- (70). The Centers for Disease Control and must include management of comorbidities ence similar degrees of weight loss, di- Prevention published projections for such as obesity, dyslipidemia, hypertension, abetes remission, and improvement of type 2 diabetes prevalence using the and microvascular complications. cardiometabolic risk factors for at least SEARCH database: assuming a 2.3% an- Current treatment options for youth- 3 years after surgery (80). No random- nual increase, the prevalence in those onset type 2 diabetes are limited to two ized trials, however, have yet compared under 20 years of age will quadruple in approved drugsdinsulin and metfor- the effectiveness and safety of surgery to 40 years (71,72). min(73).Presentationwithketosisor those of conventional treatment options Evidence suggests that type 2 diabe- ketoacidosis requires a period of insulin in adolescents (81). tes in youth is different not only from therapy until fasting and postprandial type 1 diabetes but also from type 2 di- glycemia have been restored to normal Comorbidities abetes in adults and has unique features, or near-normal levels. Metformin ther- Comorbidities may already be present at such as a more rapidly progressive de- apy may be used as an adjunct after the time of diagnosis of type 2 diabetes in cline in b-cell function and accelerated resolution of ketosis/ketoacidosis. Ini- youth (74,82). Therefore, blood pressure development of diabetes complica- tial treatment should also be with in- measurement, a fasting lipid panel, as- tions (73,74). Type 2 diabetes dispropor- sulin when the distinction between sessment of random urine albumin-to- tionately impacts youth of ethnic and type 1 diabetes and type 2 diabetes is creatinine ratio, and a dilated eye exami- racial minorities and can occur in com- unclear and in patients who have ran- nation should be performed at diagnosis. plex psychosocial and cultural environ- dom blood glucose concentrations Thereafter, screening guidelines and treatments, which may make it difficult to $250 mg/dL (13.9 mmol/L) and/or ment recommendations for hypertension, sustain healthy lifestyle changes and A1C .9% (75 mmol/mol) (78). dyslipidemia, urine albumin excretion, and self-management behaviors. Additional Patients and their families must pri- retinopathy are similar to those for youth risk factors associated with type 2 dia- oritize lifestyle modifications such as with type 1 diabetes. Additional problems betes in youth include adiposity, family eating a balanced diet, achieving and that may need to be addressed include history of diabetes, female sex, and low maintaining a healthy weight, and ex- polycystic ovary disease and other comor- socioeconomic status (74). ercising regularly. A family-centered bidities associated with pediatric obesity, As with type 1 diabetes, youth with approach to nutrition and lifestyle mod- such as sleep apnea, hepatic steatosis, or- type 2 diabetes spend much of the day ification is essential in children with thopedic complications, and psychosocial in school. Therefore, close communica- type 2 diabetes, and nutrition recom- concerns. The ADA consensus report tion with and the cooperation of school mendations should be culturally appro- “Youth-Onset Type 2 Diabetes Consensus personnel are essential for optimal dia- priate and sensitive to family resources Report: Current Status, Challenges, and betes management, safety, and maximal (see Section 4 “Lifestyle Management”). Priorities” (73)andanAmericanAcademy academic opportunities. Given the complex social and environ- of Pediatrics clinical practice guideline (83) mental context surrounding youth with provide guidance on the prevention, Diagnostic Challenges type 2 diabetes, individual-level lifestyle screening, and treatment of type 2 diabe- Given the current obesity epidemic, dis- interventions may not be sufficient to tes and its comorbidities in children and tinguishing between type 1 and type 2 target the complex interplay of family adolescents. care.diabetesjournals.org Children and Adolescents S111

TRANSITION FROM PEDIATRIC TO The National Diabetes Education Pro- the American Diabetes Association. Diabetes Care ADULT CARE gram (NDEP) has materials available to 2016;39:2126–2140 facilitate the transition process (http:// 14. Katz ML, Volkening LK, Butler DA, Anderson Recommendations BJ, Laffel LM. Family-based psychoeducation ndep.nih.gov/transitions), and the En- c Health care providers and families and Care Ambassador intervention to improve docrine Society in collaboration with should begin to prepare youth with glycemic control in youth with type 1 diabetes: a the ADA and other organizations has de- randomized trial. Pediatr Diabetes 2014;15: diabetes in early to midadoles- veloped transition tools for clinicians 142–150 cence and, at the latest, at least and youth and families (http://www 15. Laffel LMB, Vangsness L, Connell A, Goebel- 1 year before the transition to Fabbri A, Butler D, Anderson BJ. Impact of .endo-society.org/clinicalpractice/ adult health care. E ambulatory, family-focused teamwork inter- transition_of_care.cfm). c Both pediatricians and adult vention on glycemic control in youth with type 1 diabetes. J Pediatr 2003;142:409–416 health care providers should assist 16. Anderson BJ, Vangsness L, Connell A, Butler in providing support and links to References D, Goebel-Fabbri A, Laffel LMB. Family conflict, resources for the teen and emerg- 1. Oram RA, Patel K, Hill A, et al. A type 1 di- adherence, and glycaemic control in youth with ing adult. B abetes genetic risk score can aid discrimination short duration type 1 diabetes. Diabet Med – between type 1 and type 2 diabetes in young 2002;19:635 642 adults. Diabetes Care 2016;39:337–344 17. McCarthy AM, Lindgren S, Mengeling MA, Care and close supervision of diabetes 2. Barnea-Goraly N, Raman M, Mazaika P, et al.; Tsalikian E, Engvall J. 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Are ing tool for disordered eating in diabetes: internal children with type 1 diabetes safe at school? consistency and external validity in a contempo- under provisions of the Affordable Care Examining parent perceptions. Pediatr Diabetes rary sample of pediatric patients with type 1 di- Act). In addition to lapses in health care, 2015;16:613–620 abetes. Diabetes Care 2010;33:495–500 this is also a period associated with de- 8. Jackson CC, Albanese-O’Neill A, Butler KL, 24. Wisting L, Frøisland DH, Skrivarhaug T, terioration in glycemic control; increased et al. Diabetes care in the school setting: a po- Dahl-Jørgensen K, Rø O. Disturbed eating be- occurrence of acute complications; psy- sition statement of the American Diabetes As- havior and omission of insulin in adolescents sociation. Diabetes Care 2015;38:1958–1963 receiving intensified insulin treatment: a na- chosocial, emotional, and behavioral 9. Siminerio LM, Albanese-O’Neill A, Chiang JL, tionwide population-based study. 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Psy- 27. Campbell MS, Schatz DA, Chen V, et al.; adult health care (85,86). A comprehen- chosocial burden and glycemic control during T1D Exchange Clinic Network. A contrast be- the first 6 years of diabetes: results from the tween children and adolescents with excellent sive discussion regarding the challenges SEARCH for Diabetes in Youth study. J Adolesc and poor control: the T1D Exchange clinic reg- faced during this period, including specific Health 2014;55:498–504 istry experience. Pediatr Diabetes 2014;15: recommendations, is found in the ADA 12. Ducat L, Philipson LH, Anderson BJ. The 110–117 position statement “Diabetes Care for mental health comorbidities of diabetes. JAMA 28. Cooper MN, O’Connell SM, Davis EA, Jones 2014;312:691–692 TW. A population-based study of risk factors for Emerging Adults: Recommendations for 13. Young-Hyman D, de Groot M, Hill-Briggs F, severe hypoglycaemia in a contemporary cohort Transition From Pediatric to Adult Diabe- Gonzalez JS, Hood K, Peyrot M. Psychosocial care of childhood-onset type 1 diabetes. Diabetolo- tes Care Systems” (86). for people with diabetes: a position statement of gia 2013;56:2164–2170 S112 Children and Adolescents Diabetes Care Volume 40, Supplement 1, January 2017

29. Rosenbauer J, Dost A, Karges B, et al.; DPV 43. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood the Young; American Heart Association Council Initiative and the German BMBF Competence AH, Murray JA; American College of Gastroen- on Epidemiology and Prevention; American Network Diabetes Mellitus. Improved metabolic terology. ACG clinical guidelines: diagnosis and Heart Association Council on Nutrition, Physical control in children and adolescents with type 1 management of celiac disease. Am J Gastroen- Activity and Metabolism; American Heart Asso- diabetes: a trend analysis using prospective terol 2013;108:656–676; quiz 677 ciation Council on High Blood Pressure Re- multicenter data from Germany and Austria. Di- 44. Husby S, Koletzko S, Korponay-SzaboIR,´ search; American Heart Association Council on abetes Care 2012;35:80–86 et al.; ESPGHAN Working Group on Coeliac Dis- Cardiovascular Nursing; American Heart Associ- 30. Cameron FJ, de Beaufort C, Aanstoot HJ, ease Diagnosis; ESPGHAN Gastroenterology ation Council on the Kidney in Heart Disease; et al.; Hvidoere International Study Group. Les- Committee; European Society for Pediatric Gas- Interdisciplinary Working Group on Quality of sons from the Hvidoere International Study troenterology, Hepatology, and Nutrition. Euro- Care and Outcomes Research. Cardiovascular Group on childhood diabetes: be dogmatic pean Society for Pediatric Gastroenterology, risk reduction in high-risk pediatric patients: a about outcome and flexible in approach. Pediatr Hepatology, and Nutrition guidelines for the di- scientific statement from the American Heart Diabetes 2013;14:473–480 agnosis of coeliac disease. J Pediatr Gastroen- Association Expert Panel on Population and Pre- 31. Nimri R, Weintrob N, Benzaquen H, Ofan R, terol Nutr 2012;54:136–160 vention Science; the Councils on Cardiovascular Fayman G, Phillip M. Insulin pump therapy in 45. 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Pediatr Diabetes Diabetes Care 2006;29:1891–1896 57. Salem MA, Aboelasrar MA, Elbarbary NS, 2010;11:271–278 48. Margeirsdottir HD, Larsen JR, Brunborg C, Elhilaly RA, Refaat YM. Is exercise a therapeutic 34. Maahs DM, Hermann JM, DuBose SN, et al.; Overby NC, Dahl-Jørgensen K; Norwegian Study tool for improvement of cardiovascular risk fac- DPV Initiative; T1D Exchange Clinic Network. Group for Childhood Diabetes. High prevalence tors in adolescents with type 1 diabetes melli- Contrasting the clinical care and outcomes of of cardiovascular risk factors in children and ad- tus? A randomised controlled trial. Diabetol 2,622 children with type 1 diabetes less than olescents with type 1 diabetes: a population- Metab Syndr 2010;2:47 6 years of age in the United States T1D Exchange based study. Diabetologia 2008;51:554–561 58. McCrindle BW, Urbina EM, Dennison BA, and German/Austrian DPV registries. Diabeto- 49. 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Copeland KC, Zeitler P, Geffner M, et al.; lescents. Pediatrics 2013;131:e648–e664 65. Scott LJ, Warram JH, Hanna LS, Laffel LM, TODAY Study Group. Characteristics of adoles- 84. Arnett JJ. Emerging adulthood. A theory of Ryan L, Krolewski AS. A nonlinear effect of hyper- cents and youth with recent-onset type 2 dia- development from the late teens through the glycemia and current cigarette smoking are major betes: the TODAY cohort at baseline. J Clin twenties. Am Psychol 2000;55:469–480 determinants of the onset of microalbuminuria in Endocrinol Metab 2011;96:159–167 85. Weissberg-Benchell J, Wolpert H, Anderson type 1 diabetes. Diabetes 2001;50:2842–2849 75. DuBose SN, Hermann JM, Tamborlane WV, BJ. Transitioning from pediatric to adult care: a 66. Daniels M, DuBose SN, Maahs DM, et al.; et al.; Type 1 Diabetes Exchange Clinic Network new approach to the post-adolescent young T1D Exchange Clinic Network. 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13. Management of Diabetes American Diabetes Association in Pregnancy Diabetes Care 2017;40(Suppl. 1):S114–S119 | DOI: 10.2337/dc17-S016

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

Recommendations Preexisting Diabetes c Starting at puberty, preconception counseling should be incorporated into routine diabetes care for all girls of childbearing potential. A 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 Preconception counseling should address 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 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. Dilated eye examinations should occur before pregnancy or in the ﬁrst trimester, and then patients should be monitored every trimester and for 1 year postpartum as

13. MANAGEMENT OF DIABETES IN PREGNANCY indicated by degree of retinopathy and as recommended by the eye care provider. B

Gestational Diabetes Mellitus c Lifestyle change is an essential component of management of gestational diabetes mellitus and may sufﬁce for the treatment for many women. Med- ications should be added if needed to achieve glycemic targets. A c Insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent. Metformin and glyburide may be used, but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide. All oral agents lack long-term safety data. A c Metformin, when used to treat polycystic ovary syndrome and induce ovulation, need not be continued once pregnancy has been conﬁrmed. 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 and postprandial self-monitoring of blood glucose are recommended in both gestational diabetes mellitus and preexisting diabetes in pregnancy to achieve glycemic control. Some women with preexisting diabetes should also test blood glucose preprandially. B Suggested citation: American Diabetes Asso- c Due to increased red blood cell turnover, A1C is lower in normal pregnancy ciation. Management of diabetes in preg- than in normal nonpregnant women. The A1C target in pregnancy is 6–6.5% nancy. Sec. 13. In Standards of Medical Care (42–48 mmol/mol); ,6% (42 mmol/mol) may be optimal if this can be in Diabetesd2017. Diabetes Care 2017; – achieved without signiﬁcant hypoglycemia, but the target may be relaxed 40(Suppl. 1):S114 S119 to ,7% (53 mmol/mol) if necessary to prevent hypoglycemia. B © 2017 by the American Diabetes Association. Readers may use this article as long as the work c In pregnant patients with diabetes and chronic hypertension, blood pressure is properly cited, the use is educational and not targets of 120–160/80–105 mmHg are suggested in the interest of optimizing for proﬁt, and the work is not altered. More infor- long-term maternal health and minimizing impaired fetal growth. E mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Management of Diabetes in Pregnancy S115

DIABETES IN PREGNANCY diabetes of childbearing potential normal glucose levels. However, in The prevalence of diabetes in pregnancy should receive education about 1)the women with GDM and preexisting dia- has been increasing in the U.S. The ma- risks of malformations associated with betes, hyperglycemia occurs if treat- jority is gestational diabetes mellitus unplanned pregnancies and poor meta- ment is not adjusted appropriately. (GDM) with the remainder primarily bolic control and 2) the use of effective preexisting type 1 diabetes and type 2 contraception at all times when prevent- Glucose Monitoring diabetes. The rise in GDM and type 2 ing a pregnancy. Preconception counseling Reflecting this physiology, fasting and diabetes in parallel with obesity both using developmentally appropriate edu- postprandial monitoring of blood glucose in the U.S. and worldwide is of particu- cational tools enables adolescent girls to is recommended to achieve metabolic lar concern. Both type 1 diabetes and make well-informed decisions (5). Pre- control in pregnant women with diabe- type 2 diabetes confer significantly conception counseling resources tailored tes. Preprandial testing is also recom- greater maternal and fetal risk than for adolescents are available at no cost mended for women with preexisting GDM, with some differences according through the American Diabetes Associa- diabetes using insulin pumps or basal- to type of diabetes as outlined below. In tion (ADA) (7). bolus therapy, so that premeal rapid- general, specific risks of uncontrolled di- acting insulin dosage can be adjusted. abetes in pregnancy include spontaneous Preconception Testing Postprandial monitoring is associated abortion, fetal anomalies, preeclampsia, Preconception counseling visits should in- with better glycemic control and lower fetal demise, macrosomia, neonatal hy- clude rubella, syphilis, hepatitis B virus, risk of preeclampsia (11–13). There are poglycemia, and neonatal hyperbilirubine- and HIV testing, as well as Pap smear, cer- no adequately powered randomized trials mia, among others. In addition, diabetes in vical cultures, blood typing, prescription of comparing different fasting and postmeal pregnancy may increase the risk of obesity prenatal vitamins (with at least 400 mgof glycemic targets in diabetes in pregnancy. folic acid), and smoking cessation counsel- and type 2 diabetes in offspring later in life Similar to the targets recommended by ing if indicated. Diabetes-specifictesting (1,2). the American College of Obstetricians and should include A1C, thyroid-stimulating Gynecologists (14), the ADA-recommended hormone, creatinine, and urinary albumin– targets for women with type 1 or type 2 PRECONCEPTION COUNSELING to–creatinine ratio; review of the medi- diabetes (the same as for GDM; described All women of childbearing age with di- cation list for potentially teratogenic below) are as follows: abetes should be counseled about the drugs, i.e., ACE inhibitors (8), angiotensin importance of tight glycemic control prior receptor blockers (8), and statins (9,10); ○ Fasting #95 mg/dL (5.3 mmol/L) and to conception. Observational studies show and referral for a comprehensive eye either an increased risk of diabetic embryopathy, exam. Women with preexisting diabetic ○ One-hour postprandial #140 mg/dL especially anencephaly, microcephaly, con- retinopathy will need close monitoring (7.8 mmol/L) or genital heart disease, and caudal regression during pregnancy to ensure that retinop- ○ Two-hour postprandial #120 mg/dL directly proportional to elevations in A1C athy does not progress. (6.7 mmol/L) during the first 10 weeks of pregnancy. Al- though observational studies are confounded GLYCEMIC TARGETS IN These values represent optimal control if by the association between elevated PREGNANCY they can be achieved safely. In practice, it periconceptional A1C and other poor self- Pregnancy in women with normal glu- may be challenging for women with type 1 care behaviors, the quantity and consistency cose metabolism is characterized by diabetes to achieve these targets without of data are convincing and support the rec- fasting levels of blood glucose that are hypoglycemia, particularly women with a ommendation to optimize glycemic con- lower than in the nonpregnant state due history of recurrent hypoglycemia or hypo- trol prior to conception, with A1C ,6.5% to insulin-independent glucose uptake glycemia unawareness. (48 mmol/mol) associated with the low- by the fetus and placenta and by post- If women cannot achieve these tar- est risk of congenital anomalies (3,4). prandial hyperglycemia and carbohydrate gets without significant hypoglycemia, There are opportunities to educate all intolerance as a result of diabetogenic the ADA suggests less stringent targets women and adolescents of reproductive placental hormones. based on clinical experience and individ- age with diabetes about the risks of un- ualization of care. planned pregnancies and the opportuni- Insulin Physiology ties for improved maternal and fetal Early pregnancy is a time of insulin sen- A1C in Pregnancy outcomes with pregnancy planning (5). sitivity, lower glucose levels, and lower Observational studies show the lowest Effective preconception counseling insulin requirements in women with rates of adverse fetal outcomes in associa- could avert substantial health and asso- type 1 diabetes. The situation rapidly tion with A1C ,6–6.5% (42–48 mmol/mol) ciated cost burden in offspring (6). Fam- reverses as insulin resistance increases early in gestation (4,15–17). Clinical tri- ily planning should be discussed, and exponentially during the second and als have not evaluated the risks and ben- effective contraception should be pre- early third trimesters and levels off to- efits of achieving these targets, and scribed and used, until a woman is pre- ward the end of the third trimester. In treatment goals should account for the pared and ready to become pregnant. women with normal pancreatic func- risk of maternal hypoglycemia in set- To minimize the occurrence of com- tion, insulin production is sufficient to ting an individualized target of ,6% plications, beginning at the onset of pu- meet the challenge of this physiological (42 mmol/mol) to ,7% (53 mmol/mol). berty or at diagnosis, all women with insulin resistance and to maintain Due to physiological increases in red S116 Management of Diabetes in Pregnancy Diabetes Care Volume 40, Supplement 1, January 2017

blood cell turnover, A1C levels fall during ○ One-hour postprandial #140 mg/dL Randomized, double-blind, controlled normal pregnancy (18,19). Additionally, as (7.8 mmol/L) or trials comparing metformin with other A1C represents an integrated measure of ○ Two-hour postprandial #120 mg/dL therapies for ovulation induction in glucose, it may not fully capture postpran- (6.7 mmol/L) women with polycystic ovary syndrome dial hyperglycemia, which drives macro- have not demonstrated benefit in pre- somia. Thus, although A1C may be useful, Depending on the population, studies venting spontaneous abortion or GDM it should be used as a secondary measure suggestthat70–85% of women diagnosed (36), and there is no evidence-based of glycemic control, after self-monitoring with GDM under Carpenter-Coustan or need to continue metformin in such pa- of blood glucose. National Diabetes Data Group (NDDG) tients once pregnancy has been con- In the second and third trimesters, criteria can control GDM with lifestyle firmed (37–39). , modification alone; it is anticipated that this A1C 6% (42 mmol/mol) has the lowest Insulin risk of large-for-gestational-age infants, proportion will be even higher if the lower Insulin may be required to treat hyper- whereas other adverse outcomes increase International Association of the Diabetes glycemia, and its use should follow the $ with A1C 6.5% (48 mmol/mol). Taking all and Pregnancy Study Groups (IADPSG) guidelines below. of this into account, a target of 6–6.5% (24) diagnostic thresholds are used. (42–48 mmol/mol) is recommended but MANAGEMENT OF PREEXISTING ,6% (42 mmol/mol) may be optimal as Pharmacologic Therapy Women with greater initial degrees of hy- TYPE 1 DIABETES AND TYPE 2 pregnancy progresses. These levels should perglycemia may require early initiation of DIABETES IN PREGNANCY be achieved without hypoglycemia,which, pharmacologic therapy. Treatment has Insulin Use in addition to the usual adverse sequelae, been demonstrated to improve perinatal Insulin is the preferred agent for manage- may increase the risk of low birth weight. outcomes in two large randomized studies ment of both type 1 diabetes and type 2 Given the alteration in red blood cell kinet- as summarized in a U.S. Preventive Ser- diabetes in pregnancy. ics during pregnancy and physiological vices Task Force review (25). Insulin is the The physiology of pregnancy necessi- changes in glycemic parameters, A1C levels first-line agent recommended for treat- tates frequent titration of insulin to may need to be monitored more frequently ment of GDM in the U.S. While individual match changing requirements and un- than usual (e.g., monthly). randomized controlled trials support the derscores the importance of daily and efficacy and short-term safety of metfor- frequent self-monitoring of blood glu- MANAGEMENT OF GESTATIONAL fi min (26,27) and glyburide (28) for the cose. In the rst trimester, there is DIABETES MELLITUS treatment of GDM, both agents cross the often a decrease in total daily insulin GDM is characterized by increased risk placenta. Long-term safety data are not requirements, and women, particularly of macrosomia and birth complications available for any oral agent (29). those with type 1 diabetes, may experi- and an increased risk of maternal type 2 ence increased hypoglycemia. In the diabetes after pregnancy. The associa- Sulfonylureas second trimester, rapidly increasing in- Concentrations of glyburide in umbilical tion of macrosomia and birth complica- sulin resistance requires weekly or bi- cord plasma are approximately 70% of tions with oral glucose tolerance test weekly increases in insulin dose to maternal levels (30). Glyburide may be (OGTT) results is continuous, with no achieve glycemic targets. In general, a associated with a higher rate of neona- clear inflection points (20). In other smaller proportion of the total daily dose tal hypoglycemia and macrosomia than words, risks increase with progressive hy- should be given as basal insulin (,50%) insulin or metformin (31). perglycemia. Therefore, all women should and a greater proportion (.50%) as pran- be tested as outlined in Section 2 “Clas- Metformin dial insulin. In the late third trimester, sification and Diagnosis of Diabetes.” Metformin may be associated with a there is often a leveling off or small de- Although there is some heterogeneity, lower risk of neonatal hypoglycemia crease in insulin requirements. Due to many randomized controlled trials and less maternal weight gain than in- the complexity of insulin management in suggest that the risk of GDM may be sulin (31–33); however, metformin may pregnancy, referral to a specialized center reduced by diet, exercise, and lifestyle slightly increase the risk of prematurity. offering team-based care (with team counseling (21,22). Furthermore, nearly half of patients members including high-risk obstetrician, with GDM who were initially treated endocrinologist or other provider experi- Lifestyle Management with metformin in a randomized trial enced in managing pregnancy in women After diagnosis, treatment starts with needed insulin in order to achieve ac- with preexisting diabetes, dietitian, nurse, medical nutrition therapy, physical activ- ceptable glucose control (26). Umbilical and social worker, as needed) is recom- ity, and weight management depending cord blood levels of metformin are mended if this resource is available. on pregestational weight, as outlined in higher than simultaneous maternal lev- None of the currently available insulin the section below on preexisting type 2 els (34,35). None of these studies or preparations have been demonstrated diabetes, and glucose monitoring aiming meta-analyses evaluated long-term out- to cross the placenta. for the targets recommended by the Fifth comes in the offspring. Patients treated International Workshop-Conference on with oral agents should be informed that Type 1 Diabetes Gestational Diabetes Mellitus (23): they cross the placenta, and although no Women with type 1 diabetes have an in- adverse effects on the fetus have been creased risk of hypoglycemia in the first ○ Fasting #95 mg/dL (5.3 mmol/L) and demonstrated, long-term studies are trimester and, like all women, have al- either lacking. tered counterregulatory response in care.diabetesjournals.org Management of Diabetes in Pregnancy S117

pregnancy that may decrease hypoglycemia those with diabetes should be supported risk of adverse pregnancy outcomes in awareness. Education for patients and in attempts to breastfeed. Breastfeeding subsequent pregnancies (48) and ear- family members about the prevention, may also confer longer-term metabolic lier progression to type 2 diabetes. recognition, and treatment of hypogly- benefits to both mother (44) and off- Both metformin and intensive life- cemia is important before, during, and spring (45). style intervention prevent or delay pro- after pregnancy to help to prevent and gression to diabetes in women with manage the risks of hypoglycemia. In- Gestational Diabetes Mellitus prediabetes and a history of GDM. Of sulin resistance drops rapidly with de- Initial Testing women with a history of GDM and pre- livery of the placenta. Women become Because GDM may represent preexisting diabetes, only 5–6 women need to be very insulin sensitive immediately fol- undiagnosed type 2 or even type 1 diabe- treated with either intervention to pre- lowing delivery and may initially re- tes, women with GDM should be tested vent one case of diabetes over 3 years quire much less insulin than in the for persistent diabetes or prediabetes (49). In these women, lifestyle interven- prepartum period. at 4–12 weeks’ postpartum with a 75-g tion and metformin reduced progres- Pregnancy is a ketogenic state, and OGTT using nonpregnancy criteria as sion to diabetes by 35% and 40%, women with type 1 diabetes, and to a outlined in Section 2 “Classification and respectively, over 10 years compared lesser extent those with type 2 diabe- Diagnosis of Diabetes.” with placebo (50). If the pregnancy has tes, are at risk for diabetic ketoacidosis motivated the adoption of a healthier at lower blood glucose levels than in the Postpartum Follow-up diet, building on these gains to support The OGTT is recommended over A1C at nonpregnant state. Women with preex- weight loss is recommended in the post- the time of the 4- to 12-week postpar- isting diabetes, especially type 1 diabe- partum period. tum visit because A1C may be persis- tes, need ketone strips at home and tently impacted (lowered) by the education on diabetic ketoacidosis pre- Preexisting Type 1 and Type 2 increased red blood cell turnover re- vention and detection. In addition, rapid Diabetes latedtopregnancyorbloodlossatde- Insulin sensitivity increases with deliv- implementation of tight glycemic con- livery and because the OGTT is more ery of the placenta and then returns to trol in the setting of retinopathy is asso- sensitive at detecting glucose intoler- prepregnancy levels over the following ciated with worsening of retinopathy ance, including both prediabetes and 1–2weeks.Inwomentakinginsulin,par- (40). diabetes. Reproductive-aged women ticular attention should be directed to with prediabetes may develop type 2 di- hypoglycemia prevention in the setting Type 2 Diabetes Type 2 diabetes is often associated with abetes by the time of their next preg- of breastfeeding and erratic sleep and obesity. Recommended weight gain nancy and will need preconception eating schedules. during pregnancy for overweight evaluation. Because GDM is associated with increased maternal risk for diabe- Contraception women is 15–25 lb and for obese A major barrier to effective preconcep- tes, women should also be tested every women is 10–20 lb (41). Glycemic con- tion care is the fact that the majority of 1–3 years thereafter if the 4- to 12-week trol is often easier to achieve in women pregnancies are unplanned. Planning 75-g OGTT is normal, with frequency of with type 2 diabetes than in those with pregnancy is critical in women with pre- testing depending on other risk factors type 1 diabetes but can require much existing diabetes due to the need for including family history, prepregnancy higher doses of insulin, sometimes ne- preconception glycemic control and BMI,andneedforinsulinororalglucose- cessitating concentrated insulin formu- preventive health services. Therefore, lowering medication during pregnancy. lations. As in type 1 diabetes, insulin all women with diabetes of childbearing Ongoing evaluation may be performed requirements drop dramatically after potential should have family planning with any recommended glycemic test delivery. The risk for associated hyper- options reviewed at regular intervals. (e.g., hemoglobin A1C, fasting plasma tension and other comorbidities may be This applies to women in the immediate glucose, or 75-g OGTT using nonpreg- as high or higher with type 2 diabetes as postpartum period. Women with diabe- nant thresholds). with type 1 diabetes, even if diabetes is tes have the same contraception options better controlled and of shorter appar- Gestational Diabetes Mellitus and Type 2 and recommendations as those without ent duration, with pregnancy loss ap- Diabetes diabetes. The risk of an unplanned preg- pearing to be more prevalent in the Women with a history of GDM have a nancy outweighs the risk of any given third trimester in women with type 2 di- greatly increased risk of conversion to contraception option. abetes compared with the first trimester type 2 diabetes over time and not solely in women with type 1 diabetes (42,43). within the 4- to 12-week postpartum PREGNANCY AND DRUG time frame (46). In the prospective CONSIDERATIONS POSTPARTUM CARE Nurses’ Health Study II, subsequent di- In normal pregnancy, blood pressure is Postpartum care should include psychoso- abetes risk after a history of GDM was lower than in the nonpregnant state. fi cial assessment and support for self-care. signi cantly lower in women who fol- In a pregnancy complicated by diabe- lowed healthy eating patterns (47). Ad- tes and chronic hypertension, target Lactation justing for BMI moderately, but not goals for systolic blood pressure 120– In light of the immediate nutritional and completely, attenuated this associa- 160 mmHg and diastolic blood pres- immunological benefits of breastfeed- tion. Interpregnancy or postpartum sure 80–105 mmHg are reasonable ing for the baby, all women including weight gain is associated with increased (51). Lower blood pressure levels may S118 Management of Diabetes in Pregnancy Diabetes Care Volume 40, Supplement 1, January 2017

be associated with impaired fetal growth. systematic review. Hypertension 2012;60:444– 24. Mayo K, Melamed N, Vandenberghe H, In a 2015 study targeting diastolic blood 450 Berger H. The impact of adoption of the Inter- pressure of 100 mmHg versus 85 mmHg in 9. Taguchi N, Rubin ET, Hosokawa A, et al. Pre- national Association of Diabetes in Pregnancy natal exposure to HMG-CoA reductase inhibi- Study Group criteria for the screening and di- pregnant women, only 6% of whom had tors: effects on fetal and neonatal outcomes. agnosis of gestational diabetes. Am J Obstet GDM at enrollment, there was no differ- Reprod Toxicol 2008;26:175–177 Gynecol 2015;212:224.e1–224.e9 ence in pregnancy loss, neonatal care, 10. Bateman BT, Hernandez-Diaz S, Fischer MA, 25. Hartling L, Dryden DM, Guthrie A, Muise M, or other neonatal outcomes, although et al. Statins and congenital malformations: co- Vandermeer B, Donovan L. Benefits and harms women in the less intensive treatment hort study. BMJ 2015;350:h1035 of treating gestational diabetes mellitus: a sys- 11. Manderson JG, Patterson CC, Hadden DR, tematic review and meta-analysis for the U.S. group had a higher rate of uncontrolled Traub AI, Ennis C, McCance DR. Preprandial ver- Preventive Services Task Force and the National hypertension (52). sus postprandial blood glucose monitoring in Institutes of Health Office of Medical Applica- During pregnancy, treatment with type 1 diabetic pregnancy: a randomized con- tions of Research. Ann Intern Med 2013;159: ACE inhibitors and angiotensin receptor trolled clinical trial. Am J Obstet Gynecol 2003; 123–129 blockers is contraindicated because 189:507–512 26. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin they may cause fetal renal dysplasia, oli- 12. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose versus insulin for the treatment of gestational gohydramnios, and intrauterine growth monitoring in women with gestational diabetes diabetes. N Engl J Med 2008;358:2003–2015 restriction (8). Antihypertensive drugs mellitus requiring insulin therapy. N Engl J Med 27. Gui J, Liu Q, Feng L. Metformin vs insulin in known to be effective and safe in preg- 1995;333:1237–1241 the management of gestational diabetes: a nancy include methyldopa, labetalol, dil- 13. Jovanovic-Peterson L, Peterson CM, Reed meta-analysis. PLoS One 2013;8:e64585 28. Langer O, Conway DL, Berkus MD, Xenakis tiazem, clonidine, and prazosin. Chronic GF, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early EM, Gonzales O. A comparison of glyburide and diuretic use during pregnancy is not rec- Pregnancy Study. The National Institute of Child insulin in women with gestational diabetes mel- – ommended as it has been associated Health and Human DevelopmentdDiabetes in litus. N Engl J Med 2000;343:1134 1138 with restricted maternal plasma volume, Early Pregnancy Study. Am J Obstet Gynecol 29. Coustan DR. Pharmacological management which may reduce uteroplacental perfu- 1991;164:103–111 of gestational diabetes: an overview. Diabetes Care 2007;30(Suppl. 2):S206–S208 sion (53). On the basis of available evi- 14. Committee on Practice BulletinsdObstetrics. Practice Bulletin No. 137: gestational diabetes 30. Hebert MF, Ma X, Naraharisetti SB, et al.; dence, statins should also be avoided in Obstetric-Fetal Pharmacology Research Unit mellitus. Obstet Gynecol 2013;122:406–416 pregnancy (54). 15. Nielsen GL, Møller M, Sørensen HT. HbA1c Network. Are we optimizing gestational diabetes treatment with glyburide? The pharmaco- in early diabetic pregnancy and pregnancy out- logic basis for better clinical practice. Clin comes: a Danish population-based cohort study References Pharmacol Ther 2009;85:607–614 of 573 pregnancies in women with type 1 dia- 1. Holmes VA, Young IS, Patterson CC, et al.; 31. Balsells M, Garc´ıa-Patterson A, SolaI,Roqu` e´ betes. Diabetes Care 2006;29:2612–2616 Diabetes and Pre-eclampsia Intervention Trial M, Gich I, Corcoy R. Glibenclamide, metformin, 16. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic Study Group. Optimal glycemic control, pre- and insulin for the treatment of gestational dia- control during early pregnancy and fetal malfor- eclampsia, and gestational hypertension in betes: a systematic review and meta-analysis. mations in women with type 1 diabetes mellitus. womenwithtype1diabetesinthediabetes BMJ 2015;350:h102 Diabetologia 2000;43:79–82 and pre-eclampsia intervention trial. Diabetes 32. Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu 17. Maresh MJA, Holmes VA, Patterson CC, Care 2011;34:1683–1688 Z-N, Su S-W. Comparative efficacy and safety of et al.; Diabetes and Pre-eclampsia Intervention 2. Dabelea D, Hanson RL, Lindsay RS, et al. In- OADs in management of GDM: network meta- Trial Study Group. Glycemic targets in the sec- trauterine exposure to diabetes conveys risks analysis of randomized controlled trials. J Clin for type 2 diabetes and obesity: a study of dis- ond and third trimester of pregnancy for Endocrinol Metab 2015;100:2071–2080 cordant sibships. Diabetes 2000;49:2208–2211 womenwithtype1diabetes.DiabetesCare 33. Camelo Castillo W, Boggess K, Sturmer¨ T, – 3. Guerin A, Nisenbaum R, Ray JG. Use of ma- 2015;38:34 42 Brookhart MA, Benjamin DK Jr, Jonsson Funk ternal GHb concentration to estimate the risk of 18. Nielsen LR, Ekbom P, Damm P, et al. HbA1c M. Association of adverse pregnancy outcomes fi congenital anomalies in the offspring of women levels are signi cantly lower in early and late with glyburide vs insulin in women with ges- – with prepregnancy diabetes. Diabetes Care pregnancy. Diabetes Care 2004;27:1200 1201 tational diabetes. JAMA Pediatr 2015;169: 2007;30:1920–1925 19. Mosca A, Paleari R, Dalfra` MG, et al. Refer- 452–458 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- ence intervals for hemoglobin A1c in pregnant 34. Vanky E, Zahlsen K, Spigset O, Carlsen SM. conceptional A1C and risk of serious adverse women: data from an Italian multicenter study. Placental passage of metformin in women with – pregnancy outcome in 933 women with type 1 Clin Chem 2006;52:1138 1143 polycystic ovary syndrome. Fertil Steril 2005;83: diabetes. Diabetes Care 2009;32:1046–1048 20. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO 1575–1578 5. Charron-Prochownik D, Sereika SM, Becker Study Cooperative Research Group. Hyperglyce- 35. Charles B, Norris R, Xiao X, Hague W. Pop- D, et al. Long-term effects of the booster- mia and adverse pregnancy outcomes. N Engl J ulation pharmacokinetics of metformin in late enhanced READY-Girls preconception counsel- Med 2008;358:1991–2002 pregnancy. Ther Drug Monit 2006;28:67–72 ing program on intentions and behaviors for 21. Bain E, Crane M, Tieu J, Han S, Crowther CA, 36.VankyE,StridsklevS,HeimstadR,etal. family planning in teens with diabetes. Diabetes Middleton P. Diet and exercise interventions Metformin versus placebo from first trimester Care 2013;36:3870–3874 for preventing gestational diabetes mellitus. to delivery in polycystic ovary syndrome: a ran- 6. Peterson C, Grosse SD, Li R, et al. Preventable Cochrane Database Syst Rev 2015;4:CD010443 domized, controlled multicenter study. J Clin health and cost burden of adverse birth out- 22. Koivusalo SB, Ron¨ o¨ K, Klemetti MM, et al. Endocrinol Metab 2010;95:E448–E455 comes associated with pregestational diabetes Gestational diabetes mellitus can be prevented 37. Legro RS, Barnhart HX, Schlaff WD, et al.; in the United States. Am J Obstet Gynecol 2015; by lifestyle intervention: the Finnish Gestational Cooperative Multicenter Reproductive Medi- 212:74.e1–74.e9 Diabetes Prevention Study (RADIEL): a random- cine Network. Clomiphene, metformin, or 7. Charron-Prochownik D, Downs J. Diabetes ized controlled trial. Diabetes Care 2016;39: both for infertility in the polycystic ovary syn- and Reproductive Health for Girls. Alexandria, 24–30 drome. N Engl J Med 2007;356:551–566 VA, American Diabetes Association, 2016 23. Metzger BE, Buchanan TA, Coustan DR, 38. Palomba S, Orio F Jr, Falbo A, et al. Pro- 8. Bullo M, Tschumi S, Bucher BS, Bianchetti et al. Summary and recommendations of the spective parallel randomized, double-blind, MG, Simonetti GD. Pregnancy outcome follow- Fifth International Workshop-Conference on double-dummy controlled clinical trial comparing exposure to angiotensin-converting enzyme Gestational Diabetes Mellitus. Diabetes Care ing clomiphene citrate and metformin as the inhibitors or angiotensin receptor antagonists: a 2007;30(Suppl. 2):S251–S260 first-line treatment for ovulation induction in care.diabetesjournals.org Management of Diabetes in Pregnancy S119

nonobese anovulatory women with polycystic 43. Cundy T, Gamble G, Neale L, et al. Differing and lifestyle interventions. J Clin Endocrinol ovary syndrome. J Clin Endocrinol Metab causes of pregnancy loss in type 1 and type 2 Metab 2008;93:4774–4779 2005;90:4068–4074 diabetes. Diabetes Care 2007;30:2603–2607 50. Aroda VR, Christophi CA, Edelstein SL, et al.; 39.PalombaS,OrioFJr,NardoLG,etal.Met- 44. Stuebe AM, Rich-Edwards JW, Willett WC, Diabetes Prevention Program Research Group. formin administration versus laparoscopic Manson JE, Michels KB. Duration of lactation The effect of lifestyle intervention and metformin ovarian diathermy in clomiphene citrate-resistant and incidence of type 2 diabetes. JAMA 2005; on preventing or delaying diabetes among women with polycystic ovary syndrome: a prospec- 294:2601–2610 women with and without gestational diabetes: tive parallel randomized double-blind placebo- 45. Pereira PF, Alfenas R de C, Araujo´ RM. Does the Diabetes Prevention Program Outcomes controlled trial. J Clin Endocrinol Metab 2004; breastfeeding inﬂuence the risk of developing – Study 10-year follow-up. J Clin Endocrinol Metab 89:4801 4809 diabetes mellitus in children? A review of cur- 2015;100:1646–1653 40. Chew EY, Mills JL, Metzger BE, et al. Meta- – rent evidence. J Pediatr (Rio J) 2014;90:7 15 51. American College of Obstetricians and Gy- bolic control and progression of retinopathy. 46. Kim C, Newton KM, Knopp RH. Gestational The Diabetes in Early Pregnancy Study. National necologists; Task Force on Hypertension in diabetes and the incidence of type 2 diabetes: a Institute of Child Health and Human Develop- Pregnancy. Hypertension in pregnancy. Report systematic review. Diabetes Care 2002;25: ment Diabetes in Early Pregnancy Study. Diabe- of the American College of Obstetricians and 1862–1868 tes Care 1995;18:631–637 ’ 47. Tobias DK, Hu FB, Chavarro J, Rosner B, Gynecologists Task Force on Hypertension in 41. National Research Council; Institute of – Mozaffarian D, Zhang C. Healthful dietary pat- Pregnancy. Obstet Gynecol 2013;122:1122 Medicine; Food and Nutrition Board; Board on terns and type 2 diabetes mellitus risk among 1131 Children, Youth, and Families; Committee to Re- 52. Magee LA, von Dadelszen P, Rey E, et al. examine IOM Pregnancy Weight Guidelines. women with a history of gestational diabetes – Less-tight versus tight control of hypertension Weight Gain During Pregnancy: Reexamining mellitus. Arch Intern Med 2012;172:1566 1572 in pregnancy. N Engl J Med 2015;372:407–417 the Guidelines. Washington, DC, The National 48. Villamor E, Cnattingius S. Interpregnancy 53. Sibai BM. Treatment of hypertension in Academies Press, 2009. Available from http:// weight change and risk of adverse pregnancy – www.nap.edu/catalog/12584. Accessed 5 Octo- outcomes: a population-based study. Lancet pregnant women. N Engl J Med 1996;335:257 ber 2016 2006;368:1164–1170 265 42. Clausen TD, Mathiesen E, Ekbom P, Hellmuth 49. Ratner RE, Christophi CA, Metzger BE, et al.; 54. Kazmin A, Garcia-Bournissen F, Koren G. E, Mandrup-Poulsen T, Damm P. Poor pregnancy Diabetes Prevention Program Research Group. Risks of statin use during pregnancy: a system- outcome in women with type 2 diabetes. Diabetes Prevention of diabetes in women with a history atic review. J Obstet Gynaecol Can 2007;29: Care 2005;28:323–328 of gestational diabetes: effects of metformin 906–908 S120 Diabetes Care Volume 40, Supplement 1, January 2017

14. Diabetes Care in the Hospital American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S120–S127 | DOI: 10.2337/dc17-S017

Recommendations c Perform an A1C for all patients with diabetes or hyperglycemia admitted to the hospital if not performed in the prior 3 months. B 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 ,140 mg/dL (,7.8 mmol/L), may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. C 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 Basal insulin or 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 noncritically ill hospitalized patients with good nutritional intake. A c Sole use of sliding scale insulin in the inpatient hospital setting is strongly

14. DIABETES CARE IN THE HOSPITAL 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 as 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 with diabetes. B

In the hospital, both hyperglycemia and hypoglycemia are associated with adverse outcomes including death (1,2). Therefore, inpatient goals should include the prevention of both hyperglycemia and hypoglycemia. Hospitals should promote the shortest, safe hospital stay and provide an effective transition out of the hospital that prevents acute complications and readmission. For in-depth review of inpatient hospital practice, consult recent reviews that focus on hospital care for diabetes (3,4).

HOSPITAL CARE DELIVERY STANDARDS High-quality hospital care for diabetes requires both hospital care delivery standards, often assured by structured order sets, and quality assurance standards for process improvement. “Best practice” protocols, reviews, and guidelines (2) are inconsistently implemented within hospitals. To correct this, hospitals have estab- Suggested citation: American Diabetes Associa- lished protocols for structured patient care and structured order sets, which include tion. Diabetes care in the hospital. Sec. 14. In Standards of Medical Care in Diabetesd2017. computerized physician order entry (CPOE). Diabetes Care 2017;40(Suppl. 1):S120–S127 Considerations on Admission © 2017 by the American Diabetes Association. Initial orders should state the type of diabetes (i.e., type 1 or type 2 diabetes) or no Readers may use this article as long as the work is properly cited, the use is educational and not previous history of diabetes. Because inpatient insulin use (5) and discharge orders for proﬁt, and the work is not altered. More infor- (6) can be more effective if based on an A1C level on admission (7), perform an A1C mation is available at http://www.diabetesjournals test on all patients with diabetes or hyperglycemia admitted to the hospital if the .org/content/license. care.diabetesjournals.org Diabetes Care in the Hospital S121

test has not been performed in the prior (7.8 mmol/L). Blood glucose levels that are (e.g., glucocorticoids), should be incor- 3 months. In addition, diabetes self- persistently above this level may require porated into the day-to-day decisions re- management knowledge and behaviors alterations in diet or a change in medica- garding insulin doses (2). should be assessed on admission and tions that cause hyperglycemia. An admis- diabetes self-management education sion A1C value $6.5% (48 mmol/mol) BEDSIDE BLOOD GLUCOSE (DSME) should be provided, if appropri- suggests that diabetes preceded hos- MONITORING “ fi ate. DSME should include appropriate pitalization (see Section 2 Classi cation Indications ” skills needed after discharge, such as and Diagnosis of Diabetes ). Previously, In the patient who is eating meals, glu- taking antihyperglycemic medications, hypoglycemia in hospitalized patients cose monitoring should be performed fi monitoring glucose, and recognizing has been de ned as blood glucose before meals. In the patient who is not , and treating hypoglycemia (2). 70 mg/dL (3.9 mmol/L) and severe hy- eating, glucose monitoring is advised ev- , poglycemia as 40 mg/dL (2.2 mmol/L) ery 4–6 h (2). More frequent blood glu- Computerized Physician Order Entry (14). However, the American Diabetes As- The Institute of Medicine recommends cose testing ranging from every 30 min sociation (ADA) now defines clinically sig- CPOE to prevent medication-related er- to every 2 h is required for patients re- nificant hypoglycemia as glucose values rors and to increase efficiency in medica- ceiving intravenous insulin. Safety stan- ,54 mg/dL (3.0 mmol/L), while severe hy- tion administration (8). A Cochrane review dards should be established for blood poglycemia is defined as that associated of randomized controlled trials using glucose monitoring that prohibit the with severe cognitive impairment regard- computerized advice to improve glucose sharing of fingerstick lancing devices, less of blood glucose level (see Section 6 control in the hospital found significant lancets, and needles (17). “Glycemic Targets” for additional detail on improvement in the percentage of time the new hypoglycemia criteria) (15). A patients spent in the target glucose range, Point-of-Care Meters blood glucose level of #70 mg/dL is con- lower mean blood glucose levels, and no Point-of-care (POC) meters have limitations sideredanalertvalueandmaybeusedas increase in hypoglycemia (9). Thus, where for measuring blood glucose. Although the a threshold for further titration of insulin feasible, there should be structured order U.S. Food and Drug Administration (FDA) regimens. sets that provide computerized advice for has standards for blood glucose meters glucose control. Electronic insulin order used by lay persons, there have been Moderate Versus Tight Glycemic templates also improve mean glucose questions about the appropriateness of Control levels without increasing hypoglycemia these criteria, especially in the hospital A meta-analysis of over 26 studies, in- in patients with type 2 diabetes, so struc- and for lower blood glucose readings cluding the Normoglycemia in Intensive fi tured insulin order sets should be incor- (18). Signi cant discrepancies between Care Evaluation–Survival Using Glucose porated into the CPOE (10). capillary, venous, and arterial plasma Algorithm Regulation (NICE-SUGAR) sampleshavebeenobservedinpatients Diabetes Care Providers in the study, showed increased rates of severe with low or high hemoglobin concentra- Hospital hypoglycemia (blood glucose ,40 mg/dL) tions and with hypoperfusion. Any glucose Appropriately trained specialists or spe- and mortality in tightly versus moderately result that does not correlate with the pa- cialty teams may reduce length of stay, controlled cohorts (16). This evidence es- tient’s clinical status should be confirmed improve glycemic control, and improve tablished new standards: insulin therapy through conventional laboratory glucose outcomes, but studies are few. A call to should be initiated for treatment of per- tests. The FDA established a separate cat- action outlined the studies needed to sistent hyperglycemia starting at a egory for POC glucose meters for use in evaluate these outcomes (11). Details threshold $180 mg/dL (10.0 mmol/L). health care settings and has released a of team formation are available from the Once insulin therapy is started, a tar- guidance on in-hospital use with stricter Society of Hospital Medicine and the Joint get glucose range of 140–180 mg/dL standards (19). Before choosing a device Commission standards for programs. (7.8–10.0 mmol/L) is recommended for for in-hospital use, consider the device’s the majority of critically ill and noncriti- approval status and accuracy. Quality Assurance Standards cally ill patients (2). More stringent goals, Even the best orders may not be carried such as ,140 mg/dL (,7.8 mmol/L), may Continuous Glucose Monitoring out in a way that improves quality, nor are be appropriate for selected patients, as Continuous glucose monitoring (CGM) they automatically updated when new ev- long as this can be achieved without sig- provides frequent measurements of inter- idence arises. To this end, the Joint Com- nificant hypoglycemia. Conversely, higher stitial glucose levels, as well as direction mission has an accreditation program for glucose ranges may be acceptable in ter- and magnitude of glucose trends, which the hospital care of diabetes (12), and the minally ill patients, in patients with severe may have an advantage over POC glucose Society of Hospital Medicine has a work- comorbidities, and in inpatient care set- testing in detecting and reducing the inci- book for program development (13). tings where frequent glucose monitoring dence of hypoglycemia. Several inpatient or close nursing supervision is not feasible. studies have shown that CGM use did not GLYCEMIC TARGETS IN Clinical judgment combined with on- improve glucose control but detected a HOSPITALIZED PATIENTS going assessment of the patient’s clinical greater number of hypoglycemic events Standard Definition of Glucose status, including changes in the trajectory than POC testing. However, a recent review Abnormalities of glucose measures, illness severity, has recommended against using CGM in Hyperglycemiainhospitalizedpatientsisde- nutritional status, or concomitant medi- adults in a hospital setting until more safety fined as blood glucose levels .140 mg/dL cations that might affect glucose levels and efficacy data become available (20). S122 Diabetes Care in the Hospital Diabetes Care Volume 40, Supplement 1, January 2017

ANTIHYPERGLYCEMIC AGENTS glycemic control and reduced hospital of hypoglycemia compared with a basal- IN HOSPITALIZED PATIENTS complications compared with sliding bolus regimen (30). However, a recent In most instances in the hospital setting, scale insulin in general surgery patients FDA bulletin states that providers should insulin is the preferred treatment for with type 2 diabetes (23). Prolonged consider discontinuing saxagliptin and glycemic control (2). However, in certain sole use of sliding scale insulin in the alogliptin in people who develop heart circumstances, it may be appropriate to inpatient hospital setting is strongly failure (31). A review of antihyper- continue home regimens including oral discouraged (2,11). glycemic medications concluded that antihyperglycemic medications (21). If While there is evidence for using pre- glucagon-like peptide 1 receptor ago- oral medications are held in the hospital, mixed insulin formulations in the out- nists show promise in the inpatient set- there should be a protocol for resuming patient setting (24), a recent inpatient ting (32); however, proof of safety and them 1–2 days before discharge. Insulin study of 70/30 NPH/regular versus efficacy await the results of randomized pens are the subject of an FDA warning basal-bolus therapy showed compara- controlled trials (33). Moreover, the gas- due to potential blood-borne diseases, ble glycemic control but signifcantly in- trointestinal symptoms associated with and care should be taken to follow the creasedhypoglycemiainthegroup the glucagon-like peptide 1 receptor ago- label insert “For single patient use only.” receiving premixed insulin. Therefore, nists may be problematic in the inpatinet premixed insulin regimens are not rou- setting. tinely recommended for in hospital use. Regarding the sodium–glucose trans- Insulin Therapy Type 1 Diabetes porter 2 (SGLT2) inhibitors, the FDA in- Critical Care Setting For patients with type 1 diabetes, dosing cludes warnings about DKA and urosepsis In the critical care setting, continuous in- insulin based solely on premeal glucose (34), urinary tract infections, and kidney travenous insulin infusion has been shown levels does not account for basal insulin injury (35) on the drug labels. A recent to be the best method for achieving gly- requirements or caloric intake, increasing review suggested SGLT2 inhibitors be cemic targets. Intravenous insulin infu- both hypoglycemia and hyperglycemia avoided in severe illness, when ketone sions should be administered based on risks and potentially leading to diabetic bodies are present, and during prolonged validated written or computerized proto- ketoacidosis (DKA). Typically basal insulin fasting and surgical procedures (3). Until cols that allow for predefined adjustments dosing schemes are based on body safety and effectivenss are established, in the infusion rate, accounting for glyce- weight, with some evidence that pa- SGLT2 inhibitors cannot be recommended mic fluctuations and insulin dose (2). tients with renal insufficiency should be for routine in-hospital use. Noncritical Care Setting treated with lower doses (25). Outside of critical care units, scheduled HYPOGLYCEMIA insulin regimens are recommended to Transitioning Intravenous to Patients with or without diabetes may Subcutaneous Insulin manage hyperglycemia in patients with experience hypoglycemia in the hospital When discontinuing intravenous insu- diabetes. Regimens using insulin analogs setting. While hypoglycemia is associ- lin, a transition protocol is associated and human insulin result in similar glyce- ated with increased mortality, hypogly- with less morbidity and lower costs of mic control in the hospital setting (22). cemia may be a marker of underlying care (26) and is therefore recommended. The use of subcutaneous rapid- or disease rather than the cause of increased A patient with type 1 or type 2 diabetes short-acting insulin before meals or mortality. However, until it is proven not being transitioned to outpatient subcu- every 4–6 h if no meals are given or if to be causal, it is prudent to avoid hypo- taneous insulin should receive subcu- the patient is receiving continuous en- glycemia. Despite the preventable nature taneous basal insulin 1–2 h before the teral/parenteral nutrition is indicated to of many inpatient episodes of hypoglyce- intravenous insulin is discontinued. Con- correct hyperglycemia (2). Basal insulin mia, institutions are more likely to have verting to basal insulin at 60–80% of the or a basal plus bolus correction insulin nursing protocols for hypoglycemia treat- daily infusion dose has been shown to be regimen is the preferred treatment for ment than for its prevention when both effective (2,26,27). For patients continuing noncritically ill patients with poor oral are needed. regimens with concentrated insulin in the intake or those who are taking nothing A hypoglycemia prevention and man- inpatient setting, it is important to ensure by mouth (NPO). An insulin regimen with agement protocol should be adopted the correct dosing by utilizing an individual basal, nutritional, and correction com- and implemented by each hospital or pen and cartrige for each patient, meticu- ponents is the preferred treatment for hospital system. There should be a stan- lous pharmacist supervision of the dose noncritically ill hospitalized patients dardized hospital-wide, nurse-initiated administered, or other means (28,29). with good nutritional intake. hypoglycemia treatment protocol to im- If the patient is eating, insulin injections Noninsulin Therapies mediately address blood glucose levels should align with meals. In such instances, The safety and efficacy of noninsulin of #70 mg/dL [3.9 mmol/L], as well as POC glucose testing should be performed antihyperglycemic therapies in the hospi- individualized plans for preventing and immediately before meals. If oral intake is tal setting is an area of active research. A treating hypoglycemia for each patient. poor, a safer procedure is to administer the recent randomized pilot trial in general An ADA consensus report suggested rapid-acting insulin immediately after the medicine and surgery patients reported that a patient’s overall treatment regi- patient eats or to count the carbohydrates that a dipeptidyl peptidase 4 inhibitor men be reviewed when a blood glucose and cover the amount ingested (22). alone or in combination with basal in- value of ,70 mg/dL (3.9 mmol/L) is iden- A randomized controlled trial has shown sulin was well tolerated and resulted tified because such readings often pre- that basal-bolus treatment improved in similar glucose control and frequency dict imminent severe hypoglycemia (2). care.diabetesjournals.org Diabetes Care in the Hospital S123

Episodes of hypoglycemia in the hospital food preferences, and facilitate creation STANDARDS FOR SPECIAL should be documented in the medical of a discharge plan. The ADA does not SITUATIONS record and tracked (2). endorse any single meal plan or speci- Enteral/Parenteral Feedings fied percentages of macronutrients, and For patients receiving enteral or par- Triggering Events the term “ADA diet” should no longer be enteral feedings who require insulin, Iatrogenic hypoglycemia triggers may used. Current nutrition recommenda- insulin should be divided into basal, nu- include sudden reduction of corticoste- tions advise individualization based on tritional, and correctional components. roid dose, reduced oral intake, emesis, treatment goals, physiological parame- This is particularly important for people new NPO status, inappropriate timing of ters, and medication use. Consistent with type 1 diabetes to ensure that they short-acting insulin in relation to meals, carbohydrate meal plans are preferred continue to receive basal insulin even if reduced infusion rate of intravenous by many hospitals as they facilitate the feedings are discontinued. One may dextrose, unexpected interruption of matching the prandial insulin dose to use the patient’s preadmission basal in- oral, enteral, or parenteral feedings, the amount of carbohydrate consumed sulin dose or a percentage of the total and altered ability of the patient to re- (40). Regarding enteral nutritional ther- daily dose of insulin when the patient is port symptoms. apy, diabetes-specificformulasappear being fed (usually 30 to 50% of the total Predictors of Hypoglycemia to be superior to standard formulas in daily dose of insulin) to estimate basal In one study, 84% of patients with controlling postprandial glucose, A1C insulin requirements. However, if no an episode of severe hypoglycemia and the insulin response (41). basal insulin was used, consider using (,40 mg/dL [2.2 mmol/L]) had a prior When the nutritional issues in the hos- 5 units of NPH/detemir insulin subcuta- episode of hypoglycemia (,70 mg/dL pital are complex, a registered dietitian, neously every 12 h or 10 units of insulin [3.9 mmol/L]) during the same admission knowledgeable and skilled in medical nu- glargine every 24 h (43). For patients re- (36). In another study of hypoglycemic trition therapy, can serve as an individual ceiving continuous tube feedings, the to- episodes (,50 mg/dL [2.8 mmol/L]), inpatient team member. That person tal daily nutritional component may be 78% of patients were using basal insulin, should be responsible for integrating in- calculated as 1 unit of insulin for every with the incidence of hypoglycemia formation about the patient’s clinical con- 10–15 g carbohydrate per day or as a peaking between midnight and 6 A.M. dition, meal planning, and lifestyle habits percentage of the total daily dose of in- Despite recognition of hypoglycemia, and for establishing realistic treatment sulin when the patient is being fed (usu- 75% of patients did not have their dose goals after discharge. Orders should also ally 50 to 70% of the total daily dose of of basal insulin changed before the next indicate that the meal delivery and nutri- insulin) Correctional insulin should also insulin administration (37). tional insulin coverage should be coordi- be administered subcutaneously every nated, as their variability often creates 6 h using human regular insulin or every Prevention the possibility of hyperglycemic and hy- 4 h using a rapid-acting insulin such as Common preventable sources of iatro- poglycemic events. lispro, aspart, or glulisine. For patients genic hypoglycemia are improper pre- receiving enteral bolus feedings, approx- scribing of hypoglycemic medications, imately 1 unit of regular human insulin fi inappropriate management of the rst SELF-MANAGEMENT IN THE or rapid-acting insulin should be given – episode of hypoglycemia, and nutrition HOSPITAL per 10–15 g carbohydrate subcutane- insulin mismatch, often related to an Diabetes self-management in the hospital ously before each feeding. Correctional unexpected interruption of nutrition. may be appropriate for select youth and insulin coverage should be added as “ ” Studies of bundled preventative thera- adult patients. Candidates include patients needed before each feeding. For pa- pies including proactive surveillance of who successfully conduct self-management tients receiving continuous peripheral glycemic outliers and an interdisciplinary of diabetes at home, have the cognitive or central parenteral nutrition, regular data-drivenapproachtoglycemicman- and physical skills needed to successfully insulin may be added to the solution, agement showed that hypoglycemic self-administer insulin, and perform self- particularly if .20 units of correctional episodes in the hospital could be pre- monitoring of blood glucose. In addition, insulin have been required in the past vented. Compared with baseline, two they should have adequate oral intake, be 24 h. A starting dose of 1 unit of human such studies found that hypoglycemic proficient in carbohydrate estimation, regular insulin for every 10 g dextrose has events fell by 56% to 80% (38,39). The use multiple daily insulin injections or been recommended (44), to be adjusted Joint Commission recommends that all continuous subcutaneous insulin infusion daily in the solution. Correctional insulin hypoglycemic episodes be evaluated (CSII) pump therapy, have stable insulin should be administered subcutaneously. for a root cause and the episodes be requirements, and understand sick-day For full enteral/parenteral feeding guid- aggregated and reviewed to address management. If self-management is to ance, the reader is encouraged to consult systemic issues. be used, a protocol should include a re- review articles (2,45) and see Table 14.1. quirement that the patient, nursing staff, MEDICAL NUTRITION THERAPY and physician agree that patient self- Glucocorticoid Therapy IN THE HOSPITAL management is appropriate. If CSII is to Glucocorticoid type and duration of ac- The goals of medical nutrition therapy in be used, hospital policy and procedures tion must be considered in determining the hospital are to provide adequate cal- delineating guidelines for CSII therapy in- insulin treatment regimens. Once-a- ories to meet metabolic demands, opti- cluding the changing of infusion sites are day, short-acting glucocorticoids such mize glycemic control, address personal advised (42). as prednisone peak in about 4 to 8 h S124 Diabetes Care in the Hospital Diabetes Care Volume 40, Supplement 1, January 2017

Table 14.1—Insulin dosing for enteral/parenteral feedings Situation Basal/nutritional Correctional Continuous enteral feedings Continueprior basalor,if none,calculatefromTDDor SQ regular insulin every 6 h or rapid-acting insulin consider 5 units NPH/detemir every 12 h or every 4 h for hyperglycemia 10 units glargine daily Nutritional: regular insulin every 6 h or rapid-acting insulin every 4 h, starting with 1 unit per 10–15 g of carbohydrate; adjust daily Bolus enteral feedings Continueprior basalor,if none,calculatefromTDDor SQ regular insulin every 6 h or rapid-acting insulin consider 5 units NPH/detemir every 12 h or every 4 h for hyperglycemia 10 units glargine daily Nutritional:giveregularinsulinorrapid-actinginsulin SQbeforeeachfeeding, startingwith1unitper10– 15 g of carbohydrate; adjust daily Parenteral feedings Add regular insulin to TPN IV solution, starting with SQ regular insulin every 6 h or rapid-acting insulin 1 unit per 10 g of carbohydrate; adjust daily every 4 h for hyperglycemia IV, intravenous; SQ, subcutaneous; TDD, total daily dose; TPN, total parenteral nutrition.

(46), so coverage with intermediate- In noncardiac general surgery patients, with intravenous insulin (54). If sub- acting insulin (NPH) may be sufficient. For basal insulin plus premeal regular or cutaneous administration is used, it is long-acting glucocorticoids such as short-acting insulin (basal-bolus) cov- important to provide adequate fluid re- dexamethasone or multidose or contin- eragehasbeenassociatedwithim- placement, nurse training, frequent uous glucocorticoid use, long-acting in- proved glycemic control and lower bedside testing, infection treatment if sulin may be used (21,45). For higher doses rates of perioperative complications warranted, and appropriate follow-up of glucocorticoids, increasing doses of compared with the traditional sliding to avoid recurrant DKA. Several studies prandial and supplemental insulin may scale regimen (regular or short-acting have shown that the use of bicarbonate be needed in addition to basal insulin insulin coverage only with no basal in patients with DKA made no differ- (47). Whatever orders are started, adjust- dosing) (23,50). ence in resolution of acidosis or time ments based on anticipated changes in to discharge, and its use is generally glucocorticoid dosing and POC glucose Diabetic Ketoacidosis and not recommended (55). For further in- test results are critical. Hyperosmolar Hyperglycemic State formation, regarding treatment, refer There is considerable variability in the to recent in-depth reviews (3,56). Perioperative Care presentation of DKA and hyperosmolar Many standards for perioperative care hyperglycemic state, ranging from eugly- lack a robust evidence base. However, the cemia or mild hyperglycemia and acidosis TRANSITION FROM THE ACUTE following approach (48) may be considered: to severe hyperglycemia, dehydration, CARE SETTING and coma; therefore, treatment individu- A structured discharge plan tailored to 1. Target glucose range for the peri- alization based on a careful clinical and the individual patient may reduce length operative period should be 80– laboratory assessment is needed (51). of hospital stay, readmission rates, and 180 mg/dL (4.4–10.0 mmol/L). Management goals include restoration increase patient satisfaction (57). There- 2. Perform a preoperative risk assess- of circulatory volume and tissue perfusion, fore, there should be a structured discharge ment for patients at high risk for ische- resolution of hyperglycemia, and correc- plan tailored to each patient. Discharge mic heart disease and those with tion of electrolyte imbalance and ketosis. planning should begin at admission and autonomic neuropathy or renal failure. It is also important to treat any correctable be updated as patient needs change. 3. Withold metformin 24 h before surgery. underlying cause of DKA such as sepsis. Transition from the acute care setting 4. Withhold any other oral hypoglyce- In critically ill and mentally obtunded is a risky time for all patients. Inpatients mic agents the morning of surgery or patients with DKA or hyperosmolar hy- may be discharged to varied settings procedure and give half of NPH dose perglycemic state, continuous intrave- including home (with or without visiting or 60–80% doses of a long-acting nous insulin is the standard of care. nurse services), assisted living, rehabilita- analog or pump basal insulin. However, there is no significant differ- tion, or skilled nursing facilities. For the 5. Monitor blood glucose at least every ence in outcomes for intravenous regular patient who is discharged to home or to 4–6 h while NPO and dose with short- insulin versus subcutaneous rapid-acting assisted living, the optimal program will acting insulin as needed. analogs when combined with aggressive need to consider diabetes type and se- fluid management for treating mild or verity, effects of the patient’s illness on A review found that perioperative gly- moderate DKA (52). Patients with un- blood glucose levels, and the patient’s cemic control tighter than 80–180 mg/dL complicated DKA may sometimes be capacities and desires. (4.4–10.0 mmol/L) did not improve out- treated with subcutanous insulin in the An outpatient follow-up visit with the comes and was associated with more hy- emergency department or step-down primary care provider, endocrinologist, poglycemia (49); therefore, in general, units (53), an approach that may be safer or diabetes educator within 1 month tighter glycemic targets are not advised. and more cost-effective than treatment of discharge is advised for all patients care.diabetesjournals.org Diabetes Care in the Hospital S125

having hyperglycemia in the hospital. If blood glucose, explanation of home (62). Of interest, 30% of patients with glycemic medications are changed or blood glucose goals, and when to two or more hospital stays account for glucose control is not optimal at dis- call the provider. over 50% of hospitalizations and their charge, an earlier appointment (in ○ Definition, recognition, treatment, accompanying hospital costs (63). 1–2 weeks) is preferred, and frequent and prevention of hyperglycemia While there is no standard to prevent contact may be needed to avoid hypergly- and hypoglycemia. readmissions, several successful strate- cemia and hypoglycemia. A recent dis- ○ Information on consistent nutrition gies have been reported, including an charge algorithm for glycemic medication habits. intervention program targeting ketosis- adjustment based on admission A1C ○ If relevant, when and how to take prone patients with type 1 diabetes found that the average A1C in patients blood glucose–lowering medications, (64), initiating insulin treatment in pa- with diabetes after discharge was signifi- including insulin administration. tients with admission A1C .9% (65), and cantly improved (6). Therefore, if an A1C ○ Sick-day management. a transitional care model (66). For people from the prior 3 months is unavailable, ○ Proper use and disposal of needles with diabetic kidney disease, patient- measuring the A1C in all patients with di- and syringes. centered medical home collaboratives abetes or hyperglycemia admitted to the may decrease risk-adjusted readmis- hospital is recommended. It is important that patients be pro- sion rates (67). Clear communication with outpatient vided with appropriate durable medical providers either directly or via hospital equipment, medications, supplies (e.g., References discharge summaries facilitates safe insulin pens), and prescriptions along 1. Clement S, Braithwaite SS, Magee MF, et al.; transitions to outpatient care. Providing with appropriate education at the time American Diabetes Association Diabetes in Hos- information regarding the cause of hy- of discharge in order to avoid a poten- pitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes perglycemia (or the plan for determin- tially dangerous hiatus in care. Care 2004;27:553–591 ing the cause), related complications 2. Moghissi ES, Korytkowski MT, DiNardo M, and comorbidities, and recommended PREVENTING ADMISSIONS AND et al.; American Association of Clinical Endocri- treatments can assist outpatient pro- READMISSIONS nologists; American Diabetes Association. Ameri- viders as they assume ongoing care. can Association of Clinical Endocrinologists and Preventing Hypoglycemic Admissions American Diabetes Association consensus state- The Agency for Healthcare Research in Older Adults ment on inpatient glycemic control. Diabetes and Quality (AHRQ) recommends that Insulin-treated patients 80 years of age Care 2009;32:1119–1131 at a minimum, discharge plans include or older are more than twice as likely to 3. Umpierrez G, Korytkowski M. Diabetic the following (58): visit the emergency department and emergencies - ketoacidosis, hyperglycaemic nearly five times as likely to be admitted hyperosmolar state and hypoglycaemia. Nat Medication Reconciliation Rev Endocrinol 2016;12:222–232 for insulin-related hypoglycemia than ○ The patient’s medications must be 4. Bogun M, Inzucchi SE. Inpatient manage- those 45–64 years of age (59). However, cross-checked to ensure that no chronic ment of diabetes and hyperglycemia. Clin Ther older adults with type 2 diabetes in 2013;35:724–733 medications were stopped and to en- long-term care facilities taking either 5. Pasquel FJ, Gomez-Huelgas R, Anzola I, et al. sure the safety of new prescriptions. oral antihyperglycemic agents or basal Predictive value of admission hemoglobin A1c ○ Prescriptions for new or changed medica- on inpatient glycemic control and response to insulin have similar glycemic control tion should be filled and reviewed with the insulin therapy in medicine and surgery patients (60), suggesting that oral therapy may patient and family at or before discharge. with type 2 diabetes. Diabetes Care 2015;38: be used in place of insulin to lower the e202–e203 Structured Discharge Communication risk of hypoglycemia for some patients. 6. Umpierrez GE, Reyes D, Smiley D, et al. Hospi- tal discharge algorithm based on admission HbA ○ Information on medication changes, pend- In addition, many older adults with dia- 1c for the management of patients with type 2 di- ing tests and studies, and follow-up needs betes are overtreated (61), with half of abetes. Diabetes Care 2014;37:2934–2939 must be accurately and promptly commu- those maintaining an A1C ,7% being 7. Carpenter DL, Gregg SR, Xu K, Buchman TG, nicated to outpatient physicians. treated with insulin or a sulfonlyurea, Coopersmith CM. Prevalence and impact of un- ○ Discharge summaries should be which are associated with hypoglycemia. known diabetes in the ICU. Crit Care Med 2015; – transmitted to the primary physician To further lower the risk of hypoglycemia- 43:e541 e550 8. Institute of Medicine. Preventing Medication as soon as possible after discharge. related admissions in older adults, pro- Errors. Aspden P, Wolcott J, Bootman JL, ○ Appointment-keeping behavior is en- viders may, on an individual basis, relax Cronenwett LR, Eds.Washington, DC, The Na- hanced when the inpatient team A1C targets to ,8% or ,8.5% in patients tional Academies Press, 2007 schedules outpatient medical follow- with shortened life expectancies and sig- 9. Gillaizeau F, Chan E, Trinquart L, et al. Com- up prior to discharge. nificant comorbidities (refer to Section puterized advice on drug dosage to improve 11 “Older Adults” for detailed criteria). prescribing practice. Cochrane Database Syst Rev 2013;11:CD002894 It is recommended that the following 10. Wexler DJ, Shrader P, Burns SM, Cagliero E. areas of knowledge be reviewed and Preventing Readmissions Effectiveness of a computerized insulin order addressed prior to hospital discharge: In patients with diabetes, the readmission template in general medical inpatients with rate is between 14% and 20% (62). Risk type 2 diabetes: a cluster randomized trial. Diabetes Care 2010;33:2181–2183 ○ Identify the health care provider who will factors for readmission include lower 11. Draznin B, Gilden J, Golden SH, et al.; PRIDE provide diabetes care after discharge. socioeconomic status, certain racial/ethnic investigators. Pathways to quality inpatient man- ○ Level of understanding related to the minority groups, comorbidities, urgent ad- agement of hyperglycemia and diabetes: a call to diabetes diagnosis, self-monitoring of mission, and recent prior hospitalization action. Diabetes Care 2013;36:1807–1814 S126 Diabetes Care in the Hospital Diabetes Care Volume 40, Supplement 1, January 2017

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Dendy JA, Chockalingam V, Tirumalasetty diabetes. Diabetes Care 2009;32:1335–1343 domized study of basal-bolus insulin therapy in NN, et al. Identifying risk factors for severe hy- 52. Andrade-Castellanos CA, Colunga-Lozano the inpatient management of patients with poglycemia in hospitalized patients with diabe- LE, Delgado-Figueroa N, Gonzalez-Padilla DA. type 2 diabetes undergoing general surgery tes. Endocr Pract 2014;20:1051–1056 Subcutaneous rapid-acting insulin analogues (RABBIT 2 surgery). Diabetes Care 2011;34: 37.UlmerBJ,KaraA,MariashCN.Temporal for diabetic ketoacidosis. Cochrane Database 256–261 occurrences and recurrence patterns of hypo- Syst Rev 2016;1:CD011281 24. Giugliano D, Chiodini P, Maiorino MI, glycemia during hospitalization. Endocr Pract 53. Kitabchi AE, Umpierrez GE, Fisher JN, Bellastella G, Esposito K. Intensification of insu- 2015;21:501–507 Murphy MB, Stentz FB. Thirty years of personal lin therapy with basal-bolus or premixed insulin 38. 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state. J Clin Endocrinol Metab 2008;93:1541– planning from hospital to home. Cochrane Da- 62. Rubin DJ. Hospital readmission of patients 1552 tabase Syst Rev 2016;1:CD000313 with diabetes. Curr Diab Rep 2015;15:17 54. Umpierrez GE, Latif K, Stoever J, et al. Efﬁ- 58. Agency for Healthcare Research and Qual- 63. Jiang HJ, Stryer D, Friedman B, Andrews R. cacy of subcutaneous insulin lispro versus con- ity. Adverse events after hospital discharge Multiple hospitalizations for patients with dia- tinuous intravenous regular insulin for the [article online], 2010. Available from http:// betes. Diabetes Care 2003;26:1421–1426 treatment of patients with diabetic ketoacido- psnet.ahrq.gov/primer.aspx?primerID511. 64. Maldonado MR, D’Amico S, Rodriguez L, sis. Am J Med 2004;117:291–296 Accessed 21 November 2016 Iyer D, Balasubramanyam A. Improved out- 55. Duhon B, Attridge RL, Franco-Martinez AC, 59. Bansal N, Dhaliwal R, Weinstock RS. Man- comes in indigent patients with ketosis-prone Maxwell PR, Hughes DW. Intravenous sodium agement of diabetes in the elderly. Med Clin diabetes: effect of a dedicated diabetes treat- bicarbonate therapy in severely acidotic dia- North Am 2015;99:351–377 ment unit. Endocr Pract 2003;9:26–32 betic ketoacidosis. Ann Pharmacother 2013; 60. Pasquel FJ, Powell W, Peng L, et al. A ran- 65. Wu EQ, Zhou S, Yu A, et al. Outcomes associ- 47:970–975 domized controlled trial comparing treatment ated with post-discharge insulin continuity in US pa- 56. Gosmanov AR, Gosmanova EO, Kitabchi AE. with oral agents and basal insulin in elderly patients with type 2 diabetes mellitus initiating insulin Hyperglycemic crises: diabetic ketoacidosis tients with type 2 diabetes in long-term care in the hospital. Hosp Pract (1995) 2012;40:40–48 (DKA), and hyperglycemic hyperosmolar state facilities. BMJ Open Diabetes Res Care 2015;3: 66. Hirschman KB, Bixby MB. Transitions in care (HHS). In Endotext [Internet]. Available from e000104 from the hospital to home for patients with di- http://www.ncbi.nlm.nih.gov/books/NBK279052/. 61. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, abetes. Diabetes Spectr 2014;27:192–195 Accessed 7 October 2016 Steinman MA. Potential overtreatment of dia- 67. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic 57. Shepperd S, Lannin NA, Clemson LM, betes mellitus in older adults with tight glycemic kidney disease: a report from an ADA Consensus McCluskey A, Cameron ID, Barras SL. Discharge control. JAMA Intern Med 2015;175:356–362 Conference. Diabetes Care 2014;37:2864–2883 S128 Diabetes Care Volume 40, Supplement 1, January 2017

15. Diabetes Advocacy American Diabetes Association Diabetes Care 2017;40(Suppl. 1):S128–S129 | DOI: 10.2337/dc17-S018

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’s Standards of 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 the ADA’s clinical position statements, these advocacy position statements are important tools in educating schools, employers, licensing agencies, policymakers, and others about the inter- section of diabetes medicine and the law.

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

15. DIABETES ADVOCACY 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).

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). Suggested citation: American Diabetes Associa- tion. Diabetes advocacy. Sec. 15. In Standards of Diabetes and Employment (4) Medical Care in Diabetesd2016. Diabetes Care First publication: 1984 (revised 2009) 2017;40(Suppl. 1):S128–S129 Any person with diabetes, whether insulin treated or noninsulin treated, should be eligible © 2017 by the American Diabetes Association. for any employment for which he or she is otherwise qualified. Employment decisions Readers may use this article as long as the work is properly cited, the use is educational and not should never be based on generalizations or stereotypes regarding the effects of diabetes. for profit, and the work is not altered. More infor- When questions arise about the medical fitness of a person with diabetes for a particular mation is available at http://www.diabetesjournals job, a health care professional with expertise in treating diabetes should perform .org/content/license. care.diabetesjournals.org Diabetes Advocacy S129

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 cilities should receive care that meets employment. Diabetes Care 2014;37(Suppl. 1): 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 S130 Diabetes Care Volume 40, Supplement 1, January 2017

Professional Practice Committee Disclosures Diabetes Care 2017;40(Suppl. 1):S130–S131 | DOI: 10.2337/dc17-S019 PROFESSIONAL PRACTICE COMMITTEE DISCLOSURES

Committee members disclosed the following ﬁnancial or other conﬂicts of interest covering the period 12 months before December 2016 Other research Member Employment Research grant support William H. Herman, MD, MPH (Co-Chair) University of Michigan, Ann Arbor, MI None None Rita R. Kalyani, MD, MHS, FACP (Co-Chair) Johns Hopkins University, Baltimore, MD None None Andrea L. Cherrington, MD, University of Alabama, Birmingham, AL Boehringer Ingelheim, None MPH Merck Sharp & Dohme Donald R. Coustan, MD The Warren Alpert Medical School of Brown None None University and Women & Infants’ Maternal- Fetal Medicine, Providence, RI Ian de Boer, MD, MS University of Washington, Seattle, WA University of Washington None Robert James Dudl, MD Kaiser Permanente, La Jolla, CA None None Hope Feldman, CRNP, FNP-BC Abbottsford-Falls Family Practice & None None Counseling, Philadelphia, PA Hermes J. Florez, MD, PhD, MPH University of Miami Miller School of Medicine, None None Miami, FL Suneil Koliwad, MD, PhD University of California, San Francisco, None None San Francisco, CA Melinda Maryniuk, MEd, RD, CDE Joslin Diabetes Center, Boston, MA None None Joshua J. Neumiller, PharmD, CDE, FASCP Washington State University, Spokane, WA None None Joseph Wolfsdorf, MB, BCh Boston Children’s Hospital and Harvard None None Medical School, Boston, MA Erika Gebel Berg, PhD (Staff) American Diabetes Association, Arlington, VA None None Sheri Colberg-Ochs, PhD (Staff) American Diabetes Association, Virginia Beach, VA None None Alicia H. McAuliffe-Fogarty, PhD, CPsychol (Staff) American Diabetes Association, Arlington, VA None None Sacha Uelmen, RDN, CDE (Staff) American Diabetes Association, Arlington, VA None None Robert E. Ratner, MD, FACP, FACE (Staff) American Diabetes Association, Arlington, VA None None ADA, American Diabetes Association; DSMB, Data and Safety Monitoring Board; MEDCAC, Medicare Evidence Development & Coverage Advisory Committee. *$$10,000 per year from company to individual. care.diabetesjournals.org Professional Practice Committee S131

Speakers’ bureau/ Ownership Member honoraria interest Consultant/advisory board Other W.H.H. None None Merck Sharp & Dohme (Chair, DSMB),* National Committee for Quality Assurance Lexicon Pharmaceuticals (Chair, (Chair, Diabetes Panel), Centers for Medicare DSMB, Travel), RTI International & Medicaid Services (member, MEDCAC), (Member, Ad Board, Travel) Diabetic Medicine (former Editor for the Americas), Diabetes Care (ad hoc Editor in Chief) R.R.K. None None Novo Nordisk, Johns Hopkins School Diabetes Care (Editorial Board) of Medicine Continuing Medical Education A.L.C. None None None Connection Health (Board President) D.R.C. None None None None I.d.B. Boehringer None None University of Washington research grant from the ADA Ingelheim, Bayer, Janssen R.J.D. None None None None H.Fe. None None None None H.Fl. None None None None S.K. None None Yes Health Yes Health (Equity Holder, Advisor) M.M. None None None None J.J.N. Novo Nordisk None Sanoﬁ, Eli Lilly Diabetes Spectrum (Editor in Chief) J.W. None None None Diabetes Care (Editorial Board) E.G.B. None None None None S.C.-O. None None None None A.H.M.-F. None None None None S.U. None None None None R.E.R. None None None None S132 Diabetes Care Volume 40, Supplement 1, January 2017

Index

A1C. see also glycemic control balance training, S37 continuous glucose monitoring (CGM), age in, S12 bariatric surgery, S59–S61 S49, S121 CGM and, S49 BARI 2D trial, S94 contraception, S117 confirmation testing, S13 Belviq (lorcaserin), S60 Contrave (naltrexone/bupropion), S60 CVD and, S51–S52 benazepril, S78 coronary heart disease, S83–S84 diagnostic criteria, S13 biguanides, S68, S71. see also metformin cystic fibrosis–related diabetes, S21–S22 ethnic, pediatric differences, S50 bile acid sequestrants, S69, S71 exercise benefits, S37 bromocriptine, S69, S71 dapagliflozin, S69, S71 glycemic targets and, S52–S53 DASH diet, S34 goals, S50–S52 canagliflozin, S69, S71 DASH study, S77 hemoglobinopathies, S13 cancer, S27 degludec, S72 in HIV, S28–S29 carbohydrates, carbohydrate counting, S36 dental practices, screening in, S17–S18 limitations, S50 cardiac autonomic neuropathy, S94 depression, S29–S30 mean glucose and, S50, S51 cardiovascular disease detemir, S72 medical nutrition therapy effects on, S34 A1C and, S51–S52 Diabetes Control and Complications Trial (DCCT), microvascular complications and, S50–S51 children and adolescents, S108–S109 S50–S51, S54, S64, S90, S107 prediabetes, S13–S14, S28 CKD management and, S90–S91 diabetes distress, S29, S39–S40 in pregnancy, S115–S116 hypertension/blood pressure Diabetes Prevention Program, S14, S44–S45 race/ethnicity in, S12 control, S75–S78 Diabetes Prevention Program Outcomes Study red blood cell turnover, S13 lipid management, S79–S81 (DPPOS), S37, S45, S46 resistance training, S37–S38 prevention, S46 diabetes self-management education (DSME), SMBG and, S49 proteins, S35, S36 S7, S8, S33–S34, S46, S105, S123 testing, S12–S13, S49–S50 revisions summary, S5 diabetes self-management support (DSMS), acarbose, S68, S71 cardiovascular outcome trials (CVOTs), S70–S71 S33–S34, S46 ACCORD study, S28, S51, S52, S54, S76, S81, celiac disease, S107–S108 diabetic ketoacidosis (DKA), S11, S16, S122, S90 children and adolescents S124 ACE inhibitors, S76–S78, S88, S91, S92, S108 A1C, blood glucose goals, S107 diagnosis. see also specific types of diabetes acylated human glucagon-like peptide 1 A1C differences in, S50 A1C, S12–S13 receptor agonist, S60 autoimmune conditions, S107 confirmation, S13 ADAG trial, S50 celiac disease, S107–S108 criteria, S13 ADA Position Statement, S1 comorbidities, S110 FPG testing, S12, S13 ADA Scientific Statement, S1 CVD risk management, S108–S109 2-h PG testing, S12, S13 ADVANCE-BP trial, S76–S77 DSME/DSMS, S7, S8, S33–S34, S46, S105 monogenic syndromes, S20–S21 ADVANCE-ON study, S77 dyslipidemia, S108–S109 psychosocial issues, S39–S40 ADVANCE study, S51, S52 exercise, S37–S38 revisions summary, S4 advocacy, S128–S129 glycemic control, S106–S107 testing, S12–S14 Affordable Care Act, S8 kidney disease (nephropathy), S109 dipeptidyl peptidase (DPP) 4 inhibitors, S59, a-glucosidase inhibitors, S68, S71 neuropathy, S109–S110 S65, S68, S71, S73, S84, S90, S102, S122 AIM-HIGH trial, S81 pediatric to adult care transition, S111 disordered eating behaviors, S30 albiglutide, S69, S71 psychosocial issues, S106 disparity reduction albuminuria, S88–S91, S109 retinopathy, S109 access to care, S8 alcohol, S35, S37 revisions summary, S5 ethnic, cultural, sex differences, S8 Alli (orlistat), S60 school, child care, S106 food insecurity, S8–S9 alogliptin, S59, S65, S68, S71, S84 smoking, S109 homelessness, S9 amlodipine, S78 thyroid disease, S107 language barriers, S9 amylin mimetics, S65, S68, S71 type 1 diabetes, S54, S105–S110 recommendations, S8 angiotensin receptor blockers (ARBs), S76–S78, type 2 diabetes, S18, S110 revisions summary, S4 S88, S91, S92, S108 cholesterol management, S79–S81 treatment tailoring, S8–S9 antihyperglycemics, S59, S84, S122 chronic care model, S6–S8 dopamine-2 agonists, S69, S71 antihypertensive therapy, S78, S90–S91 chronic kidney disease, S36, S38, S78, S88–S91, dulaglutide, S69, S71 antioxidants supplementation, S37 S109 duloxetine, S94 antiplatelets, S81–S83, S92 classification, S4, S11 dyslipidemia, S79–S81, S108–S109 antipsychotics, S30 cognitive impairment/dementia, S27–S28, S81, Antithrombotic Trialists (ATT), S82 S100 e-cigarettes, S38–S39, S109 anti-VEGF, S92–S93 colesevelam, S69, S71 EDIC study, S51, S54, S90 anxiety disorders, S29 community screening, S17 empagliflozin, S69–S71, S84 ARV-associated hyperglycemia, S28–S29 comorbidities EMPA-REG OUTCOME, S70–S71, S84 aspart, S72 children and adolescents, S110 end of life care, S103 ASPIRE trial, S49 comprehensive medical evaluation, energy balance, S35 aspirin, S81–S83, S92 S25–S27 enteral/parenteral feedings, S123, S124 aspirin resistance, S83 immunizations, S25–S26 eplerenone, S91

INDEX atherosclerotic cardiovascular disease (ASCVD), initial management referrals, S27–S28 erectile dysfunction, S94, S95 S75. see also cardiovascular disease patient-centered approach, S25 estimated glomerular ﬁltration rate (eGFR), atorvastatin, S80 protocol, S26–S30 S88–S90 autoimmune diseases, S26–S27, S107 revisions summary, S4 EXAMINE study, S84 autonomic neuropathy, S38, S93–S95 consensus reports, S1 exenatide, S69, S71 care.diabetesjournals.org Index S133

exercise, S37–S38, S45 homelessness, S9 older adults, S102 ezetimibe, S81 hospital care omission in disordered eating, S30 acute care setting, transition from, physiology, in pregnancy, S115 fasting plasma glucose testing, S12, S13 S124–S125 premixed, S72 fat (dietary), S35, S36 admission considerations, S120–S121 principles of use, S71–S72 fatty liver disease, S28 antihyperglycemics, S59, S84, S122 pump, S123 fibrates, S81 care providers, S121 SMBG and, S49 finerenone, S91 delivery standards, S120–S121 type 1 diabetes, S64–S65, S122 flexibility training, S37 discharge communications, S125 insulin secretagogues, S38, S102 fluvastatin, S80 DSME, S123 insurance, S8 food insecurity, S8–S9 enteral/parenteral feedings, S123, S124 foot care, S5, S95–S96 glucocorticoids, S123–S124 glycemic control, S121 kidney disease (nephropathy), S36, S38, S78, fractures, S28 – hypoglycemia, S121–S123 S88 S91, S109 medical nutrition therapy, S123 Kumamoto Study, S51 gastrointestinal neuropathies, S94 medication reconciliation, S125 gastroparesis, S95 perioperative care, S124 GCK-MODY, S20, S21 language barriers, S9 physician order entry, computerized, S121 genitourinary disturbances, S94 laser photocoagulation therapy, S91–S93 quality assurance, S121 gestational diabetes mellitus (GDM). see also LEADER trial, S71, S84 readmissions, prevention, S125 pregnancy lifestyle management recommendations, S120 classification, S11 cost-effectiveness, S45 revisions summary, S5 definition, S14, S18 DSME/DSMS, S7, S8, S33–S34, S46 HOT trial, S76, S77 diagnosis, S18–S20 exercise, S37–S38, S45 human regular insulin, S72 management, S116–S117 gestational diabetes mellitus, S116 hydrochlorothiazide, S78 one-step strategy, S18–S19 hypertension/blood pressure control, S77, hyperglycemia pharmacology, S46 S108 antihyperglycemic therapy, S59 pharmacotherapy, S116–S118 nutrition therapy, S34–S36 cognitive function and, S28 prevalence, S115 pharmacology in, S46, S66 hospital care, S121 recommendations, S19 prevention/delay, type 2 diabetes, management, S53 two-step strategy, S19–S20 S44–S46 hyperosmolar hyperglycemic state, S124 glargine, S72 psychosocial issues, S39–S40 hypertension/blood pressure control, S75–S78, glimepiride, S68, S71 revisions summary, S4 S88, S90–S91, S108 glipizide, S8–S9, S68, S71 smoking cessation, S38–S39 hypertriglyceridemia, S81 GLP-1 receptor agonists, S69, S71, S73, S84, S90, technology platforms, S45 hypoglycemia S102 weight loss, S34–S36, S44–S45, S57–S60 characterization, S53–S54 glucagon, S54 linagliptin, S59, S65, S68, S71 classification, S54 glucagon-like peptide 1 (GLP-1), S65 lipase inhibitors, S60 cognitive function and, S28, S54 glucocorticoids, S123–S124 lipid management, S79–S81, S108–S109 CVD and, S52 glulisine, S72 liraglutide (Saxenda), S60, S69, S71, S84 exercise, S38 glyburide, S68, S71 lispro, S72, S73 glucose monitoring, bedside, S121 glycemic control. see also A1C lixisenatide, S69 hospital care, S121–S123 children and adolescents, S106–S107 long-term care, S102–S103 nocturnal, S49, S78 in CKD management, S90 Look AHEAD trial, S29, S58 in older adults, S100, S102–S103 continuous glucose monitoring, S49, S121 lorcaserin (Belviq), S60 predictors of, S123 control, assessment of, S48 loss of protective sensation, S95, S96 prevention, S54, S123, S125 CVD and, S51–S52 lovastatin, S80 recommendations, S53 hospital care, S121 treatment, S54 intercurrent illness and, S54–S55 unawareness, S29, S53, S54 mean glucose, S50, S51 macronutrient distribution, eating patterns neuropathy, S38, S93–S95 and, S35 – – in older adults, S100 immune-mediated diabetes, S14 S16 macular edema, S92 S93 – pregnancy, S115–S116 immunizations, S25 S26 maturity-onset diabetes of the young (MODY), – recommendations, S48, S52, S54 IMPROVE-IT trial, S81 S20 S21 revisions summary, S5 incretin-based therapies, S59, S65, S102 meal planning, S36 self-monitoring of blood glucose, S48–S49 indapamide, S78 mean glucose, S50, S51 influenza vaccination, S26 medical nutrition therapy (MNT), S34, S35, S123 inhaled insulin, S72, S73 Medicare reimbursement, DSME/DSMS, S34 health promotion injection-related anxiety, S29 medications. see pharmacotherapy care delivery systems, S6 insulin Mediterranean diet, S28, S34 chronic care model, S6–S8 basal, S72, S73 meglitinides (glinides), S68, S71 patient-centered care, S6 bolus, S72 mental health referral, S39, S40 recommendations, S6 carbohydrate intake and, S36 mental illness, serious, S30, S39–S40 revisions summary, S4 CGM and, S49 metabolic surgery, S59–S61 hearing impairment, S28 children and adolescents, S110 metformin heart failure, S84 combination, S67–S70, S73 children and adolescents, S110 hemoglobinopathies, S13 concentrated preparations, S72–S73 in CKD management, S90 hepatitis B vaccination, S26 exercise hypoglycemia, S38 exercise and, S37 herbal supplements, S35, S37 food insecure patients, S9 gestational diabetes mellitus, S116 HIV, S28–S29 gestational diabetes mellitus, S116 lifestyle management, S45–S46 HNF1A-MODY, S20, S21 hospital care, S122 older adults, S102 HNF4A-MODY, S20, S21 inhaled, S72, S73 principles of use, guidelines, S65–S68, S71, HNF1B-MODY, S20, S21 median cost of, S72 S73 S134 Index Diabetes Care Volume 40, Supplement 1, January 2017

metoclopramide, S95 cardiovascular outcome trials, S70–S71 SAVOR-TIMI 53 study, S84 micronutrients, S35, S37 combination, S67–S70, S78, S81 saxagliptin, S59, S65, S68, S71, S84 microvascular complications concomitant, S59 Saxenda (liraglutide), S60, S69, S71, S84 A1C and, S50–S51 as diabetes risk, S17 scientific evidence grading, S1–S2 foot care, S5, S95–S96 gestational diabetes mellitus, S116–S118 screening. see diagnosis kidney disease, S36, S38, S78, S88–S91, glucocorticoids, S123–S124 self-monitoring of blood glucose (SMBG), S109 hypertension/blood pressure control, S48–S49 neuropathy, S38, S93–S95 S77–S78, S108 serotonin receptor agonists, S60 retinopathy, S38, S91–S93, S109 in lifestyle management, S46, S66 sexual dysfunction, S94, S95 revisions summary, S5 mineralocorticoid receptor antagonists, SGLT2 inhibitors, S65, S69–S71, S73, S84, S90, miglitol, S68, S71 S91 S102, S122 mineralocorticoid receptor antagonists, S91 obesity, S58–S60 shoes/footwear, S96 older adults, S102 simvastatin, S80 prevention/delay, type 2 diabetes, sitagliptin, S59, S65, S68, S71 naltrexone/bupropion (Contrave), S60 S45–S46 smoking cessation, S38–S39, S109 nateglinide, S68, S71 type 1 diabetes, S64–S65 sodium, S35, S36 neonatal diabetes, S20, S21 type 2 diabetes, S65–S73 spironolactone, S91 neuropathic pain, S94 phentermine/topiramate ER (Qsymia), S60 SPRINT trial, S76, S77 neuropathy, S38, S93–S95, S109–S110 physical activity, S37–S38, S45 statins, S28, S79–S80 niacin, S81 pioglitazone, S68, S71 sulfonylureas, S8–S9, S68, S71, S73, S116 nonnutritive sweeteners, S35, S37 pitavastatin, S80 sympathomimetic amine anorectic/antiepileptic NPH insulin, S72 plate method, S36 combination, S60 nucleoside reverse transcriptase inhibitors pneumococcal pneumonia vaccination, S26 (NRTIs), S28 pneumonia vaccination, S26 nutrition tai chi, S37 point-of-care (POC) meters, S121 in CKD management, S90 tapentadol, S94 posttransplantation diabetes mellitus, S22 in cognitive function, S28 TECOS study, S84 pramlintide, S65, S68, S71 in diabetes prevention, S45 testosterone, S29 pravastatin, S80 gastroparesis, S95 thyroid disease, S107 prediabetes, S13–S14, S28 in obesity management, S57–S58 tobacco, S38–S39, S109 pregabalin, S94 therapy, S34–S36 TODAY study, S110 pregnancy. see also gestational diabetes 2-h plasma glucose testing, S12, S13 mellitus (GDM) type 1 diabetes obesity, type 2 diabetes antihypertensive therapy, S78 autoimmune diseases, S26–S27, S107 assessment of, S57 contraception, S117 celiac disease, S107–S108 diet, S57–S58 diabetes prevalence, S115 children and adolescents, S105–S110 interventions, S57–S58 drugs contraindicated, S78, S114 CKD management, S89–S90 lifestyle interventions, S57–S58 glycemic control, S115–S116 classification, S11 management benefits, S57, S58 hypertension/blood pressure control, CVD and, S51–S52 metabolic surgery, S59–S61 S75–S78 diagnosis, S14–S16 pharmacotherapy, S58–S60 lactation, S117 hypoglycemia in, S54 revisions summary, S5 pharmacotherapy, S116–S118 idiopathic, S16 obstructive sleep apnea, S29 postpartum care, S117 immune-mediated, S14–S16 older adults preconception counseling, S115 insulin, S122 cognitive impairment/dementia, S27–S28, preexisting diabetes management, pancreas, islet transplantation, S65 S81, S100 S116–S117 pathophysiology, S11–S12 end of life care, S103 recommendations, S114 pharmacotherapy, S64–S65 epidemiology, S99–S100 retinopathy, S38, S91–S93 pregnancy, S116–S117 glycemic control in, S100 revisions summary, S5 recommendations, S14 hypoglycemia in, S100, S102–S103 prevention/delay, type 2 diabetes retinopathy, S38, S91–S93, S109 pharmacotherapy, S102 Diabetes Prevention Program, S44–S45 risk testing, S16 recommendations, S99 nutrition in, S45 staging, S12 treatment goals, S100–S101 pharmacologic interventions, S45–S46 statins, S80 treatment in LTC settings, S102–S103 recommendations, S44 thyroid disease, S107 opioid antagonist/aminoketone antidepressant revisions summary, S4–S5 type 2 diabetes combination, S60 Professional Practice Committee (PPC), S3 age, screening, S14, S17 orlistat (Alli), S60 protease inhibitors (PIs), S28 asymptomatic adults, screening, S14, S15, orlistat (Xenical), S60 proteins, S35, S36 S17 orthostatic hypotension, S95 psychosis, S30 BMI/ethnicity, screening, S14, S17 psychosocial/emotional disorders, S29 cancer and, S27 pancreas, islet transplantation, S65 psychosocial issues, S39–S40 characterization, S16–S17 Patient-Centered Medical Home, S7–S8 P2Y12 receptor antagonists, S83 children and adolescents, S18, S110 PCSK9 inhibitors, S81 children and adolescents, screening, perindopril, S78 Qsymia (phentermine/topiramate ER), S60 S18 periodontal disease, S29 CKD management, S90 peripheral arterial disease (PAD), S96 repaglinide, S68, S71 classification, S11 peripheral neuropathy, S38, S93–S95 resistance training, S37–S38 community screening, S17 pharmacotherapy. see also specific drugs by name retinal photography, S91, S92 CVD and, S52 ACE inhibitors/ARBs, S76–S78, S88, S91, retinopathy, S38, S91–S93, S109 dental practices, screening in, S17–S18 S92, S108 revisions summary, S4–S5 diagnosis, S16–S18 antihyperglycemics, S59, S84 rosiglitazone, S68, S71 fat (dietary), S35, S36 antihypertensives, S78 rosuvastatin, S80 hyperglycemia, S28 antiplatelets, S81–S83, S92 Roux-en-Y gastric bypass, S61 hypoglycemia, S28 care.diabetesjournals.org Index S135

obesity management (see obesity, type 2 risk factors, S29–S30 VADT study, S51, S52 diabetes) staging, S12 vitamin B12 deﬁciency, S37 pharmacotherapy, S65–S73 statins, S80 – pregnancy, S116 S117 weight management, S34–S36, S44–S45, prevention/delay (see prevention/delay, TZDs, S68, S71, S73, S84, S102 S57–S60. see also obesity, type 2 diabetes type 2 diabetes) proteins, S35, S36 UK Prospective Diabetes Study (UKPDS), S51, recommendations, S16 S52 Xenical (orlistat), S60 retinopathy, S38, S91–S93 urinary albumin–to–creatinine ratio (UACR), risk assessment, S15 S89 yoga, S37