ADA Standards of Medical Care in Diabetes 2018

THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION VOLUME 41 | SUPPLEMENT 1

WWW.DIABETES.ORG/DIABETESCARE JANUARY 2018

PLE M E P N U T S 1 AMERICAN DIABETES ASSOCIATION STANDARDS OF MEDICAL CARE IN DIABETES—2018

ISSN 0149-5992 January 2018 Volume 41, 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 Matthew C. Riddle, 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 Sanjay Kaul, MD, FACC, FAHA Ele Ferrannini, MD Helena Wachslicht Rodbard, MD Derek LeRoith, MD, PhD Franco Folli, MD, PhD Elizabeth Seaquist, MD Robert G. Moses, MD Meredith A. Hawkins, MD, MS Guntram Schernthaner, MD Stephen Rich, PhD Richard Hellman, MD David J. Schneider, MD Julio Rosenstock, MD Norbert Hermanns, PhD, MSc Norbert Stefan, MD William V. Tamborlane, MD Irl B. Hirsch, MD, MACP Jan S. Ulbrecht, MB, BS Judith Wylie-Rosett, EdD, RD George S. Jeha, MD Joseph Wolfsdorf, MD, BCh 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 PRESIDENT-ELECT, MEDICINE & SCIENCE Karen Talmadge, PhD Louis Philipson, MD PRESIDENT, MEDICINE & SCIENCE PRESIDENT-ELECT, HEALTH CARE & Jane Reusch, MD EDUCATION Gretchen Youssef, MS, RD, CDE PRESIDENT, HEALTH CARE & EDUCATION SECRETARY/TREASURER-ELECT Felicia Hill-Briggs, PhD, ABPP Brian Bertha, JD, MBA SECRETARY/TREASURER INTERIM CHIEF EXECUTIVE OFFICER Michael Ching, CPA Martha Parry Clark CHAIR OF THE BOARD-ELECT CHIEF SCIENTIFIC, MEDICAL & MISSION OFFICER David J. Herrick, MBA William T. Cefalu, MD

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 Arlington, VA, and additional mailing ofﬁces.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS

SENIOR VICE PRESIDENT, PUBLISHER CONTENT PRODUCTION MANAGER ADVERTISING REPRESENTATIVES Michael Eisenstein Kelly Newton American Diabetes Association Paul Nalbandian ASSOCIATE PUBLISHER, EDITORIAL CONTENT MANAGER Associate Publisher, Advertising & SCHOLARLY JOURNALS Nancy C. Baldino Sponsorships Christian S. Kohler [email protected] (703) 549-1500, ext. 4806 EDITORIAL OFFICE DIRECTOR TECHNICAL EDITOR Lyn Reynolds Theresa Cooper Tina Auletta Senior Account Executive PEER REVIEW MANAGER DIRECTOR, MEMBERSHIP/SUBSCRIPTION [email protected] Shannon Potts SERVICES (703) 549-1500, ext. 4809 Donald Crowl PHARMACEUTICAL/DEVICE DIGITAL ADVERTISING ASSOCIATE MANAGER, PEER REVIEW The Walchli Tauber Group Larissa M. Pouch SENIOR ADVERTISING MANAGER Maura Paoletti Julie DeVoss Graff National Sales Manager DIRECTOR, SCHOLARLY JOURNALS [email protected] [email protected] Heather Norton Blackburn (703) 299-5511 (443) 512-8899, ext. 110 January 2018 Volume 41, Supplement 1

Standards of Medical Care in Diabetes—2018

S1 Introduction S86 9. Cardiovascular Disease and Risk S3 Professional Practice Committee Management S4 Summary of Revisions: Standards of Medical Care in Hypertension/Blood Pressure Control Diabetes—2018 Lipid Management S7 1. Improving Care and Promoting Health in Antiplatelet Agents Populations Coronary Heart Disease Diabetes and Population Health S105 10. Microvascular Complications and Foot Care Tailoring Treatment for Social Context Diabetic Kidney Disease S13 2. Classiﬁcation and Diagnosis of Diabetes Diabetic Retinopathy Neuropathy Classiﬁcation Foot Care Diagnostic Tests for Diabetes Categories of Increased Risk for Diabetes (Prediabetes) S119 11. Older Adults Type 1 Diabetes Type 2 Diabetes Neurocognitive Function Gestational Diabetes Mellitus Hypoglycemia Monogenic Diabetes Syndromes Treatment Goals Cystic Fibrosis–Related Diabetes Pharmacologic Therapy Posttransplantation Diabetes Mellitus Treatment in Skilled Nursing Facilities and Nursing Homes S28 3. Comprehensive Medical Evaluation and End-of-Life Care Assessment of Comorbidities S126 12. Children and Adolescents Patient-Centered Collaborative Care Comprehensive Medical Evaluation Type 1 Diabetes Assessment of Comorbidities Type 2 Diabetes Transition From Pediatric to Adult Care S38 4. Lifestyle Management S137 13. Management of Diabetes in Pregnancy Diabetes Self-Management Education and Support Nutrition Therapy Diabetes in Pregnancy Physical Activity Preconception Counseling Smoking Cessation: Tobacco and e-Cigarettes Glycemic Targets in Pregnancy Psychosocial Issues Management of Gestational Diabetes Mellitus S51 5. Prevention or Delay of Type 2 Diabetes Management of Preexisting Type 1 Diabetes and Type 2 Diabetes in Pregnancy Lifestyle Interventions Pregnancy and Drug Considerations Pharmacologic Interventions Postpartum Care Prevention of Cardiovascular Disease Diabetes Self-management Education and Support S144 14. Diabetes Care in the Hospital S55 6. Glycemic Targets Hospital Care Delivery Standards Glycemic Targets in Hospitalized Patients Assessment of Glycemic Control Bedside Blood Glucose Monitoring A1C Testing Antihyperglycemic Agents in Hospitalized Patients A1C Goals Hypoglycemia Hypoglycemia Medical Nutrition Therapy in the Hospital Intercurrent Illness Self-management in the Hospital S65 7. Obesity Management for the Treatment of Type 2 Standards for Special Situations Diabetes Transition From the Acute Care Setting Preventing Admissions and Readmissions Assessment Diet, Physical Activity, and Behavioral Therapy S152 15. Diabetes Advocacy Pharmacotherapy Metabolic Surgery Advocacy Position Statements S73 8. Pharmacologic Approaches to Glycemic Treatment S154 Professional Practice Committee, American College of Cardiology—Designated Representatives, and Pharmacologic Therapy for Type 1 Diabetes American Diabetes Association Staff Disclosures Surgical Treatment for Type 1 Diabetes Pharmacologic Therapy for Type 2 Diabetes S156 Index

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

Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals). RFSINLPATC COMMITTEE PRACTICE PROFESSIONAL Diabetes Care Volume 41, Supplement 1, January 2018 S3

Professional Practice Committee: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S3 | https://doi.org/10.2337/dc18-SPPC01

The Professional Practice Committee (see pp. S154–S155). The ADA funds de- CPsychol; Jane Reusch, MD; and Sharon (PPC) of the American Diabetes Asso- velopment of the Standards of Care out of Solomon, MD. ciation (ADA) is responsible for the its general revenues and does not use in- “Standards of Medical Care in Diabetes” dustry support for this purpose. MEMBERS OF THE PPC position statement, referred to as the For the current revision, PPC members Rita R. Kalyani, MD, MHS, FACP (Chair) Standards of Care. The PPC is a multidis- systematically searched MEDLINE for hu- Christopher P. Cannon, MD ciplinary expert committee comprised man studies related to each section and Andrea L. Cherrington, MD, MPH* of physicians, diabetes educators, regis- published since 1 January 2017. Recom- Donald R. Coustan, MD tered dietitians, and others who have mendations were revised based on new Ian H. de Boer, MD, MS* expertise in a range of areas, including evidence or, in some cases, to clarify the Hope Feldman, CRNP, FNP-BC adult and pediatric endocrinology, epi- prior recommendation or match the Judith Fradkin, MD demiology, public health, lipid research, strength of the wording to the strength David Maahs, MD, PhD hypertension, preconception planning, of the evidence. A table linking the Melinda Maryniuk, MEd, RD, CDE and pregnancy care. Appointment to changes in recommendations to new ev- Medha N. Munshi, MD* the PPC is based on excellence in clinical idence can be reviewed at professional Joshua J. Neumiller, PharmD, CDE, FASCP practice and research. Although the pri- .diabetes.org/SOC. The Standards of Care Guillermo E. Umpierrez, MD, CDE, FACE, FACP* mary role of the PPC is to review and was approved by ADA’s Board of Directors, *Subgroup leaders update the Standards of Care, it may which includes health care professionals, also be involved in ADA statements, re- scientists, and lay people. ports, and reviews. Feedback from the larger clinical com- AMERICAN COLLEGE OF The ADA adheres to the National munity was valuable for the 2017 revision CARDIOLOGY—DESIGNATED Academy of Medicine Standards for De- of the Standards of Care. Readers who REPRESENTATIVES (SECTION 9) veloping Trustworthy Clinical Practice wish to comment on the 2018 Standards Sandeep Das, MD, MPH, FACC Guidelines. All members of the PPC of Care are invited to do so at professional Mikhail Kosiborod, MD, FACC are required to disclose potential con- .diabetes.org/SOC. ﬂicts of interest with industry and/or The PPC would like to thank the follow- other relevant organizations. These dis- ing individuals who provided their exper- ADA STAFF closures are discussed at the onset of tise in reviewing and/or consulting with Erika Gebel Berg, PhD each Standards of Care revision meet- the committee: Pamela Allweiss, MD, MPH; (Corresponding author: [email protected]) ing. Members of the committee, their David D’Alessio, MD; Thomas Gardner, Tamara Darsow, PhD employers, and their disclosed conﬂicts MD, MS; William H. Herman, MD, MPH; Matthew P. Petersen of interest are listed in the “Professional Felicia Hill-Briggs, PhD; Nisa Maruthur, Sacha Uelmen, RDN, CDE Practice Committee Disclosures” table MD, MHS; Alicia McAuliffe-Fogarty, PhD, William T. Cefalu, MD

© 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. Diabetes Care Volume 41, Supplement 1, January 2018 S1 INTRODUCTION

Introduction: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S1–S2 | https://doi.org/10.2337/dc18-SINT01

Diabetes is a complex, chronic illness re- continue to rely on them as the most au- current position. The Standards of Care quiring continuous medical care with mul- thoritative and current guidelines for dia- receives annual review and approval by tifactorial risk-reduction strategies beyond betes care. Readers who wish to comment the ADA Board of Directors. glycemic control. Ongoing patient self- on the 2018 Standards of Care are invited management education and support are to do so at professional.diabetes.org/SOC. ADA Statement critical to preventing acute complications An ADA statement is an official ADA point ADA STANDARDS, STATEMENTS, and reducing the risk of long-term compli- of view or belief that does not contain clin- REPORTS, and REVIEWS cations. Significant evidence exists that ical practice recommendations and may be supports a range of interventions to im- The ADA has been actively involved in the issued on advocacy, policy, economic, or prove diabetes outcomes. development and dissemination of diabe- medical issues related to diabetes. ADA The American Diabetes Association’s tes care standards, guidelines, and related statements undergo a formal review pro- (ADA’s) “Standards of Medical Care in documents for over 25 years. The ADA’s cess, including a review by the appropriate Diabetes,” referred to as the Standards clinical practice recommendations are national committee, ADA mission staff, and of Care, is intended to provide clinicians, viewed as important resources for health the Board of Directors. patients, researchers, payers, and other care professionals who care for people interested individuals with the compo- with diabetes. Consensus Report An expert consensus report of a particu- nents of diabetes care, general treatment Standards of Care lar topic contains a comprehensive ex- goals, and tools to evaluate the quality of This document is an official ADA position, amination and is authored by an expert care. The Standards of Care recommen- is authored by the ADA, and provides all panel (i.e., consensus panel) and repre- dations are not intended to preclude clin- of the ADA’s current clinical practice rec- sents the panel’s collective analysis, eval- ical judgment and must be applied in the ommendations. To update the Standards uation, and opinion. The need for an context of excellent clinical care, with of Care, the ADA’s Professional Practice expert consensus report arises when clini- adjustments for individual preferences, Committee (PPC) performs an extensive cians, scientists, regulators, and/or policy comorbidities, and other patient factors. clinical diabetes literature search, supple- makers desire guidance and/or clarity For more detailed information about mented with input from ADA staff and the on a medical or scientific issue related management of diabetes, please refer to medical community at large. The PPC up- to diabetes for which the evidence Medical Management of Type 1 Diabetes dates the Standards of Care annually, or (1) and Medical Management of Type 2 more frequently online should the PPC is contradictory, emerging, or incomplete. Diabetes (2). determine that new evidence or regula- Expert consensus reports may also high- The recommendations include screen- tory changes (e.g., drug approvals, label light gaps in evidence and propose areas ing, diagnostic, and therapeutic actions changes) merit immediate incorporation. of future research to address these gaps. that are known or believed to favorably The Standards of Care supersedes all pre- An expert consensus report is not an ADA affect health outcomes of patients with di- vious ADA position statementsdand the position and represents expert opinion abetes. Many of these interventions have recommendations thereindon clinical only but is produced under the auspices also been shown to be cost-effective (3). topics within the purview of the Stand- of the Association by invited experts. An The ADA strives to improve and update ards of Care; ADA position statements, expert consensus report may be devel- the Standards of Care to ensure that clini- while still containing valuable analyses, oped after an ADA Clinical Conference cians, health plans, and policy makers can should not be considered the ADA’s or Research Symposium.

“Standards of Medical Care in Diabetes” was originally approved in 1988. © 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 41, Supplement 1, January 2018

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” B,orC, depending on the quality of evi- E Level of evidence Description dence. Expert opinion is a separate category for recommendations in which A Clear evidence from well-conducted, generalizable there is no evidence from clinical trials, randomized controlled trials that are adequately powered, including in which clinical trials may be impractical, fl c Evidence from a well-conducted multicenter trial or in which there is con icting evidence. c Evidence from a meta-analysis that incorporated Recommendations with an A rating are quality ratings in the analysis based on large well-designed clinical trials Compelling nonexperimental evidence, i.e., “all or none” or well-done meta-analyses. Generally, rule developed by the Centre for Evidence-Based these recommendations have the best Medicine at the University of Oxford chance of improving outcomes when ap- Supportive evidence from well-conducted randomized controlled trials that are adequately powered, including plied to the population to which they c Evidence from a well-conducted trial at one or more are appropriate. Recommendations institutions with lower levels of evidence may be c Evidence from a meta-analysis that incorporated equally important but are not as well quality ratings in the analysis supported. B Supportiveevidencefromwell-conductedcohortstudies Of course, evidence is only one compo- c Evidence from a well-conducted prospective cohort nent of clinical decision- making. Clini- study or registry cians care for patients, not populations; c Evidence from a well-conducted meta-analysis of cohort studies guidelines must always be interpreted Supportive evidence from a well-conducted case-control with the individual patient in mind. Indi- study vidual circumstances, such as comorbid C Supportive evidence from poorly controlled or and coexisting diseases, age, education, uncontrolled studies disability, and, above all, patients’ val- c Evidence from randomized clinical trials with one or ues and preferences, must be considered more major or three or more minor methodological and may lead to different treatment tar- fl aws that could invalidate the results gets and strategies. Furthermore, con- c Evidence from observational studies with high potential for bias (such as case series with comparison ventional evidence hierarchies, such as with historical controls) the one adapted by the ADA, may miss c Evidence from case series or case reports nuances important in diabetes care. For Conflicting evidence with the weight of evidence example, although there is excellent evi- supporting the recommendation dence from clinical trials supporting the E Expert consensus or clinical experience importance of achieving multiple risk factor control, the optimal way to achieve this result is less clear. It is difficult to as- ScientificReview evolution in the evaluation of scientificevi- sess each component of such a complex A scientific review is a balanced review dence and in the development of evidence- intervention. and analysis of the literature on a scien- based guidelines. In 2002, the ADA devel- tific or medical topic related to diabetes. oped a classification system to grade the References A scientific review is not an ADA position quality of scientific evidence supporting 1. American Diabetes Association. Medical Man- agement of Type 1 Diabetes and does not contain clinical practice ADA recommendations. A 2015 analysis of . 7th ed. Wang CC, Shah AC, Eds. Alexandria, VA, American Diabetes recommendations but is produced un- theevidencecitedintheStandardsofCare Association, 2017 der the auspices of the Association by found steady improvement in quality 2. American Diabetes Association. Medical Man- invited experts. The scientificreviewmay over the previous 10 years, with the agement of Type 2 Diabetes. 7th ed. Burant CF, provide a scientific rationale for clini- 2014 Standards of Care for the first time Young LA, Eds. Alexandria, VA, American Diabetes cal practice recommendations in the having the majority of bulleted recom- Association, 2012 3. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang Standards of Care. The category may also mendations supported by A-orB-level X. Cost-effectiveness of interventions to prevent include task force and expert committee evidence (4). A grading system (Table 1) and control diabetes mellitus: a systematic re- reports. developed by the ADA and modeled view. Diabetes Care 2010;33:1872–1894 after existing methods was used to clarify 4. Grant RW, Kirkman MS. Trends in the evi- GRADING OF SCIENTIFIC EVIDENCE dence level for the American Diabetes Associ- and codify the evidence that forms the ation’s “Standards of Medical Care in Diabetes” Since the ADA first began publishing practice basis for the recommendations. ADA rec- from 2005 to 2014. Diabetes Care 2015;38: guidelines, there has been considerable ommendations are assigned ratings of A, 6–8 S4 Diabetes Care Volume 41, Supplement 1, January 2018

Summary of Revisions: Standards of Medical Care SUMMARY OF REVISIONS in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S4–S6 | https://doi.org/10.2337/dc18-SREV01

GENERAL CHANGES A new recommendation was added The immunization section was updated The field of diabetes care is rapidly changing about using reliable data metrics to assess for clarity to more closely align with rec- as new research, technology, and treat- and improve the quality of diabetes care ommendations from the Centers for Dis- ments that can improve the health and and reduce costs. ease Control and Prevention. well-being of people with diabetes continue Additional discussion was included on Text was added about the importance to emerge. With annual updates since 1989, the social determinants of health. of language choice in patient-centered the American Diabetes Association’s(ADA’s) Text was added describing the emerg- communication. “Standards of Medical Care in Diabetes” ing use of telemedicine in diabetes care. Pancreatitis was added to the section on comorbidities, including a new recom- (Standards of Care) has long been a leader Section 2. Classification and Diagnosis mendation about the consideration of in producing guidelines that capture the of Diabetes fi islet autotransplantation to prevent post- most current state of the eld. Starting in As a result of recent evidence describing surgical diabetes in patients with medi- 2018, the ADA will update the Standards of potential limitations in A1C measure- cally refractory chronic pancreatitis who Care even more frequently online should ments due to hemoglobin variants, assay require total pancreatectomy. the Professional Practice Committee de- interference, and conditions associated A recommendation was added to termine that new evidence or regulatory with red blood cell turnover, additional consider checking serum testosterone in changes merit immediate incorporation recommendations were added to clarify men with diabetes and signs and symp- into the Standards of Care. In addition, the appropriate use of the A1C test gener- toms of hypogonadism. the Standards of Care will now become ally and in the diagnosis of diabetes in the ADA’s sole source of clinical practice these special cases. Section 4. Lifestyle Management recommendations, superseding all prior The recommendation for testing for A recommendation was modified to in- position and scientific statements. The prediabetes and type 2 diabetes in children clude individual and group settings as change is intended to clarify the Associa- and adolescents was changed, suggesting well as technology-based platforms for tion’s current positions by consolidating testing for youth who are overweight or the delivery of effective diabetes self- all clinical practice recommendations into obese and have one or more additional management education and support. the Standards of Care. For further informa- risk factors (Table 2.5). Additional explanation was added to tion on changes to the classification and Aclarification was added that, while the nutrition section to clarify the ADA’s definitions of ADA Standards of Care, generally not recommended, commu- recommendations that there is no univer- statements, reports, and reviews, see nity screening may be considered in sal ideal macronutrient distribution and the Introduction. specific situations where an adequate Although levels of evidence for several that eating plans should be individualized. referral system for positive tests is recommendations have been updated, Text was added to address the role of established. these changes are not addressed below low-carbohydrate diets in people with Additional detail was added regarding as the clinical recommendations have re- diabetes. current research on antihyperglycemic mained the same. Changes in evidence level treatment in people with posttransplan- Section 5. Prevention or Delay of from, for example, E to C are not noted tation diabetes mellitus. Type 2 Diabetes below. The 2018 Standards of Care con- The recommendation regarding the use of tains, in addition to many minor changes Section 3. Comprehensive Medical metformin in the prevention of prediabe- that clarify recommendations or reflect Evaluation and Assessment of tes was reworded to better reflect the data new evidence, the following more substan- Comorbidities from the Diabetes Prevention Program. tive revisions. The table describing the components of a comprehensive medical evaluation (Table Section 6. Glycemic Targets SECTION CHANGES 3.1) was substantially redesigned and re- Based on new data, the recommendation Section 1. Improving Care and organized, incorporating information about for the use of continuous glucose monitor- Promoting Health in Populations the recommended frequency of the compo- ing (CGM) in adults with type 1 diabetes is Thissectionwasrenamedtobettercaptureits nents of care at both initial and follow-up no longer limited to those ages 25 and subject matter and was reorganized for clarity. visits. above but has been expanded to all adults

(18 and above) who are not meeting glyce- Section 9. Cardiovascular Disease that combines information on staging mic targets. and Risk Management chronic kidney disease and the appro- Additional text was added about a new A new recommendation was added that all priate kidney-related care for each stage. intermittent or “flash” CGM device that hypertensive patients with diabetes should AnewTable 10.2 was included describ- was recently approved for adult use. monitor their blood pressure at home to help ing the complications of chronic kidney Details were added about new CGM de- identify masked or white coat hypertension, as disease and related medical and labora- vices that no longer require confirmatory well as to improve medication-taking behavior. tory evaluations. self-monitoring of blood glucose for treat- Anewfigure (Fig. 9.1) was added to A new section on acute kidney injury ment decisions. illustrate the recommended antihyper- was included. As in Section 2, this section now includes tensive treatment approach for adults The effect of specific glucose-lowering an expanded discussion of the limitations with diabetes and hypertension. medications on the delay and progression of A1C in certain populations based on the Anewtable(Table 9.1) was added sum- of kidney disease was discussed, with ref- presence of hemoglobin variants, differ- marizing studies of intensive versus stan- erence to recent CVOT trials that examined ences in red blood cell turnover rates, eth- dard hypertension treatment strategies. kidney effects as secondary outcomes. nicity, and age. A recommendation was added to consider A new recommendation was added on To clarify the classification of hypogly- mineralocorticoid receptor antagonist ther- the noninferiority of the anti–vascular endo- cemia, level 1 hypoglycemia was renamed apy in patients with resistant hypertension. thelial growth factor treatment ranibizumab “hypoglycemia alert value” from “glucose The lipid management recommendations in reducing the risk of vision loss in patients alert value.” were modified to stratify risk based on two with proliferative diabetic retinopathy broad categories: those with documented when compared with the traditional stan- Section 7. Obesity Management ASCVD and those without. dard treatment, panretinal laser photoco- for the Treatment of Type 2 Diabetes Owing to studies suggesting similar ben- agulation therapy. To provide a second set of cost informa- efits in older versus middle-aged adults, recom- A new section was added describing tion, the table of medications for the mendations were consolidated for patients the mixed evidence on the use of hyper- treatment of obesity (Table 7.2) was up- with diabetes 40–75 years and .75 years of baric oxygen therapy in people with dia- dated to include National Average Drug age without ASCVD to use moderate-intensity betic foot ulcers. Acquisition Cost (NADAC) prices. statin. Section 8. Pharmacologic Approaches Table 9.2 (“Recommendations for sta- Section 11. Older Adults to Glycemic Treatment tin and combination treatment in adults Three new recommendations were added New recommendations for antihyperglyce- with diabetes”) was updated based on to highlight the importance of individualiz- mic therapy for adults with type 2 diabetes the new risk stratification approach and ing pharmacologic therapy in older adults to have been added to reflect recent cardio- consolidated age-groups. reduce the risk of hypoglycemia, avoid over- vascular outcomes trial (CVOT) data, indi- To accommodate recent data on new treatment, and simplify complex regimens if cating that people with atherosclerotic classes of lipid-lowering medications, a re- possible while maintaining the A1C target. cardiovascular disease (ASCVD) should be- commendation was modified to provide gin with lifestyle management and metfor- additional guidance on adding nonstatin Section 12. Children and Adolescents min and subsequently incorporate an LDL-lowering therapies for patients with To make the section more comprehensive agent proven to reduce major adverse diabetes and ASCVD who have LDL choles- andtoreflectemergingdataondiabetes cardiovascular events and/or cardiovascu- terol $70 mg/dL despite maximally toler- technologies, additional recommendations lar mortality after considering drug-specific ated statin dose. were added on the treatment of type 1 and patient factors. The same recommendations were added diabetes in children and adolescents regard- The algorithm for antihyperglycemic here as in Section 8 that people with type 2 ing intensive insulin regimens, self-monitoring treatment (Fig. 8.1) was updated to incor- diabetes and ASCVD should begin with life- of blood glucose, CGM, and automated insulin porate the new ASCVD recommendation. style management and metformin and sub- delivery systems. A new table was added (Table 8.1)to sequently incorporate an agent proven to The recommended risk-based timing of summarize drug-specific and patient fac- reduce major adverse cardiovascular events celiac disease screenings for youth and ad- tors of antihyperglycemic agents. Figure and/or cardiovascular mortality after con- olescents with type 1 diabetes was defined. 8.1 and Table 8.1 are meant to be used sidering drug-specificandpatientfactors. A recommendation regarding esti- together to guide the choice of antihy- The text was substantially modified to mating glomerular filtration rate was re- perglycemic agents as part of patient– describe CVOT data on new diabetes agents moved because of the poor performance provider shared decision-making. and outcomes in people with type 2 diabe- of the estimating equation in youth. Table 8.2 was modified to focus on the tes, providing support for the new ASCVD The type 2 diabetes in children section pharmacology and mechanisms of avail- recommendations. was substantially expanded, with several able glucose-lowering medicines in the AnewTable 9.4 was added to summa- new recommendations, based on a re- U.S. rize the CVOT studies. cent ADA review. To provide a second set of cost information for antihyperglycemic agents, Section 10. Microvascular Section 13. Management of Diabetes NADAC data was added to the average Complications and Foot Care in Pregnancy wholesale prices information in Table A new table was added (Table 10.1), re- A recommendation was added to empha- 8.3 and Table 8.4. placing previous tables 10.1 and 10.2, size that insulin is the preferred agent for S6 Summary of Revisions Diabetes Care Volume 41, Supplement 1, January 2018

the management of type 1 and type 2 di- type 1 and type 2 diabetes to take Section 14. Diabetes Care in the Hospital abetes in pregnancy. low-dose aspirin starting at the end of Insulin degludec was added to the insulin Based on new evidence, a recom- the ﬁrst trimester to lower the risk of dosing for enteral/parenteral feedings mendation was added for women with preeclampsia. (Table 14.1). Diabetes Care Volume 41, Supplement 1, January 2018 S7

1. Improving Care and Promoting American Diabetes Association Health in Populations: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S7–S12 | https://doi.org/10.2337/dc18-S001 .IPOIGCR N RMTN HEALTH PROMOTING AND CARE IMPROVING 1.

DIABETES AND POPULATION HEALTH

Recommendations c Ensure treatment decisions are timely, rely on evidence-based guidelines, and are made collaboratively with patients based on individual preferences, prognoses, and comorbidities. B c Align approaches to diabetes management with the Chronic Care Model, emphasizing productive interactions between a prepared proactive care team and an informed activated patient. A c Care systems should facilitate team-based care, patient registries, decision support tools, and community involvement to meet patient needs. B c Efforts to assess the quality of diabetes care and create quality improvement strategies should incorporate reliable data metrics, to promote improved processes of care and health outcomes, with simultaneous emphasis on costs. E

Population health is defined as “the health outcomes of a group of individuals, including the distribution of health outcomes within the group”; these outcomes can be measured in terms of health outcomes (mortality, morbidity, health, and func- Suggested citation: American Diabetes Associa- tional status), disease burden (incidence and prevalence), and behavioral and meta- tion. 1. Improving care and promoting health in bolic factors (exercise, diet, A1C, etc.) (1). Clinical practice recommendations for health populations: Standards of Medical Care in care providers are tools that can ultimately improve health across populations; how- Diabetesd2018. Diabetes Care 2018;41(Suppl. ever, for optimal outcomes, diabetes care must also be individualized for each patient. 1):S7–S12 Thus, efforts to improve population health will require a combination of system-level © 2017 by the American Diabetes Association. and patient-level approaches. With such an integrated approach in mind, the American Readers may use this article as long as the work patient-centered care, fi is properly cited, the use is educational and not Diabetes Association (ADA) highlights the importance of de ned for profit, and the work is not altered. More infor- as care that is respectful of and responsive to individual patient preferences, needs, and mation is available at http://www.diabetesjournals values and that ensures that patient values guide all clinical decisions (2). Clinical .org/content/license. S8 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

practice recommendations, whether these factors into consideration and is psychosocial issues (25,26); and identify- based on evidence or expert opinion, an effective framework for improving ing, developing, and engaging community are intended to guide an overall ap- the quality of diabetes care (8). resources and public policies that support proach to care. The science and art of Six Core Elements. The CCM includes six healthy lifestyles (27). The National Diabe- medicine come together when the clini- core elements to optimize the care of pa- tes Education Program maintains an on- cian is faced with making treatment rec- tients with chronic disease: line resource (www.betterdiabetescare ommendations for a patient who may .nih.gov) to help health care professionals not meet the eligibility criteria used in 1. Delivery system design (moving from a design and implement more effective the studies on which guidelines are based. reactive to a proactive care delivery health care delivery systems for those Recognizing that one size does not fitall, system where planned visits are coordi- with diabetes. the standards presented here provide nated through a team-based approach) The care team, which includes the pa- guidance for when and how to adapt recom- 2. Self-management support tient, should prioritize timely and appro- mendations for an individual. 3. Decision support (basing care on evidence- priate intensification of lifestyle and/or based, effective care guidelines) pharmacologic therapy for patients who Care Delivery Systems 4. Clinical information systems (using regis- have not achieved the recommended fi – Over the past 10 years, the proportion of tries that can provide patient-speci cand metabolic targets (28 30). Strategies patients with diabetes who achieve recom- population-based support to the care shown to improve care team behavior mended A1C, blood pressure, and LDL cho- team) and thereby catalyze reductions in A1C, lesterol levels has increased (3). The mean 5. Community resources and policies blood pressure, and/or LDL cholesterol A1C nationally among people with diabe- (identifying or developing resources include engaging in explicit and collabo- tes has declined from 7.6% (60 mmol/mol) to support healthy lifestyles) rative goal setting with patients (31,32); 6. Health systems (to create a quality- in 1999–2002 to 7.2% (55 mmol/mol) in identifying and addressing language, oriented culture) 2007–2010 based on the National Health numeracy, or cultural barriers to care – and Nutrition Examination Survey (NHANES), Redefining the roles of the health care (33 35); integrating evidence-based with younger adults less likely to meet delivery team and empowering patient guidelines and clinical information tools treatment targets than older adults (3). self-management are fundamental to into the process of care (16,36,37); solic- This has been accompanied by improve- the successful implementation of the iting performance feedback, setting re- ments in cardiovascular outcomes and CCM (9). Collaborative, multidisciplinary minders, and providing structured care has led to substantial reductions in end- teams are best suited to provide care (e.g., guidelines, formal case manage- stage microvascular complications. for people with chronic conditions such ment, and patient education resources) Nevertheless, 33–49% of patients still as diabetes and to facilitate patients’ (7); and incorporating care management do not meet targets for glycemic, blood self-management (10–12). teams including nurses, dietitians, pharma- pressure, or cholesterol control, and only cists,andotherproviders(17,38). Initiatives 14% meet targets for all three measures Strategies for System-Level Improvement such as the Patient-Centered Medical while also avoiding smoking (3). Evidence Optimal diabetes management requires Home show promise for improving health suggests that progress in cardiovascular an organized, systematic approach and outcomes by fostering comprehensive risk factor control (particularly tobacco the involvement of a coordinated team primary care and offering new opportuni- use) may be slowing (3,4). Certain seg- of dedicated health care professionals ties for team-based chronic disease man- ments of the population, such as young working in an environment where patient- agement (39). adults and patients with complex comor- centered high-quality care is a priority For rural populations or those with lim- bidities, financial or other social hard- (7,13,14). While many diabetes processes ited physical access to health care, teleme- ships, and/or limited English proficiency, of care have improved nationally in the dicine is an approach with a growing body face particular challenges to goal-based past decade, the overall quality of care for of evidence for its effectiveness, particu- care (5–7). Even after adjusting for these patients with diabetes remains subopti- larly with regards to glycemic control as patient factors, the persistent variability mal (15). Efforts to increase the quality measured by A1C (40,41). Telemedicine fi in the quality of diabetes care across proof diabetes care include providing care is de ned as the use of telecommunica- viders and practice settings indicates that that is concordant with evidence-based tions to facilitate remote delivery of health- substantial system-level improvements guidelines (16); expanding the role of related services and clinical information are still needed. teams to implement more intensive dis- (42). Interactive strategies that facilitate ease management strategies (7,17,18); communication between providers and Chronic Care Model tracking medication-taking behavior at a patients, including the use of web-based Numerous interventions to improve ad- systems level (19); redesigning the orga- portal or text messaging and those that herence to the recommended standards nization of care process (20); implement- incorporate medication adjustment ap- have been implemented. However, a ma- ing electronic health record tools (21,22); pear more effective. There is limited data jor barrier to optimal care is a delivery empowering and educating patients available on the cost-effectiveness of these system that is often fragmented, lacks (23,24); removing financial barriers and strategies. clinical information capabilities, dupli- reducing patient out-of-pocket costs Successful diabetes care also requires a cates services, and is poorly designed for for diabetes education, eye exams, self- systematic approach to supporting patients’ the coordinated delivery of chronic care. monitoring of blood glucose, and necessary behavior change efforts. High-quality di- The Chronic Care Model (CCM) takes medications (7); assessing and addressing abetes self-management education and care.diabetesjournals.org Improving Care and Promoting Health S9

support (DSMES) has been shown to im- quality (48,49). Using patient registries can be drawn upon to inform systems- prove patient self-management, satisfac- and electronic health records, health sys- level strategies in diabetes. For example, tion, and glucose outcomes. National tems can evaluate the quality of diabetes the National Academy of Medicine has DSMES standards call for an integrated care being delivered and perform inter- published a framework for educating approach that includes clinical content vention cycles as part of quality improve- health care professionals on the impor- and skills, behavioral strategies (goal set- ment strategies (50). Critical to these tance of social determinants of health. Fur- ting, problem solving), and engagement efforts is provider adherence to clinical thermore, there are resources available for with psychosocial concerns (26). For practice recommendations and accurate, the inclusion of standardized sociodemo- more information on DSMES, see Section reliable data metrics that include socio- graphic variables in electronic medical re- 4 “Lifestyle Management.” demographic variables to examine health cords to facilitate the measurement of In devising approaches to support dis- equity within and across populations (51). health inequities as well as the impact of ease self-management, it is notable that In addition to quality improvement interventions designed to reduce those in- in 23% of cases, uncontrolled A1C, blood efforts, other strategies that simulta- equities (61–63). pressure, or lipids was associated with neously improve the quality of care and Social determinants of health are not poor medication-taking behaviors (19). could potentially reduce costs are gaining always recognized and often go undis- At a system level, “adequate” medication momentum and include reimbursement cussed in the clinical encounter (57). A taking is defined as 80% (calculated as the structures that, in contrast to visit-based studybyPietteetal.(64) found that among number of pills taken by the patient in a billing, reward the provision of appropriate patients with chronic illnesses, two-thirds given time period divided by the number and high-quality care to achieve metabolic of those who reported not taking medi- of pills prescribed by the physician in that goals (52) and incentives that accommo- cations as prescribed due to cost never same time period) (19). If medication tak- date personalized care goals (7,53). shared this with their physician. In a ing is 80% or above and treatment goals more recent study using data from the are not met, then treatment intensifica- National Health Interview Survey (NHIS), TAILORING TREATMENT FOR tion should be considered (e.g., uptitra- Patel et al. (57) found that half of adults SOCIAL CONTEXT tion). Barriers to medication taking may with diabetes reported financial stress include patient factors (remembering to Recommendations and one-fifth reported food insecurity obtain or take medications, fear, depres- c Providers should assess social con- (FI). Creating systems-level mechanisms sion, or health beliefs), medication factors text, including potential food insecu- to screen for social determinants of (complexity, multiple daily dosing, cost, rity, housing stability, and financial health may help overcome structural bar- or side effects), and system factors (inad- barriers, and apply that information riers and communication gaps between equate follow-up or support). Success in to treatment decisions. A patients and providers (57). In addition, overcoming barriers to medication taking c Refer patients to local community brief, validated screening tools for some may be achieved if the patient and pro- resources when available. B social determinants of health exist and vider agree on a targeted approach for a c Provide patients with self-management could facilitate discussion around factors specific barrier (11). support from lay health coaches, that significantly impact treatment during The Affordable Care Act has resulted in navigators, or community health the clinical encounter. Below is a discussion increased access to care for many individ- workers when available. A of assessment and treatment consider- uals with diabetes with an emphasis on ations in the context of FI, homelessness, health promotion and disease prevention Health inequities related to diabetes and and limited English proficiency/low literacy. (43). As mandated by the Affordable Care its complications are well documented Act, the Agency for Healthcare Research and are heavily influenced by social deter- Food Insecurity and Quality developed a National Quality minants of health (54–58). Social determi- FI is the unreliable availability of nutri- Strategy based on the triple aims that nants of health are defined as the economic, tious food and the inability to consistently include improving the health of a popula- environmental, political, and social condi- obtain food without resorting to socially tion, overall quality and patient experi- tions in which people live and are responsi- unacceptable practices. Over 14% (or one ence of care, and per capita cost (44,45). ble for a major part of health inequality of every seven people) of the U.S. popu- As health care systems and practices worldwide (59). The ADA recognizes the lation is food insecure. The rate is higher adapt to the changing landscape of health association between social and environ- in some racial/ethnic minority groups, in- care, it will be important to integrate tra- mental factors and the prevention and cluding African American and Latino pop- ditional disease-specificmetricswith treatment of diabetes and has issued a ulations, in low-income households, and measures of patient experience, as well call for research that seeks to better un- in homes headed by a single mother. The as cost, in assessing the quality of diabe- derstand how these social determinants risk for type 2 diabetes is increased twofold tes care (46,47). Information and guid- influence behaviors and how the relation- in those with FI (60). Risk for FI can be as- ance specific to quality improvement ships between these variables might be sessed with a validated two-item screen- and practice transformation for diabetes modified for the prevention and manage- ing tool (65) that includes the statements: care is available from the National Diabe- ment of diabetes (60). While a comprehen- 1) “Within the past 12 months we worried tes Education Program practice transfor- sive strategy to reduce diabetes-related whether our food would run out before mation website and the National Institute health inequities in populations has not we got money to buy more” and 2) for Diabetes and Digestive and Kidney been formally studied, general recommen- “Within the past 12 months the food we Diseases report on diabetes care and dations from other chronic disease models bought just didn’t last and we didn’thave S10 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

money to get more.” An affirmative re- be familiar with resources or have access in U.S. diabetes care, 1999-2010. N Engl J Med sponse to either statement had a sensi- to social workers that can facilitate tem- 2013;368:1613–1624 tivity of 97% and specificity of 83%. porary housing for their patients as a way 4. Wang J, Geiss LS, Cheng YJ, et al. Long-term and recent progress in blood pressure levels to improve diabetes care. Treatment Considerations among U.S. adults with diagnosed diabetes, 1988-2008. Diabetes Care 2011;34:1579–1581 In those with diabetes and FI, the priority Language Barriers 5. Kerr EA, Heisler M, Krein SL, et al. Beyond co- is mitigating the increased risk for uncon- Providers who care for non-English speak- morbidity counts: how do comorbidity type and trolled hyperglycemia and severe hypo- ers should develop or offer educational severity influence diabetes patients’ treatment glycemia. Reasons for the increased risk programs and materials in multiple lan- priorities and self-management? J Gen Intern of hyperglycemia include the steady guages with the specific goals of prevent- Med 2007;22:1635–1640 consumption of inexpensive carbohydrate- ing diabetes and building diabetes 6. Fernandez A, Schillinger D, Warton EM, et al. fi Language barriers, physician-patient language rich processed foods, binge eating, nan- awareness in people who cannot easily concordance, and glycemic control among in- cial constraints to the filling of diabetes read or write in English. The National Stan- sured Latinos with diabetes: the Diabetes Study medication prescriptions, and anxiety/ dards for Culturally and Linguistically Ap- of Northern California (DISTANCE). J Gen Intern depression leading to poor diabetes self- propriate Services in Health and Health Med 2011;26:170–176 care behaviors. Hypoglycemia can occur as a Care provide guidance on how health 7. TRIAD Study Group. Health systems, patients result of inadequate or erratic carbohydrate factors, and quality of care for diabetes: a synthesis care providers can reduce language bar- of findings from the TRIAD study. Diabetes Care consumption following the administration riers by improving their cultural compe- 2010;33:940–947 of sulfonylureas or insulin. tency, addressing health literacy, and 8. Stellefson M, Dipnarine K, Stopka C. The If using a sulfonylurea in patients with ensuring communication with language Chronic Care Model and diabetes management FI, glipizide may be considered due to its assistance (68). The site offers a number in US primary care settings: a systematic review. relatively short half-life. It can be taken of resources and materials that can be Prev Chronic Dis 2013;10:E26 9. Coleman K, Austin BT, Brach C, Wagner EH. immediately before meals, thus obviating used to improve the quality of care deliv- Evidence on the Chronic Care Model in the new the need to plan meals to an extent that ery to non-English–speaking patients. millennium. Health Aff (Millwood) 2009;28:75–85 may be unreachable for those with FI. 10. Piatt GA, Anderson RM, Brooks MM, et al. 3- For those needing insulin, rapid-acting Community Support year follow-up of clinical and behavioral improve- fi insulin analogs, preferably delivered by a Identi cation or development of commu- ments following a multifaceted diabetes care pen, may be used immediately after meal nity resources to support healthy life- intervention: results of a randomized controlled styles is a core element of the CCM (8). trial. Diabetes Educ 2010;36:301–309 consumption, whenever food becomes 11. Katon WJ, Lin EHB, Von Korff M, et al. Collab- Health care community linkages are receiv- available. While such insulin analogs orative care for patients with depression and chronic may be costly, many pharmaceutical coming increasing attention from the American illnesses. N Engl J Med 2010;363:2611–2620 panies provide access to free medications Medical Association, the Agency for Health- 12. Parchman ML, Zeber JE, Romero RR, Pugh JA. through patient assistance programs. If care Research and Quality, and others as a Risk of coronary artery disease in type 2 diabetes and the delivery of care consistent with the rapid-acting insulin analogs are not op- means of promoting translation of clinical recommendations for lifestyle modification chronic care model in primary care settings: a tions for those with FI who need insulin STARNet study. Med Care 2007;45:1129–1134 therapy, a relatively low dose of an ultra- in real-world settings (69). Community 13. Tricco AC, Ivers NM, Grimshaw JM, et al. Ef- long-acting insulin analog may be prescribed health workers (CHWs) (70), peer sup- fectiveness of quality improvement strategies on simply to prevent marked hyperglycemia, porters (71,72), and lay leaders (73) may the management of diabetes: a systematic review assist in the delivery of DSMES services and meta-analysis. Lancet 2012;379:2252–2261 while recognizing that tight control may 14. Schmittdiel JA, Gopalan A, Lin MW, Banerjee not be possible in such cases. Providers (61), particularly in underserved commu- fi S, Chau CV, Adams AS. Population health manage- should also seek local resources that nities. A CHW is de ned by the American ment for diabetes: health care system-level ap- “ might help patients with diabetes and Public Health Association as a frontline proaches for improving quality and addressing their family members to more regularly public health worker who is a trusted disparities. Curr Diab Rep 2017;17:31 obtain nutritious food (66). member of and/or has an unusually close 15. Saaddine JB, Cadwell B, Gregg EW, et al. Im- understanding of the community served” provements in diabetes processes of care and in- Homelessness termediate outcomes: United States, 1988-2002. (74). CHWs can be part of a cost-effective, – Homelessness often accompanies many Ann Intern Med 2006;144:465 474 evidence-based strategy to improve the 16. O’Connor PJ, Bodkin NL, Fradkin J, et al. Di- additional barriers to diabetes self- management of diabetes and cardiovas- abetes performance measures: current status and management, including FI, literacy and cular risk factors in underserved commu- future directions. Diabetes Care 2011;34:1651–1659 numeracy deficiencies, lack of insurance, nities and health care systems (75). 17. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. cognitive dysfunction, and mental health Improved blood pressure control associated issues. Additionally, patients with diabe- with a large-scale hypertension program. JAMA References – tes who are homeless need secure places 2013;310:699 705 18. Peikes D, Chen A, Schore J, Brown R. Effects of to keep their diabetes supplies and re- 1. Kindig D, Stoddart G. What is population health? Am J Public Health 2003;93:380–383 care coordination on hospitalization, quality of frigerator access to properly store their in- 2. Institute of Medicine Committee on Quality of care, and health care expenditures among Medi- sulin and take it on a regular schedule. Risk HealthCarein America. Crossing the quality chasm: care beneficiaries: 15 randomized trials. JAMA for homelessness can be ascertained a new health system for the 21st century [Inter- 2009;301:603–618 using a brief risk assessment tool developed net], 2001. Washington, DC, The National Acade- 19. Raebel MA, Schmittdiel J, Karter AJ, Konieczny JL, mies Press. Available from http://www.nap.edu/ Steiner JF. Standardizing terminology and defini- and validated for use among veterans (67). catalog/10027. Accessed 25 October 2017 tions of medication adherence and persistence in Given the potential challenges, providers 3. Ali MK, Bullard KM, Saaddine JB, Cowie CC, research employing electronic databases. Med who care for homeless individuals should Imperatore G, Gregg EW. Achievement of goals Care 2013;51(Suppl. 3):S11–S21 care.diabetesjournals.org Improving Care and Promoting Health S11

20. Feifer C, Nemeth L, Nietert PJ, et al. Different 36. Garg AX, Adhikari NKJ, McDonald H, et al. 51. Centers for Medicare & Medicaid Services. paths to high-quality care: three archetypes of Effects of computerized clinical decision support CMS Equity Plan for Medicare [Internet]. Available top-performing practice sites. Ann Fam Med systems on practitioner performance and patient from https://www.cms.gov/About-CMS/Agency- 2007;5:233–241 outcomes: a systematic review. JAMA 2005;293: Information/OMH/equity-initiatives/equity-plan 21. Reed M, Huang J, Graetz I, et al. Outpatient 1223–1238 .html. Accessed 26 September 2017 electronic health records and the clinical care and 37. Smith SA, Shah ND, Bryant SC, et al.; Evidens 52. Rosenthal MB, Cutler DM, Feder J. The ACO outcomes of patients with diabetes mellitus. Ann Research Group. Chronic care model and shared care rules–striking the balance between participation Intern Med 2012;157:482–489 in diabetes: randomized trial of an electronic decision and transformative potential. N Engl J Med 2011; 22. Cebul RD, Love TE, Jain AK, Hebert CJ. Elec- support system. Mayo Clin Proc 2008;83:747–757 365:e6 tronic health records and quality of diabetes care. 38. Stone RA, Rao RH, Sevick MA, et al. Active 53. Washington AE, Lipstein SH. The Patient- N Engl J Med 2011;365:825–833 care management supported by home telemoni- Centered Outcomes Research Institute–promoting 23. Battersby M, Von Korff M, Schaefer J, et al. toring in veterans with type 2 diabetes: the DiaTel better information, decisions, and health. N Engl J Twelve evidence-based principles for implement- randomized controlled trial. Diabetes Care 2010; Med 2011;365:e31 ing self-management support in primary care. 33:478–484 54. Hutchinson RN, Shin S. Systematic review of Jt Comm J Qual Patient Saf 2010;36:561–570 39. Bojadzievski T, Gabbay RA. Patient-centered health disparities for cardiovascular diseases and 24. Grant RW, Wald JS, Schnipper JL, et al. Practice- medical home and diabetes. Diabetes Care 2011; associated factors among American Indian and linked online personal health records for type 2 34:1047–1053 Alaska Native populations. PLoS One 2014;9: diabetes mellitus: a randomized controlled trial. 40. Faruque LI, Wiebe N, Ehteshami-Afshar A, e80973 Arch Intern Med 2008;168:1776–1782 et al.; Alberta Kidney Disease Network. Effect of 55. Borschuk AP, Everhart RS. Health disparities 25. Young-Hyman D, de Groot M, Hill-Briggs F, telemedicine on glycated hemoglobin in diabetes: among youth with type 1 diabetes: a systematic Gonzalez JS, Hood K, Peyrot M. Psychosocial a systematic review and meta-analysis of random- review of the current literature. Fam Syst Health – care for people with diabetes: a position state- ized trials. CMAJ 2017;189:E341 E364 2015;33:297–313 ment of the American Diabetes Association. Di- 41. Marcolino MS, Maia JX, Alkmim MB, Boersma 56. Walker RJ, Strom Williams J, Egede LE. Influ- abetes Care 2016;39:2126–2140 E, Ribeiro AL. Telemedicine application in the care ence of race, ethnicity and social determinants of 26. Powers MA, Bardsley J, Cypress M, et al. Di- of diabetes patients: systematic review and meta- health on diabetes outcomes. Am J Med Sci 2016; abetes self-management education and support analysis. PLoS One 2013;8:e79246 351:366–373 in type 2 diabetes: a joint position statement of 42. American Telemedicine Association. About 57. Patel MR, Piette JD, Resnicow K, Kowalski- the American Diabetes Association, the American telemedicine [Internet], 2016. Available from DobsonT, Heisler M. Social determinants of health, Association of Diabetes Educators, and the Acad- www.americantelemed.org/main/about/about- cost-related nonadherence, and cost-reducing be- telemedicine/telemedicine-faqs. Accessed 13 emy of Nutrition and Dietetics. Diabetes Care haviors among adults with diabetes: findings from November 2017 2015;38:1372–1382 the National Health Interview Survey. Med Care 43. Myerson R, Laiteerapong N. The Affordable 27. Pullen-Smith B, Carter-Edwards L, Leathers 2016;54:796–803 Care Act and diabetes diagnosis and care: exploring KH. Community health ambassadors: a model 58. Steve SL, Tung EL, Schlichtman JJ, Peek ME. the potential impacts. Curr Diab Rep 2016;16:27 for engaging community leaders to promote Social disorder in adults with type 2 diabetes: 44. Stiefel M, Nolan K. Measuring the triple aim: a better health in North Carolina. J Public Health building on race, place, and poverty. Curr Diab call for action. Popul Health Manag 2013;16:219– Manag Pract 2008;14(Suppl.):S73–S81 Rep 2016;16:72 220 28. Davidson MB. How our current medical care 59. World Health Organization Commission on 45. Agency for Healthcare Research and Quality. system fails people with diabetes: lack of timely, Social Determinants of Health. Closing the gap About the National Quality Strategy [Internet], appropriate clinical decisions. Diabetes Care in a generation: health equity through action on 2017. Available from https://www.ahrq.gov/ 2009;32:370–372 the social determinants of health. Geneva, Swit- workingforquality/about/index.html. Accessed 29. Selby JV, Uratsu CS, Fireman B, et al. Treat- zerland, World Health Organization, 2008. Avail- 25 September 2017 fi ment intensi cation and risk factor control: to- 46. National Quality Forum. Home page [Internet], able from http://www.who.int/social_determinants/ fi fi ward more clinically relevant quality measures. 2017. Available from http://www.qualityforum. nal_report/csdh_ nalreport_2008.pdf. Accessed – Med Care 2009;47:395 402 org/Home.aspx. Accessed 25 September 2017 26 September 2017 30. Raebel MA, Ellis JL, Schroeder EB, et al. In- 47. Burstin H, Johnson K. Getting to better care 60. Hill JO, Galloway JM, Goley A, et al. Socioeco- fi tensi cation of antihyperglycemic therapy among and outcomes for diabetes through measurement logical determinants of prediabetes and type 2 – patients with incident diabetes: a Surveillance [article online], 2016. Available from http://www diabetes. Diabetes Care 2013;36:2430 2439 Prevention and Management of Diabetes Mellitus .ajmc.com/journals/evidence-based-diabetes- 61. Institute of Medicine. Capturing social and (SUPREME-DM) study. Pharmacoepidemiol Drug management/2016/march-2016/getting-to-better- behavioral domains and measures in electronic – Saf 2014;23:699 710 care-and-outcomes-for-diabetes-through- health records: phase 2 [Internet], 2014. Wash- 31. Grant RW, Pabon-Nau L, Ross KM, Youatt EJ, measurement. Accessed 26 September 2017 ington, DC, The National Academies Press. Avail- Pandiscio JC, Park ER. Diabetes oral medication 48. National Institute of Diabetes and Digestive able from https://www.nap.edu/catalog/18951/ initiation and intensification: patient views com- and Kidney Diseases. Practice transformation for capturing-social-and-behavioral-domains-and- pared with current treatment guidelines. Diabe- physicians & health care teams [Internet]. Avail- measures-in-electronic-health-records. Accessed tes Educ 2011;37:78–84 able from https://www.niddk.nih.gov/health- 26 September 2017 32. TamhaneS, Rodriguez-Gutierrez R, HargravesI, information/health-communication-programs/ndep/ 62. Chin MH, Clarke AR, Nocon RS, et al. A road- Montori VM. Shared decision-making in diabetes health-care-professionals/practice-transformation/ map and best practices for organizations to re- care. Curr Diab Rep 2015;15:112 Pages/resourcedetail.aspx. Accessed 26 September duce racial and ethnic disparities in health care. 33. Schillinger D, Piette J, Grumbach K, et al. Clos- 2017 J Gen Intern Med 2012;27:992–1000 ing the loop: physician communication with dia- 49. National Institute of Diabetes and Digestive 63. National Quality Forum. National voluntary betic patients who have low health literacy. Arch and Kidney Diseases. Diabetes care and quality: consensus standards for ambulatory cared Intern Med 2003;163:83–90 past, present, and future [Internet]. Available from measuring healthcare disparities [Internet], 2008. 34. Rosal MC, Ockene IS, Restrepo A, et al. Ran- https://www.niddk.nih.gov/health-information/ Available from https://www.qualityforum.org/ domized trial of a literacy-sensitive, culturally tai- health-communication-programs/ndep/health-care- Publications/2008/03/National_Voluntary_ lored diabetes self-management intervention for professionals/practice-transformation/defining- Consensus_Standards_for_Ambulatory_Care%E2% low-income Latinos: Latinos en control. Diabetes quality-care/diabetes-care-quality/Pages/default 80%94Measuring_Healthcare_Disparities.aspx. Care 2011;34:838–844 .aspx. Accessed 26 September 2017 Accessed 21 October 2017 35. Osborn CY, Cavanaugh K, Wallston KA, et al. 50. O’Connor PJ, Sperl-Hillen JM, Fazio CJ, 64. Piette JD, Heisler M, Wagner TH. Cost-related Health literacy explains racial disparities in diabe- Averbeck BM, Rank BH, Margolis KL. Outpatient medication underuse among chronically ill adults: tes medication adherence. J Health Commun diabetes clinical decision support: current status and the treatments people forgo, how often, and who 2011;16(Suppl. 3):268–278 future directions. Diabet Med 2016;33:734–741 is at risk. Am J Public Health 2004;94:1782–1787 S12 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

65. Hager ER, Quigg AM, Black MM, et al. Devel- prevention-chronic-care/improve/community/ conditions. Cochrane Database Syst Rev 2007;4: opment and validity of a 2-item screen to identify index.html. Accessed 10 October 2016 CD005108 families at risk for food insecurity. Pediatrics 2010; 70. Shah M, Kaselitz E, Heisler M. The role of 74. Rosenthal EL, Rush CH, Allen CG; Project on 126:e26–e32 community health workers in diabetes: update CHW Policy & Practice. Understanding scope and 66. Seligman HK, Schillinger D. Hunger and socio- on current literature. Curr Diab Rep 2013;13: competencies: a contemporary look at the United economic disparities in chronic disease. N Engl J 163–171 States community health worker field: progress report Med 2010;363:6–9 71. Heisler M, Vijan S, Makki F, Piette JD. Diabe- of the community health worker (CHW) core consen- 67. Montgomery AE, Fargo JD, Kane V, Culhane tes control with reciprocal peer support versus sus (C3) project: building national consensus on CHW DP. Development and validation of an instrument nursecaremanagement:a randomized trial. core roles, skills, and qualities [Internet], 2016. Avail- to assess imminent risk of homelessness among Ann Intern Med 2010;153:507–515 able from http://files.ctctcdn.com/a907c850501/ veterans. Public Health Rep 2014;129:428–436 72. Long JA, Jahnle EC, Richardson DM, 1c1289f0-88cc-49c3-a238-66def942c147pdf. Ac- 68. U.S. Department of Health and Human Ser- Loewenstein G, Volpp KG. Peer mentoring and cessed 26 September 2017 vices. Think cultural health [Internet]. Available financial incentives to improve glucose control 75. U.S. Department of Health and Human Ser- from https://www.thinkculturalhealth.hhs.gov/. in African American veterans: a randomized trial. vices. Community health workers help patients Accessed 26 September 2017 Ann Intern Med 2012;156:416–424 manage diabetes [Internet]. Available from 69. Agency for Healthcare Research and Quality. 73. Foster G, Taylor SJC, Eldridge SE, Ramsay J, https://www.thecommunityguide.org/content/ Clinical-community linkages [Internet]. Avail- Griffiths CJ. Self-management education pro- community-health-workers-help-patients- able from http://www.ahrq.gov/professionals/ grammes by lay leaders for people with chronic manage-diabetes. Accessed 26 September 2017 Diabetes Care Volume 41, Supplement 1, January 2018 S13

2. Classiﬁcation and Diagnosis of American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S13–S27 | https://doi.org/10.2337/dc18-S002 .CASFCTO N IGOI FDIABETES OF DIAGNOSIS AND CLASSIFICATION 2.

CLASSIFICATION Diabetes can be classified into the following general categories: 1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute 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 pancreatitis), 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 Suggested citation: American Diabetes Associa- type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 tion. 2. Classification and diagnosis of diabetes: diabetes occurring only in adults and type 1 diabetes only in children are no longer Standards of Medical Care in Diabetesd2018. accurate, as both diseases occur in both age-groups. Children with type 1 diabe- Diabetes Care 2018;41(Suppl. 1):S13–S27 tes typically present with the hallmark symptoms of polyuria/polydipsia, and approx- © 2017 by the American Diabetes Association. imately one-third present with diabetic ketoacidosis (DKA) (2). The onset of type 1 Readers may use this article as long as the work is properly cited, the use is educational and not diabetes may be more variable in adults, and they may not present with the classic for profit, and the work is not altered. More infor- symptoms seen in children. Occasionally, patients with type 2 diabetes may present mation is available at http://www.diabetesjournals with DKA, particularly ethnic minorities (3). Although difficulties in distinguishing .org/content/license. S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

diabetes type may occur in all age-groups defects related to inflammation and met- that compared with FPG and A1C cut at onset, the true diagnosis becomes abolic stress among other contributors, points, the 2-h PG value diagnoses more more obvious over time. including genetic factors. Future classi- people with diabetes. In both type 1 and type 2 diabetes, fication schemes for diabetes will likely various genetic and environmental fac- focus on the pathophysiology of the un- A1C tors can result in the progressive loss of derlying b-cell dysfunction and the stage b-cell mass and/or function that mani- of disease as indicated by glucose status Recommendations fests clinically as hyperglycemia. Once (normal, impaired, or diabetes) (4). c To avoid misdiagnosis or missed hyperglycemia occurs, patients with all diagnosis, the A1C test should be forms of diabetes are at risk for devel- DIAGNOSTIC TESTS FOR DIABETES performed using a method that is oping the same chronic complications, Diabetes may be diagnosed based on certified by the NGSP and standard- although rates of progression may differ. plasma glucose criteria, either the fasting ized to the Diabetes Control and fi The identi cation of individualized thera- plasma glucose (FPG) or the 2-h plasma Complications Trial (DCCT) assay. B pies for diabetes in the future will require glucose (2-h PG) value during a 75-g oral c Marked discordance between mea- better characterization of the many paths glucose tolerance test (OGTT), or A1C cri- sured A1C and plasma glucose b to -cell demise or dysfunction (4). teria (6) (Table 2.2). levels should raise the possibility Characterization of the underlying Generally, FPG, 2-h PG during 75-g of A1C assay interference due to pathophysiology is more developed in OGTT, and A1C are equally appropriate hemoglobin variants (i.e., hemoglo- type 1 diabetes than in type 2 diabetes. for diagnostic testing. It should be noted binopathies) and consideration of fi It is now clear from studies of rst-degree that the tests do not necessarily detect using an assay without interference relatives of patients with type 1 diabetes diabetes in the same individuals. The ef- or plasma blood glucose criteria to that the persistent presence of two or ficacy of interventions for primary pre- diagnose diabetes. B more autoantibodies is an almost certain vention of type 2 diabetes (7,8) has c In conditions associated with in- predictor of clinical hyperglycemia and primarily been demonstrated among increased red blood cell turnover, diabetes. The rate of progression is de- dividuals who have impaired glucose tol- such as sickle cell disease, pregnancy fi pendent on the age at rst detection of erance (IGT) with or without elevated (secondandthirdtrimesters),hemo- antibody, number of antibodies, antibody fasting glucose, not for individuals with dialysis, recent blood loss or transfu- fi speci city, and antibody titer. Glucose isolated impaired fasting glucose (IFG) sion, or erythropoietin therapy, only and A1C levels rise well before the clinical or for those with prediabetes defined by plasma blood glucose criteria should onset of diabetes, making diagnosis A1C criteria. be used to diagnose diabetes. B feasible well before the onset of DKA. Three The same tests may be used to screen distinct stages of type 1 diabetes can be for and diagnose diabetes and to detect The A1C test should be performed using a fi Table 2.1 fi identi ed ( )andserveasa individuals with prediabetes. Diabetes method that is certi ed by the NGSP framework for future research and regu- may be identified anywhere along the (www.ngsp.org) and standardized or latory decision-making (4,5). spectrum of clinical scenarios: in seem- traceable to the Diabetes Control and b The paths to -cell demise and dys- ingly low-risk individuals who happen to Complications Trial (DCCT) reference as- fi function are less well de ned in type 2 have glucose testing, in individuals tested say. Although point-of-care A1C assays fi b fi fi diabetes, but de cient -cell insulin se- based on diabetes risk assessment, and in may be NGSP certi ed, pro ciency testing cretion, frequently in the setting of insulin symptomatic patients. is not mandated for performing the test, resistance, appears to be the common de- so use of point-of-care assays for diagnos- nominator. Characterization of subtypes Fasting and 2-Hour Plasma Glucose tic purposes is not recommended but of this heterogeneous disorder have been The FPG and 2-h PG may be used to di- may be considered in the future if pro- developed and validated in Scandinavian agnose diabetes (Table 2.2). The concor- ficiency testing is performed, documented, and Northern European populations but dance between the FPG and 2-h PG tests anddeemedacceptable. have not been confirmed in other ethnic is imperfect, as is the concordance be- The A1C has several advantages com- and racial groups. Type 2 diabetes is pri- tweenA1Candeitherglucose-based pared with the FPG and OGTT, including marily associated with insulin secretory test. Numerous studies have confirmed greater convenience (fasting not required),

Table 2.1—Staging of type 1 diabetes (4,5) Stage 1 Stage 2 Stage 3 Characteristics 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 S15

Confirming the Diagnosis Table 2.2—Criteria for the diagnosis of diabetes FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* Unless there is a clear clinical diagnosis OR (e.g., patient in a hyperglycemic crisis 2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the or with classic symptoms of hyperglyce- $ WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.* mia and a random plasma glucose 200 OR mg/dL [11.1 mmol/L]), a second test is fi A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is required for con rmation. It is recom- NGSP certified and standardized to the DCCT assay.* mended that the same test be repeated OR or a different test be performed without In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma delay using a new blood sample for con- glucose $200 mg/dL (11.1 mmol/L). firmation. For example, if the A1C is 7.0% (53 mmol/mol) and a repeat result is 6.8% *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. (51 mmol/mol), the diagnosis of diabetes is confirmed. If two different tests (such greater preanalytical stability, and less red blood cell turnover, such as those as A1C and FPG) are both above the di- day-to-day perturbations during stress with the sickle cell trait, an A1C assay with- agnostic threshold, this also confirms and illness. However, these advantages out interference from hemoglobin variants the diagnosis. On the other hand, if a pa- may be offset by the lower sensitivity of should be used. An updated list of A1C tient has discordant results from two A1C at the designated cut point, greater assays with interferences is available at different tests, then the test result that cost, limited availability of A1C testing in www.ngsp.org/interf.asp. is above the diagnostic cut point should certain regions of the developing world, African Americans heterozygous for the be repeated, with consideration of the and the imperfect correlation between common hemoglobin variant HbS may possibility of A1C assay interference. The A1C and average glucose in certain indi- have, for any given level of mean glycemia, diagnosis is made on the basis of the con- viduals. National Health and Nutrition lower A1C by about 0.3% than those with- firmed test. For example, if a patient meets Examination Survey (NHANES) data indi- out the trait (11). Another genetic variant, the diabetes criterion of the A1C (two cate that an A1C cut point of $6.5% X-linked glucose-6-phosphate dehydro- results $6.5% [48 mmol/mol]) but not (48 mmol/mol) identifies a prevalence genase G202A, carried by 11% of African FPG (,126 mg/dL [7.0 mmol/L]), that per- of undiagnosed diabetes that is one-third Americans, was associated with a decrease son should nevertheless be considered to of that using glucose criteria (9). in A1C of about 0.8% in hemizygous men have diabetes. When using A1C to diagnose diabetes, and 0.7% in homozygous women com- Since all the tests have preanalytic and it is important to recognize that A1C is pared with those without the variant (12). analytic variability, it is possible that an an indirect measure of average blood Even in the absence of hemoglobin abnormal result (i.e., above the diagnostic glucose levels and to take other factors variants, A1C levels may vary with race/ threshold), when repeated, will produce a into consideration that may impact he- ethnicity independently of glycemia value below the diagnostic cut point. This moglobin glycation independently of (13–15). For example, African Americans scenario is likely for FPG and 2-h PG if the glycemia including age, race/ethnicity, may have higher A1C levels than non- glucose samples remain at room temper- and anemia/hemoglobinopathies. Hispanic whites with similar fasting and ature and are not centrifuged promptly. postglucose load glucose levels (16), and Because of the potential for preanalytic Age A1C levels may be higher for a given mean variability, it is critical that samples for The epidemiological studies that formed glucose concentration when measured plasma glucose be spun and separated the basis for recommending A1C to diag- with continuous glucose monitoring immediately after they are drawn. If pa- nose diabetes included only adult popula- (17). Though conflicting data exists, African tients have test results near the margins tions. Therefore, it remains unclear whether Americans may also have higher levels of the diagnostic threshold, the health care A1C and the same A1C cut point should be of fructosamine and glycated albumin professional should follow the patient – used to diagnose diabetes in children and and lower levels of 1,5-anhydroglucitol, closely and repeat the test in 3 6 months. adolescents (see p. S20 SCREENING AND TESTING suggesting that their glycemic burden CATEGORIES OF INCREASED RISK FOR TYPE 2 DIABETES AND PREDIABETES IN CHILDREN (particularly postprandially) may be higher FOR DIABETES (PREDIABETES) AND ADOLESCENTS for additional information) (18,19). The association of A1C with risk (9,10). for complications appears to be similar in Recommendations African Americans and non-Hispanic c Race/Ethnicity/Hemoglobinopathies Screening for prediabetes and risk Hemoglobin variants can interfere with whites (20,21). for future diabetes with an informal the measurement of A1C, although most assessment of risk factors or vali- Red Blood Cell Turnover assays in use in the U.S. are unaffected by dated tools should be considered In conditions associated with increased B the most common variants. Marked dis- in asymptomatic adults. red blood cell turnover, such as sickle c crepancies between measured A1C and Testing for prediabetes and risk for cell disease, pregnancy (second and third future diabetes in asymptomatic plasma glucose levels should prompt con- trimesters), hemodialysis, recent blood people should be considered in sideration that the A1C assay may not be loss or transfusion, or erythropoietin ther- adults of any age who are over- reliable for that individual. For patients apy, only plasma blood glucose criteria weight or obese (BMI $25 kg/m2 with a hemoglobin variant but normal should be used to diagnose diabetes (22). S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

or $23 kg/m2 in Asian Americans) Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults and who have one or more addi- 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian tional risk factors for diabetes (Table Americans) adults who have one or more of the following risk factors: 2.3). B c First-degree relative with diabetes c High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific c For all people, testing should begin Islander) B at age 45 years. c History of CVD c If tests are normal, repeat testing car- c Hypertension ($140/90 mmHg or on therapy for hypertension) riedoutataminimumof3-yearin- c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL tervalsisreasonable.C (2.82 mmol/L) c To test for prediabetes, fasting plasma c Women with polycystic ovary syndrome c glucose, 2-h plasma glucose during Physical inactivity c Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis 75-g oral glucose tolerance test, and nigricans) B A1C are equally appropriate. 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly. c In patients with prediabetes, identify 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. and, if appropriate, treat other car- 4. For all other patients, testing should begin at age 45 years. diovascular disease risk factors. B 5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with c Testing for prediabetes should be consideration of more frequent testing depending on initial results and risk status. considered in children and adolescents who are overweight or obese (BMI .85th percentile for age and review of 44,203 individuals from 16 co- interventions and vigilant follow-up should sex, weight for height .85th per- hort studies with a follow-up interval be pursued for those considered at very centile, or weight .120% of ideal averaging 5.6 years (range 2.8–12 years), high risk (e.g., those with A1C .6.0% for height) and who have additional those with A1C between 5.5 and 6.0% [42 mmol/mol]). risk factors for diabetes (Table 2.5). E (between 37 and 42 mmol/mol) had a Table 2.4 summarizes the categories of substantially increased risk of diabetes prediabetes and Table 2.3 the criteria for Description (5-year incidence from 9 to 25%). Those prediabetes testing. The ADA diabetes “Prediabetes” is the term used for individ- with an A1C range of 6.0–6.5% (42– risk test is an additional option for screen- uals whose glucose levels do not meet the 48 mmol/mol) had a 5-year risk of devel- ing (Fig. 2.1) (diabetes.org/socrisktest). criteria for diabetes but are too high to be oping diabetes between 25 and 50% For additional background regarding risk considered normal (23,24). Patients with and a relative risk 20 times higher com- factors and screening for prediabetes, see prediabetes are defined by the presence pared with A1C of 5.0% (31 mmol/mol) pp. S19–S20 (SCREENING AND TESTING FOR TYPE 2 of IFG and/or IGT and/or A1C 5.7–6.4% (26). In a community-based study of Afri- DIABETES AND PREDIABETES IN ASYMPTOMATIC ADULTS (39–47 mmol/mol) (Table 2.4). Prediabe- can American and non-Hispanic white and SCREENING AND TESTING FOR TYPE 2 DIABETES tes should not be viewed as a clinical adults without diabetes, baseline A1C AND PREDIABETES IN CHILDREN AND ADOLESCENTS). entity in its own right but rather as an was a stronger predictor of subsequent increased risk for diabetes and cardio- diabetes and cardiovascular events TYPE 1 DIABETES vascular disease (CVD). Criteria for testing than fasting glucose (27). Other analyses for diabetes or prediabetes in asymp- Recommendations suggest that A1C of 5.7% (39 mmol/mol) tomatic adults is outlined in Table 2.3. c Plasma blood glucose rather than or higher is associated with a diabetes risk Prediabetes is associated with obesity (es- A1C should be used to diagnose the similar to that of the high-risk participants pecially abdominal or visceral obesity), acute onset of type 1 diabetes in in- in the Diabetes Prevention Program (DPP) dyslipidemia with high triglycerides and/or dividuals with symptoms of hypergly- (28), and A1C at baseline was a strong low HDL cholesterol, and hypertension. cemia. E predictor of the development of glucose- c Screening for type 1 diabetes with a Diagnosis defined diabetes during the DPP and its panel of autoantibodies is currently IFG is defined as FPG levels between follow-up (29). recommended only in the setting 100 and 125 mg/dL (between 5.6 and Hence, it is reasonable to consider an A1C of a research trial or in first-degree 6.9 mmol/L) (24,25) and IGT as 2-h PG range of 5.7–6.4% (39–47 mmol/mol) as family members of a proband with during 75-g OGTT levels between 140 and identifying individuals with prediabe- type 1 diabetes. B 199 mg/dL (between 7.8 and 11.0 mmol/L) tes. Similar to those with IFG and/or c Persistence of two or more autoan- (23). It should be noted that the World IGT, individuals with A1C of 5.7–6.4% tibodies predicts clinical diabetes Health Organization (WHO) and numerous (39–47 mmol/mol) should be informed and may serve as an indication for other diabetes organizations define the IFG of their increased risk for diabetes and intervention in the setting of a clin- cutoff at 110 mg/dL (6.1 mmol/L). CVD and counseled about effective ical trial. B As with the glucose measures, several strategies to lower their risks (see Sec- prospective studies that used A1C to tion 5 “Prevention or Delay of Type 2 predict the progression to diabetes as Diabetes”). Similar to glucose measure- Diagnosis defined by A1C criteria demonstrated a ments, the continuum of risk is curvi- In a patient with classic symptoms, strong, continuous association between A1C linear, so as A1C rises, the diabetes risk measurement of plasma glucose is suf- and subsequent diabetes. In a systematic rises disproportionately (26). Aggressive ficient to diagnose diabetes (symptoms care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

Table 2.4—Categories of increased risk for diabetes (prediabetes)* cohorts from Finland, Germany, and the FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) U.S. Of the 585 children who developed OR more than two autoantibodies, nearly 2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) 70% developed type 1 diabetes within OR 10 years and 84% within 15 years (31). fi fi A1C 5.7–6.4% (39–47 mmol/mol) These ndings are highly signi cant because while the German group was re- *For all three tests, risk is continuous, extending below the lower limit of the range and becoming cruited from offspring of parents with disproportionately greater at the higher end of the range. type 1 diabetes, the Finnish and American groups were recruited from the general of hyperglycemia or hyperglycemic crisis also related to environmental factors population. Remarkably, the findings plus a random plasma glucose $200 mg/ that are still poorly defined. Although pain all three groups were the same, sug- dL [11.1 mmol/L]). In these cases, know- tients are not typically obese when they gesting that the same sequence of events ing the plasma glucose level is critical be- present with type 1 diabetes, obesity led to clinical disease in both “sporadic” cause, in addition to confirming that should not preclude the diagnosis. Pa- and familial cases of type 1 diabetes. In- symptoms are due to diabetes, it will in- tients with type 1 diabetes are also prone deed, the risk of type 1 diabetes increases form management decisions. Some pro- to other autoimmune disorders such as as the number of relevant autoantibodies viders may also want to know the A1C to Hashimoto thyroiditis, Graves disease, detected increases (32–34). determine how long a patient has had Addison disease, celiac disease, vitiligo, Although there is currently a lack of hyperglycemia. The criteria to diagnose autoimmune hepatitis, myasthenia gravis, accepted screening programs, one should diabetes are listed in Table 2.2. and pernicious anemia (see Section 3 consider referring relatives of those with “Comprehensive Medical Evaluation and type 1 diabetes for antibody testing for Immune-Mediated Diabetes Assessment of Comorbidities”). risk assessment in the setting of a clinical This form, previously called “insulin- research study (www.diabetestrialnet dependent diabetes” or “juvenile-onset Idiopathic Type 1 Diabetes .org). Widespread clinical testing of asymp- diabetes,” accounts for 5–10% of diabetes Some forms of type 1 diabetes have no tomatic low-risk individuals is not currently and is due to cellular-mediated autoimmune known etiologies. These patients have recommended due to lack of approved destruction of the pancreatic b-cells. Auto- permanent insulinopenia and are prone therapeutic interventions. Individuals who immune markers include islet cell auto- to DKA, but have no evidence of b-cell test positive should be counseled about antibodies and autoantibodies to GAD autoimmunity. Although only a minority the risk of developing diabetes, diabetes (GAD65), insulin, the tyrosine phospha- of patients with type 1 diabetes fall into symptoms, and DKA prevention. Numer- tases IA-2 and IA-2b, and ZnT8. Type 1 this category, of those who do, most are ous clinical studies are being conducted diabetes is defined by the presence of of African or Asian ancestry. Individuals to test various methods of preventing one or more of these autoimmune markers. with this form of diabetes suffer from ep- type 1 diabetes in those with evidence of The disease has strong HLA associations, isodic DKA and exhibit varying degrees of autoimmunity (www.clinicaltrials.gov). with linkage to the DQA and DQB genes. insulin deficiency between episodes. This These HLA-DR/DQ alleles can be either form of diabetes is strongly inherited and TYPE 2 DIABETES predisposing or protective. is not HLA associated. An absolute re- The rate of b-cell destruction is quite quirement for insulin replacement therapy Recommendations c Screening for type 2 diabetes with variable, being rapid in some individuals in affected patients may be intermittent. an informal assessment of risk fac- (mainly infants and children) and slow in tors or validated tools should be others (mainly adults). Children and ado- Testing for Type 1 Diabetes Risk considered in asymptomatic adults. B lescents may present with DKA as the first The incidence and prevalence of type 1 c Testing for type 2 diabetes in asymp- manifestation of the disease. Others have diabetes is increasing (30). Patients with tomatic people should be consid- modest fasting hyperglycemia that can type 1 diabetes often present with acute ered in adults of any age who are rapidly change to severe hyperglycemia symptoms of diabetes and markedly overweight or obese (BMI $25 and/or DKA with infection or other stress. elevated blood glucose levels, and ap- kg/m2 or $23 kg/m2 in Asian Amer- Adults may retain sufficient b-cell function proximately one-third are diagnosed icans) and who have one or more to prevent DKA for many years; such in- with life-threatening DKA (2). Several additional risk factors for diabetes dividuals eventually become dependent studies indicate that measuring islet au- (Table 2.3). B on insulin for survival and are at risk for toantibodies in relatives of those with c For all people, testing should begin DKA. At this latter stage of the disease, type 1 diabetes may identify individuals at age 45 years. B there is little or no insulin secretion, as who are at risk for developing type 1 di- c If tests are normal, repeat testing manifested by low or undetectable levels abetes (5). Such testing, coupled with ed- carried out at a minimum of 3-year of plasma C-peptide. Immune-mediated di- ucation about diabetes symptoms and intervalsisreasonable.C abetes commonly occurs in childhood and close follow-up, may enable earlier iden- c To test for type 2 diabetes, fasting adolescence, but it can occur at any age, tification of type 1 diabetes onset. A study plasma glucose, 2-h plasma glucose even in the 8th and 9th decades of life. reported the risk of progression to type 1 during 75-g oral glucose tolerance test, Autoimmune destruction of b-cells has diabetes from the time of seroconversion and A1C are equally appropriate. B multiple genetic predispositions and is to autoantibody positivity in three pediatric S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Figure 2.1—ADA risk test (diabetes.org/socrisktest). care.diabetesjournals.org Classiﬁcation and Diagnosis of Diabetes S19

36). Type 2 diabetes frequently goes un- assessment tool, such as the ADA risk c In patients with diabetes, identify diagnosed for many years because hy- test (Fig. 2.1) (diabetes.org/socrisktest), and treat other cardiovascular dis- perglycemia develops gradually and, is recommended to guide providers on ease risk factors. B at earlier stages, is often not severe whether performing a diagnostic test c Testing for type 2 diabetes should enough for the patient to notice the clas- (Table 2.2) is appropriate. Prediabetes be considered in children and ado- sic diabetes symptoms. Nevertheless, and type 2 diabetes meet criteria for con- lescents who are overweight or even undiagnosed patients are at in- ditions in which early detection is appro- obese (BMI .85th percentile for creased risk of developing macrovascular priate. Both conditions are common and age and sex, weight for height and microvascular complications. impose significant clinical and public .85th percentile,orweight .120% Whereas patients with type 2 diabetes health burdens. There is often a long pre- of ideal for height) and who have may have insulin levels that appear nor- symptomatic phase before the diagnosis additional risk factors for diabetes mal or elevated, the higher blood glucose of type 2 diabetes. Simple tests to detect (Table 2.5). E levels in these patients would be expected preclinical disease are readily available. to result in even higher insulin values had The duration of glycemic burden is a strong Description their b-cell function been normal. Thus, predictor of adverse outcomes. There are Type 2 diabetes, previously referred to insulin secretion is defective in these pa- effective interventions that prevent pro- as “noninsulin-dependent diabetes” or tients and insufficient to compensate for gression from prediabetes to diabetes (see “adult-onset diabetes,” accounts for 90– insulin resistance. Insulin resistance may Section 5 “Prevention or Delay of Type 2 95% of all diabetes. This form encom- improve with weight reduction and/or Diabetes”) and reduce the risk of diabetes passes individuals who have relative pharmacologic treatment of hyperglyce- complications (see Section 9 “Cardiovas- (rather than absolute) insulin deficiency mia but is seldom restored to normal. cular Disease and Risk Management” and and have peripheral insulin resistance. The risk of developing type 2 diabe- Section 10 “Microvascular Complications At least initially, and often throughout tes increases with age, obesity, and lack and Foot Care”). their lifetime, these individuals may not of physical activity. It occurs more fre- Approximately one-quarter of people need insulin treatment to survive. quently in women with prior GDM, in with diabetes in the U.S. and nearly half There are various causes of type 2 di- those with hypertension or dyslipidemia, of Asian and Hispanic Americans with diabetes. Although the specific etiologies and in certain racial/ethnic subgroups abetes are undiagnosed (37,38). Although are not known, autoimmune destruction (African American, American Indian, screening of asymptomatic individuals to of b-cells does not occur and patients do Hispanic/Latino, and Asian American). It identify those with prediabetes or diabe- not have any of the other known causes is often associated with a strong genetic tes might seem reasonable, rigorous clin- of diabetes. Most but not all patients with predisposition or family history in first- ical trials to prove the effectiveness of type 2 diabetes are overweight or obese. degree relatives, more so than type 1 di- such screening have not been conducted Excess weight itself causes some degree abetes. However, the genetics of type 2 and are unlikely to occur. of insulin resistance. Patients who are not diabetes is poorly understood. In adults A large European randomized con- obese or overweight by traditional weight without traditional risk factors for type 2 trolled trial compared the impact of criteria may have an increased percent- diabetes and/or younger age, consider screening for diabetes and intensive age of body fat distributed predominantly antibody testing to exclude the diagnosis multifactorial intervention with that of in the abdominal region. of type 1 diabetes (i.e., GAD). screening and routine care (39). General DKA seldom occurs spontaneously in practice patients between the ages of type 2 diabetes; when seen, it usually Screening and Testing for Type 2 40 and 69 years were screened for diabe- arises in association with the stress of an- Diabetes and Prediabetes in tes and randomly assigned by practice to other illness such as infection or with the Asymptomatic Adults intensive treatment of multiple risk fac- use of certain drugs (e.g., corticosteroids, Screening for prediabetes and type 2 di- tors or routine diabetes care. After 5.3 atypical antipsychotics, and sodium– abetes through an informal assessment years of follow-up, CVD risk factors were glucose cotransporter 2 inhibitors) (35, of risk factors (Table 2.3)orwithan modestly but significantly improved with intensive treatment compared with routine care, but the incidence of first CVD Table 2.5—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic events or mortality was not significantly children and adolescents in a clinical setting* different between the groups (39). The Criteria excellent care provided to patients in c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or the routine care group and the lack of weight .120% of ideal for height) A an unscreened control arm limited the Plus one or more additional risk factors based on the strength of their association with diabetes as authors’ ability to determine whether indicated by evidence grades: screening and early treatment improved c Maternal history of diabetes or GDM during the child’s gestation A outcomes compared with no screening fi A c Family history of type 2 diabetes in rst- or second-degree relative and later treatment after clinical diag- c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, noses. Computer simulation modeling hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B studies suggest that major benefits are likely to accrue from the early diagnosis *Persons aged ,18 years. and treatment of hyperglycemia and S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

cardiovascular risk factors in type 2 reduced and individuals with false-negative limited data supporting A1C for diag- diabetes (40); moreover, screening, be- tests will be retested before substantial time nosing type 2 diabetes in children and ginning at age 30 or 45 years and indepen- elapses and complications develop (47). adolescents. Although A1C is not recom- dent of risk factors, may be cost-effective mended for diagnosis of diabetes in chil- (,$11,000 per quality-adjusted life-year Community Screening dren with cystic fibrosis or symptoms Ideally, testing should be carried out gained) (41). suggestive of acute onset of type 1 diabe- within a health care setting because of Additional considerations regarding tes and only A1C assays without interfer- the need for follow-up and treatment. testing for type 2 diabetes and prediabe- ence are appropriate for children with Community screening outside a health tes in asymptomatic patients include the hemoglobinopathies, the ADA continues care setting is generally not recom- following. to recommend A1C for diagnosis of type 2 mended because people with positive diabetes in this cohort (54,55). Age tests may not seek, or have access to, Age is a major risk factor for diabetes. appropriate follow-up testing and care. GESTATIONAL DIABETES MELLITUS Testing should begin at age 45 years for However, in specific situations where an all patients. Screening should be consid- adequate referral system is established Recommendations ered in overweight or obese adults of beforehand for positive tests, community c Test for undiagnosed diabetes at any age with one or more risk factors for screening may be considered. Commu- the first prenatal visit in those diabetes. nity testing may also be poorly targeted; with risk factors, using standard di- i.e., it may fail to reach the groups most at B BMI and Ethnicity agnostic criteria. In general, BMI $25 kg/m2 is a risk factor risk and inappropriately test those at very c Test for gestational diabetes melli- for diabetes. However, data suggest that low risk or even those who have already tus at 24–28 weeks of gestation in the BMI cut point should be lower for been diagnosed (48). pregnant women not previously A the Asian American population (42,43). Screening in Dental Practices known to have diabetes. The BMI cut points fall consistently be- Because periodontal disease is associated c Test women with gestational diabe- tween 23 and 24 kg/m2 (sensitivity of with diabetes, the utility of screening in a tes mellitus for persistent diabetes 80%) for nearly all Asian American sub- dental setting and referral to primary care at 4–12 weeks postpartum, using groups (with levels slightly lower for Jap- as a means to improve the diagnosis of the oral glucose tolerance test and anese Americans). This makes a rounded prediabetes and diabetes has been ex- clinically appropriate nonpregnancy cut point of 23 kg/m2 practical. An argu- plored (49–51), with one study estimating diagnostic criteria. E ment can be made to push the BMI cut that 30% of patients $30 years of age c Women with a history of gesta- point to lower than 23 kg/m2 in favor of seen in general dental practices had dys- tional diabetes mellitus should increased sensitivity; however, this would glycemia (51). Further research is needed have lifelong screening for the de- lead to an unacceptably low specificity to demonstrate the feasibility, effective- velopment of diabetes or prediabe- (13.1%). Data from the WHO also suggest ness, and cost-effectiveness of screening tes at least every 3 years. B that a BMI of $23 kg/m2 should be used in this setting. c Women with a history of gesta- to define increased risk in Asian Ameri- tional diabetes mellitus found to cans (44). The finding that half of diabetes Screening and Testing for Type 2 have prediabetes should receive in- in Asian Americans is undiagnosed sug- Diabetes and Prediabetes in Children tensive lifestyle interventions or gests that testing is not occurring at lower and Adolescents metformin to prevent diabetes. A BMI thresholds (37,38). In the last decade, the incidence and prev- Evidence also suggests that other pop- alence of type 2 diabetes in adolescents Definition ulations may benefit from lower BMI cut has increased dramatically, especially in For many years, GDM was defined as any points. For example, in a large multiethnic racial and ethnic minority populations degree of glucose intolerance that was cohort study, for an equivalent incidence (30). See Table 2.5 for recommendations first recognized during pregnancy (23), re- rate of diabetes, a BMI of 30 kg/m2 in non- on risk-based screening for type 2 diabe- gardless of whether the condition may Hispanic whites was equivalent to a BMI tes or prediabetes in asymptomatic chil- have predated the pregnancy or persisted of 26 kg/m2 in African Americans (45). dren and adolescents in a clinical setting. See after the pregnancy. This definition facili- Section 12 “Children and Adolescents” for tated a uniform strategy for detection and Medications additional information on type 2 diabetes classification of GDM, but it was limited by Certain medications, such as glucocorti- in children and adolescents. imprecision. coids, thiazide diuretics, and atypical an- Some studies question the validity of The ongoing epidemic of obesity and tipsychotics (46), are known to increase A1C in the pediatric population, especially diabetes has led to more type 2 diabetes the risk of diabetes and should be consid- among certain ethnicities, and suggest inwomenofchildbearingage,withanin- ered when deciding whether to screen. OGTT or FPG as more suitable diagnos- crease in the number of pregnant women Testing Interval tic tests (52). However, many of these with undiagnosed type 2 diabetes (56). The appropriate interval between screen- studies do not recognize that diabetes di- Because of the number of pregnant ing tests is not known (47). The rationale agnostic criteria are based on long-term women with undiagnosed type 2 diabetes, for the 3-year interval is that with this in- health outcomes, and validations are not it is reasonable to test women with risk terval, the number of false-positive tests currently available in the pediatric popu- factors for type 2 diabetes (Table 2.3)at that require confirmatory testing will be lation (53). The ADA acknowledges the their initial prenatal visit, using standard care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

diagnostic criteria (Table 2.2). Women di- One-Step Strategy Two-Step Strategy agnosed with diabetes by standard diag- The IADPSG defined diagnostic cut points In 2013, the National Institutes of Health nostic criteria in the first trimester should for GDM as the average fasting, 1-h, and (NIH) convened a consensus develop- be classified as having preexisting preges- 2-hPGvaluesduringa75-gOGTTin ment conference to consider diagnostic tational diabetes (type 2 diabetes or, very women at 24–28 weeks of gestation criteria for diagnosing GDM (68). The rarely, type 1 diabetes or monogenic dia- who participated in the HAPO study at 15-member panel had representatives betes). GDM is diabetes that is first diag- which odds for adverse outcomes reached from obstetrics/gynecology, maternal- nosed in the second or third trimester of 1.75 times the estimated odds of these fetal medicine, pediatrics, diabetes re- pregnancy that is not clearly either preex- outcomes at the mean fasting, 1-h, and search, biostatistics, and other related isting type 1 or type 2 diabetes (see Section 2-h PG levels of the study population. fields. The panel recommended a two- 13 “Management of Diabetes in Preg- This one-step strategy was anticipated to step approach to screening that used a nancy”). The International Association of significantly increase the incidence of 1-h 50-g glucose load test (GLT) followed the Diabetes and Pregnancy Study Groups GDM (from 5–6% to 15–20%), primarily by a 3-h 100-g OGTT for those who screened (IADPSG) GDM diagnostic criteria for the because only one abnormal value, not positive. The American College of Ob- 75-g OGTT as well as the GDM screening two, became sufficient to make the di- stetriciansandGynecologists(ACOG)rec- and diagnostic criteria used in the two- agnosis (63). The anticipated increase in ommends any of the commonly used step approach were not derived from the incidence of GDM could have a sub- thresholds of 130, 135, or 140 mg/dL for data in the first half of pregnancy, so stantial impact on costs and medical in- the 1-h 50-g GLT (69). A systematic review the diagnosis of GDM in early pregnancy frastructure needs and has the potential for the U.S. Preventive Services Task Force by either FPG or OGTT values is not evi- to “medicalize” pregnancies previously compared GLT cutoffs of 130 mg/dL dence based (57). categorized as normal. Nevertheless, (7.2 mmol/L) and 140 mg/dL (7.8 mmol/L) Because GDM confers increased risk the ADA recommends these diagnostic (70). The higher cutoff yielded sensitivity for the development of type 2 diabetes criteria with the intent of optimizing of 70–88% and specificity of 69–89%, after delivery (58,59) and because effec- gestational outcomesbecausethesecri- while the lower cutoff was 88–99% sensitive prevention interventions are avail- teria were the only ones based on preg- tive and 66–77% specific. Data regarding able (60,61), women diagnosed with nancy outcomes rather than end points a cutoff of 135 mg/dL are limited. As for GDM should receive lifelong screening such as prediction of subsequent mater- other screening tests, choice of a cutoff for prediabetes and type 2 diabetes. nal diabetes. is based upon the trade-off between sen- The expected benefits to the offspring sitivity and specificity. The use of A1C at – Diagnosis are inferred from intervention trials that 24 28 weeks of gestation as a screening GDM carries risks for the mother and ne- focused on women with lower levels of test for GDM does not function as well as fi onate. Not all adverse outcomes are of hyperglycemia than identi ed using older the GLT (71). equal clinical importance. The Hypergly- GDM diagnostic criteria. Those trials Key factors cited by the NIH panel in fi cemia and Adverse Pregnancy Outcome found modest bene ts including reduced their decision-making process were the (HAPO) study (62), a large-scale multina- rates of large-for-gestational-age births lack of clinical trial data demonstrating tional cohort study completed by more and preeclampsia (64,65). It is important the benefits of the one-step strategy – than 23,000 pregnant women, demon- to note that 80 90% of women being and the potential negative consequences strated that risk of adverse maternal, fe- treated for mild GDM in two randomized of identifying a large group of women tal, and neonatal outcomes continuously controlled trials could be managed with with GDM, including medicalization of increased as a function of maternal glyce- lifestyle therapy alone. The OGTT glucose pregnancy with increased health care uti- mia at 24–28 weeks of gestation, even cutoffs in these two trials overlapped lization and costs. Moreover, screening within ranges previously considered nor- with the thresholds recommended by with a 50-g GLT does not require fasting mal for pregnancy. For most complications, theIADPSG,andinonetrial(65),the2-h and is therefore easier to accomplish for there was no threshold for risk. These re- PG threshold (140 mg/dL [7.8 mmol/L]) many women. Treatment of higher-threshold sults have led to careful reconsideration of was lower than the cutoff recommended maternal hyperglycemia, as identified by the the diagnostic criteria for GDM. GDM di- by the IADPSG (153 mg/dL [8.5 mmol/L]). two-step approach, reduces rates of neona- agnosis (Table 2.6) can be accomplished No randomized controlled trials of identi- tal macrosomia, large-for-gestational-age with either of two strategies: fying and treating GDM using the IADPSG births (72), and shoulder dystocia, without criteria versus older criteria have been increasing small-for-gestational-age births. 1. “One-step” 75-g OGTT or published to date. Data are also lacking ACOG currently supports the two-step ap- 2. “Two-step” approach with a 50-g (non- on how the treatment of lower levels of proach (69) but most recently noted that fasting) screen followed by a 100-g hyperglycemia affects a mother’s future one elevated value, as opposed to two, may OGTT for those who screen positive risk for the development of type 2 diabe- be used for the diagnosis of GDM. If this tes and her offspring’s risk for obesity, approach is implemented, the incidence of Different diagnostic criteria will identify diabetes, and other metabolic disorders. GDM by the two-step strategy will likely in- different degrees of maternal hypergly- Additional well-designed clinical studies crease markedly. ACOG recommends either cemia and maternal/fetal risk, leading are needed to determine the optimal in- of two sets of diagnostic thresholds for the some experts to debate, and disagree on, tensity of monitoring and treatment of 3-h 100-g OGTT (73,74). Each is based on optimal strategies for the diagnosis of women with GDM diagnosed by the different mathematical conversions of GDM. one-step strategy (66,67). the original recommended thresholds, S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Table 2.6—Screening for and diagnosis of GDM One-step strategy Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded: c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) c 2 h: 153 mg/dL (8.5 mmol/L) Two-step strategy Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT. Step 2: The 100-g OGTT should be performed when the patient is fasting. 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 during OGTT) are met or exceeded: Carpenter-Coustan (73) or NDDG (74) c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) NDDG, National Diabetes Data Group. *ACOG recently noted that alternatively one elevated value can be used for diagnosis.

which used whole blood and nonenzymatic outcomes with one-step versus two-step approach further evaluation, treat- methods for glucose determination. A re- approaches have been inconsistent to date ment, and genetic counseling. E cent secondary analysis of data from a ran- (78,79). In addition, pregnancies compli- domized clinical trial of identification and cated by GDM per the IADPSG criteria, but Monogenic defects that cause b-cell dys- treatment of mild GDM (75) demon- not recognized as such, have comparable function, such as neonatal diabetes and strated that treatment was similarly ben- outcomes to pregnancies diagnosed as MODY, represent a small fraction of pa- eficial in patients meeting only the lower GDM by the more stringent two-step crite- tients with diabetes (,5%). Table 2.7 thresholds (73) and in those meeting only ria (80,81). There remains strong consen- describes the most common causes of the higher thresholds (74). If the two-step sus that establishing a uniform approach monogenic diabetes. For a comprehen- approach is used, it would appear advan- to diagnosing GDM will benefitpatients, sive list of causes, see Genetic Diagnosis tageous to use the lower diagnostic thresh- caregivers, and policy makers. Longer- of Endocrine Disorders (82). olds as shown in step 2 in Table 2.6. term outcome studies are currently under way. Future Considerations Neonatal Diabetes The conflicting recommendations from MONOGENIC DIABETES Diabetes occurring under 6 months of age expert groups underscore the fact that SYNDROMES is termed “neonatal” or “congenital” di- there are data to support each strategy. abetes, and about 80–85% of cases can be Recommendations A cost-benefit estimation comparing the found to have an underlying monogenic c All children diagnosed with diabe- two strategies concluded that the one- cause (83). Neonatal diabetes occurs much tes in the first 6 months of life step approach is cost-effective only if less often after 6 months of age, whereas should have immediate genetic patients with GDM receive postdelivery autoimmune type 1 diabetes rarely occurs testing for neonatal diabetes. A counseling and care to prevent type 2 di- before 6 months of age. Neonatal diabetes c Children and adults, diagnosed in abetes (76). The decision of which strategy can either be transient or permanent. Tran- early adulthood, who have diabetes to implement must therefore be made sient diabetes is most often due to over- not characteristic of type 1 or type 2 basedontherelativevaluesplacedonfac- expression of genes on chromosome 6q24, diabetes that occurs in successive tors that have yet to be measured (e.g., is recurrent in about half of cases, and may generations (suggestive of an auto- willingness to change practice based on be treatable with medications other than somal dominant pattern of inheri- correlation studies rather than intervention insulin. Permanent neonatal diabetes is tance) should have genetic testing trial results, available infrastructure, and most commonly due to autosomal domi- for maturity-onset diabetes of the importance of cost considerations). nant mutations in the genes encoding the young. A As the IADPSG criteria (“one-step strat- Kir6.2 subunit (KCNJ11) and SUR1 subunit c In both instances, consultation egy”) have been adopted internationally, (ABCC8)oftheb-cell K channel. Correct with a center specializing in diabe- ATP further evidence has emerged to support diagnosis has critical implications because tesgeneticsisrecommendedto improved pregnancy outcomes with cost most patients with K -related neonatal understand the significance of ATP savings (77) and may be the preferred ap- diabetes will exhibit improved glycemic these mutations and how best to proach. Data comparing population-wide control when treated with high-dose oral care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

Table 2.7—Most common causes of monogenic diabetes (82) 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: developmental renal disease (typically cystic); genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout Neonatal diabetes KCNJ11 AD Permanentor transient: IUGR; possibledevelopmentaldelay and seizures; responsive to sulfonylureas INS AD Permanent: IUGR; insulin requiring ABCC8 AD Transient or permanent: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 (PLAGL1, HYMA1) AD for paternal duplications Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, 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.

sulfonylureas instead of insulin. Insulin gene (MODY2), HNF1A-MODY (MODY3), and therapy for GCK-MODY; sulfonylureas as (INS) mutations are the second most com- HNF4A-MODY (MODY1). first-line therapy for HNF1A-MODY and mon cause of permanent neonatal dia- Clinically, patients with GCK-MODY ex- HNF4A-MODY). Additionally, diagnosis betes, and, while treatment presently is hibit mild, stable, fasting hyperglycemia canleadtoidentification of other affected intensive insulin management, there are and do not require antihyperglycemic family members. important genetic considerations, as most therapy except sometimes during preg- A diagnosis of MODY should be consid- of the mutations that cause diabetes are nancy. Patients with HNF1A- or HNF4A- ered in individuals who have atypical di- dominantly inherited. MODY usually respond well to low doses abetes and multiple family members with of sulfonylureas, which are considered diabetes not characteristic of type 1 or Maturity-Onset Diabetes of the Young first-line therapy. Mutations or deletions in type 2 diabetes, although admittedly “atyp- MODY is frequently characterized by on- HNF1B are associated with renal cysts and ical diabetes” is becoming increasingly set of hyperglycemia at an early age (clas- uterine malformations (renal cysts and di- difficult to precisely define in the absence sically before age 25 years, although abetes [RCAD] syndrome). Other extremely of a definitive set of tests for either type diagnosis may occur at older ages). rare forms of MODY have been reported to of diabetes. In most cases, the presence of MODY is characterized by impaired insu- involve other transcription factor genes in- autoantibodies for type 1 diabetes pre- lin secretion with minimal or no defects in cluding PDX1 (IPF1)andNEUROD1. cludes further testing for monogenic dia- insulin action (in the absence of coexis- betes, but the presence of autoantibodies tent obesity). It is inherited in an autoso- Diagnosis in patients with monogenic diabetes has mal dominant pattern with abnormalities A diagnosis of one of the three most com- been reported (84). Individuals in whom in at least 13 genes on different chromo- mon forms of MODY including GCK- monogenic diabetes is suspected should somes identified to date. The most com- MODY, HNF1A-MODY, and HNF4A-MODY be referred to a specialist for further eval- monly reported forms are GCK-MODY allows for more cost-effective therapy (no uation if available, and consultation is S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

available from several centers. Readily Insulin remains the most widely used c Patients with cystic fibrosis–related available commercial genetic testing fol- therapy for CFRD (94). diabetes should be treated with in- lowing the criteria listed below now Additional resources for the clinical sulin to attain individualized glyce- enables a cost-effective (85), often cost- management of CFRD can be found in mic goals. A saving, genetic diagnosis that is increas- the position statement “Clinical Care c Beginning 5 years after the diagnosis ingly supported by health insurance. A Guidelines for Cystic Fibrosis–Related Di- of cystic fibrosis–related diabetes, biomarker screening pathway such as the abetes: A Position Statement of the annual monitoring for complications combination of urinary C-peptide/creatinine American Diabetes Association and a Clin- of diabetes is recommended. E ratio and antibody screening may aid in ical Practice Guideline of the Cystic Fibro- determining who should get genetic sis Foundation, Endorsed by the Pediatric Cystic fibrosis–related diabetes (CFRD) is testing for MODY (86). It is critical to cor- Endocrine Society” (95) and in the Interna- the most common comorbidity in people rectly diagnose one of the monogenic tional Society for Pediatric and Adoles- with cystic fibrosis, occurring in about formsofdiabetesbecausethesepa- cent Diabetes’s 2014 clinical practice 20% of adolescents and 40–50% of adults. tients may be incorrectly diagnosed consensus guidelines (96). Diabetes in this population, compared with type 1 or type 2 diabetes, leading to with individuals with type 1 or type 2 di- suboptimal, even potentially harmful, treat- abetes, is associated with worse nutri- POSTTRANSPLANTATION ment regimens and delays in diagnosing tional status, more severe inflammatory DIABETES MELLITUS other family members (87). The correct di- lung disease, and greater mortality. Insu- agnosis is especially critical for those with Recommendations lin insufficiency is the primary defect in GCK-MODY mutations where multiple c Patients should be screened after CFRD. Genetically determined b-cell func- studies have shown that no complications organ transplantation for hypergly- tion and insulin resistance associated with ensue in the absence of glucose-lowering cemia, with a formal diagnosis of infection and inflammation may also con- therapy (88). Genetic counseling is rec- posttransplantation diabetes melli- ommended to ensure that affected individ- tribute to the development of CFRD. tus being best made once a patient uals understand the patterns of inheritance Milder abnormalities of glucose tolerance is stable on an immunosuppressive and the importance of a correct diagnosis. are even more common and occur at ear- regimen and in the absence of an The diagnosis of monogenic diabetes lier ages than CFRD. Whether individuals acute infection. E should be considered in children and with IGT should be treated with insulin c The oral glucose tolerance test is adults diagnosed with diabetes in early replacement has not currently been de- the preferred test to make a diag- adulthood with the following findings: termined. Although screening for diabe- nosis of posttransplantation diabe- tesbeforetheageof10yearscanidentify tes mellitus. B ○ Diabetes diagnosed within the first risk for progression to CFRD in those with c Immunosuppressive regimens shown 6 months of life (with occasional cases abnormal glucose tolerance, no benefit to provide the best outcomes for pa- presenting later, mostly INS and ABCC8 hasbeenestablishedwithrespectto tient and graft survival should be mutations) (83,89) weight, height, BMI, or lung function. used, irrespective of posttransplanta- ○ Diabetes without typical features of Continuous glucose monitoring or HOMA tion diabetes mellitus risk. E type 1 or type 2 diabetes (negative di- of b-cell function (90) may be more sen- abetes-associated autoantibodies, sitive than OGTT to detect risk for pro- Several terms are used in the literature to nonobese, lacking other metabolic fea- gression to CFRD; however, evidence describe the presence of diabetes follow- tures, especially with strong family linking these results to long-term out- ing organ transplantation. “New-onset di- history of diabetes) comes is lacking, and these tests are not abetes after transplantation” (NODAT) is ○ Stable, mild fasting hyperglycemia recommended for screening (91). one such designation that describes indi- (100–150 mg/dL [5.5–8.5 mmol/L]), CFRD mortality has significantly de- viduals who develop new-onset diabetes stable A1C between 5.6 and 7.6% (be- creased over time, and the gap in mortal- following transplant. NODAT excludes pa- tween 38 and 60 mmol/mol), espe- ity between cystic fibrosis patients with tients with pretransplant diabetes that cially if nonobese and without diabetes has considerably was undiagnosed as well as posttrans- narrowed (92). There are limited clinical plant hyperglycemia that resolves by the CYSTIC FIBROSIS–RELATED trial data on therapy for CFRD. The largest time of discharge (97). Another term, DIABETES study compared three regimens: premeal “posttransplantation diabetes mellitus” insulin aspart, repaglinide, or oral placebo (PTDM) (97,98), describes the presence Recommendations in cystic fibrosis patients with diabetes or of diabetes in the posttransplant setting c Annual screening for cystic fibrosis– abnormal glucose tolerance. Participants irrespective of the timing of diabetes onset. related diabetes with oral glucose all had weight loss in the year preced- Hyperglycemia is very common during tolerance test should begin by age ing treatment; however, in the insulin- the early posttransplant period, with 10 years in all patients with cystic fi- treated group, this pattern was reversed, ;90% of kidney allograft recipients ex- brosis not previously diagnosed with and patients gained 0.39 (6 0.21) BMI hibiting hyperglycemia in the first few cystic fibrosis–related diabetes. B units (P 5 0.02). The repaglinide-treated weeks following transplant (97–100). c A1C is not recommended as a group had initial weight gain, but this was In most cases, such stress- or steroid- screening test for cystic fibrosis– not sustained by 6 months. The placebo induced hyperglycemia resolves by the related diabetes. B group continued to lose weight (93). time of discharge (100,101). Although care.diabetesjournals.org Classification and Diagnosis of Diabetes S25

the use of immunosuppressive therapies metformin was safe to use in renal trans- transethnic genome-wide meta-analysis. PLoS is a major contributor to the development plant recipients (108), but its safety has Med 2017;14:e1002383 of PTDM, the risks of transplant rejection not been determined in other types of 13. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in outweigh the risks of PTDM and the role organ transplant. Thiazolidinediones hemoglobin A1c levels: a cross-sectional analysis of the diabetes care provider is to treat have been used successfully in patients of 2 studies. Ann Intern Med 2010;152:770–777 hyperglycemia appropriately regard- with liver and kidney transplants, but 14. Kumar PR, Bhansali A, Ravikiran M, et al. Util- less of the type of immunosuppression side effects include fluid retention, heart ity of glycated hemoglobin in diagnosing type 2 (97). Risk factors for PTDM include both failure, and osteopenia (109,110). Dipep- diabetes mellitus: a community-based study. J Clin Endocrinol Metab 2010;95:2832–2835 general diabetes risks (such as age, fam- tidyl peptidase 4 inhibitors do not interact 15. Herman WH. Are there clinical implications of ily history of diabetes, etc.) as well as with immunosuppressant drugs and have racial differences in HbA1c? Yes, to not consider transplant-specific factors, such as use demonstrated safety in small clinical trials can do great harm! Diabetes Care 2016;39:1458– of immunosuppressant agents (102). (111,112). Well-designed intervention tri- 1461 Whereas posttransplantation hyperglyce- als examining the efficacy and safety of 16. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes Prevention Program Research Group. Differences mia is an important risk factor for subse- these and other antihyperglycemic agents in A1C by race and ethnicity among patients with quent PTDM, a formal diagnosis of PTDM in patients with PTDM are needed. impaired glucose tolerance in the Diabetes Pre- is optimally made once the patient is sta- vention Program. Diabetes Care 2007;30:2453– 2457 ble on maintenance immunosuppression References andintheabsenceofacuteinfection 17. Bergenstal RM, Gal RL, Connor CG, et al.; T1D 1. American Diabetes Association. Diagnosis and Exchange Racial Differences Study Group. Racial (100–102). The OGTT is considered the classification of diabetes mellitus. Diabetes Care differences in the relationship of glucose concen- gold standard test for the diagnosis of 2014;37(Suppl. 1):S81–S90 trations and hemoglobin A1c levels. Ann Intern PTDM (97,98,103,104). However, screen- 2.DabeleaD,RewersA,StaffordJM,etal.; Med 2017;167:95–102 ing patients using fasting glucose and/or SEARCH for Diabetes in Youth Study Group. Trends 18. Selvin E, Steffes MW, Ballantyne CM, in the prevalence of ketoacidosis at diabetes diag- A1C can identify high-risk patients requir- Hoogeveen RC, Coresh J, Brancati FL. Racial differ- nosis: the SEARCH for Diabetes in Youth Study. ences in glycemic markers: a cross-sectional anal- ing further assessment and may reduce Pediatrics 2014;133:e938–e945 ysis of community-based data. Ann Intern Med the number of overall OGTTs required. 3. Newton CA, Raskin P. Diabetic ketoacidosis in 2011;154:303–309 Few randomized controlled studies type 1 and type 2 diabetes mellitus: clinical and 19. Herman WH, Dungan KM, Wolffenbuttel have reported on the short- and long- biochemical differences. Arch Intern Med 2004; BHR, et al. Racial and ethnic differences in mean 164:1925–1931 plasma glucose, hemoglobin A1c, and 1,5- term use of antihyperglycemic agents in 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differen- anhydroglucitol in over 2000 patients with the setting of PTDM (102,105,106). Most tiation of diabetes by pathophysiology, natural his- type 2 diabetes. J Clin Endocrinol Metab 2009; studies have reported that transplant pa- tory, and prognosis. Diabetes 2017;66:241–255 94:1689–1694 tients with hyperglycemia and PTDM af- 5. Insel RA, Dunne JL, Atkinson MA, et al. Staging 20. Selvin E, Rawlings AM, Bergenstal RM, Coresh fi ter transplantation have higher rates of presymptomatic type 1 diabetes: a scienti c J, Brancati FL. No racial differences in the associ- statement of JDRF, the Endocrine Society, and ation of glycated hemoglobin with kidney disease rejection, infection, and rehospitalization the American Diabetes Association. Diabetes and cardiovascular outcomes. Diabetes Care (100,102,107). Care 2015;38:1964–1974 2013;36:2995–3001 Insulin therapy is the agent of choice 6. International Expert Committee. International 21. Selvin E. Are there clinical implications of ra- for the management of hyperglycemia Expert Committee report on the role of the A1C cial differences in HbA1c? A difference, to be a and diabetes in the hospital setting. After assay in the diagnosis of diabetes. Diabetes Care difference, must make a difference. Diabetes 2009;32:1327–1334 Care 2016;39:1462–1467 discharge, patients with preexisting dia- 7. Knowler WC, Barrett-Connor E, Fowler SE, 22. Welsh KJ, Kirkman MS, Sacks DB. Role of gly- betes could go back on their pretransplant et al.; Diabetes Prevention Program Research cated proteins in the diagnosis and management regimen if they were in good control be- Group. Reduction in the incidence of type 2 di- of diabetes: research gaps and future directions. fore transplantation. Those with previ- abetes with lifestyle intervention or metformin. Diabetes Care 2016;39:1299–1306 – ously poor control or with persistent N Engl J Med 2002;346:393 403 23. Expert Committee on the Diagnosis and Clas- 8. Tuomilehto J, Lindstrom¨ J, Eriksson JG, et al.; sification of Diabetes Mellitus. Report of the hyperglycemia should continue insulin Finnish Diabetes Prevention Study Group. Preven- Expert Committee on the Diagnosis and Classifi- with frequent home self-monitoring of tion of type 2 diabetes mellitus by changes in cation of Diabetes Mellitus. Diabetes Care 1997; blood glucose to determine when insulin lifestyle among subjects with impaired glucose 20:1183–1197 dose reductions may be needed and tolerance. N Engl J Med 2001;344:1343–1350 24. Genuth S, Alberti KG, Bennett P, et al.; Expert when it may be appropriate to switch to 9. Cowie CC, Rust KF, Byrd-Holt DD, et al. Preva- Committee on the Diagnosis and Classification of lence of diabetes and high risk for diabetes using Diabetes Mellitus. Follow-up report on the diag- noninsulin agents. A1C criteria in the U.S. population in 1988–2006. nosis of diabetes mellitus. Diabetes Care 2003;26: No studies to date have established Diabetes Care 2010;33:562–568 3160–3167 which noninsulin agents are safest or 10. Nowicka P, Santoro N, Liu H, et al. Utility of 25. American Diabetes Association. Diagnosis fi most efficacious in PTDM. The choice of hemoglobin A1c for diagnosing prediabetes and and classi cation of diabetes mellitus. Diabetes diabetes in obese children and adolescents. Dia- Care 2011;34(Suppl. 1):S62–S69 agent is usually made based on the side – fi betes Care 2011;34:1306 1311 26. Zhang X, Gregg EW, Williamson DF, et al. A1C effect pro le of the medication and pos- 11. Lacy ME, Wellenius GA, Sumner AE, Correa A, level and future risk of diabetes: a systematic re- sible interactions with the patient’sim- Carnethon MR, Liem RI, et al. Association of sickle view. Diabetes Care 2010;33:1665–1673 munosuppression regimen (102). Drug cell trait with hemoglobin A1c in African Ameri- 27. Selvin E, Steffes MW, Zhu H, et al. Glycated dose adjustments may be required be- cans. JAMA 2017;317:507–515 hemoglobin, diabetes, and cardiovascular risk in cause of decreases in the glomerular 12. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD nondiabetic adults. N Engl J Med 2010;362:800– fi Consortium; EPIC-InterAct Consortium; Lifelines 811 ltration rate, a relatively common com- Cohort Study. Impact of common genetic deter- 28. Ackermann RT, Cheng YJ, Williamson DF, plication in transplant patients. A small minants of hemoglobin A1c on type 2 diabetes risk Gregg EW. Identifying adults at high risk for diabe- short-term pilot study reported that and diagnosis in ancestrally diverse populations: a tes and cardiovascular disease using hemoglobin S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

A1c National Health and Nutrition Examination Americans for type 2 diabetes: The UCSD Filipino post-gestational diabetes mellitus as defined by Survey 2005-2006. Am J Prev Med 2011;40:11–17 Health Study and the North Kohala Study [Ab- the International Association of Diabetes and 29. Diabetes Prevention Program Research stract]. Diabetes 2014;63(Suppl. 1):A20 Pregnancy Study Groups criteria. Eur J Endocrinol Group. HbA1c as a predictor of diabetes and as 43. Hsu WC, Araneta MRG, Kanaya AM, Chiang 2016;175:287–297 an outcome in the Diabetes Prevention Program: JL, Fujimoto W. BMI cut points to identify at-risk 59. Kim C, Newton KM, Knopp RH. Gestational a randomized clinical trial. Diabetes Care 2015;38: Asian Americans for type 2 diabetes screening. diabetes and the incidence of type 2 diabetes: a 51–58 Diabetes Care 2015;38:150–158 systematic review. Diabetes Care 2002;25:1862– 30. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; 44. WHO Expert Consultation. Appropriate body- 1868 SEARCH for Diabetes in Youth Study. Prevalence mass index for Asian populations and its implica- 60. Ratner RE, Christophi CA, Metzger BE, et al.; of type 1 and type 2 diabetes among children and tions for policy and intervention strategies. Lancet Diabetes Prevention Program Research Group. adolescents from 2001 to 2009. JAMA 2014;311: 2004;363:157–163 Prevention of diabetes in women with a history 1778–1786 45. Chiu M, Austin PC, Manuel DG, Shah BR, Tu of gestational diabetes: effects of metformin and 31. Ziegler AG, Rewers M, Simell O, et al. Sero- JV. Deriving ethnic-specific BMI cutoff points for lifestyle interventions. J Clin Endocrinol Metab conversion to multiple islet autoantibodies and assessing diabetes risk. Diabetes Care 2011;34: 2008;93:4774–4779 risk of progression to diabetes in children. JAMA 1741–1748 61. Aroda VR, Christophi CA, Edelstein SL, et al.; 2013;309:2473–2479 46. Erickson SC, Le L, Zakharyan A, et al. New- Diabetes Prevention Program Research Group. 32. Sosenko JM, Skyler JS, Palmer JP, et al.; Type 1 onset treatment-dependent diabetes mellitus The effect of lifestyle intervention and metformin Diabetes TrialNet Study Group; Diabetes Preven- and hyperlipidemia associated with atypical anti- on preventing or delaying diabetes among tion Trial-Type 1 Study Group. The prediction of psychotic use in older adults without schizophre- women with and without gestational diabetes: type 1 diabetes by multiple autoantibody levels nia or bipolar disorder. J Am Geriatr Soc 2012;60: the Diabetes Prevention Program Outcomes – and their incorporation into an autoantibody risk 474 479 Study 10-year follow-up. J Clin Endocrinol Metab score in relatives of type 1 diabetic patients. Di- 47. Johnson SL, Tabaei BP, Herman WH. The ef- 2015;100:1646–1653 – fi abetes Care 2013;36:2615 2620 cacy and cost of alternative strategies for sys- 62. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO 33. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY tematic screening for type 2 diabetes in the U.S. Study Cooperative Research Group. Hyperglycemia – Study Group. Predictors of progression from the population 45 74 years of age. Diabetes Care and adverse pregnancy outcomes. N Engl J Med – appearance of islet autoantibodies to early child- 2005;28:307 311 2008;358:1991–2002 hood diabetes: The Environmental Determinants 48. Tabaei BP, Burke R, Constance A, et al. 63. Sacks DA, Hadden DR, Maresh M, et al.; HAPO of Diabetes in the Young (TEDDY). Diabetes Care Community-based screening for diabetes in Study Cooperative Research Group. Frequency of – – 2015;38:808 813 Michigan. Diabetes Care 2003;26:668 670 gestational diabetes mellitus at collaborating centers 34. Orban T, Sosenko JM, Cuthbertson D, et al.; 49. Lalla E, Kunzel C, Burkett S, Cheng B, Lamster based on IADPSG consensus panel-recommended Diabetes Prevention Trial-Type 1 Study Group. IB. Identification of unrecognized diabetes and criteria: the Hyperglycemia and Adverse Pregnancy Pancreatic islet autoantibodies as predictors of pre-diabetes in a dental setting. J Dent Res Outcome (HAPO) Study. Diabetes Care 2012;35: type 1 diabetes in the Diabetes Prevention Trial– 2011;90:855–860 526–528 Type 1. Diabetes Care 2009;32:2269–2274 50. Lalla E, Cheng B, Kunzel C, Burkett S, Lamster 64. Landon MB, Spong CY, Thom E, et al.; Eunice 35. Umpierrez G, Korytkowski M. Diabetic IB. Dental findings and identification of undiag- Kennedy Shriver National Institute of Child Health emergencies - ketoacidosis, hyperglycaemic hy- nosed hyperglycemia. J Dent Res 2013;92:888– and Human Development Maternal-Fetal Medi- perosmolar state and hypoglycaemia. Nat Rev Endo- 892 cine Units Network. A multicenter, randomized crinol 2016;12:222–232 51. Herman WH, Taylor GW, Jacobson JJ, Burke R, trial of treatment for mild gestational diabetes. 36. Fadini GP, Bonora BM, Avogaro A. SGLT2 in- Brown MB. Screening for prediabetes and type 2 N Engl J Med 2009;361:1339–1348 hibitors and diabetic ketoacidosis: data from the diabetes in dental offices. J Public Health Dent 65. Crowther CA, Hiller JE, Moss JR, McPhee AJ, FDA Adverse Event Reporting System. Diabetolo- 2015;75:175–182 gia 2017;60:1385–1389 52. Buse JB, Kaufman FR, Linder B, Hirst K, El Jeffries WS, Robinson JS; Australian Carbohydrate 37. Menke A, Casagrande S, Geiss L, Cowie CC. Ghormli L, Willi S; HEALTHY Study Group. Diabetes Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational di- Prevalence of and trends in diabetes among screening with hemoglobin A1c versus fasting adults in the United States, 1988-2012. JAMA plasma glucose in a multiethnic middle-school co- abetes mellitus on pregnancy outcomes. N Engl J – 2015;314:1021–1029 hort. Diabetes Care 2013;36:429–435 Med 2005;352:2477 2486 38. Centers for Disease Control and Prevention. 53. Kapadia C, Zeitler P; Drugs and Therapeutics 66. Tam WH, Ma RCW, Ozaki R, et al. In utero National diabetes statistics report: estimates of Committee of the Pediatric Endocrine Society. He- exposure to maternal hyperglycemia increases diabetes and its burden in the United States, moglobin A1c measurement for the diagnosis of childhood cardiometabolic risk in offspring. Dia- – 2017 [Internet]. Available from https://www type 2 diabetes in children. Int J Pediatr Endocri- betes Care 2017;40:679 686 Eu- .cdc.gov/diabetes/data/statistics/statistics-report nol 2012;2012:31 67. Landon MB, Rice MM, Varner MW, et al.; nice Kennedy Shriver .html. Accessed 22 September 2017 54. Kester LM, Hey H, Hannon TS. Using hemo- National Institute of Child 39. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. globin A1c for prediabetes and diabetes diagnosis Health and Human Development Maternal-Fetal Effect of early intensive multifactorial therapy on in adolescents: can adult recommendations be Medicine Units (MFMU) Network. Mild gesta- 5-year cardiovascular outcomes in individuals with upheld for pediatric use? J Adolesc Health 2012; tional diabetes mellitus and long-term child type 2 diabetes detected by screening (ADDITION- 50:321–323 health. Diabetes Care 2015;38:445–452 Europe): a cluster-randomised trial. Lancet 2011; 55. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness 68. Vandorsten JP, Dodson WC, Espeland MA, 378:156–167 of screening strategies for identifying pediatric diet al. NIH consensus development conference: di- 40. Herman WH, Ye W, Griffin SJ, et al. Early de- abetes mellitus and dysglycemia. JAMA Pediatr agnosing gestational diabetes mellitus. NIH Con- tection and treatment of type 2 diabetes reduce 2013;167:32–39 sens State Sci Statements 2013;29:1–31 cardiovascular morbidity and mortality: a simu- 56. Lawrence JM, Contreras R, Chen W, Sacks DA. 69. Committee on Practice BulletinsdObstetrics. lation of the results of the Anglo-Danish-Dutch Trends in the prevalence of preexisting diabe- Practice Bulletin No. 180: gestational diabetes Study of Intensive Treatment in People with tes and gestational diabetes mellitus among a mellitus. Obstet Gynecol 2017;130:e17–e37 Screen-Detected Diabetes in Primary Care racially/ethnically diverse population of pregnant 70. Donovan L, Hartling L, Muise M, Guthrie A, (ADDITION-Europe). Diabetes Care 2015;38: women, 1999–2005. Diabetes Care 2008;31:899– Vandermeer B, Dryden DM. Screening tests for 1449–1455 904 gestational diabetes: a systematic review for the 41. Kahn R, Alperin P, Eddy D, et al. Age at initi- 57. McIntyre HD, Sacks DA, Barbour LA, et al. Is- U.S. Preventive Services Task Force. Ann Intern ation and frequency of screening to detect type 2 sues with the diagnosis and classification of hy- Med 2013;159:115–122 diabetes: a cost-effectiveness analysis. Lancet perglycemia in early pregnancy. Diabetes Care 71. Khalafallah A, Phuah E, Al-Barazan AM, et al. 2010;375:1365–1374 2016;39:53–54 Glycosylated haemoglobin for screening and di- 42. Araneta MRG, Kanaya A, Fujimoto W, et al. 58. NoctorE, CroweC, CarmodyLA, et al.; ATLANTIC- agnosis of gestational diabetes mellitus. BMJ Optimum BMI cut-points to screen Asian DIP investigators. Abnormal glucose tolerance Open 2016;6:e011059 care.diabetesjournals.org Classification and Diagnosis of Diabetes S27

72. Horvath K, Koch K, Jeitler K, et al. Effects of later diabetes onset and higher HbA1c level. Dia- recommendations and future directions. Am J treatment in women with gestational diabetes bet Med 2014;31:466–471 Transplant 2014;14:1992–2000 mellitus: systematic review and meta-analysis. 85. Naylor RN, John PM, Winn AN, et al. Cost- 98. Hecking M, Werzowa J, Haidinger M, et al. BMJ 2010;340:c1395 effectiveness of MODY genetic testing: translating Novel views on new-onset diabetes after trans- 73. Carpenter MW, Coustan DR. Criteria for genomic advances into practical health applica- plantation: development, prevention and treat- screening tests for gestational diabetes. Am J Obstet tions. Diabetes Care 2014;37:202–209 ment. Nephrol Dial Transplant 2013;28:550–566 Gynecol 1982;144:768–773 86. Shields BM, Shepherd M, Hudson M, et al.; 99. Ramirez SC, Maaske J, Kim Y, et al. The asso- 74. National Diabetes Data Group. Classification UNITED study team. Population-based assess- ciation between glycemic control and clinical out- and diagnosis of diabetes mellitus and other cat- ment of a biomarker-based screening pathway comes after kidney transplantation. Endocr Pract egories of glucose intolerance. Diabetes 1979;28: to aid diagnosis of monogenic diabetes in young- 2014;20:894–900 1039–1057 onset patients. Diabetes Care 2017;40:1017– 100. Thomas MC, Moran J, Mathew TH, Russ GR, 75. Harper LM, Mele L, Landon MB, et al.; Eunice 1025 Rao MM. Early peri-operative hyperglycaemia Kennedy Shriver National Institute of Child Health 87. Hattersley A, Bruining J, Shield J, Njolstad P, and renal allograft rejection in patients without and Human Development (NICHD) Maternal-Fetal Donaghue KC. The diagnosis and management of diabetes. BMC Nephrol 2000;1:1 Medicine Units (MFMU) Network. Carpenter- monogenic diabetes in children and adolescents. 101. Chakkera HA, Weil EJ, Castro J, et al. Hypergly- Coustan compared with National Diabetes Data Pediatr Diabetes 2009;10(Suppl. 12):33–42 cemia during the immediate period after kidney trans- Group criteria for diagnosing gestational diabetes. 88. Rubio-Cabezas O, Hattersley AT, Njølstad PR, plantation. Clin J Am Soc Nephrol 2009;4:853–859 Obstet Gynecol 2016;127:893–898 et al.; International Society for Pediatric and Adoles- 102. Wallia A, Illuri V, Molitch ME. Diabetes care 76. Werner EF, Pettker CM, Zuckerwise L, et al. cent Diabetes. ISPAD Clinical Practice Consensus after transplant: definitions, risk factors, and clin- Screening for gestational diabetes mellitus: are Guidelines 2014. The diagnosis and management ical management. Med Clin North Am 2016;100: the criteria proposed by the International Associ- of monogenic diabetes in children and adolescents. 535–550 ation of the Diabetes and Pregnancy Study Groups Pediatr Diabetes 2014;15(Suppl. 20):47–64 103. Sharif A, Moore RH, Baboolal K. The use of – cost-effective? Diabetes Care 2012;35:529 535 89. Greeley SAW, Naylor RN, Philipson LH, Bell GI. oral glucose tolerance tests to risk stratify for 77. Duran A, Saenz´ S, Torrejon´ MJ, et al. Introduc- Neonatal diabetes: an expanding list of genes al- new-onset diabetes after transplantation: an tion of IADPSG criteria for the screening and di- lows for improved diagnosis and treatment. Curr underdiagnosed phenomenon. Transplantation agnosis of gestational diabetes mellitus results in Diab Rep 2011;11:519–532 2006;82:1667–1672 improved pregnancy outcomes at a lower cost in a 90. Mainguy C, Bellon G, Delaup V, et al. Sensi- 104. Hecking M, Kainz A, Werzowa J, et al. Glu- large cohort of pregnant women: the St. Carlos tivity and specificity of different methods for cys- cose metabolism after renal transplantation. Di- Gestational Diabetes Study. Diabetes Care 2014; tic fibrosis-related diabetes screening: is the oral abetes Care 2013;36:2763–2771 37:2442–2450 glucose tolerance test still the standard? J Pediatr 105. Galindo RJ, Fried M, Breen T, Tamler R. Hy- 78. Wei Y, Yang H, Zhu W, et al. International Endocrinol Metab 2017;30:27–35 perglycemia management in patients with post- Association of Diabetes and Pregnancy Study 91. Ode KL, Moran A. New insights into cystic transplantation diabetes. Endocr Pract 2016;22: Group criteria is suitable for gestational diabetes fibrosis-related diabetes in children. Lancet Dia- 454–465 mellitus diagnosis: further evidence from China. betes Endocrinol 2013;1:52–58 106. Jenssen T, Hartmann A. Emerging treat- Chin Med J (Engl) 2014;127:3553–3556 92. Moran A, Dunitz J, Nathan B, Saeed A, Holme ments for post-transplantation diabetes mellitus. 79. Feldman RK, Tieu RS, Yasumura L. Gestational B, Thomas W. Cystic fibrosis-related diabetes: cur- Nat Rev Nephrol 2015;11:465–477 diabetes screening: the International Association rent trends in prevalence, incidence, and mortal- 107. Thomas MC, Mathew TH, Russ GR, Rao MM, of the Diabetes and Pregnancy Study Groups com- – Moran J. Early peri-operative glycaemic control pared with Carpenter-Coustan screening. Obstet ity. Diabetes Care 2009;32:1626 1631 Gynecol 2016;127:10–17 93. Moran A, Pekow P, Grover P, et al.; Cystic and allograft rejection in patients with diabetes 80. Ethridge JK Jr, Catalano PM, Waters TP. Peri- Fibrosis Related Diabetes Therapy Study Group. mellitus: a pilot study. Transplantation 2001;72: fi – natal outcomes associated with the diagnosis of Insulin therapy to improve BMI in cystic brosis- 1321 1324 gestational diabetes made by the International related diabetes without fasting hyperglycemia: 108. Kurian B, Joshi R, Helmuth A. Effectiveness Association of the Diabetes and Pregnancy Study results of the Cystic Fibrosis Related Diabetes and long-term safety of thiazolidinediones and – Groups criteria. Obstet Gynecol 2014;124: Therapy Trial. Diabetes Care 2009;32:1783 1788 metformin in renal transplant recipients. Endocr fi – 571–578 94. Onady GM, Stol A. Insulin and oral agents Pract 2008;14:979 984 fi 81. Mayo K, Melamed N, Vandenberghe H, for managing cystic brosis-related diabetes. Co- 109. Budde K, Neumayer H-H, Fritsche L, ˆ Berger H. The impact of adoption of the Interna- chrane Database Syst Rev 2016;4:CD004730 Sulowicz W, Stompor T, Eckland D. The pharma- tional Association of Diabetes in Pregnancy Study 95. Moran A, Brunzell C, Cohen RC, et al.; CFRD cokinetics of pioglitazone in patients with im- Group criteria for the screening and diagnosis of Guidelines Committee. Clinical care guidelines for paired renal function. Br J Clin Pharmacol 2003; gestational diabetes. Am J Obstet Gynecol 2015; cystic fibrosis-related diabetes: a position state- 55:368–374 212:224.e1–224.e9 ment of the American Diabetes Association and a 110. Luther P, Baldwin D Jr. Pioglitazone in the 82. Carmody D, Støy J, Greeley SA, Bell GI, clinical practice guideline of the Cystic Fibrosis management of diabetes mellitus after transplan- Philipson LH. A clinical guide to monogenic diabe- Foundation, endorsed by the Pediatric Endocrine tation. Am J Transplant 2004;4:2135–2138 ˚ tes. In Genetic Diagnosis of Endocrine Disorders. Society. Diabetes Care 2010;33:2697–2708 111. Strøm Halden TA, Asberg A, Vik K, Hartmann 2nd ed. Weiss RE, Refetoff S, Eds. Philadelphia, PA, 96. Moran A, Pillay K, Becker DJ, Acerini CL; In- A, Jenssen T. Short-term efficacy and safety of Elsevier, 2016 ternational Society for Pediatric and Adolescent sitagliptin treatment in long-term stable renal re- 83. De Franco E, Flanagan SE, Houghton JAL, et al. Diabetes. ISPAD Clinical Practice Consensus cipients with new-onset diabetes after transplan- The effect of early, comprehensive genomic test- Guidelines 2014. Management of cystic fibrosis- tation. Nephrol Dial Transplant 2014;29:926–933 ing on clinical care in neonatal diabetes: an inter- related diabetes in children and adolescents. Pe- 112. Lane JT, Odegaard DE, Haire CE, Collier DS, national cohort study. Lancet 2015;386:957–963 diatr Diabetes 2014;15(Suppl. 20):65–76 Wrenshall LE, Stevens RB. Sitagliptin therapy in 84. UrbanovaJ,Ryp´ aćkovˇ aB,Proch´ azkov´ aZ,´ 97. Sharif A, Hecking M, de Vries APJ, et al. Pro- kidney transplant recipients with new-onset dia- et al. Positivity for islet cell autoantibodies in pa- ceedings from an international consensus meet- betes after transplantation. Transplantation 2011; tients with monogenic diabetes is associated with ing on posttransplantation diabetes mellitus: 92:e56–e57 S28 Diabetes Care Volume 41, Supplement 1, January 2018

3. Comprehensive Medical American Diabetes Association Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S28–S37 | https://doi.org/10.2337/dc18-S003

3. MEDICAL EVALUATION AND COMORBIDITIES clinical practice recommendations, please refer to the Standards of Care In- troduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

PATIENT-CENTERED COLLABORATIVE CARE

Recommendation c A patient-centered communication style that uses person-centered and strength-based language, active listening, elicits patient 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 “Improving Care and Promoting Health in Populations”) is a patient-centered approach to care that requires a close working relationship between thepatientandcliniciansinvolvedintreat- ment planning. People with diabetes should receive health care from an interdisciplinary 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 together formulate the Suggested citation: American Diabetes Association. management plan, which includes lifestyle management (see Section 4 “Lifestyle 3. Comprehensive medical evaluation and assess- Management”). ment of comorbidities: Standards of Medical Care in Treatment goals and plans should be created with the patients based on their indi- Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): vidual preferences, values, and goals. The management plan should take into account S28–S37 the patient’s age, cognitive abilities, school/work schedule and conditions, health © 2017 by the American Diabetes Association. beliefs, support systems, eating patterns, physical activity, social situation, finan- Readers may use this article as long as the work is properly cited, the use is educational and not cial concerns, cultural factors, literacy and numeracy (mathematical literacy), for profit, and the work is not altered. More infor- diabetes complications and duration of disease, comorbidities, health priorities, mation is available at http://www.diabetesjournals other medical conditions, preferences for care, and life expectancy. Various .org/content/license. care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S29

strategies and techniques should be used Additional referrals should be arranged as nec- ○ Begin patient engagement in the to support patients’ self-management essary (Table 3.2). Clinicians should ensure formulation of a care management efforts, including providing education on that individuals with diabetes are appropri- plan. B problem-solving skills for all aspects of ately screened for complications and comor- ○ Develop a plan for continuing care. B diabetes management. bidities. Discussing and implementing an c A follow-up visit should include Provider communications with patients/ approach to glycemic control with the patient most components of the initial com- families should acknowledge that multiple is a part, not the sole goal, of care. prehensive medical evaluation in- factors impact glycemic management, but cluding: interval medical history; also emphasize that collaboratively de- assessment of medication-taking be- Immunization veloped treatment plans and a healthy havior and intolerance/side effects; lifestyle can significantly improve dis- Recommendations physical examination; laboratory ease outcomes and well-being (4–7). c Provide routinely recommended evaluation as appropriate to assess Thus, the goal of provider-patient com- vaccinations for children and adults attainment of A1C and metabolic tar- munication is to establish a collaborative with diabetes by age. C gets; and assessment of risk for com- relationship and to assess and address c Annual vaccination against influenza plications, diabetes self-management self-management barriers without blaming is recommended for all people $6 behaviors, nutrition, psychosocial patients for “noncompliance” or “nonad- months of age, including those with health, and the need for referrals, herence” when the outcomes of self- diabetes. C immunizations, or other routine management are not optimal (8). The c Vaccination against pneumococcal health maintenance screening. B familiar terms “noncompliance” and “non- disease, including pneumococcal adherence” denote a passive, obedient pneumonia, with 13-valent pneumo- role for a person with diabetes in “follow- coccal conjugate vaccine (PCV13) is ing doctor’sorders” that is at odds with The comprehensive medical evaluation recommended for children before the active role people with diabetes take includes the initial and follow-up evalua- age 2 years. People with diabetes in directing the day-to-day decision- tions, assessment of complications, psy- ages 2 through 64 years should also making, planning, monitoring, evaluation, chosocial assessment, management of receive 23-valent pneumococcal and problem-solving involved in diabetes comorbid conditions, and engagement polysaccharide vaccine (PPSV23). At self-management. Using a nonjudgmen- of the patient throughout the process. age $65 years, regardless of vacci- tal approach that normalizes periodic lapses While a comprehensive list is provided nation history, additional PPSV23 in self-management may help minimize pain Table 3.1,inclinicalpractice,thepro- vaccination is necessary. C tients’ resistance to reporting problems vider may need to prioritize the compo- c Administer 3-dose series of hepatitis with self-management. Empathizing and nents of the medical evaluation given the B vaccine to unvaccinated adults with using active listening techniques, such as available resources and time. The goal is to diabetes ages 19 through 59 years. C open-ended questions, reflective state- provide the health care team information c Consider administering 3-dose se- ments, and summarizing what the patient to optimally support a patient. In addition ries of hepatitis B vaccine to unvac- said, can help facilitate communication. to the medical history, physical examina- cinated adults with diabetes ages Patients’ perceptions about their own abil- tion, and laboratory tests, providers should $60 years. C ity, or self-efficacy, to self-manage dia- assess diabetes self-management behav- betes are one important psychosocial iors, nutrition, and psychosocial health Children and adults with diabetes should factorrelatedtoimproveddiabetesself- (see Section 4 “Lifestyle Management”) receive vaccinations according to age- management and treatment outcomes in and give guidance on routine immuniza- specific recommendations (15,16). The diabetes (9–13) and should be a target of tions. The assessment of sleep pattern and child and adolescent vaccination schedule ongoing assessment, patient education, duration should be considered; a recent is available at www.cdc.gov/vaccines/ and treatment planning. meta-analysis found that poor sleep quality, schedules/hcp/imz/child-adolescent. short sleep, and long sleep were associated html, and the adult vaccination schedule with higher A1C in people with type 2 di- is available at www.cdc.gov/vaccines/ COMPREHENSIVE MEDICAL abetes (14). Interval follow-up visits should schedules/hcp/imz/adult.html. These im- EVALUATION occur at least every 3–6 months, individual- munization schedules include vaccination fi Recommendations ized to the patient, and then annually. schedules speci cally for children, adoles- Lifestyle management and psychosocial cents, and adults with diabetes. c A complete medical evaluation should be performed at the initial care are the cornerstones of diabetes man- People with diabetes are at higher risk visit to: agement. Patients should be referred for for hepatitis B infection and are more likely diabetes self-management education and to develop complications from influenza ○ Confirm the diagnosis and classify support (DSMES), medical nutrition therapy and pneumococcal disease. The Centers diabetes. B (MNT), and psychosocial/emotional health for Disease Control and Prevention (CDC) ○ Evaluate for diabetes complications concerns if indicated. Patients should receive Advisory Committee on Immunization Prac- and potential comorbid conditions. E recommended preventive care services (e.g., tices (ACIP) recommends influenza, pneumo- ○ Review previous treatment and risk immunizations, cancer screening, etc.); coccal, and hepatitis B vaccinations specifically factor control in patients with es- smoking cessation counseling; and ophthal- for people with diabetes. Vaccination against tablished diabetes. E mological, dental, and podiatric referrals. tetanus-diphtheria-pertussis, measles-mumps- S30 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

Continued on p. S31 care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S31 S32 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

need to be aware of common comorbidities Table 3.2—Referrals for initial care to remediate deficits. Treatment that affect people with diabetes and may management should be tailored to avoid signifi- c complicate management (19–23). Diabetes Eye care professional for annual dilated cant hypoglycemia. B eye exam comorbidities are conditions that affect c Family planning for women of people with diabetes more often than age- Diabetes is associated with a significantly reproductive age matched people without diabetes. The list increased risk and rate of cognitive decline c Registered dietitian for MNT below includes many of the common comor- and an increased risk of dementia (30,31). c DSMES bidities observed in patients with diabetes A recent meta-analysis of prospective ob- c Dentist for comprehensive dental and but is not necessarily inclusive of all the con- periodontal examination servational studies in people with diabe- ditions that have been reported. c Mental health professional, if indicated tes showed 73% increased risk of all types Autoimmune Diseases of dementia, 56% increased risk of Alz- heimer dementia, and 127% increased rubella, human papillomavirus, and shin- Recommendation risk of vascular dementia compared with gles are also important for adults with diabe- c Consider screening patients with individuals without diabetes (32). The re- tes, as they are for the general population. type 1 diabetes for autoimmune verse is also true: people with Alzheimer Influenza thyroid disease and celiac disease dementia are more likely to develop di- fl B In uenza is a common, preventable infec- soon after diagnosis. abetes than people without Alzheimer tious disease associated with high mortality dementia. In a 15-year prospective study People with type 1 diabetes are at in- and morbidity in vulnerable populations in- of community-dwelling people .60 years creased risk for other autoimmune dis- cluding the young and the elderly and people of age, the presence of diabetes at base- with chronic diseases. Influenza vaccination eases including thyroid disease, primary line significantly increased the age- and in people with diabetes has been found to adrenal insufficiency, celiac disease, auto- sex-adjusted incidence of all-cause de- significantly reduce influenza and diabetes- immune gastritis, autoimmune hepatitis, mentia, Alzheimer disease, and vascular related hospital admissions (17). dermatomyositis, and myasthenia gravis dementia compared with rates in those (24–26). Type 1 diabetes may also occur Pneumococcal Pneumonia with normal glucose tolerance (33). Like influenza, pneumococcal pneumonia with other autoimmune diseases in the fi is a common, preventable disease. People context of speci c genetic disorders or pol- yglandular autoimmune syndromes (27). Hyperglycemia with diabetes may be at increased risk for In those with type 2 diabetes, the degree In autoimmune diseases, the immune sys- the bacteremic form of pneumococcal infec- and duration of hyperglycemia are re- tion and have been reported to have a high tem fails to maintain self-tolerance to spe- fi lated to dementia. More rapid cognitive risk of nosocomial bacteremia, with a mortal- ci c peptides within target organs. It is likely that many factors trigger autoimmune dis- decline is associated with both increased ity rate as high as 50% (18). The American A1C and longer duration of diabetes (34). Diabetes Association (ADA) endorses recom- ease; however, common triggering factors are known for only some autoimmune con- The Action to Control Cardiovascular Risk mendations from the CDC ACIP that adults in Diabetes (ACCORD) study found that age $65 years, who are at higher risk for ditions (i.e., gliadin peptides in celiac disease) (see Section 12 “Children and Adolescents”). each 1% higher A1C level was associated pneumococcal disease, receive an additional with lower cognitive function in individu- 23-valent pneumococcal polysaccharide als with type 2 diabetes (35). However, vaccine (PPSV23), regardless of prior pneumo- Cancer the ACCORD study found no difference coccal vaccination history. See detailed rec- Diabetes is associated with increased risk of in cognitive outcomes in participants ran- ommendations at www.cdc.gov/vaccines/ cancers of the liver, pancreas, endometrium, domly assigned to intensive and standard hcp/acip-recs/vacc-specific/pneumo.html. colon/rectum, breast, and bladder (28). The association may result from shared risk fac- glycemic control, supporting the recom- Hepatitis B tors between type 2 diabetes and cancer mendation that intensive glucose control Compared with the general population, (older age, obesity, and physical inactivity) should not be advised for the improve- people with type 1 or type 2 diabetes but may also be due to diabetes-related ment of cognitive function in individuals have higher rates of hepatitis B. This may factors (29), such as underlying disease with type 2 diabetes (36). be due to contact with infected blood or physiology or diabetes treatments, al- through improper equipment use (glucose Hypoglycemia though evidence for these links is scarce. monitoring devices or infected needles). Be- In type 2 diabetes, severe hypoglycemia is Patients with diabetes should be encour- cause of the higher likelihood of transmis- associated with reduced cognitive func- aged to undergo recommended age- and sion, hepatitis B vaccine is recommended for tion, and those with poor cognitive func- sex-appropriate cancer screenings and to adults with diabetes age ,60 years. For tion have more severe hypoglycemia. In a reduce their modifiable cancer risk factors $ long-term study of older patients with adults age 60 years, hepatitis B vaccine (obesity, physical inactivity, and smoking). may be administered at the discretion of the type 2 diabetes, individuals with one or treating clinician based on the patient’slike- Cognitive Impairment/Dementia more recorded episode of severe hypo- lihood of acquiring hepatitis B infection. glycemia had a stepwise increase in risk Recommendation of dementia (37). Likewise, the ACCORD c In people with a history of cognitive ASSESSMENT OF COMORBIDITIES trial found that as cognitive function de- impairment/dementia, intensive Besides assessing diabetes-related com- creased, the risk of severe hypoglycemia glucose control cannot be expected plications, clinicians and their patients increased (38). Tailoring glycemic therapy care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S33

may help to prevent hypoglycemia in in- Conversely, prediabetes and/or diabetes Hearing Impairment dividuals with cognitive dysfunction. has been found to develop in approxi- Hearing impairment, both in high- frequency and low/mid-frequency ranges, Nutrition mately one-third of patients after an epi- In one study, adherence to the Mediter- sode of acute pancreatitis (47), thus the is more common in people with diabetes ranean diet correlated with improved relationship is likely bidirectional. Postpan- than in those without, perhaps due to neuropathy and/or vascular disease. In a cognitive function (39). However, a recent creatitis diabetes may include either new- National Health and Nutrition Examination Cochrane review found insufficient ev- onset disease or previously unrecognized Survey (NHANES) analysis, hearing impair- idence to recommend any dietary change diabetes (48). Studies of patients treated ment was about twice as prevalent in peo- for the prevention or treatment of cogni- with incretin-based therapies for diabetes ple with diabetes compared with those tive dysfunction (40). have also reported that pancreatitis may occur more frequently with these medica- without, after adjusting for age and other Statins tions, but results have been mixed (49,50). risk factors for hearing impairment (61). A systematic review has reported that Islet autotransplantation should be con- HIV data do not support an adverse effect sidered for patients requiring total pancre- of statins on cognition (41). The U.S. atectomy for medically refractory chronic Recommendation Food and Drug Administration (FDA) post- pancreatitis to prevent postsurgical diabe- c Patients with HIV should be screened marketing surveillance databases have tes. Approximately one-third of patients for diabetes and prediabetes with also revealed a low reporting rate for cog- undergoing total pancreatectomy with is- a fasting glucose level every 6–12 nitive-related adverse events, including let autotransplantation are insulin free one months before starting antiretrovi- cognitive dysfunction or dementia, with year postoperatively, and observational ral therapy and 3 months after statin therapy, similar to rates seen with studies from different centers have dem- starting or changing antiretroviral other commonly prescribed cardiovascular onstrated islet graft function up to a de- therapy. If initial screening results medications (41). Therefore, fear of cog- cade after the surgery in some patients are normal, checking fasting glu- nitive decline should not be a barrier to (51–55). Both patient and disease factors cose every year is advised. E statin use in individuals with diabetes should be carefully considered when de- and a high risk for cardiovascular disease. ciding the indications and timing of this Diabetes risk is increased with certain surgery. Surgeries should be performed in protease inhibitors (PIs) and nucleoside Fatty Liver Disease skilled facilities that have demonstrated reverse transcriptase inhibitors (NRTIs). Diabetes is associated with the develop- expertise in islet autotransplantation. New-onsetdiabetesisestimatedtooc- ment of nonalcoholic chronic liver disease cur in more than 5% of patients infected and with hepatocellular carcinoma (42). Fractures withHIVonPIs,whereasmorethan15% Elevations of hepatic transaminase con- Age-specific hip fracture risk is signifi- may have prediabetes (62). PIs are asso- centrations are associated with higher cantly increased in people with both ciated with insulin resistance and may BMI, waist circumference, and triglycer- type 1 (relative risk 6.3) and type 2 (relative also lead to apoptosis of pancreatic b-cells. ide levels and lower HDL cholesterol lev- risk 1.7) diabetes in both sexes (56). Type 1 NRTIs also affect fat distribution (both lip- els. Interventions that improve metabolic diabetes is associated with osteoporosis, ohypertrophy and lipoatrophy), which is abnormalities in patients with diabetes but in type 2 diabetes, an increased risk of associated with insulin resistance. (weight loss, glycemic control, and treat- hip fracture is seen despite higher bone Individuals with HIV are at higher risk fi ment with speci c drugs for hyperglyce- mineral density (BMD) (57). In three large for developing prediabetes and diabe- fi mia or dyslipidemia) are also bene cial observational studies of older adults, tes on antiretroviral (ARV) therapies, for fatty liver disease (43,44). femoral neck BMD T score and the World so a screening protocol is recommended Health Organization Fracture Risk Assess- (63). The A1C test underestimates glyce- Pancreatitis ment Tool (FRAX) score were associated mia in people with HIV and is not recom- Recommendation with hip and nonspine fractures. Fracture mended for diagnosis and may present c Islet autotransplantation should be risk was higher in participants with dia- challenges for monitoring (64). In those considered for patients requiring betes compared with those without dia- with prediabetes, weight loss through total pancreatectomy for medically betes for a given T score and age or for a healthy nutrition and physical activity refractory chronic pancreatitis to given FRAX score (58). Providers should may reduce the progression toward dia- prevent postsurgical diabetes. C assess fracture history and risk factors in betes. Among patients with HIV and older patients with diabetes and recom- diabetes, preventive health care using Diabetes is linked to diseases of the exo- mend measurement of BMD if appro- an approach similar to that used in pa- crine pancreas such as pancreatitis, which priate for the patient’s age and sex. tients without HIV is critical to reduce may disrupt the global architecture or Fracture prevention strategies for people the risks of microvascular and macrovas- physiology of the pancreas, often result- with diabetes are the same as for the cular complications. ing in both exocrine and endocrine general population and include vitamin D For patients with HIV and ARV-associated dysfunction. Up to half of patients with di- supplementation. For patients with type hyperglycemia, it may be appropriate to abetes may have impaired exocrine pan- 2 diabetes with fracture risk factors, consider discontinuing the problematic creas function (45). People with diabetes thiazolidinediones (59) and sodium– ARV agents if safe and effective alternatives are at an approximately twofold higher glucose cotransporter 2 inhibitors (60) are available (65). Before making ARV sub- risk of developing acute pancreatitis (46). should be used with caution. stitutions, carefully consider the possible S34 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

effect on HIV virological control and the diabetes than in those without (74,75). The Behavioral Risk Factor Surveillance potential adverse effects of new ARV Current evidence suggests that periodon- System (BRFSS) estimated the lifetime agents. In some cases, antihyperglycemic tal disease adversely affects diabetes out- prevalence of generalized anxiety disorder agents may still be necessary. comes, although evidence for treatment to be 19.5% in people with either type 1 or benefits remains controversial (23). type 2 diabetes (79). Common diabetes- Low Testosterone in Men specific concerns include fears related to Recommendation Psychosocial/Emotional Disorders hypoglycemia (80,81), not meeting blood c In men with diabetes who have Prevalence of clinically significant psycho- glucose targets (78), and insulin injections symptoms or signs of hypogonadism pathology diagnoses are considerably or infusion (82). Onset of complications such as decreased sexual desire more common in people with diabetes presents another critical point when (libido) or activity, or erectile dys- than in those without the disease (76). anxiety can occur (83). People with dia- function, consider screening with a Symptoms, both clinical and subclinical, betes who exhibit excessive diabetes self- morning serum testosterone level. B that interfere with the person’sability management behaviors well beyond what to carry out daily diabetes self-manage- is prescribed or needed to achieve glycemic Mean levels of testosterone are lower in ment tasks must be addressed. Providers targets may be experiencing symptoms of men with diabetes compared with age- should consider an assessment of symp- obsessive-compulsive disorder (84). matched men without diabetes, but obesity toms of depression, anxiety, and disor- General anxiety is a predictor of injection- is a major confounder (66,67). Treatment dered eating, and of cognitive capacities related anxiety and associated with in asymptomatic men is controversial. using patient-appropriate standardized/ fear of hypoglycemia (81,85). Fear of hy- Testosterone replacement in men with validated tools at the initial visit, at peri- poglycemia and hypoglycemia unaware- symptomatic hypogonadism may have ben- odic intervals, and when there is a change ness often co-occur, and interventions efits including improved sexual function, in disease, treatment, or life circum- aimed at treating one often benefitboth well being, muscle mass and strength, and stance. Including caregivers and family (86). Fear of hypoglycemia may explain bone density. (68). In men with diabetes members in this assessment is recom- avoidance of behaviors associated with who have symptoms or signs of low testos- mended. Diabetes distress is addressed lowering glucose such as increasing in- terone (hypogonadism), a morning total in Section 4 “Lifestyle Management,” as sulin doses or frequency of monitoring. testosterone should be measured using an this state is very common and distinct If fear of hypoglycemia is identified and accurate and reliable assay. Free or bioavail- from the psychological disorders dis- a person does not have symptoms of able testosterone levels should also be mea- cussed below (77). hypoglycemia, a structured program, suredinmenwithdiabeteswhohavetotal blood glucose awareness training, deliv- Anxiety Disorders testosterone levels close to the lower limit, ered in routine clinical practice, can im- given expected decreases in sex hormone– Recommendations prove A1C, reduce the rate of severe binding globulin with diabetes. Further c Consider screening for anxiety in hypoglycemia, and restore hypoglycemia testing (such as luteinizing hormone and people exhibiting anxiety or worries awareness (87,88). follicle-stimulating hormone levels) may regarding diabetes complications, be needed to distinguish between pri- insulin injections or infusion, taking Depression mary and secondary hypogonadism. medications, and/or hypoglycemia Recommendations that interfere with self-management Obstructive Sleep Apnea c Providers should consider annual behaviors and those who express Age-adjusted rates of obstructive sleep screening of all patients with diabetes, fear, dread, or irrational thoughts apnea, a risk factor for cardiovascular especially those with a self-reported and/or show anxiety symptoms disease, are significantly higher (4- to history of depression, for depressive such as avoidance behaviors, exces- 10-fold) with obesity, especially with cen- symptoms with age-appropriate de- sive repetitive behaviors, or social tral obesity (69). The prevalence of ob- pression screening measures, recog- withdrawal. Refer for treatment if structive sleep apnea in the population nizing that further evaluation will be anxiety is present. B with type 2 diabetes may be as high as necessary for individuals who have a c People with hypoglycemia unaware- 23%, and the prevalence of any sleep dis- positive screen. B ness, which can co-occur with fear of ordered breathing may be as high as 58% c Beginning at diagnosis of complica- hypoglycemia, should be treated us- (70,71). In obese participants enrolled in tions or when there are significant ing blood glucose awareness training the Action for Health in Diabetes (Look changes in medical status, consider (or other evidence-based interven- AHEAD) trial, it exceeded 80% (72). Sleep assessment for depression. B tion) to help reestablish awareness apnea treatment (lifestyle modification, c Referrals for treatment of depres- of hypoglycemia and reduce fear of continuous positive airway pressure, sion should be made to mental hypoglycemia. A oral appliances, and surgery) significantly health providers with experience us- improves quality of life and blood pressure ing cognitive behavioral therapy, Anxiety symptoms and diagnosable disor- control. The evidence for a treatment ef- interpersonal therapy, or other evi- ders (e.g., generalized anxiety disorder, fect on glycemic control is mixed (73). dence-based treatment approaches body dysmorphic disorder, obsessive- in conjunction with collaborative Periodontal Disease compulsive disorder, specific phobias, care with the patient’sdiabetes Periodontal disease is more severe, and and posttraumatic stress disorder) are treatment team. A may be more prevalent, in patients with common in people with diabetes (78). care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S35

History of depression, current depression, (98,99); in people with type 2 diabetes, those taking second-generation (atypical) and antidepressant medication use are bingeing (excessive food intake with an antipsychotics such as olanzapine require risk factors for the development of type accompanying sense of loss of control) greater monitoring because of an increase 2 diabetes, especially if the individual is most commonly reported. For people in risk of type 2 diabetes associated with hasotherriskfactorssuchasobesity with type 2 diabetes treated with insulin, this medication (106). and family history of type 2 diabetes intentional omission is also frequently re- (89–91). Elevated depressive symptoms ported (100). People with diabetes and References and depressive disorders affect one in diagnosable eating disorders have high four patients with type 1 or type 2 diabe- rates of comorbid psychiatric disorders 1. Stellefson M, Dipnarine K, Stopka C. The Chronic Care Model and diabetes management tes (92). Thus, routine screening for de- (101). People with type 1 diabetes and in US primary care settings: a systematic review. pressive symptoms is indicated in this eating disorders have high rates of diabe- Prev Chronic Dis 2013;10:E26 high-risk population including people tes distress and fear of hypoglycemia 2. Coleman K, Austin BT, Brach C, Wagner EH. (102). Evidence on the Chronic Care Model in the new with type 1 or type 2 diabetes, gestational – When evaluating symptoms of disor- millennium. Health Aff (Millwood) 2009;28:75 85 diabetes mellitus, and postpartum diabe- 3. Gabbay RA, Bailit MH, Mauger DT, Wagner EH, tes. Regardless of diabetes type, women dered or disrupted eating in people with Siminerio L. Multipayer patient-centered medical have significantly higher rates of depres- diabetes, etiology and motivation for the home implementation guided by the Chronic Care sion than men (93). behavior should be considered (97,103). Model. Jt Comm J Qual Patient Saf 2011;37:265– 273 Routine monitoring with patient- Adjunctive medication such as glucagon- like peptide 1 receptor agonists (104) may 4. UK Prospective Diabetes Study (UKPDS) Group. appropriate validated measures can help Intensive blood-glucose control with sulphonylureas to identify if referral is warranted. Adult help individuals not only to meet glycemic or insulin compared with conventional treatment patients with a history of depressive targets but also to regulate hunger and and risk of complications in patients with type 2 di- – symptoms or disorder need ongoing food intake, thus having the potential to abetes (UKPDS 33). Lancet 1998;352:837 853 reduce uncontrollable hunger and bu- 5. The Diabetes Control and Complications Trial monitoring of depression recurrence Research Group. The effect of intensive treatment within the context of routine care (88). limic symptoms. of diabetes on the development and progression of Integrating mental and physical health long-term complications in insulin-dependent dia- – care can improve outcomes. When a Serious Mental Illness betes mellitus. N Engl J Med 1993;329:977 986 6. Lachin JM, Genuth S, Nathan DM, Zinman B, patient is in psychological therapy (talk Recommendations Rutledge BN; DCCT/EDIC Research Group. Effect therapy), the mental health provider c Annually screen people who are of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Com- should be incorporated into the diabetes prescribed atypical antipsychotic treatment team (94). plications Trialdrevisited. Diabetes 2008;57:995– medications for prediabetes or di- 1001 abetes. B 7. White NH, Cleary PA, Dahms W, Goldstein D, Disordered Eating Behavior c If a second-generation antipsy- Malone J, Tamborlane WV; Diabetes Control and Complications Trial (DCCT)/Epidemiology of Dia- Recommendations chotic medication is prescribed for betes Interventions and Complications (EDIC) Re- c Providers should consider reevalu- adolescents or adults with diabetes, search Group. Beneficial effects of intensive ating the treatment regimen of changes in weight, glycemic con- therapy of diabetes during adolescence: out- people with diabetes who present trol, and cholesterol levels should comes after the conclusion of the Diabetes Con- with symptoms of disordered eat- be carefully monitored and the trol and Complications Trial (DCCT). J Pediatr 2001; – ing behavior, an eating disorder, treatment regimen should be reas- 139:804 812 B C 8. Anderson RM, Funnell MM. Compliance and or disrupted patterns of eating. sessed. adherence are dysfunctional concepts in diabetes c Consider screening for disordered c Incorporate monitoring of diabetes care. Diabetes Educ 2000;26:597–604 or disrupted eating using validated self-care activities into treatment 9. Sarkar U, Fisher L, Schillinger D. Is self-efficacy screening measures when hypergly- goals in people with diabetes and associated with diabetes self-management across cemia and weight loss are unex- B race/ethnicity and health literacy? Diabetes Care serious mental illness. 2006;29:823–829 plained based on self-reported 10. King DK, Glasgow RE, Toobert DJ, et al. Self- behaviors related to medication Studies of individuals with serious mental efficacy, problem solving, and social-environmental dosing, meal plan, and physical ac- illness, particularly schizophrenia and support are associated with diabetes self-management tivity. In addition, a review of the other thought disorders, show signifi- behaviors. Diabetes Care 2010;33:751–753 11. Nouwen A, Urquhart Law G, Hussain S, medical regimen is recommended cantly increased rates of type 2 diabetes McGovern S, Napier H. Comparison of the role to identify potential treatment- (105). People with schizophrenia should of self-efficacy and illness representations in re- related effects on hunger/caloric be monitored for type 2 diabetes because lation to dietary self-care and diabetes distress in intake. B of the known comorbidity. Disordered adolescents with type 1 diabetes. Psychol Health – thinking and judgment can be expected 2009;24:1071 1084 fi 12. Beckerle CM, Lavin MA. Association of self- Estimated prevalence of disordered to make it dif cult to engage in behaviors efficacy and self-care with glycemic control in di- eating behaviors and diagnosable eating that reduce risk factors for type 2 diabe- abetes. Diabetes Spectr 2013;26:172–178 disorders in people with diabetes varies tes, such as restrained eating for weight 13. Iannotti RJ, Schneider S, Nansel TR, et al. Self- (95–97). For people with type 1 diabetes, management. Coordinated management efficacy, outcome expectations, and diabetes self- insulin omission causing glycosuria in or- management in adolescents with type 1 diabetes. of diabetes or prediabetes and serious J Dev Behav Pediatr 2006;27:98–105 der to lose weight is the most commonly mental illness is recommended to achieve 14. Lee SWH, Ng KY, Chin WK. The impact of sleep reported disorderedeatingbehavior diabetes treatment targets. In addition, amount and sleep quality on glycemic control in S36 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

type 2 diabetes: a systematic review and meta- 33. Ohara T, Doi Y, Ninomiya T, et al. Glucose 48. Petrov MS. Diabetes of the exocrine pan- analysis. Sleep Med Rev 2017;31:91–101 tolerance status and risk of dementia in the com- creas: American Diabetes Association-compliant 15. Robinson CL, RomeroJR, KempeA, PellegriniC; munity: the Hisayama study. Neurology 2011;77: lexicon. Pancreatology 2017;17:523–526 Advisory Committee on Immunization Practices 1126–1134 49. Thomsen RW, Pedersen L, Møller N, Kahlert J, (ACIP) Child/Adolescent Immunization Work 34. Rawlings AM, Sharrett AR, Schneider ALC, Beck-Nielsen H, Sørensen HT. Incretin-based ther- Group. Advisory Committee on Immunization et al. Diabetes in midlife and cognitive change apy and risk of acute pancreatitis: a nationwide Practices recommended immunization schedule over 20 years: a cohort study. Ann Intern Med population-based case-control study. Diabetes for children and adolescents aged 18 years or 2014;161:785–793 Care 2015;38:1089–1098 youngerdUnited States, 2017. MMWR Morb 35. Cukierman-Yaffe T, Gerstein HC, Williamson 50. Tkaćˇ I, Raz I. Combined analysis of three large Mortal Wkly Rep 2017;66:134–135 JD, et al.; Action to Control Cardiovascular Risk in interventional trials with gliptins indicates increased 16. Kim DK, Riley LE, Harriman KH, Hunter P, Diabetes-Memory in Diabetes (ACCORD-MIND) incidence of acute pancreatitis in patients with type 2 Bridges CB. Advisory Committee on Immunization Investigators. Relationship between baseline gly- diabetes. Diabetes Care 2017;40:284–286 Practices recommended immunization schedule for cemic control and cognitive function in individuals 51. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. adults aged 19 years or olderdUnited States, 2017. with type 2 diabetes and other cardiovascular risk Total pancreatectomy with islet autotransplanta- MMWR Morb Mortal Wkly Rep 2017;66:136–138 factors: the Action to Control Cardiovascular Risk tion: summary of an NIDDK workshop. Ann Surg 17. Goeijenbier M, van Sloten TT, Slobbe L, et al. in Diabetes-Memory in Diabetes (ACCORD-MIND) 2015;261:21–29 Benefits of flu vaccination for persons with diabetes trial. Diabetes Care 2009;32:221–226 52. Sutherland DER, Radosevich DM, Bellin MD, mellitus: a review. Vaccine 2017;35:5095–5101 36. Launer LJ, Miller ME, Williamson JD, et al.; et al. Total pancreatectomy and islet autotrans- 18. Smith SA, Poland GA. Use of influenza and ACCORD MIND Investigators. Effects of intensive plantation for chronic pancreatitis. J Am Coll Surg pneumococcal vaccines in people with diabetes. glucose lowering on brain structure and function 2012;214:409–424 Diabetes Care 2000;23:95–108 in people with type 2 diabetes (ACCORD MIND): a 53. Quartuccio M, Hall E, Singh V, et al. Glycemic 19. Selvin E, Coresh J, Brancati FL. The burden randomised open-label substudy. Lancet Neurol predictors of insulin independence after total and treatment of diabetes in elderly individuals 2011;10:969–977 pancreatectomy with islet autotransplantation. in the U.S. Diabetes Care 2006;29:2415–2419 37. Whitmer RA, Karter AJ, Yaffe K, Quesenberry J Clin Endocrinol Metab 2017;102:801–809 20. Grant RW, Ashburner JM, Hong CS, Chang Y, CP Jr, Selby JV. Hypoglycemic episodes and risk of 54. Webb MA, Illouz SC, Pollard CA, et al. Islet Barry MJ, Atlas SJ. Defining patient complexity dementia in older patients with type 2 diabetes auto transplantation following total pancreatec- from the primary care physician’s perspective: a mellitus. JAMA 2009;301:1565–1572 tomy: a long-term assessment of graft function. cohort study. Ann Intern Med 2011;155:797–804 38. Punthakee Z, Miller ME, Launer LJ, et al.; Pancreas 2008;37:282–287 21. Tinetti ME, Fried TR, Boyd CM. Designing ACCORD Group of Investigators; ACCORD-MIND 55. Wu Q, Zhang M, Qin Y, et al. Systematic re- health care for the most common chronic conditiond Investigators. Poor cognitive function and risk of view and meta-analysis of islet autotransplanta- multimorbidity. JAMA 2012;307:2493–2494 severe hypoglycemia in type 2 diabetes: post hoc tion after total pancreatectomy in chronic 22. Sudore RL, Karter AJ, Huang ES, et al. Symp- epidemiologic analysis of the ACCORD trial. Dia- pancreatitis patients. Endocr J 2015;62:227–234 tom burden of adults with type 2 diabetes across betes Care 2012;35:787–793 56. Janghorbani M, Van Dam RM, Willett WC, Hu the disease course: Diabetes & Aging Study. J Gen 39. Scarmeas N, Stern Y, Mayeux R, Manly JJ, FB. Systematic review of type 1 and type 2 diabe- Intern Med 2012;27:1674–1681 Schupf N, Luchsinger JA. Mediterranean diet and tes mellitus and risk of fracture. Am J Epidemiol 23. Borgnakke WS, Ylostalo¨ PV, Taylor GW, mild cognitive impairment. Arch Neurol 2009;66: 2007;166:495–505 Genco RJ. Effect of periodontal disease on diabetes: 216–225 57. Vestergaard P. Discrepancies in bone mineral systematic review of epidemiologic observational ev- 40. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Carbo- density and fracture risk in patients with type 1 idence. J Periodontol 2013;84(Suppl.):S135–S152 hydrates for improving the cognitive performance and type 2 diabetesda meta-analysis. Osteo- 24. Triolo TM, Armstrong TK, McFann K, et al. of independent-living older adults with normal poros Int 2007;18:427–444 Additional autoimmune disease found in 33% of cognition or mild cognitive impairment. Cochrane 58. Schwartz AV, Vittinghoff E, Bauer DC, et al.; patients at type 1 diabetes onset. Diabetes Care Database Syst Rev 2011;4:CD007220 Study of Osteoporotic Fractures (SOF) Research 2011;34:1211–1213 41. Richardson K, Schoen M, French B, et al. Sta- Group; Osteoporotic Fractures in Men (MrOS) Re- 25. Hughes JW, Riddlesworth TD, DiMeglio LA, tins and cognitive function: a systematic review. search Group; Health, Aging, and Body Composi- Miller KM, Rickels MR, McGill JB; T1D Exchange Ann Intern Med 2013;159:688–697 tion (Health ABC) Research Group. Association of Clinic Network. Autoimmune diseases in children 42. El-Serag HB, Tran T, Everhart JE. Diabetes in- BMD and FRAX score with risk of fracture in older and adults with type 1 diabetes from the T1D creases the risk of chronic liver disease and hepa- adults with type 2 diabetes. JAMA 2011;305: Exchange Clinic Registry. J Clin Endocrinol Metab tocellular carcinoma. Gastroenterology 2004;126: 2184–2192 2016;101:4931–4937 460–468 59. Kahn SE, Zinman B, Lachin JM, et al.; Diabetes 26. Kahaly GJ, Hansen MP. Type 1 diabetes asso- 43. American Gastroenterological Association. Outcome Progression Trial (ADOPT) Study Group. ciated autoimmunity. Autoimmun Rev 2016;15: American Gastroenterological Association Rosiglitazone-associated fractures in type 2 diabe- 644–648 medical position statement: nonalcoholic fatty tes: an analysis from A Diabetes Outcome Pro- 27. Eisenbarth GS, Gottlieb PA. Autoimmune pol- liver disease. Gastroenterology 2002;123:1702– gression Trial (ADOPT). Diabetes Care 2008;31: yendocrine syndromes. N Engl J Med 2004;350: 1704 845–851 2068–2079 44. Cusi K, Orsak B, Bril F, et al. Long-term piogli- 60. Taylor SI, Blau JE, Rother KI. Possible adverse 28. Suh S, Kim K-W. Diabetes and cancer: is di- tazone treatment for patients with nonalcoholic effects of SGLT2 inhibitors on bone. Lancet Diabe- abetes causally related to cancer? Diabetes steatohepatitis and prediabetes or type 2 diabetes Endocrinol 2015;3:8–10 Metab J 2011;35:193–198 tes mellitus: a randomized trial. Ann Intern Med 61. Bainbridge KE, Hoffman HJ, Cowie CC. Diabe- 29. Giovannucci E, Harlan DM, Archer MC, et al. 2016;165:305–315 tes and hearing impairment in the United States: Diabetes and cancer: a consensus report. Diabe- 45. Hardt PD, Brendel MD, Kloer HU, Bretzel RG. audiometric evidence from the National Health tes Care 2010;33:1674–1685 Is pancreatic diabetes (type 3c diabetes) under- and Nutrition Examination Survey, 1999 to 2004. 30. Cukierman T, Gerstein HC, Williamson JD. diagnosed and misdiagnosed? Diabetes Care Ann Intern Med 2008;149:1–10 Cognitive decline and dementia in diabetesd 2008;31(Suppl. 2):S165–S169 62. Monroe AK, Glesby MJ, Brown TT. Diagnosing systematic overview of prospective observational 46. Lee Y-K, Huang M-Y, Hsu C-Y, Su Y-C. Bidirec- and managing diabetes in HIV-infected patients: studies. Diabetologia 2005;48:2460–2469 tional relationship between diabetes and acute current concepts. Clin Infect Dis 2015;60:453–462 31. Biessels GJ, Staekenborg S, Brunner E, Brayne pancreatitis: a population-based cohort study in 63. Schambelan M, Benson CA, Carr A, et al.; C, Scheltens P. Risk of dementia in diabetes mellitus: Taiwan. Medicine (Baltimore) 2016;95:e2448 International AIDS Society-USA. Management a systematic review. Lancet Neurol 2006;5:64–74 47. Das SLM, Singh PP, Phillips ARJ, Murphy R, of metabolic complications associated with anti- 32. Gudala K, Bansal D, Schifano F, Bhansali A. Windsor JA, Petrov MS. Newly diagnosed diabe- retroviral therapy for HIV-1 infection: recommen- Diabetes mellitus and risk of dementia: a meta- tes mellitus after acute pancreatitis: a system- dations of an International AIDS Society-USA analysis of prospective observational studies. J Di- atic review and meta-analysis. Gut 2014;63: panel. J Acquir Immune Defic Syndr 2002;31: abetes Investig 2013;4:640–650 818–831 257–275. care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S37

64. Kim PS, Woods C, Georgoff P, et al. A1C un- and meta-analysis. J Psychosom Res 2013;74: 92. Anderson RJ, Freedland KE, Clouse RE, derestimates glycemia in HIV infection. Diabetes 89–99 Lustman PJ. The prevalence of comorbid depression Care 2009;32:1591–1593 79. Li C, Barker L, Ford ES, Zhang X, Strine TW, in adults with diabetes: a meta-analysis. Diabetes 65. Wohl DA, McComsey G, Tebas P, et al. Cur- Mokdad AH. Diabetes and anxiety in US adults: Care 2001;24:1069–1078 rent concepts in the diagnosis and management findings from the 2006 Behavioral Risk Factor 93. Clouse RE, Lustman PJ, Freedland KE, Griffith of metabolic complications of HIV infection and its Surveillance System. Diabet Med 2008;25:878– LS, McGill JB, Carney RM. Depression and coro- therapy. Clin Infect Dis 2006;43:645–653 881 nary heart disease in women with diabetes. Psy- 66. Dhindsa S, Miller MG, McWhirter CL, et al. Tes- 80. Cox DJ, Irvine A, Gonder-Frederick L, chosom Med 2003;65:376–383 tosterone concentrations in diabetic and nondiabetic Nowacek G, Butterfield J. Fear of hypoglycemia: 94. Katon WJ, Lin EHB, Von Korff M, et al. Collab- obese men. Diabetes Care 2010;33:1186–1192 quantification, validation, and utilization. Diabe- orative care for patients with depression and chronic 67. Grossmann M. Low testosterone in men with tes Care 1987;10:617–621 illnesses. N Engl J Med 2010;363:2611–2620 type 2 diabetes: significance and treatment. J Clin 81. Wild D, von Maltzahn R, Brohan E, Christensen T, 95. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. Endocrinol Metab 2011;96:2341–2353 Clauson P, Gonder-Frederick L. A critical review of Eating disorders in adolescents with type 1 diabe- 68. Bhasin S, Cunningham GR, Hayes FJ, et al.; the literature on fear of hypoglycemia in diabetes: tes: challenges in diagnosis and treatment. World Task Force, Endocrine Society. Testosterone ther- implications for diabetes management and patient J Diabetes 2015;6:517–526 apy in men with androgen deficiency syndromes: education. Patient Educ Couns 2007;68:10–15 96. Papelbaum M, Appolinario´ JC, Moreira Rde an Endocrine Society clinical practice guideline. 82. Zambanini A, Newson RB, Maisey M, Feher O, Ellinger VCM, Kupfer R, Coutinho WF. Preva- J Clin Endocrinol Metab 2010;95:2536–2559 MD. Injection related anxiety in insulin-treated lence of eating disorders and psychiatric comorbid- 69. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, diabetes. Diabetes Res Clin Pract 1999;46:239– ity in a clinical sample of type 2 diabetes mellitus Mokdad AH. Prevalence of self-reported clinically 246 patients. Rev Bras Psiquiatr 2005;27:135–138 diagnosed sleep apnea according to obesity status 83. Young-HymanD,PeyrotM.Psychosocial Care 97. Young-Hyman DL, Davis CL. Disordered eating in men and women: National Health and Nutrition forPeoplewithDiabetes. Alexandria, VA, Ameri- behavior in individuals with diabetes: importance Examination Survey, 2005–2006. Prev Med 2010; can Diabetes Association, 2012 of context, evaluation, and classification. Diabetes 51:18–23 84. American Psychiatric Association. Diagnostic Care 2010;33:683–689 70. West SD, Nicoll DJ, Stradling JR. Prevalence of and Statistical Manual of Mental Disorders [In- 98. Pinhas-Hamiel O, Hamiel U, Greenfield Y, obstructive sleep apnoea in men with type 2 di- ternet], 2013. 5th ed. Available from http:// et al. Detecting intentional insulin omission for abetes. Thorax 2006;61:945–950 psychiatryonline.org/doi/book/10.1176/appi weight loss in girls with type 1 diabetes mellitus. 71. Resnick HE, Redline S, Shahar E, et al.; Sleep .books.9780890425596. Accessed 29 September Int J Eat Disord 2013;46:819–825 Heart Health Study. Diabetes and sleep distur- 2016 99. Goebel-Fabbri AE, Fikkan J, Franko DL, bances: findings from the Sleep Heart Health 85. Mitsonis C, Dimopoulos N, Psarra V. P01-138 Pearson K, Anderson BJ, Weinger K. Insulin restric- Study. Diabetes Care 2003;26:702–709 Clinical implications of anxiety in diabetes: a crit- tion and associated morbidity and mortality in 72. Foster GD, Sanders MH, Millman R, et al.; ical review of the evidence base. Eur Psychiatry womenwithtype1diabetes.DiabetesCare Sleep AHEAD Research Group. Obstructive sleep 2009;24(Suppl. 1):S526 2008;31:415–419 apnea among obese patients with type 2 diabe- 86. Yeoh E, Choudhary P, Nwokolo M, Ayis S, 100. Weinger K, Beverly EA. Barriers to achieving tes. Diabetes Care 2009;32:1017–1019 Amiel SA. Interventions that restore awareness glycemic targets: who omits insulin and why? Di- 73. Shaw JE, Punjabi NM, Wilding JP, Alberti of hypoglycemia in adults with type 1 diabetes: abetes Care 2010;33:450–452 KGMM, Zimmet PZ; International Diabetes Feder- a systematic review and meta-analysis. Diabetes 101. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. ation Taskforce on Epidemiology and Prevention. Care 2015;38:1592–1609 The prevalence and correlates of eating disorders Sleep-disordered breathing and type 2 diabetes: a 87. Cox DJ, Gonder-Frederick L, Polonsky W, in the National Comorbidity Survey Replication. report from the International Diabetes Federation Schlundt D, Kovatchev B, Clarke W. Blood glucose Biol Psychiatry 2007;61:348–358 Taskforce on Epidemiology and Prevention. Dia- awareness training (BGAT-2): long-term benefits. 102. Martyn-Nemeth P, Quinn L, Hacker E, Park betes Res Clin Pract 2008;81:2–12 Diabetes Care 2001;24:637–642 H, Kujath AS. Diabetes distress may adversely af- 74. Khader YS, Dauod AS, El-Qaderi SS, Alkafajei 88. Gonder-Frederick LA, Schmidt KM, Vajda KA, fect the eating styles of women with type 1 di- A, Batayha WQ. Periodontal status of diabetics et al. Psychometric properties of the Hypoglyce- abetes. Acta Diabetol 2014;51:683–686 compared with nondiabetics: a meta-analysis. mia Fear Survey-II for adults with type 1 diabetes. 103. Peterson CM, Fischer S, Young-Hyman D. J Diabetes Complications 2006;20:59–68 Diabetes Care 2011;34:801–806 Topical review: a comprehensive risk model for 75. Casanova L, Hughes FJ, Preshaw PM. Diabetes 89. Lustman PJ, Griffith LS, Clouse RE. Depression disordered eating in youth with type 1 diabetes. and periodontal disease: a two-way relationship. in adults with diabetes. Results of 5-yr follow-up J Pediatr Psychol 2015;40:385–390 Br Dent J 2014;217:433–437 study. Diabetes Care 1988;11:605–612 104. Garber AJ. Novel GLP-1 receptor agonists for 76. de Groot M, Golden SH, Wagner J. Psycholog- 90. de Groot M, Crick KA, Long M, Saha C, diabetes. Expert Opin Investig Drugs 2012;21:45–57 ical conditions in adults with diabetes. Am Psychol Shubrook JH. Lifetime duration of depressive dis- 105. Suvisaari J, Peral¨ a¨ J, Saarni SI, et al. Type 2 2016;71:552–562 orders in patients with type 2 diabetes. Diabetes diabetes among persons with schizophrenia and other 77. Young-Hyman D, de Groot M, Hill-Briggs F, Care 2016;39:2174–2181 psychotic disorders in a general population survey. Eur Gonzalez JS, Hood K, Peyrot M. Psychosocial 91. Rubin RR, Ma Y, Marrero DG, et al.; Diabetes Arch Psychiatry Clin Neurosci 2008;258:129–136 care for people with diabetes: a position state- Prevention Program Research Group. Elevated 106. Koro CE, Fedder DO, L’Italien GJ, et al. As- ment of the American Diabetes Association. Di- depression symptoms, antidepressant medicine sessment of independent effect of olanzapine and abetes Care 2016;39:2126–2140 use, and risk of developing diabetes during the risperidone on risk of diabetes among patients 78. Smith KJ, Beland´ M, Clyde M, et al. Associa- Diabetes Prevention Program. Diabetes Care with schizophrenia: population based nested tion of diabetes with anxiety: a systematic review 2008;31:420–426 case-control study. BMJ 2002;325:243 Diabetes Care Volume 41, Supplement 1, January 2018 S51

5. Prevention or Delay of Type 2 American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S51–S54 | https://doi.org/10.2337/dc18-S005 .PEETO RDLYO YE2DIABETES 2 TYPE OF DELAY OR PREVENTION 5.

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, and mobile applications that incorporate bidirectional communication 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 risk through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes Association risk test (Fig. 2.1), is recommended to guide providers on Suggested citation: American Diabetes Association. whether performing a diagnostic test for prediabetes (Table 2.4) and previ- 5. Prevention or delay of type 2 diabetes: Standards ously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section of Medical Care in Diabetesd2018.DiabetesCare 2 “Classification and Diagnosis of Diabetes”). Those determined to be at high risk 2018;41(Suppl. 1):S51–S54 for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), im- © 2017 by the American Diabetes Association. paired glucose tolerance, or impaired fasting glucose, are ideal candidates for Readers may use this article as long as the work is properly cited, the use is educational and not diabetes prevention efforts. Using A1C to screen for prediabetes may be problem- for profit, and the work is not altered. More infor- atic in the presence of certain hemoglobinopathies or conditions that affect red mation is available at http://www.diabetesjournals blood cell turnover. See Section 2 “Classification and Diagnosis of Diabetes” and .org/content/license. S52 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Section 6 “Glycemic Targets” for addi- encouraged to distribute their activity showed beneficial effects in those with pre- tional details on the appropriate use of throughout the week with a minimum fre- diabetes (1), moderate-intensity physical the A1C test. quency of three times per week with at least activity has been shown to improve insu- At least annual monitoring for the de- 10 min per session. A maximum of 75 min of lin sensitivity and reduce abdominal fat in velopment of diabetes in those with pre- strength training could be applied toward the children and young adults (18,19). On the diabetes is suggested. total 150 min/week physical activity goal (6). basis of these findings, providers are en- To implement the weight loss and couraged to promote a DPP-style pro- physical activity goals, the DPP used an in- gram, including its focus on physical LIFESTYLE INTERVENTIONS dividual model of treatment rather than a activity, to all individuals who have been The Diabetes Prevention Program group-based approach. This choice was identified to be at an increased risk of The strongest evidence for diabetes preven- based on a desire to intervene before par- type 2 diabetes. In addition to aerobic tion comes from the Diabetes Prevention ticipants had the possibility of developing activity, an exercise regimen designed to Program (DPP) (1). The DPP demonstrated diabetes or losing interest in the program. prevent diabetes may include resistance that an intensive lifestyle intervention The individual approach also allowed for training (6,20). Breaking up prolonged could reduce the incidence of type 2 di- tailoring of interventions to reflect the di- sedentary time may also be encouraged, abetes by 58% over 3 years. Follow-up of versity of the population (6). as it is associated with moderately lower three large studies of lifestyle interven- The DPP intervention was administered postprandial glucose levels (21,22). The tion for diabetes prevention has shown as a structured core curriculum followed preventative effects of exercise appear sustained reduction in the rate of conver- by a more flexible maintenance program to extend to the prevention of gestational sion to type 2 diabetes: 43% reduction at of individual sessions, group classes, moti- diabetes mellitus (GDM) (23). 20 years in the Da Qing study (2), 43% vational campaigns, and restart opportuni- Technology Assistance to Deliver reduction at 7 years in the Finnish Diabetes ties. The 16-session core curriculum was Lifestyle Interventions Prevention Study (DPS) (3), and 34% reduc- completed within the first 24 weeks of Information technology platforms may tion at 10 years (4) and 27% reduction at the program and included sections on low- effectively deliver the core components of 15 years (5) in the U.S. Diabetes Preven- ering calories, increasing physical activity, the DPP (24–26), lowering weight, reduction Program Outcomes Study (DPPOS). self-monitoring, maintaining healthy life- ing risk for diabetes and cardiovascular The two major goals of the DPP inten- style behaviors, and psychological, social, disease, and achieving cost savings sive, behavioral, lifestyle intervention and motivational challenges. For further de- (27,28). Recent studies support content were to achieve and maintain a minimum tails on the core curriculum sessions, refer delivery through virtual small groups of 7% weight loss and 150 min of physical to ref. 6. (29), Internet-driven social networks activity per week similar in intensity to Nutrition (30,31), cell phones, and other mobile de- brisk walking. The DPP lifestyle interven- Reducing caloric intake is of paramount im- vices. Mobile applications for weight loss tion was a goal-based intervention: all portance for those at high risk for develop- and diabetes prevention have been vali- participants were given the same weight ing type 2 diabetes, though recent evidence dated for their ability to reduce A1C in loss and physical activity goals, but indi- suggests that the quality of fats consumed the setting of prediabetes (31). The Cen- vidualization was permitted in the specific in the diet is more important than the total ters for Disease Control and Prevention methods used to achieve the goals (6). quantity of dietary fat (7–9). For example, (CDC) Diabetes Prevention Recognition The 7% weight loss goal was selected be- the Mediterranean diet, which is relative- Program (DPRP) (http://www.cdc.gov/ cause it was feasible to achieve and maintain ly high in monounsaturated fats, may diabetes/prevention/recognition/index and likely to lessen the risk of developing help to prevent type 2 diabetes (10–12). .htm) has begun to certify electronic and diabetes. Participants were encouraged to Whereas overall healthy low-calorie mobile health-based modalities as effec- achieve the 7% weight loss during the first eating patterns should be encouraged, tive vehicles for DPP-based interventions 6 months of the intervention. The recom- there is also some evidence that particu- that may be considered alongside more mended pace of weight loss was 1–2 lar dietary components impact diabetes traditional face-to-face and coach-driven lb/week. Calorie goals were calculated by risk. Higher intakes of nuts (13), berries programs. A recent study showed that an estimating the daily calories needed to (14),yogurt(15), coffee,andtea(16) are as- all-mobile approach to administering DPP maintain the participant’s initial weight sociated with reduced diabetes risk. Con- content can be effective as a prevention and subtracting 500–1,000 calories/day versely, red meats and sugar-sweetened tool, at least over the short term, in over- (depending on initial body weight). The beverages are associated with an in- weight and obese individuals at high risk initial focus was on reducing total dietary creased risk of type 2 diabetes (8). for diabetes (32). fat. After several weeks, the concept of As is the case for those with diabetes, calorie balance and the need to restrict Cost-effectiveness individualized medical nutrition therapy calories as well as fat was introduced (6). A cost-effectiveness model suggested (see Section 4 “Lifestyle Management” The goal for physical activity was selected that the lifestyle intervention used in for more detailed information) is effective to approximate at least 700 kcal/week the DPP was cost-effective (33). Actual in lowering A1C in individuals diagnosed expenditure from physical activity. For cost data from the DPP and DPPOS con- with prediabetes (17). ease of translation, this goal was described firmed this (34). Group delivery of DPP as at least 150 min of moderate-intensity Physical Activity content in community or primary care physical activity per week similar in inten- Just as 150 min/week of moderate-intensity settings has the potential to reduce over- sity to brisk walking. Participants were physical activity, such as brisk walking, all program costs while still producing care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S53

weight loss and diabetes risk reduction Metformin was overall less effective to people with prediabetes. Currently, (35–37). The use of community health than lifestyle modification in the DPP there are significant barriers to the pro- workers to support DPP efforts has been and DPPOS, though group differences de- vision of education and support to those shown to be effective with cost savings clined over time (5) and metformin may with prediabetes. However, the strate- (38) (see Section 1 “Improving Care and be cost-saving over a 10-year period (34). gies for supporting successful behavior Promoting Health in Populations” for more It was as effective as lifestyle modification change and the healthy behaviors recom- information). The CDC helps to coordi- in participants with BMI $35 kg/m2 but mended for people with prediabetes are nate the National Diabetes Prevention not significantly better than placebo in comparable to those for diabetes. Al- Program (National DPP), a resource de- those over 60 years of age (1). In the though reimbursement remains a barrier, signed to bring evidence-based lifestyle DPP, for women with history of GDM, studies show that providers of diabetes change programs for preventing type 2 metformin and intensive lifestyle mod- self-management education and support diabetes to communities (http://www ification led to an equivalent 50% reduc- are particularly well equipped to assist .cdc.gov/diabetes/prevention/index.htm). tion in diabetes risk (46), and both people with prediabetes in developing Early results from the CDC’sNationalDPP interventions remained highly effective and maintaining behaviors that can pre- during the first 4 years of implementation during a 10-year follow-up period (47). vent or delay the development of diabe- are promising (39). On 7 July 2016, the Metformin should be recommended as tes (17,50). Centers for Medicare and Medicaid Ser- an option for high-risk individuals (e.g., vices (CMS) proposed expanded Medi- those with a history of GDM or those References care reimbursement coverage for DPP with BMI $35). Consider monitoring 1. Knowler WC, Barrett-Connor E, Fowler SE, programs in an effort to expand preventive B12 levels in those taking metformin et al.; Diabetes Prevention Program Research services using a cost-effective model with chronically to check for possible defi- Group. Reduction in the incidence of type 2 di- proposed implementation in 2018 (https:// ciency (see Section 8 “Pharmacologic abetes with lifestyle intervention or metformin. innovation.cms.gov/initiatives/medicare- Approaches to Glycemic Treatment” for N Engl J Med 2002;346:393–403 diabetes-prevention-program/). more details). 2. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention PREVENTION OF PHARMACOLOGIC INTERVENTIONS Study: a 20-year follow-up study. Lancet 2008; CARDIOVASCULAR DISEASE 371:1783–1789 Recommendations 3. Lindstrom¨ J, Ilanne-Parikka P, Peltonen M, Recommendation et al.; Finnish Diabetes Prevention Study Group. c Metformin therapy for prevention c Screening for and treatment of Sustained reduction in the incidence of type 2 di- of type 2 diabetes should be consid- modifiable risk factors for cardio- abetes by lifestyle intervention: follow-up of the ered in those with prediabetes, espe- vascular disease is suggested for Finnish Diabetes Prevention Study. Lancet 2006; cially for those with BMI $35 kg/m2, 368:1673–1679 those with prediabetes. B those aged ,60 years, and women 4. Knowler WC, Fowler SE, Hamman RF, et al.; Diabetes Prevention Program Research Group. with prior gestational diabetes People with prediabetes often have other 10-year follow-up of diabetes incidence and A mellitus. cardiovascular risk factors, including hyper- weight loss in the Diabetes Prevention Program c – Long-term use of metformin may be tension and dyslipidemia, and are at in- Outcomes Study. Lancet 2009;374:1677 1686 5. Nathan DM, Barrett-Connor E, Crandall JP, associated with biochemical vitamin creased risk for cardiovascular disease B12 deficiency, and periodic mea- et al. Long-term effects of lifestyle intervention (48). Although treatment goals for people or metformin on diabetes development and mi- surement of vitamin B12 levels should with prediabetes are the same as for the crovascular complications: the DPP Outcomes be considered in metformin-treated general population (49), increased vigi- Study. Lancet Diabetes Endocrinol 2015;3:866– patients, especially in those with ane- lance is warranted to identify and treat 875 mia or peripheral neuropathy. B 6. Diabetes Prevention Program (DPP) Research these and other cardiovascular risk fac- Group. The Diabetes Prevention Program (DPP): tors (e.g., smoking). description of lifestyle intervention. Diabetes Care Pharmacologic agents including metfor- 2002;25:2165–2171 min, a-glucosidase inhibitors, orlistat, DIABETES SELF-MANAGEMENT 7. Jacobs S, Harmon BE, Boushey CJ, et al. A priori- glucagon-like peptide 1 (GLP-1) receptor defined diet quality indexes and risk of type 2 di- EDUCATION AND SUPPORT agonists, and thiazolidinediones have abetes: the Multiethnic Cohort. Diabetologia 2015;58:98–112 each been shown to decrease incident di- Recommendation 8. Ley SH, Hamdy O, Mohan V, Hu FB. Prevention abetes to various degrees in those with c Diabetes self-management educa- and management of type 2 diabetes: dietary com- prediabetes in research studies (1,40–45), tion and support programs may be ponents and nutritional strategies. Lancet 2014; though none are approved by the U.S. appropriate venues for people with 383:1999–2007 Food and Drug Administration specifically prediabetes to receive education 9. Chiuve SE, Fung TT, Rimm EB, et al. Alternative for diabetes prevention. One has to bal- dietary indices both strongly predict risk of and support to develop and maintain chronic disease. J Nutr 2012;142:1009–1018 ance the risk/benefitofeachmedication. behaviors that can prevent or delay 10. Salas-SalvadoJ,Bull´ o´ M, Babio N, et al.; Metformin has the strongest evidence the development of type 2 diabetes. B PREDIMED Study Investigators. Reduction in the base and demonstrated long-term safety incidence of type 2 diabetes with the Mediterra- as pharmacologic therapy for diabetes As for thosewithestablisheddiabetes,the nean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care prevention (45). For other drugs, cost, standards for diabetes self-management 2011;34:14–19 side effects, and durable efficacy require education and support (see Section 4 11. Salas-Salvado´ J, Guasch-FerreM,LeeCH,´ consideration. “Lifestyle Management”) can also apply Estruch R, Clish CB, Ros E. Protective effects of S54 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

the Mediterranean diet on type 2 diabetes and 26. Oldenburg B, Taylor CB, O’Neil A, Cocker F, 39. Ely EK, Gruss SM, Luman ET, et al. A national metabolic syndrome. J Nutr 2016;146:920S–927S Cameron LD. Using new technologies to improve effort to prevent type 2 diabetes: participant-level 12. Bloomfield HE, Koeller E, Greer N, MacDonald the prevention and management of chronic con- evaluation of CDC’s National Diabetes Prevention R, Kane R, Wilt TJ. Effects on health outcomes of a ditions in populations. Annu Rev Public Health Program. Diabetes Care 2017;40:1331–1341 Mediterranean diet with no restriction on fat in- 2015;36:483–505 40. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, take: a systematic review and meta-analysis. Ann 27. Bian RR, Piatt GA, Sen A, et al. The effect of Karasik A, Laakso M; STOP-NIDDM Trial Research Intern Med 2016;165:491–500 technology-mediated diabetes prevention inter- Group. Acarbose for prevention of type 2 diabetes 13. Afshin A, Micha R, Khatibzadeh S, Mozaffarian ventions on weight: a meta-analysis. J Med Inter- mellitus: the STOP-NIDDM randomised trial. Lan- D. Consumption of nuts and legumes and risk of net Res 2017;19:e76 cet 2002;359:2072–2077 incident ischemic heart disease, stroke, and diabe- 28. Chen F, Su W, Becker SH, et al. Clinical and 41. Torgerson JS, Hauptman J, Boldrin MN, tes: a systematic review and meta-analysis. Am J Clin economic impact of a digital, remotely-delivered Sjostr¨ om¨ L. XENical in the prevention of diabetes Nutr 2014;100:278–288 intensive behavioral counseling program on in obese subjects (XENDOS) study: a randomized 14. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi Medicare beneficiaries at risk for diabetes and study of orlistat as an adjunct to lifestyle changes T, Voutilainen S. Intake of fruit, berries, and veg- cardiovascular disease. PLoS One 2016;11: for the prevention of type 2 diabetes in obese etables and risk of type 2 diabetes in Finnish men: e0163627 patients. Diabetes Care 2004;27:155–161 the Kuopio Ischaemic Heart Disease Risk Factor 29. Azar KMJ, Aurora M, Wang EJ, Muzaffar A, 42. le Roux CW, Astrup A, Fujioka K, et al.; SCALE Study. Am J Clin Nutr 2014;99:328–333 Pressman A, Palaniappan LP. Virtual small groups Obesity Prediabetes NN8022-1839 Study Group. 3 15. Chen M, Sun Q, Giovannucci E, et al. Dairy for weight management: an innovative delivery years of liraglutide versus placebo for type 2 di- consumption and risk of type 2 diabetes: 3 cohorts mechanism for evidence-based lifestyle interven- abetes risk reduction and weight management in of US adults and an updated meta-analysis. BMC tions among obese men. Transl Behav Med 2015; individuals with prediabetes: a randomised, double- Med 2014;12:215 5:37–44 blind trial. Lancet 2017;389:1399–1409 16. Mozaffarian D. Dietary and policy priorities 30. Sepah SC, Jiang L, Peters AL. Translating the 43. Gerstein HC, Yusuf S, Bosch J, et al.; DREAM for cardiovascular disease, diabetes, and obesity: Diabetes Prevention Program into an online social (Diabetes REduction Assessment with ramipril a comprehensive review. Circulation 2016;133: network: validation against CDC standards. Diabe- and rosiglitazone Medication) Trial Investigators. 187–225 tes Educ 2014;40:435–443 Effect of rosiglitazone on the frequency of diabe- 17. Parker AR, Byham-Gray L, Denmark R, Winkle 31. Sepah SC, Jiang L, Peters AL. Long-term out- tes in patients with impaired glucose tolerance or PJ. The effect of medical nutrition therapy by a comes of a Web-based diabetes prevention pro- impaired fasting glucose: a randomised controlled registered dietitian nutritionist in patients with gram: 2-year results of a single-arm longitudinal trial. Lancet 2006;368:1096–1105 prediabetes participating in a randomized con- study. J Med Internet Res 2015;17:e92 44. DeFronzo RA, Tripathy D, Schwenke DC, et al.; trolled clinical research trial. J Acad Nutr Diet 32. Michaelides A, Raby C, Wood M, Farr K, Toro- ACT NOW Study. Pioglitazone for diabetes pre- 2014;114:1739–1748 RamosT.Weightlossefficacy of a novel mobile vention in impaired glucose tolerance. N Engl J 18. Fedewa MV, Gist NH, Evans EM, Dishman RK. Diabetes Prevention Program delivery platform Med 2011;364:1104–1115 Exercise and insulin resistance in youth: a meta- with human coaching. BMJ Open Diabetes Res 45. Diabetes Prevention Program Research analysis. Pediatrics 2014;133:e163–e174 Care 2016;4:e000264 Group. Long-term safety, tolerability, and weight 19. Davis CL, Pollock NK, Waller JL, et al. Exercise 33. Herman WH, Hoerger TJ, Brandle M, et al.; loss associated with metformin in the Diabetes dose and diabetes risk in overweight and obese Diabetes Prevention Program Research Group. Prevention Program Outcomes Study. Diabetes children: a randomized controlled trial. JAMA The cost-effectiveness of lifestyle modification Care 2012;35:731–737 2012;308:1103–1112 or metformin in preventing type 2 diabetes in 46. Ratner RE, Christophi CA, Metzger BE, et al.; 20. Sigal RJ, Alberga AS, Goldfield GS, et al. Effects adults with impaired glucose tolerance. Ann In- Diabetes Prevention Program Research Group. of aerobic training, resistance training, or both on tern Med 2005;142:323–332 Prevention of diabetes in women with a history percentage body fat and cardiometabolic risk 34. Diabetes Prevention Program Research of gestational diabetes: effects of metformin and markers in obese adolescents: the healthy eating Group. The 10-year cost-effectiveness of lifestyle lifestyle interventions. J Clin Endocrinol Metab aerobic and resistance training in youth random- intervention or metformin for diabetes preven- 2008;93:4774–4779 ized clinical trial. JAMA Pediatr 2014;168:1006– tion: an intent-to-treat analysis of the DPP/ 47. Aroda VR, Christophi CA, Edelstein SL, et al.; 1014 DPPOS. Diabetes Care 2012;35:723–730 Diabetes Prevention Program Research Group. 21. Thorp AA, Kingwell BA, Sethi P, Hammond L, 35. Ackermann RT, Finch EA, Brizendine E, Zhou The effect of lifestyle intervention and metformin Owen N, Dunstan DW. Alternating bouts of sitting H, Marrero DG. Translating the Diabetes Preven- on preventing or delaying diabetes among and standing attenuate postprandial glucose re- tion Program into the community. The DEPLOY women with and without gestational diabetes: sponses. Med Sci Sports Exerc 2014;46:2053– Pilot Study. Am J Prev Med 2008;35:357–363 the Diabetes Prevention Program Outcomes 2061 36. Balk EM, Earley A, Raman G, Avendano EA, Study 10-year follow-up. J Clin Endocrinol Metab 22. Healy GN, Dunstan DW, Salmon J, et al. Pittas AG, Remington PL. Combined diet and phys- 2015;100:1646–1653 Breaks in sedentary time: beneficial associations ical activity promotion programs to prevent type 2 48. Ford ES, Zhao G, Li C. Pre-diabetes and the with metabolic risk. Diabetes Care 2008;31:661– diabetes among persons at increased risk: a system- risk for cardiovascular disease: a systematic re- 666 atic review for the Community Preventive Services view of the evidence. J Am Coll Cardiol 2010;55: 23. Russo LM, Nobles C, Ertel KA, Chasan-Taber L, Task Force. Ann Intern Med 2015;163:437–451 1310–1317 Whitcomb BW. Physical activity interventions in 37. Li R, Qu S, Zhang P, et al. Economic evaluation 49. Bress AP, King JB, Kreider KE, et al.; SPRINT pregnancy and risk of gestational diabetes melli- of combined diet and physical activity promotion Research Group. Effect of intensive versus stan- tus: a systematic review and meta-analysis. Ob- programs to prevent type 2 diabetes among per- dard blood pressure treatment according to base- stet Gynecol 2015;125:576–582 sons at increased risk: a systematic review for the line prediabetes status: a post hoc analysis of a 24. Levine DM, Savarimuthu S, Squires A, Community Preventive Services Task Force. Ann randomized trial. Diabetes Care 2017;40:1401– Nicholson J, Jay M. Technology-assisted weight Intern Med 2015;163:452–460 1408 loss interventions in primary care: a systematic 38. The Community Guide. Diabetes prevention: 50. Butcher MK, Vanderwood KK, Hall TO, review. J Gen Intern Med 2015;30:107–117 interventions engaging community health work- Gohdes D, Helgerson SD, Harwell TS. Capacity of 25. Allen JK, Stephens J, Patel A. Technology- ers [Internet], 2016. Available from https://www diabetes education programs to provide both di- assisted weight management interventions: sys- .thecommunityguide.org/findings/diabetes- abetes self-management education and to imple- tematic review of clinical trials. Telemed J E Health prevention-interventions-engaging-community- ment diabetes prevention services. J Public Health 2014;20:1103–1120 health-workers. Accessed 2 October 2017 Manag Pract 2011;17:242–247 Diabetes Care Volume 41, Supplement 1, January 2018 S55

6. Glycemic Targets: Standards of American Diabetes Association Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S55–S64 | https://doi.org/10.2337/dc18-S006

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide TARGETS GLYCEMIC 6. the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

ASSESSMENT OF GLYCEMIC CONTROL Patient self-monitoring of blood glucose(SMBG)andA1Careavailabletohealth care providers and patients to assess the effectiveness and safety of a 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. Data indicate similar A1C and safety with the use of CGM compared with SMBG (1).

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 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 Suggested citation: American Diabetes Associa- tion. 6. Glycemic targets: c When used properly, continuous glucose monitoring (CGM) in conjunction with Standards of Medical Care in Diabetesd2018. Diabetes Care 2018; intensive insulin regimens is a useful tool to lower A1C in adults with type 1 41(Suppl. 1):S55–S64 A diabetes who are not meeting glycemic targets. © 2017 by the American Diabetes Association. c CGM may be a useful tool in those with hypoglycemia unawareness and/or Readers may use this article as long as the work frequent hypoglycemic episodes. C is properly cited, the use is educational and not c Given the variable adherence to CGM, assess individual readiness for continuing for proﬁt, and the work is not altered. More infor- CGM use prior to prescribing. E mation is available at http://www.diabetesjournals .org/content/license. S56 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

should be advised against purchasing or most CGM devices include alarms for hypo- c When prescribing CGM, robust di- reselling preowned or secondhand test and hyperglycemic excursions. The inter- abetes education, training, and sup- strips, as these may give incorrect results. mittent or “flash” CGM device, very report are required for optimal CGM Only unopened vials of glucose test strips cently approved for adult use only (18), implementation and ongoing use. E should be used to ensure SMBG accuracy. differs from previous CGM devices. Spe- c People who have been successfully cifically, it does not have alarms, does not using CGM should have continued For Patients on Intensive Insulin Regimens require calibration with SMBG, and does access after they turn 65 years of Most patients using intensive insulin not communicate continuously (only on age. E regimens (multiple-dose insulin or insulin pump therapy) should perform SMBG demand). It is reported to have a lower cost than traditional systems. A study in Self-monitoring of Blood Glucose prior to meals and snacks, at bedtime, oc- adults with well-controlled type 1 diabe- Major clinical trials of insulin-treated pa- casionally postprandially, prior to exercise, tes found that flash CGM users spent less tients have included SMBG as part of when they suspect low blood glucose, af- time in hypoglycemia than those using multifactorial interventions to demon- ter treating low blood glucose until they SMBG (19). However, due to significant strate the benefit of intensive glycemic are normoglycemic, and prior to critical differences between flashCGMandother control on diabetes complications. SMBG tasks such as driving. For many patients, CGM devices, more discussion is needed is thus an integral component of effective this will require testing 6–10 (or more) on outcomes and regarding specificrec- therapy (2). SMBG allows patients to eval- times daily, although individual needs ommendations. uate their individual response to therapy may vary. A database study of almost For most CGM systems, confirmatory and assess whether glycemic targets are 27,000 children and adolescents with SMBG is required to make treatment de- being achieved. Integrating SMBG results type 1 diabetes showed that, after adjust- cisions, though a randomized controlled into diabetes management can be a ment for multiple confounders, increased trial of 226 adults suggested that an en- useful tool for guiding medical nutrition daily frequency of SMBG was significantly hanced CGM device could be used safely therapy and physical activity, preventing associated with lower A1C (–0.2% per ad- and effectively without regular confirma- hypoglycemia, and adjusting medications ditional test per day) and with fewer tory SMBG in patients with well-controlled (particularly prandial insulin doses). Among acute complications (8). type 1 diabetes at low risk of severe hy- patients with type 1 diabetes, there is a poglycemia (1). Two CGM devices are now correlation between greater SMBG fre- For Patients Using Basal Insulin and/or Oral approved by the U.S. Food and Drug Ad- quency and lower A1C (3). The patient’s Agents The evidence is insufficient regarding ministration (FDA) for making treatment specific needs and goals should dictate when to prescribe SMBG and how often decisions without SMBG confirmation SMBG frequency and timing. testing is needed for patients who do not use (18,20), including the flash CGM device. Optimization intensive insulin regimens, such as those Although performed with older gener- SMBG accuracy is dependent on the instru- with type 2 diabetes using oral agents ation CGM devices, a 26-week random- ment and user, so it is important to evalu- and/or basal insulin. For patients using ized trial of 322 patients with type 1 ate each patient’s monitoring technique, basal insulin, assessing fasting glucose diabetes showed that adults aged $25 years both initially and at regular intervals with SMBG to inform dose adjustments using intensive insulin therapy and CGM thereafter. Optimal use of SMBG requires to achieve blood glucose targets results experienced a 0.5% reduction in A1C proper review and interpretation of the in lower A1Cs (9,10). (from ;7.6% to 7.1% [;60 mmol/mol data, by both the patient and the pro- For individuals with type 2 diabetes on to 54 mmol/mol]) compared with those vider. Among patients who check their less intensive insulin therapy, more fre- using intensive insulin therapy with SMBG blood glucose at least once daily, many quent SMBG (e.g., fasting, before/after (21). The greatest predictor of A1C lower- report taking no action when results are meals) may be helpful, as increased fre- ing for all age-groups was frequency of high or low. In a yearlong study of insulin- quency is associated with meeting A1C sensor use, which was highest in those naive patients with suboptimal initial targets (11). aged $25 years and lower in younger glycemic control, a group trained in struc- Several randomized trials have called age-groups. Two clinical trials in adults tured SMBG (a paper tool was used at into question the clinical utility and cost- with type 1 diabetes not meeting A1C least quarterly to collect and interpret effectiveness of routine SMBG in noninsu- targets and using multiple daily injections 7-point SMBG profiles taken on 3 consec- lin-treated patients (12–15). Meta-analyses also found that the use of CGM compared utive days) reduced their A1C by 0.3 per- have suggested that SMBG can reduce A1C with usual care resulted in lower A1C levels centage points more than the control by 0.25–0.3% at 6 months (16,17), but the than SMBG over 24–26 weeks (22,23). group (4). Patients should be taught effect was attenuated at 12 months in Other small, short-term studies have how to use SMBG data to adjust food in- one analysis (16). A key consideration is demonstrated similar A1C reductions us- take, exercise, or pharmacologic therapy that performing SMBG alone does not ing CGM compared with SMBG in adults to achieve specific goals. The ongoing lower blood glucose levels. To be useful, with A1C levels $7% (53 mmol/mol) need for and frequency of SMBG should the information must be integrated into (24,25). be reevaluated at each routine visit to clinical and self-management plans. A registry study of 17,317 participants avoid overuse (5–7). SMBG is especially confirmed that more frequent CGM use is important for insulin-treated patients to Continuous Glucose Monitoring associated with lower A1C (26), whereas monitor for and prevent asymptomatic CGM measures interstitial glucose (which another study showed that children hypoglycemia and hyperglycemia. Patients correlates well with plasma glucose), and with .70% sensor use (i.e., $5daysper care.diabetesjournals.org Glycemic Targets S57

week) missed fewer school days (27). A1C TESTING when the A1C result does not correlate Small randomized controlled trials in with the patient’s SMBG levels. Options Recommendations adults and children with baseline A1C for monitoring include more frequent and/ c Perform the A1C test at least two ,7.0–7.5% (53–58 mmol/mol) have con- or different timing of SMBG or CGM use. times a year in patients who are firmed favorable outcomes including a Other measures of average glycemia such meeting treatment goals (and who reduced frequency of hypoglycemia (de- as fructosamine and 1,5-anhydroglucitol have stable glycemic control). E fined as a blood glucose level ,70 mg/dL are available, but their translation into c Perform the A1C test quarterly in [3.9 mmol/L]) and maintaining A1C ,7% average glucose levels and their prog- patients whose therapy has changed (53 mmol/mol) during the study period in nostic significance are not as clear as or who are not meeting glycemic groups using CGM, suggesting that CGM for A1C. Though some variability exists goals. E may provide further benefit for individu- among different individuals, generally c Point-of-care testing for A1C provides als with type 1 diabetes who already have the association between mean glucose the opportunity for more timely good glycemic control (28–30). and A1C within an individual correlates treatment changes. E A meta-analysis suggests that com- over time (42). pared with SMBG, CGM is associated A1C reflects average glycemia over A1C does not provide a measure of ; with short-term A1C lowering of 0.26% approximately 3 months and has strong glycemic variability or hypoglycemia. For in insulin-treated patients (31). The long- predictive value for diabetes complica- patients prone to glycemic variability, term effectiveness of CGM needs to be tions (39,40). Thus, A1C testing should especially patients with type 1 diabetes determined. This technology may be par- be performed routinely in all patients or type 2 diabetes with severe insulin defi ticularly useful in insulin-treated patients with diabetesdat initial assessment and ciency, glycemic control is best evalu- with hypoglycemia unawareness and/or as part of continuing care. Measurement ated by the combination of results from frequent hypoglycemic episodes, although approximately every 3 months deter- A1C and SMBG or CGM. A1C may also fi ’ studies have not shown consistent reduc- mines whether patients’ glycemic targets con rm the accuracy of the patient sme- – ’ tions in severe hypoglycemia (31 33). A have been reached and maintained. The ter (or the patient s reported SMBG re- CGM device equipped with an automatic frequency of A1C testing should depend sults) and the adequacy of the SMBG low glucose suspend feature has been on the clinical situation, the treatment testing schedule. approved by the FDA. The Automation regimen, and the clinician’sjudgment. A1C and Mean Glucose to Simulate Pancreatic Insulin Response The use of point-of-care A1C testing may Table 6.1 (ASPIRE) trial of 247 patients with type 1 provide an opportunity for more timely shows the correlation between diabetes and documented nocturnal hypo- treatment changes during encounters be- A1C levels and mean glucose levels based glycemia showed that sensor-augmented tween patients and providers. Patients on two studies: the international A1C- insulin pump therapy with a low glucose with type 2 diabetes with stable glycemia Derived Average Glucose (ADAG) study, fi suspend function signi cantly reduced well within target may do well with A1C which assessed the correlation between nocturnal hypoglycemia over 3 months testing only twice per year. Unstable or A1C and frequent SMBG and CGM in without increasing A1C levels (34). intensively managed patients (e.g., preg- 507 adults (83% non-Hispanic whites) These devices may offer the opportunity nant women with type 1 diabetes) may with type 1, type 2, and no diabetes (43), to reduce hypoglycemia for those with require testing more frequently than every and an empirical study of the average a history of nocturnal hypoglycemia. 3 months (41). blood glucose levels at premeal, post- The FDA has also approved the first meal, and bedtime associated with spec- hybrid closed-loop system. The safety of A1C Limitations ified A1C levels using data from the hybrid closed-loop systems has been sup- The A1C test is an indirect measure of ADAG trial (37). The American Diabetes ported in the literature (35) and may have average glycemia and, as such, is subject Association (ADA) and the American As- advantages over sensor-augmented to limitations. As with any laboratory test, sociation for Clinical Chemistry have de- pump therapy in specific populations, there is variability in the measurement of termined that the correlation (r 5 0.92) in such as pregnant women with type 1 A1C. Although such variability is less on an the ADAG trial is strong enough to justify diabetes (36). intraindividual basis than that of blood reporting both the A1C result and the es- Duetovariableadherence,optimal glucose measurements, clinicians should timated average glucose (eAG) result CGM use requires an assessment of indi- exercise judgment when using A1C as the when a clinician orders the A1C test. Clini- vidual readiness for the technology as sole basis for assessing glycemic control, cians should note that the mean plasma well as initial and ongoing education particularly if the result is close to the glucose numbers in the table are based on and support (26,37). Additionally, pro- threshold that might prompt a change in ;2,700 readings per A1C in the ADAG viders need to provide robust diabetes medication therapy. Conditions that affect trial. In a recent report, mean glucose education, training, and support for opti- red blood cell turnover (hemolytic and measured with CGM versus central labo- mal CGM implementation and ongoing other anemias, recent blood transfusion, ratory–measured A1C in 387 participants use. As people with type 1 or type 2 use of drugs that stimulate erythropo- in three randomized trials demonstrated diabetes are living longer, healthier lives, esis, end-stage kidney disease, and that A1C may underestimate or overesti- individuals who have been successfully pregnancy) may result in discrepancies mate mean glucose. Thus, as suggested, a using CGM should have continued access between the A1C result and the pa- patient’s CGM profile has considerable to these devices after they turn 65 years tient’s true mean glycemia. Hemoglobin potential for optimizing his or her glyce- of age (38). variants must be considered, particularly mic management (42). S58 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

A1C Differences in Ethnic Populations and Children In the ADAG study, there were no signif- 13.8) 8.9) 7.8) – 10.4) 10.4) – – – – icant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although the study was underpowered to detect a

glucose was 0.92 (43). difference and there was a trend toward 188)188) 9.8 (9.2 9.7 (9.0 161) 8.5 (8.0 248) 12.3 (10.9 141) 7.5 (7.3 – – – – – a difference between the African/African American and non-Hispanic white cohorts, with higher A1C values observed in Africans/African Americans compared with non-Hispanic whites for a given 10.9) 175 (163 12.0) 222 (197 mean glucose. Other studies have also 9.4) 153 (145 8.2) 136 (131 – – 10.2) 177 (166 – – – demonstrated higher A1C levels in African Americans than in whites at a given mean glucose concentration (44,45). Moreover, African Americans heterozygous for the e at http://professional.diabetes.org/eAG. *These estimates are common hemoglobin variant HbS may 183)197) 9.8 (9.4 10.5 (10.0 169) 9.1 (8.8 217) 11.4 (10.8 148) 8.0 (7.7 – – – – – have, for any level of mean glycemia, lower A1C by about 0.3 percentage points than those without the trait (46). Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, carried by 11% of 8.7)8.9) 176 (170 189 (180 8.0) 164 (159 6.7) 144 (139 10.6) 206 (195 – – – – African Americans, was associated with a – decrease in A1C of about 0.8% in hemizygous men and 0.7% in homozygous women compared to those without the trait (47). 157)161) 8.4 (8.2 8.6 (8.2 144) 7.7 (7.4 191) 9.9 (9.3 121) 6.5 (6.4 with type 1, type 2, and no diabetes. The correlation between A1C and average – – – – – A small study comparing A1C to CGM data in children with type 1 diabetes found a highly statistically signiﬁcant cor- lts into eAG, in either mg/dL or mmol/L, is availabl relation between A1C and mean blood glucose, although the correlation (r 5 0.7) was 9.0)9.8) 152 (147 155 (148 8.3) 139 (134 7.0) 118 (115 ﬁ

10.7) 179 (167 signi cantly lower than in the ADAG trial – – – – – (48). Whether there are clinically meaningful differences in how A1C relates to average glucose in children or in different ethnicities is an area for further study 162)177) 8.4 (7.9 9.3 (8.7 150) 7.9 (7.5 127) 6.8 (6.5 192) 9.9 (9.1 (44,49,50). Until further evidence is avail- – – – – – able, it seems prudent to establish A1C goals in these populations with consideration of both individualized SMBG and A1C results. 19.3) 17.5) 15.7) 13.9) 12.1) 8.5) – – – 10.3) – – – A1C GOALS rwise noted. A calculator for converting A1C resu – ed A1C levels (37,43) ﬁ For glycemic goals in children, please refer to Section 12 “Children and Adolescents.” For glycemic goals in pregnant women, please refer to Section 13 “Management 347) 16.5 (13.3 314) 14.9 (12.0 185) 8.6 (6.8 249)282) 11.8 (9.4 13.4 (10.7 217) 10.2 (8.1 152) 7.0 (5.5 ” – – – – – – – of Diabetes in Pregnancy.

2,700 glucose measurements over 3 months per A1C measurement in 507 adults Recommendations ; c A reasonable A1C goal for many nonpregnant adults is ,7% (53 mmol/mol). A 58)64) 152 (143 167 (157 53) 142 (135 47) 122 (117 Mean glucose levels for speci – – – – 69) 178 (164

– c

— Providers might reasonably suggest more stringent A1C goals (such 7.49 (53 7.99 (58 6.99 (47 6.49 (37 8.5 (64 as ,6.5% [48 mmol/mol]) for se- – – – – – Data in parentheses represent 95% CI, unless othe basedonADAGdataof 12 (108) 298 (240 11 (97) 269 (217 7 (53)7.0 7.5 154 (123 9 (75)10 (86) 212 (170 240 (193 6.5 5.5 8.0 Table 6.1 8 (64) 183 (147 A1C% (mmol/mol)6 (42) mg/dL Mean plasma glucose* 126 (100 mmol/L Mean mg/dL fasting glucose mmol/L Mean premeal glucose mg/dL Mean postmeal glucose mmol/Llected mg/dL Mean bedtime glucose individual mmol/L patients mg/dL if this mmol/L care.diabetesjournals.org Glycemic Targets S59

curvilinear relationship between A1C and death compared with those previously ran- can be achieved without significant microvascular complications. Such anal- domized to the standard arm (62). The hypoglycemia or other adverse ef- yses suggest that, on a population level, benefit of intensive glycemic control in fects of treatment (i.e., polyphar- the greatest number of complications will this cohort with type 1 diabetes has macy). Appropriate patients might beavertedbytakingpatientsfromvery been shown to persist for several decades include those with short duration of poor control to fair/good control. These (63) and to be associated with a modest diabetes, type 2 diabetes treated analyses also suggest that further lower- reduction in all-cause mortality (64). with lifestyle or metformin only, ing of A1C from 7% to 6% [53 mmol/mol long life expectancy, or no signifi- to 42 mmol/mol] is associated with fur- Cardiovascular Disease and Type 2 Diabetes cant cardiovascular disease. C In type 2 diabetes, there is evidence that ther reduction in the risk of microvascular c Less stringent A1C goals (such more intensive treatment of glycemia in complications, although the absolute risk as ,8% [64 mmol/mol]) may be ap- newly diagnosed patients may reduce reductions become much smaller. Given propriate for patients with a history long-term CVD rates. During the UKPDS, the substantially increased risk of hypo- of severe hypoglycemia, limited life there was a 16% reduction in CVD events glycemia in type 1 diabetes trials and expectancy, advanced microvascu- (combined fatal or nonfatal MI and sud- with polypharmacy in type 2 diabetes, lar or macrovascular complications, den death) in the intensive glycemic con- the risks of lower glycemic targets out- extensive comorbid conditions, or trol arm that did not reach statistical weigh the potential benefits on microvas- long-standing diabetes in whom significance (P 5 0.052), and there was cular complications. the goal is difficult to achieve de- no suggestion of benefit on other CVD spite diabetes self-management ACCORD, ADVANCE, and VADT outcomes (e.g., stroke). However, after education, appropriate glucose Three landmark trials (Action to Control 10 years of observational follow-up, those monitoring, and effective doses of Cardiovascular Risk in Diabetes [ACCORD], originally randomized to intensive glyce- multiple glucose-lowering agents Action in Diabetes and Vascular Disease: mic control had significant long-term re- including insulin. B Preterax and Diamicron MR Controlled ductions in MI (15% with sulfonylurea or Evaluation [ADVANCE], and Veterans Af- insulin as initial pharmacotherapy, 33% A1C and Microvascular Complications fairs Diabetes Trial [VADT]) showed that with metformin as initial pharmacother- Hyperglycemia defines diabetes, and gly- lower A1C levels were associated with re- apy) and in all-cause mortality (13% and cemic control is fundamental to diabetes duced onset or progression of some micro- 27%, respectively) (56). management. The Diabetes Control and vascular complications (58–60). ACCORD, ADVANCE, and VADT sug- Complications Trial (DCCT) (2), a prospec- The concerning mortality findings in gested no significant reduction in CVD tive randomized controlled trial of inten- the ACCORD trial (61), discussed below, outcomes with intensive glycemic control sive versus standard glycemic control in and the relatively intense efforts required in participants followed for 3.5–5.6 years patients with type 1 diabetes, showed de- to achieve near-euglycemia should also who had more advanced type 2 diabetes finitively that better glycemic control is be considered when setting glycemic tar- than UKPDS participants. All three trials associated with significantly decreased gets. However, on the basis of physician were conducted in relatively older partic- rates of development and progression of judgment and patient preferences, select ipants with longer known duration of di- microvascular (retinopathy [51], neurop- patients, especially those with little co- abetes (mean duration 8–11 years) and athy, and diabetic kidney disease) compli- morbidity and long life expectancy, may either CVD or multiple cardiovascular risk cations. Follow-up of the DCCT cohorts in benefit from adopting more intensive gly- factors. The target A1C among intensive the Epidemiology of Diabetes Interven- cemic targets (e.g., A1C target ,6.5% control subjects was ,6% (42 mmol/mol) tions and Complications (EDIC) study [48 mmol/mol]) as long as significant hy- in ACCORD, ,6.5% (48 mmol/mol) in (52) demonstrated persistence of these poglycemia does not become a barrier. ADVANCE, and a 1.5% reduction in A1C microvascular benefits despite the fact compared with control subjects in VADT, that the glycemic separation between A1C and Cardiovascular Disease with achieved A1C of 6.4% vs. 7.5% the treatment groups diminished and dis- Outcomes (46 mmol/mol vs. 58 mmol/mol) in ACCORD, appeared during follow-up. Cardiovascular Disease and Type 1 Diabetes 6.5% vs. 7.3% (48 mmol/mol vs. 56 The Kumamoto Study (53) and UK Pro- Cardiovascular disease (CVD) is a more mmol/mol) in ADVANCE, and 6.9% vs. spective Diabetes Study (UKPDS) (54,55) common cause of death than microvascular 8.4% (52 mmol/mol vs. 68 mmol/mol) in confirmed that intensive glycemic control complications in populations with diabetes. VADT. Details of these studies are re- significantly decreased rates of microvas- There is evidence for a cardiovascular ben- viewed extensively in “Intensive Glycemic cular complications in patients with type 2 efit of intensive glycemic control after long- Control and the Prevention of Cardiovas- diabetes. Long-term follow-up of the term follow-up of cohorts treated early in cular Events: Implications of the ACCORD, UKPDS cohorts showed enduring effects thecourseoftype1diabetes.IntheDCCT, ADVANCE, and VA Diabetes Trials” (65). of early glycemic control on most micro- there was a trend toward lower risk of CVD The glycemic control comparison in vascular complications (56). events with intensive control. In the 9-year ACCORD was halted early due to an in- Therefore, achieving A1C targets post-DCCT follow-up of the EDIC cohort, creased mortality rate in the intensive of ,7% (53 mmol/mol) has been shown participants previously randomized to the compared with the standard treatment to reduce microvascular complications of intensive arm had a significant 57% reduc- arm (1.41% vs. 1.14% per year; hazard ra- diabetes. Epidemiological analyses of the tion in the risk of nonfatal myocardial in- tio 1.22 [95% CI 1.01–1.46]), with a similar DCCT (2) and UKPDS (57) demonstrate a farction (MI), stroke, or cardiovascular increase in cardiovascular deaths. Analysis S60 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

Table 6.2—Summary of glycemic recommendations for many nonpregnant adults have been associated with increased car- with diabetes diovascular risk independent of fasting A1C <7.0% (53 mmol/mol)* plasma glucose in some epidemiological Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) studies, but intervention trials have not Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L) shown postprandial glucose to be a cardiovascular risk factor independent of A1C. In *More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD subjects with diabetes, surrogate measures or advanced microvascular complications, hypoglycemia unawareness, and individual patient of vascular pathology, such as endothelial considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching dysfunction, are negatively affected by post- preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes. prandial hyperglycemia. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated of the ACCORD data did not identify a proposes optimal targets, but each target A1C levels, with its relative contribution be- clear explanation for the excess mortality must be individualized to the needs of each ing greater at A1C levels that are closer to in the intensive treatment arm (61). patient and his or her disease factors. 7% (53 mmol/mol). However, outcome Longer-term follow-up has shown no ev- When possible, such decisions should be studies have clearly shown A1C to be the idence of cardiovascular benefitorharmin made with the patient, reflecting his or her primary predictor of complications, and the ADVANCE trial (66). The end-stage re- preferences, needs, and values. Fig. 6.1 landmark trials of glycemic control such as nal disease rate was lower in the intensive is not designed to be applied rigidly but the DCCT and UKPDS relied overwhelmingly treatment group over follow-up. However, to be used as a broad construct to guide on preprandial SMBG. Additionally, a ran- 10-year follow-up of the VADT cohort clinical decision-making (72), in both type 1 domized controlled trial in patients with (67) showed a reduction in the risk of car- and type 2 diabetes. known CVD found no CVD benefit of insulin diovascular events (52.7 [control group] Recommended glycemic targets for regimens targeting postprandial glucose vs. 44.1 [intervention group] events per many nonpregnant adults are shown in compared with those targeting preprandial 1,000 person-years) with no benefitin Table 6.2. The recommendations include glucose (74). Therefore, it is reasonable for cardiovascular or overall mortality. Hetero- blood glucose levels that appear to corre- postprandial testing to be recommended geneity of mortality effects across studies late with achievement of an A1C of ,7% for individuals who have premeal glucose was noted, which may reflect differences (53 mmol/mol). The issue of preprandial values within target but have A1C values in glycemic targets, therapeutic approaches, versus postprandial SMBG targets is com- above target. Measuring postprandial and population characteristics (68). plex (73). Elevated postchallenge (2-h oral plasma glucose 1–2 h after the start of a Mortality findings in ACCORD (61) and glucose tolerance test) glucose values meal and using treatments aimed at subgroup analyses of VADT (69) suggest that the potential risks of intensive glycemic control may outweigh its benefits in higher-risk patients. In all three trials, severe hypoglycemia was significantly more likely in participants who were randomly assigned to the intensive glycemic control arm. Those patients with long duration of diabetes, a known history of hypoglycemia, advanced atherosclerosis, or advanced age/frailty may benefit from less aggressive targets (70,71). Providers should be vigilant in preventing hypoglycemia and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals. Many factors, including patient preferences, should be taken into account when developing a patient’s individualized goals (Table 6.2).

A1C and Glycemic Targets Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets. Numerous aspects must be considered Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those when setting glycemic targets. The ADA toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (72). care.diabetesjournals.org Glycemic Targets S61

Table 6.3—Classification of hypoglycemia* Level Glycemic criteria Description Hypoglycemia 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 *Adapted from ref. 75. reducing postprandial plasma glucose val- Hypoglycemia may be inconvenient or c Hypoglycemia unawareness or one ues to ,180 mg/dL (10.0 mmol/L) may frightening to patients with diabetes. Se- or more episodes of severe hypo- help to lower A1C. vere hypoglycemia may be recognized or glycemia should trigger reevalua- An analysis of data from 470 participants unrecognized and can progress to loss of tion of the treatment regimen. E in the ADAG study (237 with type 1 diabe- consciousness, seizure, coma, or death. It is c Insulin-treated patients with hy- tes and 147 with type 2 diabetes) found reversed by administration of rapid-acting poglycemia unawareness or an that actual average glucose levels associ- glucose or glucagon. Clinically significant episode of clinically significant hy- ated with conventional A1C targets were hypoglycemia can cause acute harm to poglycemia should be advised to higher than older DCCT and ADA targets thepersonwithdiabetesorothers,espe- raise their glycemic targets to (Table 6.1) (37,39). These findings support cially if it causes falls, motor vehicle acci- strictly avoid hypoglycemia for at that premeal glucose targets may be relaxed dents, or other injury. A large cohort study least several weeks in order to par- without undermining overall glycemic con- suggested that among older adults with tially reverse hypoglycemia un- trol as measured by A1C. These data promp- type 2 diabetes, a history of severe hypo- awareness and reduce risk of future ted the revision in the ADA-recommended glycemia was associated with greater risk episodes. A premeal glucose target to 80–130 mg/dL of dementia (77). Conversely, in a sub- c Ongoing assessment of cognitive (4.4–7.2 mmol/L) but did not affect the study of the ACCORD trial, cognitive function is suggested with increased definition of hypoglycemia. impairment at baseline or decline in cog- vigilance for hypoglycemia by the nitive function during the trial was sig- clinician, patient, and caregivers if HYPOGLYCEMIA nificantly associated with subsequent low cognition or declining cognition episodes of severe hypoglycemia (78). Ev- Recommendations is found. B idence from DCCT/EDIC, which involved c Individuals at risk for hypoglycemia adolescents and younger adults with should be asked about symptom- Hypoglycemia is the major limiting factor type 1 diabetes, found no association be- atic and asymptomatic hypoglyce- in the glycemic management of type 1 tween frequency of severe hypoglycemia mia at each encounter. C and type 2 diabetes. Recommendations and cognitive decline (79), as discussed in c Glucose (15–20 g) is the preferred from the International Hypoglycemia Study Section 12 “Children and Adolescents.” treatment for the conscious individ- Group regarding the classification of hypo- Severe hypoglycemia was associated ual with blood glucose #70 mg/dL glycemia in clinical trials are outlined in Ta- with mortality in participants in both the [3.9 mmol/L]), although any form of ble 6.3 (75). Of note, this classification standard and the intensive glycemia arms carbohydrate that contains glucose scheme considers a blood glucose ,54 of the ACCORD trial, but the relationships may be used. Fifteen minutes after mg/dL (3.0 mmol/L) detected by SMBG, between hypoglycemia, achieved A1C, treatment, if SMBG shows contin- CGM (for at least 20 min), or laboratory and treatment intensitywerenotstraight- ued hypoglycemia, the treatment measurement of plasma glucose as suffi- forward. An association of severe hypo- should be repeated. Once SMBG ciently low to indicate clinically significant glycemia with mortality was also found returns to normal, the individual hypoglycemia that should be included in in the ADVANCE trial (80). An association should consume a meal or snack to reports of clinical trials of glucose-lowering between self-reported severe hypoglyce- prevent recurrence of hypoglycemia. E drugs for the treatment of diabetes (75). mia and 5-year mortality has also been c Glucagon should be prescribed for However, a hypoglycemia alert value reported in clinical practice (81). all individuals at increased risk of of #70 mg/dL (3.9 mmol/L) can be impor- Youngchildrenwithtype1diabetesand clinically significant hypoglycemia, tant for therapeutic dose adjustment of the elderly, including those with type 1 and defined as blood glucose ,54 mg/dL glucose-lowering drugs in clinical care and type 2 diabetes (77,82), are noted as par- (3.0 mmol/L), so it is available should is often related to symptomatic hypogly- ticularly vulnerable to clinically significant it be needed. Caregivers, school cemia. Severe hypoglycemia is defined as hypoglycemia because of their reduced personnel, or family members of severe cognitive impairment requiring as- ability to recognize hypoglycemic symp- these individuals should know sistance from another person for recov- toms and effectively communicate their where it is and when and how to ery (76). needs. Individualized glucose targets, pa- administer it. Glucagon administra- Symptoms of hypoglycemia include, tient education, dietary intervention (e.g., tion is not limited to health care but are not limited to, shakiness, irritabil- bedtime snack to prevent overnight hypo- professionals. E ity, confusion, tachycardia, and hunger. glycemia when specificallyneededtotreat S62 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

low blood glucose), exercise management, with hypoglycemia-prone diabetes (fam- prone patients also require urine or medication adjustment, glucose monitor- ily members, roommates, school person- blood ketone monitoring. If accompa- ing, and routine clinical surveillance may nel, child care providers, correctional nied by ketosis, vomiting, or alteration in improve patient outcomes (76). CGM with institution staff, or coworkers) should be the level of consciousness, marked hyper- automated low glucose suspend has been instructed on the use of glucagon kits in- glycemia requires temporary adjustment of showntobeeffectiveinreducinghypogly- cluding where the kit is and when and the treatment regimen and immediate in- cemia in type 1 diabetes (34). For patients how to administer glucagon. An individual teraction with the diabetes care team. The with type 1 diabetes with severe hypogly- does not need to be a health care pro- patient treated with noninsulin therapies or cemia and hypoglycemia unawareness fessional to safely administer glucagon. medical nutrition therapy alone may tem- that persists despite medical treatment, Care should be taken to ensure that glu- porarily require insulin. Adequate fluid and human islet transplantation may be an op- cagon kits are not expired. caloric intake must be ensured. Infection or tion, but the approach remains experimen- Hypoglycemia Prevention dehydration is more likely to necessitate tal (83,84). Hypoglycemia prevention is a critical com- hospitalization of the person with diabetes In 2015, the ADA changed its prepran- ponent of diabetes management. SMBG than the person without diabetes. – dial glycemic target from 70 130 mg/dL and, for some patients, CGM are essential A physician with expertise in diabetes – – – (3.9 7.2 mmol/L) to 80 130 mg/dL (4.4 tools to assess therapy and detect incipient management should treat the hospital- fl 7.2 mmol/L). This change re ects the results hypoglycemia. Patients should understand ized patient. For further information on of the ADAG study, which demonstrated situations that increase their risk of hypo- the management of diabetic ketoacidosis that higher glycemic targets corresponded glycemia, such as fasting for tests or pro- and the hyperglycemic nonketotic hyper- to A1C goals (37). An additional goal of cedures, delayed meals, during or after osmolar state, please refer to the ADA con- “ raising the lower range of the glycemic intense exercise, and during sleep. Hypo- sensus report Hyperglycemic Crises in ” target was to limit overtreatment and glycemia may increase the risk of harm to Adult Patients With Diabetes (87). provide a safety margin in patients titrat- self or others, such as with driving. Teach- ing glucose-lowering drugs such as insulin ing people with diabetes to balance insulin References to glycemic targets. use and carbohydrate intake and exercise 1. Aleppo G, Ruedy KJ, Riddlesworth TD, et al.; REPLACE-BG Study Group. REPLACE-BG: a ran- Hypoglycemia Treatment are necessary, but these strategies are not always sufficient for prevention. domized trial comparing continuous glucose mon- Providers should continue to counsel itoring with and without routine blood glucose patients to treat hypoglycemia with fast- In type 1 diabetes and severely insulin- monitoring in adults with well-controlled type 1 fi acting carbohydrates at the hypoglycemia de cient type 2 diabetes, hypoglycemia diabetes. Diabetes Care 2017;40:538–545 alert value of 70 mg/dL (3.9 mmol/L) or unawareness (or hypoglycemia-associated 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment less. Hypoglycemia treatment requires autonomic failure) can severely compromise stringent diabetes control and quality of diabetes on the development and progression of ingestion of glucose- or carbohydrate- long-term complications in insulin-dependent dia- containing foods. The acute glycemic re- of life. This syndrome is characterized by de- betes mellitus. N Engl J Med 1993;329:977–986 fi sponse correlates better with the glucose cient counterregulatory hormone release, 3. Miller KM, Beck RW, Bergenstal RM, et al.; T1D Exchange Clinic Network. Evidence of a strong content of food than with the carbohy- especially in older adults, and a diminished autonomic response, which both are risk fac- association between frequency of self-monitoring drate content of food. Pure glucose is of blood glucose and hemoglobin A1c levels in T1D the preferred treatment, but any form tors for, and caused by, hypoglycemia. A cor- Exchange clinic registry participants. Diabetes “ ” of carbohydrate that contains glucose ollary to this vicious cycle is that several Care 2013;36:2009–2014 will raise blood glucose. Added fat may weeks of avoidance of hypoglycemia has 4. Polonsky WH, Fisher L, Schikman CH, et al. Structured self-monitoring of blood glucose signif- retard and then prolong the acute glyce- been demonstrated to improve counterregulation and hypoglycemia awareness in many icantly reduces A1C levels in poorly controlled, mic response. In type 2 diabetes, ingested noninsulin-treated type 2 diabetes: results from protein may increase insulin response patients (86). Hence, patients with one or the Structured Testing Program study. Diabetes fi without increasing plasma glucose con- more episodes of clinically signi cant hy- Care 2011;34:262–267 fi centrations (85). Therefore, carbohydrate poglycemia may bene tfromatleast 5. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good short-term relaxation of glycemic targets. CB, Fine MJ. Dual use of Department of Veterans sources high in protein should not be Affairs and Medicare benefits and use of test used to treat or prevent hypoglycemia. INTERCURRENT ILLNESS strips in veterans with type 2 diabetes mellitus. Ongoing insulin activity or insulin secreta- For further information on management JAMA Intern Med 2015;175:26–34 gogues may lead to recurrent hypoglyce- of patients with hyperglycemia in the hos- 6. Grant RW, Huang ES, Wexler DJ, et al. Patients mia unless further food is ingested after who self-monitor blood glucose and their unused pital, please refer to Section 14 “Diabetes testing results. Am J Manag Care 2015;21:e119– recovery. Once the glucose returns to Care in the Hospital.” e129 normal, the individual should be coun- Stressful events (e.g., illness, trauma, sur- 7. Endocrine Society. Choosing wisely [Internet], seled to eat a meal or snack to prevent gery, etc.) may worsen glycemic control and 2013. Available from http://www.choosingwisely recurrent hypoglycemia. .org/societies/endocrine-society/. Accessed 18 Au- precipitate diabetic ketoacidosis or nonke- gust 2015 Glucagon totic hyperosmolar state, life-threatening 8. Ziegler R, Heidtmann B, Hilgard D, Hofer S, The use of glucagon is indicated for the conditions that require immediate medical Rosenbauer J, Holl R; DPV-Wiss-Initiative. Fre- treatment of hypoglycemia in people un- care to prevent complications and death. quency of SMBG correlates with HbA1c and acute complications in children and adolescents with able or unwilling to consume carbohy- Any condition leading to deterioration type 1 diabetes. Pediatr Diabetes 2011;12:11–17 drates by mouth. Those in close contact in glycemic control necessitates more fre- 9. Rosenstock J, Davies M, Home PD, Larsen J, with, or having custodial care of, people quent monitoring of blood glucose; ketosis- Koenen C, Schernthaner G. A randomised, 52-week, care.diabetesjournals.org Glycemic Targets S63

treat-to-target trial comparing insulin detemir with GOLD randomized clinical trial. JAMA 2017;317: 37. Wei N, Zheng H, Nathan DM. Empirically es- insulin glargine when administered as add-on to 379–387 tablishing blood glucose targets to achieve HbA1c glucose-lowering drugs in insulin-naive people 23. Beck RW, Riddlesworth T, Ruedy K, et al. Ef- goals. Diabetes Care 2014;37:1048–1051 with type 2 diabetes. Diabetologia 2008;51:408– fect of continuous glucose monitoring on glyce- 38. Herman WH, Ilag LL, Johnson SL, et al. A clin- 416 mic control in adults with type 1 diabetes using ical trial of continuous subcutaneous insulin infusion 10. Garber AJ. Treat-to-target trials: uses, inter- insulin injections: the DIAMOND randomized clin- versus multiple daily injections in older adults with pretation and review of concepts. Diabetes Obes ical trial. JAMA 2017;317:371–378 type2diabetes. Diabetes Care 2005;28:1568–1573 Metab 2014;16:193–205 24. Deiss D, Bolinder J, Riveline J-P, et al. Im- 39. Albers JW, Herman WH, Pop-Busui R, et al.; Dia- 11. Elgart JF, Gonzalez´ L, Prestes M, Rucci E, proved glycemic control in poorly controlled pa- betes Control and Complications Trial/Epidemiology Gagliardino JJ. Frequency of self-monitoring blood tients with type 1 diabetes using real-time of Diabetes Interventions and Complications glucose and attainment of HbA1c target values. continuous glucose monitoring. Diabetes Care Research Group. Effect of prior intensive insulin Acta Diabetol 2016;53:57–62 2006;29:2730–2732 treatment during the Diabetes Control and Com- 12. Farmer A, Wade A, Goyder E, et al. Impact of 25. O’Connell MA, Donath S, O’Neal DN, et al. plications Trial (DCCT) on peripheral neuropathy self monitoring of blood glucose in the manage- Glycaemic impact of patient-led use of sensor- in type 1 diabetes during the Epidemiology of Di- ment of patients with non-insulin treated diabe- guided pump therapy in type 1 diabetes: a rando- abetes Interventions and Complications (EDIC) tes: open parallel group randomised trial. BMJ mised controlled trial. Diabetologia 2009;52: Study. Diabetes Care 2010;33:1090–1096 2007;335:132 1250–1257 40. Stratton IM, Adler AI, Neil HAW, et al. Asso- 13. O’Kane MJ, Bunting B, Copeland M, Coates 26. Wong JC, Foster NC, Maahs DM, et al.; T1D ciation of glycaemia with macrovascular and mi- VE; ESMON study group. Efficacy of self moni- Exchange Clinic Network. Real-time continuous crovascular complications of type 2 diabetes toring of blood glucose in patients with newly glucose monitoring among participants in the (UKPDS 35): prospective observational study. diagnosed type 2 diabetes (ESMON study): T1D Exchange clinic registry. Diabetes Care BMJ 2000;321:405–412 randomised controlled trial. BMJ 2008;336: 2014;37:2702–2709 41. Jovanovicˇ L, Savas H, Mehta M, Trujillo A, 1174–1177 27. Hommel E, Olsen B, Battelino T, et al.; Pettitt DJ. Frequent monitoring of A1C during 14. Simon J, Gray A, Clarke P, Wade A, Neil A, SWITCH Study Group. Impact of continuous glu- pregnancy as a treatment tool to guide therapy. Farmer A; Diabetes Glycaemic Education and cose monitoring on quality of life, treatment sat- Diabetes Care 2011;34:53–54 Monitoring Trial Group. Cost effectiveness of isfaction, and use of medical care resources: 42. Beck RW, Connor CG, Mullen DM, Wesley self monitoring of blood glucose in patients with analyses from the SWITCH study. Acta Diabetol DM, Bergenstal RM. The fallacy of average: how non-insulin treated type 2 diabetes: economic 2014;51:845–851 using HbA1c alone to assess glycemic control can evaluation of data from the DiGEM trial. BMJ 28. Battelino T, Phillip M, Bratina N, Nimri R, be misleading. Diabetes Care 2017;40:994–999 2008;336:1177–1180 Oskarsson P, Bolinder J. Effect of continuous glu- 43. Nathan DM, Kuenen J, Borg R, Zheng H, 15. Young LA, Buse JB, Weaver MA, et al.; Mon- cose monitoring on hypoglycemia in type 1 diabe- Schoenfeld D, Heine RJ; A1c-Derived Average Glu- itor Trial Group. Glucose self-monitoring in non- tes. Diabetes Care 2011;34:795–800 cose Study Group. Translating the A1C assay into insulin-treated patients with type 2 diabetes in 29. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile estimated average glucose values. Diabetes Care primary care settings: a randomized trial. JAMA Diabetes Research Foundation Continuous Glu- 2008;31:1473–1478 Intern Med 2017;177:920–929 cose Monitoring Study Group. The effect of con- 44. Selvin E. Are there clinical implications of ra- 16. Malanda UL, Welschen LMC, Riphagen II, tinuous glucose monitoring in well-controlled cial differences in HbA1c? A difference, to be a Dekker JM, Nijpels G, Bot SDM. Self-monitoring type 1 diabetes. Diabetes Care 2009;32:1378– difference, must make a difference. Diabetes of blood glucose in patients with type 2 diabetes 1383 Care 2016;39:1462–1467 mellitus who are not using insulin. Cochrane Da- 30. Bode B, Beck RW, Xing D, et al.; Juvenile Di- 45. Bergenstal RM, Gal RL, Connor CG, et al.; T1D tabase Syst Rev 2012;1:CD005060 abetes Research Foundation Continuous Glucose Exchange Racial Differences Study Group. Racial 17. Willett LR. ACP Journal Club. Meta-analysis: Monitoring Study Group. Sustained benefitof differences in the relationship of glucose concen- self-monitoring in non-insulin-treated type 2 di- continuous glucose monitoring on A1C, glucose trations and hemoglobin A1c levels. Ann Intern abetes improved HbA1c by 0.25%. Ann Intern profiles, and hypoglycemia in adults with type 1 Med 2017;167:95–102 Med 2012;156:JC6–JC12 diabetes. Diabetes Care 2009;32:2047–2049 46. Lacy ME, Wellenius GA, Sumner AE, et al. As- 18. U.S. Food and Drug Administration. FDA ap- 31. Yeh H-C, Brown TT, Maruthur N, et al. Com- sociation of sickle cell trait with hemoglobin A1c in proves first continuous glucose monitoring system parative effectiveness and safety of methods African Americans. JAMA 2017;317:507–515 for adults not requiring blood sample calibration of insulin delivery and glucose monitoring 47. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD [Internet]. Available from https://www.fda.gov/ for diabetes mellitus: a systematic review and Consortium; EPIC-InterAct Consortium; Lifelines NewsEvents/Newsroom/PressAnnouncements/ meta-analysis. Ann Intern Med 2012;157:336– Cohort Study. Impact of common genetic deter- ucm577890.htm. Accessed 2 October 2017 347 minants of hemoglobin A1c on type 2 diabetes 19. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, 32. Choudhary P, Ramasamy S, Green L, et al. risk and diagnosis in ancestrally diverse popula- Kroger¨ J, Weitgasser R. Novel glucose-sensing Real-time continuous glucose monitoring signifi- tions: a transethnic genome-wide meta-analysis. technology and hypoglycaemia in type 1 diabetes: cantly reduces severe hypoglycemia in hypoglycemia- PLoS Med 2017;14:e1002383 a multicentre, non-masked, randomised con- unaware patients with type 1 diabetes. Diabetes 48. Wilson DM, Kollman; Diabetes Research in trolled trial. Lancet 2016;388:2254–2263 Care 2013;36:4160–4162 Children Network (DirecNet) Study Group. Re- 20. U.S. Food and Drug Administration. FDA ex- 33. Choudhary P, Rickels MR, Senior PA, et al. lationship of A1C to glucose concentrations in pands indication for continuous glucose monitor- Evidence-informed clinical practice recommenda- children with type 1 diabetes: assessments by ing system, first to replace fingerstick testing for tions for treatment of type 1 diabetes compli- high-frequency glucose determinations by sen- diabetes treatment decisions [Internet]. Avail- cated by problematic hypoglycemia. Diabetes sors. Diabetes Care 2008;31:381–385 able from https://www.fda.gov/newsevents/ Care 2015;38:1016–1029 49. Buse JB, Kaufman FR, Linder B, Hirst K, El newsroom/pressannouncements/ucm534056 34. Bergenstal RM, Klonoff DC, Garg SK, et al.; Ghormli L, Willi S; HEALTHY Study Group. Diabetes .htm. Accessed 14 September 2017 ASPIRE In-Home Study Group. Threshold-based screening with hemoglobin A1c versus fasting 21. Tamborlane WV, Beck RW, Bode BW, et al.; insulin-pump interruption for reduction of hypo- plasma glucose in a multiethnic middle-school co- Juvenile Diabetes Research Foundation Continu- glycemia. N Engl J Med 2013;369:224–232 hort. Diabetes Care 2013;36:429–435 ous Glucose Monitoring Study Group. Continuous 35. Bergenstal RM, Garg S, Weinzimer SA, et al. 50. Kamps JL, Hempe JM, Chalew SA. Racial dis- glucose monitoring and intensive treatment of Safety of a hybrid closed-loop insulin delivery sys- parity in A1C independent of mean blood glucose type 1 diabetes. N Engl J Med 2008;359:1464– tem in patients with type 1 diabetes. JAMA 2016; in children with type 1 diabetes. Diabetes Care 1476 316:1407–1408 2010;33:1025–1027 22. Lind M, Polonsky W, Hirsch IB, et al. Contin- 36. Stewart ZA, Wilinska ME, Hartnell S, et al. 51. Diabetes Control and Complications Trial uous glucose monitoring vs conventional therapy Closed-loop insulin delivery during pregnancy in (DCCT)/Epidemiology of Diabetes Interventions for glycemic control in adults with type 1 diabetes women with type 1 diabetes. N Engl J Med 2016; and Complications (EDIC) Research Group. Effect treated with multiple daily insulin injections: the 375:644–654 of intensive diabetes therapy on the progression S64 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

of diabetic retinopathy in patients with type 1 di- 63. Nathan DM, Zinman B, Cleary PA, et al.; 74. Raz I, Wilson PWF, Strojek K, et al. Effects of abetes: 18 years of follow-up in the DCCT/EDIC. Diabetes Control and Complications Trial/ prandial versus fasting glycemia on cardiovascular Diabetes 2015;64:631–642 Epidemiology of Diabetes Interventions and Com- outcomes in type 2 diabetes: the HEART2D trial. 52. Lachin JM, Genuth S, Cleary P, Davis MD, plications (DCCT/EDIC) Research Group. Modern- Diabetes Care 2009;32:381–386 Nathan DM; Diabetes Control and Complications day clinical course of type 1 diabetes mellitus after 75. International Hypoglycaemia Study Group. Trial/Epidemiology of Diabetes Interventions and 30 years’ duration: the Diabetes Control and Com- Glucose concentrations of less than 3.0 mmol/L Complications Research Group. Retinopathy and plications Trial/Epidemiology of Diabetes Interven- (54 mg/dL) should be reported in clinical trials: nephropathy in patients with type 1 diabetes four tions and Complications and Pittsburgh Epidemiology a joint position statement of the American Diabe- years after a trial of intensive therapy. N Engl J of Diabetes Complications experience (1983-2005). tes Association and the European Association for Med 2000;342:381–389 Arch Intern Med 2009;169:1307–1316 the Study of Diabetes. Diabetes Care 2017;40: 53. Ohkubo Y, Kishikawa H, Araki E, et al. Inten- 64. Orchard TJ, Nathan DM, Zinman B, et al.; 155–157 sive insulin therapy prevents the progression of Writing Group for the DCCT/EDIC Research Group. 76. Seaquist ER, Anderson J, Childs B, et al. Hypo- diabetic microvascular complications in Japanese Association between 7 years of intensive treat- glycemia and diabetes: a report of a workgroup of patients with non-insulin-dependent diabetes ment of type 1 diabetes and long-term mortality. the American Diabetes Association and The Endo- mellitus: a randomized prospective 6-year study. JAMA 2015;313:45–53 crine Society. Diabetes Care 2013;36:1384–1395 Diabetes Res Clin Pract 1995;28:103–117 65. Skyler JS, Bergenstal R, Bonow RO, et al.; 77. Whitmer RA, Karter AJ, Yaffe K, Quesenberry 54. UK Prospective Diabetes Study (UKPDS) American Diabetes Association; American College CP Jr, Selby JV. Hypoglycemic episodes and risk of Group. Effect of intensive blood-glucose control of Cardiology Foundation; American Heart Asso- dementia in older patients with type 2 diabetes with metformin on complications in overweight ciation. Intensive glycemic control and the pre- mellitus. JAMA 2009;301:1565–1572 patients with type 2 diabetes (UKPDS 34). Lancet vention of cardiovascular events: implications of 78. Punthakee Z, Miller ME, Launer LJ, et al.; 1998;352:854–865 the ACCORD, ADVANCE, and VA diabetes trials: ACCORD Group of Investigators; ACCORD-MIND 55. UK Prospective Diabetes Study (UKPDS) a position statement of the American Diabetes Investigators. Poor cognitive function and risk of Group. Intensive blood-glucose control with sul- Association and a scientiﬁc statement of the severe hypoglycemia in type 2 diabetes: post hoc phonylureas or insulin compared with conven- American College of Cardiology Foundation and epidemiologic analysis of the ACCORD trial. Dia- tional treatment and risk of complications in the American Heart Association. Diabetes Care betes Care 2012;35:787–793 patients with type 2 diabetes (UKPDS 33). Lancet 2009;32:187–192 79. Jacobson AM, Musen G, Ryan CM, et al.; 1998;352:837–853 66. Zoungas S, Chalmers J, Neal B, et al.; Diabetes Control and Complications Trial/ 56. Holman RR, Paul SK, Bethel MA, Matthews ADVANCE-ON Collaborative Group. Follow-up of Epidemiology of Diabetes Interventions and Com- DR, Neil HAW. 10-year follow-up of intensive glu- blood-pressure lowering and glucose control in plications Study Research Group. Long-term ef- cose control in type 2 diabetes. N Engl J Med 2008; type 2 diabetes. N Engl J Med 2014;371:1392–1406 fect of diabetes and its treatment on cognitive 359:1577–1589 67. Hayward RA, Reaven PD, Wiitala WL, et al.; function. N Engl J Med 2007;356:1842–1852 57. Adler AI, Stratton IM, Neil HAW, et al. Asso- VADT Investigators. Follow-up of glycemic control 80. Zoungas S, Patel A, Chalmers J, et al.; ADVANCE ciation of systolic blood pressure with macrovas- and cardiovascular outcomes in type 2 diabetes. N Collaborative Group. Severe hypoglycemia and cular and microvascular complications of type 2 Engl J Med 2015;372:2197–2206 risks of vascular events and death. N Engl J Med diabetes (UKPDS 36): prospective observational 68. Turnbull FM, Abraira C, Anderson RJ, et al.; 2010;363:1410–1418 study. BMJ 2000;321:412–419 Control Group. Intensive glucose control and mac- 81. McCoy RG, Van Houten HK, Ziegenfuss JY, 58. Duckworth W, Abraira C, Moritz T, et al.; rovascular outcomes in type 2 diabetes [published Shah ND, Wermers RA, Smith SA. Increased mor- VADT Investigators. Glucose control and vascular correction appears in Diabetologia 2009;52: tality of patients with diabetes reporting severe complications in veterans with type 2 diabetes. N 2470]. Diabetologia 2009;52:2288–2298 hypoglycemia. Diabetes Care 2012;35:1897– Engl J Med 2009;360:129–139 69. Duckworth WC, Abraira C, Moritz TE, et al.; 1901 59. Patel A, MacMahon S, Chalmers J, et al.; Investigators of the VADT. The duration of diabe- 82. DuBose SN, Weinstock RS, Beck RW, et al. ADVANCE Collaborative Group. Intensive blood glu- tes affects the response to intensive glucose con- Hypoglycemia in older adults with type 1 diabe- cose control and vascular outcomes in patients with trol in type 2 subjects: the VA Diabetes Trial. J tes. Diabetes Technol Ther 2016;18:765–771 type 2 diabetes. N Engl J Med 2008;358:2560–2572 Diabetes Complications 2011;25:355–361 83. Hering BJ, Clarke WR, Bridges ND, et al.; Clin- 60. Ismail-Beigi F, Craven T, Banerji MA, et al.; 70. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, ical Islet Transplantation Consortium. Phase 3 trial ACCORD trial group. Effect of intensive treatment Steinman MA. Potential overtreatment of diabe- of transplantation of human islets in type 1 dia- of hyperglycaemia on microvascular outcomes in tes mellitus in older adults with tight glycemic betes complicated by severe hypoglycemia. Dia- type 2 diabetes: an analysis of the ACCORD rand- control. JAMA Intern Med 2015;175:356–362 betes Care 2016;39:1230–1240 omised trial. Lancet 2010;376:419–430 71. Vijan S, Sussman JB, Yudkin JS, Hayward RA. 84. Harlan DM. Islet transplantation for hypogly- 61. Gerstein HC, Miller ME, Byington RP, et al.; Effect of patients’ risks and preferences on health cemia unawareness/severe hypoglycemia: caveat Action to Control Cardiovascular Risk in Diabetes gains with plasma glucose level lowering in type 2 emptor. Diabetes Care 2016;39:1072–1074 Study Group. Effects of intensive glucose lowering diabetes mellitus. JAMA Intern Med 2014;174: 85. Layman DK, Clifton P, Gannon MC, Krauss in type 2 diabetes. N Engl J Med 2008;358:2545– 1227–1234 RM, Nuttall FQ. Protein in optimal health: heart 2559 72. Inzucchi SE, Bergenstal RM, Buse JB, et al. disease and type 2 diabetes. Am J Clin Nutr 2008; 62. Nathan DM, Cleary PA, Backlund J-YC, et al.; Management of hyperglycemia in type 2 diabetes, 87:1571S–1575S Diabetes Control and Complications Trial/ 2015: a patient-centered approach: update to a 86. Cryer PE. Diverse causes of hypoglycemia- Epidemiology of Diabetes Interventions and Com- position statement of the American Diabetes Asso- associated autonomic failure in diabetes. N Engl plications (DCCT/EDIC) Study Research Group. In- ciation and the European Association for the Study J Med 2004;350:2272–2279 tensive diabetes treatment and cardiovascular of Diabetes. Diabetes Care 2015;38:140–149 87. Kitabchi AE, Umpierrez GE, Miles JM, Fisher disease in patients with type 1 diabetes. N Engl J 73. American Diabetes Association. Postprandial JN. Hyperglycemic crises in adult patients with Med 2005;353:2643–2653 blood glucose. Diabetes Care 2001;24:775–778 diabetes. Diabetes Care 2009;32:1335–1343 Diabetes Care Volume 41, Supplement 1, January 2018 S65

7. Obesity Management for the American Diabetes Association Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S65–S72 | https://doi.org/10.2337/dc18-S007 .OEIYMNGMN O H RAMN FTP DIABETES 2 TYPE OF TREATMENT THE FOR MANAGEMENT OBESITY 7.

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 demonstrated that in obese patients with type 2 diabetes more extreme dietary energy 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 pharmacologic 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 (5,8,10,11).The goal of this section is to provide evidence- based recommendations for dietary, pharmacologic, and surgical interventions for obesity management as treatments for hyperglycemia in type 2 diabetes. ASSESSMENT

Recommendation Suggested citation: American Diabetes Associa- c At each patient encounter, BMI should be calculated and documented in the tion. 7. Obesity management for the treatment medical record. B of type 2 diabetes: Standards of Medical Care in Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): At each routine patient encounter, BMI should be calculated as weight divided by S65–S72 height squared (kg/m2) (12). BMI should be classified to determine the presence of © 2017 by the American Diabetes Association. overweight or obesity, discussed with the patient, and documented in the patient Readers may use this article as long as the work fi is properly cited, the use is educational and not record. In Asian Americans, the BMI cutoff points to de ne overweight and obesity for profit, and the work is not altered. More infor- are lower than in other populations (Table 7.1) (13,14). Providers should advise over- mation is available at http://www.diabetesjournals weight and obese patients that, in general, higher BMIs increase the risk of .org/content/license. S66 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Table 7.1—Treatment options for overweight and obesity in type 2 diabetes BMI category (kg/m2) 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40 Treatment (or 23.0–26.9*) (or 27.5–32.4*) (or 32.5–37.4*) (or $37.5*) Diet, physical activity, and behavioral therapy ††† † † Pharmacotherapy †† † † Metabolic surgery ††† *Cutoff points for Asian American individuals. †Treatment may be indicated for selected motivated patients.

cardiovascular disease and all-cause mor- functioning, and health-related quality carefully selected patients by tality. Providers should assess each pa- of life (17). A post hoc analysis of the trained practitioners in medical tient’s readiness to achieve weight loss Look AHEAD study suggests that hetero- care settings with close medical and jointly determine weight loss goals geneous treatment effects may have monitoring. To maintain weight and intervention strategies. Strategies in- been present. Participants who had mod- loss, such programs must incorpo- clude diet, physical activity, behavioral erately or poorly controlled diabetes (A1C rate long-term comprehensive therapy, pharmacologic therapy, and met- 6.8% or higher) as well as both those with weight maintenance counseling. B abolic surgery (Table 7.1). The latter two well-controlled diabetes (A1C less than strategies may be prescribed for carefully 6.8%) and good self-reported health Among overweight or obese patients with selected patients as adjuncts to diet, were found to have significantly reduced type 2 diabetes and inadequate glycemic, physical activity, and behavioral therapy. cardiovascular events with intensive life- blood pressure, and lipid control and/or style intervention during follow-up (18). other obesity-related medical conditions, lifestyle changes that result in modest DIET, PHYSICAL ACTIVITY, AND Lifestyle Interventions and sustained weight loss produce clini- BEHAVIORAL THERAPY Weight loss can be attained with lifestyle cally meaningful reductions in blood glu- programs that achieve a 500–750 kcal/day Recommendations cose, A1C, and triglycerides (3–5). Greater energy deficit or provide approximately c Diet, physical activity, and behavior- weight loss produces even greater bene- 1,200–1,500 kcal/day for women and al therapy designed to achieve .5% fits, including reductions in blood pres- 1,500–1,800 kcal/day for men, adjusted weight loss should be prescribed for sure, improvements in LDL and HDL for the individual’s baseline body weight. overweight and obese patients with cholesterol, and reductions in the need Although benefits may be seen with as type 2 diabetes ready to achieve for medications to control blood glucose, weight loss. A – little as 5% weight loss (19), sustained blood pressure, and lipids (3 5). $ c Such interventions should be high weight loss of 7% is optimal. intensity($16sessionsin6months) These diets may differ in the types of and focus on diet, physical activity, Look AHEAD Trial foods they restrict (such as high-fat or and behavioral strategies to achieve Although the Action for Health in Diabe- high-carbohydrate foods) but are effec- a 500–750 kcal/day energy deficit. A tes (Look AHEAD) trial did not show that tive if they create the necessary energy fi – c Diets should be individualized, as an intensive lifestyle intervention reduced de cit (12,20 22). Use of meal replace- those that provide the same caloric cardiovascular events in overweight or ment plans prescribed by trained practi- restriction but differ in protein, carbo- obese adults with type 2 diabetes (15), it tioners, with close patient monitoring, fi hydrate, and fat content are equally did show the feasibility of achieving and can be bene cial. Within the intensive effective in achieving weight loss. A maintaining long-term weight loss in pa- lifestyle intervention group of the Look c For patients who achieve short- tients with type 2 diabetes. In the Look AHEAD trial, for example, use of a partial term weight-loss goals, long-term AHEAD intensive lifestyle intervention meal replacement plan was associated ($1 year) comprehensive weight group, mean weight loss was 4.7% at with improvements in diet quality (23). maintenance programs should be 8 years (16). Approximately 50% of inten- The diet choice should be based on the ’ prescribed. Such programs should sive lifestyle intervention participants patient s health status and preferences. $ $ provide at least monthly contact lost 5%, and 27% lost 10% of their Intensive behavioral lifestyle interven- $ and encourage ongoing monitoring initial body weight at 8 years (16). Partic- tions should include 16 sessions in of body weight (weekly or more fre- ipants randomly assigned to the intensive 6 months and focus on diet, physical ac- quently), continued consumption lifestyle group achieved equivalent risk tivity, and behavioral strategies to achieve ; – fi of a reduced-calorie diet, and par- factor control but required fewer glucose-, an 500 750 kcal/day energy de cit. In- – ticipation in high levels of physical blood pressure , and lipid-lowering med- terventions should be provided by trained activity (200–300 min/week). A ications than those randomly assigned to interventionists in either individual or c To achieve weight loss of .5%, standard care. Secondary analyses of the group sessions (19). short-term (3-month) interventions Look AHEAD trial and other large cardio- Overweight and obese patients with that use very-low-calorie diets vascular outcome studies document type 2 diabetes who have lost weight fi (#800 kcal/day) and total meal re- other bene ts of weight loss in patients during the 6-month intensive behavioral placements may be prescribed for with type 2 diabetes, including improve- lifestyle intervention should be enrolled ments in mobility, physical and sexual in long-term ($1 year) comprehensive care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S67

weight loss maintenance programs that promote weight loss or to be weight neu- adhere to low-calorie diets and to rein- provide at least monthly contact with a tral. Agents associated with weight loss force lifestyle changes including physical trained interventionist and focus on on- include metformin, a-glucosidase inhibi- activity. Providers should be knowledge- going monitoring of body weight (weekly tors, sodium–glucose cotransporter 2 in- able about the product label and should or more frequently), continued consump- hibitors, glucagon-like peptide 1 agonists, balance the potential benefits of success- tion of a reduced-calorie diet, and partic- and amylin mimetics. Dipeptidyl peptidase ful weight loss against the potential risks ipationinhighlevelsofphysicalactivity 4 inhibitors appear to be weight neutral. of the medication for each patient. These (200–300 min/week [24]). Some com- Unlike these agents, insulin secretagogues, medications are contraindicated in women mercial and proprietary weight loss pro- thiazolidinediones, and insulin have often who are or may become pregnant. Women grams have shown promising weight loss been associated with weight gain (see in their reproductive years must be cautioned results (25). Section 8. Pharmacologic Approaches to use a reliable method of contraception. When provided by trained practitioners to Glycemic Treatment”). Assessing Efficacy and Safety in medical care settings with close medical A recent meta-analysis of 227 random- Efficacyandsafetyshouldbeassessedatleast monitoring, short-term (3-month) inter- ized controlled trials of antihyperglycemic monthly for the first 3 months of treatment. ventions that use very-low-calorie diets treatments in type 2 diabetes found that If a patient’s response is deemed insuffi- (defined as #800 kcal/day) and total A1C changes were not associated with cient (weight loss ,5%) after 3 months or meal replacements may achieve greater baseline BMI, indicating that obese pa- if there are any safety or tolerability is- short-term weight loss (10–15%) than in- tients can benefit from the same types sues at any time, the medication should tensive behavioral lifestyle interventions of treatments for diabetes as normal- be discontinued and alternative medica- that typically achieve 5% weight loss. weight patients (28). tions or treatment approaches should be However, weight regain following the ces- considered. sation of very-low-calorie diets is greater Concomitant Medications In general, pharmacologic treatment of than following intensive behavioral life- Providers should carefully review the pa- obesity has been limited by low adherence, style interventions unless a long-term tient’s concomitant medications and, modest efficacy, adverse effects, and weight comprehensive weight loss maintenance whenever possible, minimize or provide regain after medication cessation (30). program is provided (26,27). alternatives for medications that promote weight gain. Medications associ- PHARMACOTHERAPY ated with weight gain include atypical METABOLIC SURGERY antipsychotics (e.g., clozapine, olanza- Recommendations Recommendations pine, risperidone, etc.) and antidepres- c When choosing glucose-lowering c Metabolic surgery should be recom- sants (e.g., tricyclic antidepressants, mended as an option to treat type 2 medications for overweight or obese selective serotonin reuptake inhibitors, patients with type 2 diabetes, con- diabetes in appropriate surgical and monoamine oxidase inhibitors), glu- 2 sider their effect on weight. E candidates with BMI $40 kg/m cocorticoids, oral contraceptives that $ 2 c Whenever possible, minimize the (BMI 37.5 kg/m in Asian Ameri- contain progestins, anticonvulsants in- cans), regardless of the level of gly- medications for comorbid conditions cluding gabapentin, and a number of an- E cemic control or complexity of that are associated with weight gain. tihistamines and anticholinergics. c Weight loss medications may be ef- glucose-lowering regimens, and in 2 fective as adjuncts to diet, physical ac- adults with BMI 35.0–39.9 kg/m Approved Weight Loss Medications 2 tivity, and behavioral counseling for (32.5–37.4 kg/m in Asian Ameri- The U.S. Food and Drug Administration cans) when hyperglycemia is inade- selected patients with type 2 diabetes (FDA) has approved medications for $ 2 quately controlled despite lifestyle and BMI 27 kg/m . Potential ben- both short-term and long-term weight fi and optimal medical therapy. A e ts must be weighed against the management. Phentermine is indicated A c Metabolic surgery should be con- potential risks of the medications. as short-term (a few weeks) adjunct in c ’ sidered as an option for adults with If a patient s response to weight loss conjunction with lifestyle and behavioral medications is ,5% weight loss af- type 2 diabetes and BMI 30.0– weight loss interventions (29). Five 2 2 ter 3 months or if there are any 34.9 kg/m (27.5–32.4 kg/m in weight loss medications (or combination Asian Americans) if hyperglycemia safety or tolerability issues at any medications) are FDA-approved for long- time, the medication should be dis- is inadequately controlled despite term use (more than a few weeks) by optimal medical control by either continued and alternative medica- $ 2 patients with BMI 27 kg/m with one oral or injectable medications (in- tions or treatment approaches or more obesity-associated comorbid should be considered. A cluding insulin). B conditions (e.g., type 2 diabetes, hyperten- c Metabolic surgery should be per- sion, and dyslipidemia) and by patients formed in high-volume centers $ 2 Antihyperglycemic Therapy with BMI 30 kg/m who are motivated with multidisciplinary teams that – When evaluating pharmacologic treat- to lose weight (30 34). Medications ap- understand and are experienced in ments for overweight or obese patients proved by the FDA for the treatment of the management of diabetes and with type 2 diabetes, providers should obesity and their advantages and disad- gastrointestinal surgery. C fi Table 7.2 rst consider their choice of glucose- vantages are summarized in . c Long-term lifestyle support and rou- lowering medications. Whenever possi- The rationale for weight loss medications tine monitoring of micronutrient ble, medications should be chosen to is to help patients to more consistently 6 bst aaeetfrteTeteto ye2Diabetes 2 Type of Treatment the for Management Obesity S68

Table 7.2—Medications approved by the FDA for the treatment of obesity 1-Year weight change status1–4 Generic drug name National Average Drug – Adverse effects1,5 12 (proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5% strength, and form frequency price (per month)13 month)14 relative to placebo loss of baseline weight Common6 Serious6 Short-term treatment (a few weeks) Phentermine (Lomaira) 37.5mgq.d.or8mgt.i.d. $5-$76 (37.5 mg); $3-$60 (37.5 mg); N/A* N/A* Headache, elevated blood Dyspnea, angina pectoris, $52 (8 mg) Unavailable (8 mg) pressure, elevated syncope, severe heart rate, insomnia, hypertension dry mouth, constipation, anxiety, palpitations Long-term treatment (more than a few weeks) Lipase inhibitor Orlistat (Alli) 60 mg caps 60 mg or 120 mg t.i.d. $41–82 (60 mg); $42 (60 mg); 2.5 kg (60 mg); 35–73% Abdominal pain/ Liver failure and oxalate or orlistat (Xenical) (during or up to 1 h $703 (120 mg) $556 (120 mg) 3.4 kg (120 mg) discomfort, oily spotting/ nephropathy 120 mg caps after a low-fat meal) stool, fecal urgency, ﬂatulence, malabsorption of fat soluble vitamins (A, D, E, K) and medications (e.g., cyclosporine, thyroid hormone replacement, or anticonvulsants), potentiation of the effects of warfarin Selective serotonin (5-HT) 5-HT2C receptor agonist Lorcaserin (Belviq) 10 mg 10 mg b.i.d. $289 $230 3.2 kg 38–48% Hypoglycemia, headache, Serotonin syndrome or tabs fatigue NMS-like reactions, suicidal ideation, heart Care Diabetes valve disorder (,2.4%), bradycardia Lorcaserin (Belviq XR) 20 mg q.d. $289 $232 3.2 kg 38–48% Hypoglycemia, headache, Serotonin syndrome or 20 mg extended-release fatigue NMS-like reactions,

tabs suicidal ideation, heart 2018 January 1, Supplement 41, Volume valve disorder (,2.4%), bradycardia Sympathomimetic amine anorectic/antiepileptic combination Phentermine/topiramate Recommended dose: $239 (maximum dose $192 (maximum dose 6.7 kg (7.5 mg/46 mg); 45–70% Paresthesia, xerostomia, Topiramate is teratogenic ER (Qsymia) 3.75 mg/ 3.75 mg/23 mg q.d. using the highest using the highest 8.9kg(15mg/92mg) constipation, headache and has been associated 23 mg caps, 7.5 mg/ for 14 days, then strength) strength) with cleft lip/palate 46 mg caps, 11.25 mg/ increase to 7.5 mg/ 69 mg caps, 15 mg/ 46 mg q.d. 92 mg caps Maximum dose: 15 mg/92 mg q.d. Continued on p. S69 aedaeejunl.r bst aaeetfrteTeteto ye2Daee S69 Diabetes 2 Type of Treatment the for Management Obesity care.diabetesjournals.org

Table 7.2—Continued – 1-Year weight change status1 4 Generic drug name National Average Drug Adverse effects1,5–12 (proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5% strength, and form frequency price (per month)13 month)14 relative to placebo loss of baseline weight Common6 Serious6

Opioid antagonist/aminoketone antidepressant combination Naltrexone/bupropion Maximum dose: two $290 (maximum dose) $231 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, Depression, precipitation of (Contrave) 8 mg/90 mg tablets of Contrave (32mg/360mg) headache, vomiting mania, contraindicated in tabs b.i.d. for a total daily patients with a seizure dosage of naltrexone disorder 32 mg/bupropion 360 mg Glucagon-like peptide 1 receptor agonist Liraglutide (Saxenda) Maintenance dose: $1,385 $1,105 5.8–5.9 kg 51–73% Hypoglycemia, nausea, Pancreatitis, thyroid C-cell 6mg/mLprefilled pen 3 mg s.c. q.d. vomiting, diarrhea, tumors in rodents, constipation, headache contraindicated in 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; N/A, not applicable; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets. *Phentermine is FDA-approved as a short- term adjunct (a few weeks) in a regimen of weight reduction based on exercise, behavioral modification, and caloric restriction. 1Physicians’ Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO. 2Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86 (30). 3Astrup 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. 4Wadden 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. 5DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. 6Selective 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. 7Data 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. 8Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes. 9Data 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. 10Data 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 2 diabetes. 11Data 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. 12Phentermine. FDA prescribing information, side effects and uses [Internet], 2017. Available from https://www.drugs.com/pro/phentermine.html. Accessed 22 September 2017 (29). 13RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO. Accessed 18 July 2017. 14National Average Drug Acquisition Cost data available at: https://data.medicaid.gov/. Accessed 19 July 2017. S70 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Please refer to “Metabolic Surgery in the mortality, complications, reoperations, and nutritional status must be pro- Treatment Algorithm for Type 2 Diabe- and readmissions (71). vided to patients after surgery, accord- tes: A Joint Statement by International Although metabolic surgery has been ing to guidelines for postoperative Diabetes Organizations” for a thorough shown to improve the metabolic profiles management of metabolic surgery review (35). of morbidly obese patients with type 1 by national and international profes- Randomized controlled trials with diabetes, establishing the role of meta- sional societies. C postoperative follow up ranging from bolic surgery in such patients will require c People presenting for metabolic 1 to 5 years have documented sustained larger and longer studies (72). surgery should receive a compre- diabetes remission in 30–63% of patients Retrospective analyses and modeling hensive mental health assessment. (35). Available data suggest an erosion of studies suggest that metabolic surgery B Surgery should be postponed in diabetes remission over time (51): 35– may be cost-effective or even cost-saving patients with histories of alcohol or 50% or more of patients who initially for patients with type 2 diabetes, but the substance abuse, significant depres- achieve remission of diabetes eventually results are largely dependent on assump- sion, suicidal ideation, or other mental experience recurrence. However, the me- tions about the long-term effectiveness health conditions until these condi- dian disease-free period among such in- and safety of the procedures (73,74). tions have been fully addressed. E dividuals following Roux-en-Y gastric c People who undergo metabolic sur- bypass (RYGB) is 8.3 years (52,53). With gery should be evaluated to assess Adverse Effects or without diabetes relapse, the majority the need for ongoing mental health Metabolic surgery is costly and has associ- of patients who undergo surgery main- services to help them adjust to ated risks. Longer-term concerns include tain substantial improvement of glycemic medical and psychosocial changes dumping syndrome (nausea,colic,diarrhea), C control from baseline for at least 5 (54,55) vitamin and mineral deficiencies, anemia, after surgery. – to 15 (38,39,53,56 58) years. osteoporosis, and, rarely (75), severe hypo- Younger age, shorter duration of diabe- Several gastrointestinal (GI) operations glycemia from insulin hypersecretion. tes (e.g., ,8 years) (59), nonuse of insulin, including partial gastrectomies and bari- Long-term nutritional and micronutrient and better glycemic control are consis- atric procedures (35) promote dramatic deficiencies and related complications oc- tently associated with higher rates of di- and durable improvement of type 2 diabe- cur with variable frequency depending on abetes remission and/or lower risk of tes. Given the magnitude and rapidity of the type of procedure and require lifelong recidivism (38,57,59). Greater baseline the effect of GI surgery on hyperglycemia, vitamin/nutritional supplementation visceral fat area may also help to predict and experimental evidence that rearrange- (76,77). Postprandial hypoglycemia is better postoperative outcomes, espe- ments of GI anatomy similar to those in most likely to occur with RYGB (77,78). cially among Asian American patients some metabolic procedures directly affect The exact prevalence of symptomatic hy- with type 2 diabetes, who typically poglycemia is unknown. In one study, it glucose homeostasis (36), GI interventions have more visceral fat compared with have been suggested as treatments for affected 11% of 450 patients who had un- Caucasians with diabetes of the same dergone RYGB or vertical sleeve gastrectomy type 2 diabetes, and in that context are BMI (60). “ ” (75). Patients who undergo metabolic sur- termed metabolic surgery. Beyond improving glycemia, metabolic A substantial body of evidence has now gery may be at increased risk for sub- surgery has been shown to confer addi- stance use, including drug and alcohol accumulated, including data from numer- fi tional health bene ts in randomized con- use and cigarette smoking (79). ous randomized controlled clinical trials, trolled trials, including greater reductions demonstrating that metabolic surgery People with diabetes presenting for in cardiovascular disease risk factors (35) metabolic surgery also have increased rates achieves superior glycemic control and re- andenhancementsinqualityoflife duction of cardiovascular risk factors in of depression and other major psychiatric (54,59,61). disorders (80). Candidates for metabolic obese patients with type 2 diabetes com- The safety of metabolic surgery has im- surgery with histories of alcohol or sub- pared with various lifestyle/medical inter- fi proved signi cantly over the past two de- stance abuse, significant depression, sui- ventions (35). Improvements in micro- and fi cades, with continued re nement of cidal ideation, or other mental health macrovascular complications of diabetes, minimally invasive approaches (laparo- conditions should therefore first be as- cardiovascular disease, and cancer have scopic surgery), enhanced training and sessed by a mental health professional been observed only in nonrandomized credentialing, and involvement of multi- with expertise in obesity management prior observational studies (37–46). Cohort disciplinary teams. Mortality rates with to consideration for surgery (81). Individu- studies attempting to match surgical – metabolic operations are typically 0.1 als with preoperative psychopathology and nonsurgical subjects suggest that 0.5%, similar to cholecystectomy or hys- should be assessed regularly following – the procedure may reduce longer-term terectomy (62 66). Morbidity has also metabolic surgery to optimize mental mortality (38). dramatically declined with laparoscopic health management and to ensure psy- On the basis of this mounting evidence, approaches. Major complications rates chiatric symptoms do not interfere with – several organizations and government are 2 6%, with minor complications in weight loss and lifestyle changes. agencies have recommended expanding up to 15% (62–70), comparing favorably the indications for metabolic surgery to with other commonly performed elective References include patients with inadequately controlled operations (66). Empirical data suggest 1. Tuomilehto J. The emerging global epidemic 2 type 2 diabetes and BMI as low as 30 kg/m that proficiency of the operating surgeon of type 1 diabetes. Curr Diab Rep 2013;13:795– (27.5 kg/m2 for Asian Americans) (47–50). is an important factor for determining 804 care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S71

2. KnowlerWC, Barrett-Connor E, Fowler SE, et al.; 18. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu of liraglutide in weight management. N Engl J Med Diabetes Prevention Program Research Group. S, Faghmous J. Targeting weight loss interventions 2015;373:11–22 Reduction in the incidence of type 2 diabetes to reduce cardiovascular complications of type 2 33. Khera R, Murad MH, Chandar AK, et al. Asso- with lifestyle intervention or metformin. N Engl J diabetes: a machine learning-based post-hoc ciation of pharmacological treatments for obesity Med 2002;346:393–403 analysis of heterogeneous treatment effects in with weight loss and adverse events: a systematic 3. UK Prospective Diabetes Study 7. UK Prospec- the Look AHEAD trial. Lancet Diabetes Endocrinol review and meta-analysis. JAMA 2016;315:2424– tive Diabetes Study 7: response of fasting plasma 2017;5:808–815 2434 glucose to diet therapy in newly presenting type II 19. Franz MJ, Boucher JL, Rutten-Ramos S, 34. O’Neil PM, Smith SR, Weissman NJ, et al. Ran- diabetic patients, UKPDS Group. Metabolism VanWormer JJ. Lifestyle weight-loss intervention domized placebo-controlled clinical trial of lorca- 1990;39:905–912 outcomes in overweight and obese adults with serin for weight loss in type 2 diabetes mellitus: 4. Goldstein DJ. Beneficial health effects of mod- type 2 diabetes: a systematic review and meta- the BLOOM-DM study. Obesity (Silver Spring) est weight loss. Int J Obes Relat Metab Disord analysis of randomized clinical trials. J Acad Nutr 2012;20:1426–1436 1992;16:397–415 Diet 2015;115:1447–1463 35. Rubino F, Nathan DM, Eckel RH, et al.; Dele- 5. Pastors JG, Warshaw H, Daly A, Franz M, 20. Sacks FM, Bray GA, Carey VJ, et al. Compari- gates of the 2nd Diabetes Surgery Summit. Met- Kulkarni K. The evidence for the effectiveness of son of weight-loss diets with different composi- abolic surgery in the treatment algorithm for medical nutrition therapy in diabetes manage- tions of fat, protein, and carbohydrates. N Engl J type 2 diabetes: a joint statement by international ment. Diabetes Care 2002;25:608–613 Med 2009;360:859–873 diabetes organizations. Diabetes Care 2016;39: 6. Lim EL, Hollingsworth KG, Aribisala BS, Chen 21. de Souza RJ, Bray GA, Carey VJ, et al. Effects 861–877 MJ, Mathers JC, Taylor R. Reversal of type 2 di- of 4 weight-loss diets differing in fat, protein, and 36. Rubino F, Marescaux J. Effect of duodenal- abetes: normalisation of beta cell function in as- carbohydrate on fat mass, lean mass, visceral ad- jejunal exclusion in a non-obese animal model sociation with decreased pancreas and liver ipose tissue, and hepatic fat: results from the of type 2 diabetes: a new perspective for an old – – triacylglycerol. Diabetologia 2011;54:2506 2514 POUNDS LOST trial. Am J Clin Nutr 2012;95:614 disease. Ann Surg 2004;239:1–11 7. Jackness C, Karmally W, Febres G, et al. Very 625 37. Sjostr¨ om¨ L, Lindroos A-K, Peltonen M, et al.; fi low-calorie diet mimics the early bene cial effect 22. Johnston BC, Kanters S, Bandayrel K, et al. Swedish Obese Subjects Study ScientificGroup. of Roux-en-Y gastric bypass on insulin sensitivity Comparison of weight loss among named diet Lifestyle, diabetes, and cardiovascular risk factors b and -cell function in type 2 diabetic patients. programs in overweight and obese adults: a 10 years after bariatric surgery. N Engl J Med – – Diabetes 2013;62:3027 3032 meta-analysis. JAMA 2014;312:923 933 2004;351:2683–2693 8. Rothberg AE, McEwen LN, Kraftson AT, Fowler 23. Raynor HA, Anderson AM, Miller GD, et al.; 38. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. CE, Herman WH. Very-low-energy diet for type 2 Look AHEAD Research Group. Partial meal re- Association of bariatric surgery with long-term re- diabetes: an underutilized therapy? J Diabetes placement plan and quality of the diet at 1 year: mission of type 2 diabetes and with microvascular Complications 2014;28:506–510 Action for Health in Diabetes (Look AHEAD) trial. and macrovascular complications. JAMA 2014; 9. Day JW, Ottaway N, Patterson JT, et al. A new J Acad Nutr Diet 2015;115:731–742 311:2297–2304 glucagon and GLP-1 co-agonist eliminates obesity 24. Donnelly JE, Blair SN, Jakicic JM, Manore MM, 39. Adams TD, Davidson LE, Litwin SE, et al. in rodents. Nat Chem Biol 2009;5:749–757 Rankin JW, Smith BK; American College of Sports Health benefits of gastric bypass surgery after 10. Steven S, Hollingsworth KG, Al-Mrabeh A, Medicine. American College of Sports Medicine 6 years. JAMA 2012;308:1122–1131 et al. Very low-calorie diet and 6 months of weight Position Stand. Appropriate physical activity inter- 40. Sjostr¨ om¨ L, Narbro K, Sjostr¨ om¨ CD, et al.; stability in type 2 diabetes: pathophysiological vention strategies for weight loss and prevention Swedish Obese Subjects Study. Effects of bariatric changes in responders and nonresponders. Diabe- of weight regain for adults. Med Sci Sports Exerc surgery on mortality in Swedish obese subjects. tes Care 2016;39:808–815 2009;41:459–471 N Engl J Med 2007;357:741–752 11. Schauer PR, Mingrone G, Ikramuddin S, Wolfe 25. Gudzune KA, Doshi RS, Mehta AK, et al. Effi- 41. Sjostr¨ om¨ L, Gummesson A, Sjostr¨ om¨ CD, B. Clinical outcomes of metabolic surgery: efficacy cacy of commercial weight-loss programs: an up- et al.; Swedish Obese Subjects Study. Effects of of glycemic control, weight loss, and remission of dated systematic review. Ann Intern Med 2015; bariatric surgery on cancer incidence in obese pa- diabetes. Diabetes Care 2016;39:902–911 162:501–512 12. Jensen MD, Ryan DH, Apovian CM, et al.; 26. Tsai AG, Wadden TA. The evolution of very- tients in Sweden (Swedish Obese Subjects Study): American College of Cardiology/American Heart low-calorie diets: an update and meta-analysis. a prospective, controlled intervention trial. Lancet – Association Task Force on Practice Guidelines; Obesity (Silver Spring) 2006;14:1283–1293 Oncol 2009;10:653 662 Obesity Society. 2013 AHA/ACC/TOS guideline 27. Johansson K, Neovius M, Hemmingsson E. Ef- 42. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. for the management of overweight and obesity fects of anti-obesity drugs, diet, and exercise on Bariatric surgery and long-term cardiovascular – in adults: a report of the American College of Car- weight-loss maintenance after a very-low-calorie events. JAMA 2012;307:56 65 diology/American Heart Association Task Force on diet or low-calorie diet: a systematic review and 43. Adams TD, Gress RE, Smith SC, et al. Long- Practice Guidelines and The Obesity Society. J Am meta-analysis of randomized controlled trials. Am term mortality after gastric bypass surgery. N Engl – Coll Cardiol 2014;63(25 Pt B):2985–3023 J Clin Nutr 2014;99:14–23 J Med 2007;357:753 761 13. Expert Consultation WHO; WHO Expert Con- 28. Cai X, Yang W, Gao X, Zhou L, Han X, Ji L. 44. Arterburn DE, Olsen MK, Smith VA, et al. As- sultation. Appropriate body-mass index for Asian Baseline body mass index and the efficacy of hy- sociation between bariatric surgery and long- populations and its implications for policy and in- poglycemic treatment in type 2 diabetes: a meta- term survival. JAMA 2015;313:62–70 tervention strategies. Lancet 2004;363:157–163 analysis. PLoS One 2016;11:e0166625 45. Adams TD, Arterburn DE, Nathan DM, Eckel 14. Araneta MR, Grandinetti A, Chang HK. Opti- 29. Phentermine. FDA prescribing information, RH. Clinical outcomes of metabolic surgery: mi- mum BMI cut points to screen Asian Americans side effects and uses [Internet], 2017. Available crovascular and macrovascular complications. Di- for type 2 diabetes: the UCSD Filipino Health from https://www.drugs.com/pro/phentermine abetes Care 2016;39:912–923 Study and the North Kohala Study (Abstract). Di- .html. Accessed 22 September 2017 46. Sheng B, Truong K, Spitler H, Zhang L, Tong X, abetes 2014;63(Suppl. 1):A20 30. Yanovski SZ, Yanovski JA. Long-term drug Chen L. The long-term effects of bariatric surgery 15. Wing RR, Bolin P, Brancati FL, et al.; Look treatment for obesity: a systematic and clinical on type 2 diabetes remission, microvascular and AHEAD Research Group. Cardiovascular effects review. JAMA 2014;311:74–86 macrovascular complications, and mortality: a of intensive lifestyle intervention in type 2 diabe- 31. Greenway FL, Fujioka K, Plodkowski RA, et al.; systematic review and meta-analysis. Obes Surg. tes. N Engl J Med 2013;369:145–154 COR-I Study Group. Effect of naltrexone plus bu- 11 August 2017 [Epub ahead of print]. DOI: 16. Look AHEAD Research Group. Eight-year propion on weight loss in overweight and obese 10.1007/s11695-017-2866-4 weight losses with an intensive lifestyle interven- adults (COR-I): a multicentre, randomised, double- 47. Rubino F, Kaplan LM, Schauer PR, Cummings tion: the Look AHEAD study. Obesity (Silver blind, placebo-controlled, phase 3 trial. Lancet DE; Diabetes Surgery Summit Delegates. The Di- Spring) 2014;22:5–13 2010;376:595–605 abetes Surgery Summit consensus conference: 17. Wilding JPH. The importance of weight man- 32. Pi-Sunyer X, Astrup A, Fujioka K, et al.; SCALE recommendations for the evaluation and use of agement in type 2 diabetes mellitus. Int J Clin Obesity and Prediabetes NN8022-1839 Study gastrointestinal surgery to treat type 2 diabetes Pract 2014;68:682–691 Group. A randomized, controlled trial of 3.0 mg mellitus. Ann Surg 2010;251:399–405 S72 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

48. Cummings DE, Cohen RV. Beyond BMI: the 60. Yu H, Di J, Bao Y, et al. Visceral fat area as a and complication rates after bariatric surgery. need for new guidelines governing the use of new predictor of short-term diabetes remission N Engl J Med 2013;369:1434–1442 bariatric and metabolic surgery. Lancet Diabetes after Roux-en-Y gastric bypass surgery in Chinese 72. Kirwan JP, Aminian A, Kashyap SR, Burguera Endocrinol 2014;2:175–181 patients with a body mass index less than 35 kg/m2. B, Brethauer SA, Schauer PR. Bariatric surgery in 49. Zimmet P, Alberti KGMM, Rubino F, Dixon JB. Surg Obes Relat Dis 2015;11:6–11 obese patients with type 1 diabetes. Diabetes IDF’s view of bariatric surgery in type 2 diabetes. 61. Halperin F, Ding S-A, Simonson DC, et al. Care 2016;39:941–948 Lancet 2011;378:108–110 Roux-en-Y gastric bypass surgery or lifestyle with 73. Rubin JK, Hinrichs-Krapels S, Hesketh R, 50. Kasama K, Mui W, Lee WJ, et al. IFSO-APC intensive medical management in patients with Martin A, Herman WH, Rubino F. Identifying bar- consensus statements 2011. Obes Surg 2012;22: type 2 diabetes: feasibility and 1-year results riers to appropriate use of metabolic/bariatric sur- 677–684 of a randomized clinical trial. JAMA Surg 2014; gery for type 2 diabetes treatment: policy lab 51. Ikramuddin S, Korner J, Lee W-J, et al. Dura- 149:716–726 results. Diabetes Care 2016;39:954–963 bility of addition of Roux-en-Y gastric bypass to 62. Flum DR, Belle SH, King WC, et al.; Longitudi- 74. Fouse T, Schauer P. The socioeconomic im- lifestyle intervention and medical management in nal Assessment of Bariatric Surgery (LABS) Con- pact of morbid obesity and factors affecting achieving primary treatment goals for uncon- sortium. Perioperative safety in the longitudinal access to obesity surgery. Surg Clin North Am trolled type 2 diabetes in mild to moderate obe- assessment of bariatric surgery. N Engl J Med 2016;96:669–679 sity: a randomized control trial. Diabetes Care 2009;361:445–454 75. Service GJ, Thompson GB, Service FJ, 2016;39:1510–1518 63. Courcoulas AP, Christian NJ, Belle SH, et al.; Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyper- 52. Sjoholm¨ K, Pajunen P, Jacobson P, et al. In- Longitudinal Assessment of Bariatric Surgery insulinemic hypoglycemia with nesidioblastosis cidence and remission of type 2 diabetes in re- (LABS) Consortium. Weight change and health after gastric-bypass surgery. N Engl J Med 2005; – lation to degree of obesity at baseline and 2 year outcomes at 3 years after bariatric surgery among 353:249 254 weight change: the Swedish Obese Subjects (SOS) individuals with severe obesity. JAMA 2013;310: 76. Mechanick JI, Kushner RF, Sugerman HJ, – study. Diabetologia 2015;58:1448–1453 2416 2425 et al.; American Association of Clinical Endocrinol- 53. Arterburn DE, Bogart A, Sherwood NE, et al. A 64. Arterburn DE, Courcoulas AP. Bariatric sur- ogists; Obesity Society; American Society for Met- multisite study of long-term remission and re- gery for obesity and metabolic conditions in abolic & Bariatric Surgery. American Association adults. BMJ 2014;349:g3961 of Clinical Endocrinologists, The Obesity Society, lapse of type 2 diabetes mellitus following gastric 65. Young MT, Gebhart A, Phelan MJ, Nguyen NT. and American Society for Metabolic & Bariatric bypass. Obes Surg 2013;23:93–102 Use and outcomes of laparoscopic sleeve gastrec- Surgery medical guidelines for clinical practice 54. Mingrone G, Panunzi S, De Gaetano A, et al. tomy vs laparoscopic gastric bypass: analysis of for the perioperative nutritional, metabolic, and Bariatric-metabolic surgery versus conventional the American College of Surgeons NSQIP. J Am nonsurgical support of the bariatric surgery pa- medical treatment in obese patients with type 2 Coll Surg 2015;220:880–885 tient. Obesity (Silver Spring) 2009;17(Suppl. 1): diabetes: 5 year follow-up of an open-label, single- 66. Aminian A, Brethauer SA, Kirwan JP, Kashyap S1–S70, v centre, randomised controlled trial. Lancet 2015; SR,Burguera B, Schauer PR. How safe is metabolic/ 77. Mechanick JI, Youdim A, Jones DB, et al.; 386:964–973 diabetes surgery? Diabetes Obes Metab 2015;17: American Association of Clinical Endocrinologists; 55.SchauerPR,BhattDL,KirwanJP,etal.; 198–201 Obesity Society; American Society for Metabolic & STAMPEDE Investigators. Bariatric surgery versus 67. Birkmeyer NJO, Dimick JB, Share D, et al.; Bariatric Surgery. Clinical practice guidelines for intensive medical therapy for diabetes: 5-year Michigan Bariatric Surgery Collaborative. Hospital the perioperative nutritional, metabolic, and non- – outcomes. N Engl J Med 2017;376:641 651 complication rates with bariatric surgery in Mich- surgical support of the bariatric surgery patientd 56. Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, igan. JAMA 2010;304:435–442 2013 update: cosponsored by American Association Wajchenberg BL, Cummings DE. Effects of gastric 68. Altieri MS, Yang J, Telem DA, et al. Lap band of Clinical Endocrinologists, The Obesity Society, bypass surgery in patients with type 2 diabetes and outcomes from 19,221 patients across centers and American Society for Metabolic & Bariatric – only mild obesity. Diabetes Care 2012;35:1420 and over a decade within the state of New York. Surgery. Obesity (Silver Spring) 2013;21(Suppl. 1): 1428 Surg Endosc 2016;30:1725–1732 S1–S27 57. Brethauer SA, Aminian A, Romero-Talamas´ H, 69. Hutter MM, Schirmer BD, Jones DB, et al. First 78. Lee CJ, Clark JM, Schweitzer M, et al. Preva- et al. Can diabetes be surgically cured? Long-term report from the American College of Surgeons lence of and risk factors for hypoglycemic symp- metabolic effects of bariatric surgery in obese pa- Bariatric Surgery Center Network: laparoscopic toms after gastric bypass and sleeve gastrectomy. tients with type 2 diabetes mellitus [discussion sleeve gastrectomy has morbidity and effective- Obesity (Silver Spring) 2015;23:1079–1084 appears in Ann Surg 2013;258:636–637]. Ann ness positioned between the band and the bypass 79. Conason A, Teixeira J, Hsu C-H, Puma L, Knafo Surg 2013;258:628–636 [discussion appears in Ann Surg 2011;254:420– D, Geliebter A. Substance use following bariatric 58. Hsu C-C, Almulaiﬁ A, Chen J-C, et al. Effect of 422]. Ann Surg 2011;254:410–420 weight loss surgery. JAMA Surg 2013;148:145– bariatric surgery vs medical treatment on type 2 70. Nguyen NT, Slone JA, Nguyen X-MT, Hartman 150 diabetes in patients with body mass index lower JS, Hoyt DB. A prospective randomized trial of 80. Young-HymanD,PeyrotM.Psychosocial Care than 35: ﬁve-year outcomes. JAMA Surg 2015; laparoscopic gastric bypass versus laparoscopic forPeoplewithDiabetes. 1st ed. Virginia, Ameri- 150:1117–1124 adjustable gastric banding for the treatment of can Diabetes Association, 2012, p. 240 59.SchauerPR,BhattDL,KirwanJP,etal.; morbid obesity: outcomes, quality of life, and 81. Greenberg I, Sogg S, M Perna F. Behavioral STAMPEDE Investigators. Bariatric surgery versus costs. Ann Surg 2009;250:631–641 and psychological care in weight loss surgery: best intensive medical therapy for diabetes: 3-year 71. BirkmeyerJD,FinksJF,O’Reilly A, et al.; Mich- practice update. Obesity (Silver Spring) 2009;17: outcomes. N Engl J Med 2014;370:2002–2013 igan Bariatric Surgery Collaborative. Surgical skill 880–884 Diabetes Care Volume 41, Supplement 1, January 2018 S73

8. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S73–S85 | https://doi.org/10.2337/dc18-S008 .PAMCLGCAPOCE OGYEI TREATMENT GLYCEMIC TO APPROACHES PHARMACOLOGIC 8.

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 Suggested citation: American Diabetes Associ- 1.0 units/kg/day of total insulin with higher amounts required during puberty. ation. 8. Pharmacologic approaches to glyce- The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes mic treatment: Standards of Medical Care in 0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): are metabolically stable, with higher weight-based dosing required immediately S73–S85 following presentation with ketoacidosis (1), and provides detailed information © 2017 by the American Diabetes Association. on intensiﬁcation of therapy to meet individualized needs. The American Diabetes Readers may use this article as long as the work “ is properly cited, the use is educational and not Association (ADA) position statement Type 1 Diabetes Management Through for proﬁt, and the work is not altered. More infor- theLifeSpan” additionally provides a thorough overview of type 1 diabetes mation is available at http://www.diabetesjournals treatment (2). .org/content/license. S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Education regarding matching prandial compared with U-100 glargine in patients placebo (23). The Reducing With Metformin insulin dosing to carbohydrate intake, with type 1 diabetes (19,20). Vascular Adverse Lesions in Type 1 Diabetes premeal glucose levels, and anticipated Rapid-acting inhaled insulin used be- (REMOVAL) trial investigated the addition activity should be considered, and se- fore meals in patients with type 1 diabe- of metformin therapy to titrated insulin lected individuals who have mastered tes was shown to be noninferior when therapy in adults with type 1 diabetes at carbohydrate counting should be edu- compared with aspart insulin for A1C low- increased risk for cardiovascular disease cated on fat and protein gram estimation ering, with less hypoglycemia observed and found that metformin did not signifi- (3–5). Although most studies of multiple with inhaled insulin therapy (21). How- cantly improve glycemic control beyond daily injections versus continuous subcu- ever, the mean reduction in A1C was the first 3 months of treatment and that taneous insulin infusion (CSII) have been greater with aspart (–0.21% vs. –0.40%, progression of atherosclerosis (measured small and of short duration, a systematic satisfying the noninferiority margin of by carotid artery intima-media thickness) review and meta-analysis concluded that 0.4%), and more patients in the insulin was not significantly reduced, although there are minimal differences between aspart group achieved A1C goals of other cardiovascular risk factors such as the two forms of intensive insulin therapy #7.0% (53 mmol/mol) and #6.5% (48 body weight and LDL cholesterol im- in A1C (combined mean between-group mmol/mol). Because inhaled insulin car- proved (24). Metformin is not FDA- difference favoring insulin pump therapy tridges are only available in 4-, 8-, and approved for use in patients with type 1 –0.30% [95% CI –0.58 to –0.02]) and se- 12-unit doses, limited dosing increments diabetes. vere hypoglycemia rates in children and to fine-tune prandial insulin doses in type 1 Incretin-Based Therapies adults (6). A 3-month randomized trial in diabetes are a potential limitation. Due to their potential protection of b-cell patients with type 1 diabetes with noctur- Postprandial glucose excursions may mass and suppression of glucagon release, nal hypoglycemia reported that sensor- be better controlled by adjusting the tim- glucagon-like peptide 1 (GLP-1) receptor augmented insulin pump therapy with ing of prandial (bolus) insulin dose admin- agonists (25) and dipeptidyl peptidase the threshold suspend feature reduced istration. The optimal time to administer 4 (DPP-4) inhibitors (26) are being studied nocturnal hypoglycemia without increas- prandial insulin varies, based on the type in patients with type 1 diabetes but are ing glycated hemoglobin levels (7). The of insulin used (regular, rapid-acting ana- not currently FDA-approved for use in pa- U.S. Food and Drug Administration (FDA) log, inhaled, etc.), measured blood glucose tients with type 1 diabetes. has also approved the first hybrid closed- level, timing of meals, and carbohydrate loop system pump. The safety and effi- consumption. Recommendations for pran- Sodium–Glucose Cotransporter 2 Inhibitors cacy of hybrid closed-loop systems has dial insulin dose administration should Sodium–glucose cotransporter 2 (SGLT2) been supported in the literature in ado- therefore be individualized. inhibitors provide insulin-independent lescents and adults with type 1 diabetes glucose lowering by blocking glucose re- (8,9). Pramlintide absorption in the proximal renal tubule by Intensive management using CSII and Pramlintide, an amylin analog, is an agent inhibiting SGLT2. These agents provide continuous glucose monitoring should be that delays gastric emptying, blunts pan- modest weight loss and blood pressure encouragedinselectedpatientswhen creatic secretion of glucagon, and en- reduction in type 2 diabetes. There are there is active patient/family participa- hances satiety. It is FDA-approved for use three FDA-approved agents for patients tion (10–12). in adults with type 1 diabetes. It has been with type 2 diabetes, but none are FDA- The Diabetes Control and Complica- shown to induce weight loss and lower in- approved for the treatment of patients tions Trial (DCCT) clearly showed that insulin doses. Concurrent reduction of pran- with type 1 diabetes (2). SGLT2 inhibitors tensive therapy with multiple daily dial insulin dosing is required to reduce the may have glycemic benefits in patients injections or CSII delivered by multidisci- risk of severe hypoglycemia. with type 1 or type 2 diabetes on insulin plinary teams of physicians, nurses, dieti- therapy (27). The FDA issued a warning tians, and behavioral scientists improved Investigational Agents about the risk of ketoacidosis occurring glycemia and resulted in better long-term Metformin in the absence of significant hyperglyce- outcomes (13–15). The study was carried Adding metformin to insulin therapy may mia (euglycemic diabetic ketoacidosis) out with short-acting and intermediate- reduce insulin requirements and improve in patients with type 1 or type 2 diabe- acting human insulins. Despite better mi- metabolic control in patients with type 1 tes treated with SGLT2 inhibitors. crovascular, macrovascular, and all-cause diabetes. In one study, metformin was Symptoms of ketoacidosis include dysp- mortality outcomes, intensive therapy found to reduce insulin requirements nea, nausea, vomiting, and abdominal was associated with a high rate of severe (6.6 units/day, P , 0.001), and led to pain. Patients should be instructed to hypoglycemia (61 episodes per 100 patient- small reductions in weight and total and stop taking SGLT2 inhibitors and seek years of therapy). Since the DCCT, a number LDL cholesterol but not to improved gly- medical attention immediately if they of rapid-acting and long-acting insulin an- cemic control (absolute A1C reduction have symptoms or signs of ketoacidosis alogs have been developed. These analogs 0.11%, P 5 0.42) (22). A randomized clin- (28). are associated with less hypoglycemia, ical trial similarly found that, among over- less weight gain, and lower A1C than human weight adolescents with type 1 diabetes, SURGICAL TREATMENT FOR insulins in people with type 1 diabetes the addition of metformin to insulin did TYPE 1 DIABETES (16–18). Longer-acting basal analogs not improve glycemic control and in- Pancreas and Islet Transplantation (U-300 glargine or degludec) may addi- creased risk for gastrointestinal adverse Pancreas and islet transplantation have tionally convey a lower hypoglycemia risk events after 6 months compared with been shown to normalize glucose levels care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S75

but require life-long immunosuppression and may reduce risk of cardiovascular therapy should begin with lifestyle to prevent graft rejection and recurrence events and death (32). Compared with management and metformin and of autoimmune islet destruction. Given sulfonylureas, metformin as first-line subsequently incorporate an agent the potential adverse effects of immuno- therapy has beneficial effects on A1C, proven to reduce major adverse car- suppressive therapy, pancreas transplan- weight, and cardiovascular mortality diovascular events and cardiovascu- tation should be reserved for patients (33). Metformin may be safely used in larmortality(currentlyempagliflozin with type 1 diabetes undergoing simulta- patients with estimated glomerular filtra- and liraglutide), after considering neous renal transplantation, following re- tion rate (eGFR) as low as 30 mL/min/ drug-specific and patient factors nal transplantation, or for those with 1.73 m2, and the FDA recently revised (Table 8.1). A* recurrent ketoacidosis or severe hypogly- the label for metformin to reflect its c In patients with type 2 diabetes and cemia despite intensive glycemic man- safety in patients with eGFR $30 mL/ established atherosclerotic cardiovascu- agement (29). min/1.73 m2 (34). Patients should be ad- lar disease, after lifestyle management vised to stop the medication in cases of PHARMACOLOGIC THERAPY FOR and metformin, the antihyperglycemic nausea, vomiting, or dehydration. Met- TYPE 2 DIABETES agent canagliflozin may be considered formin is associated with vitamin B12 to reduce major adverse cardiovascular deficiency, with a recent report from the Recommendations events, based on drug-specific and pa- c Diabetes Prevention Program Outcomes Metformin, if not contraindicated tient factors (Table 8.1). C* and if tolerated, is the preferred ini- Study (DPPOS) suggesting that periodic c Continuous reevaluation of the med- testing of vitamin B12 levels should be tial pharmacologic agent for the ication regimen and adjustment as A considered in metformin-treated pa- treatment of type 2 diabetes. needed to incorporate patient fac- c tients, especially in those with anemia Long-term use of metformin may be tors (Table 8.1) and regimen com- or peripheral neuropathy (35). associated with biochemical vitamin plexity is recommended. E B12 deficiency, and periodic mea- In patients with metformin contrain- c For patients with type 2 diabetes dications or intolerance, consider an ini- surement of vitamin B12 levels should who are not achieving glycemic goals, tial drug from another class depicted in be considered in metformin-treated drug intensification, including consid- Fig. 8.1 under “Dual Therapy” and pro- patients, especially in those with ane- eration of insulin therapy, should not B ceed accordingly. When A1C is $9% (75 mia or peripheral neuropathy. be delayed. B c Consider initiating insulin therapy mmol/mol), consider initiating dual com- c Metformin should be continued bination therapy (Fig. 8.1)tomoreexpe- (with or without additional agents) when used in combination with other ditiously achieve the target A1C level. in patients with newly diagnosed agents, including insulin, if not contra- Insulin has the advantage of being effec- type 2 diabetes who are symptom- indicated and if tolerated. A atic and/or have A1C $10% (86 tive where other agents may not be and mmol/mol) and/or blood glucose should be considered as part of any com- levels $300 mg/dL (16.7 mmol/L). E See Section 12 for recommendations bination regimen when hyperglycemia is c Consider initiating dual therapy in specific for children and adolescents severe, especially if catabolic features patients with newly diagnosed with type 2 diabetes. The use of metfor- (weight loss, ketosis) are present. Con- type 2 diabetes who have A1C min as first-line therapy was supported by sider initiating combination insulin in- $9% (75 mmol/mol). E findings from a large meta-analysis, with jectable therapy (Fig. 8.2)whenblood c In patients without atherosclerotic selection of second-line therapies based glucose is $300 mg/dL (16.7 mmol/L) or cardiovascular disease, if mono- on patient-specific considerations (30). A1C is $10% (86 mmol/mol) or if the pa- therapy or dual therapy does not An ADA/European Association for the Study tient has symptoms of hyperglycemia achieve or maintain the A1C goal of Diabetes position statement “Manage- (i.e., polyuria or polydipsia). As the pa- over 3 months, add an additional ment of Hyperglycemia in Type 2 Diabe- tient’s glucose toxicity resolves, the regi- antihyperglycemic agent based on tes, 2015: A Patient-Centered Approach” menmay,potentially,besimplified. drug-specific and patient factors (31) recommended a patient-centered ap- (Table 8.1). A proach, including assessment of efficacy, Combination Therapy c A patient-centered approach should hypoglycemia risk, impact on weight, side Although there are numerous trials be used to guide the choice of effects, costs, and patient preferences. Re- comparing dual therapy with metformin pharmacologic agents. Consider- nal effects may also be considered when alone, few directly compare drugs as add- ations include efficacy, hypoglyce- selecting glucose-lowering medications for on therapy. A comparative effectiveness mia risk, history of atherosclerotic individual patients. Lifestyle modifications meta-analysis (36) suggests that each cardiovascular disease, impact on that improve health (see Section 4 “Lifestyle new class of noninsulin agents added to weight, potential side effects, re- Management”) should be emphasized initial therapy generally lowers A1C ap- nal effects, delivery method (oral along with any pharmacologic therapy. proximately 0.7–1.0%. If the A1C target versus subcutaneous), cost, and is not achieved after approximately 3 months patient preferences. E Initial Therapy and patient does not have atherosclerotic c In patients with type 2 diabetes and Metformin monotherapy should be cardiovascular disease (ASCVD), consider established atherosclerotic cardio- started at diagnosis of type 2 diabetes un- a combination of metformin and any one vascular disease, antihyperglycemic less there are contraindications. Metfor- of the preferred six treatment options: min is effective and safe, is inexpensive, sulfonylurea, thiazolidinedione, DPP-4 S76 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

inhibitor, SGLT2 inhibitor, GLP-1 receptor second agent with evidence of cardiovas- dual therapy, proceed to a three-drug agonist, or basal insulin (Fig. 8.1); the choice cular risk reduction after consideration of combination (Fig. 8.1). Again, if A1C target of which agent to add is based on drug- drug-specific and patient factors (see p. S77 is not achieved after ;3 months of triple specific effects and patient factors (Table CARDIOVASCULAR OUTCOMES TRIALS). If A1C target therapy, proceed to combination injectable 8.1). For patients with ASCVD, add a is still not achieved after ;3monthsof therapy (Fig. 8.2). Drug choice is based on Table 8.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

*See ref. 31 for description of efﬁcacy. †FDA approved for CVD beneﬁt. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis; RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S77 S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. (31).

patient preferences (37), as well as various dual therapy, with continuous reevalu- Of note, prices listed are average whole- patient, disease, and drug characteristics, ation of patient factors to guide treat- sale prices (AWP) (39) and National Aver- with the goal of reducing blood glucose ment (Table 8.1). age Drug Acquisition Costs (NADAC) (40) levels while minimizing side effects, espe- Table 8.2 lists drugs commonly used in and do not account for discounts, re- cially hypoglycemia. If not already in- the U.S. Cost-effectiveness models of the bates, or other price adjustments often cluded in the treatment regimen, addition newer agents based on clinical utility and involved in prescription sales that affect of an agent with evidence of cardiovas- glycemic effect have been reported (38). the actual cost incurred by the patient. cular risk reduction should be consid- Table 8.3 provides cost information for Whiletherearealternativemeanstoesti- ered in patients with ASCVD beyond currently approved noninsulin therapies. mate medication prices, AWP and NADAC aedaeejunl.r hraooi prahst lcmcTetetS79 Treatment Glycemic to Approaches Pharmacologic care.diabetesjournals.org Table 8.2—Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)*

Biguanides c Metformin Activates AMP kinase (? other) ↓ Hepatic glucose production c No dose adjustment if eGFR .45; do not initiate OR assess risk/beneﬁt if currently on metformin if eGFR 30–45; discontinue if eGFR ,30

Sulfonylureas (2nd c Glyburide Closes KATP channels on b-cell ↑ Insulin secretion c Avoid use in patients with renal impairment generation) c Glipizide plasma membranes c Initiate conservatively at 2.5 mg daily to avoid hypoglycemia c Glimepiride c Initiate conservatively at 1 mg daily to avoid hypoglycemia

Meglitinides c Repaglinide Closes KATP channels on b-cell ↑ Insulin secretion c Initiate conservatively at 0.5 mg with meals if eGFR ,30 (glinides) c Nateglinide plasma membranes c Initiate conservatively at 60 mg with meals if eGFR ,30 Thiazolidinediones c Pioglitazone Activates the nuclear ↑ Insulin sensitivity c No dose adjustment required c Rosiglitazone§ transcription factor PPAR-g c No dose adjustment required a-Glucosidase c Acarbose Inhibits intestinal a-glucosidase Slows intestinal carbohydrate c Avoid if eGFR ,30 inhibitors c Miglitol digestion/absorption c Avoid if eGFR ,25 DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, ↑ Insulin secretion (glucose c 100 mg daily if eGFR .50; increasing postprandial incretin dependent); 50 mg daily if eGFR 30–50; (GLP-1, GIP) concentrations ↓ Glucagon secretion (glucose 25 mg daily if eGFR ,30 dependent) c Saxagliptin c 5 mg daily if eGFR .50; 2.5 mg daily if eGFR #50 c Linagliptin c No dose adjustment required

c Alogliptin c 25 mg daily if eGFR .60; 12.5 mg daily if eGFR 30–60; 6.25 mg daily if eGFR ,30 Bile acid c Colesevelam Binds bile acids in intestinal ? ↓ Hepatic glucose production; c No specific dose adjustment recommended by manufacturer sequestrants tract, increasing hepatic bile ? ↑ Incretin levels acid production Dopamine-2 c Bromocriptine (quick Activates dopaminergic receptors Modulates hypothalamic regulation c No specific dose adjustment recommended by manufacturer agonists release)§ of metabolism; ↑ Insulin sensitivity SGLT2 inhibitors c Canagliflozin Inhibits SGLT2 in the proximal Blocks glucose reabsorption by the c No dose adjustment required if eGFR $60; nephron kidney, increasing glucosuria 100 mg daily if eGFR 45–59; avoid use and discontinue in patients with eGFR persistently ,45 c Dapagliflozin c Avoid initiating if eGFR ,60; not recommended with eGFR 30–60; contraindicated with eGFR ,30 c Empagliflozin c Contraindicated with eGFR ,30 GLP-1 receptor c Exenatide Activates GLP-1 ↑ Insulin secretion (glucose c Not recommended with eGFR ,30 agonists c Exenatide extended receptors dependent) c Not recommended with eGFR ,30 release Continued on p. S80 8 hraooi prahst lcmcTreatment Glycemic to Approaches Pharmacologic S80

Table 8.2—Continued Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)* c Liraglutide ↓ Glucagon secretion (glucose c No specific dose adjustment recommended by the manufacturer; limited dependent); experience in patients with severe renal impairment c Albiglutide Slows gastric emptying; c No dose adjustment required for eGFR 15–89 per manufacturer; limited ↑ Satiety experience in patients with severe renal impairment c Lixisenatide c No dose adjustment required for eGFR 60–89; no dose adjustment required for eGFR 30–59, but patients should be monitored for adverse effects and changes in kidney function; clinical experience is limited with eGFR 15–29; patients should be monitored for adverse effects and changes in kidney function; avoid if eGFR ,15 c Dulaglutide c No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment Amylin mimetics c Pramlintide§ Activates amylin receptors ↓ Glucagon secretion; c No specific dose adjustment recommended by manufacturer Slows gastric emptying; ↑ Satiety Insulins c Rapid-acting analogs Activates insulin receptors ↑ Glucose disposal; c Lower insulin doses required with a decrease in eGFR; titrate per clinical Lispro ↓ Hepatic glucose production; response Aspart Suppresses ketogenesis Glulisine Inhaled insulin c Short-acting analogs

Human Regular Care Diabetes c Intermediate-acting analogs Human NPH c Basal insulin analogs Glargine

Detemir 2018 January 1, Supplement 41, Volume Degludec c Premixed insulin products NPH/Regular 70/30 70/30 aspart mix 75/25 lispro mix 50/50 lispro mix *eGFR is given in mL/min/1.73 m2. §Not licensed in Europe for type 2 diabetes. GIP, glucose-dependent insulinotropic peptide; PPAR-g, peroxisome proliferator–activated receptor g. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S81

Table 8.3—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. Dosage strength/product Median AWP Median NADAC Maximum approved Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose* Biguanides c Metformin 500 mg (IR) $84 ($4, $93) $2 2,000 mg 850 mg (IR) $108 ($6, $109) $3 2,550 mg 1,000 mg (IR) $87 ($4, $88) $2 2,000 mg 500 mg (ER) $89 ($82, $6,671) $5 ($5, $3,630) 2,000 mg 750 mg (ER) $72 ($65, $92) $5 1,500 mg 1,000 mg (ER) $1,028 ($1,028, $539 ($539, $5,189) 2,000 mg $7,214) Sulfonylureas c Glyburide 5 mg $93 ($63, $103) $17 20 mg (2nd generation) 6 mg (micronized) $50 ($48, $71) $12 12 mg (micronized) c Glipizide 10 mg (IR) $75 ($67, $97) $4 40 mg (IR) 10 mg (XL) $48 $16 20 mg (XL) c Glimepiride 4 mg $71 ($71, $198) $7 8 mg Meglitinides (glinides) c Repaglinide 2 mg $659 ($122, $673) $40 16 mg c Nateglinide 120 mg $155 $56 360 mg Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $5 45 mg c Rosiglitazone 4 mg $387 $314 8 mg a-Glucosidase c Acarbose 100 mg $104 ($104, $106) $25 300 mg inhibitors c Miglitol 100 mg $241 N/A†† 300 mg DPP-4 inhibitors c Sitagliptin 100 mg $477 $382 100 mg c Saxagliptin 5 mg $462 $370 5 mg c Linagliptin 5 mg $457 $367 5 mg c Alogliptin 25 mg $449 $357 25 mg Bile acid sequestrants c Colesevelam 625 mg tabs $713 $570 3.75 g 1.875 g suspension $1,426 $572 3.75 g Dopamine-2 agonists c Bromocriptine 0.8 mg $784 $629 4.8 mg SGLT2 inhibitors c Canagliflozin 300 mg $512 $411 300 mg c Dapagliflozin 10 mg $517 $413 10 mg c Empagliflozin 25 mg $517 $415 25 mg GLP-1 receptor c Exenatide 10 mg pen $802 $642 20 mg agonists c Lixisenatide 20 mg pen $669 N/A†† 20 mg c Liraglutide 18 mg/3 mL pen $968 $775 1.8 mg c Exenatide (extended 2 mg powder for $747 $600 2 mg** release) suspension or pen c Albiglutide 50 mg pen $626 $500 50 mg** c Dulaglutide 1.5/0.5 mL pen $811 $648 1.5 mg** Amylin mimetics c Pramlintide 120 mg pen $2,336 N/A†† 120 mg/injection††† ER and XL, extended release; IR, immediate release. †Calculated for 30-day supply (AWP or NADAC unit price 3 number of doses required to provide maximum approved daily dose 3 30 days); median AWP or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if available commercially. ††Not applicable; data not available. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily. wereutilizedtoprovidetwoseparatemea- late postprandial hypoglycemia when The empagliflozin and liraglutide trials sures to allow for a comparison of drug taking a sulfonylurea. Other drugs not demonstrated significant reductions in prices with the primary goal of highlighting shown in Table 8.1 (e.g., inhaled insulin, cardiovascular death. Exenatide once- the importance of cost considerations a-glucosidase inhibitors, colesevelam, bro- weekly did not have statistically sig- when prescribing antihyperglycemic treat- mocriptine, and pramlintide) may be tried nificant reductions in major adverse ments. The ongoing Glycemia Reduction in specific situations but considerations cardiovascular events or cardiovascu- Approaches in Diabetes: A Comparative Ef- include modest efficacy in type 2 diabetes, lar mortality but did have a significant fectiveness Study (GRADE) will compare frequency of administration, potential for reduction in all-cause mortality. In con- four drug classes (sulfonylurea, DPP-4 in- drug interactions, cost, and/or side effects. trast, other GLP-1 receptor agonists hibitor, GLP-1 receptor agonist, and basal have not shown similar reductions in insulin) when added to metformin therapy Cardiovascular Outcomes Trials cardiovascular events (Table 9.4). over 4 years on glycemic control and other There are now three large randomized Whether the benefits of GLP-1 receptor medical, psychosocial, and health economic controlled trials reporting statistically sig- agonists are a class effect remains to be outcomes (41). nificant reductions in cardiovascular events definitively established. See ANTIHYPERGLYCEMIC Rapid-acting secretagogues (meglitinides) for two SGLT2 inhibitors (empagliflozin THERAPIES AND CARDIOVASCULAR OUTCOMES in may be used instead of sulfonylureas in and canagliflozin) and one GLP-1 receptor Section 9 “Cardiovascular Disease and patients with sulfa allergies or irregular agonist (liraglutide) where the majority, if Risk Management” and Table 9.4 for a de- meal schedules or in those who develop not all patients, in the trial had ASCVD. tailed description of these cardiovascular S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Table 8.4—Median cost of insulin products in the U.S. calculated as AWP (39) and NADAC (40) per 1,000 units of specified dosage form/product Median AWP Median NADAC Insulins Compounds Dosage form/product (min, max)* (min, max)* Rapid-acting c Lispro U-100 vial; $330 $264 analogs U-100 3 mL cartridges; $408 $326 U-100 prefilled pen; U-200 prefilled pen $424 $339 c Aspart U-100 vial; $331 $265 U-100 3 mL cartridges; $410 $330 U-100 prefilled pen $426 $341 c Glulisine U-100 vial; $306 $245 U-100 prefilled pen $394 $315 c Inhaled insulin Inhalation cartridges $725 ($544, $911) N/A† Short-acting analogs c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $145) Intermediate-acting analogs c Human NPH U-100 vial; $165 ($165, $178) $135 ($135, $145) U-100 prefilled pen $377 $305 Concentrated Human c U-500 Human U-500 vial; $178 $143 Regular insulin Regular insulin U-500 prefilled pen $230 $184 Basal analogs c Glargine U-100 vial; U-100 prefilled pen; $298 $239 ($239, $241) U-300 prefilled pen c Glargine biosimilar U-100 prefilled pen $253 $203 c Detemir U-100 vial; U-100 prefilled pen $323 $259 c Degludec U-100 prefilled pen; U-200 prefilled pen $355 $285 Premixed insulin products c NPH/Regular 70/30 U-100 vial; $165 ($165, $178) $134 ($134, $146) U-100 prefilled pen $377 $305 c Lispro 50/50 U-100 vial; $342 $278 U-100 prefilled pen $424 $339 c Lispro 75/25 U-100 vial; $342 $273 U-100 prefilled pen $424 $340 c Aspart 70/30 U-100 vial; $343 $275 U-100 prefilled pen $426 $341 Premixed insulin/GLP-1 c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A† receptor agonist products c Glargine/Lixisenatide 100/33 prefilled pen $508 $404 *AWP or NADAC calculated as in Table 8.3; median listed alone when only one product and/or price. †Not applicable; data not available.

outcomes trials. Additional large random- avoid using insulin as a threat or de- to reduce the risk of symptomatic and noc- ized trials of other agents in these classes scribing it as a sign of personal failure turnal hypoglycemia (43–48). Longer- are ongoing. or punishment. acting basal analogs (U-300 glargine or Of note, these studies examined the Equipping patients with an algorithm for degludec) may additionally convey a drugs in combination with metformin self-titration of insulin doses based on self- lower hypoglycemia risk compared with (Table 9.4) in the great majority of pa- monitoring of blood glucose improves U-100 glargine when used in combination tients for whom metformin was not con- glycemic control in patients with type 2 di- with oral antihyperglycemic agents (49– traindicated or not tolerated. For patients abetes initiating insulin (42). Comprehen- 55). While there is evidence for reduced with type 2 diabetes who have ASCVD, on sive education regarding self-monitoring hypoglycemia with newer, longer-acting lifestyle and metformin therapy, it is rec- of blood glucose, diet, and the avoidance basal insulin analogs, people without a ommended to incorporate an agent with of and appropriate treatment of hypogly- history of hypoglycemia are at decreased strong evidence for cardiovascular risk re- cemia are critically important in any pa- risk and could potentially be switched to duction especially those with proven ben- tient using insulin. human insulin safely. Thus, due to high efit on both major adverse cardiovascular costs of analog insulins, use of human in- events and cardiovascular death after con- Basal Insulin sulin may be a practical option for some sideration of drug-specific patient factors Basal insulin alone is the most convenient patients, and clinicians should be familiar (Table 8.1). See Fig. 8.1 for additional rec- initial insulin regimen, beginning at 10 units with its use (56). Table 8.4 provides AWP ommendations on antihyperglycemic per day or 0.1–0.2 units/kg/day, depend- (39) and NADAC (40) information (cost treatment in adults with type 2 diabetes. ing on the degree of hyperglycemia. Basal per 1,000 units) for currently available in- insulin is usually prescribed in conjunc- sulin and insulin combination products Insulin Therapy tion with metformin and sometimes one in the U.S. There have been substantial Many patients with type 2 diabetes even- additional noninsulin agent. When basal increases in the price of insulin over the tually require and benefitfrominsulin insulin is added to antihyperglycemic past decade and the cost-effectiveness therapy. The progressive nature of type 2 agents in patients with type 2 diabetes, of different antihyperglycemic agents is diabetes should be regularly and objectively long-acting basal analogs (U-100 glargine an important consideration in a patient- explained to patients. Providers should or detemir) can be used instead of NPH centered approach to care, along with care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S83

efficacy, hypoglycemia risk, weight, and pulmonary disease and is not recommended insulin (NPH/Regular 70/30, 70/30 aspart other patient and drug-specific factors in patients who smoke or who recently stop- mix, 75/25 or 50/50 lispro mix) twice (Table 8.1)(57). ped smoking. It requires spirometry (FEV1) daily, usually before breakfast and before testing to identify potential lung disease in all dinner. Each approach has its advan- Bolus Insulin Many individuals with type 2 diabetes patients prior to and after starting therapy. tages and disadvantages. For example, may require mealtime bolus insulin dos- providers may wish to consider regimen fl ing in addition to basal insulin. Rapid- Combination Injectable Therapy exibility when devising a plan for the ini- acting analogs are preferred due to their If basal insulin has been titrated to an ac- tiation and adjustment of insulin therapy prompt onset of action after dosing. In ceptable fasting blood glucose level (or if in people with type 2 diabetes, with rapid- . fl September 2017, the FDA approved a new the dose is 0.5 units/kg/day) and A1C re- acting insulin offering greater exibility in faster-acting formulation of insulin aspart. mains above target, consider advancing terms of meal planning than premixed in- Fig. The recommended starting dose of meal- to combination injectable therapy ( sulin. If one regimen is not effective (i.e., 8.2 time insulin is 4 units, 0.1 units/kg, or 10% ). When initiating combination inject- basal insulin plus GLP-1 receptor agonist), of the basal dose. If A1C is ,8% (64 mmol/ able therapy, metformin therapy should consider switching to another regimen to mol) when starting mealtime bolus in- be maintained while other oral agents achieve A1C targets (i.e., basal insulin plus sulin, consideration should be given to may be discontinued on an individual ba- single injection of rapid-acting insulin or pre- decreasing the basal insulin dose. sis to avoid unnecessarily complex or mixed insulin twice daily) (60,61). Regular costly regimens (i.e., adding a fourth anti- human insulin and human NPH/Regular Premixed Insulin hyperglycemic agent). In general, GLP-1 premixed formulations (70/30) are less Premixed insulin products contain both a receptor agonists should not be discon- costly alternatives to rapid-acting insulin basal and prandial component, allowing tinued with the initiation of basal insulin. analogs and premixed insulin analogs, coverage of both basal and prandial needs Sulfonylureas, DPP-4 inhibitors, and GLP- respectively, but their pharmacody- with a single injection. NPH/Regular 70/30 1 receptor agonists are typically stopped namic profiles may make them less optimal. insulin, for example, is composed of 70% once more complex insulin regimens be- Fig. 8.2 outlines these options, as well NPH insulin and 30% regular insulin. The use yond basal are used. In patients with sub- as recommendations for further intensifi- of premixed insulin products has its advan- optimal blood glucose control, especially cation, if needed, to achieve glycemic tages and disadvantages, as discussed be- those requiring large insulin doses, adjunc- goals. If a patient is still above the A1C low in COMBINATION INJECTABLE THERAPY. tive use of a thiazolidinedione or SGLT2 target on premixed insulin twice daily, Concentrated Insulin Products inhibitor may help to improve control consider switching to premixed analog in- Several concentrated insulin preparations and reduce the amount of insulin needed, sulin three times daily (70/30 aspart mix, are currently available. U-500 regular insu- though potential side effects should be 75/25 or 50/50 lispro mix). In general, lin, by definition, is fivetimesasconcen- considered. Once an insulin regimen is ini- three times daily premixed analog insu- trated as U-100 regular insulin and has a tiated, dose titration is important with ad- lins have been found to be noninferior delayed onset and longer duration of ac- justments made in both mealtime and to basal-bolus regimens with similar rates tion than U-100 regular, possessing both basal insulins based on the blood glucose of hypoglycemia (62). If a patient is still prandial and basal properties. U-300 glar- levels and an understanding of the phar- above the A1C target on basal insulin gine and U-200 degludec are three and macodynamic profile of each formulation plus single injection of rapid-acting insulin two times as concentrated as their U-100 (pattern control). before the largest meal, advance to a formulations and allow higher doses of basal Studies have demonstrated the non- basal-bolus regimen with $2 injections insulin administration per volume used. inferiority of basal insulin plus a single of rapid-acting insulin before meals. Con- U-300 glargine has a longer duration of ac- injection of rapid-acting insulin at the larg- sider switching patients from one regimen tion than U-100 glargine. The FDA has also est meal relative to basal insulin plus a to another (i.e., premixed analog insulin approved a concentrated formulation of GLP-1 receptor agonist relative to two three times daily to basal-bolus regimen rapid-acting insulin lispro, U-200 (200 daily injections of premixed insulins or vice-versa) if A1C targets are not being units/mL). These concentrated preparations (Fig. 8.2). Basal insulin plus GLP-1 recep- met and/or depending on other patient may be more comfortable for the patient tor agonists are associated with less hy- considerations (60,61). Metformin should and may improve adherence for patients poglycemia and with weight loss instead be continued in patients on combination with insulin resistance who require large of weight gain but may be less tolerable injectable insulin therapy, if not contra- doses of insulin. While U-500 regular insulin and have a greater cost (58,59). In No- indicated and if tolerated, for further gly- is available in both prefilledpensandvials(a vember 2016, the FDA approved two dif- cemic benefits. dedicated syringe was FDA approved in July ferent once-daily fixed-dual combination 2016), other concentrated insulins are avail- products containing basal insulin plus a References fi GLP-1 receptor agonist: insulin glargine able only in pre lled pens to minimize the 1. Peters AL, Laffel L, Eds. American Diabetes risk of dosing errors. plus lixisenatide and insulin degludec Association/JDRF Type 1 Diabetes Sourcebook. plus liraglutide. Other options for treat- Alexandria, VA, American Diabetes Association, Inhaled Insulin ment intensification include adding a sin- 2013 Inhaled insulin is available for prandial use gle injection of rapid-acting insulin analog 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; Type 1 Diabetes Sourcebook Authors. Type 1 di- with a more limited dosing range. It is contra- (lispro, aspart, or glulisine) before the abetes through the life span: a position statement indicated in patients with chronic lung dis- largest meal or stopping the basal insulin of the American Diabetes Association. Diabetes ease such as asthma and chronic obstructive and initiating a premixed (or biphasic) Care 2014;37:2034–2054 S84 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

3. Wolpert HA, Atakov-Castillo A, Smith SA, Steil with type 1 diabetes: systematic review and net- 30. Palmer SC, Mavridis D, Nicolucci A, et al. Com- GM. Dietary fat acutely increases glucose con- work meta-analysis. BMJ 2014;349:g5459 parison of clinical outcomes and adverse events centrations and insulin requirements in pa- 17. Bartley PC, Bogoev M, Larsen J, Philotheou A. associated with glucose-lowering drugs in patients tients with type 1 diabetes: implications for Long-term efficacy and safety of insulin detemir with type 2 diabetes: a meta-analysis. JAMA 2016; carbohydrate-based bolus dose calculation compared to Neutral Protamine Hagedorn insulin 316:313–324 and intensive diabetes management. Diabetes in patients with type 1 diabetes using a treat-to- 31. Inzucchi SE, Bergenstal RM, Buse JB, et al. Care 2013;36:810–816 target basal-bolus regimen with insulin aspart at Management of hyperglycemia in type 2 diabe- 4. Bell KJ, Toschi E, Steil GM, Wolpert HA. Opti- meals: a 2-year, randomized, controlled trial. Dia- tes, 2015: a patient-centered approach: update mized mealtime insulin dosing for fat and protein bet Med 2008;25:442–449 to a position statement of the American Diabe- in type 1 diabetes: application of a model-based 18. DeWitt DE, Hirsch IB. Outpatient insulin ther- tes Association and the European Association approach to derive insulin doses for open-loop apy in type 1 and type 2 diabetes mellitus: scien- for the Study of Diabetes. Diabetes Care 2015; diabetes management. Diabetes Care 2016;39: tific review. JAMA 2003;289:2254–2264 38:140–149 1631–1634 19. Lane W, Bailey TS, Gerety G, et al.; SWITCH 1. 32. Holman RR, Paul SK, Bethel MA, Matthews 5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, Effect of insulin degludec vs insulin glargine U100 DR, Neil HAW. 10-year follow-up of intensive glu- King B, Wolpert HA. Impact of fat, protein, and on hypoglycemia in patients with type 1 diabetes: cose control in type 2 diabetes. N Engl J Med 2008; glycemic index on postprandial glucose control in the SWITCH 1 Randomized Clinical Trial. JAMA 359:1577–1589 type 1 diabetes: implications for intensive diabetes 2017;318:33–44 33. Maruthur NM, Tseng E, Hutfless S, et al. Di- management in the continuous glucose monitoring 20. Home PD, Bergenstal RM, Bolli GB, et al. New abetes medications as monotherapy or metformin- era. Diabetes Care 2015;38:1008–1015 insulin glargine 300 units/mL versus glargine based combination therapy for type 2 diabetes: a 6. Yeh H-C, Brown TT, Maruthur N, et al. Compar- 100 units/mL in people with type 1 diabetes: a systematic review and meta-analysis. Ann Intern ative effectiveness and safety of methods of in- randomized, phase 3a, open-label clinical trial Med 2016;164:740–751 sulin delivery and glucose monitoring for diabetes (EDITION 4). Diabetes Care 2015;38:2217–2225 34. U.S. Food and Drug Administration. Metformin- mellitus: a systematic review and meta-analysis. 21. Bode BW, McGill JB, Lorber DL, Gross JL, containing drugs: drug safety communication - Ann Intern Med 2012;157:336–347 Chang PC, Bregman DB; Affinity 1 Study Group. revised warnings for certain patients with 7. Bergenstal RM, Klonoff DC, Garg SK, et al.; Inhaled technosphere insulin compared with in- reduced kidney function [Internet], 2016. Available ASPIRE In-Home Study Group. Threshold-based jected prandial insulin in type 1 diabetes: a ran- from http://www.fda.gov/Safety/MedWatch/ insulin-pump interruption for reduction of hypo- domized 24-week trial. Diabetes Care 2015;38: SafetyInformation/SafetyAlertsforHumanMedical glycemia. N Engl J Med 2013;369:224–232 2266–2273 Products/ucm494829.htm?source5govdelivery& 8.BergenstalRM,GargS,WeinzimerSA,etal. 22. Vella S, Buetow L, Royle P, Livingstone S, utm_medium5email&utm_source5govdelivery. Safety of a hybrid closed-loop insulin delivery sys- Colhoun HM, Petrie JR. The use of metformin in Accessed 3 October 2016 tem in patients with type 1 diabetes. JAMA 2016; type 1 diabetes: a systematic review of efficacy. 35. Aroda VR, Edelstein SL, Goldberg RB, et al.; 316:1407–1408 Diabetologia 2010;53:809–820 Diabetes Prevention Program Research Group. 9. Garg SK, Weinzimer SA, Tamborlane WV, et al. 23. Libman IM, Miller KM, DiMeglio LA, et al.; T1D Long-term metformin use and vitamin B12 defi- Glucose outcomes with the in-home use of a hy- Exchange Clinic Network Metformin RCT Study ciency in the Diabetes Prevention Program Out- brid closed-loop insulin delivery system in adoles- Group. Effect of metformin added to insulin on comes Study. J Clin Endocrinol Metab 2016;101: cents and adults with type 1 diabetes. Diabetes glycemic control among overweight/obese ado- 1754–1761 Technol Ther 2017;19:155–163 lescents with type 1 diabetes: a randomized clin- 36. Bennett WL, Maruthur NM, Singh S, et al. 10. Wood JR, Miller KM, Maahs DM, et al.; T1D ical trial. JAMA 2015;314:2241–2250 Comparative effectiveness and safety of medica- Exchange Clinic Network. Most youth with type 1 24.PetrieJR,ChaturvediN,FordI,etal.; tions for type 2 diabetes: an update including new diabetes in the T1D Exchange Clinic Registry do not REMOVAL Study Group. Cardiovascular and met- drugs and 2-drug combinations. Ann Intern Med meet American Diabetes Association or International abolic effects of metformin in patients with type 1 2011;154:602–613 Society for Pediatric and Adolescent Diabetes clinical diabetes (REMOVAL): a double-blind, rando- 37. Vijan S, Sussman JB, Yudkin JS, Hayward RA. guidelines. Diabetes Care 2013;36:2035–2037 mised, placebo-controlled trial. Lancet Diabetes Effect of patients’ risks and preferences on health 11. Kmietowicz Z. Insulin pumps improve control Endocrinol 2017;5:597–609 gains with plasma glucose level lowering in type 2 and reduce complications in children with type 1 25. Dejgaard TF, Frandsen CS, Hansen TS, et al. diabetes mellitus. JAMA Intern Med 2014;174: diabetes. BMJ 2013;347:f5154 Efficacy and safety of liraglutide for overweight 1227–1234 12. Phillip M, Battelino T, Atlas E, et al. Nocturnal adult patients with type 1 diabetes and insufficient 38. Institute for Clinical and Economic Review. glucose control with an artificial pancreas at a di- glycaemic control (Lira-1): a randomised, double- Controversies in the management of patients with abetes camp. N Engl J Med 2013;368:824–833 blind, placebo-controlled trial. Lancet Diabetes type 2 diabetes [Internet], 2014. Available from 13.NathanDM,GenuthS,LachinJ,etal.;Diabe- Endocrinol 2016;4:221–232 https://icer-review.org/wp-content/uploads/ tes Control and Complications Trial Research 26. Guo H, Fang C, Huang Y, Pei Y, Chen L, Hu J. 2015/03/CEPAC-T2D-Final-Report-December-22 Group. The effect of intensive treatment of dia- The efficacy and safety of DPP4 inhibitors in pa- .pdf. Accessed 2 November 2017 betes on the development and progression of tients with type 1 diabetes: a systematic review 39. Truven Health Analytics. Red Book: A Com- long-term complications in insulin-dependent and meta-analysis. Diabetes Res Clin Pract 2016; prehensive, Consistent Drug Pricing Resource diabetes mellitus. N Engl J Med 1993;329:977– 121:184–191 [Internet], 2016. Available from: http://www 986 27. Yang Y, Chen S, Pan H, et al. Safety and effi- .micromedexsolutions.com/micromedex2/librarian. 14. Nathan DM, Cleary PA, Backlund J-YC, et al.; ciency of SGLT2 inhibitor combining with insulin in Accessed 18 July 2017 Diabetes Control and Complications Trial/ subjects with diabetes: systematic review and 40. Centers for Medicare & Medicaid Services. Epidemiology of Diabetes Interventions and Com- meta-analysis of randomized controlled trials. Pharmacy pricing: national average drug acquisi- plications (DCCT/EDIC) Study Research Group. In- Medicine (Baltimore) 2017;96:e6944 tion cost [Internet], 2017. Available from https:// tensive diabetes treatment and cardiovascular 28. U.S. Food and Drug Administration. SGLT2 www.medicaid.gov/medicaid/prescription-drugs/ disease in patients with type 1 diabetes. N Engl J inhibitors: drug safety communication - labels to pharmacy-pricing/index.html. Accessed 19 July Med 2005;353:2643–2653 include warnings about too much acid in the blood 2017 15. Diabetes Control and Complications Trial and serious urinary tract infections [Internet], 2015. 41. Nathan DM, Buse JB, Kahn SE, et al.; GRADE (DCCT)/Epidemiology of Diabetes Interventions Available from http://www.fda.gov/safety/ Study Research Group. Rationale and design of and Complications (EDIC) Study Research Group. medwatch/safetyinformation/safetyalertsforhuma the Glycemia Reduction Approaches in Diabetes: Mortality in type 1 diabetes in the DCCT/EDIC nmedicalproducts/ucm475553.htm. Accessed 3 A Comparative Effectiveness Study (GRADE). Di- versus the general population. Diabetes Care October 2016 abetes Care 2013;36:2254–2261 2016;39:1378–1383 29. Robertson RP, Davis C, Larsen J, Stratta R, 42. Blonde L, Merilainen M, Karwe V, Raskin P; 16. Tricco AC, Ashoor HM, Antony J, et al. Safety, Sutherland DER; American Diabetes Association. TITRATE Study Group. Patient-directed titra- effectiveness, and cost effectiveness of long act- Pancreas and islet transplantation in type 1 dia- tion for achieving glycaemic goals using a once- ing versus intermediate acting insulin for patients betes. Diabetes Care 2006;29:935 daily basal insulin analogue: an assessment of care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S85

two different fasting plasma glucose targets - the in Japanese people with type 2 diabetes using in type 2 diabetes. Diabetes Care 2014;37:2763– TITRATE study. Diabetes Obes Metab 2009;11: basal insulin and oral antihyperglycaemic drugs: 2773 623–631 glucose control and hypoglycaemia in a random- 59. Eng C, Kramer CK, Zinman B, Retnakaran R. 43. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett ized controlled trial (EDITION JP 2). Diabetes Obes Glucagon-like peptide-1 receptor agonist and H. Efficacy and safety of insulin analogues for the Metab 2016;18:366–374 basal insulin combination treatment for the management of diabetes mellitus: a meta-analysis. 51. Yki-Jarvinen¨ H, Bergenstal RM, Bolli GB, et al. management of type 2 diabetes: a systematic CMAJ 2009;180:385–397 Glycaemic control and hypoglycaemia with new review and meta-analysis. Lancet 2014;384: 44. Horvath K, Jeitler K, Berghold A, et al. Long- insulin glargine 300 U/ml versus insulin glargine 2228–2234 acting insulin analogues versus NPH insulin (hu- 100 U/ml in people with type 2 diabetes using 60. Dieuzeide G, Chuang L-M, Almaghamsi A, man isophane insulin) for type 2 diabetes mellitus. basal insulin and oral antihyperglycaemic drugs: Zilov A, Chen J-W, Lavalle-Gonzalez´ FJ. Safety Cochrane Database Syst Rev 2007;2:CD005613 the EDITION 2 randomized 12-month trial including and effectiveness of biphasic insulin aspart 30 in 45. Monami M, Marchionni N, Mannucci E. Long- 6-month extension. Diabetes Obes Metab 2015; people with type 2 diabetes switching from basal- acting insulin analogues versus NPH human insu- 17:1142–1149 bolus insulin regimens in the A1chieve study. Prim lin in type 2 diabetes: a meta-analysis. Diabetes 52. Marso SP, McGuire DK, Zinman B, et al. Effi- Care Diabetes 2014;8:111–117 Res Clin Pract 2008;81:184–189 cacy and safety of degludec versus glargine in 61. Mathieu C, Storms F, Tits J, Veneman TF, Colin 46. Owens DR, Traylor L, Mullins P, Landgraf W. type 2 diabetes. N Engl J Med 2017;377:723–732 IM. Switching from premixed insulin to basal- Patient-level meta-analysis of efficacy and hypo- 53. Rodbard HW, Cariou B, Zinman B, et al.; BEGIN bolus insulin glargine plus rapid-acting insulin: glycaemia in people with type 2 diabetes initiating Once Long trial investigators. Comparison of insu- the ATLANTIC study. Acta Clin Belg 2013;68:28– insulin glargine 100U/mL or neutral protamine lin degludec with insulin glargine in insulin-naive 33 Hagedorn insulin analysed according to concomi- subjects with Type 2 diabetes: a 2-year random- 62. Giugliano D, Chiodini P, Maiorino MI, tant oral antidiabetes therapy. Diabetes Res Clin ized, treat-to-target trial. Diabet Med 2013;30: Bellastella G, Esposito K. Intensification of insulin Pract 2017;124(Suppl. C):57–65 1298–1304 therapy with basal-bolus or premixed insulin reg- 47. Riddle MC, Rosenstock J, Gerich J; Insulin Glar- 54. Wysham C, Bhargava A, Chaykin L, et al. Effect imens in type 2 diabetes: a systematic review and gine 4002 Study Investigators. The treat-to-target of insulin degludec vs insulin glargine U100 on meta-analysis of randomized controlled trials. En- trial: randomized addition of glargine or human hypoglycemia in patients with type 2 diabetes: docrine 2016;51:417–428 NPH insulin to oral therapy of type 2 diabetic the SWITCH 2 Randomized Clinical Trial. JAMA 63. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic patients. Diabetes Care 2003;26:3080–3086 2017;318:45–56 kidney disease: a report from an ADA Consensus 48. Hermansen K, Davies M, Derezinski T, 55. Zinman B, Philis-Tsimikas A, Cariou B, et al.; Conference. Diabetes Care 2014;37:2864–2883 Martinez Ravn G, Clauson P, Home P. A 26-week, NN1250-3579 (BEGIN Once Long) Trial Investiga- 64. Neumiller JJ, Alicic RZ, Tuttle KR. Therapeutic randomized, parallel, treat-to-target trial compar- tors. Insulin degludec versus insulin glargine in considerations for antihyperglycemic agents in di- ing insulin detemir with NPH insulin as add-on insulin-naive patients with type 2 diabetes: a abetic kidney disease. J Am Soc Nephrol 2017;28: therapy to oral glucose-lowering drugs in insulin- 1-year, randomized, treat-to-target trial (BEGIN 2263–2274 naive people with type 2 diabetes. Diabetes Care Once Long). Diabetes Care 2012;35:2464–2471 65. U.S. Food and Drug Administration. Cycloset 2006;29:1269–1274 56. Lipska KJ, Hirsch IB, Riddle MC. Human insulin [bromocriptine] prescribing information [In- 49. Bolli GB, Riddle MC, Bergenstal RM, et al.; for type 2 diabetes: an effective, less-expensive ternet], 2017. [Available from https://www EDITION 3 Study Investigators. New insulin glar- option. JAMA 2017;318:23–24 .accessdata.fda.gov/drugsatfda_docs/label/2017/ gine 300 U/ml compared with glargine 100 U/ml 57. Hua X, Carvalho N, Tew M, Huang ES, Herman 020866s006s007lbl.pdf. Accessed 22 September in insulin-na¨ıve people with type 2 diabetes on WH, Clarke P. Expenditures and prices of antihy- 2017 oral glucose-lowering drugs: a randomized con- perglycemic medications in the United States: 66. U.S. Food and Drug Administration. Welchol trolled trial (EDITION 3). Diabetes Obes Metab 2002-2013. JAMA 2016;315:1400–1402 [Colesevelam] prescribing information [Internet], 2015;17:386–394 58. Diamant M, Nauck MA, Shaginian R, et al.; 4B 2014. Available from https://www.accessdata.fda 50. Terauchi Y, Koyama M, Cheng X, et al. New Study Group. Glucagon-like peptide 1 receptor ag- .gov/drugsatfda_docs/label/2011/022362s007lbl insulin glargine 300 U/ml versus glargine 100 U/ml onist or bolus insulin with optimized basal insulin .pdf. Accessed 22 September 2017 S86 Diabetes Care Volume 41, Supplement 1, January 2018

9. Cardiovascular Disease and Risk American Diabetes Association Management: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S86–S104 | https://doi.org/10.2337/dc18-S009

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 9. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT 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 coronary heart disease, cerebrovascular disease, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. 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. Furthermore, large benefits are seen when multiple cardiovascular risk factors are addressed simultaneously. Under the current paradigm of aggressive risk factor modification in patients with diabetes, 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). Therefore, cardiovascular risk factors should be systematically assessed at least annually in all patients with diabetes. These risk factors include hypertension, dyslipidemia, smoking, a family history of premature coronary disease, chronic kidney disease, and the presence of albuminuria. Modifiable abnormal risk factors should be Suggested citation: American Diabetes Association. treated as described in these guidelines. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetesd2018. HYPERTENSION/BLOOD PRESSURE CONTROL Diabetes Care 2018;41(Suppl. 1):S86–S104 Hypertension, defined as a sustained blood pressure $140/90 mmHg, is common © 2017 by the American Diabetes Association. among patients with either type 1 or type 2 diabetes. Hypertension is a major risk Readers may use this article as long as the work is properly cited, the use is educational and not factor for both ASCVD and microvascular complications. Moreover, numerous studies for profit, and the work is not altered. More infor- have shown that antihypertensive therapy reduces ASCVD events, heart failure, and mation is available at http://www.diabetesjournals microvascular complications. Please refer to the American Diabetes Association (ADA) .org/content/license. care.diabetesjournals.org Cardiovascular Disease and Risk Management S87

position statement “Diabetes and Hyper- patients who have been educated about c Lower systolic and diastolic blood tension” for a detailed review of the epi- added treatment burden, side effects, and pressure targets, such as 130/80 demiology, diagnosis, and treatment of costs, as discussed below. mmHg, may be appropriate for hypertension (5). Additional studies, such as the Systolic individuals at high risk of cardio- Blood Pressure Intervention Trial (SPRINT) vascular disease, if they can be Screening and Diagnosis and the Hypertension Optimal Treatment achieved without undue treat- (HOT) trial, also examined effects of inten- Recommendations ment burden. C sive versus standard control (Table 9.1), c Blood pressure should be measured c In pregnant patients with diabetes though the relevance of their results to at every routine clinical visit. Pa- and preexisting hypertension who people with diabetes is less clear. The tients found to have elevated blood are treated with antihypertensive Action in Diabetes and Vascular Disease: pressure ($140/90) should have therapy, blood pressure targets of Preterax and Diamicron MR Controlled blood pressure confirmed using 120–160/80–105 mmHg are sug- Evaluation–Blood Pressure (ADVANCE multiple readings, including meas- gested in the interest of optimiz- BP) trial did not explicitly test blood pres- urments on a separate day, to diag- ing long-term maternal health nose hypertension. B and minimizing impaired fetal sure targets (17); the achieved blood pressure in the intervention group was c All hypertensive patients with dia- growth. E betes should monitor their blood higher than that achieved in the ACCORD pressure at home. B Randomized clinical trials have demon- BP intensive arm and would be consistent , strated unequivocally that treatment of with a target blood pressure of 140/90 Blood pressure should be measured by a hypertension to blood pressure ,140/90 mmHg. Notably, ACCORD BP and SPRINT trained individual and should follow the mmHg reduces cardiovascular events measured blood pressure using auto- fi guidelines established for the general as well as microvascular complications mated of ce blood pressure measure- population: measurement in the seated (9–15). Therefore, patients with type 1 ments, which yields values that are fi position, with feet on the floor and arm or type 2 diabetes who have hypertension generally lower than typical of ce blood supported at heart level, after 5 min of should, at a minimum, be treated to blood pressure readings by approximately 5–10 mmHg (18), suggesting that imple- rest. Cuff size should be appropriate for pressure targets of ,140/90 mmHg. In- menting the ACCORD BP or SPRINT pro- the upper-arm circumference. Elevated tensification of antihypertensive ther- tocols in an outpatient clinic might require values should be confirmed on a separate apy to target blood pressures lower a systolic blood pressure target higher day. Postural changes in blood pressure than ,140/90 mmHg (e.g., ,130/80 or than ,120 mmHg. and pulse may be evidence of autonomic ,120/80 mmHg) may be beneficial for neuropathy and therefore require adjust- selected patients with diabetes such as Meta-analyses of Trials ment of blood pressure targets. Orthostatic those with a high risk of cardiovascular To clarify optimal blood pressure targets blood pressure measurements should be disease. Such intensive blood pressure in patients with diabetes, meta-analyses checked on initial visit and as indicated. control has been evaluated in large ran- have stratified clinical trials by mean Home blood pressure self-monitoring domized clinical trials and meta-analyses baseline blood pressure or mean blood and 24-h ambulatory blood pressure of clinical trials. pressure attained in the intervention (or monitoring may provide evidence of intensive treatment) arm. Based on these white coat hypertension, masked hyper- Randomized Controlled Trials of Intensive analyses, antihypertensive treatment ap- tension, or other discrepancies between Versus Standard Blood Pressure Control pears to be beneficial when mean base- office and “true” blood pressure (5). In The Action to Control Cardiovascular Risk line blood pressure is $140/90 mmHg or addition to confirming or refuting a diag- in Diabetes blood pressure (ACCORD BP) mean attained intensive blood pressure nosis of hypertension, home blood pres- trial provides the strongest direct assess- is $130/80 mmHg (5,9,12–14). Among sure assessment may be useful to monitor ment of the benefits and risks of intensive trials with lower baseline or attained antihypertensive treatment. Studies of indi- blood pressure control among people blood pressure, antihypertensive treat- viduals without diabetes found that home with type 2 diabetes (16). In ACCORD BP, ment reduced the risk of stroke, reti- measurements may better correlate with compared with standard blood pres- nopathy, and albuminuria, but effects fi ASCVD risk than of ce measurements sure control (target systolic blood pres- on other ASCVD outcomes and heart (6,7). Moreover, home blood pressures sure ,140 mmHg), intensive blood failure were not evident. Taken to- may improve patient medication adherence pressure control (target systolic blood gether, these meta-analyses consis- and thus help reduce cardiovascular risk (8). pressure ,120 mmHg) did not reduce to- tently show that treating patients with tal major atherosclerotic cardiovascular baseline blood pressure $140 mmHg to Treatment Goals events but did reduce the risk of stroke, targets ,140 mmHg is beneficial, while at the expense of increased adverse more intensive targets may offer addi- Recommendations events (Table 9.1). The ACCORD BP re- tional, though probably less robust, ben- c Most patients with diabetes and sults suggest that blood pressure targets efits. hypertension should be treated more intensive than ,140/90 mmHg are to a systolic blood pressure goal of Individualization of Treatment Targets not likely to improve cardiovascular out- Patients and clinicians should engage in a ,140 mmHg and a diastolic blood comes among most people with type 2 di- shared decision-making process to deter- pressure goal of ,90 mmHg. A abetes but may be reasonable in selected mine individual blood pressure targets, S88 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

Table 9.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies Clinical trial Population Intensive Standard Outcomes ACCORD BP (16) 4,733 participants with T2D Systolic blood Systolic blood pressure c No benefit in primary end point: composite of aged 40–79 years with pressure target: target: 130–140 mmHg nonfatal MI, nonfatal stroke, and CVD death prior evidence of CVD or ,120 mmHg multiple cardiovascular Achieved (mean) Achieved (mean) c Stroke risk reduced 41% with intensive risk factors systolic/diastolic: systolic/diastolic: control, not sustained through follow-up 119.3/64.4 133.5/70.5 mmHg beyond the period of active treatment mmHg c Adverseeventsmorecommoninintensive group, particularly elevated serum creatinine and electrolyte abnormalities ADVANCE BP (17) 11,140 participants with T2D Intervention: Control: placebo c Intervention reduced risk of primary aged 55 years and older a single-pill, composite end point of major macrovascular with prior evidence of CVD fixed-dose and microvascular events (9%), death from or multiple cardiovascular combination of any cause (14%), and death from CVD (18%) risk factors perindopril and indapamide Achieved (mean) Achieved (mean) c 6-year observational follow-up found systolic/diastolic: systolic/diastolic: reduction in risk of death in intervention group 136/73 mmHg 141.6/75.2 mmHg attenuated but still significant (142) HOT (143) 18,790 participants, Diastolic blood Diastolic blood pressure c In the overall trial, there was no cardiovascular including 1,501 with pressure target: target: #90 mmHg benefit with more intensive targets diabetes #80 mmHg c In the subpopulation with diabetes, an intensive diastolic target was associated with asignificantly reduced risk (51%) of CVD events SPRINT (144) 9,361 participants without Systolic blood Systolic blood pressure c Intensive systolic blood pressure target diabetes pressure target: target: ,140 mmHg lowered risk of the primary composite ,120 mmHg outcome 25% (MI, ACS, stroke, heart failure, and death due to CVD) Achieved (mean): Achieved (mean): c Intensive target reduced risk of death 27% 121.4 mmHg 136.2 mmHg c Intensive therapy increased risks of electrolyte abnormalities and AKI CVD, cardiovascular disease; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (5).

with the acknowledgment that the ben- adults, such as functional limitations, overweight or obese; a Dietary efits and risks of intensive blood pres- polypharmacy, and multimorbidity, Approaches to Stop Hypertension– sure targets are uncertain and may vary may be best suited for less intensive style dietary pattern including reduc- across patients (5). Similar to the factors blood pressure targets. Notably, there ing sodium and increasing potassium that influence management of hyper- is an absence of high-quality data avail- intake; moderation of alcohol intake; glycemia, factors that influence blood able to guide blood pressure targets in and increased physical activity. B pressure treatment targets may include type 1 diabetes. risks of treatment (e.g., hypotension, Based on current evidence, ADA rec- Lifestyle management is an important drug adverse effects), life expectancy, co- ommends hypertension diagnosis and component of hypertension treatment morbidities including vascular compli- treatment as outlined, emphasizing individ- because it lowers blood pressure, enhan- cations, patient attitude and expected ualization of blood pressure targets. ADA ces the effectiveness of some antihyper- treatment efforts, and resources and is aware of hypertension recommendations tensive medications, promotes other support system (19). Specific factors to from other organizations (20a). The ADA aspects of metabolic and vascular health, consider are the absolute risk of car- Professional Practice Committee continu- diovascular events (15,20), risk of pro- ously reviews and considers all studies, par- and generally leads to few adverse ef- gressive kidney disease as reflected by ticularly high-quality trials including people fects. Lifestyle therapy consists of reduc- albuminuria, adverse effects, age, and with diabetes, for potential incorporation ing excess body weight through caloric overall treatment burden. Patients in future recommendations. restriction, restricting sodium intake who have higher risk of cardiovascular (,2,300 mg/day), increasing consump- events (particularly stroke) or albumin- Treatment Strategies tion of fruits and vegetables (8–10 serv- uria and who are able to attain intensive Lifestyle Intervention ings per day) and low-fat dairy products blood pressure control relatively easily (2–3 servings per day), avoiding excessive and without substantial adverse effects Recommendation alcohol consumption (no more than c For patients with blood pressure may be best suited for intensive blood 2 servings per day in men and no more .120/80 mmHg, lifestyle inter- pressure targets. In contrast, patients than 1 serving per day in women) (21), vention consists of weight loss if with conditions more common in older and increasing activity levels (22). care.diabetesjournals.org Cardiovascular Disease and Risk Management S89

These lifestyle interventions are rea- Initial Number of Antihypertensive Medications. analysis of randomized clinical trials found a sonable for individuals with diabetes Initial treatment for people with diabetes small benefit of evening versus morning and mildly elevated blood pressure depends on the severity of hypertension dosing of antihypertensive medications (systolic .120 mmHg or diastolic .80 (Fig. 9.1). Those with blood pressure be- with regard to blood pressure control but mmHg) and should be initiated along with tween 140/90 mmHg and 159/99 mmHg had no data on clinical effects (35). In two pharmacologic therapy when hypertension may begin with a single drug. For patients subgroup analyses of a single subsequent is diagnosed (Fig. 9.1) (22). A lifestyle ther- with blood pressure $160/100 mmHg, randomized controlled trial, moving at apy plan should be developed in collabo- initial pharmacologic treatment with least one antihypertensive medication ration with the patient and discussed as two antihypertensive medications is rec- to bedtime significantly reduced cardio- part of diabetes management. ommended in order to more effectively vascular events, but results were based achieve adequate blood pressure control on a small number of events (36). Pharmacologic Interventions (23,24). Single-pill antihypertensive combinations may improve medication ad- Hyperkalemia and AKI. Treatment with ACE Recommendations herence in some patients (25). inhibitors or ARBs can cause AKI and hyper- c Patients with confirmed office-based Classes of Antihypertensive Medications. Ini- kalemia, while diuretics can cause AKI and blood pressure $140/90 mmHg tial treatment for hypertension should either hypokalemia or hyperkalemia (de- should, in addition to lifestyle ther- include any of the drug classes demon- pending on mechanism of action) (37,38). apy, have prompt initiation and timely strated to reduce cardiovascular events Detection and management of these ab- titration of pharmacologic therapy to in patients with diabetes: ACE inhibitors normalities is important because AKI and achieve blood pressure goals. A (26,27), angiotensin receptor blockers hyperkalemia each increase the risks of c Patients with confirmed office-based (ARBs) (26,27), thiazide-like diuretics cardiovascular events and death (39). blood pressure $160/100 mmHg (28), or dihydropyridine calcium channel Therefore, serum creatinine and potassium should, in addition to lifestyle ther- blockers (29). For patients with albumin- should be monitored during treatment with apy, have prompt initiation and uria (urine albumin-to-creatinine ratio an ACE inhibitor, ARB, or diuretic, particu- timely titration of two drugs or a sin- [UACR] $30 mg/g), initial treatment larly among patients with reduced glomer- gle-pill combination of drugs dem- fi should include an ACE inhibitor or ARB ular ltration who are at increased risk of onstrated to reduce cardiovascular hyperkalemia and AKI (37,38,40). events in patients with diabetes. A in order to reduce the risk of progressive kidney disease (5) (Fig. 9.1). In the ab- c Treatment for hypertension should Resistant Hypertension include drug classes demonstrated sence of albuminuria, risk of progressive to reduce cardiovascular events in pa- kidney disease is low, and ACE inhibitors Recommendation tients with diabetes (ACE inhibitors, and ARBs have not been found to afford c Patients with hypertension who are angiotensin receptor blockers, thiazide- superior cardioprotection when compared not meeting blood pressure targets like diuretics, or dihydropyridine calcium with thiazide-like diuretics or dihydro- on three classes of antihypertensive channel blockers). A pyridine calcium channel blockers(30). medications (including a diuretic) b should be considered for mineralocor- c Multiple-drug therapy is generally -Blockers may be used for the treatment B required to achieve blood pressure of prior myocardial infarction (MI), ac- ticoid receptor antagonist therapy. targets. However, combinations of tive angina, or heart failure but have not Resistant hypertension is defined as ACE inhibitors and angiotensin re- been shown to reduce mortality as blood blood pressure $140/90 mmHg despite ceptor blockers and combinations pressure-lowering agents in the absence of ACE inhibitors or angiotensin re- of these conditions (11,31). a therapeutic strategy that includes ap- ceptor blockers with direct renin in- Multiple-Drug Therapy. Multiple-drug ther- propriate lifestyle management plus a di- hibitors should not be used. A apy is often required to achieve blood uretic and two other antihypertensive pressure targets (Fig. 9.1), particularly in drugs belonging to different classes at c An ACE inhibitor or angiotensin receptor blocker, at the maximumly the setting of diabetic kidney disease. adequate doses. Prior to diagnosing resis- tolerated dose indicated for blood However, the use of both ACE inhibitors tant hypertension, a number of other pressure treatment, is the recom- and ARBs in combination, or the combina- conditions should be excluded, including mended first-line treatment for hy- tion of an ACE inhibitor or ARB and a direct medication nonadherence, white coat pertension in patients with diabetes renin inhibitor, is not recommended given hypertension, and secondary hyperten- fi and urinary albumin-to-creatinine the lack of added ASCVD bene tandin- sion. In general, barriers to medication d ratio $300 mg/g creatinine A or creased rate of adverse events namely, adherence (such as cost and side effects) fi 30–299 mg/g creatinine B. If one hyperkalemia, syncope, and acute kidney should be identi ed and addressed – Fig. 9.1 classisnottolerated,theother injury (AKI) (32 34). Titration of and/or ( ). Mineralocorticoid receptor an- should be substituted B. addition of further blood pressure medi- tagonists are effective for management of c For patients treated with an ACE in- cations should be made in a timely fash- resistant hypertension in patients with hibitor, angiotensin receptor blocker, ion to overcome clinical inertia in type 2 diabetes when added to existing or diuretic, serum creatinine/estimated achieving blood pressure targets. treatment with a ACE inhibitor or ARB, glomerular filtration rate and serum Bedtime Dosing. Growing evidence suggests thiazide-like diuretic, and dihydropyridine potassium levels should be monitored that there is an association between the calcium channel blocker (41). Miner- at least annually. B absence of nocturnal blood pressure dip- alocorticoid receptor antagonists ping and the incidence of ASCVD. A meta- also reduce albuminuria and have S90 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

Figure 9.1—Recommendations for the treatment of conﬁrmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or ARB is suggested to treat hypertension for patients with UACR 30–299 mg/g creatinine and strongly recommended for patients with UACR $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker. BP, blood pressure. This ﬁgure can also be found in the ADA position statement “Diabetes and Hypertension” (5).

additional cardiovascular beneﬁts monitoring for serum creatinine and po- Pregnancy and Antihypertensive Medications. (42–45). However, adding a mineralocor- tassium in these patients, and long-term Since there is a lack of randomized con- ticoid receptor antagonist to a regimen outcome studies are needed to better trolled trials of antihypertensive therapy including an ACE inhibitor or ARB may evaluate the role of mineralocorticoid rein pregnant women with diabetes, rec- increase the risk for hyperkalemia, em- ceptor antagonists in blood pressure ommendations for the management of phasizing the importance of regular management. hypertension in pregnant women with care.diabetesjournals.org Cardiovascular Disease and Risk Management S91

diabetes should be similar to those for all LIPID MANAGEMENT In adults with diabetes, it is reasonable to pregnant women. The American College Lifestyle Intervention obtain a lipid profile (total cholesterol, of Obstetricians and Gynecologists (ACOG) LDL cholesterol, HDL cholesterol, and tri- has recommended that women with mild to Recommendations glycerides) at the time of diagnosis, at the fi moderate gestational hypertension (systolic c Lifestyle modi cation focusing on initial medical evaluation, and at least ev- blood pressure ,160 mmHg or diastolic weight loss (if indicated); the reduc- ery 5 years thereafter in patients under trans blood pressure ,110 mmHg) do not need tion of saturated fat, fat, and the age of 40 years. In younger patients to be treated with antihypertensive med- cholesterol intake; increase of die- with longer duration of disease (such as fi ications as there is no benefit identified tary n-3 fatty acids, viscous ber, those with youth-onset type 1 diabetes), that clearly outweighs potential risks of and plant stanols/sterols intake; more frequent lipid profiles may be rea- therapy (46). A 2014 Cochrane systematic and increased physical activity sonable. A lipid panel should also be ob- review of antihypertensive therapy for should be recommended to im- tained immediately before initiating fi mild to moderate chronic hypertension prove the lipid pro le in patients statin therapy. Once a patient is taking a A that included 49 trials and over 4,700 with diabetes. statin, LDL cholesterol levels should be women did not find any conclusive evi- c Intensify lifestyle therapy and opti- assessed 4–12 weeks after initiation of dence for or against blood pressure treat- mize glycemic control for patients statin therapy, after any change in dose, ment to reduce the risk of preeclampsia with elevated triglyceride levels and on an individual basis (e.g., to moni- $ for the mother or effects on perinatal ( 150 mg/dL [1.7 mmol/L]) and/ tor for medication adherence and effi- , outcomes such as preterm birth, small- or low HDL cholesterol ( 40 mg/dL cacy). In cases where patients are , for-gestational-age infants, or fetal death [1.0 mmol/L] for men, 50 mg/dL adherent but the LDL cholesterol level is C (47). For pregnant women who require [1.3 mmol/L] for women). not responding, clinical judgment is rec- antihypertensive therapy, systolic blood ommended to determine the need for pressure levels of 120–160 mmHg and di- Lifestyle intervention, including weight and timing of lipid panels. In individual astolic blood pressure levels of 80–105 loss, increased physical activity, and med- patients, the highly variable LDL choles- mmHg are suggested to optimize mater- ical nutrition therapy, allows some pa- terol–lowering response seen with statins nal health without risking fetal harm. tients to reduce ASCVD risk factors. is poorly understood (50). Clinicians Lower targets (systolic blood pressure Nutrition intervention should be tailored should attempt to find a dose or alterna- 110–119 mmHg and diastolic blood pres- according to each patient’s age, diabetes tive statin that is tolerable, if side effects sure 65–79 mmHg) may contribute to im- type, pharmacologic treatment, lipid lev- occur. There is evidence for benefitfrom proved long-term maternal health; however, els, and medical conditions. even extremely low, less than daily statin they may be associated with impaired fetal Recommendations should focus on re- doses (51). growth. Pregnant women with hypertension ducing saturated fat, cholesterol, and trans and evidence of end-organ damage from fat intake and increasing plant stanols/ Statin Treatment cardiovascular and/or renal disease may sterols, n-3 fatty acids, and viscous fiber be considered for lower blood pressure (such as in oats, legumes, and citrus) in- Recommendations c For patients of all ages with diabe- targets to avoid progression of these con- take. Glycemic control may also beneficially tes and atherosclerotic cardiovas- ditions during pregnancy. modify plasma lipid levels, particularly in cular disease, high-intensity statin During pregnancy, treatment with ACE patients with very high triglycerides and therapy should be added to lifestyle inhibitors, ARBs, and spironolactone are poor glycemic control. See Section 4 therapy. A contraindicated as they may cause fetal “ ” Lifestyle Management for additional c For patients with diabetes aged damage. Antihypertensive drugs known to nutrition information. ,40 years with additional athero- be effective and safe in pregnancy include sclerotic cardiovascular disease methyldopa, labetalol, and long-acting Ongoing Therapy and Monitoring With risk factors, the patient and provider nifedipine, while hydralzine may be consid- Lipid Panel should consider using moderate- ered in the acute management of hyperten- intensity statin in addition to lifestyle sion in pregnancy or severe preeclampsia Recommendations therapy. C (46). Diuretics are not recommended for c In adults not taking statins or other c For patients with diabetes aged 40– blood pressure control in pregnancy but lipid-lowering therapy, it is reasonable 75 years A and .75 years B without may be used during late-stage pregnancy fi to obtain a lipid pro le at the time of atherosclerotic cardiovascular dis- if needed for volume control (46,48). diabetes diagnosis, at an initial medi- ease, use moderate-intensity statin ACOG also recommends that postpartum cal evaluation, and every 5 years in addition to lifestyle therapy. patients with gestational hypertension, pre- thereafter if under the age of 40 years, c In clinical practice, providers may eclampsia, and superimposed preeclampsia or more frequently if indicated. E need to adjust the intensity of statin have their blood pressures observed for 72 h c Obtain a lipid profile at initiation of therapy based on individual patient in the hospital and for 7–10 days postpar- statins or other lipid-lowering ther- response to medication (e.g., side tum. Long-term follow-up is recommended apy, 4–12 weeks after initiation or a effects, tolerability, LDL cholesterol for these women as they have increased life- change in dose, and annually thereafter levels, or percent LDL reduction on time cardiovascular risk (49). See Section 13 as it may help to monitor the response statin therapy). For patients who do “Management of Diabetes in Pregnancy” to therapy and inform adherence. E not tolerate the intended intensity for additional information. S92 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

of statin, the maximally tolerated Table 9.2—Recommendations for statin and combination treatment in adults with statin dose should be used. E diabetes c For patients with diabetes and ath- Recommended statin intensityând erosclerotic cardiovascular disease, if Age ASCVD combination treatment* LDL cholesterol is $70 mg/dL on ,40 years No None† maximally tolerated statin dose, Yes High $ consider adding additional LDL- c If LDL cholesterol 70 mg/dL despite maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as lowering therapy (such as ezetimibe ezetimibe or PCSK9 inhibitor)# or PCSK9 inhibitor) after evaluating $40 years No Moderate‡ the potential for further athero- Yes High sclerotic cardiovascular disease c If LDL cholesterol $70 mg/dL despite maximally tolerated statin risk reduction, drug-specificad- dose, consider adding additional LDL-lowering therapy (such as verse effects, and patient preferen- ezetimibe or PCSK9 inhibitor) ces. Ezetimibe may be preferred *In addition to lifestyle therapy.^For patients who do not tolerate the intended intensity of statin, due to lower cost. A the maximally tolerated statin dose should be used. †Moderate-intensity statin may be considered fi fi c Statin therapy is contraindicated in based on risk-bene tpro le and presence of ASCVD risk factors. ASCVD risk factors include LDL cholesterol $ B 100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and pregnancy. family history of premature ASCVD. ‡High-intensity statin may be considered based on risk-benefit profile and presence of ASCVD risk factors. #Adults aged ,40 years with prevalent ASCVD were not well represented in clinical trials of non-statin–based LDL reduction. Before initiating combination Initiating Statin Therapy Based on Risk lipid-lowering therapy, consider the potential for further ASCVD risk reduction, drug-specificadverse Patients with type 2 diabetes have an in- effects, and patient preferences. creased prevalence of lipid abnormalities, contributing to their high risk of ASCVD. Multiple clinical trials have demonstrated death and nonfatal MI) are greatest in The Risk Calculator the beneficial effects of statin therapy on people with high baseline ASCVD risk The American College of Cardiology/ ASCVD outcomes in subjects with and (known ASCVD and/or very high LDL cho- American Heart Association ASCVD risk without CHD (52,53). Subgroup analyses lesterol levels), but the overall benefits of calculator is generally a useful tool to esti- of patients with diabetes in larger trials statin therapy in people with diabetes at mate 10-year ASCVD risk (my.americanheart (54–58) and trials in patients with diabe- moderate or even low risk for ASCVD are .org). However, as diabetes itself confers tes (59,60) showed significant primary convincing (62,63). The relative benefitof increased risk for ASCVD and risk calcula- and secondary prevention of ASCVD lipid-lowering therapy has been uniform tors in general do not account for the events and CHD death in patients with across most subgroups tested (53,61), in- duration of diabetes or the presence of diabetes. Meta-analyses, including data cluding subgroups that varied with re- other complications such as albuminuria, from over 18,000 patients with diabetes spect to age and other risk factors. the risk calculator has limited use for as- from 14 randomized trials of statin therapy sessing cardiovascular risk in individuals (mean follow-up 4.3 years), demonstrate a Risk Stratification with diabetes. 9% proportional reduction in all-cause Two broad groups of patients exist for Recently, risk scores and other cardio- mortality and 13% reduction in vascular management of cardiovascular risk: those vascular biomarkers have been devel- mortality for each mmol/L (39 mg/dL) re- with documented ASCVD (as defined oped for risk stratification of secondary duction in LDL cholesterol (61). above) and those without; treatment is prevention patients (i.e., those who are Accordingly, statins are the drugs of often referred to as “secondary” and “pri- already high risk because they have choice for LDL cholesterol lowering and mary” prevention, respectively. Because ASCVD) but are not yet in widespread cardioprotection. Table 9.2 shows recom- risk is higher in patients with ASCVD, use (67,68). With newer, more expensive mended lipid-lowering strategies, and Ta- more intensive therapy is indicated and lipid-lowering therapies now available, ble 9.3 shows the two statin dosing has been shown to be of benefitinmul- use of these risk assessments may help intensities that are recommended for tiple large randomized cardiovascular target these new therapies to “higher use in clinical practice: high-intensity outcomes trials (61,64–66). risk” ASCVD patients in the future. statin therapy will achieve approximately a 50% reduction in LDL choles- Table 9.3—High-intensity and moderate-intensity statin therapy* terol, and moderate-intensity statin regimens achieve 30–50% reductions in High-intensity statin therapy (lowers LDL Moderate-intensity statin therapy $ LDL cholesterol. Low-dose statin therapy cholesterol by 50%) (lowers LDL cholesterol by 30% to 50%) is generally not recommended in patients Atorvastatin 40–80 mg Atorvastatin 10–20 mg with diabetes but is sometimes the only Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg – dose of statin that a patient can tolerate. Simvastatin 20 40 mg Pravastatin 40–80 mg For patients who do not tolerate the Lovastatin 40 mg intended intensity of statin, the maximally Fluvastatin XL 80 mg tolerated statin dose should be used. Pitavastatin 2–4mg As in those without diabetes, absolute *Once-daily dosing. XL, extended release. reductions in ASCVD outcomes (CHD care.diabetesjournals.org Cardiovascular Disease and Risk Management S93

Primary Prevention (Patients Without ASCVD) Association and American Diabetes Asso- diabetes (27% of participants), the com- For primary prevention, moderate-dose ciation” (69) for additional discussion. bination of moderate-intensity simvasta- statin therapy is recommended for those Secondary Preventions (Patients With tin (40 mg) and ezetimibe (10 mg) 40 years and older (55,62,63), though fi ASCVD) showed a signi cant reduction of major high-intensity therapy may be considered High-intensity statin therapy is recommen- adverse cardiovascular events with an ab- on an individual basis in the context of added for all patients with diabetes and solute risk reduction of 5% (40% vs. 45%) ditional ASCVD risk factors. The evidence is ASCVD. This recommendation is based on and relative risk reduction of 14% (RR – strong for patients with diabetes aged 40 the Cholesterol Treatment Trialists’ Collab- 0.86 [95% CI 0.78–0.94]) over moderate- 75 years, an age-group well represented oration involving 26 statin trials, of which intensity simvastatin (40 mg) alone (65). in statin trials showing benefit. 5 compared high-intensity versus moderate- The evidence is lower for patients Statins and PCSK9 Inhibitors intensity statins. Together, they found re- Placebo-controlled trials evaluating the aged .75 years; relatively few older pa- ductions in nonfatal cardiovascular events addition of the PCSK9 inhibitors evolo- tients with diabetes have been enrolled in with more intensive therapy, in patients cumab and alirocumab to maximally primary prevention trials. However, het- with and without diabetes (53,57,64). tolerated doses of statin therapy in par- erogeneity by age has not been seen in Over the past few years, there have ticipants who were at high risk for ASCVD the relative benefit of lipid-lowering ther- been multiple large randomized trials in- demonstrated an average reduction in apy in trials that included older partici- fi vestigating the bene ts of adding nonsta- LDL cholesterol ranging from 36 to 59%. pants (53,60,61), and because older age tin agents to statin therapy, including These agents have been approved as ad- fi confers higher risk, the absolute bene ts three that evaluated further lowering of junctive therapy for patients with ASCVD are actually greater (53,65). Moderate- LDL cholesterol with ezetimibe (65), or familial hypercholesterolemia who are intensity statin therapy is recommended PCSK9 inhibitors (66), and, cholesteryl es- receiving maximally tolerated statin ther- in patients with diabetes that are 75 years ter transfer protein [CETP] inhibitors, an apy but require additional lowering of LDL fi fi or older. However, the risk-bene tpro le investigational class of drugs with some cholesterol (71,72). should be routinely evaluated in this pop- recent supportive data (70). Each trial The effects of PCSK9 inhibition on fi fi ulation, with downward titration of dose found a signi cant bene tinthereduc- ASCVD outcomes was investigated in performed as needed. See Section 11 tion of ASCVD events that was directly the Further Cardiovascular Outcomes Re- “Older Adults” for more details on clinical related to the degree of further LDL cho- search With PCSK9 Inhibition in Subjects considerations for this population. lesterol lowering. These three large trials With Elevated Risk (FOURIER) trial, which Age <40 Years and/or Type 1 Diabetes. Very comprised over 75,000 patients and enrolled 27,564 patients with prior little clinical trial evidence exists for pa- 250,000 patient-years of follow-up, and ASCVD and an additional high-risk feature tients with type 2 diabetes under the age approximately one-third of participants who were receiving their maximally toler- of 40 years or for patients with type 1 di- had diabetes. For patients with ASCVD ated statin therapy (two-thirds were on abetes of any age. In the Heart Protection who are on high-intensity (and maximally high-intensity statin) but who still had an Study (lower age limit 40 years), the sub- tolerated) statin therapy and have an LDL LDL cholesterol $70 mg/dL or a non-HDL $ group of ;600 patients with type 1 dia- cholesterol 70 mg/dL, the addition of cholesterol $100 mg/dL (66). Patients betes had a proportionately similar, nonstatin LDL-lowering therapy is recom- were randomized to receive subcutane- although not statistically significant, re- mended after considering the potential for ous injections of evolocumab (either fi duction in risk as patients with type 2 di- further ASCVD risk reduction, drug-speci c 140 mg every 2 weeks or 420 mg every abetes (55). Even though the data are not adverse effects, and patient preferences. month based on patient preference) ver- definitive, similar statin treatment ap- Combination Therapy for LDL sus placebo. Evolocumab reduced LDL proaches should be considered for pa- Cholesterol Lowering cholesterol by 59% from a median of 92 to 30 mg/dL in the treatment arm. tients with type 1 or type 2 diabetes, Statins and Ezetimibe During the median follow-up of 2.2 particularly in the presence of other car- The IMProved Reduction of Outcomes: years, the composite outcome of cardio- diovascular risk factors. Patients below Vytorin Efficacy International Trial vascular death, MI, stroke, hospitalization the age of 40 have lower risk of devel- (IMPROVE-IT) was a randomized con- for angina, or revascularization occurred oping a cardiovascular event over a trolled trial in 18,144 patients comparing in 11.3% vs. 9.8% of the placebo and evo- 10-year horizon; however, their lifetime the addition of ezetimibe to simvastatin locumab groups, respectively, represent- risk of developing cardiovascular disease therapy versus simvastatin alone. Individuals ing a 15% relative risk reduction (P , and suffering an MI, stroke, or cardiovas- were $50 years of age, had experienced a 0.001). The combined end point of cardio- cular death is high. For patients under the recent acute coronary syndrome (ACS), vascular death, MI, or stroke was reduced age of 40 years and/or who have type 1 and were treated for an average of by 20%, from 7.4 to 5.9% (P , 0.001). diabetes with other ASCVD risk factors, 6 years. Overall, the addition of ezetimibe Importantly, similar benefits were seen we recommend that the patient and ledtoa6.4%relativebenefitanda2%ab- in prespecified subgroup of patients health care provider discuss the relative solute reduction in major adverse cardiovas- with diabetes, comprising 11,031 patients benefits and risks and consider the use cular events, with the degree of benefit (40% of the trial) (73). of moderate-intensity statin therapy. being directly proportional to the change Please refer to “Type 1 Diabetes Mellitus in LDL cholesterol, which was 70 mg/dL in Statins and CETP Inhibitors and Cardiovascular Disease: A Scientific the statin group on average and 54 mg/dL in Inhibition of CETP increases HDL choles- Statement From the American Heart the combination group (65). In those with terol and further reduces LDL cholesterol. S94 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

This class of drugs is not likely to be avail- dyslipidemia in individuals with type 2 di- (1.7–4.5 mmol/L) to statin therapy plus able for clinical use, but studies pro- abetes. However, the evidence for the extended-release niacin or placebo. The vide further insight into the effects of use of drugs that target these lipid frac- trial was halted early due to lack of effi- LDL cholesterol lowering on cardiovascular tions is substantially less robust than that cacy on the primary ASCVD outcome (first events. for statin therapy (78). In a large trial in event of the composite of death from A total of four trials have been con- patients with diabetes, fenofibrate failed CHD, nonfatal MI, ischemic stroke, hospi- ducted, three of which failed to show to reduce overall cardiovascular out- talization for an ACS, or symptom-driven benefit (74–76). Of these, one showed comes (79). coronary or cerebral revascularization) harm and two were stopped after approx- and a possible increase in ischemic stroke imately 2 years and thus did not have Other Combination Therapy in those on combination therapy (82). sufficient time or power to identify the The much larger Heart Protection benefit. The final study, the Randomized Recommendations Study 2–Treatment of HDL to Reduce Evaluation of the Effects of Anacetrapib c Combination therapy (statin/fibrate) the Incidence of Vascular Events (HPS2- Through Lipid-modification (REVEAL) trial has not been shown to improve ath- THRIVE) trial also failed to show a benefit enrolled 30,449 patients with ASCVD (70). erosclerotic cardiovascular disease of adding niacin to background statin All patients received intensive atorvasta- outcomes and is generally not rec- therapy (83). A total of 25,673 patients tin therapy and were randomized to ana- ommended. A with prior vascular disease were random- cetrapib or placebo. c Combination therapy (statin/niacin) ized to receive 2 g of extended-release During the median follow-up of 4.1 has not been shown to provide addi- niacin and 40 mg of laropiprant (an antag- years, the primary outcome (coronary tional cardiovascular benefitabove onist of the prostaglandin D2 receptor death, MI, or coronary revascularization) statin therapy alone, may increase DP1 that has been shown to improve ad- was significantly reduced with the addi- the risk of stroke with additional herence to niacin therapy) versus a tion of anacetrapib from 11.8 to 10.8%, side effects, and is generally not matching placebo daily and followed with a hazard ratio (HR) of 0.91 (P 5 recommended. A for a median follow-up period of 3.9 0.004). The relative difference in risk years. There was no significant difference was similar across multiple prespecified Statin and Fibrate intherateofcoronarydeath,MI,stroke, fi subgroups, including among 11,320 pa- Combination therapy (statin and brate) or coronary revascularization with the ad- tients with diabetes (37% of the trial). is associated with an increased risk for dition of niacin–laropiprant versus pla- The benefit appeared to be related to abnormal transaminase levels, myositis, cebo (13.2% vs. 13.7%; rate ratio, 0.96; the reduction in LDL (and more broadly and rhabdomyolysis. The risk of rhabdo- P 5 0.29). Niacin–laropiprant was associ- non-HDL) as opposed to the raising of myolysis is more common with higher ated with an increased incidence of new- fi HDL. The mean achieved LDL cholesterol doses of statins and renal insuf ciency onset diabetes (absolute excess, 1.3 was 63 mg/dL vs. 53 mg/dL at the trial and appears to be higher when statins percentage points; P , 0.001) and distur- fi midpoint in the placebo and anacetrapib are combined with gem brozil (com- bances in diabetes control among those fi groups, respectively. This study reaffirms pared with feno brate) (80). with diabetes. In addition, there was an the benefit of further lowering of LDL In the ACCORD study, in patients with increase in serious adverse events associ- cholesterol on reducing cardiovascular type 2 diabetes who were at high risk for ated with the gastrointestinal system, fi events. ASCVD, the combination of feno brate musculoskeletal system, skin, and, unex- and simvastatin did not reduce the rate pectedly, infection and bleeding. of fatal cardiovascular events, nonfatal Therefore, combination therapy with a Treatment of Other Lipoprotein MI, or nonfatal stroke as compared with statin and niacin is not recommended Fractions or Targets fi simvastatin alone. Prespeci ed subgroup given the lack of efficacy on major ASCVD analyses suggested heterogeneity in Recommendation outcomes and side effects. fi c For patients with fasting triglyceride treatment effects with possible bene t levels $500 mg/dL (5.7 mmol/L), for men with both a triglyceride level Diabetes With Statin Use $ evaluate for secondary causes of 204 mg/dL (2.3 mmol/L) and an HDL Several studies have reported a modestly # hypertriglyceridemia and consider cholesterol level 34 mg/dL (0.9 mmol/L) increased risk of incident diabetes with medical therapy to reduce the risk (81). statin use (84,85), which may be limited of pancreatitis. C Statin and Niacin to those with diabetes risk factors. An The Atherothrombosis Intervention in analysis of one of the initial studies Hypertriglyceridemia should be ad- Metabolic Syndrome With Low HDL/High suggested that although statin use was dressed with dietary and lifestyle changes Triglycerides: Impact on Global Health associated with diabetes risk, the cardio- including abstinence from alcohol (77). Outcomes (AIM-HIGH) trial randomized vascular event rate reduction with statins Severe hypertriglyceridemia (.1,000 over 3,000 patients (about one-third far outweighed the risk of incident diabe- mg/dL) may warrant pharmacologic ther- with diabetes) with established ASCVD, tes even for patients at highest risk for apy (fibric acid derivatives and/or fish oil) low LDL cholesterol levels (,180 mg/dL diabetes (86). The absolute risk increase to reduce the risk of acute pancreatitis. [4.7 mmol/L]), low HDL cholesterol levels was small (over 5 years of follow-up, Low levels of HDL cholesterol, often (men ,40 mg/dL [1.0 mmol/L] and 1.2% of participants on placebo devel- associated with elevated triglyceride women ,50 mg/dL [1.3 mmol/L]), and oped diabetes and 1.5% on rosuvastatin levels, are the most prevalent pattern of triglyceride levels of 150–400 mg/dL developed diabetes) (86). A meta-analysis care.diabetesjournals.org Cardiovascular Disease and Risk Management S95

of 13 randomized statin trials with 91,140 Risk Reduction greater than the number of episodes of participants showed an odds ratio of 1.09 Aspirin has been shown to be effective in bleeding induced, although these compli- for a new diagnosis of diabetes, so that reducing cardiovascular morbidity and cations do not have equal effects on long- (on average) treatment of 255 patients mortality in high-risk patients with previ- term health (94). with statins for 4 years resulted in one ous MI or stroke (secondary prevention). additional case of diabetes while simulta- Its net benefit in primary prevention Treatment Considerations neously preventing 5.4 vascular events among patients with no previous cardio- In 2010, a position statement of the ADA, among those 255 patients (85). vascular events is more controversial the American Heart Association, and the both for patients with diabetes and for American College of Cardiology Foun- Statins and Cognitive Function patients without diabetes (89,90). Previ- dation recommended that low-dose A recent systematic review of the U.S. ous randomized controlled trials of aspi- (75–162 mg/day) aspirin for primary pre- Food and Drug Administration’s(FDA’s) rin specifically in patients with diabetes vention is reasonable for adults with di- postmarketing surveillance databases, failed to consistently show a significant abetes and no previous history of vascular randomized controlled trials, and cohort, reduction in overall ASCVD end points, disease who are at increased ASCVD risk case-control, and cross-sectional studies raising questions about the efficacy of as- and who are not at increased risk for evaluating cognition in patients receiving pirin for primary prevention in people bleeding (95). This now out-of-date state- statins found that published data do not re- with diabetes, although some sex differ- ment included sex-specific recommenda- veal an adverse effect of statins on cognition ences were suggested (91–93). tions for use of aspirin therapy as primary (87). In addition, no change in cognitive The Antithrombotic Trialists’ Collabora- prevention in persons with diabetes (95). function has been reported in studies with tion published an individual patient–level However, since that time, multiple recent the addition of ezetimibe (65) or PCSK9 meta-analysis (89) of the six large trials of well-conducted studies and meta-analyses inhibitors (66,88) to statin therapy, includ- aspirin for primary prevention in the gen- have reported a risk of heart disease and ing among patients treated to very low LDL eral population. These trials collectively stroke that is equivalent if not higher in cholesterol levels. Therefore, a concern that enrolled over 95,000 participants, includ- womencomparedwithmenwithdiabe- statins or other lipid-lowering agents might ing almost 4,000 with diabetes. Overall, tes, including among nonelderly adults. cause cognitive dysfunction or dementia is they found that aspirin reduced the risk Thus, current recommendations for using not currently supported by evidence and of serious vascular events by 12% (RR aspirin as primary prevention include both should not deter their use in individuals 0.88 [95% CI 0.82–0.94]). The largest re- men and women aged $50 years with with diabetes at high risk for ASCVD (87). duction was for nonfatal MI, with little diabetes and at least one additional major effect on CHD death (RR 0.95 [95% CI risk factor (family history of premature ANTIPLATELET AGENTS 0.78–1.15]) or total stroke. There was ASCVD, hypertension, dyslipidemia, some evidence of a difference in aspirin smoking, or chronic kidney disease/ Recommendations effect by sex: aspirin significantly reduced albuminuria) who are not at increased c Use aspirin therapy (75–162 mg/day) ASCVD events in men but not in women. risk of bleeding (e.g., older age, anemia, as a secondary prevention strategy Conversely, aspirin had no effect on renal disease) (96–99). While risk calcu- in those with diabetes and a history stroke in men but significantly reduced lators such as those from the American of atherosclerotic cardiovascular stroke in women. However, there was College of Cardiology/American Heart As- disease. A no heterogeneity of effect by sex in the sociation (my.americanheart.org) may c For patients with atherosclerotic risk of serious vascular events (P 5 0.9). be a useful tool to estimate 10-year cardiovascular disease and docu- Sex differences in the effects of aspirin ASCVD risk, diabetes itself confers in- mented aspirin allergy, clopidogrel have not been observed in studies of sec- creased risk for ASCVD. As a result, such (75 mg/day) should be used. B ondary prevention (89). In the six trials risk calculators have limited utility in help- c Dual antiplatelet therapy (with low- examined by the Antithrombotic Trialists’ ing to assess the potential benefits of as- dose aspirin and a P2Y12 inhibitor) Collaboration, the effects of aspirin on pirin therapy in individuals with diabetes. is reasonable for a year after an acute major vascular events were similar for pa- Noninvasive imaging techniques such as coronary syndrome A and may have tients with or without diabetes: RR 0.88 coronary computed tomography angiog- benefits beyond this period. B (95% CI 0.67–1.15) and RR 0.87 (95% CI raphy may potentially help further tai- c Aspirin therapy (75–162 mg/day) 0.79–0.96), respectively. The CI was wider lor aspirin therapy, particularly in those may be considered as a primary pre- for those with diabetes because of at low risk (100), but are not generally ventionstrategyinthosewithtype1 smaller numbers. recommended. Sex differences in the or type 2 diabetes who are at in- Aspirin appears to have a modest ef- antiplatelet effect of aspirin have been sug- creased cardiovascular risk. This fect on ischemic vascular events, with the gested in the general population (101); includes most men and women with absolute decrease in events depending however, further studies are needed to diabetes aged $50 years who have on the underlying ASCVD risk. The main investigate the presence of such differen- at least one additional major risk adverse effect is an increased risk of gas- ces in individuals with diabetes. factor (family history of premature trointestinal bleeding. The excess risk may atherosclerotic cardiovascular dis- be as high as 5 per 1,000 per year in real- Aspirin Use in People <50 Years of Age ease, hypertension, dyslipidemia, world settings. In adults with ASCVD Aspirin is not recommended for those at smoking, or albuminuria) and are risk .1% per year, the number of ASCVD low risk of ASCVD (such as men and women not at increased risk of bleeding. C events prevented will be similar to or aged ,50 years with diabetes with no S96 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

other major ASCVD risk factors) as the low adding ticagrelor to aspirin significantly disease, after lifestyle management benefit is likely to be outweighed by the reduces the risk of recurrent ischemic and metformin, the antihyperglyce- risks of bleeding. Clinical judgment should events including cardiovascular and coro- mic agent canagliflozin may be con- be used for those at intermediate risk nary heart disease death (108). More sideredtoreducemajoradverse (younger patients with one or more risk studies are needed to investigate the cardiovascular events, based on factors or older patients with no risk fac- longer-term benefits of these therapies drug-specific and patient factors tors) until further research is available. after ACS among patients with diabetes. (see Table 8.1). C Patients’ willingness to undergo long- term aspirin therapy should also be con- CORONARY HEART DISEASE sidered (102). Aspirin use in patients Recommendations Cardiac Testing aged ,21 years is generally contraindi- Candidates for advanced or invasive car- cated due to the associated risk of Reye Screening diac testing include those with 1)typical syndrome. c In asymptomatic patients, routine or atypical cardiac symptoms and 2)anab- screening for coronary artery dis- normal resting electrocardiogram (ECG). Aspirin Dosing ease is not recommended as it Exercise ECG testing without or with echo- Average daily dosages used in most clini- does not improve outcomes as long cardiography may be used as the initial test. cal trials involving patients with diabetes as atherosclerotic cardiovascular dis- In adults with diabetes $40 years of age, ranged from 50 mg to 650 mg but were ease risk factors are treated. A measurement of coronary artery calcium – mostly in the range of 100 325 mg/day. c Consider investigations for coronary is also reasonable for cardiovascular risk There is little evidence to support any artery disease in the presence of any assessment. Pharmacologic stress echo- fi speci c dose, but using the lowest possi- of the following: atypical cardiac cardiography or nuclear imaging should ble dose may help to reduce side effects symptoms (e.g., unexplained dyspnea, be considered in individuals with diabetes (103). In the U.S., the most common low- chest discomfort); signs or symptoms in whom resting ECG abnormalities pre- dose tablet is 81 mg. Although platelets of associated vascular disease includ- clude exercise stress testing (e.g., left from patients with diabetes have altered ing carotid bruits, transient ischemic bundle branch block or ST-T abnormali- function, it is unclear what, if any, effect attack, stroke, claudication, or periph- ties). In addition, individuals who require fi that nding has on the required dose of eral arterial disease; or electrocardio- stress testing and are unable to exercise aspirin for cardioprotective effects in the gram abnormalities (e.g., Q waves). E should undergo pharmacologic stress patient with diabetes. Many alternate echocardiography or nuclear imaging. pathways for platelet activation exist Treatment c In patients with known atheroscle- that are independent of thromboxane Screening Asymptomatic Patients rotic cardiovascular disease, con- A2 and thus not sensitive to the effects The screening of asymptomatic patients sider ACE inhibitor or angiotensin of aspirin (104). “Aspirin resistance” has with high ASCVD risk is not recommended receptor blocker therapy to reduce been described in patients with diabetes (109), in part because these high-risk pa- the risk of cardiovascular events. B when measured by a variety of ex vivo tients should already be receiving inten- c In patients with prior myocardial in- and in vitro methods (platelet aggregom- sive medical therapydan approach that farction, b-blockers should be con- etry, measurement of thromboxane B2) provides similar benefit as invasive revas- tinued for at least 2 years after the (101), but other studies suggest no impair- cularization (110,111). There is also some event. B ment in aspirin response among patients evidence that silent MI may reverse over c In patients with type 2 diabetes with with diabetes (105). A recent trial suggested time, adding to the controversy concern- stable congestive heart failure, that more frequent dosing regimens of aspi- ing aggressive screening strategies (112). metformin may be used if estimated rin may reduce platelet reactivity in individ- In prospective studies, coronary artery glomerular filtration rate remains uals with diabetes (106); however, these calcium has been established as an in- .30 mL/min but should be avoided observations alone are insufficienttoem- dependent predictor of future ASCVD events in unstable or hospitalized patients pirically recommend that higher doses of in patients with diabetes and is consistently with congestive heart failure. B aspirin be used in this group at this time. superior to both the UK Prospective Diabetes – c In patients with type 2 diabetes and It appears that 75 162 mg/day is optimal. Study (UKPDS) risk engine and the Framing- established atherosclerotic cardio- ham Risk Score in predicting risk in this vascular disease, antihyperglycemic Indications for P2Y12 Use population (113–115). However, a random- therapy should begin with lifestyle A P2Y12 receptor antagonist in combina- ized observational trial demonstrated no management and metformin and tion with aspirin should be used for at clinical benefit to routine screening of subsequently incorporate an agent least 1 year in patients following an asymptomatic patients with type 2 dia- proven to reduce major adverse car- ACS and may have benefits beyond this betes and normal ECGs (116). Despite diovascular events and cardiovascular period. Evidence supports use of either abnormal myocardial perfusion imaging mortality (currently empagliflozin ticagrelor or clopidogrel if no percutane- in more than one in five patients, cardiac and liraglutide), after considering ous coronary intervention was performed outcomes were essentially equal (and drug-specific and patient factors and clopidogrel, ticagrelor, or prasugrel very low) in screened versus unscreened (see Table 8.1). A if a percutaneous coronary intervention patients. Accordingly, indiscriminate c In patients with type 2 diabetes and es- was performed (107). In patients with di- screening is not considered cost-effective. tablished atherosclerotic cardiovascular abetes and prior MI (1–3 years before), Studies have found that a risk factor– care.diabetesjournals.org Table 9.4—CVOTs completed after issuance of the FDA 2008 guidance DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors SAVOR-TIMI 53 EXAMINE TECOS ELIXA LEADER SUSTAIN-6 EXSCEL EMPA-REG CANVAS CANVAS-R (129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135) (n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812) Intervention Saxagliptin/ Alogliptin/ Sitagliptin/ Lixisenatide/ Liraglutide/ Semaglutide/ Exenatide QW/ Empagliflozin/ Canagliflozin/placebo placebo placebo placebo placebo placebo placebo placebo placebo Main inclusion criteria Type 2 diabetes Type 2 diabetes Type 2 Type 2 Type 2 Type 2 Type 2 diabetes Type 2 diabetes Type 2 diabetes and preexisting and history of and ACS diabetes and diabetes and diabetes and diabetes and with or without and preexisting CVD at $30 years of age or $2 or multiple within 15–90 preexisting history of ACS preexisting preexisting preexisting CVD CVD with BMI cardiovascular risk factors at $50 risk factors for days before CVD (,180 days) CVD, kidney CVD, HF, or #45 kg/m2 and years of age CVD randomization disease, or HF CKD at $50 eGFR $30 at $50 years of years of age or mL/min/1.73 m2 age or cardiovascular cardiovascular risk at $60 risk at $60 years of age years of age A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 5.5–11.0 $7.0 $7.0 6.5–10.0 7.0–10.0 7.0–10.5 Age (years)†† 65.1 61.0 65.4 60.3 64.3 64.6 62 63.1 63.3 Diabetes duration (years)†† 10.3 7.1 11.6 9.3 12.8 13.9 12 57% .10 13.5 Median follow-up (years) 2.1 1.5 3.0 2.1 3.8 2.1 3.2 3.1 5.7 2.1 Statin use (%) 78 91 80 93 72 73 74 77 75 Metforminuse(%)706682667673777477 Prior CVD/CHF (%) 78/13 100/28 74/18 100/22 81/18 60/24 73.1/16.2 99/10 65.6/14.4 Mean baseline A1C (%) 8.0 8.0 7.2 7.7 8.7 8.7 8.0 8.1 8.2 Mean difference in A1C between groups at end of treatment (%) 20.3^ 20.3^ 20.3^ 20.3^ 20.4^ 20.7 or 21.0^† 20.53^ 20.3^‡ 20.58^ Year started/reported 2010/2013 2009/2013 2008/2015 2010/2015 2010/2016 2013/2016 2010/2017 2010/2015 2009/2017

Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE Progression to S97 Management Risk and Disease Cardiovascular albuminuria** 1.00 0.96 (95% 0.98 1.02 0.87 0.74 0.91 0.86 0.86 0.73 (0.89–1.12) UL #1.16) (0.89–1.08) (0.89–1.17) (0.78–0.97) (0.58–0.95) (0.83–1.00) (0.74–0.99) (0.75–0.97)§ (0.47–0.77) Key secondary outcome§ Expanded MACE 4-point MACE 3-point MACE Expanded Expanded Expanded Individual 4-point MACE All-cause and 40% reduction in MACE MACE MACE components cardiovascular composite eGFR, of MACE (see mortality (see renal replacement, below) below) renal death 1.02 0.95 0.99 1.00 0.88 0.74 0.89 0.60 (0.94–1.11) (95% UL # 1.14) (0.89–1.10) (0.90–1.11) (0.81–0.96) (0.62–0.89) (0.78–1.01) (0.47–0.77) Continued on p. S98 9 adoaclrDsaeadRs Management Risk and Disease Cardiovascular S98

Table 9.4—Continued DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors SAVOR-TIMI 53 EXAMINE TECOS ELIXA LEADER SUSTAIN-6 EXSCEL EMPA-REG CANVAS CANVAS-R (129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135) (n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812) Cardiovascular death§ 1.03 0.85 1.03 0.98 0.78 0.98 0.88 0.62 0.96 (0.77–1.18)¶ (0.87–1.22) (0.66–1.10) (0.89–1.19) (0.78–1.22) (0.66–0.93) (0.65–1.48) (0.76–1.02) (0.49–0.77) 0.87 (0.72–1.06)# MI§ 0.95 1.08 0.95 1.03 0.86 0.74 0.97 0.87 0.85 0.85 (0.80–1.12) (0.88–1.33) (0.81–1.11) (0.87–1.22) (0.73–1.00) (0.51–1.08) (0.85–1.10) (0.70–1.09) (0.65–1.11) (0.61–1.19) Stroke§ 1.11 0.91 0.97 1.12 0.86 0.61 0.85 1.18 0.97 0.82 (0.88–1.39) (0.55–1.50) (0.79–1.19) (0.79–1.58) (0.71–1.06) (0.38–0.99) (0.70–1.03) (0.89–1.56) (0.70–1.35) (0.57–1.18) HF hospitalization§ 1.27 1.19 1.00 0.96 0.87 1.11 0.94 0.65 0.77 HR 0.56 (1.07–1.51) (0.90–1.58) (0.83–1.20) (0.75–1.23) (0.73–1.05) (0.77–1.61) (0.78–1.13) (0.50–0.85) (0.55–1.08) (0.38–0.83) Unstable angina 1.19 0.90 0.90 1.11 0.98 0.82 1.05 0.99 d hospitalization§ (0.89–1.60) (0.60–1.37) (0.70–1.16) (0.47–2.62) (0.76–1.26) (0.47–1.44) (0.94–1.18) (0.74–1.34) All-cause mortality§ 1.11 0.88 1.01 0.94 0.85 1.05 0.86 0.68 0.87 (0.74–1.01)‡‡ (0.96–1.27) (0.71–1.09) (0.90–1.14) (0.78–1.13) (0.74–0.97) (0.74–1.50) (0.77–0.97) (0.57–0.82) 0.90 (0.76–1.07)## – Worsening 1.08 ddd0.78 0.64 d 0.61 0.60 (0.47 0.77) nephropathy§| (0.88–1.32) (0.67–0.92) (0.46–0.88) (0.53–0.70) d, not assessed/reported; CANVAS-R, CANVAS-Renal; CHF, congestive heart failure; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiac event; UL, upper limit. Data from Care Diabetes this table was adapted from Cefalu et al. (146) in the January 2018 issue of Diabetes Care. *Powered to rule out an HR of 1.8; superiority hypothesis not prespecified. **On the basis of prespecified outcomes, the renal outcomes are not viewed as statistically significant. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all but four trials,with SAVOR- TIMI 58, EXAMINE, and EXSCEL reporting medians and EMPA-REG OUTCOME reporting as percentage of population with diabetes duration .10 years. †A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. ‡A1Cchangeof0.30inEMPA-REGOUTCOMEisbasedonpooledresultsforbothdoses(i.e.,0.24%for10mgand0.36%for25mgofempagliflozin). §Outcomes reported as HR (95% CI). |Worsening fi . fi # 2 nephropathy is de ned as the new onset of UACR 300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular ltration rate of 45 mL/min/1.73 m , the need for continuous 2018 January 1, Supplement 41, Volume renal-replacement therapy, or death from renal disease in EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 and as doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine .6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53, LEADER, and SUSTAIN-6 but not in EMPA-REG OUTCOME. ¶Truncated data set (prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program).^Significant difference in A1C between groups (P , 0.05). #Nontruncated data set. ‡‡Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R; prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program). ##Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R). care.diabetesjournals.org Cardiovascular Disease and Risk Management S99

based approach to the initial diagnostic Recent studies have also examined the SGLT2 inhibitors (particularly the preven- evaluation and subsequent follow-up for relationship between dipeptidyl pep- tion of heart failure), are being followed coronary artery disease fails to identify tidase 4 (DPP-4) inhibitors and heart up with new outcomes trials in patients which patients with type 2 diabetes will failure and have had mixed results. with established heart failure, both with have silent ischemia on screening tests The Saxagliptin Assessment of Vascular and without diabetes, to determine their (117,118). Any benefit of newer nonin- Outcomes Recorded in Patients with Di- efficacy in treatment of heart failure. vasive coronary artery disease screening abetes Mellitus–Thrombolysis in Myocar- methods, such as computed tomography dial Infarction 53 (SAVOR-TIMI 53) study Antihyperglycemic Therapies and and computed tomography angiography, showed that patients treated with Cardiovascular Outcomes to identify patient subgroups for different saxagliptin (a DPP-4 inhibitor) were more In 2008, the FDA issued a guidance for treatment strategies remains unproven. likely to be hospitalized for heart failure industry to perform cardiovascular out- Although asymptomatic patients with di- than were those given placebo (3.5% vs. comes trials for all new medications for abetes with higher coronary disease bur- 2.8%, respectively) (129). Two other re- the treatment for type 2 diabetes amid den have more future cardiac events cent multicenter, randomized, double- concerns of increased cardiovascular risk (113,119,120), the role of these tests be- blind, noninferiority trials, Examination of (137). Previously approved diabetes med- yond risk stratification is not clear. Their rou- Cardiovascular Outcomes with Alogliptin ications were not subject to the guidance. tine use leads to radiation exposure and may versus Standard of Care (EXAMINE) and Recently published cardiovascular outcomes result in unnecessary invasive testing such as Trial Evaluating Cardiovascular Outcomes trials have provided additional data on car- coronary angiography and revascularization with Sitagliptin (TECOS), did not show asso- diovascular outcomes in patients with type 2 procedures. The ultimate balance of bene- ciations between DPP-4 inhibitor use and diabetes with cardiovascular disease or at fit,cost,andrisksofsuchanapproachin heart failure. The FDA reported that the hos- high risk for cardiovascular disease (see Table asymptomatic patients remains controversial, pital admission rate for heart failure in 9.4). Cardiovascular outcomes trials of particularly in the modern setting of aggres- EXAMINE was 3.9% for patients randomly DPP-4 inhibitors have all, so far, not shown sive ASCVD risk factor control. assigned to alogliptin compared with cardiovascular benefits relative to placebo. 3.3% for those randomly assigned to However, results from other new agents Lifestyle and Pharmacologic placebo (130). Alogliptin had no effect have provided a mix of results. Interventions on the composite end point of cardiovas- EMPA-REG OUTCOME trial was a ran- Intensive lifestyle intervention focusing cular death and hospital admission for domized, double-blind trial that assessed on weight loss through decreased caloric heart failure in the post hoc analysis (HR the effect of empagliflozin, a SGLT2 inhib- intake and increased physical activity as 1.00 [95% CI 0.82–1.21]) (131). TECOS itor, versus placebo on cardiovascular performed in the Action for Health in Di- showed no difference in the rate of heart outcomes in 7,020 patients with type 2 abetes (Look AHEAD) trial may be con- failure hospitalization for the sitagliptin diabetes and existing cardiovascular dis- sidered for improving glucose control, group (3.1%; 1.07 per 100 person-years) ease. Study participants had a mean age fitness, and some ASCVD risk factors compared with the placebo group (3.1%; of 63 years, 57% had diabetes for more (121). Patients at increased ASCVD risk 1.09 per 100 person-years) (132). than 10 years, and 99% had established should receive aspirin and a statin and Abenefit on the incidence of heart fail- cardiovascular disease. EMPA-REG OUTCOME ACE inhibitor or ARB therapy if the patient ure has been observed with the use of showed that over a median follow-up of has hypertension, unless there are con- some sodium–glucose cotransporter 3.1 years, treatment reduced the compos- traindications to a particular drug class. 2 (SGLT2) inhibitors. In the BI 10773 ite outcome of MI, stroke, and cardiovas- While clear benefit exists for ACE inhibitor (Empagliflozin) Cardiovascular Outcome cular death by 14% (absolute rate 10.5% or ARB therapy in patients with diabetic Event Trial in Type 2 Diabetes Mellitus vs. 12.1% in the placebo group, HR in the kidney disease or hypertension, the bene- Patients (EMPA-REG OUTCOME), the ad- empagliflozin group 0.86; 95% CI 0.74– fits in patients with ASCVD in the absence dition of empagliflozin to standard care 0.99; P = 0.04 for superiority) and cardio- of these conditions are less clear, espe- led to a significant 35% reduction in the vascular death by 38% (absolute rate cially when LDL cholesterol is concomi- hospitalization for heart failure compared 3.7% vs. 5.9%, HR 0.62; 95% CI 0.49– tantly controlled (122,123). In patients with placebo (133). Although the majority 0.77; P , 0.001) (133). The FDA recently with prior MI, active angina, or heart fail- of patients in the study did not have heart added a new indication for empagliflozin, ure, b-blockers should be used (124). failure at baseline, this benefit was con- to reduce the risk of major adverse car- sistent in patients with and without a diovascular death in adults with type 2 Diabetes and Heart Failure prior history of heart failure (134). Simi- diabetes and cardiovascular disease. As many as 50% of patients with type 2 larly, in the Canagliflozin Cardiovascu- A second large cardiovascular out- diabetes may develop heart failure (125). lar Assessment Study (CANVAS), there comes trial program of an SGLT2 inhibi- Data on the effects of glucose-lowering was a 33% reduction in hospitalization tor, canagliflozin, has been reported agents on heart failure outcomes have for heart failure with canagliflozin versus (135). The CANVAS Program integrated demonstrated that thiazolidinediones placebo (135). Although heart failure hos- data from two trials, including the CANVAS have a strong and consistent relation- pitalizations were prospectively adjudicated trial that started in 2009 before the ap- ship with increased risk of heart failure in both trials, the type(s) of heart failure proval of canagliflozin and the CANVAS-R (126–128). Therefore, thiazolidinedione events prevented were not characterized. trial that started in 2014 after the approval use should be avoided in patients with These preliminary findings, which strongly of canagliflozin. Combining both these trials, symptomatic heart failure. suggest heart failure–related benefits of 10,142 participants with type 2 diabetes and S100 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

high cardiovascular risk were randomized to stroke and cardiovascular death, in adults significant (141). A total of 14,752 pa- canagliflozin or placebo and were followed with type 2 diabetes and established car- tients with type 2 diabetes (of whom for an average 3.6 years. The mean age of diovascular disease. 10,782 [73.1%] had previous cardiovascu- patients was 63 years and 66% had a history Results from a moderate-sized trial of an- lar disease) were randomized to receive of cardiovascular disease. The combined other GLP-1 receptor agonist, semaglutide, extended-release exenatide 2 mg or pla- analysis of the two trials found that were consistent with the LEADER trial cebo and followed for a median of 3.2 canagliflozin significantly reduced the com- (139). Semaglutide, a once-weekly GLP-1 years. The primary end point of cardio- posite outcome of cardiovascular death, receptor agonist, has not yet been ap- vascular death, MI, or stroke occurred MI, or stroke versus placebo (occurring in proved by the FDA for the treatment of in 839 patients (11.4%; 3.7 events per 26.9 vs. 31.5 participants per 1,000 patient- type 2 diabetes. The preapproval Trial to 100 person-years) in the exenatide group years; HR 0.86 [95% CI 0.75–0.97]; Evaluate Cardiovascular and Other Long- and in 905 patients (12.2%; 4.0 events per P , 0.001 for noninferiority; P 5 0.02 term Outcomes with Semaglutide in Sub- 100 person-years) in the placebo group for superiority). The specific estimates jects With Type 2 Diabetes (SUSTAIN-6) (HR 0.91 [95% CI 0.83–1.00]; P , 0.001 for canagliflozin versus placebo on the was the initial randomized trial powered for noninferiority) but was not superior to primary composite cardiovascular out- to test noninferiority of semaglutide for placebo with respect to the primary end come were HR 0.88 (0.75–1.03) for the the purpose of initial regulatory approval. point (P 5 0.06 for superiority). However, CANVAS trial, and 0.82 (0.66–1.01) for In this study, 3,297 patients with type 2 di- all-cause mortality was lower in the exe- the CANVAS-R, with no heterogeneity abetes were randomized to receive once- natide group (HR 0.86 [95% CI 0.77–0.97]. found between trials. In the combined weekly semaglutide (0.5 mg or 1.0 mg) or The incidence of acute pancreatitis, pan- analysis, there was not a statistically sig- placebo for 2 years. The primary outcome creatic cancer, medullary thyroid carci- nificant difference in cardiovascular death (the first occurrence of cardiovascular noma, and serious adverse events did (HR 0.87 [95% CI 0.72–1.06]). The initial death, nonfatal MI, or nonfatal stroke) not differ significantly between the two CANVAS trial was partially unblinded prior occurred in 108 patients (6.6%) in the groups. to completion because of the need to file semaglutide group vs. 146 patients (8.9%) In summary, there are now large interim cardiovascular outcome data for in the placebo group (HR 0.74 [95% CI randomized controlled trials reporting regulatory approval of the drug (136). Of 0.58–0.95]; P , 0.001). More patients dis- statistically significant reductions in car- note, there was an increased risk of am- continued treatment in the semaglutide diovascular events for two of the FDA- putation with canaglifozin (6.3 vs. 3.4 par- group because of adverse events, mainly approved SGLT2 inhibitors (empagliflozin ticipants per 1,000 patient-years; HR 1.97 gastrointestinal. and canagliflozin) and one of the FDA- [95% CI 1.41–2.75]) (135). The Evaluation of Lixisenatide in Acute approved GLP-1 receptor agonists (liraglutide) The Liraglutide Effect and Action in Di- Coronary Syndrome (ELIXA) trial studied where the majority, if not all, patients in abetes: Evaluation of Cardiovascular the once-daily GLP-1 receptor agonist the trial had ASCVD. The empagliflozin Outcome ResultsdALongTermEvalua- lixisenatide on cardiovascular outcomes and liraglutide trials further demon- tion (LEADER) trial was a randomized, in patients with type 2 diabetes who strated significant reductions in cardio- double-blind trial that assessed the effect had had a recent acute coronary event vascular death. Once-weekly exenatide of liraglutide, a glucagon-like peptide (140). A total of 6,068 patients with type 2 did not have statistically significant re- 1 (GLP-1) receptor agonist, versus placebo diabetes with a recent hospitalization for ductions in major adverse cardiovascu- on cardiovascular outcomes in 9,340 pa- MI or unstable angina within the previ- lar events or cardiovascular mortality tients with type 2 diabetes at high risk for ous 180 days were randomized to re- but did have a significant reduction in cardiovascular disease or with cardiovascu- ceive lixisenatide or placebo in addition all-cause mortality. In contrast, other lar disease. Study participants with a mean to standard care and were followed for GLP-1 receptor agonists have not age of 64 years and a mean duration of a median of approximately 2.1 years. shown similar reductions in cardiovas- diabetes of nearly 13 years. Over 80% of The primary outcome of cardiovascular cularevents(Table 9.4). Whether the study participants had established cardio- death, MI, stroke, or hospitalization for benefits of GLP-1 receptor agonists are a vascular disease. After a median follow-up unstable angina occurred in 406 patients class effect remains to be definitively of 3.8 years, LEADER showed that the pri- (13.4%) in the lixisenatide group vs. established. Additional large randomized mary composite outcome (MI, stroke, or 399 (13.2%) in the placebo group (HR trials of other agents in these classes are cardiovascular death) occurred in fewer 1.02 [95% CI 0.89–1.17]), which demon- ongoing. participants in the treatment group strated the noninferiority of lixisenatide Of note, these studies examined the (13.0%)whencomparedwiththeplacebo to placebo (P , 0.001) but did not show drugs in combination with metformin (Ta- group (14.9%) (HR 0.87; 95% CI 0.78–0.97; superiority (P 5 0.81). ble 9.4) in the great majority of patients P , 0.001 for noninferiority; P =0.01for Most recently, the Exenatide Study of for whom metformin was not contraindi- superiority). Deaths from cardiovascular Cardiovascular Event Lowering (EXSCEL) cated or was tolerated. For patients with causes in the were significantly reduced trial also reported results with the once- type 2 diabetes who have ASCVD, on life- in the liraglutide group (4.7%) compared weekly GLP-1 receptor agonist extended- style and metformin therapy, it is recom- to the placebo group (6.0%) (HR 0.78; release exenatide and found that major mended to incorporate an agent with 95% CI 0.66–0.93; P =0.007)(138).The adverse cardiovascular events were nu- strong evidence for cardiovascular risk FDA recently approved use of liraglutide merically lower with use of extended- reduction, especially those with proven to reduce the risk of major adverse car- release exenatide compared with placebo, benefit on both major adverse cardiovas- diovascular events, including heart attack, although this difference was not statistically cular events and cardiovascular death, care.diabetesjournals.org Cardiovascular Disease and Risk Management S101

after consideration of drug-specific pa- 15. Xie X, Atkins E, Lv J, et al. Effects of intensive for the treatment of hypertension in older adults tient factors (Table 8.1). See Fig. 8.1 for blood pressure lowering on cardiovascular and with and without glucose disorders: a report from additional recommendations on antihy- renal outcomes: updated systematic review and the ALLHAT study. J Clin Hypertens (Greenwich) meta-analysis. Lancet 2016;387:435–443 2004;6:116–125 perglycemic treatment in adults with 16. Cushman WC, Evans GW, Byington RP, et al.; 29. Weber MA, Bakris GL, Jamerson K, et al.; type 2 diabetes. ACCORD Study Group. Effects of intensive blood- ACCOMPLISH Investigators. Cardiovascular events pressure control in type 2 diabetes mellitus. N during differing hypertension therapies in pa- Engl J Med 2010;362:1575–1585 tients with diabetes. J Am Coll Cardiol 2010;56: References 17. Patel A, MacMahon S, Chalmers J, et al.; 77–85 1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, ADVANCE Collaborative Group. Effects of a fixed 30. Bangalore S, Fakheri R, Toklu B, Messerli FH. Imperatore G, Gregg EW. Achievement of goals combination of perindopril and indapamide on Diabetes mellitus as a compelling indication for in U.S. diabetes care, 1999–2010. N Engl J Med macrovascular and microvascular outcomes in pa- use of renin angiotensin system blockers: system- 2013;368:1613–1624 tients with type 2 diabetes mellitus (the ADVANCE atic review and meta-analysis of randomized tri- 2. Rawshani A, Rawshani A, Franzen´ S, et al. Mor- trial): a randomised controlled trial. Lancet 2007; als. BMJ 2016;352:i438 tality and cardiovascular disease in type 1 and type 370:829–840 31. Carlberg B, Samuelsson O, Lindholm LH. Ate- 2 diabetes. N Engl J Med 2017;376:1407–1418 18. Bakris GL. The implications of blood pressure nolol in hypertension: is it a wise choice? Lancet 3. Gregg EW, Li Y, Wang J, et al. Changes in di- measurement methods on treatment targets for 2004;364:1684–1689 abetes-related complications in the United States, blood pressure. Circulation 2016;134:904–905 32. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET 1990–2010. N Engl J Med 2014;370:1514–1523 19. Association AD; American Diabetes Associa- Investigators. Telmisartan, ramipril, or both in pa- 4. Ford ES, Ajani UA, Croft JB, et al. Explaining the tion. Glycemic targets. Sec. 6. In Standards of tients at high risk for vascular events. N Engl J Med decrease in U.S. deaths from coronary disease, Medical Care in Diabetesd2017. Diabetes Care 2008;358:1547–1559 1980–2000. N Engl J Med 2007;356:2388–2398 2017;40(Suppl. 1):S48–S56 33. Fried LF, Emanuele N, Zhang JH, et al.; VA 5. de Boer IH, Bangalore S, Benetos A, et al. Di- 20. Blood Pressure Lowering Treatment Trialists’ NEPHRON-D Investigators. Combined angiotensin abetes and hypertension: a position statement by Collaboration. Blood pressure-lowering treat- inhibition for the treatment of diabetic nephrop- the American Diabetes Association. Diabetes Care ment based on cardiovascular risk: a meta-analysis athy. N Engl J Med 2013;369:1892–1903 2017;40:1273–1284 of individual patient data. Lancet 2014;384: 34. Makani H, Bangalore S, Desouza KA, Shah A, 6. Bobrie G, Genes` N, Vaur L, et al. Is “isolated 591–598 Messerli FH. Efficacy and safety of dual blockade home” hypertension as opposed to “isolated of- 20a. Whelton PK, Carey RM, Aronow WS, et al. of the renin-angiotensin system: meta-analysis of fice” hypertension a sign of greater cardiovascular 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ randomised trials. BMJ 2013;346:f360 risk? Arch Intern Med 2001;161:2205–2211 ASH/ASPC/NMA/PCNA guideline for the preven- 35. Zhao P, Xu P, Wan C, Wang Z. Evening versus 7. Sega R, Facchetti R, Bombelli M, et al. Prognos- tion, detection, evaluation, and management morning dosing regimen drug therapy for hyper- tic value of ambulatory and home blood pressures of high blood pressure in adults. J Am Coll Cardiol. tension. Cochrane Database Syst Rev 2011 (10): compared with office blood pressure in the In press CD004184 general population: follow-up results from the 21. Sacks FM, Svetkey LP, Vollmer WM, et al.; 36. Hermida RC, Ayala DE, Mojon´ A, Fernandez´ Pressioni Arteriose Monitorate e Loro Associa- DASH-Sodium Collaborative Research Group. Ef- JR. Influence of time of day of blood pressure- zioni (PAMELA) study. Circulation 2005;111: fects on blood pressure of reduced dietary sodium lowering treatment on cardiovascular risk in hy- 1777–1783 and the Dietary Approaches to Stop Hypertension pertensive patients with type 2 diabetes. Diabetes 8. Omboni S, Gazzola T, Carabelli G, Parati G. (DASH) diet. N Engl J Med 2001;344:3–10 Care 2011;34:1270–1276 Clinical usefulness and cost effectiveness of 22. James PA, Oparil S, Carter BL, et al. 2014 37. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. Inci- home blood pressure telemonitoring: meta-analysis evidence-based guideline for the management of dence and determinants of hyperkalemia and of randomized controlled studies. J Hypertens 2013; high blood pressure in adults: report from the panel hypokalemia in a large healthcare system. Int J 31:455–467; discussion 467–468 members appointed to the Eighth Joint National Cardiol 2017;245:277–284 9. Emdin CA, Rahimi K, Neal B, Callender T, Committee (JNC 8). JAMA 2014;311:507–520 38. Bandak G, Sang Y, Gasparini A, et al. Hyper- Perkovic V, Patel A. Blood pressure lowering in 23. Bakris GL, Weir MR; Study of Hypertension kalemia after initiating renin-angiotensin system type 2 diabetes: a systematic review and meta- and the Efficacy of Lotrel in Diabetes (SHIELD) blockade: the Stockholm Creatinine Measure- analysis. JAMA 2015;313:603–615 Investigators. Achieving goal blood pressure in ments (SCREAM) project. J Am Heart Assoc 10. Arguedas JA, Leiva V, Wright JM. Blood pres- patients with type 2 diabetes: conventional versus 2017;6:e005428 sure targets for hypertension in people with di- fixed-dose combination approaches. J Clin Hyper- 39. Hughes-Austin JM, Rifkin DE, Beben T, et al. abetes mellitus. Cochrane Database Syst Rev tens (Greenwich) 2003;5:202–209 The relation of serum potassium concentra- 2013;10:CD008277 24. Feldman RD, Zou GY, Vandervoort MK, Wong tion with cardiovascular events and mortality in 11. Ettehad D, Emdin CA, Kiran A, et al. Blood CJ, Nelson SAE, Feagan BG. A simplified approach community-living individuals. Clin J Am Soc Nephrol pressure lowering for prevention of cardiovascu- to the treatment of uncomplicated hypertension: 2017;12:245–252 lar disease and death: a systematic review and a cluster randomized, controlled trial. Hyperten- 40. James MT, Grams ME, Woodward M, et al.; meta-analysis. Lancet 2016;387:957–967 sion 2009;53:646–653 CKD Prognosis Consortium. A meta-analysis of the 12. Brunstrom¨ M, Carlberg B. Effect of antihy- 25. Bangalore S, Kamalakkannan G, Parkar S, association of estimated GFR, albuminuria, diabe- pertensive treatment at different blood pressure Messerli FH. Fixed-dose combinations improve tes mellitus, and hypertension with acute kidney levels in patients with diabetes mellitus: system- medication compliance: a meta-analysis. Am J injury. Am J Kidney Dis 2015;66:602–612 atic review and meta-analyses. BMJ 2016;352: Med 2007;120:713–719 41. Iliescu R, Lohmeier TE, Tudorancea I, LaffinL, i717 26. Catala-L´ opez´ F, Mac´ıas Saint-Gerons D, Bakris GL. Renal denervation for the treatment of 13. Bangalore S, Kumar S, Lobach I, Messerli FH. Gonzalez-Bermejo´ D, et al. Cardiovascular and re- resistant hypertension: review and clinical perspec- Blood pressure targets in subjects with type 2 nal outcomes of renin-angiotensin system block- tive. Am J Physiol Renal Physiol 2015;309:F583– diabetes mellitus/impaired fasting glucose: obser- ade in adult patients with diabetes mellitus: F594 vations from traditional and bayesian random- a systematic review with network meta-analyses. 42. Bakris GL, Agarwal R, Chan JC, et al.; Miner- effects meta-analyses of randomized trials. PLoS Med 2016;13:e1001971 alocorticoid Receptor Antagonist Tolerability Circulation 2011;123:2799–2810 27. Palmer SC, Mavridis D, Navarese E, et al. Study–Diabetic Nephropathy (ARTS-DN) Study 14. Thomopoulos C, Parati G, Zanchetti A. Effects Comparative efficacy and safety of blood pressure- Group. Effect of finerenone on albuminuria in pa- of blood-pressure-lowering treatment on out- lowering agents in adults with diabetes and kidney tients with diabetic nephropathy: a randomized come incidence in hypertension: 10 - should blood disease: a network meta-analysis. Lancet 2015;385: clinical trial. JAMA 2015;314:884–894 pressure management differ in hypertensive pa- 2047–2056 43. Williams B, MacDonald TM, Morant S, et al.; tients with and without diabetes mellitus? Over- 28. Barzilay JI, Davis BR, Bettencourt J, et al.; British Hypertension Society’s PATHWAY Studies view and meta-analyses of randomized trials. J ALLHAT Collaborative Research Group. Cardiovas- Group. Spironolactone versus placebo, bisoprolol, Hypertens 2017;35:922–944 cular outcomes using doxazosin vs. chlorthalidone and doxazosin to determine the optimal treatment S102 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

for drug-resistant hypertension (PATHWAY-2): to New Targets (TNT) study. Diabetes Care 2006; 71. Moriarty PM, Jacobson TA, Bruckert E, et al. a randomised, double-blind, crossover trial. Lancet 29:1220–1226 Efficacy and safety of alirocumab, a monoclonal 2015;386:2059–2068 58. Sever PS, Poulter NR, Dahlof¨ B, et al. Reduc- antibody to PCSK9, in statin-intolerant patients: 44. Filippatos G, Anker SD, Bohm¨ M, et al. A tion in cardiovascular events with atorvastatin design and rationale of ODYSSEY ALTERNATIVE, randomized controlled study of finerenone vs. in 2,532 patients with type 2 diabetes: Anglo- a randomized phase 3 trial. J Clin Lipidol 2014;8: eplerenone in patients with worsening chronic Scandinavian Cardiac Outcomes Trial–lipid-lower- 554–561 heart failure and diabetes mellitus and/or chronic ing arm (ASCOT-LLA). Diabetes Care 2005;28: 72. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and kidney disease. Eur Heart J 2016;37:2105–2114 1151–1157 efficacy of anti-PCSK9 antibodies: a meta-analysis 45. Bomback AS, Klemmer PJ. Mineralocorticoid 59. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. of 25 randomized, controlled trials. BMC Med receptor blockade in chronic kidney disease. Efficacy and safety of atorvastatin in the preven- 2015;13:123 Blood Purif 2012;33:119–124 tion of cardiovascular end points in subjects with 73. Sabatine MS, Leiter LA, Wiviott SD, et al. Car- 46. American College of Obstetricians and Gyne- type 2 diabetes: the Atorvastatin Study for Pre- diovascular safety and efficacy of the PCSK9 in- cologists; Task Force on Hypertension in Preg- vention of Coronary Heart Disease Endpoints in Non- hibitor evolocumab in patients with and without nancy. Hypertension in pregnancy. Report of the Insulin-Dependent Diabetes Mellitus (ASPEN). diabetes and the effect of evolocumab on glycae- American College of Obstetricians and Gynecolo- Diabetes Care 2006;29:1478–1485 mia and risk of new-onset diabetes: a prespecified gists’ Task Force on Hypertension in Pregnancy. 60. Colhoun HM, Betteridge DJ, Durrington PN, analysis of the FOURIER randomised controlled Obstet Gynecol 2013;122:1122–1131 et al.; CARDS investigators. Primary prevention of trial [article online]. Lancet Diabetes Endocrinol 47. Abalos E, Duley L, Steyn DW. Antihyperten- cardiovascular disease with atorvastatin in type 2 2017. Available from http://www.thelancet sive drug therapy for mild to moderate hyperten- diabetes in the Collaborative Atorvastatin Diabe- .com/journals/landia/article/PIIS2213-8587(17) sion during pregnancy. Cochrane Database Syst tes Study (CARDS): multicentre randomised 30313-3/abstract. Accessed 28 September 2017 Rev 2014;2:CD002252 placebo-controlled trial. Lancet 2004;364:685–696 74. Barter PJ, Caulfield M, Eriksson M, et al.; 48. Al-Balas M, Bozzo P, Einarson A. Use of diu- 61. Kearney PM, Blackwell L, Collins R, et al.; Cho- ILLUMINATE Investigators. Effects of torcetrapib retics during pregnancy. Can Fam Physician 2009; lesterol Treatment Trialists’ (CTT) Collaborators. in patients at high risk for coronary events. N Engl 55:44–45 Efficacy of cholesterol-lowering therapy in J Med 2007;357:2109–2122 49. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long 18,686 people with diabetes in 14 randomised 75. Schwartz GG, Olsson AG, Abt M, et al.; dal- term mortality of mothers and fathers after pre- trials of statins: a meta-analysis. Lancet 2008; OUTCOMES Investigators. Effects of dalcetrapib in eclampsia: population based cohort study. BMJ 371:117–125 patients with a recent acute coronary syndrome. 2001;323:1213–1217 62. Taylor F, Huffman MD, Macedo AF, et al. Sta- N Engl J Med 2012;367:2089–2099 50. Chasman DI, Posada D, Subrahmanyan L, tins for the primary prevention of cardiovascular 76. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.; Cook NR, Stanton VP Jr, Ridker PM. Pharmacoge- disease. Cochrane Database Syst Rev 2013 (1): ACCELERATE Investigators. Evacetrapib and car- netic study of statin therapy and cholesterol re- CD004816 diovascular outcomes in high-risk vascular dis- duction. JAMA 2004;291:2821–2827 63. Carter AA, Gomes T, Camacho X, Juurlink DN, ease. N Engl J Med 2017;376:1933–1942 51. Meek C, Wierzbicki AS, Jewkes C, et al. Daily Shah BR, Mamdani MM. Risk of incident diabetes 77. Berglund L, Brunzell JD, Goldberg AC, et al.; and intermittent rosuvastatin 5 mg therapy in among patients treated with statins: population Endocrine society. Evaluation and treatment of statin intolerant patients: an observational study. based study [published correction appears in BMJ hypertriglyceridemia: an Endocrine Society clini- Curr Med Res Opin 2012;28:371–378 2013;347:f4356]. BMJ 2013;346:f2610 cal practice guideline. J Clin Endocrinol Metab 52. Mihaylova B, Emberson J, Blackwell L, et al.; 64. Cannon CP, Braunwald E, McCabe CH, et al.; 2012;97:2969–2989 Cholesterol Treatment Trialists’ (CTT) Collabora- Pravastatin or Atorvastatin Evaluation and In- 78. Singh IM, Shishehbor MH, Ansell BJ. High- tors. The effects of lowering LDL cholesterol fection Therapy-Thrombolysis in Myocardial In- density lipoprotein as a therapeutic target: a sys- with statin therapy in people at low risk of vascu- farction 22 Investigators. Intensive versus tematic review. JAMA 2007;298:786–798 lar disease: meta-analysis of individual data from moderate lipid lowering with statins after acute 79. Keech A, Simes RJ, Barter P, et al.; FIELD study 27 randomised trials. Lancet 2012;380:581–590 coronary syndromes. N Engl J Med 2004;350: investigators. Effects of long-term fenofibrate 53. Baigent C, Keech A, Kearney PM, et al.; Cho- 1495–1504 therapy on cardiovascular events in 9795 people lesterol Treatment Trialists’ (CTT) Collaborators. 65. Cannon CP, Blazing MA, Giugliano RP, et al.; with type 2 diabetes mellitus (the FIELD study): Efficacy and safety of cholesterol-lowering treat- IMPROVE-IT Investigators. Ezetimibe added to randomised controlled trial. Lancet 2005;366: ment: prospective meta-analysis of data from statin therapy after acute coronary syndromes. 1849–1861 90,056 participants in 14 randomised trials of sta- N Engl J Med 2015;372:2387–2397 80. Jones PH, Davidson MH. Reporting rate of tins. Lancet 2005;366:1267–1278 66. Sabatine MS, Giugliano RP, Keech AC, et al.; rhabdomyolysis with fenofibrate 1 statin versus 54. Pyor˘ al¨ a¨ K, Pedersen TR, Kjekshus J, Faergeman O, FOURIER Steering Committee and Investigators. gemfibrozil 1 any statin. Am J Cardiol 2005;95: Olsson AG, Thorgeirsson G. Cholesterol lowering Evolocumab and clinical outcomes in patients 120–122 with simvastatin improves prognosis of diabetic with cardiovascular disease. N Engl J Med 2017; 81. Ginsberg HN, Elam MB, Lovato LC, et al.; patients with coronary heart disease. A subgroup 376:1713–1722 ACCORD Study Group. Effects of combination lipid analysis of the Scandinavian Simvastatin Survival 67. Bohula EA, Morrow DA, Giugliano RP, et al. therapy in type 2 diabetes mellitus. N Engl J Med Study (4S). Diabetes Care 1997;20:614–620 Atherothrombotic risk stratification and ezetimibe 2010;362:1563–1574 55. Collins R, Armitage J, Parish S, Sleigh P, Peto R; for secondary Prevention. J Am Coll Cardiol 2017; 82. Boden WE, Probstfield JL, Anderson T, et al.; Heart Protection Study Collaborative Group. 69:911–921 AIM-HIGH Investigators. Niacin in patients with MRC/BHF Heart Protection Study of cholesterol- 68. Bohula EA, Bonaca MP, Braunwald E, et al. low HDL cholesterol levels receiving intensive sta- lowering with simvastatin in 5963 people with Atherothrombotic risk stratification and the effi- tin therapy. N Engl J Med 2011;365:2255–2267 diabetes: a randomised placebo-controlled trial. cacy and safety of vorapaxar in patients with 83. Landray MJ, Haynes R, Hopewell JC, et al.; Lancet 2003;361:2005–2016 stable ischemic heart disease and previous HPS2-THRIVE Collaborative Group. Effects of 56. Goldberg RB, Mellies MJ, Sacks FM, et al.; The myocardial infarction. Circulation 2016;134: extended-release niacin with laropiprant in high- Care Investigators. Cardiovascular events and 304–313 risk patients. N Engl J Med 2014;371:203–212 their reduction with pravastatin in diabetic 69. de Ferranti SD, de Boer IH, Fonseca V, et al. 84. Rajpathak SN, Kumbhani DJ, Crandall J, and glucose-intolerant myocardial infarction Type 1 diabetes mellitus and cardiovascular dis- Barzilai N, Alderman M, Ridker PM. Statin therapy survivors with average cholesterol levels: sub- ease: a scientific statement from the American and risk of developing type 2 diabetes: a meta- group analyses in the Cholesterol And Recur- Heart Association and American Diabetes Associ- analysis. Diabetes Care 2009;32:1924–1929 rent Events (CARE) trial. Circulation 1998;98: ation. Circulation 2014;130:1110–1130 85. Sattar N, Preiss D, Murray HM, et al. Statins 2513–2519 70. Bowman L, Hopewell JC, Chen F, et al.; HPS3/ and risk of incident diabetes: a collaborative 57. Shepherd J, Barter P, Carmena R, et al. Effect TIMI55–REVEAL Collaborative Group. Effects meta-analysis of randomised statin trials. Lancet of lowering LDL cholesterol substantially below of anacetrapib in patients with atherosclerotic 2010;375:735–742 currently recommended levels in patients with vascular disease. N Engl J Med 2017;377:1217– 86. Ridker PM, Pradhan A, MacFadyen JG, Libby coronary heart disease and diabetes: the Treating 1227 P, Glynn RJ. Cardiovascular benefits and diabetes care.diabetesjournals.org Cardiovascular Disease and Risk Management S103

risks of statin therapy in primary prevention: an 99. Peters SAE, Huxley RR, Woodward M. Diabe- diabetes: the PREDICT study. Eur Heart J 2008; analysis from the JUPITER trial. Lancet 2012;380: tes as a risk factor for stroke in women com- 29:2244–2251 565–571 paredwithmen:asystematicreviewand 114. Raggi P, Shaw LJ, Berman DS, Callister TQ. 87. Richardson K, Schoen M, French B, et al. Sta- meta-analysis of 64 cohorts, including 775,385 Prognostic value of coronary artery calcium tins and cognitive function: a systematic review. individuals and 12,539 strokes. Lancet 2014;383: screening in subjects with and without diabetes. Ann Intern Med 2013;159:688–697 1973–1980 J Am Coll Cardiol 2004;43:1663–1669 88.GiuglianoRP,MachF,ZavitzK,etal.; 100. Dimitriu-Leen AC, Scholte AJHA, van 115. Anand DV, Lim E, Hopkins D, et al. Risk strat- EBBINGHAUS Investigators. Cognitive function Rosendael AR, et al. Value of coronary computed iﬁcation in uncomplicated type 2 diabetes: pro- in a randomized trial of evolocumab. N Engl J tomography angiography in tailoring aspirin ther- spective evaluation of the combined use of Med 2017;377:633–643 apy for primary prevention of atherosclerotic coronary artery calcium imaging and selective 89. Baigent C, Blackwell L, Collins R, et al.; Antith- events in patients at high risk with diabetes melli- myocardial perfusion scintigraphy. Eur Heart J rombotic Trialists’ (ATT) Collaboration. Aspirin in tus. Am J Cardiol 2016;117:887–893 2006;27:713–721 the primary and secondary prevention of vascular 101. Larsen SB, Grove EL, Neergaard-Petersen S, 116. Young LH, Wackers FJT, Chyun DA, et al.; disease: collaborative meta-analysis of individual Wurtz¨ M, Hvas A-M, Kristensen SD. Determinants DIAD Investigators. Cardiac outcomes after participant data from randomised trials. Lancet of reduced antiplatelet effect of aspirin in patients screening for asymptomatic coronary artery dis- 2009;373:1849–1860 with stable coronary artery disease. PLoS One ease in patients with type 2 diabetes: the DIAD 90. Perk J, De Backer G, Gohlke H, et al.; European 2015;10:e0126767 study: a randomized controlled trial. JAMA 2009; Association for Cardiovascular Prevention & Re- 102. Mora S, Ames JM, Manson JE. Low-dose as- 301:1547–1555 habilitation (EACPR); ESC Committee for Practice pirin in the primary prevention of cardiovascular 117. Wackers FJT, Young LH, Inzucchi SE, et al.; Guidelines (CPG). European Guidelines on cardio- disease: shared decision making in clinical prac- Detection of Ischemia in Asymptomatic Dia- vascular disease prevention in clinical practice tice. JAMA 2016;316:709–710 betics Investigators. Detection of silent myocar- (version 2012). The Fifth Joint Task Force of the 103. Campbell CL, Smyth S, Montalescot G, dial ischemia in asymptomatic diabetic subjects: European Society of Cardiology and Other Socie- Steinhubl SR. Aspirin dose for the prevention of the DIAD study. Diabetes Care 2004;27:1954– ties on Cardiovascular Disease Prevention in Clin- cardiovascular disease: a systematic review. JAMA 1961 ical Practice (constituted by representatives of 2007;297:2018–2024 118. Scognamiglio R, Negut C, Ramondo A, nine societies and by invited experts). Eur Heart 104. Dav`ı G, Patrono C. Platelet activation and Tiengo A, Avogaro A. Detection of coronary ar- J 2012;33:1635–1701 atherothrombosis. N Engl J Med 2007;357: tery disease in asymptomatic patients with 91. Belch J, MacCuish A, Campbell I, et al. The 2482–2494 type 2 diabetes mellitus. J Am Coll Cardiol prevention of progression of arterial disease and 105. Zaccardi F, Rizzi A, Petrucci G, et al. In vivo 2006;47:65–71 diabetes (POPADAD) trial: factorial randomised platelet activation and aspirin responsiveness in 119. Hadamitzky M, Hein F, Meyer T, et al. Prog- placebo controlled trial of aspirin and antioxidants type 1 diabetes. Diabetes 2016;65:503–509 nostic value of coronary computed tomographic in patients with diabetes and asymptomatic pe- 106. Bethel MA, Harrison P, Sourij H, et al. Ran- angiography in diabetic patients without known ripheral arterial disease. BMJ 2008;337:a1840 domized controlled trial comparing impact on coronary artery disease. Diabetes Care 2010;33: 92. Zhang C, Sun A, Zhang P, et al. Aspirin for platelet reactivity of twice-daily with once-daily 1358–1363 primary prevention of cardiovascular events in aspirin in people with type 2 diabetes. Diabet 120. Choi E-K, Chun EJ, Choi S-I, et al. Assessment patients with diabetes: A meta-analysis. Diabetes Med 2016;33:224–230 of subclinical coronary atherosclerosis in Res Clin Pract 2010;87:211–218 107. Vandvik PO, Lincoff AM, Gore JM, et al. Pri- asymptomatic patients with type 2 diabetes 93. De Berardis G, Sacco M, Strippoli GFM, et al. mary and secondary prevention of cardiovascular mellitus with single photon emission computed Aspirin for primary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention tomography and coronary computed tomogra- events in people with diabetes: meta-analysis of of Thrombosis, 9th ed: American College of phy angiography. Am J Cardiol 2009;104:890– randomised controlled trials. BMJ 2009;339: Chest Physicians Evidence-Based Clinical Practice 896 b4531 Guidelines [published correction appears in Chest 121. Wing RR, Bolin P, Brancati FL, et al.; Look 94. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. 2012;141:1129]. Chest 2012;141(Suppl.):e637S– AHEAD Research Group. Cardiovascular effects Aspirin, statins, or both drugs for the primary pre- e668S of intensive lifestyle intervention in type 2 diabe- vention of coronary heart disease events in men: 108. Bhatt DL, Bonaca MP, Bansilal S, et al. Re- tes. N Engl J Med 2013;369:145–154 a cost-utility analysis. Ann Intern Med 2006;144: duction in ischemic events with ticagrelor in di- 122. Braunwald E, Domanski MJ, Fowler SE, et al.; 326–336 abetic patients with prior myocardial infarction in PEACE Trial Investigators. Angiotensin-converting- 95. Pignone M, Alberts MJ, Colwell JA, et al.; PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67: enzyme inhibition in stable coronary artery dis- American Diabetes Association; American Heart 2732–2740 ease. N Engl J Med 2004;351:2058–2068 Association; American College of Cardiology 109. Bax JJ, Young LH, Frye RL, Bonow RO, 123. Telmisartan Randomised AssessmeNt Study Foundation. Aspirin for primary prevention of car- Steinberg HO, Barrett EJ; ADA. Screening for cor- in ACE iNtolerant subjects with cardiovascular Dis- diovascular events in people with diabetes: a po- onary artery disease in patients with diabetes. Di- ease (TRANSCEND) Investigators, Yusuf S, Teo K, sition statement of the American Diabetes abetes Care 2007;30:2729–2736 et al. Effects of the angiotensin-receptor blocker Association, a scientiﬁc statement of the Ameri- 110. Boden WE, O’Rourke RA, Teo KK, et al.; telmisartan on cardiovascular events in high-risk can Heart Association, and an expert consensus COURAGE Trial Research Group. Optimal medical patients intolerant to angiotensin-converting en- document of the American College of Cardiology therapy with or without PCI for stable coronary zyme inhibitors: a randomised controlled trial. Foundation. Diabetes Care 2010;33:1395–1402 disease. N Engl J Med 2007;356:1503–1516 Lancet 2008;372:1174–1183 96. Huxley RR, Peters SAE, Mishra GD, Woodward M. 111. BARI 2D Study Group, Frye RL, August P, 124. Kezerashvili A, Marzo K, De Leon J. Beta Risk of all-cause mortality and vascular events in et al. A randomized trial of therapies for type 2 blocker use after acute myocardial infarction in women versus men with type 1 diabetes: a sys- diabetes and coronary artery disease. N Engl J the patient with normal systolic function: when tematic review and meta-analysis. Lancet Diabe- Med 2009;360:2503–2015 is it “ok” to discontinue? Curr Cardiol Rev 2012;8: tes Endocrinol 2015;3:198–206 112. Wackers FJT, Chyun DA, Young LH, et al.; 77–84 97. Peters SAE, Huxley RR, Woodward M. Diabe- Detection of Ischemia in Asymptomatic Diabetics 125. Kannel WB, Hjortland M, Castelli WP. Role of tes as risk factor for incident coronary heart dis- (DIAD) Investigators. Resolution of asymptomatic diabetes in congestive heart failure: the Framing- ease in women compared with men: a systematic myocardial ischemia in patients with type 2 dia- ham study. Am J Cardiol 1974;34:29–34 review and meta-analysis of 64 cohorts including betes in the Detection of Ischemia in Asymptom- 126. Dormandy JA, Charbonnel B, Eckland DJA, 858,507 individuals and 28,203 coronary events. atic Diabetics (DIAD) study. Diabetes Care 2007; et al.; PROactive Investigators. Secondary prevention Diabetologia 2014;57:1542–1551 30:2892–2898 of macrovascular events in patients with type 2 98. Kalyani RR, Lazo M, Ouyang P, et al. Sex differ- 113. Elkeles RS, Godsland IF, Feher MD, et al.; diabetes in the PROactive Study (PROspective ences in diabetes and risk of incident coronary PREDICT Study Group. Coronary calcium mea- pioglitAzone Clinical Trial In macroVascular Events): artery disease in healthy young and middle-aged surement improves prediction of cardiovascular a randomised controlled trial. Lancet 2005;366: adults. Diabetes Care 2014;37:830–838 events in asymptomatic patients with type 2 1279–1289 S104 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

127. Singh S, Loke YK, Furberg CD. Long-term risk 134. Fitchett D, Butler J, van de Borne P, et al. outcomes in patients with type 2 diabetes. N of cardiovascular events with rosiglitazone: Effects of empagliflozin on risk for cardiovascular Engl J Med 2016;375:1834–1844 a meta-analysis. JAMA 2007;298:1189–1195 death and heart failure hospitalization across the 140. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA 128. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. spectrum of heart failure risk in the EMPA-REG Investigators. Lixisenatide in patients with type 2 Pioglitazone and risk of cardiovascular events in OUTCOME trial [article online]. Eur Heart J 2017. diabetes and acute coronary syndrome. N Engl J patients with type 2 diabetes mellitus: a meta- Available from https://academic.oup.com/ Med 2015;373:2247–2257 analysis of randomized trials. JAMA 2007;298: eurheartj/article/doi/10.1093/eurheartj/ehx511/ 141. Holman RR, Bethel MA, Mentz RJ, et al.; 1180–1188 4096345/Effects-of-empagliflozin-on-risk-for. Ac- EXSCEL Study Group. Effects of once-weekly exe- 129. Scirica BM, Bhatt DL, Braunwald E, et al.; cessed 29 September 2017 natide on cardiovascular outcomes in type 2 di- SAVOR-TIMI 53 Steering Committee and Investi- 135. Neal B, Perkovic V, Mahaffey KW, et al.; abetes. N Engl J Med 2017;377:1228–1239 gators. Saxagliptin and cardiovascular outcomes CANVAS Program Collaborative Group. Cana- 142. Zoungas S, Chalmers J, Neal B, et al.; in patients with type 2 diabetes mellitus. N Engl J gliflozin and cardiovascular and renal events ADVANCE-ON Collaborative Group. Follow-up Med 2013;369:1317–1326 in type 2 diabetes. N Engl J Med 2017;377:644– of blood-pressure lowering and glucose control 130. U.S. Food and Drug Administration. Diabe- 657 in type 2 diabetes. N Engl J Med 2014;371: tes medications containing saxagliptin and alog- 136. Neal B, Perkovic V, Matthews DR, et al. Ra- 1392–1406 liptin: drug safety communication - risk of heart tionale, design and baseline characteristics of the 143. Hansson L, Zanchetti A, Carruthers SG, et al.; failure [Internet]. Available from https://www CANagliflozin cardioVascular Assessment Study- HOT Study Group. Effects of intensive blood- .fda.gov/safety/medwatch/safetyinformation/ Renal (CANVAS-R): a randomized, placebo controlled pressure lowering and low-dose aspirin in pa- safetyalertsforhumanmedicalproducts/ucm494252 trial. Diabetes Obes Metab 2017;19:387–393 tients with hypertension: principal results of the .htm. Accessed 13 October 2017 137. U.S. Food and Drug Administration. Guid- Hypertension Optimal Treatment (HOT) rando- 131. Zannad F, Cannon CP, Cushman WC, et al.; ance for industry diabetes mellitus: evaluating mised trial. Lancet 1998;351:1755–1762 EXAMINE Investigators. Heart failure and mortal- cardiovascular risk in new antidiabetic therapies 144. Wright JT Jr, Williamson JD, Whelton PK, ity outcomes in patients with type 2 diabetes tak- to treat type 2 diabetes. Silver Spring, MD, 2008. et al.; SPRINT Research Group. A randomized trial ing alogliptin versus placebo in EXAMINE: Available from http://www.fda.gov/downloads/ of intensive versus standard blood-pressure con- a multicentre, randomised, double-blind trial. Drugs/GuidanceComplianceRegulatoryInformation/ trol. N Engl J Med 2015;373:2103–2116 Lancet 2015;385:2067–2076 Guidances/ucm071627.pdf). Accessed 3 November 145. White WB, Cannon CP, Heller SR, et al.; 132. Green JB, Bethel MA, Armstrong PW, et al.; 2017 EXAMINE Investigators. Alogliptin after acute cor- TECOS Study Group. Effect of sitagliptin on cardio- 138. Marso SP, Daniels GH, Brown-Frandsen K, onary syndrome in patients with type 2 diabetes. vascular outcomes in type 2 diabetes. N Engl J et al.; LEADER Steering Committee; LEADER Trial N Engl J Med 2013;369:1327–1335 Med 2015;373:232–242 Investigators. Liraglutide and cardiovascular out- 146. Cefalu WT, Kaul S, Gerstein HC, et al. Cardio- 133. Zinman B, Wanner C, Lachin JM, et al.; comes in type 2 diabetes. N Engl J Med 2016;375: vascular outcomes trials in type 2 diabetes: where EMPA-REG OUTCOME Investigators. Empagliflozin, 311–322 do we go from here? Reflections from a Diabetes cardiovascular outcomes, and mortality in type 2 139. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN- Care Editors’ Expert Forum. Diabetes Care. In diabetes. N Engl J Med 2015;373:2117–2128 6 Investigators. Semaglutide and cardiovascular press Diabetes Care Volume 41, Supplement 1, January 2018 S105

10. Microvascular Complications American Diabetes Association and Foot Care: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S105–S118 | https://doi.org/10.2337/dc18-S010

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 Suggested citation: American Diabetes Association. 10. Microvascular complications and foot care: with modestly elevated urinary albumin–to–creatinine ratio (30–299 mg/g Standards of Medical Care in Diabetesd2018. creatinine) B and is strongly recommended for those with urinary albumin–to– Diabetes Care 2018;41(Suppl. 1):S105–S118 $ fi creatinine ratio 300 mg/g creatinine and/or estimated glomerular ltration © 2017 by the American Diabetes Association. 2 rate ,60 mL/min/1.73 m . A Readers may use this article as long as the work c Periodically monitor serum creatinine and potassium levels for the development is properly cited, the use is educational and not of increased creatinine or changes in potassium when ACE inhibitors, angiotensin for profit, and the work is not altered. More infor- receptor blockers, or diuretics are used. B mation is available at http://www.diabetesjournals .org/content/license. S106 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

collections are more burdensome and over time as the prevalence of diabetes in- c Continued monitoring of urinary add little to prediction or accuracy. Mea- creases in the U.S. (3,4,11,12). albumin–to–creatinine ratio in pa- surement of a spot urine sample for albumin An active urinary sediment (containing tients with albuminuria treated with alone (whether by immunoassay or by using red or white blood cells or cellular casts), an ACE inhibitor or an angiotensin re- a sensitive dipstick test specific for albu- rapidly increasing albuminuria or nephrotic ceptor blocker is reasonable to assess minuria) without simultaneously measur- syndrome, rapidly decreasing eGFR, or the the response to treatment and pro- ing urine creatinine (Cr) is less expensive but absence of retinopathy (in type 1 diabe- gression of diabetic kidney disease. E susceptible to false-negative and false- tes) may suggest alternative or additional c An ACE inhibitor or an angiotensin positive determinations as a result of varia- causes of kidney disease. For patients receptor blocker is not recom- tion in urine concentration due to hydration. with these features, referral to a nephrol- mended for the primary prevention Normal UACR is generally defined ogist for further diagnosis, including the of diabetic kidney disease in pa- as ,30 mg/g Cr, and increased urinary possibility of kidney biopsy, should be tients with diabetes who have nor- albumin excretion is defined as $30 considered. It is rare for patients with mal blood pressure, normal urinary mg/g Cr. However, UACR is a continuous type 1 diabetes to develop kidney disease albumin–to–creatinine ratio (,30 measurement, and differences within the without retinopathy. In type 2 diabetes, mg/g creatinine), and normal esti- normal and abnormal ranges are associ- retinopathy is only moderately sensitive mated glomerular filtration rate. B ated with renal and cardiovascular out- and specific for CKD caused by diabetes, c When estimated glomerular filtration comes (7–9). Furthermore, because of as confirmed by kidney biopsy (13). rate is ,60 mL/min/1.73 m2, evalu- biological variability in urinary albumin Stage 1–2 CKD has been defined by ate and manage potential complica- excretion, two of three specimens of evidence of kidney damage (usually albu- tions of chronic kidney disease. E UACR collected within a 3- to 6-month minuria) with eGFR $60 mL/min/1.73 m2, c Patients should be referred for period should be abnormal before con- while stages 3–5 CKD have been de- evaluation for renal replacement sidering a patient to have albuminuria. fined by progressively lower ranges of treatment if they have an estimated Exercise within 24 h, infection, fever, eGFR (14) (Table 10.1). More recently, glomerular filtration rate ,30 congestive heart failure, marked hyper- Kidney Disease: Improving Global Out- mL/min/1.73 m2. A glycemia, menstruation, and marked comes (KDIGO) recommended a more c Promptly refer to a physician expe- hypertension may elevate UACR inde- comprehensive CKD staging that incor- rienced in the care of kidney disease for uncertainty about the etiology of pendently of kidney damage. porates albuminuria and is more closely kidney disease, difficult management eGFR should be calculated from serum associated with risks of cardiovascular Cr using a validated formula. The Chronic issues, and rapidly progressing kidney disease (CVD) and CKD progression (2). disease. B Kidney Disease Epidemiology Collabora- It has not been determined whether ap- tion (CKD-EPI) equation is generally pre- plication of the more complex system aids Epidemiology of Diabetic Kidney ferred (2). eGFR is routinely reported by clinical care or improves health outcomes. Disease laboratories with serum Cr, and eGFR cal- Chronic kidney disease (CKD) is diagnosed culators are available from http://www Acute Kidney Injury by the persistent presence of elevated .nkdep.nih.gov. An eGFR ,60 mL/min/ Acute kidney injury (AKI) is usually diag- 2 urinary albumin excretion (albuminuria), 1.73 m is generally considered abnormal, nosed by a rapid increase in serum Cr, fl low estimated glomerular filtration rate though optimal thresholds for clinical di- which is also re ected as a rapid decrease (eGFR), or other manifestations of kidney agnosis are debated (10). in eGFR, over a relatively short period of damage (1,2). Diabetic kidney disease, or Urinary albumin excretion and eGFR time. People with diabetes are at higher CKD attributed to diabetes, occurs in 20– each vary within people over time, and risk of AKI than those without diabetes 40% of patients with diabetes (1,3–5). Di- abnormal results should be confirmed to (15). Other risk factors for AKI include abetic kidney disease typically develops stage CKD (1,2). preexisting CKD, the use of medications after diabetes duration of 10 years in that cause kidney injury (e.g., nonsteroi- fl type 1 diabetes, but may be present at Diagnosis of Diabetic Kidney Disease dal anti-in ammatory drugs), and the use diagnosis of type 2 diabetes. Diabetic kid- Diabetic kidney disease is usually a clinical of medications that alter renal blood flow ney disease can progress to end-stage re- diagnosis made based on the presence of and intrarenal hemodynamics. In particu- nal disease (ESRD) requiring dialysis or albuminuria and/or reduced eGFR in the lar, many antihypertensive medications kidney transplantation and is the leading absence of signs or symptoms of other (e.g., diuretics, ACE inhibitors, and angio- cause of ESRD in the United States (6). In primary causes of kidney damage. The typ- tensin receptor blockers [ARBs]) can re- addition, among people with type 1 or ical presentation of diabetic kidney disease duce intravascular volume, renal blood 2diabetes,thepresenceofCKDmarkedly is considered to include a long-standing flow, and/or glomerular filtration. There increases cardiovascular risk (7). duration of diabetes, retinopathy, albumin- is a concern that sodium–glucose cotrans- uria without hematuria, and gradually pro- porter 2 (SGLT2) inhibitors may promote Assessment of Albuminuria and gressive kidney disease. However, signs of AKI through volume depletion, particu- Estimated Glomerular Filtration Rate CKD may be present at diagnosis or without larly when combined with diuretics or Screening for albuminuria can be most retinopathy in type 2 diabetes, and reduced other medications that reduce glomeru- easily performed by urinary albumin–to– eGFR without albuminuria has been fre- lar filtration. However, existing evidence creatinine ratio (UACR) in a random spot quentlyreportedintype1andtype2di- from clinical trials and observational stud- urine collection (1,2). Timed or 24-h abetes and is becoming more common ies suggests that SGLT2 inhibitors do not care.diabetesjournals.org Microvascular Complications and Foot Care S107

Table 10.1—CKD stages and corresponding focus of kidney-related care CKD stage† Focus of kidney-related care Evidence of Diagnose Evaluate and treat Evaluate and eGFR kidney cause of risk factors for CKD treat CKD Prepare for renal Stage (mL/min/1.73 m2) damage* kidney injury progression** complications*** replacement therapy No clinical evidence of CKD $60 d 1 $90 1 !! 260–89 1 !! 330–59 1/2 !! ! 415–29 1/2 !! ! 5 ,15 1/2 !! †CKD stages 1 and 2 are defined by evidence of kidney damage (1), while CKD stages 3–5aredefined by reduced eGFR with or without evidence of kidney damage (1/2). *Kidney damage is most often manifest as albuminuria (UACR $30 mg/g Cr) but can also include glomerular hematuria, other abnormalities of the urinary sediment, radiographic abnormalities, and other presentations. **Risk factors for CKD progression include elevated blood pressure, glycemia, and albuminuria. ***See Table 10.2. significantly increase AKI (16,17). Timely to therapy and disease progression and Comorbidities” for further information identification and treatment of AKI are may aid in assessing adherence to ACE in- on immunization). important because AKI is associated hibitor or ARB therapy. In addition, in clin- Interventions with increased risks of progressive CKD ical trials of ACE inhibitors or ARB therapy Nutrition and other poor health outcomes (18). in type 2 diabetes, reducing albuminuria For people with nondialysis-dependent di- $ from levels 300 mg/g Cr has been asso- abetic kidney disease, dietary protein intake Surveillance ciated with improved renal and cardiovas- should be approximately 0.8 g/kg body Albuminuria and eGFR should be moni- cular outcomes, leading some to suggest weight per day (the recommended daily al- tored regularly to enable timely diagnosis that medications should be titrated to min- lowance) (1). Compared with higher levels of diabetic kidney disease, monitor pro- imize UACR. However, this approach has of dietary protein intake, this level slowed gression of diabetic kidney disease, not been formally evaluated in prospec- GFR decline with evidence of a greater ef- detect superimposed kidney diseases in- tive trials. In type 1 diabetes, remission of fect over time. Higher levels of dietary pro- cluding AKI, assess risk of CKD compli- albuminuria may occur spontaneously tein intake (.20% of daily calories from cations, dose drugs appropriately, and and cohort studies evaluating associa- protein or .1.3 g/kg/day) have been as- determine whether nephrology referral tions of change in albuminuria with clini- sociated with increased albuminuria, more is needed. Among people with existing cal outcomes have reported inconsistent rapid kidney function loss, and CVD mor- kidney disease, albuminuria and eGFR results (22,23). tality and therefore should be avoided. may change due to progression of dia- The prevalence of CKD complications Reducing the amount of dietary protein betic kidney disease, development of a correlates with eGFR. When eGFR is below the recommended daily allowance separate superimposed cause of kidney ,60 mL/min/1.73 m2, screening for com- of 0.8 g/kg/day is not recommended be- disease, AKI, or other effects of medica- plications of CKD is indicated (Table 10.2). cause it does not alter glycemic measures, tions, as noted above. Serum potassium Early vaccination against hepatitis B virus cardiovascular risk measures, or the should also be monitored for patients is indicated in patients likely to progress course of GFR decline. In dialysis, protein- treated with ACE inhibitors, ARBs, and di- to ESRD (see Section 3 “Comprehensive energy wasting is common, and in- uretics because these medications can Medical Evaluation and Assessment of creased dietary protein intake may be cause hyperkalemia or hypokalemia, which are associated with cardiovascular risk and mortality (19–21). For patients Table 10.2—Selected complications of CKD with eGFR ,60 mL/min/1.73 m2, appro- Complication Medical and laboratory evaluation priate medication dosing should be veri- Elevated blood pressure Blood pressure, weight fied, exposure to nephrotoxins (e.g., Volume overload History, physical examination, weight nonsteroidal anti-inflammatory drugs Electrolyte abnormalities Serum electrolytes and iodinated contrast) should be mini- Metabolic acidosis Serum electrolytes mized, and potential CKD complications Anemia Hemoglobin; iron testing if indicated should be evaluated. Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D The need for annual quantitative assess- Complications of CKD generally become prevalent when eGFR falls below 60 mL/min/1.73 m2 (stage ment of albumin excretion after diagnosis 3 CKD or greater) and become more common and severe as CKD progresses. Evaluation of elevated of albuminuria, institution of ACE inhibitors blood pressure and volume overload should occur at every possible clinical contact; laboratory or ARB therapy, and achieving blood pres- evaluations are generally indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage sure control is a subject of debate. Contin- 4 CKD, and every 1–3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. ued surveillance can assess both response S108 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

necessary to help preserve muscle mass tubular glucose reabsorption, weight, sys- Disease and Risk Management” for fur- and function. temic blood pressure, intraglomerular ther discussion). All of these trials included For some patients with diabetes, restric- pressure, and albuminuria and slow GFR large numbers of people with kidney dis- tion of dietary sodium may be useful to loss through mechanisms that appear ease (for example, the baseline prevalence control blood pressure and reduce cardio- independent of glycemia (17,38–40). of albuminuria in EMPA-REG OUTCOME vascular risk (24), and restriction of dietary Glucagon-like peptide 1 receptor agonists was 53%), and some of the cardiovascular potassium may be necessary to control and dipeptidyl peptidase 4 inhibitors also outcomes trials (CANVAS and LEADER) serum potassium concentration (15,19– have direct effects on the kidney and have were enriched with patients with kidney 21). These interventions may be most im- been reported to improve renal outcomes disease through eligibility criteria based on portant for patients with reduced eGFR, compared with placebo (41–44). albuminuria or reduced eGFR. The glucose- for whom urinary excretion of sodium and A number of large cardiovascular out- lowering effects of SGLT2 inhibitors are potassium may be impaired. Recommen- comestrialsinpatientswithtype2diabetes blunted with eGFR (17,45). However, the dations for dietary sodium and potassium at high risk for cardiovascular disease or with cardiovascular benefits of empagliflozin, intake should be individualized on the basis existing cardiovascular disease (EMPA-REG canagliflozin, and liraglutide were similar of comorbid conditions, medication use, OUTCOME [BI 10773 (Empagliflozin) Car- among participants with and without kid- blood pressure, and laboratory data. diovascular Outcome Event Trial in Type 2 ney disease at baseline (40,41,45,46). Diabetes Mellitus Patients], CANVAS With reduced eGFR, drug dosing may Glycemia [Canagliflozin Cardiovascular Assessment require modification (1). The U.S. Food Intensive glycemic control with the goal Study], LEADER [Liraglutide Effect and and Drug Administration (FDA) revised of achieving near-normoglycemia has been Action in Diabetes: Evaluation of Cardio- guidance for the use metformin in dia- shown in large prospective randomized vascular Outcome ResultsdALongTerm betic kidney disease in 2016 (47), recom- studies to delay the onset and progression Evaluation], and SUSTAIN-6 [Trial to Eval- mending use of eGFR instead of serum Cr of albuminuria and reduced eGFR in patients uate Cardiovascular and Other Long-term to guide treatment and expanding the with type 1 diabetes (25,26) and type 2 di- Outcomes With Semaglutide in Subjects With pool of patients with kidney disease for abetes (1,27–32). Insulin alone was used Type 2 Diabetes]) examined kidney effects whom metformin treatment should be to lower blood glucose in the Diabetes as secondary outcomes (40,41,44,45). considered. Revised FDA guidance states Control and Complications Trial (DCCT)/ Specifically, compared with placebo, that metformin is contraindicated in patients Epidemiology of Diabetes Interventions empagliflozin reduced the risk of incident with an eGFR ,30 mL/min/ 1.73 m2,eGFR and Complications (EDIC) study of type 1 or worsening nephropathy (a composite of should be monitored while taking metfor- diabetes, while a variety of agents were progression to UACR .300 mg/g Cr, dou- min, the benefits and risks of continuing used in clinical trials of type 2 diabetes, bling of serum Cr, ESRD, or death from treatment should be reassessed when supporting the conclusion that glycemic ESRD) by 39% and the risk of doubling of eGFR falls ,45 mL/min/1.73 m2, metfor- control itself helps prevent diabetic kidney serum Cr accompanied by eGFR #45 mL/ min should not be initiated for patients disease and its progression. The effects of min/1.73 m2 by 44%; canagliflozin reduced with an eGFR ,45 mL/min/1.73 m2,and glucose-lowering therapies on diabetic the risk of progression of albuminuria by metformin should be temporarily discon- kidney disease have helped define A1C 27% and the risk of reduction in eGFR, tinued at the time of or before iodinated targets (see Table 6.2). ESRD, or death from ESRD by 40%; liraglu- contrast imaging procedures in patients The presence of diabetic kidney dis- tide reduced the risk of new or worsening with eGFR 30–60 mL/min/ 1.73 m2.Other ease affects the risks and benefits of in- nephropathy (a composite of persistent glucose-lowering medications also re- tensive glycemic control and a number of UACR .300 mg/g Cr, doubling of serum quire dose adjustment or discontinuation specific glucose-lowering medications. In Cr, ESRD, or death from ESRD) by 22%; and at low eGFR (see Table 8.2) (1). the Action to Control Cardiovascular Risk semaglutide reduced the risk of new or in Diabetes (ACCORD) trial of type 2 di- worsening nephropathy (a composite of Cardiovascular Disease and Blood Pressure abetes, adverse effects of intensive glyce- persistent UACR .300 mg/g Cr, doubling Hypertension is a strong risk factor for the mic control (hypoglycemia and mortality) of serum Cr, or ESRD) by 36% (each P , development and progression of diabetic were increased among patients with 0.01). Additional trials with primary kid- kidney disease (48). Antihypertensive ther- kidney disease at baseline (33,34). More- ney outcomes are needed to definitively apy reduces the risk of albuminuria (49– over, there is a lag time of at least 2 years determine whether specificglucose-low- 52), and among patients with type 1 or in type 2 diabetes to over 10 years in type 1 ering drugs improve renal outcomes. 2 diabetes with established diabetic kid- diabetes for the effects of intensive glucose Patients with diabetic kidney disease ney disease (eGFR ,60 mL/min/1.73 m2 controltomanifestasimprovedeGFRout- are at high risk of cardiovascular events, and UACR $300 mg/g Cr), ACE inhibitor comes (31,35,36). Therefore, in some pa- and some SGLT2 inhibitors and glucagon- or ARB therapy reduces the risk of pro- tients with prevalent diabetic kidney like peptide 1 receptor agonists have gression to ESRD (53–55). Moreover, an- disease and substantial comorbidity, target demonstrated cardiovascular benefits. tihypertensive therapy reduces risks of A1C levels may be less intensive (1,37). Namely, in EMPA-REG OUTCOME, CANVAS, cardiovascular events (49). Specific Glucose-Lowering Medications and LEADER, empagliflozin, canagliflozin, Blood pressure levels ,140/90 mmHg Some glucose-lowering medications also and liraglutide, respectively, each re- are generally recommended to reduce have effects on the kidney that are direct, duced cardiovascular events, evaluated CVD mortality and slow CKD progression i.e., not mediated through glycemia. For as primary outcomes, compared with among people with diabetes (52). Lower example, SGLT2 inhibitors reduce renal placebo (see Section 9 “Cardiovascular blood pressure targets (e.g., ,130/80 care.diabetesjournals.org Microvascular Complications and Foot Care S109

mmHg) may be considered for patients are effective for management of resistant c If there is no evidence of retinopathy based on individual anticipated benefits hypertension, have been shown to reduce for one or more annual eye exam and and risks. Patients with diabetic kidney dis- albuminuria in short-term studies of dia- glycemia is well controlled, then ease are at increased risk of CKD progression betic kidney disease, and may have addi- exams every 1–2yearsmaybecon- (particularly those with albuminuria) and tional cardiovascular benefits (65–67). sidered. If any level of diabetic ret- CVD and therefore may be suitable in There has been, however, an increase in inopathy is present, subsequent some cases for lower blood pressure targets. hyperkalemic episodes in those on dual dilated retinal examinations should ACE inhibitors or ARBs are the pre- therapy, and larger, longer trials with clin- be repeated at least annually by an ferred first-line agent for blood pressure ical outcomes are needed before recom- ophthalmologist or optometrist. If treatment among patients with diabetes, mending such therapy. retinopathy is progressing or sight- hypertension, eGFR ,60 mL/min/1.73 m2, Referral to a Nephrologist threatening, then examinations will and UACR $300 mg/g Cr because of their Consider referral to a physician expe- be required more frequently. B proven benefits for prevention of CKD rienced in the care of kidney disease c While retinal photography may progression (53–56). In general, ACE inhibi- when there is uncertainty about the eti- serve as a screening tool for reti- tors and ARBs are considered to have similar ology of kidney disease, difficult man- nopathy, it is not a substitute for a benefits (57,58) and risks. In the setting of agement issues (anemia, secondary comprehensive eye exam. E lower levels of albuminuria (30–299 mg/g hyperparathyroidism, metabolic bone c Women with preexisting type 1 or Cr), ACE inhibitor or ARB therapy has been disease, resistant hypertension, or elec- type 2 diabetes who are planning demonstrated to reduce progression to trolyte disturbances), or advanced kidney pregnancy or who are pregnant more advanced albuminuria ($300 mg/g 2 disease (eGFR ,30 mL/min/1.73 m )re- should be counseled on the risk of Cr) and cardiovascular events but not pro- quiring discussion of renal replacement development and/or progression of gression to ESRD (56,59). While ACE inhib- therapy for ESRD. The threshold for re- diabetic retinopathy. B itors or ARBs are often prescribed for ferral may vary depending on the fre- c Eye examinations should occur be- albuminuria without hypertension, clini- quency with which a provider encounters fore pregnancy or in the first trimes- cal trials have not been performed in patients with diabetes and kidney dis- ter in patients with preexisting this setting to determine whether this im- ease. Consultation with a nephrologist type 1 or type 2 diabetes, and then proves renal outcomes. when stage 4 CKD develops (eGFR #30 patients should be monitored every Absent kidney disease, ACE inhibitors 2 mL/min/1.73 m ) has been found to re- trimester and for 1 year postpartum or ARBs are useful to control blood pres- duce cost, improve quality of care, and as indicated by the degree of reti- sure but may not be superior to alterna- delay dialysis (68). However, other spe- nopathy. B tive proven classes of antihypertensive cialists and providers should also educate therapy, including thiazide-like diuretics their patients about the progressive na- Treatment and dihydropyridine calcium channel ture of diabetic kidney disease, the kidney c Promptly refer patients with any blockers (60). In a trial of people with preservation benefits of proactive treat- level of macular edema, severe type 2 diabetes and normal urine albumin ment of blood pressure and blood glu- nonproliferative diabetic retinopa- excretion, an ARB reduced or suppressed cose, and the potential need for renal thy (a precursor of proliferative the development of albuminuria but in- replacement therapy. diabetic retinopathy), or any prolif- creased the rate of cardiovascular events erative diabetic retinopathy to an (61). In a trial of people with type 1 di- DIABETIC RETINOPATHY ophthalmologist who is knowledge- abetes exhibiting neither albuminuria nor able and experienced in the man- hypertension, ACE inhibitors or ARBs did Recommendations agement of diabetic retinopathy. A not prevent the development of diabetic c Optimize glycemic control to re- c The traditional standard treatment, glomerulopathy assessed by kidney bi- duce the risk or slow the progres- A panretinal laser photocoagulation opsy (62). Therefore, ACE inhibitors or sion of diabetic retinopathy. ARBs are not recommended for patients c Optimize blood pressure and serum therapy, is indicated to reduce the without hypertension to prevent the de- lipid control to reduce the risk or risk of vision loss in patients with velopment of diabetic kidney disease. slow the progression of diabetic ret- high-risk proliferative diabetic retinop- A athy and, in some cases, severe non- Two clinical trials studied the combina- inopathy. proliferative diabetic retinopathy. A tions of ACE inhibitors and ARBs and found Screening c Intravitreous injections of anti– no benefits on CVD or diabetic kidney dis- c Adults with type 1 diabetes should vascular endothelial growth factor ease, and the drug combination had higher have an initial dilated and compre- ranibizumab are not inferior to tradi- adverse event rates (hyperkalemia and/or hensive eye examination by an oph- tional panretinal laser photocoagula- AKI) (63,64). Therefore, the combined use of ACE inhibitors and ARBs should be thalmologist or optometrist within tionandarealsoindicatedtoreduce B avoided. 5 years after the onset of diabetes. the risk of vision loss in patients with c Patients with type 2 diabetes should proliferative diabetic retinopathy. A Mineralocorticoid receptor antagonists have an initial dilated and compre- c Intravitreous injections of anti– (spironolactone, eplerenone, and finere- hensive eye examination by an oph- vascular endothelial growth factor none) in combination with ACE inhibitors thalmologist or optometrist at the are indicated for central-involved di- or ARBs remain an area of great interest. time of the diabetes diagnosis. B abetic macular edema, which occurs Mineralocorticoid receptor antagonists S110 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

in diagnosing diabetic retinopathy should diagnosis should have an initial dilated beneath the foveal center and may perform the examinations. Youth with and comprehensive eye examination at threaten reading vision. A type 1 or type 2 diabetes are also at the time of diagnosis. c The presence of retinopathy is not a risk for complications and need to be contraindication to aspirin therapy Pregnancy screened for diabetic retinopathy (80). If for cardioprotection, as aspirin does Pregnancy is associated with a rapid pro- diabetic retinopathy is present, prompt not increase the risk of retinal hem- gression of diabetic retinopathy (87,88). referral to an ophthalmologist is recom- orrhage. A Women with preexisting type 1 or type 2 mended. Subsequent examinations for diabetes who are planning pregnancy or patients with type 1 or type 2 diabetes Diabetic retinopathy is a highly specific who have become pregnant should be are generally repeated annually for pa- vascular complication of both type 1 and counseled on the risk of development tients with minimal to no retinopathy. Ex- type 2 diabetes, with prevalence strongly and/or progression of diabetic retinopa- ams every 1–2 years may be cost-effective related to both the duration of diabetes thy. In addition, rapid implementation of after one or more normal eye exams, and the level of glycemic control (69). Di- intensive glycemic management in the and in a population with well-controlled abetic retinopathy is the most frequent setting of retinopathy is associated with type 2 diabetes, there was essentially no cause of new cases of blindness among early worsening of retinopathy (79). Women risk of development of significant retinop- adults aged 20–74 years in developed who develop gestational diabetes melli- athy with a 3-year interval after a normal countries. Glaucoma, cataracts, and other tus do not require eye examinations dur- examination (81). Less frequent intervals disorders of the eye occur earlier and ing pregnancy and do not appear to be at have been found in simulated modeling more frequently in people with diabetes. increased risk of developing diabetic ret- to be potentially effective in screening for In addition to diabetes duration, factors inopathy during pregnancy (89). diabetic retinopathy in patients without that increase the risk of, or are associated diabetic retinopathy (82). More frequent with, retinopathy include chronic hypergly- Treatment examinations by the ophthalmologist will cemia (70), diabetic kidney disease (71), Two of the main motivations for screen- be required if retinopathy is progressing. hypertension (72), and dyslipidemia (73). ing for diabetic retinopathy are to prevent Retinal photography with remote read- Intensive diabetes management with the loss of vision and to intervene with treating by experts has great potential to pro- goal of achieving near-normoglycemia ment when vision loss can be prevented vide screening services in areas where has been shown in large prospective ran- or reversed. qualified eye care professionals are not domized studies to prevent and/or delay readily available (83,84). High-quality fun- Photocoagulation Surgery the onset and progression of diabetic ret- dus photographs can detect most clinically Two large trials, the Diabetic Retinopathy inopathy and potentially improve patient- significant diabetic retinopathy. Interpreta- Study (DRS) in patients with PDR and the reported visual function (28,74–76). tion of the images should be performed Early Treatment Diabetic Retinopathy Lowering blood pressure has been by a trained eye care provider. Retinal pho- Study (ETDRS) in patients with macular shown to decrease retinopathy progres- tography may also enhance efficiency and edema, provide the strongest support sion, although tight targets (systolic blood reduce costs when the expertise of ophthal- for the therapeutic benefits of photoco- pressure ,120 mmHg) do not impart ad- mologists can be used for more complex agulation surgery. The DRS (90) showed in ditional benefit (75). ACE inhibitors and examinations and for therapy (85). In-person 1978 that panretinal photocoagulation ARBs are both effective treatments in di- exams are still necessary when the retinal surgery reduced the risk of severe vision abetic retinopathy (77). In patients with photos are of unacceptable quality and for loss from PDR from 15.9% in untreated eyes dyslipidemia, retinopathy progression follow-up if abnormalities are detected. Ret- to 6.4% in treated eyes with the greatest may be slowed by the addition of fenofi- inal photos are not a substitute for compre- benefit ratio in those with more advanced brate, particularly with very mild nonpro- hensive eye exams, which should be baseline disease (disc neovascularization liferative diabetic retinopathy (NPDR) at performed at least initially and at intervals or vitreous hemorrhage). In 1985, the baseline (73). Several case series and a thereafter as recommended by an eye care ETDRS also verified the benefits of panreti- controlled prospective study suggest professional. Results of eye examinations nal photocoagulation for high-risk PDR that pregnancy in patients with type 1 di- should be documented and transmitted and in older-onset patients with severe abetes may aggravate retinopathy and to the referring health care professional. NPDR or less-than-high-risk PDR. Panreti- threaten vision, especially when glycemic nal laser photocoagulation is still com- control is poor at the time of conception Type 1 Diabetes monly used to manage complications of (78,79). Laser photocoagulation surgery Because retinopathy is estimated to take diabetic retinopathy that involve retinal can minimize the risk of vision loss (79). at least 5 years to develop after the onset neovascularization and its complications. of hyperglycemia, patients with type 1 di- Screening – abetes should have an initial dilated and Anti Vascular Endothelial Growth Factor The preventive effects of therapy and Treatment comprehensive eye examination within the fact that patients with proliferative Recent data from the Diabetic Retinopa- 5 years after the diagnosis of diabetes (86). diabetic retinopathy (PDR) or macular thy Clinical Research Network and others edema may be asymptomatic provide Type 2 Diabetes demonstrate that intravitreal injections strong support for screening to detect di- Patients with type 2 diabetes who may of anti–vascular endothelial growth fac- abetic retinopathy. have had years of undiagnosed diabe- tor (anti-VEGF) agent, specifically ranibi- An ophthalmologist or optometrist tes and have a significant risk of preva- zumab, resulted in visual acuity outcomes who is knowledgeable and experienced lent diabetic retinopathy at the time of that were not inferior to those observed care.diabetesjournals.org Microvascular Complications and Foot Care S111

in patients treated with panretinal laser at control can effectively prevent DPN and starting at diagnosis of type 2 di- 2 years of follow-up (91). In addition, itwas cardiac autonomic neuropathy (CAN) in abetes and 5 years after the di- observed that patients treated with ranibi- type 1 diabetes (97,98) and may modestly agnosis of type 1 diabetes and at zumab tended to have less peripheral visual slow their progression in type 2 diabetes least annually thereafter. B field loss, fewer vitrectomy surgeries for sec- (30), but does not reverse neuronal loss. c Assessment for distal symmetric poly- ondary complications from their prolifera- neuropathy should include a careful Therapeutic strategies (pharmacologic tive disease, and a lower risk of developing history and assessment of either tem- and nonpharmacologic) for the relief of diabetic macular edema. However, a po- perature or pinprick sensation (small- painful DPN and symptoms of autonomic tential drawback in using anti-VEGF ther- fiber function) and vibration sensation neuropathy can potentially reduce pain apy to manage proliferative disease is that using a 128-Hz tuning fork (for large- (99) and improve quality of life. patients were required to have a greater fiber function). All patients should number of visits and received a greater have annual 10-g monofilament test- Diagnosis number of treatments than is typically re- ing to identify feet at risk for ulcera- quired for management with panretinal la- Diabetic Peripheral Neuropathy tion and amputation. B ser, which may not be optimal for some Patients with type 1 diabetes for 5 or c Symptoms and signs of autonomic patients. Other emerging therapies for ret- more years and all patients with type 2 neuropathy should be assessed in inopathy that may use sustained intravitreal diabetes should be assessed annually for patients with microvascular compli- delivery of pharmacologic agents are cur- DPN using the medical history and simple cations. E rently under investigation. In April, the clinical tests. Symptoms vary according to fi FDA approved ranibizumab for the treat- Treatment the class of sensory bers involved. The most common early symptoms are in- ment of diabetic retinopathy. c Optimize glucose control to prevent duced by the involvement of small fibers While the ETDRS (92) established the or delay the development of neu- benefit of focal laser photocoagulation ropathy in patients with type 1 and include pain and dysesthesias (un- surgery in eyes with clinically significant diabetes A andtoslowthepro- pleasant sensations of burning and tin- fi macular edema (defined as retinal edema gression of neuropathy in patients gling). The involvement of large bers located at or within 500 mm of the center with type 2 diabetes. B may cause numbness and loss of protec- of the macula), current data from well- c Assess and treat patients to reduce tive sensation (LOPS). LOPS indicates the designed clinical trials demonstrate that pain related to diabetic peripheral presence of distal sensorimotor poly- intravitreal anti-VEGF agents provide a neuropathy B and symptoms of au- neuropathy and is a risk factor for di- more effective treatment regimen for tonomic neuropathy and to im- abetic foot ulceration. The following central-involved diabetic macular edema prove quality of life. E clinical tests may be used to assess small- than monotherapy or even combination c Either pregabalin or duloxetine are and large-fiber function and protective therapy with laser (93–95). There are cur- recommended as initial pharmaco- sensation: rently three anti-VEGF agents commonly logic treatments for neuropathic pain fi used to treat eyes with central-involved in diabetes. A 1. Small- ber function: pinprick and tem- diabetic macular edemadbevacizumab, perature sensation fi ranibizumab, and aflibercept (69). The diabetic neuropathies are a heteroge- 2. Large- ber function: vibration percep- fi In both DRS and ETDRS, laser photoco- neous group of disorders with diverse clini- tion and 10-g mono lament fi agulation surgery was beneficial in re- cal manifestations. The early recognition 3. Protective sensation: 10-g mono lament ducing the risk of further visual loss in and appropriate management of neuropa- affected patients, but generally not benefi- thy in the patient with diabetes is important. These tests not only screen for the pres- cial in reversing already diminished acuity. ence of dysfunction but also predict 1. Diabetic neuropathy is a diagnosis of Anti-VEGF therapy improves vision and has future risk of complications. Electrophys- exclusion. Nondiabetic neuropathies replaced the need for laser photocoagula- iological testing or referral to a neurolo- may be present in patients with diabe- tion in the vast majority of patients with gist is rarely needed, except in situations tes and may be treatable. diabetic macular edema (96). Most pa- where the clinical features are atypical or 2. Numerous treatment options exist for tients require near-monthly administration the diagnosis is unclear. symptomatic diabetic neuropathy. In all patients with diabetes and DPN, of intravitreal therapy with anti-VEGF 3. Up to 50% of diabetic peripheral neu- fi causes of neuropathy other than diabetes agents during the rst 12 months of treat- ropathy (DPN) may be asymptomatic. should be considered, including toxins ment, with fewer injections needed in sub- If not recognized and if preventive foot (alcohol), neurotoxic medications (che- sequent years to maintain remission from care is not implemented, patients are motherapy), vitamin B12 deficiency, hypo- central-involved diabetic macular edema. at risk for injuries to their insensate feet. thyroidism, renal disease, malignancies 4. Recognition and treatment of autonomic NEUROPATHY neuropathy may improve symptoms, re- (multiple myeloma, bronchogenic carci- fl duce sequelae, and improve quality of noma), infections (HIV), chronic in amma- Recommendations life. tory demyelinating neuropathy, inherited neuropathies, and vasculitis (100). See Screening Specific treatment for the underlying nerve American Diabetes Association position c All patients should be assessed for damage, other than improved glycemic statement “Diabetic Neuropathy” for diabetic peripheral neuropathy control, is currently not available. Glycemic more details (99). S112 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

Diabetic Autonomic Neuropathy and inadequate lubrication (103). Lower medication side effects is recommended The symptoms and signs of autonomic urinary tract symptoms manifest as uri- to achieve pain reduction and improve neuropathy should be elicited carefully nary incontinence and bladder dysfunction quality of life (113–115). during the history and physical examination. (nocturia, frequent urination, urination ur- Pregabalin, a calcium channel a2-d Major clinical manifestations of diabetic au- gency, and weak urinary stream). Evaluation subunit ligand, is the most extensively tonomic neuropathy include hypoglycemia of bladder function should be performed for studied drug for DPN. The majority of unawareness, resting tachycardia, ortho- individuals with diabetes who have recur- studies testing pregabalin have reported static hypotension, gastroparesis, constipa- rent urinary tract infections, pyelonephritis, favorable effects on the proportion of tion, diarrhea, fecal incontinence, erectile incontinence, or a palpable bladder. participants with at least 30–50% im- dysfunction, neurogenic bladder, and sudo- provement in pain (112,114,116–119). Treatment motor dysfunction with either increased or However, not all trials with pregabalin decreased sweating. Glycemic Control have been positive (112,114,120,121), es- Cardiac Autonomic Neuropathy. CAN is as- Near-normal glycemic control, imple- pecially when treating patients with ad- sociated with mortality independently of mented early in the course of diabetes, vanced refractory DPN (118). Adverse other cardiovascular risk factors (101,102). has been shown to effectively delay or effects may be more severe in older pa- In its early stages, CAN may be completely prevent the development of DPN and tients (122) and may be attenuated by asymptomatic and detected only by de- CAN in patients with type 1 diabetes lower starting doses and more gradual – creased heart rate variability with deep (104 107). Although the evidence for titration. fi breathing. Advanced disease may be the bene t of near-normal glycemic con- Duloxetine is a selective norepineph- associated with resting tachycardia trol is not as strong for type 2 diabetes, rine and serotonin reuptake inhibitor. (.100 bpm) and orthostatic hypotension some studies have demonstrated a mod- Doses of 60 and 120 mg/day showed (a fall in systolic or diastolic blood pres- est slowing of progression without re- efficacy in the treatment of pain associ- fi sure by .20 mmHg or .10 mmHg, reversal of neuronal loss (30,108). Speci c ated with DPN in multicenter random- spectively, upon standing without an glucose-lowering strategies may have dif- ized trials, although some of these had appropriate increase in heart rate). CAN ferent effects. In a post hoc analysis, par- high drop-out rates (112,114,119,121). treatment is generally focused on allevi- ticipants, particularly men, in the Bypass Duloxetine also appeared to improve ating symptoms. Angioplasty Revascularization Investi- neuropathy-related quality of life (123). Gastrointestinal Neuropathies. Gastrointes- gation in Type 2 Diabetes (BARI 2D) trial In longer-term studies, a small increase tinal neuropathies may involve any por- treated with insulin sensitizers had a in A1C was reported in people with dia- tion of the gastrointestinal tract with lower incidence of distal symmetric pol- betes treated with duloxetine compared manifestations including esophageal yneuropathy over 4 years than those with placebo (124). Adverse events may dysmotility, gastroparesis, constipation, treated with insulin/sulfonylurea (109). be more severe in older people, but may diarrhea, and fecal incontinence. Gastro- Neuropathic Pain be attenuated with lower doses and paresis should be suspected in individuals Neuropathic pain can be severe and can slower titrations of duloxetine. with erratic glycemic control or with up- impact quality of life, limit mobility, and Tapentadol is a centrally acting opioid per gastrointestinal symptoms without contribute to depression and social dys- analgesic that exerts its analgesic effects another identified cause. Exclusion of or- function (110). No compelling evidence through both m-opioid receptor agonism ganic causes of gastric outlet obstruction exists in support of glycemic control or and noradrenaline reuptake inhibition. or peptic ulcer disease (with esophago- lifestyle management as therapies for Extended-release tapentadol was ap- gastroduodenoscopy or a barium study neuropathic pain in diabetes or prediabe- proved by the FDA for the treatment of of the stomach) is needed before consider- tes, which leaves only pharmaceutical in- neuropathic pain associated with diabe- ing a diagnosis of or specialized testing for terventions (111). tes based on data from two multicenter gastroparesis. The diagnostic gold standard Pregabalin and duloxetine have re- clinical trials in which participants ti- for gastroparesis is the measurement of ceived regulatory approval by the FDA, trated to an optimal dose of tapentadol gastric emptying with scintigraphy of di- Health Canada, and the European Medi- were randomly assigned to continue gestible solids at 15-min intervals for 4 h cines Agency for the treatment of neu- that dose or switch to placebo (125,126). after food intake. The use of 13Coctanoic ropathic pain in diabetes. The opioid However, both used a design enriched for acid breath test is emerging as a viable tapentadol has regulatory approval in patients who responded to tapentadol alternative. the U.S. and Canada, but the evidence and therefore their results are not gener- Genitourinary Disturbances. Diabetic auto- of its use is weaker (112). Comparative alizable. A recent systematic review and nomic neuropathy may also cause genito- effectiveness studies and trials that in- meta-analysis by the Special Interest urinary disturbances, including sexual clude quality-of-life outcomes are rare, Group on Neuropathic Pain of the Inter- dysfunction and bladder dysfunction. In so treatment decisions must consider national Association for the Study of Pain men, diabetic autonomic neuropathy each patient’s presentation and comor- found the evidence supporting the effec- may cause erectile dysfunction and/or bidities and often follow a trial-and-error tiveness of tapentadol in reducing neu- retrograde ejaculation (99). Female sexual approach. Given the range of partially ef- ropathic pain to be inconclusive (112). dysfunction occurs more frequently in fective treatment options, a tailored and Therefore, given the high risk for addic- those with diabetes and presents as de- stepwise pharmacologic strategy with tion and safety concerns compared with creased sexual desire, increased pain dur- careful attention to relative symptom im- the relatively modest pain reduction, the ing intercourse, decreased sexual arousal, provement, medication adherence, and use of extended-release tapentadol is care.diabetesjournals.org Microvascular Complications and Foot Care S113

not generally recommended as a first- intraurethral prostaglandins, vacuum de- Foot ulcers and amputation, which are or second-line therapy. vices, or penile prostheses. As with DPN consequences of diabetic neuropathy Tricyclic antidepressants, gabapentin, treatments, these interventions do not and/or peripheral arterial disease (PAD), venlafaxine, carbamazepine, tramadol, change the underlying pathology and nat- are common and represent major causes and topical capsaicin, although not ap- ural history of the disease process but of morbidity and mortality in people with proved for the treatment of painful DPN, may improve the patient’s quality of life. diabetes. Early recognition and treatment may be effective and considered for the of patients with diabetes and feet at risk FOOT CARE treatment of painful DPN (99,112,114). for ulcers and amputations can delay or Orthostatic Hypotension Recommendations prevent adverse outcomes. Treating orthostatic hypotension is chal- c Perform a comprehensive foot eval- The risk of ulcers or amputations is in- lenging. The therapeutic goal is to mini- uation at least annually to identify creased in people who have the following mize postural symptoms rather than to risk factors for ulcers and amputa- risk factors: restore normotension. Most patients re- tions. B quire both nonpharmacologic measures c All patients with diabetes should + Poor glycemic control (e.g., ensuring adequate salt intake, avoid- have their feet inspected at every + Peripheral neuropathy with LOPS ing medications that aggravate hypoten- visit. C + Cigarette smoking sion, or using compressive garments over c Obtain a prior history of ulceration, + Foot deformities the legs and abdomen) and pharmacologic amputation, Charcot foot, angio- + Preulcerative callus or corn measures. Physical activity and exercise plasty or vascular surgery, cigarette + PAD should be encouraged to avoid decondi- smoking, retinopathy, and renal dis- + History of foot ulcer tioning, which is known to exacerbate or- ease and assess current symptoms + Amputation thostatic intolerance, and volume repletion of neuropathy (pain, burning, numb- + Visual impairment with fluids and salt is critical. Midodrine and ness) and vascular disease (leg fa- + Diabetic kidney disease (especially pa- droxidopa are approved by the FDA for the tigue, claudication). B tients on dialysis) treatment of orthostatic hypotension. c The examination should include inspection of the skin, assessment Clinicians are encouraged to review Gastroparesis American Diabetes Association screening Treatment for diabetic gastroparesis may of foot deformities, neurological assessment (10-g monofilament recommendations for further details and be very challenging. Dietary changes may practical descriptions of how to perform be useful, such as eating multiple small testing with at least one other assessment: pinprick, temperature, components of the comprehensive foot meals and decreasing dietary fat and fiber examination (129). intake. Withdrawing drugs with adverse vibration), and vascular assessment effects on gastrointestinal motility includ- including pulses in the legs and feet. B Evaluation for Loss of Protective ing opioids, anticholinergics, tricyclic an- Sensation c Patients with symptoms of claudi- tidepressants, glucagon-like peptide 1 All adults with diabetes should undergo a receptor agonists, pramlintide, and pos- cation or decreased or absent pedal pulses should be referred for ankle- comprehensive foot evaluation at least sibly dipeptidyl peptidase 4 inhibitors, annually. Detailed foot assessments may may also improve intestinal motility (127, brachial index and for further vascular assessment as appropriate. C occur more frequently in patients with 128). In cases of severe gastroparesis, histories of ulcers or amputations, foot c A multidisciplinary approach is rec- pharmacologic interventions are needed. deformities, insensate feet, and PAD ommended for individuals with foot Only metoclopramide, a prokinetic agent, (130). Foot inspections should occur at ulcers and high-risk feet (e.g., dialysis is approved by the FDA for the treatment every visit in all patients with diabetes. patients and those with Charcot foot, of gastroparesis. However, the level of To assess risk, clinicians should ask about fi prior ulcers, or amputation). B evidence regarding the bene ts of meto- history of foot ulcers or amputation, neu- c Refer patients who smoke or who clopramide for the management of gas- ropathic and peripheral vascular symp- have histories of prior lower-extremity troparesis is weak, and given the risk for toms, impaired vision, renal disease, complications, loss of protective sen- serious adverse effects (extrapyramidal tobacco use, and foot care practices. A sation, structural abnormalities, or pe- signs such as acute dystonic reactions, general inspection of skin integrity and ripheral arterial disease to foot care drug-induced parkinsonism, akathisia, musculoskeletal deformities should be specialists for ongoing preventive and tardive dyskinesia), its use in the treat- performed. Vascular assessment should care and life-long surveillance. C ment of gastroparesis beyond 5 days is no include inspection and palpation of pedal c Provide general preventive foot longer recommended by the FDA or the pulses. self-care education to all patients European Medicines Agency. It should be The neurological exam performed as with diabetes. B reserved for severe cases that are unre- part of the foot examination is designed c The use of specialized therapeutic sponsive to other therapies (128). to identify LOPS rather than early neurop- footwear is recommended for high- Erectile Dysfunction athy. The 10-g monofilament is the most risk patients with diabetes includ- In addition to treatment of hypogonad- useful test to diagnose LOPS. Ideally, the ing those with severe neuropathy, ism if present, treatments for erectile 10-g monofilament test should be per- foot deformities, or history of am- dysfunction may include phosphodiester- formed with at least one other assess- putation. B ase type 5 inhibitors, intracorporeal or ment (pinprick, temperature or vibration S114 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

sensation using a 128-Hz tuning fork, or when patients with neuropathy present healing compared to comprehensive ankle reflexes). Absent monofilament with the acute onset of a red, hot, swollen wound care in patients with chronic di- sensation suggests LOPS, while at least foot or ankle, and Charcot neuroarthrop- abetic foot ulcers (138). A systematic re- two normal tests (and no abnormal test) athy should be excluded. Early diagnosis view by the International Working Group rules out LOPS. and treatment of Charcot neuroarthrop- on the Diabetic Foot of interventions athy is the best way to prevent defor- to improve the healing of chronic dia- Evaluation for Peripheral Arterial mities that increase the risk of ulceration betic foot ulcers concluded that analysis of Disease and amputation. The routine prescription the evidence continues to present meth- Initial screening for PAD should include a of therapeutic footwear is not generally odological challenges as randomized con- history of decreased walking speed, leg recommended. However, patients should trolled studies remain few with a majority fatigue, claudication, and an assessment be provided adequate information to aid being of poor quality (135). HBOT also of the pedal pulses. Ankle-brachial index in selection of appropriate footwear. Gen- does not seem to have a significant effect testing should be performed in patients eral footwear recommendations include a on health-related quality of life in patients with symptoms or signs of PAD. broad and square toe box, laces with three with diabetic foot ulcers (139,140). A re- Patient Education or four eyes per side, padded tongue, qual- cent review concluded that the evidence fi All patients with diabetes and particularly ity lightweight materials, and suf cient to date remains inconclusive regarding those with high-risk foot conditions (his- size to accommodate a cushioned insole. the clinical and cost-effectiveness of tory of ulcer or amputation, deformity, Use of custom therapeutic footwear can HBOT as an adjunctive treatment to stan- LOPS, or PAD) and their families should help reduce the risk of future foot ulcers in dard wound care for diabetic foot ulcers be provided general education about risk high-risk patients (130,132). (141). Results from the recently published factors and appropriate management Most diabetic foot infections are poly- Dutch DAMOCLES (Does Applying More (131). Patients at risk should understand microbial, with aerobic gram-positive Oxygen Cure Lower Extremity Sores?) the implications of foot deformities, LOPS, cocci. staphylococci and streptococci are trial demonstrated that HBOT in patients and PAD; the proper care of the foot, in- the most common causative organisms. with diabetes and ischemic wounds did fi cluding nail and skin care; and the impor- Wounds without evidence of soft tissue not signi cantly improve complete tance of foot monitoring on a daily basis. or bone infection do not require antibiotic wound healing and limb salvage (142). Patients with LOPS should be educated on therapy. Empiric antibiotic therapy can be The Centers for Medicare & Medicaid Ser- ways to substitute other sensory modalities narrowly targeted at gram-positive cocci vices currently covers HBOT for diabetic (palpation or visual inspection using an un- in many patients with acute infections, but foot ulcers that have failed a standard breakable mirror) for surveillance of early those at risk for infection with antibiotic- course of wound therapy when there foot problems. resistant organisms or with chronic, previ- are no measurable signs of healing for The selection of appropriate footwear ously treated, or severe infections require at least 30 consecutive days (143). HBOT and footwear behaviors at home should broader-spectrum regimens and should be should be a topic of shared decision- also be discussed. Patients’ understand- referred to specialized care centers (133). making before treatment is considered ing of these issues and their physical abil- Foot ulcers and wound care may re- for selected patients with diabetic foot ity to conduct proper foot surveillance quire care by a podiatrist, orthopedic or ulcers (143). vascular surgeon, or rehabilitation spe- and care should be assessed. Patients References cialist experienced in the management with visual difficulties, physical constraints 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic of individuals with diabetes (133). preventing movement, or cognitive prob- kidney disease: a report from an ADA Consensus lems that impair their ability to assess Hyperbaric oxygen therapy (HBOT) in Conference. Diabetes Care 2014;37:2864–2883 the condition of the foot and to institute patients with diabetic foot ulcers has 2. National Kidney Foundation. KDIGO 2012 clinical practice guideline for the evaluation and man- appropriate responses will need other peo- mixed evidence supporting its use as an adjunctive treatment to enhance wound agement of chronic kidney disease. Kidney Int ple, such as family members, to assist with – – Suppl 2013;3:1 150 their care. healing and prevent amputation (134 3. Afkarian M, Zelnick LR, Hall YN, et al. Clinical 136). In a relatively high-quality double- manifestations of kidney disease among US adults Treatment blind study of patients with chronic with diabetes, 1988-2014. JAMA 2016;316:602– People with neuropathy or evidence of diabetic foot ulcers, hyperbaric oxygen 610 increased plantar pressures (e.g., erythema, as an adjunctive therapy resulted in 4. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss fi NS, Himmelfarb J. Temporal trends in the preva- warmth, or calluses) may be adequately signi cantly more complete healing of lence of diabetic kidney disease in the United managed with well-fitted walking shoes or the index ulcer in patients treated with States. JAMA 2011;305:2532–2539 athletic shoes that cushion the feet and re- HBOT compared with placebo at 1 year 5. de Boer IH; DCCT/EDIC Research Group. Kid- distribute pressure. People with bony de- of follow-up (137). However, multiple ney disease and related findings in the Diabetes formities (e.g., hammertoes, prominent subsequently published studies have ei- Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. metatarsal heads, bunions) may need extra ther failed to demonstrate a benefitof Diabetes Care 2014;37:24–30 wide or deep shoes. People with bony de- HBOT or have been relatively small with 6. United States Renal Data System. Annual Data formities, including Charcot foot, who can- potential flaws in study design (135). A Report: Epidemiology of Kidney Disease in the not be accommodated with commercial well-conducted randomized controlled United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Di- therapeutic footwear, will require custom- study performed in 103 patients found gestive and Kidney Diseases, 2016 molded shoes. Special consideration and a that HBOT did not reduce the indica- 7. Fox CS, Matsushita K, Woodward M, et al.; thorough workup should be performed tion for amputation or facilitate wound Chronic Kidney Disease Prognosis Consortium. care.diabetesjournals.org Microvascular Complications and Foot Care S115

Associations of kidney disease measures with diabetes: The DCCT/EDIC study. Clin J Am Soc 36. Wong MG, Perkovic V, Chalmers J, et al.; mortality and end-stage renal disease in individu- Nephrol 2016;11:1969–1977 ADVANCE-ON Collaborative Group. Long-term als with and without diabetes: a meta-analysis. 23. Sumida K, Molnar MZ, Potukuchi PK, et al. benefits of intensive glucose control for prevent- Lancet 2012;380:1662–1673 Changes in albuminuria and subsequent risk of ing end-stage kidney disease: ADVANCE-ON. Di- 8. Afkarian M, Sachs MC, Kestenbaum B, et al. incident kidney disease. Clin J Am Soc Nephrol. abetes Care 2016;39:694–700 Kidney disease and increased mortality risk in type 11 September 2017 [Epub ahead of print]. DOI: 37. National Kidney Foundation. KDOQI Clinical 2 diabetes. J Am Soc Nephrol 2013;24:302–308 https://doi.org/10.2215/CJN.02720317 practice guideline for diabetes and CKD: 2012 up- 9. Groop P-H, Thomas MC, Moran JL, et al.; Finn- 24. Mills KT, Chen J, Yang W, et al.; Chronic Renal date. Am J Kidney Dis 2012;60:850–886 Diane Study Group. The presence and severity of Insufficiency Cohort (CRIC) Study Investigators. 38. Cherney DZI, Perkins BA, Soleymanlou N, chronic kidney disease predicts all-cause mortality Sodium excretion and the risk of cardiovascular et al. Renal hemodynamic effect of sodium- in type 1 diabetes. Diabetes 2009;58:1651–1658 disease in patients with chronic kidney disease. glucose cotransporter 2 inhibition in patients 10. Delanaye P, Glassock RJ, Pottel H, Rule AD. An JAMA 2016;315:2200–2210 with type 1 diabetes mellitus. Circulation 2014; age-calibrated definition of chronic kidney dis- 25. DCCT/EDIC Research Group. Effect of inten- 129:587–597 ease: rationale and benefits. Clin Biochem Rev sive diabetes treatment on albuminuria in type 1 39. Heerspink HJL, Desai M, Jardine M, Balis D, 2016;37:17–26 diabetes: long-term follow-up of the Diabetes Meininger G, Perkovic V. Canagliflozin slows pro- 11. Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. Control and Complications Trial and Epidemiology gression of renal function decline independently Renal insufficiency in the absence of albuminuria of Diabetes Interventions and Complications of glycemic effects. J Am Soc Nephrol 2017;28: and retinopathy among adults with type 2 diabe- study. Lancet Diabetes Endocrinol 2014;2:793– 368–375 tes mellitus. JAMA 2003;289:3273–3277 800 40. Neal B, Perkovic V, Mahaffey KW, et al.; 12. Molitch ME, Steffes M, Sun W, et al.; Epide- 26. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ CANVAS Program Collaborative Group. Canagliflo- miology of Diabetes Interventions and Complica- EDIC Research Group. Intensive diabetes therapy zin and cardiovascular and renal events in type 2 tions Study Group. Development and progression and glomerular filtration rate in type 1 diabetes. N diabetes. N Engl J Med 2017;377:644–657 of renal insufficiency with and without albumin- Engl J Med 2011;365:2366–2376 41. Marso SP, Daniels GH, Brown-Frandsen K, uria in adults with type 1 diabetes in the Diabetes 27. UK Prospective Diabetes Study (UKPDS) et al.; LEADER Steering Committee; LEADER Trial Control and Complications Trial and the Epidemi- Group. Effect of intensive blood-glucose control Investigators. Liraglutide and cardiovascular out- ology of Diabetes Interventions and Complica- with metformin on complications in overweight comes in type 2 diabetes. N Engl J Med 2016;375: tions study. Diabetes Care 2010;33:1536–1543 patients with type 2 diabetes (UKPDS 34). Lancet 311–322 13. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic 1998;352:854–865 42. Cooper ME, Perkovic V, McGill JB, et al. Kid- retinopathy in predicting diabetic nephropathy in 28. UK Prospective Diabetes Study (UKPDS) ney disease end points in a pooled analysis of inpatients with type 2 diabetes and renal disease: a Group. Intensive blood-glucose control with sul- dividual patient-level data from a large clinical meta-analysis. Diabetologia 2013;56:457–466 phonylureas or insulin compared with conven- trials program of the dipeptidyl peptidase 4 inhib- 14. Levey AS, Coresh J, Balk E, et al.; National tional treatment and risk of complications in itor linagliptin in type 2 diabetes. Am J Kidney Dis Kidney Foundation. National Kidney Foundation patients with type 2 diabetes (UKPDS 33). Lancet 2015;66:441–449 practice guidelines for chronic kidney disease: 1998;352:837–853 43. Mann JFE, Ørsted DD, Brown-Frandsen K, evaluation, classification, and stratification. Ann 29. Patel A, MacMahon S, Chalmers J, et al.; et al.; LEADER Steering Committee and Investiga- Intern Med 2003;139:137–147 ADVANCE Collaborative Group. Intensive blood tors. Liraglutide and renal outcomes in type 2 di- 15. James MT, Grams ME, Woodward M, et al.; glucose control and vascular outcomes in patients abetes. N Engl J Med 2017;377:839–848 CKD Prognosis Consortium. A meta-analysis of the with type 2 diabetes. N Engl J Med 2008;358: 44. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN- association of estimated GFR, albuminuria, diabe- 2560–2572 6 Investigators. Semaglutide and cardiovascular tes mellitus, and hypertension with acute kidney 30. Ismail-Beigi F, Craven T, Banerji MA, et al.; outcomes in patients with type 2 diabetes. N injury. Am J Kidney Dis 2015;66:602–612 ACCORD trial group. Effect of intensive treatment Engl J Med 2016;375:1834–1844 16. Nadkarni GN, Ferrandino R, Chang A, et al. of hyperglycaemia on microvascular outcomes in 45. Zinman B, Wanner C, Lachin JM, et al.; Acute kidney injury in patients on SGLT2 inhibi- type 2 diabetes: an analysis of the ACCORD rand- EMPA-REG OUTCOME Investigators. Empagliflozin, tors: a propensity-matched analysis. Diabetes omised trial. Lancet 2010;376:419–430 cardiovascular outcomes, and mortality in type 2 Care 2017;40:1479–1485 31. Zoungas S, Chalmers J, Neal B, et al.; diabetes. N Engl J Med 2015;373:2117–2128 17. Wanner C, Inzucchi SE, Lachin JM, et al.; ADVANCE-ON Collaborative Group. Follow-up of 46. Wanner C, Lachin JM, Inzucchi SE, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin blood-pressure lowering and glucose control in EMPA-REG OUTCOME Investigators. Empagliflo- and progression of kidney disease in type 2 dia- type 2 diabetes. N Engl J Med 2014;371:1392– zin and clinical outcomes in patients with type 2 betes. N Engl J Med 2016;375:323–334 1406 diabetes, established cardiovascular disease and 18. Thakar CV, Christianson A, Himmelfarb J, 32. Zoungas S, Arima H, Gerstein HC, et al.; Col- chronic kidney disease. Circulation. 13 September Leonard AC. Acute kidney injury episodes and laborators on Trials of Lowering Glucose (CONTROL) 2017 [Epub ahead of print]. https://doi.org/ chronic kidney disease risk in diabetes mellitus. group. Effects of intensive glucose control on mi- 10.1161/CIRCULATIONAHA.117.028268 Clin J Am Soc Nephrol 2011;6:2567–2572 crovascular outcomes in patients with type 2 di- 47. U.S. Food and Drug Administration. FDA drug 19. Hughes-Austin JM, Rifkin DE, Beben T, et al. abetes: a meta-analysis of individual participant safety communication: FDA revises warnings re- The relation of serum potassium concentration with data from randomised controlled trials. Lancet Di- garding use of the diabetes medicine metformin cardiovascular events and mortality in community- abetes Endocrinol 2017;5:431–437 in certain patients with reduced kidney function living individuals. Clin J Am Soc Nephrol 2017;12: 33. Miller ME, Bonds DE, Gerstein HC, et al.; [Internet], 2016. Available from http://www.fda 245–252 ACCORD Investigators. The effects of baseline .gov/Drugs/DrugSafety/ucm493244.htm. Ac- 20. Bandak G, Sang Y, Gasparini A, et al. Hyper- characteristics, glycaemia treatment approach, cessed 14 October 2016 kalemia after initiating renin-angiotensin system and glycated haemoglobin concentration on 48. Leehey DJ, Zhang JH, Emanuele NV, et al.; VA blockade: the Stockholm Creatinine Measure- the risk of severe hypoglycaemia: post hoc epi- NEPHRON-D Study Group. BP and renal outcomes ments (SCREAM) Project. J Am Heart Assoc demiological analysis of the ACCORD study. BMJ in diabetic kidney disease: the Veterans Affairs 2017;6:e005428 2010;340:b5444 Nephropathy in Diabetes Trial. Clin J Am Soc 21. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. Inci- 34. Papademetriou V, Lovato L, Doumas M, et al.; Nephrol 2015;10:2159–2169 dence and determinants of hyperkalemia and hy- ACCORD Study Group. Chronic kidney disease and 49. Emdin CA, Rahimi K, Neal B, Callender T, pokalemia in a large healthcare system. Int J intensive glycemic control increase cardiovascular Perkovic V, Patel A. Blood pressure lowering in Cardiol 2017;245:277–284 risk in patients with type 2 diabetes. Kidney Int type 2 diabetes: a systematic review and meta- 22. de Boer IH, Gao X, Cleary PA, et al.; Diabetes 2015;87:649–659 analysis. JAMA 2015;313:603–615 Control and Complications Trial/Epidemiology of 35. Perkovic V, Heerspink HL, Chalmers J, et al.; 50. Cushman WC, Evans GW, Byington RP, et al.; Diabetes Interventions and Complications (DCCT/ ADVANCE Collaborative Group. Intensive glucose ACCORD Study Group. Effects of intensive blood- EDIC) Research Group. Albuminuria changes and control improves kidneyoutcomes in patientswith pressure control in type 2 diabetes mellitus. N cardiovascular and renal outcomes in type 1 type 2 diabetes. Kidney Int 2013;83:517–523 Engl J Med 2010;362:1575–1585 S116 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

51. UK Prospective Diabetes Study Group. Tight 66. Williams B, MacDonald TM, Morant S, et al.; 80. Dabelea D, Stafford JM, Mayer-Davis EJ, et al.; blood pressure control and risk of macrovascular British Hypertension Society’s PATHWAY Studies SEARCH for Diabetes in Youth Research Group. and microvascular complications in type 2 diabe- Group. Spironolactone versus placebo, bisoprolol, Association of type 1 diabetes vs type 2 diabetes tes: UKPDS 38. BMJ 1998;317:703–713 and doxazosin to determine the optimal treat- diagnosed during childhood and adolescence 52. de Boer IH, Bangalore S, Benetos A, et al. Di- ment for drug-resistant hypertension (PATHWAY- with complications during teenage years and abetes and hypertension: a position statement by 2): a randomised, double-blind, crossover trial. young adulthood. JAMA 2017;317:825–835 the American Diabetes Association. Diabetes Care Lancet 2015;386:2059–2068 81. Agardh E, Tababat-Khani P. Adopting 3-year 2017;40:1273–1284 67. Filippatos G, Anker SD, Bohm¨ M, et al. A ran- screening intervals for sight-threatening retinal 53. Brenner BM, Cooper ME, de Zeeuw D, et al.; domized controlled study of finerenone vs. epler- vascular lesions in type 2 diabetic subjects without RENAAL Study Investigators. Effects of losartan on enone in patients with worsening chronic heart retinopathy. Diabetes Care 2011;34:1318–1319 renal and cardiovascular outcomes in patients failure and diabetes mellitus and/or chronic kid- 82. NathanDM,BebuI,HainsworthD,etal.;DCCT/ with type 2 diabetes and nephropathy. N Engl J ney disease. Eur Heart J 2016;37:2105–2114 EDIC Research Group. Frequency of evidence- Med 2001;345:861–869 68. Smart NA, Dieberg G, Ladhani M, Titus T. Early based screening for retinopathy in type 1 diabe- 54. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; referral to specialist nephrology services for prevent- tes. N Engl J Med 2017;376:1507–1516 The Collaborative Study Group. The effect of ing the progression to end-stage kidney disease. 83. Bragge P, Gruen RL, Chau M, Forbes A, Taylor angiotensin-converting-enzyme inhibition on dia- Cochrane Database Syst Rev 2014;6:CD007333 HR. Screening for presence or absence of diabetic betic nephropathy. N Engl J Med 1993;329:1456– 69. Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a meta-analysis. Arch Ophthalmol 1462 retinopathy: a position statement by the Ameri- 2011;129:435–444 55. Lewis EJ, Hunsicker LG, Clarke WR, et al.; Col- can Diabetes Association. Diabetes Care 2017;40: 84. Walton OB 4th, Garoon RB, Weng CY, et al. laborative Study Group. Renoprotective effect of 412–418 Evaluation of automated teleretinal screening the angiotensin-receptor antagonist irbesartan in 70. Klein R. Hyperglycemia and microvascular program for diabetic retinopathy. JAMA Ophthal- patients with nephropathy due to type 2 diabetes. and macrovascular disease in diabetes. Diabetes mol 2016;134:204–209 N Engl J Med 2001;345:851–860 Care 1995;18:258–268 85. Ahmed J, Ward TP, Bursell S-E, Aiello LM, 56. HeartOutcomesPreventionEvaluationStudy 71. Estacio RO, McFarling E, Biggerstaff S, Jeffers Cavallerano JD, Vigersky RA. The sensitivity and Investigators. Effects of ramipril on cardiovascular BW, Johnson D, Schrier RW. Overt albuminuria specificity of nonmydriatic digital stereoscopic and microvascular outcomes in people with diabe- predicts diabetic retinopathy in Hispanics with retinal imaging in detecting diabetic retinopathy. tes mellitus: results of the HOPE study and MICRO- NIDDM. Am J Kidney Dis 1998;31:947–953 Diabetes Care 2006;29:2205–2209 HOPE substudy. Lancet 2000;355:253–259 72. Leske MC, Wu S-Y, Hennis A, et al.; Barbados 86. Hooper P, Boucher MC, Cruess A, et al. Cana- 57. Barnett AH, Bain SC, Bouter P, et al.; Diabetics Eye Study Group. Hyperglycemia, blood pressure, dian Ophthalmological Society evidence-based Exposed to Telmisartan and Enalapril Study Group. and the 9-year incidence of diabetic retinopathy: clinical practice guidelines for the management Angiotensin-receptor blockade versus converting- the Barbados Eye Studies. Ophthalmology 2005; of diabetic retinopathy. Can J Ophthalmol 2012; enzyme inhibition in type 2 diabetes and ne- 112:799–805 47(2 Suppl.):S1–S30 phropathy. N Engl J Med 2004;351:1952–1961 73. Chew EY, Davis MD, Danis RP, et al.; Action to 87. Axer-Siegel R, Hod M, Fink-Cohen S, et al. Di- 58. Wu H-Y, Peng C-L, Chen P-C, et al. Compara- Control Cardiovascular Risk in Diabetes Eye Study abetic retinopathy during pregnancy. Ophthal- tive effectiveness of angiotensin-converting en- Research Group. The effects of medical manage- mology 1996;103:1815–1819 zyme inhibitors versus angiotensin II receptor ment on the progression of diabetic retinopathy 88. Best RM, Chakravarthy U. Diabetic retinopa- blockers for major renal outcomes in patients in persons with type 2 diabetes: the Action to thy in pregnancy. Br J Ophthalmol 1997;81:249– with diabetes: a 15-year cohort study. PLoS One Control Cardiovascular Risk in Diabetes (ACCORD) 251 2017;12:e0177654 Eye Study. Ophthalmology 2014;121:2443–2451 89. Gunderson EP, Lewis CE, Tsai A-L, et al. A 59. Parving HH, Lehnert H, Brochner-Mortensen¨ 74. Nathan DM, Genuth S, Lachin J, et al.; Diabe- 20-year prospective study of childbearing and in- J, Gomis R, Andersen S, Arner P; Irbesartan in tes Control and Complications Trial Research cidence of diabetes in young women, controlling Patients with Type 2 Diabetes and Microalbumi- Group. The effect of intensive treatment of dia- for glycemia before conception: the Coronary Ar- nuria Study Group. The effect of irbesartan on the betes on the development and progression of tery Risk Development in Young Adults (CARDIA) development of diabetic nephropathy in patients long-term complications in insulin-dependent Study. Diabetes 2007;56:2990–2996 with type 2 diabetes. N Engl J Med 2001;345:870– diabetes mellitus. N Engl J Med 1993;329:977– 90. The Diabetic Retinopathy Study Research Group. 878 986 Preliminary report on effects of photocoagulation 60. Bangalore S, Fakheri R, Toklu B, Messerli FH. 75. Chew EY, Ambrosius WT, Davis MD, et al.; therapy. Am J Ophthalmol 1976;81:383–396 Diabetes mellitus as a compelling indication for ACCORD Study Group; ACCORD Eye Study Group. 91. Gross JG, Glassman AR, Jampol LM, et al.; use of renin angiotensin system blockers: system- Effects of medical therapies on retinopathy pro- Writing Committee for the Diabetic Retinopathy atic review and meta-analysis of randomized tri- gression in type 2 diabetes. N Engl J Med 2010; Clinical Research Network. Panretinal photocoag- als. BMJ 2016;352:i438 363:233–244 ulation vs intravitreous ranibizumab for prolifera- 61. Haller H, Ito S, Izzo JL Jr, et al.; ROADMAP Trial 76. Gubitosi-Klug RA, Sun W, Cleary PA, et al.; tive diabetic retinopathy: a randomized clinical Investigators. Olmesartan for the delay or preven- Writing Team for the DCCT/EDIC Research Group. trial. JAMA 2015;314:2137–2146 tion of microalbuminuria in type 2 diabetes. N Effects of prior intensive insulin therapy and risk 92. Early Treatment Diabetic Retinopathy Study Engl J Med 2011;364:907–917 factors on patient-reported visual function out- Research Group. Photocoagulation for diabetic 62. Mauer M, Zinman B, Gardiner R, et al. Renal comes in the Diabetes Control and Complications macular edema. Early Treatment Diabetic Reti- and retinal effects of enalapril and losartan in Trial/Epidemiology of Diabetes Interventions and nopathy Study report number 1.Arch Ophthalmol type 1 diabetes. N Engl J Med 2009;361:40–51 Complications (DCCT/EDIC) cohort. JAMA Oph- 1985;103:1796–1806 63. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET thalmol 2016;134:137–145 93. Elman MJ, Aiello LP, Beck RW, et al.; Diabetic Investigators. Telmisartan, ramipril, or both in pa- 77. Shih C-J, Chen H-T, Kuo S-C, et al. Compara- Retinopathy Clinical Research Network. Random- tients at high risk for vascular events. N Engl J Med tive effectiveness of angiotensin-converting- ized trial evaluating ranibizumab plus prompt or 2008;358:1547–1559 enzyme inhibitors and angiotensin II receptor deferred laser or triamcinolone plus prompt laser 64. Fried LF, Emanuele N, Zhang JH, et al.; VA blockers in patients with type 2 diabetes and ret- for diabetic macular edema. Ophthalmology NEPHRON-D Investigators. Combined angiotensin inopathy. CMAJ 2016;188:E148–E157 2010;117:1064–1077.e35 inhibition for the treatment of diabetic nephrop- 78. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Di- 94. Mitchell P, Bandello F, Schmidt-Erfurth U, athy. N Engl J Med 2013;369:1892–1903 abetic retinopathy. Diabetes Care 2004;27:2540– et al.; RESTORE Study Group. The RESTORE study: 65. Bakris GL, Agarwal R, Chan JC, et al.; Miner- 2553 ranibizumab monotherapy or combined with la- alocorticoid Receptor Antagonist Tolerability 79. Diabetes Control and Complications Trial Re- ser versus laser monotherapy for diabetic macular Study–Diabetic Nephropathy (ARTS-DN) Study search Group. Effect of pregnancy on microvascu- edema. Ophthalmology 2011;118:615–625 Group. Effect of finerenone on albuminuria in pa- lar complications in the Diabetes Control and 95. Elman MJ, Bressler NM, Qin H, et al.; Diabetic tients with diabetic nephropathy: a randomized Complications Trial. Diabetes Care 2000;23: Retinopathy Clinical Research Network. Expanded clinical trial. JAMA 2015;314:884–894 1084–1091 2-year follow-up of ranibizumab plus prompt or care.diabetesjournals.org Microvascular Complications and Foot Care S117

deferred laser or triamcinolone plus prompt laser treating diabetic neuropathy. Cochrane Database 122. Dworkin RH, Jensen MP, Gammaitoni AR, for diabetic macular edema. Ophthalmology Syst Rev 2012;6:CD007543 Olaleye DO, Galer BS. Symptom profiles differ in 2011;118:609–614 109. Pop-Busui R, Lu J, Brooks MM, et al.; BARI 2D patients with neuropathic versus non-neuropathic 96. Nguyen QD, Brown DM, Marcus DM, et al.; Study Group. Impact of glycemic control strate- pain. J Pain 2007;8:118–126 RISE and RIDE Research Group. Ranibizumab for gies on the progression of diabetic peripheral neu- 123. Wernicke JF, Pritchett YL, D’Souza DN, et al. diabetic macular edema: results from 2 phase III ropathy in the Bypass Angioplasty Revascularization A randomized controlled trial of duloxetine in di- randomized trials: RISE and RIDE. Ophthalmology Investigation 2 Diabetes (BARI 2D) cohort. Diabetes abetic peripheral neuropathic pain. Neurology 2012;119:789–801 Care 2013;36:3208–3215 2006;67:1411–1420 97. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glu- 110. Sadosky A, Schaefer C, Mann R, et al. Burden 124. Hardy T, Sachson R, Shen S, Armbruster M, cose control and diabetic neuropathy: lessons of illness associated with painful diabetic periph- Boulton AJM. Does treatment with duloxetine for from recent large clinical trials. Curr Diab Rep eral neuropathy among adults seeking treatment neuropathic pain impact glycemic control? Diabe- 2014;14:528 in the US: results from a retrospective chart re- tes Care 2007;30:21–26 98. Martin CL, Albers JW, Pop-Busui R; DCCT/ view and cross-sectional survey. Diabetes Metab 125. Schwartz S, Etropolski M, Shapiro DY, et al. EDIC Research Group. Neuropathy and related Syndr Obes 2013;6:79–92 Safety and efficacy of tapentadol ER in patients findings in the Diabetes Control and Complica- 111. Waldfogel JM, Nesbit SA, Dy SM, et al. Phar- with painful diabetic peripheral neuropathy: re- tions Trial/Epidemiology of Diabetes Interven- macotherapy for diabetic peripheral neuropathy sults of a randomized-withdrawal, placebo- tions and Complications study. Diabetes Care pain and quality of life: a systematic review. Neu- controlled trial. Curr Med Res Opin 2011;27: 2014;37:31–38 rology 2017;88:1958–1967 151–162 99. Pop-Busui R, Boulton AJM, Feldman EL, et al. 112. Finnerup NB, Attal N, Haroutounian S, et al. 126.VinikAI,ShapiroDY,RauschkolbC,etal.A Diabetic neuropathy: a position statement by the Pharmacotherapy for neuropathic pain in adults: randomized withdrawal, placebo-controlled study American Diabetes Association. Diabetes Care a systematic review and meta-analysis. Lancet evaluating the efficacy and tolerability of tapen- 2017;40:136–154 Neurol 2015;14:162–173 tadol extended release in patients with chronic 100. Freeman R. Not all neuropathy in diabetes is 113. Bril V, England J, Franklin GM, et al.; Amer- painful diabetic peripheral neuropathy. Diabetes of diabetic etiology: differential diagnosis of diabetic ican Academy of Neurology; American Association Care 2014;37:2302–2309 neuropathy. Curr Diab Rep 2009;9:423–431 of Neuromuscular and Electrodiagnostic Medi- 127. Camilleri M, Parkman HP, Shafi MA, Abell TL, 101. Pop-Busui R, Evans GW, Gerstein HC, et al.; cine; American Academy of Physical Medicine Gerson L; American College of Gastroenterology. Action to Control Cardiovascular Risk in Diabetes and Rehabilitation. Evidence-based guideline: Clinical guideline: management of gastroparesis. Study Group. Effects of cardiac autonomic dys- treatment of painful diabetic neuropathy: report Am J Gastroenterol 2013;108:18–37; quiz 38 function on mortality risk in the Action to Control of the American Academy of Neurology, the 128. Umpierrez GE, Ed. Therapy for DiabetesMel- Cardiovascular Risk in Diabetes (ACCORD) trial. American Association of Neuromuscular and Elec- litus and Related Disorders. 6th ed. Alexandria, Diabetes Care 2010;33:1578–1584 trodiagnostic Medicine, and the American Acad- VA, American Diabetes Association, 2014 102. Pop-Busui R, Cleary PA, Braffett BH, et al.; emy of Physical Medicine and Rehabilitation 129. Boulton AJM, Armstrong DG, Albert SF, DCCT/EDIC Research Group. Association between [publishedcorrectioninNeurology2011;77: et al.; American Diabetes Association; American cardiovascular autonomic neuropathy and left 603]. Neurology 2011;76:1758–1765 Association of Clinical Endocrinologists. Compre- ventricular dysfunction: DCCT/EDIC study (Diabe- 114. Griebeler ML, Morey-Vargas OL, Brito JP, hensive foot examination and risk assessment: a tes Control and Complications Trial/Epidemiology et al. Pharmacologic interventions for painful di- report of the task force of the foot care interest of Diabetes Interventions and Complications). J abetic neuropathy: an umbrella systematic review group of the American Diabetes Association, with Am Coll Cardiol 2013;61:447–454 and comparative effectiveness network meta- endorsement by the American Association of Clin- 103. Smith AG, Lessard M, Reyna S, Doudova M, analysis. Ann Intern Med 2014;161:639–649 ical Endocrinologists. Diabetes Care 2008;31: Singleton JR. The diagnostic utility of Sudoscan for 115. Ziegler D, Fonseca V. From guideline to pa- 1679–1685 distal symmetric peripheral neuropathy. J Diabe- tient: a review of recent recommendations for 130. Hingorani A, LaMuraglia GM, Henke P, et al. tes Complications 2014;28:511–516 pharmacotherapy of painful diabetic neuropathy. The management of diabetic foot: a clinical prac- 104. Diabetes Control and Complications Trial J Diabetes Complications 2015;29:146–156 tice guideline by the Society for Vascular Surgery (DCCT) Research Group. Effect of intensive diabe- 116. Freeman R, Durso-Decruz E, Emir B. Efficacy, in collaboration with the American Podiatric Med- tes treatment on nerve conduction in the Diabe- safety, and tolerability of pregabalin treatment for ical Association and the Society for Vascular Med- tes Control and Complications Trial. Ann Neurol painful diabetic peripheral neuropathy: findings icine. J Vasc Surg 2016;63(Suppl.):3S–21S 1995;38:869–880 from seven randomized, controlled trials across a 131. Bonner T, Foster M, Spears-Lanoix E. Type 2 105. CDC Study Group. The effect of intensive range of doses. Diabetes Care 2008;31:1448–1454 diabetes-related foot care knowledge and foot diabetes therapy on measures of autonomic ner- 117. Moore RA, Straube S, Wiffen PJ, Derry S, self-care practice interventions in the United vous system function in the Diabetes Control and McQuay HJ. Pregabalin for acute and chronic States: a systematic review of the literature. Dia- Complications Trial (DCCT). Diabetologia 1998;41: pain in adults. Cochrane Database Syst Rev bet Foot Ankle 2016;7:29758 416–423 2009;3:CD007076 132. Rizzo L, Tedeschi A, Fallani E, et al. Custom- 106. Albers JW, Herman WH, Pop-Busui R, et al.; 118. Raskin P, Huffman C, Toth C, et al. Pregabalin made orthesis and shoes in a structured follow-up Diabetes Control and Complications Trial/ in patients with inadequately treated painful di- program reduces the incidence of neuropathic Epidemiology of Diabetes Interventions and abetic peripheral neuropathy: a randomized with- ulcers in high-risk diabetic foot patients. Int J Complications Research Group. Effect of prior drawal trial. Clin J Pain 2014;30:379–390 Low Extrem Wounds 2012;11:59–64 intensive insulin treatment during the Diabetes 119. Tesfaye S, Wilhelm S, Lledo A, et al. Dulox- 133. Lipsky BA, Berendt AR, Cornia PB, et al.; In- Control and Complications Trial (DCCT) on periph- etine and pregabalin: high-dose monotherapy fectiousDiseasesSocietyofAmerica. 2012 Infectious eral neuropathy in type 1 diabetes during the or their combination? The “COMBO-DN study”–a Diseases Society of America clinical practice Epidemiology of Diabetes Interventions and Compli- multinational, randomized, double-blind, parallel- guideline for the diagnosis and treatment of dications (EDIC) Study. Diabetes Care 2010;33:1090– group study in patients with diabetic peripheral abetic foot infections. Clin Infect Dis 2012;54: 1096 neuropathic pain. Pain 2013;154:2616–2625 e132–e173 107. Pop-Busui R, Low PA, Waberski BH, et al.; 120. Ziegler D, Duan WR, An G, Thomas JW, 134. Elraiyah T, Tsapas A, Prutsky G, et al. A sys- DCCT/EDIC Research Group. Effects of prior inten- Nothaft W. A randomized double-blind, placebo-, tematic review and meta-analysis of adjunctive sive insulin therapy on cardiac autonomic ner- and active-controlled study of T-type calcium therapies in diabetic foot ulcers. J Vasc Surg 2016; vous system function in type 1 diabetes mellitus: channel blocker ABT-639 in patients with diabetic 63(2 Suppl.):46S–58S.e1–2 the Diabetes Control and Complications Trial/ peripheral neuropathic pain. Pain 2015;156: 135. Game FL, Apelqvist J, Attinger C, et al.; In- Epidemiology of Diabetes Interventions and 2013–2020 ternational Working Group on the Diabetic Foot. Complications study (DCCT/EDIC). Circulation 121. Quilici S, Chancellor J, Lothgren¨ M, et al. Effectiveness of interventions to enhance healing of 2009;119:2886–2893 Meta-analysis of duloxetine vs. pregabalin and chronic ulcers of the foot in diabetes: a systematic 108. Callaghan BC, Little AA, Feldman EL, Hughes gabapentin in the treatment of diabetic periph- review. Diabetes Metab Res Rev 2016;32(Suppl. RAC. Enhanced glucose control for preventing and eral neuropathic pain. BMC Neurol 2009;9:6 1):154–168 S118 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

136. Kranke P, Bennett MH, Martyn-St James M, controlled clinical trial. Diabetes Care 2016;39: a health technology assessment. Ont Health Tech- Schnabel A, Debus SE, Weibel S. Hyperbaric oxy- 392–399 nol Assess Ser 2017;17:1–142 gen therapy for chronic wounds. Cochrane Data- 139. Li G, Hopkins RB, Levine MAH, et al. Re- 142. Santema KTB, Stoekenbroek RM, Koelemay base Syst Rev 2015;6:CD004123 lationship between hyperbaric oxygen therapy MJW, et al. Hyperbaric oxygen therapy in the 137. Londahl¨ M, Katzman P, Nilsson A, and quality of life in participants with chronic treatment of ischemic lower extremity ulcers in Hammarlund C. Hyperbaric oxygen therapy diabetic foot ulcers: data from a randomized patients with diabetes: results of the DAMO2CLES facilitates healing of chronic foot ulcers in pa- controlled trial. Acta Diabetol 2017;54:823– multicenter randomized clinical trial. Diabetes tients with diabetes. Diabetes Care 2010;33: 831 Care. 26 October 2017 [Epub ahead of print]. 998–1003 140. Boulton AJM. The Diabetic Foot [Internet], DOI: https://doi.org/10.2337/dc17-0654 138. Fedorko L, Bowen JM, Jones W, et al. Hyper- 2000. South Dartmouth, MA, MDText.com, Inc. 143. Huang ET, Mansouri J, Murad MH, et al.; baric oxygen therapy does not reduce indica- Available from http://www.ncbi.nlm.nih.gov/ UHMS CPG Oversight Committee. A clinical prac- tions for amputation in patients with diabetes books/NBK409609/. Accessed 5 October 2017 tice guideline for the use of hyperbaric oxygen with nonhealing ulcers of the lower limb: a 141. Health Quality Ontario. Hyperbaric oxygen therapy in the treatment of diabetic foot ulcers. prospective, double-blind, randomized therapy for the treatment of diabetic foot ulcers: Undersea Hyperb Med 2015;42:205–247 Diabetes Care Volume 41, Supplement 1, January 2018 S119

11. Older Adults: Standards of American Diabetes Association Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S119–S125 | https://doi.org/10.2337/dc18-S011

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide ADULTS OLDER 11. the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. ReaderswhowishtocommentontheStandardsofCareareinvitedtodosoat professional.diabetes.org/SOC.

Recommendations c Consider the assessment of medical, psychological, 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

Diabetes is an important health condition for the aging population; approximately one- quarter of people over the age of 65 years have diabetes and one-half of older adults have prediabetes (1), and this proportion is expected to increase rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, accelerated muscle loss, and coexisting illnesses, such as hypertension, coronary heart disease, and stroke, than those without diabetes. Older adults with diabetes also are at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary incontinence, injuri- ous falls, and persistent pain. These conditions may impact older adults’ diabetes self- management abilities (2). Screening for diabetes complications in older adults should be individualized and periodically revisited, as the results of screening tests may impact therapeutic ap- Suggested citation: American Diabetes Associa- proaches and targets (2–4). Older adults are at increased risk for depression and should tion. 11. Older adults: Standards of Medical Care in therefore be screened and treated accordingly (5). Diabetes management may require Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): assessment of medical, psychological, functional, and social domains. This may S119–S125 provide a framework to determine targets and therapeutic approaches. Particular © 2017 by the American Diabetes Association. attention should be paid to complications that can develop over short periods of Readers may use this article as long as the work ﬁ is properly cited, the use is educational and not time and/or that would signi cantly impair functional status, such as visual and for proﬁt, and the work is not altered. More infor- lower-extremity complications. Please refer to the American Diabetes Association mation is available at http://www.diabetesjournals (ADA) consensus report “Diabetes in Older Adults” for details (2). .org/content/license. S120 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018

NEUROCOGNITIVE FUNCTION Older adults with diabetes should be and, conversely, severe hypoglycemia carefully screened and monitored for cog- has been linked to increased risk of de- Recommendation nitive impairment (2). Several organiza- mentia. Therefore, it is important to rou- c Screening for early detection of tions have released simple assessment tinely screen older adults for cognitive mild cognitive impairment or de- tools, such as the Mini-Mental State Ex- dysfunction and discuss findings with the mentia and depression is indicated amination (15) and the Montreal Cogni- patients and their caregivers. Hypoglyce- for adults 65 years of age or older at tive Assessment (16), which may help to mic events should be diligently monitored the initial visit and annually as ap- identify patients requiring neuropsycho- and avoided, whereas glycemic targets and propriate. B logical evaluation, particularly those in pharmacologic interventions may need Older adults with diabetes are at higher whom dementia is suspected (i.e., experi- to be adjusted to accommodate for the risk of cognitive decline and institution- encing memory loss and decline in their changing needs of the older adult (2). basic and instrumental activities of daily alization (6,7). The presentation of cog- living). Annual screening for cognitive im- nitive impairment ranges from subtle TREATMENT GOALS pairment is indicated for adults 65 years executive dysfunction to memory loss ofageorolderforearlydetectionof Recommendations and overt dementia. People with diabetes mild cognitive impairment or dementia c have higher incidences of all-cause de- Older adults who are otherwise (4). People who screen positive for cogni- mentia, Alzheimer disease, and vascular healthy with few coexisting chronic tive impairment should receive diagnostic illnesses and intact cognitive func- dementia than people with normal glu- assessment as appropriate, including re- tion and functional status should cose tolerance (8). The effects of hyper- ferral to a behavioral health provider have lower glycemic goals (A1C glycemia and hyperinsulinemia on the for formal cognitive/neuropsychological ,7.5% [58 mmol/mol]), while those brain are areas of intense research. Clinical evaluation (17). with multiple coexisting chronic ill- trials of specific interventionsdincluding nesses, cognitive impairment, or cholinesterase inhibitors and glutamater- functional dependence should have gic antagonistsdhave not shown positive HYPOGLYCEMIA less stringent glycemic goals (A1C therapeutic benefit in maintaining or sig- Recommendation ,8.0–8.5% [64–69 mmol/mol]). C nificantly improving cognitive function or c Hypoglycemia should be avoided in c Glycemic goals for some older in preventing cognitive decline (9). Pilot older adults with diabetes. It should adults might reasonably be relaxed studies in patients with mild cognitive im- be assessed and managed by ad- as part of individualized care, but pairment evaluating the potential bene- justing glycemic targets and phar- hyperglycemia leading to symp- fits of intranasal insulin therapy and macologic interventions. B toms or risk of acute hyperglycemic metformin therapy provide insights for complications should be avoided in future clinical trials and mechanistic stud- It is important to prevent hypoglycemia to all patients. C ies (10–12). reduce the risk of cognitive decline (18) c Screening for diabetes complica- The presence of cognitive impairment and other major adverse outcomes. In- tions should be individualized in can make it challenging for clinicians to tensive glucose control in the Action to older adults. Particular attention help their patients to reach individualized Control Cardiovascular Risk in Diabetes- should be paid to complications glycemic, blood pressure, and lipid targets. Memory in Diabetes study (ACCORD that would lead to functional im- fi Cognitive dysfunction makes it dif cult for MIND) was not found to have benefits on pairment. C patients to perform complex self-care brain structure or cognitive function during c Treatment of hypertension to indi- tasks, such as glucose monitoring and ad- follow-up (14). Of note, in the Diabetes vidualized target levels is indicated justing insulin doses. It also hinders their Control and Complications Trial (DCCT), in most older adults. C ability to appropriately maintain the tim- no significant long-term declines in cogni- c Treatment of other cardiovascular ing and content of diet. When clinicians tive function were observed though par- risk factors should be individualized are managing patients with cognitive dys- ticipants had relatively high rates of in older adults considering the time function, it is critical to simplify drug reg- recurrent severe hypoglycemia (19). It is frame of benefit. Lipid-lowering imens and to involve caregivers in all also important to carefully assess and re- therapy and aspirin therapy may aspects of care. assess patients’ risk for worsening of gly- benefit those with life expectancies Poor glycemic control is associated with cemic control and functional decline. at least equal to the time frame of a decline in cognitive function (13), and Older adults are at higher risk of hypogly- primary prevention or secondary in- longer duration of diabetes is associated cemia for many reasons, including insulin tervention trials. E with worsening cognitive function. There deficiency necessitating insulin therapy are ongoing studies evaluating whether and progressive renal insufficiency. In ad- Rationale preventing or delaying diabetes onset dition, older adults tend to have higher The care of older adults with diabetes is may help to maintain cognitive function in rates of unidentified cognitive deficits, complicated by their clinical, cognitive, older adults. However, studies examining the causing difficulty in complex self-care and functional heterogeneity. Some older effects of intensive glycemic and blood pres- activities (e.g., glucose monitoring, individuals may have developed diabetes sure control to achieve specific targets have adjusting insulin doses, etc.). These years earlier and have significant compli- not demonstrated a reduction in brain func- cognitive deficits have been associated cations, others are newly diagnosed and tion decline (14). with increased risk of hypoglycemia, may have had years of undiagnosed care.diabetesjournals.org Older Adults S121 ucinlsau n signi and status functional o eomne ste a xoeptet omr rqethge lcs ausadteauerssfo lcsra eyrto,hprlcmch hyperglycemic dehydration, glycosuria, from risks acute the and values glucose higher frequent more to patients expose may they as recommended not lns,sc ssae3 stage as such illness, ttsRtoaeRaoal 1 goal A1C Reasonable Rationale chronic coexisting (few Healthy status characteristics/healthPatient 11.1 Table ope/nemdae(multipleComplex/intermediate eycmlxpo elh(T or (LTC health complex/poor Very tg rwrecrnckde ies,moada nacin n toe By hear stroke. congestive cancer, and arthritis, infarction, myocardial include disease, may kidney and chronic management worse lifestyle or i or treatment medications 3 require of stage to aspect important enough serious an living. conditions is daily are preferences illnesses caregiver of diabetes activities chronic and with ADL, patient adults time. of Consideration older over category. change in particular dyslipidemia may a preferences and pressure, into blood fall glycemia, clearly for will goals patient treatment every considering for framework consensus a represents This diabetes with resultant complications, ucinlstatus) functional and cognitive intact illnesses, ontv impairment) cognitive mild-to-moderate or impairments 2 or illnesses* chronic coexisting mareto 2 or impairment cognitive moderate-to-severe or illnesses** chronic end-stage dependencies) and still other older adults may have

1 truly recent-onset disease with few or ntuetlADL instrumental no complications (20). Some older adults —

rmwr o osdrn ramn ol o lcma lo rsue n ylpdmai le dlswt ibts(2) diabetes with adults older in dyslipidemia and pressure, blood glycemia, for goals treatment considering for Framework with diabetes have other underlying

1 chronic conditions, substantial diabetes- ADL

– related comorbidity, limited cognitive or 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

ﬁ physical functioning, or frailty (21,22). atyrdc ieexpectancy. life reduce cantly Other older individuals with diabetes have little comorbidity and are active. Life expectancies are highly variable but are often longer than clinicians realize. 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 Providers caring for older adults with diabetes must take this heterogeneity into ﬁ

uncertain t consideration when setting and prioritiz- ing treatment goals (23) (Table 11.1). In †

1 f85 6 mlml qae oa siae vrg lcs of glucose average estimated an to equates mmol/mol) (69 8.5% of A1C addition, older adults with diabetes should be assessed for disease treatment ‡

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 and self-management knowledge, health literacy, and mathematical literacy (numeracy) at the onset of treatment. , , , .%(8mo/o)90 mmol/mol) (58 7.5% .%(4mo/o)90 mmol/mol) (64 8.0% 8.5% A1C is used as the standard biomarker “ multiple,

† for glycemic control in all patients with 6 mlml 100 mmol/mol) (69 diabetes but may have limitations in pa-

” tients who have medical conditions that ema tlattre u ayptet a have may patients many but three, least at mean we impact red blood cell turnover (see Sec- tion 2 “Classiﬁcation and Diagnosis of ‡ Diabetes” for additional details on the limitations of A1C) (24). Many conditions atn rpreprandial or Fasting (5.6 (5.0 (5.0 associated with increased red blood cell – – – – – turnover, such as hemodialysis, recent 00mmol/L) 10.0 – lcs etm lcs lo rsueLipids pressure Blood glucose Bedtime glucose . mmol/L) 7.2 . mmol/L) 8.3 3 mg/dL 130 5 mg/dL 150 8 mg/dL 180 blood loss or transfusion, or erythropoietin therapy, are commonly seen in frail older adults, which can falsely increase or decrease A1C. In these instances, plasma blood glucose and ﬁnger-stick

; readings should be used for goal setting (5.6 (6.1 (5.0 0 gd 1. mlL.Loe 1 agt bv .%(9mo/o)are mmol/mol) (69 8.5% above targets A1C Looser mmol/L). (11.1 mg/dL 200 100 110 90 (Table 11.1). – – – – 00mmol/L) 10.0 11mmol/L) 11.1 – – . mmol/L) 8.3 5 mg/dL 150 8 mg/dL 180 0 mg/dL 200 Healthy Patients With Good Functional fi dvdaiain diinly patient a Additionally, ndividualization. eo oe(7.*Tepeec fasnl n-tg chronic end-stage single a of presence **The (47). more or ve alr,dpeso,epyea al,hpreso,incontinence, hypertension, falls, emphysema, depression, failure, t Status h ain hrceitcctgre r eea ocps Not concepts. general are categories characteristic patient The . There are few long-term studies in older adults demonstrating the benefits of in- prsoa ydoe n orwudhealing. wound poor and syndrome, yperosmolar tensive glycemic, blood pressure, and lipid , , , 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 control. Patients who can be expected to live long enough to reap the benefits of

s signi use long-term intensive diabetes management, who have good cognitive and phys- icalfunction,andwhochoosetodosovia ﬁ

atsmtm ripimn of impairment or symptoms cant shared decision-making may be treated ’

elhsau and status health s using therapeutic interventions and goals rnttolerated not or rnttolerated not or primary) than so more prevention (secondary statin with similar to those for younger adults with diabetes (Table 11.1). As with all patients with diabetes, diabetes self-management education and ongoing diabetes self- management support are vital components of diabetes care for older adults and their caregivers. Self-management ﬁ t knowledge and skills should be reassessed when regimen changes are S122 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018

made or an individual’s functional abil- PHARMACOLOGIC THERAPY (35). However, it is contraindicated in pa- ities diminish. In addition, declining or tients with advanced renal insufficiency Recommendations impaired ability to perform diabetes self- and should be used with caution in pa- c In older adults at increased risk of care behaviors may be an indication for tients with impaired hepatic function or hypoglycemia, medication classes referral of older adults with diabetes for congestive heart failure due to the in- with low risk of hypoglycemia are cognitive and physical functional assess- creased risk of lactic acidosis. Metformin preferred. B ment using age-normalized evaluation may be temporarily discontinued before c Overtreatment of diabetes is com- tools (3,17). procedures, during hospitalizations, and mon in older adults and should be when acute illness may compromise renal avoided. B or liver function. Patients With Complications and c Deintensification (or simplification) Reduced Functionality of complex regimens is recommen- Thiazolidinediones For patients with advanced diabetes com- ded to reduce the risk of hypoglyce- Thiazolidinediones, if used at all, should plications, life-limiting comorbid illnesses, mia,ifitcanbeachievedwithinthe be used very cautiously in those with, or or substantial cognitive or functional im- individualized A1C target. B at risk for, congestive heart failure and pairments, it is reasonable to set less inten- those at risk for falls or fractures. sive glycemic goals (Table 11.1). Factors to Specialcareisrequiredinprescribing consider in individualizing glycemic goals and monitoring pharmacologic therapies Insulin Secretagogues are outlined in Fig. 6.1. These patients are in older adults (29). See Fig. 8.1 for gen- Sulfonylureas and other insulin secreta- less likely to benefit from reducing the eral recommendations regarding antihy- gogues are associated with hypoglycemia risk of microvascular complications and perglycemic treatment for adults with andshouldbeusedwithcaution.Ifused, more likely to suffer serious adverse ef- type 2 diabetes and Table 8.1 for patient shorter-duration sulfonylureas such as fects from hypoglycemia. However, pa- and drug-specific factors to consider glipizide are preferred. Glyburide is a tients with poorly controlled diabetes when selecting antihyperglycemic agents. longer-duration sulfonylurea and contra- may be subject to acute complications Cost may be an important consideration, indicated in older adults (36). of diabetes, including dehydration, poor especially as older adults tend to be on Incretin-Based Therapies wound healing, and hyperglycemic hyper- many medications. It is important to Oral dipeptidyl peptidase 4 inhibitors osmolar coma. Glycemic goals at a mini- match complexity of the treatment have few side effects and minimal hypo- mum should avoid these consequences. regimentotheself-managementability glycemia, but their costs may be a bar- of an older patient. Many older adults rier to some older patients. A systematic Vulnerable Patients at the End of Life with diabetes struggle to maintain the For patients receiving palliative care and review concluded that incretin-based frequent blood glucose testing and in- agents do not increase major adverse car- end-of-life care, the focus should be to sulin injection regimens they previ- avoid symptoms and complications from diovascular events (37). ously followed, perhaps for many Glucagon-like peptide 1 receptor ago- glycemic management. Thus, when organ decades, as they develop medical condi- failure develops, several agents will have nists are injectable agents, which require tions that may impair their ability to fol- visual, motor, and cognitive skills. They to be titrated or discontinued. For the low their regimen safely. Individualized dying patient, most agents for type 2 di- may be associated with nausea, vomit- glycemic goals should be established ing, and diarrhea. Also, weight loss with abetes may be removed (25). There is, Fig. 6.1 ( ) and periodically adjusted based glucagon-like peptide 1 receptor agonists however, no consensus for the manage- on coexisting chronic illnesses, cognitive ment of type 1 diabetes in this scenario may not be desirable in some older pa- function, and functional status (2). Tighter tients, particularly those with cachexia. (26). See p. S123, END-OF-LIFE CARE, for addi- glycemic control in older adults with mul- tional information. tiple medical conditions is associated with Sodium–Glucose Cotransporter 2 Inhibitors Beyond Glycemic Control an increased risk of hypoglycemia and considered overtreatment but, unfor- Sodium–glucose cotransporter 2 inhibi- Although hyperglycemia control may be tunately, is common in clinical practice tors offer an oral route, which may be important in older individuals with diabe- (30–32). When patients are found to convenient for older adults with diabetes; tes, greater reductions in morbidity and have an insulin regimen with complexity however, long-term experience is limited mortality are likely to result from control beyond their self-management abilities, despite the initial efficacy and safety data of other cardiovascular risk factors rather deintensification (or simplification) can reported with these agents. than from tight glycemic control alone. reduce hypoglycemia and disease-related There is strong evidence from clinical tri- Insulin Therapy als of the value of treating hypertension distress without worsening glycemic con- The use of insulin therapy requires that in older adults (27,28). There is less evi- trol (33,34). patients or their caregivers have good dence for lipid-lowering therapy and as- visual and motor skills and cognitive abil- pirin therapy, although the benefits of Metformin ity. Insulin therapy relies on the ability these interventions for primary preven- Metformin is the first-line agent for older of the older patient to administer insulin tion and secondary intervention are likely adults with type 2 diabetes. Recent stud- on their own or with the assistance to apply to older adults whose life expec- ies have indicated that it may be used of a caregiver. Insulin doses should be tancies equal or exceed the time frames safely in patients with estimated glomer- titrated to meet individualized glycemic of the clinical trials. ular filtration rate $30 mL/min/1.73 m2 targets and to avoid hypoglycemia. care.diabetesjournals.org Older Adults S123

Once-daily basal insulin injection ther- institutional quality assessment. LTC facil- excursions without the practitioner being apy is associated with minimal side ef- ities should develop their own policies notified. Providers may make adjustments fects and may be a reasonable option in and procedures for prevention and man- to treatment regimens by telephone, fax, many older patients. Multiple daily injec- agement of hypoglycemia. or order directly at the LTC facilities pro- tions of insulin may be too complex for vided they are given timely notification the older patient with advanced diabetes Resources from a standardized alert system. complications, life-limiting coexisting Staff of LTC facilities should receive ap- The following alert strategy could be chronic illnesses, or limited functional propriate diabetes education to improve considered: status. the management of older adults with 1. Call provider immediately:incaseof Other Factors to Consider diabetes. Treatments for each patient low blood glucose levels (#70 mg/dL The needs of older adults with diabetes should be individualized. Special man- [3.9 mmol/L]). Low finger-stick blood and their caregivers should be evaluated agement considerations include the glucose values should be confirmed by to construct a tailored care plan. Social need to avoid both hypoglycemia and laboratory glucose measurement. difficulties may impair their quality of the metabolic complications of diabe- 2. Call as soon as possible: a) glucose life and increase the risk of functional de- tes and the need to provide adequate values between 70 and 100 mg/dL (be- pendency (38). The patient’s living situa- diabetes training to LTC staff (2,40). tween 3.9 and 5.6 mmol/L) (regimen tion must be considered, as it may affect For more information, see the ADA posi- may need to be adjusted), b) glu- “ diabetes management and support. So- tion statement Management of Diabetes cose values greater than 250 mg/dL cial and instrumental support networks in Long-term Care and Skilled Nursing Fa- (13.9 mmol/L) within a 24-h period, ” (e.g., adult children, caretakers) that pro- cilities (38). c) glucose values greater than 300 vide instrumental or emotional support mg/dL (16.7 mmol/L) over 2 consecu- Nutritional Considerations for older adults with diabetes should be tive days, d) when any reading is too An older adult residing in an LTC facility included in diabetes management discus- high for the glucometer, or e) the pa- may have irregular and unpredictable sions and shared decision-making. tient is sick, with vomiting or other meal consumption, undernutrition, an- Older adults in assisted living facilities malady that can reflect hyperglycemic orexia, and impaired swallowing. Further- may not have support to administer their crisis and may lead to poor oral intake, more, therapeutic diets may inadvertently own medications, whereas those living thus requiring regimen adjustment. lead to decreased food intake and contrib- in a nursing home (community living cen- ute to unintentional weight loss and un- ters) may rely completely on the care plan END-OF-LIFE CARE dernutrition. Diets tailored to a patient’s and nursing support. Those receiving pal- culture, preferences, and personal goals Recommendations liative care (with or without hospice) may might increase quality of life, satisfaction c When palliative care is needed in require an approach that emphasizes with meals, and nutrition status (41). older adults with diabetes, strict comfort and symptom management, blood pressure control may not be while deemphasizing strict metabolic Hypoglycemia necessary, and withdrawal of ther- and blood pressure control. Older adults with diabetes in LTC are es- apy may be appropriate. Similarly, pecially vulnerable to hypoglycemia. They the intensity of lipid management TREATMENT IN SKILLED NURSING have a disproportionately high number of FACILITIES AND NURSING HOMES can be relaxed, and withdrawal of clinical complications and comorbidities that lipid-lowering therapy may be ap- Recommendations can increase hypoglycemia risk: impaired propriate. E c Consider diabetes education for the cognitive and renal function, slowed hor- c Overall comfort, prevention of dis- staff of long-term care facilities to monal regulation and counterregulation, tressing symptoms, and preserva- improve the management of older suboptimal hydration, variable appetite tion of quality of life and dignity adults with diabetes. E and nutritional intake, polypharmacy, and are primary goals for diabetes man- c Patients with diabetes residing in slowed intestinal absorption (42). Emerging agement at the end of life. E long-term care facilities need care- studies suggest that insulin and noninsu- ful assessment to establish glycemic lin agents confer similar glycemic outcomes The management of the older adult at the goals and to make appropriate and rates of hypoglycemia in LTC popula- end of life receiving palliative medicine or choices of glucose-lowering agents tions (30,43). hospice care is a unique situation. Overall, based on their clinical and functional Another consideration for the LTC set- palliative medicine promotes comfort, status. E ting is that unlike the hospital setting, med- symptom control and prevention (pain, hy- ical providers are not required to evaluate poglycemia, hyperglycemia, and dehydra- Management of diabetes in the long-term the patients daily. According to federal tion), and preservation of dignity and care (LTC) setting (i.e., nursing homes and guidelines, assessments should be done quality of life in patients with limited life skilled nursing facilities) is unique. Individ- at least every 30 days for the first 90 days expectancy (40,44). A patient has the right ualization of health care is important in all after admission and then at least once to refuse testing and treatment, whereas patients; however, practical guidance is every 60 days. Although in practice the providers may consider withdrawing needed for medical providers as well as patients may actually be seen more fre- treatment and limiting diagnostic testing, the LTC staff and caregivers (39). Training quently, the concern is that patients may including a reduction in the frequency of should include diabetes detection and have uncontrolled glucose levels or wide finger-stick testing (45). Glucose targets S124 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018

should aim to prevent hypoglycemia and 3. Young-Hyman D, de Groot M, Hill-Briggs F, Type 2 Diabetes Study. Diabetes Care 2014;37: hyperglycemia. Treatment interventions Gonzalez JS, Hood K, Peyrot M. Psychosocial 507–515 need to be mindful of quality of life. Care- care for people with diabetes: a position state- 19. The Diabetes Control and Complications Trial/ ment of the American Diabetes Association. Di- Epidemiology of Diabetes Interventions (DCCT/ ful monitoring of oral intake is warranted. abetes Care 2016;39:2126–2140 EDIC) Study Research Group. Long-term effect of The decision process may need to involve 4. The National Academy of Sciences. Cognitive diabetes and its treatment on cognitive function. the patient, family, and caregivers, lead- aging: progress in understanding and opportuni- N Engl J Med 2007;356:1842–1852 ing to a care plan that is both convenient ties for action [Internet], 2015. Institute of Med- 20. Selvin E, Coresh J, Brancati FL. The burden and effective for the goals of care (46). icine. Available from http://nationalacademies and treatment of diabetes in elderly individ- .org/hmd/Reports/2015/Cognitive-Aging.aspx. uals in the U.S. Diabetes Care 2006;29:2415– The pharmacologic therapy may include Accessed 3 October 2016 2419 oral agents as first line, followed by a sim- 5. Kimbro LB, Mangione CM, Steers WN, et al. 21. Bandeen-Roche K, Seplaki CL, Huang J, et al. plified insulin regimen. If needed, basal in- Depression and all-cause mortality in persons Frailty in older adults: a nationally representative sulin can be implemented, accompanied by with diabetes mellitus: are older adults at higher profile in the United States. J Gerontol A Biol Sci – oral agents and without rapid-acting insu- risk? Results from the Translating Research Into Med Sci 2015;70:1427 1434 Action for Diabetes Study. J Am Geriatr Soc 2014; 22. Kalyani RR, Tian J, Xue Q-L, et al. Hyperglyce- lin. Agents that can cause gastrointestinal 62:1017–1022 mia and incidence of frailty and lower extremity symptoms such as nausea or excess weight 6. Cukierman T, Gerstein HC, Williamson JD. Cog- mobility limitations in older women. J Am Geriatr loss may not be good choices in this setting. nitive decline and dementia in diabetes–systematic Soc 2012;60:1701–1707 As symptoms progress, some agents may overview of prospective observational studies. Di- 23. Blaum C, Cigolle CT, Boyd C, et al. Clinical – be slowly tapered and discontinued. abetologia 2005;48:2460 2469 complexity in middle-aged and older adults with 7. Roberts RO, Knopman DS, Przybelski SA, et al. diabetes: the Health and Retirement Study. Med Different patient categories have been Association of type 2 diabetes with brain atrophy Care 2010;48:327–334 proposed for diabetes management in and cognitive impairment. Neurology 2014;82: 24. NGSP. Factors that interfere with HbA1c test those with advanced disease (26). 1132–1141 results [Internet], 2016. Available from http:// 8. Xu WL, von Strauss E, Qiu CX, Winblad B, www.ngsp.org/factors.asp. Accessed 22 Septem- 1. A stable patient: continue with the Fratiglioni L. Uncontrolled diabetes increases the ber 2017 patient’s previous regimen, with a fo- risk of Alzheimer’s disease: a population-based 25. Sinclair A, Dunning T, Colagiuri S. IDF Global – Guidelines for Managing Older People With cus on the prevention of hypoglycemia cohort study. Diabetologia 2009;52:1031 1039 9. Ghezzi L, Scarpini E, Galimberti D. Disease- Type 2 Diabetes. International Diabetes Federa- and the management of hyperglycemia modifying drugs in Alzheimer’s disease. Drug tion, Brussels, Belgium, 2013 using blood glucose testing, keeping Des Devel Ther 2013;7:1471–1478 26. Angelo M, Ruchalski C, Sproge BJ. An ap- levels below the renal threshold of glu- 10. Craft S, Baker LD, Montine TJ, et al. Intranasal proach to diabetes mellitus in hospice and pallia- cose. There is very little role for A1C insulin therapy for Alzheimer disease and amnes- tive medicine. J Palliat Med 2011;14:83–87 tic mild cognitive impairment: a pilot clinical trial. 27. Beckett NS, Peters R, Fletcher AE, et al.; monitoring and lowering. – A patient with organ failure Arch Neurol 2012;69:29 38 HYVET Study Group. Treatment of hypertension 2. :prevent- 11. Freiherr J, Hallschmid M, Frey WH 2nd, et al. in patients 80 years of age or older. N Engl J Med inghypoglycemiaisofgreatersignifi- Intranasal insulin as a treatment for Alzheimer’s 2008;358:1887–1898 cance. Dehydration must be prevented disease: a review of basic research and clinical 28. James PA, Oparil S, Carter BL, et al. 2014 andtreated.Inpeoplewithtype1di- evidence. CNS Drugs 2013;27:505–514 evidence-based guideline for the management abetes, insulin administration may be 12. Alagiakrishnan K, Sankaralingam S, Ghosh M, of high blood pressure in adults: report from the Mereu L, Senior P. Antidiabetic drugs and their panel members appointed to the Eighth Joint Na- reduced as the oral intake of food de- potential role in treating mild cognitive impairment tional Committee (JNC 8). JAMA 2014;311:507– creases but should not be stopped. For and Alzheimer’s disease. Discov Med 2013;16: 520 those with type 2 diabetes, agents that 277–286 29. Valencia WM, Florez H. Pharmacological may cause hypoglycemia should be 13. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, treatment of diabetes in older people. Diabetes – titrated. The main goal is to avoid hypo- glucose control, and 9-year cognitive decline Obes Metab 2014;16:1192 1203 among older adults without dementia. Arch Neu- 30. Andreassen LM, Sandberg S, Kristensen GBB, glycemia, allowing for glucose values in rol 2012;69:1170–1175 Sølvik UØ, Kjome RLS. Nursing home patients with the upper level of the desired target range. 14. Launer LJ, Miller ME, Williamson JD, et al.; diabetes: prevalence, drug treatment and glyce- 3. A dying patient: for patients with type 2 ACCORD MIND investigators. Effects of intensive mic control. Diabetes Res Clin Pract 2014;105: diabetes, the discontinuation of all med- glucose lowering on brain structure and function 102–109 ications may be a reasonable approach, in people with type 2 diabetes (ACCORD MIND): a 31. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, randomised open-label substudy. Lancet Neurol Steinman MA. Potential overtreatment of diabe- as patients are unlikely to have any oral 2011;10:969–977 tes mellitus in older adults with tight glycemic intake. In patients with type 1 diabetes, 15. Cummings JL, Frank JC, Cherry D, et al. Guide- control. JAMA Intern Med 2015;175:356–362 there is no consensus, but a small lines for managing Alzheimer’s disease: part I. 32. Thorpe CT, Gellad WF, Good CB, et al. Tight amount of basal insulin may maintain Assessment. Am Fam Physician 2002;65:2263– glycemic control and use of hypoglycemic medi- glucose levels and prevent acute hyper- 2272 cations in older veterans with type 2 diabetes and 16. Nasreddine ZS, Phillips NA, Bedirian´ V, et al. comorbid dementia. Diabetes Care 2015;38:588– glycemic complications. The Montreal Cognitive Assessment, MoCA: a 595 brief screening tool for mild cognitive impair- 33. Munshi MN, Slyne C, Segal AR, Saul N, Lyons ment. J Am Geriatr Soc 2005;53:695–699 C, Weinger K. Simplification of insulin regimen in References 17. American Psychological Association. Guide- older adults and risk of hypoglycemia. JAMA In- 1. Centers for Disease Control and Prevention. Na- lines for the evaluation of dementia and age-related tern Med 2016;176:1023–1025 tional Diabetes Statistics Report [Internet], 2017. cognitive change [Internet]. Available from http:// 34. Sussman JB, Kerr EA, Saini SD, et al. Rates of Available from https://www.cdc.gov/diabetes/ www.apa.org/practice/guidelines/dementia.aspx. deintensification of blood pressure and glycemic pdfs/data/statistics/national-diabetes-statistics- Accessed 3 October 2016 medication treatment based on levels of control report.pdf. Accessed 22 September 2017 18. Feinkohl I, Aung PP, Keller M, et al.; Edinburgh and life expectancy in older patients with diabetes 2. Kirkman MS, Briscoe VJ, Clark N, et al. Diabe- Type 2 Diabetes Study (ET2DS) Investigators. mellitus. JAMA Intern Med 2015;175:1942–1949 tes in older adults. Diabetes Care 2012;35:2650– Severe hypoglycemia and cognitive decline in 35. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, 2664 older people with type 2 diabetes: the Edinburgh McGuire DK. Metformin in patients with type 2 care.diabetesjournals.org Older Adults S125

diabetes and kidney disease: a systematic review. 40. Sinclair A, Morley JE, Rodriguez-Manas~ L, with type 2 diabetes in long-term care facilities. JAMA 2014;312:2668–2675 et al. Diabetes mellitus in older people: position BMJ Open Diabetes Res Care 2015;3:e000104 36. Campanelli CM; American Geriatrics Society statement on behalf of the International Associa- 44. Quinn K, Hudson P, Dunning T. Diabetes man- 2012 Beers Criteria Update Expert Panel. tion of Gerontology and Geriatrics (IAGG), the agement in patients receiving palliative care. American Geriatrics Society updated Beers Crite- European Diabetes Working Party for Older Peo- J Pain Symptom Manage 2006;32:275–286 ria for potentially inappropriate medication ple (EDWPOP), and the International Task Force of 45. Ford-Dunn S, Smith A, Quin J. Management of use in older adults. J Am Geriatr Soc 2012;60: Experts in Diabetes. J Am Med Dir Assoc 2012;13: diabetes during the last days of life: attitudes of 616–631 consultant diabetologists and consultant pallia- 497–502 37. Rotz ME, Ganetsky VS, Sen S, Thomas TF. tive care physicians in the UK. Palliat Med 2006; 41. Dorner B, Friedrich EK, Posthauer ME. Prac- Implications of incretin-based therapies on car- 20:197–203 tice paper of the American Dietetic Association: diovascular disease. Int J Clin Pract 2015;69: 46. Mallery LH, Ransom T, Steeves B, Cook B, individualized nutrition approaches for older 531–549 DunbarP, Moorhouse P. Evidence-informed guide- 38. Laiteerapong N, Karter AJ, Liu JY, et al. Corre- adults in health care communities. J Am Diet As- lines for treating frail older adults with type 2 di- – lates of quality of life in older adults with diabetes: soc 2010;110:1554 1563 abetes: from the Diabetes Care Program of Nova the Diabetes & Aging Study. Diabetes Care 2011; 42. Migdal A, Yarandi SS, Smiley D, Umpierrez GE. Scotia (DCPNS) and the Palliative and Therapeutic 34:1749–1753 Update on diabetes in the elderly and in nursing Harmonization (PATH) program. J Am Med Dir 39.MunshiMN,FlorezH,HuangES,etal.Man- home residents. J Am Med Dir Assoc 2011;12: Assoc 2013;14:801–808 agement of diabetes in long-term care and skilled 627–632.e2 47. Laiteerapong N, Iveniuk J, John PM, Laumann nursing facilities: a position statement of the 43. Pasquel FJ, Powell W, Peng L, et al. A random- EO, Huang ES. Classiﬁcation of older adults who American Diabetes Association. Diabetes Care ized controlled trial comparing treatment with have diabetes by comorbid conditions, United 2016;39:308–318 oral agents and basal insulin in elderly patients States, 2005-2006. Prev Chronic Dis 2012;9:E100 S126 Diabetes Care Volume 41, Supplement 1, January 2018

12. Children and Adolescents: American Diabetes Association Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S126–S136 | https://doi.org/10.2337/dc18-S012

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 possible adverse neurocognitive effects of diabetic ketoacidosis (DKA) (2,3). Attention 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 nature of clinical research in children, the recommendations for children and adolescents are less likely to be based on clinical trial evidence. However, expert opinion and a review of available and relevant experimental data are summarized in the American Diabetes Association (ADA) position statement “Type 1 Diabetes Through the Life Span” (5) and have been updated in the ADA position statement “Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association” (6). A multidisciplinary team of specialists trained in pediatric diabetes management Suggested citation: American Diabetes Associa- and sensitive to the challenges of children and adolescents with type 1 diabetes and tion. 12. Children and adolescents: Standards of their families should provide care for this population. It is essential that diabetes self- Medical Care in Diabetesd2018. Diabetes Care management education and support (DSMES), medical nutrition therapy, and psycho- 2018;41(Suppl. 1):S126–S136 social support be provided at diagnosis and regularly thereafter in a developmentally © 2017 by the American Diabetes Association. appropriate format that builds on prior knowledge by individuals experienced with the Readers may use this article as long as the work is properly cited, the use is educational and not educational, nutritional, behavioral, and emotional needs of the growing child and for profit, and the work is not altered. More infor- family. The appropriate balance between adult supervision and independent self- mation is available at http://www.diabetesjournals care should be defined at the first interaction and reevaluated at subsequent visits. .org/content/license. care.diabetesjournals.org Children and Adolescents S127

The balance between adult supervision on diabetes management and disease and family stresses that could im- and independent self-care will evolve as outcomes (15). Furthermore, the com- pact adherence to diabetes man- the adolescent gradually becomes an plexities of diabetes management require agement and provide appropriate emerging young adult. ongoing parental involvement in care referrals to trained mental health throughout childhood with developmen- Diabetes Self-management Education professionals, preferably experi- tally appropriate family teamwork be- and Support enced in childhood diabetes. E tween the growing child/teen and parent c Mental health professionals should in order to maintain adherence and to pre- Recommendation be considered integral members of c Youthwithtype1diabetesand vent deterioration in glycemic control the pediatric diabetes multidisci- parents/caregivers (for patients (16,17). As diabetes-specific family con- plinary team. E aged ,18 years) should receive flict is related to poorer adherence and c Encourage developmentally appro- culturally sensitive and develop- glycemic control, it is appropriate to inquire priate family involvement in diabe- mentally appropriate individualized about such conflict during visits and to ei- tes management tasks for children diabetes self-management educa- ther help to negotiate a plan for resolution and adolescents, recognizing that tion and support according to na- or refer to an appropriate mental health premature transfer of diabetes care tional standards at diagnosis and specialist (18). Monitoring of social adjust- to the child can result in nonadher- routinely thereafter. B ment (peer relationships) and school per- ence and deterioration in glycemic formance can facilitate both well-being control. A No matter how sound the medical regi- and academic achievement (19). Subop- c men, it can only be effective if the family Providers should consider asking timal glycemic control is a risk factor for and/or affected individuals are able to youth and their parents about social below average school performance and adjustment (peer relationships) and implement it. Family involvement is a vital increased absenteeism (20). school performance to determine component of optimal diabetes man- Shared decision-making with youth whether further intervention is agement throughout childhood and ado- regarding the adoption of regimen com- needed. B lescence. Health care providers (the ponents and self-management behaviors diabetes care team) who care for chil- c Assess youth with diabetes for psy- can improve diabetes self-efficacy, ad- dren and adolescents must be capable of chosocial and diabetes-related dis- herence, and metabolic outcomes (21). – evaluating the educational, behavioral, tress, generally starting at 7 8years Although cognitive abilities vary, the B emotional, and psychosocial factors that of age. ethical position often adopted is the impact implementation of a treatment c At diagnosis and during routine follow- “mature minor rule,” whereby children plan and must work with the individual up care, consider assessing psychoso- after age 12 or 13 years who appear to and family to overcome barriers or rede- cial issues and family stresses that be “mature” have the right to consent or fine goals as appropriate. DSME and could impact diabetes management withhold consent to general medical DSMS require periodic reassessment, es- and provide appropriate referrals to treatment, except in cases in which re- pecially as the youth grows, develops, trained mental health professionals, fusal would significantly endanger health and acquires the need for greater inde- preferably experienced in childhood (22). E pendent self-care skills. In addition, it is diabetes. Beginning at the onset of puberty or at necessary to assess the educational needs c Offer adolescents time by themselves diagnosis of diabetes, all adolescent girls and skills of day care providers, school with their care provider(s) starting at and women with childbearing potential nurses,orotherschoolpersonnelwhopar- age 12 years, or when developmen- should receive education about the risks ticipate in the care of the young child with tally appropriate. E of malformations associated with un- diabetes (7). c Starting at puberty, preconception planned pregnancies and poor metabolic counseling should be incorporated control and the use of effective contra- School and Child Care into routine diabetes care for all ception to prevent unplanned pregnancy. A As a large portion of a child’s day is spent girls of childbearing potential. Preconception counseling using devel- in school, close communication with and opmentally appropriate educational tools the cooperation of school or day care per- enables adolescent girls to make well- sonnel are essential for optimal diabetes Rapid and dynamic cognitive, develop- informed decisions (23). Preconception management, safety, and maximal aca- mental, and emotional changes occur counseling resources tailored for adoles- demic opportunities. Refer to the ADA during childhood, adolescence, and emerg- cents are available at no cost through the position statements “Diabetes Care in ing adulthood. Diabetes management dur- ADA (24). Refer to the recent ADA position the School Setting” (8) and “Care of Young ing childhood and adolescence places statement “Psychosocial Care for People Children With Diabetes in the Child Care substantial burdens on the youth and fam- With Diabetes” for further details (15). Setting” (9) for additional details. ily, necessitating ongoing assessment of psychosocial status and diabetes distress Screening Psychosocial Issues during routine diabetes visits (10–14). Screening for psychosocial distress and Early detection of depression, anxiety, mental health problems is an important Recommendations eating disorders, and learning disabilities component of ongoing care. It is impor- c At diagnosis and during routine follow- can facilitate effective treatment op- tant to consider the impact of diabetes on up care, assess psychosocial issues tions and help minimize adverse effects quality of life as well as the development S128 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018

of mental health problems related to di- that near normalization of blood glucose improve glycemic control. Benefits abetes distress, fear of hypoglycemia (and levels was more difficult to achieve in ad- of continuous glucose monitoring hyperglycemia), symptoms of anxiety, dis- olescents than in adults. Nevertheless, correlate with adherence to ongo- ordered eating behaviors as well as eating the increased use of basal-bolus regimens, ing use of the device. B disorders, and symptoms of depression insulin pumps, frequent blood glucose c Automated insulin delivery systems (25). Consider assessing youth for diabe- monitoring, goal setting, and improved pa- improve glycemic control and re- tes distress, generally starting at 7 or tient education in youth from infancy duce hypoglycemia in adolescents 8 years of age (15). Consider screening through adolescence have been associa- and should be considered in adoles- for depression and disordered eating be- ted with more children reaching the blood cents with type 1 diabetes. B haviors using available screening tools glucose targets recommended by ADA c An A1C goal of ,7.5% (58 mmol/mol) (10,26). With respect to disordered eat- (42–45), particularly in those families in is recommended across all pediatric ing, it is important to recognize the which both the parents and the child with age-groups. E unique and dangerous disordered eating diabetes participate jointly to perform the behavior of insulin omission for weight required diabetes-related tasks. Further- Current standards for diabetes man- control in type 1 diabetes (27). The pres- more, studies documenting neurocognitive agement reflect the need to lower glu- ence of a mental health professional on imaging differences related to hyperglyce- cose as safely as possible. This should be pediatric multidisciplinary teams high- mia in children provide another motivation done with stepwise goals. When estab- lights the importance of attending to for lowering glycemic targets (2). lishing individualized glycemic targets, the psychosocial issues of diabetes. In selecting glycemic goals, the long- special consideration should be given to These psychosocial factors are signifi- term health benefits of achieving a lower the risk of hypoglycemia in young children cantly related to nonadherence, suboptimal A1C should be balanced against the risks (aged ,6 years) who are often unable glycemic control, reduced quality of life, of hypoglycemia and the developmental to recognize, articulate, and/or manage and higher rates of acute and chronic di- burdens of intensive regimens in children hypoglycemia. abetes complications. and youth. In addition, achieving lower Type 1 diabetes can be associated with A1C levels is more likely to be related to Glycemic Control adverse effects on cognition during child- setting lower A1C targets (46,47). A1C hood and adolescence. Factors that and blood glucose goals are presented Recommendations contribute to adverse effects on brain c The majority of children and adoles- in Table 12.1. development and function include young cents with type 1 diabetes should age or DKA at onset of type 1 diabetes, be treated with intensive insulin Autoimmune Conditions severe hypoglycemia at ,6 years of age, regimens, either via multiple daily and chronic hyperglycemia (28,29). How- injections or continuous subcutane- Recommendation ever, meticulous use of new therapeutic c Assess for the presence of autoim- ous insulin infusion. A modalities, such as rapid- and long-acting mune conditions associated with c All children and adolescents with insulin analogs, technological advances type 1 diabetes soon after the di- type 1 diabetes should self-monitor (e.g., continuous glucose monitors, low- agnosis and if symptoms develop. B blood glucose levels multiple times glucose suspend insulin pumps, and au- daily, including premeal, prebed- tomated insulin delivery systems), and Because of the increased frequency of time, and as needed for safety in intensive self-management education other autoimmune diseases in type 1 di- specific clinical situations such as now make it more feasible to achieve ex- abetes, screening for thyroid dysfunction exercise, driving, or for symptoms cellent glycemic control while reducing and celiac disease should be considered of hypoglycemia. B the incidence of severe hypoglycemia (48,49). Periodic screening in asymptom- c Continuous glucose monitoring (30–39). A strong relationship exists be- atic individuals has been recommended, should be considered in children tween frequency of blood glucose moni- but the optimal frequency and benefitof and adolescents with type 1 diabe- toring and glycemic control (32–41). screening are unclear. tes, whether using injections or The Diabetes Control and Complica- Although much less common than thy- continuous subcutaneous insulin in- tions Trial (DCCT), which did not enroll roid dysfunction and celiac disease, other fusion, as an additional tool to help children ,13 years of age, demonstrated autoimmune conditions, such as Addison

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. care.diabetesjournals.org Children and Adolescents S129

disease (primary adrenal insufficiency), au- Celiac Disease provided that further testing is performed toimmune hepatitis, autoimmune gastritis, (verification of endomysial antibody pos- Recommendations dermatomyositis, and myasthenia gravis, itivity on a separate blood sample). It is c Screen individuals with type 1 dia- occur more commonly in the population betes for celiac disease soon after also advisable to check for HLA types in patients who are diagnosed without a with type 1 diabetes than in the general the diagnosis of diabetes by mea- small intestinal biopsy. Asymptomatic pediatric population and should be assessed suring IgA tissue transglutaminase at-risk children should have an intestinal and monitored as clinically indicated. antibodies, with documentation of biopsy (61). normal total serum IgA levels or, if In symptomatic children with type 1 di- Thyroid Disease IgA deficient, IgG tissue transglut- abetes and confirmed celiac disease, gluten- amine and deamidated gliadin anti- Recommendations free diets reduce symptoms and rates of c Consider testing individuals with bodies. B hypoglycemia (62). The challenging die- type 1 diabetes for antithyroid per- c Repeat screening within 2 years of tary restrictions associated with having oxidase and antithyroglobulin an- diabetes diagnosis and then again both type 1 diabetes and celiac disease tibodies soon after the diagnosis. after 5 years and consider more fre- place a significant burden on individuals. E quent screening in children who Therefore, a biopsy to confirm the diag- c have symptoms or a first-degree Measure thyroid-stimulating hor- nosis of celiac disease is recommended, relative with celiac disease. B mone concentrations at diagnosis especially in asymptomatic children, be- c Individuals with biopsy-confirmed when clinically stable or soon after fore endorsing significant dietary changes. celiac disease should be placed glycemic control has been estab- A gluten-free diet was beneficial in asymp- lished. If normal, consider recheck- on a gluten-free diet and have a tomatic adults with positive antibodies – ing every 1 2 years or sooner if the consultation with a dietitian experi- confirmed by biopsy (63). patient develops symptoms sugges- enced in managing both diabetes Management of Cardiovascular tive of thyroid dysfunction, thyro- and celiac disease. B Risk Factors megaly, an abnormal growth rate, or an unexplained glycemic varia- Celiac disease is an immune-mediated dis- Hypertension tion. A order that occurs with increased fre- Recommendations quency in patients with type 1 diabetes Screening (1.6–16.4% of individuals compared with Autoimmune thyroid disease is the c Blood pressure should be measured 0.3–1% in the general population) (48,49, most common autoimmune disorder at each routine visit. Children found 56–58,59). associated with diabetes, occurring in to have high-normal blood pressure Screening. Screening for celiac disease in- 17–30% of patients with type 1 diabetes (systolic blood pressure or diastolic cludes measuring serum levels of IgA and (50). At the time of diagnosis, about 25% blood pressure $90th percentile tissue transglutaminase antibodies, or, of children with type 1 diabetes have thy- forage,sex,andheight)orhy- with IgA deficiency, screening can include roid autoantibodies (51); their presence pertension (systolic blood pressure measuring IgG tissue transglutaminase an- $ is predictive of thyroid dysfunctiond or diastolic blood pressure 95th tibodies or IgG deamidated gliadin peptide most commonly hypothyroidism, al- percentile for age, sex, and height) antibodies. Because most cases of celiac though hyperthyroidism occurs in ;0.5% should have elevated blood disease are diagnosed within the first fi of patients with type 1 diabetes (52, pressure con rmed on 3 separate 5 years after the diagnosis of type 1 diabe- B 53). For thyroid autoantibodies, a recent days. tes, screening should be considered at the study from Sweden indicated antithyroid time of diagnosis and repeated at 2 and Treatment peroxidase antibodies were more predic- c then 5 years (58). Initial treatment of high-normal tive than antithyroglobulin antibodies in Although celiac disease can be diag- blood pressure (systolic blood pres- multivariate analysis (54). Thyroid func- nosed more than 10 years after diabetes sure or diastolic blood pressure $ tion tests may be misleading (euthyroid diagnosis, there are insufficient data after consistently 90th percentile for sick syndrome) if performed at the time 5 years to determine the optimal screen- age, sex, and height) includes die- fi of diagnosis owing to the effect of previous ing frequency. Measurement of tissue tary modi cation and increased hyperglycemia, ketosis or ketoacidosis, transglutaminase antibody should be con- exercise, if appropriate, aimed at weight loss, etc. Therefore, if performed sidered at other times in patients with weight control. If target blood pres- – at diagnosis and slightly abnormal, thy- symptoms suggestive of celiac disease sure is not reached within 3 6 roid function tests should be performed (58). A small-bowel biopsy in antibody- months of initiating lifestyle inter- soon after a period of metabolic stability positive children is recommended to confirm vention, pharmacologic treatment E and good glycemic control. Subclinical the diagnosis (60). European guidelines should be considered. c In addition to lifestyle modification, hypothyroidism may be associated with on screening for celiac disease in chil- pharmacologic treatment of hyper- increased risk of symptomatic hypoglyce- dren (not specifictochildrenwithtype1 tension (systolic blood pressure or mia (55) and reduced linear growth rate. diabetes) suggest that biopsy may not diastolic blood pressure consistently Hyperthyroidism alters glucose metabo- be necessary in symptomatic children $95th percentile for age, sex, and lism and usually causes deterioration of with high antibody titers (i.e., greater height) should be considered as glycemic control. than 10 times the upper limit of normal) S130 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018

and Blood Institute recommends obtaining soon as hypertension is confirmed. E mg/dL (4.1 mmol/L) or LDL choles- a fasting lipid panel beginning at 2 years of c ACE inhibitors or angiotensin recep- terol .130 mg/dL (3.4 mmol/L) and age (71). Abnormal results from a random tor blockers may be considered for one or more cardiovascular disease lipid panel should be confirmed with a the treatment of elevated (.30 mg/ risk factors, following reproductive fasting lipid panel. Data from the SEARCH g) urinary albumin-to-creatinine ra- counseling and implementation of for Diabetes in Youth (SEARCH) study tio (B) and hypertension (E)inchil- effective birth control due to the show that improved glucose control dren and adolescents, following potential teratogenic effects of sta- over a 2-year period is associated with a reproductive counseling and imple- tins. B more favorable lipid profile; however, im- mentation of effective birth control c The goal of therapy is an LDL cho- proved glycemic control alone will not due to the potential teratogenic ef- lesterol value ,100 mg/dL (2.6 normalize lipids in youth with type 1 di- fects of both drug classes. E mmol/L). E abetes and dyslipidemia (78). c The goal of treatment is blood pres- Neither long-term safety nor cardio- sure consistently ,90th percentile Population-based studies estimate that vascular outcome efficacy of statin ther- for age, sex, and height. E 14–45% of children with type 1 diabetes apy has been established for children; have two or more atherosclerotic cardio- however, studies have shown short- Blood pressure measurements should vascular disease (ASCVD) risk factors term safety equivalent to that seen in be performed using the appropriate size (65–67), and the prevalence of CVD adults and efficacy in lowering LDL cuff with the child seated and relaxed. risk factors increases with age (67), with cholesterol levels in familial hypercho- Hypertension should be confirmed on at girls having a higher risk burden than lesterolemia or severe hyperlipidemia, least 3 separate days. Evaluation should boys (66). improving endothelial function and caus- proceed as clinically indicated. Treatment Pathophysiology. The atherosclerotic pro- ing regression of carotid intimal thicken- is generally initiated with an ACE inhibi- cess begins in childhood, and although ing (79,80). Statins are not approved for tor, but an angiotensin receptor blocker ASCVD events are not expected to occur patients aged ,10 years, and statin treat- can be used if the ACE inhibitor is not during childhood, observations using a ment should generally not be used in tolerated (e.g., due to cough) (64). variety of methodologies show that youth children with type 1 diabetes before Normal blood pressure levels for age, with type 1 diabetes may have subclinical this age. Statins are contraindicated in sex, and height and appropriate methods CVD within the first decade of diagnosis pregnancy; therefore, prevention of unfor measurement are available online at (68–70). Studies of carotid intima-media planned pregnancies is of paramount im- nhlbi.nih.gov/files/docs/resources/heart/ thickness have yielded inconsistent re- portance for postpubertal girls (see hbp_ped.pdf. sults (64). Section 13 “Management of Diabetes in Treatment. Pediatric lipid guidelines pro- Dyslipidemia Pregnancy” for more information). The vide some guidance relevant to children multicenter, randomized, placebo-con- Recommendations with type 1 diabetes (71–73); however, trolled Adolescent Type 1 Diabetes Car- Testing there are few studies on modifying lipid dio-Renal Intervention Trial (AdDIT) c fi levels in children with type 1 diabetes. A Obtain a lipid pro le in children provides safety data on pharmacologic $ 6-month trial of dietary counseling pro- 10 years of age soon after the di- treatment with an ACE inhibitor and duced a significant improvement in lipid agnosis of diabetes (after glucose statin in adolescents with type 1 diabetes. control has been established). If ab- levels (74); likewise, a lifestyle interven- normal, repeat lipid profile after tion trial with 6 months of exercise in ad- Smoking fasting. E olescents demonstrated improvement in Recommendation c If lipids are abnormal, annual moni- lipid levels (75). c Elicit a smoking history at initial and toring is reasonable. If LDL choles- Although intervention data are sparse, follow-up diabetes visits; discour- terol values are within the accepted the American Heart Association catego- age smoking in youth who do not , risk level ( 100 mg/dL [2.6mmol/L]), rizes children with type 1 diabetes in the smoke, and encourage smoking ces- fi alipidpro le repeated every 5 years highest tier for cardiovascular risk and sation in those who do smoke. A is reasonable. E recommends both lifestyle and pharmacologic treatment for those with elevated The adverse health effects of smoking are Treatment LDL cholesterol levels (73,76). Initial ther- well recognized with respect to future c Initial therapy should consist of op- apy should be with a Step 2 American cancer and CVD risk. Despite this, smok- timizing glucose control and medi- Heart Association diet, which restricts sat- ing rates are significantly higher among cal nutrition therapy using a Step urated fat to 7% of total calories and re- youth with diabetes than among youth 2 American Heart Association diet stricts dietary cholesterol to 200 mg/day. without diabetes (81,82). In youth with to decrease the amount of satu- Data from randomized clinical trials in diabetes, it is important to avoid addi- rated fat in the diet. B children as young as 7 months of age in- tional CVD risk factors. Smoking increases c After the age of 10 years, addition dicate that this diet is safe and does not the risk of onset of albuminuria; there- of a statin is suggested in patients interfere with normal growth and devel- fore, smoking avoidance is important to who, despite medical nutrition ther- opment (77). prevent both microvascular and macrovas- apy and lifestyle changes, continue For children with a significant family cular complications (71,83). Discouraging to have LDL cholesterol .160 history of CVD, the National Heart, Lung, cigarette smoking, including e-cigarettes, care.diabetesjournals.org Children and Adolescents S131

is an important part of routine diabetes Retinopathy “Classification and Diagnosis of Diabetes.” care. In younger children, it is important For additional support for these recom- Recommendations to assess exposure to cigarette smoke in mendations, see the ADA position state- c An initial dilated and comprehen- ment “Evaluation and Management of the home due to the adverse effects of sive eye examination is recom- Youth-Onset Type 2 Diabetes 91 secondhand smoke and to discourage mended once youth have had type 1 ( ). youth from ever smoking if exposed to diabetes for 3–5 years, provided Type 2 diabetes in youth has increased smokers in childhood. they are age $10 years or puberty over the past 20 years, and recent estimates ; has started, whichever is earlier. suggest an incidence of 5,000 new cases B per year in the U.S. (92). The Centers for Microvascular Complications Disease Control and Prevention published c After the initial examination, annual Diabetic Kidney Disease routine follow-up is generally rec- projections for type 2 diabetes prevalence using the SEARCH databasedassuming a Recommendations ommended. Less-frequent exami- 2.3% annual increase, the prevalence in Screening nations, every 2 years, may be acceptable on the advice of an eye those under 20 years of age will quadru- c Annual screening for albuminuria ple in 40 years (93,94). with a random spot urine sample for care professional and based on risk factor assessment. E Evidence suggests that type 2 diabetes albumin-to-creatinine ratio should be in youth is different not only from type 1 performed at puberty or at age $10 diabetes but also from type 2 diabetes in years, whichever is earlier, once the Retinopathy (like albuminuria) most commonly occurs after the onset of puberty adults and has unique features, such as a child has had diabetes for 5 years. B b and after 5–10 years of diabetes duration more rapidly progressive decline in -cell function and accelerated development of Treatment (88). Referrals should be made to eye care professionals with expertise in diabetic diabetes complications (95,96). Type 2 c When persistently elevated urinary diabetes disproportionately impacts albumin-to-creatinine ratio (.30 retinopathy and experience in counseling the pediatric patient and family on the youth of ethnic and racial minorities and mg/g) is documented with at least can occur in complex psychosocial and two of three urine samples, treat- importance of early prevention and intervention. cultural environments, which may make ment with an ACE inhibitor or an- it difficult to sustain healthy lifestyle giotensin receptor blocker may be changes and self-management behaviors. considered and the dose titrated to Neuropathy Additional risk factors associated with maintain blood pressure within the Recommendation type 2 diabetes in youth include adiposity, age-appropriate normal range. The c Consider an annual comprehensive family history of diabetes, female sex, and urine samples should be obtained foot exam at the start of puberty or low socioeconomic status (96). over a 6-month interval following at age $10 years, whichever is ear- As with type 1 diabetes, youth with efforts to improve glycemic control lier, once the youth has had type 1 type 2 diabetes spend much of the day in B and normalize blood pressure. diabetes for 5 years. B school. Therefore, close communication with and the cooperation of school person- , Data from 7,549 participants 20 years Diabetic neuropathy rarely occurs in pre- nel are essential for optimal diabetes man- of age in the T1D Exchange clinic registry pubertal children or after only 1–2years agement, safety, and maximal academic emphasize the importance of good glyce- of diabetes (88), although data suggest a opportunities. mic and blood pressure control, particu- prevalence of distal peripheral neuropa- larly as diabetes duration increases, in thy of 7% in 1,734 youth with type 1 di- Recommendations order to reduce the risk of diabetic kidney abetes and associated with the presence Screening and Diagnosis disease. The data also underscore the im- of CVD risk factors (89). A comprehensive c Risk-based screening for prediabe- portance of routine screening to ensure foot exam, including inspection, palpation tes and/or type 2 diabetes should early diagnosis and timely treatment of of dorsalis pedis and posterior tibial be considered in children and ado- albuminuria (84). An estimation of glomer- pulses, and determination of propriocep- lescents after the onset of puberty ular filtration rate (GFR), calculated using tion, vibration, and monofilament sensa- or $10 years of age, whichever GFR estimating equations from the serum tion, should be performed annually along occurs earlier, who are over- creatinine, height, age, and sex (85), should with an assessment of symptoms of neu- weight (BMI .85th %) or obese be considered at baseline and repeated as ropathic pain (90). Foot inspection can (BMI .95th %) and who have one indicated based on clinical status, age, di- be performed at each visit to educate or more additional risk factors for abetes duration, and therapies. Improved youth regarding the importance of foot diabetes (see Table 2.5). A methods are needed to screen for early care (see Section 10 “Microvascular c If tests are normal, repeat testing GFR loss, since estimated GFR is inaccu- Complications and Foot Care”). at a minimum of 3-year intervals E, rate at GFR .60 ml/min/1.73 m2 (85,86). or more frequently if BMI is increas- The AdDIT study in adolescents with type ing. C 1 diabetes demonstrated safety of ACE TYPE 2 DIABETES c Fasting plasma glucose, 2-h plasma inhibitor treatment, but did not change For information on testing for type 2 di- glucose during a 75-g oral glucose the urinary albumin-to-creatinine ratio abetes and prediabetes in children and tolerance test, and A1C can be used over the course of the study (87). adolescents, please refer to Section 2 S132 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018

to test for prediabetes or diabetes c Given the necessity of long-term c All youth with type 2 diabetes and in children and adolescents. B weight management for children their families should receive compre- and adolescents with type 2 diabetes, hensive diabetes self-management In the last decade, the incidence and prev- lifestyle intervention should be based education and support that is specific alence of type 2 diabetes in adolescents on a chronic care model and offered to youth with type 2 diabetes and has increased dramatically, especially in ra- in the context of diabetes care. E culturally competent. B cial and ethnic minority populations (97). A c Youth with diabetes, like all chil- few recent studies suggest oral glucose dren, should be encouraged to The general treatment goals for youth tolerance tests or fasting plasma glucose participate in at least 60 min of with type 2 diabetes are the same as values as more suitable diagnostic tests moderate to vigorous physical ac- those for youth with type 1 diabetes. A than A1C in the pediatric population, es- tivity per day (and strength training multidisciplinary diabetes team, including pecially among certain ethnicities (98). on at least 3 days/week) B and to a physician, diabetes nurse educator, reg- However, many of these studies do not decrease sedentary behavior. C istered dietitian, and psychologist or social recognize that diabetes diagnostic criteria c Nutrition for youth with type 2 di- worker,isessential.Inadditiontoblood are based on long-term health outcomes, abetes, like all children, should fo- glucose control, initial treatment must in- and validations are not currently available cus on healthy eating patterns that clude management of comorbidities such in the pediatric population (99). ADA ac- emphasize consumption of nutrient- as obesity, dyslipidemia, hypertension, and knowledges the limited data supporting dense, high-quality foods and microvascular complications. A1C for diagnosing type 2 diabetes in chil- decreased consumption of calorie- Current treatment options for youth- dren and adolescents. Although A1C is dense, nutrient-poor foods, partic- onset type 2 diabetes are limited to two not recommended for diagnosis of diabe- ularly sugar-added beverages. B approved drugsdinsulin and metformin tes in children with cystic fibrosis or symp- (95). Presentation with ketosis or ke- toms suggestive of acute onset of type 1 Pharmacologic Management toacidosis requires a period of insulin diabetes and only A1C assays without in- c Initiate pharmacologic therapy, in therapy until fasting and postprandial gly- terference are appropriate for children addition to lifestyle therapy, at di- cemia have been restored to normal or with hemoglobinopathies, ADA continues agnosis of type 2 diabetes. A near-normal levels. Metformin therapy to recommend A1C for diagnosis of type 2 c In metabolically stable patients may be used as an adjunct after resolu- diabetes in this population (100,101). (A1C ,8.5% and asymptomatic), tion of ketosis/ketoacidosis. Initial treat- metformin is the initial pharmaco- ment should also be with insulin when the Diagnostic Challenges logic treatment of choice if renal distinction between type 1 diabetes and 2 Given the current obesity epidemic, distin- function is .30 ml/min/1.73 m . A type 2 diabetes is unclear and in patients guishing between type 1 and type 2 diabe- c Youth with marked hyperglycemia who have random blood glucose concen- fi $ tes in children can be dif cult. Overweight (blood glucose 250 mg/dL [13.9 trations 250 mg/dL (13.9 mmol/L) and/or $ andobesityarecommoninchildren mmol/L], A1C 8.5% [69 mmol/mol]) A1C $8.5% (69 mmol/mol) (105). with type 1 diabetes (102), and diabetes- without ketoacidosis at diagnosis Patients and their families must priori- associated autoantibodies and ketosis who are symptomatic with poly- tize lifestyle modifications such as eating maybepresentinpediatricpatients uria, polydipsia, nocturia, and/or a balanced diet, achieving and maintaining with features of type 2 diabetes (including weight loss should be treated ini- a healthy weight, and exercising regularly. A obesity and acanthosis nigricans) (103). At tially with basal insulin while met- family-centered approach to nutrition and onset, DKA occurs in ;6% of youth aged formin is initiated and titrated to lifestyle modification is essential in children 10–19 years with type 2 diabetes (104). maximally tolerated dose to achieve with type 2 diabetes, and nutrition recom- Accurate diagnosis is critical, as treatment E A1C goal. mendations should be culturally appropri- regimens, educational approaches, die- c When the A1C target is no longer met ate and sensitive to family resources (see tary advice, and outcomes differ markedly with metformin monotherapy, or if Section 4 “Lifestyle Management”). Given between patients with the two diagnoses. contraindications or intolerable side the complex social and environmental effects of metformin develop, basal context surrounding youth with type 2 di- insulin therapy should be initiated. E Management abetes, individual-level lifestyle interven- c In patients initially treated with tions may not be sufficient to target the basal insulin and metformin who Recommendations complex interplay of family dynamics, are meeting glucose targets based mental health, community readiness, and Lifestyle Management on home blood glucose monitoring, the broader environmental system (95). c Overweight or obese youth with basal insulin can be tapered over When insulin treatment is not required, type 2 diabetes and their families 2–6 weeks by decreasing the insulin initiation of metformin is recommended. should be provided with develop- dose by 10–30% every few days. A The Treatment Options for Type 2 Diabe- mentally and culturally appropriate c Use of medications not approved by tes in Adolescents and Youth (TODAY) comprehensive lifestyle programs the U.S. Food and Drug Administra- study found that metformin alone pro- that are integrated with diabetes tion for youth with type 2 diabetes vided durable glycemic control (A1C #8% management to achieve 7–10% de- is not recommended outside of re- [64 mmol/mol] for 6 months) in approxi- crease in excess weight. C search trials. B mately half of the subjects (106). To date, care.diabetesjournals.org Children and Adolescents S133

the TODAY study is the only trial combin- 2. Barnea-Goraly N, Raman M, Mazaika P, et al.; port and links to resources for tran- ing lifestyle and metformin therapy in Diabetes Research in Children Network (DirecNet). sitioning young adults. B youth with type 2 diabetes; the combina- Alterations in white matter structure in young children with type 1 diabetes. Diabetes Care tion did not perform better than metfor- 2014;37:332–340 min alone in achieving durable glycemic Care and close supervision of diabetes 3. Cameron FJ, Scratch SE, Nadebaum C, et al.; control (106). management are increasingly shifted DKA Brain Injury Study Group. Neurological conse- Small retrospective analyses and a recent from parents and other adults to the youth quences of diabetic ketoacidosis at initial presenta- with type 1 or type 2 diabetes throughout tion of type 1 diabetes in a prospective cohort study prospective multicenter nonrandomized – childhood and adolescence. The shift from of children. Diabetes Care 2014;37:1554 1562 study suggest that bariatric or metabolic 4. Markowitz JT, Garvey KC, Laffel LMB. Develop- surgery may have similar benefits in obese pediatric to adult health care providers, mental changes in the roles of patients and families adolescents with type 2 diabetes compared however, often occurs abruptly as the older in type 1 diabetes management. Curr Diabetes Rev with those observed in adults. Teenagers teen enters the next developmental stage 2015;11:231–238 5. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; experience similar degrees of weight loss, referred to as emerging adulthood (111), Type 1 Diabetes Sourcebook authors. Type 1 dia- diabetes remission, and improvement of which is a critical period for young people betes through the life span: a position statement cardiometabolic risk factors for at least who have diabetes. During this period of the American Diabetes Association. Diabetes 3 years after surgery (107). No randomized of major life transitions, youth begin to Care 2014;37:2034–2054 trials, however, have yet compared the move out of their parents’ homes and 6. Chiang J, Garvey KC, Hood K, et al. Type 1 diabetes in children and adolescents: a position effectiveness and safety of surgery to must become fully responsible for their statement by the American Diabetes Association. those of conventional treatment options diabetes care. Their new responsibilities Diabetes Care. In press in adolescents (108). include self-management of their diabe- 7. Driscoll KA, Volkening LK, Haro H, et al. Are tes, making medical appointments, and children with type 1 diabetes safe at school? Ex- Comorbidities financing health care, once they are no amining parent perceptions. Pediatr Diabetes – Comorbidities may already be present at longer covered by their parents’ health 2015;16:613 620 8. Jackson CC, Albanese-O’Neill A, Butler KL, et al. the time of diagnosis of type 2 diabetes in insurance plans (ongoing coverage until Diabetes care in the school setting: a position youth (96,109). Therefore, blood pres- age 26 years is currently available under statement of the American Diabetes Association. sure measurement, a fasting lipid panel, provisions of the U.S. Affordable Care Diabetes Care 2015;38:1958–1963 ’ assessment of random urine albumin-to- Act). In addition to lapses in health care, 9. Siminerio LM, Albanese-O Neill A, Chiang JL, creatinine ratio, and a dilated eye exam- et al.; American Diabetes Association. Care of this is also a period associated with de- youngchildrenwithdiabetesinthechildcareset- ination should be performed at diagnosis. terioration in glycemic control; increased ting: a position statement of the American Diabetes Thereafter, screening guidelines and treat- occurrence of acute complications; psy- Association. Diabetes Care 2014;37:2834–2842 ment recommendations for hypertension, chosocial, emotional, and behavioral 10. Corathers SD, Kichler J, Jones N-HY, Houchen dyslipidemia, urine albumin excretion, and challenges; and the emergence of chronic A, Jolly M, Morwessel N, et al. Improving depres- retinopathy are similar to those for youth – sion screening for adolescents with type 1 diabe- complications (112 115). The transition tes. Pediatrics 2013;132:e1395-e1402 with type 1 diabetes. Additional problems period from pediatric to adult care is 11. Hood KK, Beavers DP, Yi-Frazier J, et al. Psy- that may need to be addressed include prone to fragmentation in health care de- chosocial burden and glycemic control during the polycystic ovary disease and other comor- livery, which may adversely impact health first 6 years of diabetes: results from the SEARCH for Diabetes in Youth study. J Adolesc Health bidities associated with pediatric obesity, care quality, cost, and outcomes (116). such as sleep apnea, hepatic steatosis, or- 2014;55:498–504 Although scientific evidence is limited, 12. Ducat L, Philipson LH, Anderson BJ. The men- thopedic complications, and psychosocial it is clear that comprehensive and coordi- tal health comorbidities of diabetes. JAMA 2014; concerns. The ADA consensus report nated planning that begins in early ado- 312:691–692 “ Youth-Onset Type 2 Diabetes Consensus lescence, or at least 1 year before the date 13. Hagger V, Hendrieckx C, Sturt J, Skinner TC, Speight J. Diabetes distress among adolescents Report: Current Status, Challenges, and of transition, is necessary to facilitate a Priorities” (95) and an American Academy with type 1 diabetes: a systematic review. Curr seamless transition from pediatric to adult Diab Rep 2016;16:9 of Pediatrics clinical practice guideline health care (112,113,117–119). A compre- 14. Anderson BJ, Laffel LM, Domenger C, et al. (110) provide guidance on the preven- hensive discussion regarding the chal- Factors associated with diabetes-specifichealth- tion, screening, and treatment of type 2 lenges faced during this period, including related quality of life in youth with type 1 diabe- diabetes and its comorbidities in children tes: the Global TEENs Study. Diabetes Care 2017; specific recommendations, is found in the – and adolescents. 40:1002 1009 ADA position statement “Diabetes Care 15. Young-Hyman D, de Groot M, Hill-Briggs F, TRANSITION FROM PEDIATRIC for Emerging Adults: Recommendations Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position state- TO ADULT CARE for Transition From Pediatric to Adult Di- abetes Care Systems” (113). ment of the American Diabetes Association. Di- abetes Care 2016;39:2126–2140 Recommendations The Endocrine Society in collaboration 16. Katz ML, Volkening LK, Butler DA, Anderson c Pediatric diabetes providers and fam- with the ADA and other organizations has BJ, Laffel LM. Family-based psychoeducation and ilies should begin to prepare youth for developed transition tools for clinicians Care Ambassador intervention to improve glycemic transition in early adolescence and, at and youth and families (118). control in youth with type 1 diabetes: a randomized trial. Pediatr Diabetes 2014;15:142–150 the latest, at least 1 year before the References transition to adult health care. E 17. Laffel LMB, Vangsness L, Connell A, Goebel- 1. Oram RA, Patel K, Hill A, et al. A type 1 diabetes Fabbri A, Butler D, Anderson BJ. Impact of ambu- c Both pediatric and adult diabetes genetic risk score can aid discrimination between latory, family-focused teamwork intervention on care providers should provide sup- type 1 and type 2 diabetes in young adults. Di- glycemic control in youth with type 1 diabetes. abetes Care 2016;39:337–344 J Pediatr 2003;142:409–416 S134 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018

18. Anderson BJ, Vangsness L, Connell A, Butler management system in-clinic. Diabetes Technol 48. Hughes JW, Riddlesworth TD, DiMeglio LA, D, Goebel-Fabbri A, Laffel LMB. Family conflict, Ther 2017;19:288–292 Miller KM, Rickels MR, McGill JB. Autoimmune adherence, and glycaemic control in youth with 35. Nimri R, Muller I, Atlas E, et al. MD-Logic over- diseases in children and adults with type 1 diabe- short duration type 1 diabetes. Diabet Med 2002; night control for 6 weeks of home use in patients tes from the T1D Exchange Clinic Registry. J Clin 19:635–642 with type 1 diabetes: randomized crossover trial. Endocrinol Metab. 2016;101:4931–4937 19. Helgeson VS, Palladino DK. Implications of Diabetes Care 2014;37:3025–3032 49. Kahaly GJ, Hansen MP. Type 1 diabetes asso- psychosocial factors for diabetes outcomes 36. Thabit H, Tauschmann M, Allen JM, et al. ciated autoimmunity. Autoimmun Rev 2016;15: among children with type 1 diabetes: a review. Home use of an artificial beta cell in type 1 di- 644–648 Soc Personal Psychol Compass 2012;6:228–242 abetes. N Engl J Med 2015;373:2129–2140 50. Roldan´ MB, Alonso M, Barrio R. Thyroid au- 20. McCarthy AM, Lindgren S, Mengeling MA, 37. Bergenstal RM, Garg S, Weinzimer SA, et al. toimmunity in children and adolescents with type 1 Tsalikian E, Engvall J. Factors associated with aca- Safety of a hybrid closed-loop insulin delivery sys- diabetes mellitus. Diabetes Nutr Metab 1999;12: demic achievement in children with type 1 diabe- tem in patients with type 1 diabetes. JAMA 2016; 27–31 tes. Diabetes Care 2003;26:112–117 316:1407–1408 51. Triolo TM, Armstrong TK, McFann K, et al. 21. Kuther TL. Medical decision-making and mi- 38. Kovatchev B, Cheng P, Anderson SM, et al. Additional autoimmune disease found in 33% of nors: issues of consent and assent. Adolescence Feasibility of long-term closed-loop control: a patients at type 1 diabetes onset. Diabetes Care 2003;38:343–358 multicenter 6-month trial of 24/7 automated in- 2011;34:1211–1213 22. Coleman DL, Rosoff PM. The legal authority of sulin delivery. Diabetes Technol Ther 2017;19: 52. Kordonouri O, Deiss D, Danne T, Dorow A, mature minors to consent to general medical 18–24 Bassir C, Gruters-Kieslich¨ A. Predictivity of thyroid treatment. Pediatrics 2013;131:786–793 39. El-Khatib FH, Balliro C, Hillard MA, et al. Home autoantibodies for the development of thyroid dis- 23. Charron-Prochownik D, Sereika SM, Becker D, use of a bihormonal bionic pancreas versus insulin orders in children and adolescents with type 1 diet al. Long-term effects of the booster-enhanced pump therapy in adults with type 1 diabetes: a abetes. Diabet Med 2002;19:518–521 READY-Girls preconception counseling program multicentre randomised crossover trial. Lancet 53. Dost A, Rohrer TR, Frohlich-Reiterer¨ E, et al.; on intentions and behaviors for family planning 2017;389:369–380 DPV Initiative and the German Competence Net- in teens with diabetes. Diabetes Care 2013;36: 40. Levine BS, Anderson BJ, Butler DA, Antisdel work Diabetes Mellitus. Hyperthyroidism in – 3870 3874 JE, Brackett J, Laffel LM. Predictors of glycemic 276 children and adolescents with type 1 diabetes Diabetes 24. Charron-Prochownik D, Downs J. control and short-term adverse outcomes in from Germany and Austria. Horm Res Paediatr and Reproductive Health for Girls – . Alexandria, youth with type 1 diabetes. J Pediatr 2001;139: 2015;84:190 198 VA, American Diabetes Association, 2016 197–203 54. Jonsdottir B, Larsson C, Carlsson A, et al.; Bet- 25. Lawrence JM, Yi-Frazier JP, Black MH, et al.; 41. Miller KM, Beck RW, Bergenstal RM, et al.; ter Diabetes Diagnosis Study Group. Thyroid and SEARCH for Diabetes in Youth Study Group. De- T1D Exchange Clinic Network. Evidence of a islet autoantibodies predict autoimmune thyroid mographic and clinical correlates of diabetes- strong association between frequency of self- disease at type 1 diabetes diagnosis. J Clin Endo- – related quality of life among youth with type 1 monitoring of blood glucose and hemoglobin crinol Metab 2017;102:1277 1285 diabetes. J Pediatr 2012;161:201–207.e2 55. Mohn A, Di Michele S, Di Luzio R, Tumini S, A1c levels in T1D exchange clinic registry partici- 26. Markowitz JT, Butler DA, Volkening LK, Chiarelli F. The effect of subclinical hypothyroid- pants. Diabetes Care 2013;36:2009–2014 Antisdel JE, Anderson BJ, Laffel LMB. Brief screen- ism on metabolic control in children and adoles- 42. Rosenbauer J, Dost A, Karges B, et al.; DPV ing tool for disordered eating in diabetes: internal cents with type 1 diabetes mellitus. Diabet Med Initiative and the German BMBF Competence consistency and external validity in a contempo- 2002;19:70–73 Network Diabetes Mellitus. Improved metabolic rary sample of pediatric patients with type 1 di- 56. Holmes GKT. Screening for coeliac disease in control in children and adolescents with type 1 abetes. Diabetes Care 2010;33:495–500 type 1 diabetes. Arch Dis Child 2002;87:495–498 diabetes: a trend analysis using prospective mul- 27. Wisting L, Frøisland DH, Skrivarhaug T, Dahl- 57. Rewers M, Liu E, Simmons J, Redondo MJ, ticenter data from Germany and Austria. Diabetes Jørgensen K, Rø O. Disturbed eating behavior and Hoffenberg EJ. Celiac disease associated with Care 2012;35:80–86 omission of insulin in adolescents receiving inten- type 1 diabetes mellitus. Endocrinol Metab Clin 43. Cameron FJ, de Beaufort C, Aanstoot HJ, sified insulin treatment: a nationwide population- North Am 2004;33:197–214 et al.; Hvidoere International Study Group. Les- based study. Diabetes Care 2013;36:3382–3387 58. Pham-Short A, Donaghue KC, Ambler G, 28. Ryan CM. Why is cognitive dysfunction asso- sons from the Hvidoere International Study Group Phelan H, Twigg S, Craig ME. Screening for celiac ciated with the development of diabetes early in on childhood diabetes: be dogmatic about out- disease in type 1 diabetes: a systematic review. Pe- fl life? The diathesis hypothesis. Pediatr Diabetes come and exible in approach. Pediatr Diabetes diatrics. 2015;136:e170–e176 – 2006;7:289–297 2013;14:473 480 59. Craig ME, Prinz N, Boyle CT, et al.; Austral- 29. Cameron FJ. The impact of diabetes on brain 44. Nimri R, Weintrob N, Benzaquen H, Ofan R, asian Diabetes Data Network (ADDN); T1D Ex- function in childhood and adolescence. Pediatr Fayman G, Phillip M. Insulin pump therapy in change Clinic Network (T1DX); National Paediatric Clin North Am 2015;62:911–927 youth with type 1 diabetes: a retrospective paired Diabetes Audit (NPDA) and the Royal College of – 30. Campbell MS, Schatz DA, Chen V, et al.; T1D study. Pediatrics 2006;117:2126 2131 Paediatrics and Child Health; Prospective Diabe- Exchange Clinic Network. A contrast between chil- 45. Doyle EA, Weinzimer SA, Steffen AT, Ahern tes Follow-up Registry (DPV) initiative. Prevalence dren and adolescents with excellent and poor JAH, Vincent M, Tamborlane WVA. A randomized, of celiac disease in 52,721 youth with type 1 di- fi control: the T1D Exchange clinic registry experi- prospective trial comparing the ef cacy of contin- abetes: international comparison across three ence. Pediatr Diabetes 2014;15:110–117 uous subcutaneous insulin infusion with multiple continents. Diabetes Care 2017;40:1034–1040 31. Cooper MN, O’Connell SM, Davis EA, Jones daily injections using insulin glargine. Diabetes 60. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood TW. A population-based study of risk factors for Care 2004;27:1554–1558 AH, Murray JA; American College of Gastroenter- severe hypoglycaemia in a contemporary cohort 46. Swift PGF, Skinner TC, de Beaufort CE, et al.; ology. ACG clinical guidelines: diagnosis and man- of childhood-onset type 1 diabetes. Diabetologia Hvidoere Study Group on Childhood Diabetes. agement of celiac disease. Am J Gastroenterol 2013;56:2164–2170 Target setting in intensive insulin management 2013;108:656–676 32. Bergenstal RM, Klonoff DC, Garg SK, et al.; is associated with metabolic control: the Hvidoere 61. Husby S, Koletzko S, Korponay-SzaboIR,etal.;´ ASPIRE In-Home Study Group. Threshold-based Childhood Diabetes Study Group Centre Differ- ESPGHAN Working Group on Coeliac Disease Di- insulin-pump interruption for reduction of hypo- ences Study 2005. Pediatr Diabetes 2010;11: agnosis; ESPGHAN Gastroenterology Committee; glycemia. N Engl J Med 2013;369:224–232 271–278 European Society for Pediatric Gastroenterology, 33. Abraham MB, Davey R, O’Grady MJ, et al. 47. Maahs DM, Hermann JM, DuBose SN, et al.; Hepatology, and Nutrition. European Society for Effectiveness of a predictive algorithm in the pre- DPV Initiative; T1D Exchange Clinic Network. Con- Pediatric Gastroenterology, Hepatology, and vention of exercise-induced hypoglycemia in trasting the clinical care and outcomes of 2,622 Nutrition guidelines for the diagnosis of coeliac type 1 diabetes. Diabetes Technol Ther 2016;18: children with type 1 diabetes less than 6 years disease. J Pediatr Gastroenterol Nutr 2012;54: 543–550 of age in the United States T1D Exchange and 136–160 34. Buckingham BA, Bailey TS, Christiansen M, German/Austrian DPV registries. Diabetologia 62. Abid N, McGlone O, Cardwell C, McCallion W, et al. Evaluation of a predictive low-glucose 2014;57:1578–1585 Carson D. Clinical and metabolic effects of gluten care.diabetesjournals.org Children and Adolescents S135

free diet in children with type 1 diabetes and coe- Epidemiology and Prevention, Nutrition, Physical Exchange clinic registry. Diabetes Care 2013;36: liac disease. Pediatr Diabetes 2011;12:322–325 Activity and Metabolism, High Blood Pressure Re- 2639–2645 63. Kurppa K, Paavola A, Collin P, et al. Benefits search, Cardiovascular Nursing, and the Kidney in 85. Schwartz GJ, Work DF. Measurement and es- of a gluten-free diet for asymptomatic patients Heart Disease; and the Interdisciplinary Working timation of GFR in children and adolescents. Clin J with serologic markers of celiac disease. Gastro- Group on Quality of Care and Outcomes Research: Am Soc Nephrol 2009;4:1832–1843 enterology 2014;147:610–617.e1 endorsed by the American Academy of Pediatrics. 86. Inker LA, Schmid CH, Tighiouart H, et al.; CKD- 64. de Ferranti SD, de Boer IH, Fonseca V, et al. Circulation 2006;114:2710–2738 EPI Investigators. Estimating glomerular filtration Type 1 diabetes mellitus and cardiovascular dis- 74. Cadario F, Prodam F, Pasqualicchio S, et al. rate from serum creatinine and cystatin C. N Engl J ease: a scientific statement from the American Lipid profile and nutritional intake in children and Med 2012;367:20–29 Heart Association and American Diabetes Associ- adolescents with type 1 diabetes improve after a 87. Loredana Marcovecchio M, Chiesa ST, Bond ation. Circulation 2014;130:1110–1130 structured dietician training to a Mediterranean- S, et al.; AdDIT Study Group. ACE inhibitors and 65. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, style diet. J Endocrinol Invest 2012;35:160–168 statins in adolescents with type 1 diabetes. N Engl et al. Prevalence of cardiovascular disease risk 75. Salem MA, AboElAsrar MA, Elbarbary NS, J Med 2017;377:1733–1745 factors in U.S. children and adolescents with di- ElHilaly RA, Refaat YM. Is exercise a therapeutic 88. Cho YH, Craig ME, Hing S, et al. Microvascular abetes: the SEARCH for diabetes in youth study. tool for improvement of cardiovascular risk fac- complications assessment in adolescents with 2- Diabetes Care 2006;29:1891–1896 tors in adolescents with type 1 diabetes mellitus? to 5-yr duration of type 1 diabetes from 1990 to 66. Margeirsdottir HD, Larsen JR, Brunborg C, A randomised controlled trial. Diabetol Metab 2006. Pediatr Diabetes 2011;12:682–689 Overby NC, Dahl-Jørgensen K; Norwegian Study Syndr 2010;2:47 89. Jaiswal M, Divers J, Dabelea D, et al. Preva- Group for Childhood Diabetes. High prevalence 76. McCrindle BW, Urbina EM, Dennison BA, lence of and risk factors for diabetic peripheral of cardiovascular risk factors in children and ado- et al.; American Heart Association Atherosclero- neuropathy in youth with type 1 and type 2 di- lescents with type 1 diabetes: a population-based sis, Hypertension, and Obesity in Youth Commit- abetes: SEARCH for Diabetes in Youth Study. Di- – study. Diabetologia 2008;51:554 561 tee; American Heart Association Council of abetes Care 2017;40:1226–1232 67. Schwab KO, Doerfer J, Hecker W, et al.; DPV Cardiovascular Disease in the Young; American 90. Pop-Busui R, Boulton AJM, Feldman EL, et al. Initiative of the German Working Group for Pedi- Heart Association Council on Cardiovascular Nurs- Diabetic neuropathy: a position statement by the atric Diabetology. Spectrum and prevalence of ing. Drug therapy of high-risk lipid abnormalities American Diabetes Association. Diabetes Care fi atherogenic risk factors in 27,358 children, ado- in children and adolescents: a scienti c statement 2017;40:136–154 lescents, and young adults with type 1 diabetes: from the American Heart Association Atheroscle- 91. Arslanian S, Bacha FF, Grey M, Marcus M, cross-sectional data from the German diabetes rosis, Hypertension, and Obesity in Youth Com- White N, Zeitler P. Evaluation and management documentation and quality management system mittee, Council of Cardiovascular Disease in the of youth-onset type 2 diabetes: a position state- – (DPV). Diabetes Care 2006;29:218 225 Young, with the Council on Cardiovascular Nurs- ment by the American Diabetes Association. Di- 68. Singh TP, Groehn H, Kazmers A. Vascular – ing. Circulation 2007;115:1948 1967 abetes Care. In press ¨ ¨ ¨ function and carotid intimal-medial thickness in 77. Salo P, Viikari J, Hamalainen M, Lapinleimu H, 92. Lawrence JM, Imperatore G, Pettitt DJ, et al. children with insulin-dependent diabetes melli- ¨ Routi T, Ronnemaa T, et al. Serum cholesterol Incidence of diabetes in United States youth by tus. J Am Coll Cardiol 2003;41:661–665 ester fatty acids in 7- and 13-month-old chil- diabetes type, race/ethnicity, and age, 2008–2009 69. Haller MJ, Stein J, Shuster J, et al. Peripheral dren in a prospective randomized trial of a low- (Abstract). Diabetes 2014;63(Suppl. 1):A407 artery tonometry demonstrates altered endothe- saturated fat, low-cholesterol diet: the STRIP baby 93. Imperatore G, Boyle JP, Thompson TJ, et al.; lialfunctioninchildrenwithtype1diabetes.Pe- project: Special Turku coronary Risk factor Inter- SEARCH for Diabetes in Youth Study Group. Pro- diatr Diabetes 2007;8:193–198 vention Project for children. Acta Paediatr 1999; jections of type 1 and type 2 diabetes burden in 70. Urbina EM, Wadwa RP, Davis C, Snively BM, 88:505–512 the U.S. population aged ,20 years through Dolan LM, Daniels SR, et al. Prevalence of in- 78. Maahs DM, Dabelea D, D’Agostino RB Jr, 2050: dynamic modeling of incidence, mortality, creased arterial stiffness in children with type 1 et al.; SEARCH for Diabetes in Youth Study. Glu- and population growth. Diabetes Care 2012;35: diabetes mellitus differs by measurement site and cose control predicts 2-year change in lipid profile 2515–2520 sex: the SEARCH for Diabetes in Youth Study. in youth with type 1 diabetes. J Pediatr 2013;162: 94. Pettitt DJ, Talton J, Dabelea D, et al.; SEARCH J Pediatr 2010; 156:731–737 101–107 71. Expert Panel on Integrated Guidelines for Car- 79. McCrindle BW, Ose L, Marais AD. Efficacy and for Diabetes in Youth Study Group. Prevalence of diovascular Health and Risk Reduction in Children safety of atorvastatin in children and adolescents diabetes in U.S. youth in 2009: the SEARCH for and Adolescents; National Heart, Lung, and Blood with familial hypercholesterolemia or severe hy- diabetes in youth study. Diabetes Care 2014;37: – Institute. Expert panel on integrated guidelines perlipidemia: a multicenter, randomized, placebo- 402 408 for cardiovascular health and risk reduction in controlled trial. J Pediatr 2003;143:74–80 95. Nadeau KJ, Anderson BJ, Berg EG, et al. Youth- children and adolescents: summary report. Pedi- 80. Wiegman A, Hutten BA, de Groot E, et al. onset type 2 diabetes consensus report: current atrics 2011;128(Suppl. 5):S213–S256 Efficacy and safety of statin therapy in children status, challenges, and priorities. Diabetes Care – 72. Daniels SR, Greer FR; Committee on Nutri- with familial hypercholesterolemia: a randomized 2016;39:1635 1642 tion. Lipid screening and cardiovascular health in controlled trial. JAMA 2004;292:331–337 96. Copeland KC, Zeitler P, Geffner M, et al.; childhood. Pediatrics 2008;122:198–208 81. Karter AJ, Stevens MR, Gregg EW, et al. Edu- TODAY Study Group. Characteristics of adoles- 73. Kavey R-EW, Allada V, Daniels SR, et al.; cational disparities in rates of smoking among di- cents and youth with recent-onset type 2 diabe- American Heart Association Expert Panel on Pop- abetic adults: the translating research into action tes: the TODAY cohort at baseline. J Clin ulation and Prevention Science; American Heart for diabetes study. Am J Public Health 2008;98: Endocrinol Metab 2011;96:159–167 Association Council on Cardiovascular Disease in 365–370 97. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; the Young; American Heart Association Council on 82. Reynolds K, Liese AD, Anderson AM, et al. SEARCH for Diabetes in Youth Study. Prevalence Epidemiology and Prevention; American Heart As- Prevalence of tobacco use and association be- of type 1 and type 2 diabetes among children and sociation Council on Nutrition, Physical Activity tween cardiometabolic risk factors and cigarette adolescents from 2001 to 2009. JAMA 2014;311: and Metabolism; American Heart Association smoking in youth with type 1 or type 2 diabetes 1778–1786 Council on High Blood Pressure Research; Amer- mellitus. J Pediatr 2011;158:594–601 98. Buse JB, Kaufman FR, Linder B, Hirst K, El ican Heart Association Council on Cardiovascular 83. Scott LJ, Warram JH, Hanna LS, Laffel LM, Ghormli L, Willi S; HEALTHY Study Group. Diabetes Nursing; American Heart Association Council on Ryan L, Krolewski AS. A nonlinear effect of hyper- screening with hemoglobin A(1c) versus fasting the Kidney in Heart Disease; Interdisciplinary glycemia and current cigarette smoking are major plasma glucose in a multiethnic middle-school co- Working Group on Quality of Care and Outcomes determinants of the onset of microalbuminuria in hort. Diabetes Care 2013;36:429–435 Research. Cardiovascular risk reduction in high- type 1 diabetes. Diabetes 2001;50:2842–2849 99. Kapadia C, Zeitler P; Drugs and Therapeutics risk pediatric patients: a scientificstatement 84. Daniels M, DuBose SN, Maahs DM, et al.; T1D Committee of the Pediatric Endocrine Society. He- from the American Heart Association Expert Panel Exchange Clinic Network. Factors associated moglobin A1c measurement for the diagnosis of on Population and Prevention Science; the Coun- with microalbuminuria in 7,549 children and ad- type 2 diabetes in children. Int J Pediatr Endocri- cils on Cardiovascular Disease in the Young, olescents with type 1 diabetes in the T1D nol 2012;2012:31 S136 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018

100. Kester LM, Hey H, Hannon TS. Using hemo- 107. Inge TH, Courcoulas AP, Jenkins TM, et al.; Association of Clinical Endocrinologists, the Amer- globin A1c for prediabetes and diabetes diagnosis Teen-LABS Consortium. Weight loss and health ican Osteopathic Association, the Centers for Dis- in adolescents: can adult recommendations be status 3 years after bariatric surgery in adoles- ease Control and Prevention, Children with upheld for pediatric use? J Adolesc Health 2012; cents. N Engl J Med 2016;374:113–123 Diabetes, The Endocrine Society, the International 50:321–323 108. Rubino F, Nathan DM, Eckel RH, et al.; Del- Society for Pediatric and Adolescent Diabetes, 101. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness egates of the 2nd Diabetes Surgery Summit. Met- Juvenile Diabetes Research Foundation Interna- of screening strategies for identifying pediatric di- abolic surgery in the treatment algorithm for tional, the National Diabetes Education Program, abetes mellitus and dysglycemia. JAMA Pediatr type 2 diabetes: a joint statement by International and the Pediatric Endocrine Society (formerly 2013;167:32–39 Diabetes Organizations. Diabetes Care 2016;39: Lawson Wilkins Pediatric Endocrine Society). Di- 102. DuBose SN, Hermann JM, Tamborlane WV, 861–877 abetes Care 2011;34:2477–2485 et al.; Type 1 Diabetes Exchange Clinic Network 109. Eppens MC, Craig ME, Cusumano J, et al. 114. Bryden KS, Peveler RC, Stein A, Neil A, and Diabetes Prospective Follow-up Registry. Prevalence of diabetes complications in adoles- Mayou RA, Dunger DB. Clinical and psychological Obesity in youth with type 1 diabetes in Germany, cents with type 2 compared with type 1 diabetes. course of diabetes from adolescence to young Austria, and the United States. J Pediatr 2015;167: Diabetes Care 2006;29:1300–1306 adulthood: a longitudinal cohort study. Diabetes 627–632 110. Springer SC, Silverstein J, Copeland K, et al.; Care 2001;24:1536–1540 103. Klingensmith GJ, Pyle L, Arslanian S, et al.; American Academy of Pediatrics. Management of 115. Laing SP, Jones ME, Swerdlow AJ, Burden TODAY Study Group. The presence of GAD and type 2 diabetes mellitus in children and adoles- AC, Gatling W. Psychosocial and socioeconomic IA-2 antibodies in youth with a type 2 diabetes cents. Pediatrics 2013;131:e648–e664 risk factors for premature death in young people phenotype: results from the TODAY study. Diabe- 111. Arnett JJ. Emerging adulthood. A theory of with type 1 diabetes. Diabetes Care 2005;28: tes Care 2010;33:1970–1975 development from the late teens through the 1618–1623 104. DabeleaD,RewersA,StaffordJM,Standiford twenties. Am Psychol 2000;55:469–480 116. Mays JA, Jackson KL, Derby TA, et al. An DA, Lawrence JM, Saydah S, et al. Trends in the 112. Weissberg-Benchell J, Wolpert H, Anderson evaluation of recurrent diabetic ketoacidosis, prevalence of ketoacidosis at diabetes diagnosis: BJ. Transitioning from pediatric to adult care: a fragmentation of care, and mortality across the SEARCH for Diabetes in Youth Study. Pediat- new approach to the post-adolescent young per- Chicago, Illinois. Diabetes Care 2016;39:1671– rics 2014;133:e938–e945 son with type 1 diabetes. Diabetes Care 2007;30: 1676 105. Copeland KC, Silverstein J, Moore KR, Prazar 2441–2446 117. Garvey KC, Foster NC, Agarwal S, et al. GE, Raymer T, Shiffman RN, et al. Management of 113. Peters A, Laffel L; American Diabetes Asso- Health care transition preparation and experi- newly diagnosed type 2 diabetes mellitus (T2DM) ciation Transitions Working Group. Diabetes care ences in a U.S. national sample of young adults in children and adolescents. Pediatrics 2013;131: for emerging adults: recommendations for transi- with type 1 diabetes. Diabetes Care 2017;40:317– 364–382. tion from pediatric to adult diabetes care systems: 324 106. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study a position statement of the American Diabetes 118. Endocrine Society. Managing the transition Group. A clinical trial to maintain glycemic control Association, with representation by the American of care for patients with type 1 diabetes [Internet]. in youth with type 2 diabetes. N Engl J Med 2012; College of Osteopathic Family Physicians, the Available from: https://www.endocrinetransitions 366:2247–2256 American Academy of Pediatrics, the American .org. Accessed 20 June 2017 Diabetes Care Volume 41, Supplement 1, January 2018 S137

13. Management of Diabetes American Diabetes Association in Pregnancy: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S137–S143 | https://doi.org/10.2337/dc18-S013 3 AAEETO IBTSI PREGNANCY IN DIABETES OF MANAGEMENT 13.

DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. The majority is gestational diabetes mellitus (GDM) with the remainder primarily preexisting type 1 diabetes and type 2 diabetes. The rise in GDM and type 2 diabetes in parallel with obesity both in the U.S. and worldwide is of particular concern. Both type 1 diabetes and type 2 diabetes in pregnancy confer signiﬁcantly greater maternal and fetal risk than GDM, with some differences according to type of diabetes as outlined below. In general, speciﬁc risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in pregnancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2). PRECONCEPTION COUNSELING

Recommendations 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 Suggested citation: American Diabetes Associa- pregnant. A tion. 13. Management of diabetes in pregnancy: c Preconception counseling should address the importance of glycemic control as Standards of Medical Care in Diabetesd2018. close to normal as is safely possible, ideally A1C ,6.5% (48 mmol/mol), to reduce Diabetes Care 2018;41(Suppl. 1):S137–S143 the risk of congenital anomalies. B © 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 All women of childbearing age with diabetes should be counseled about the impor- for proﬁt, and the work is not altered. More infor- tance of tight glycemic control prior to conception. Observational studies show an mation is available at http://www.diabetesjournals increased risk of diabetic embryopathy, especially anencephaly, microcephaly, .org/content/license. S138 Management of Diabetes in Pregnancy Diabetes Care Volume 41, Supplement 1, January 2018

congenital heart disease, and caudal re- Preconception counseling visits should in- with insulin dosage and to avoid hyper- gression, directly proportional to eleva- clude rubella, syphilis, hepatitis B virus, glycemia or hypoglycemia. Referral to a tions in A1C during the first 10 weeks of and HIV testing, as well as Pap smear, registered dietitian is important in order pregnancy. Although observational stud- cervical cultures, blood typing, prescrip- to establish a food plan and insulin-to- ies are confounded by the association be- tion of prenatal vitamins (with at least carbohydrate ratio and to determine tween elevated periconceptional A1C and 400 mg of folic acid), and smoking cessa- weight gain goals. other poor self-care behaviors, the quan- tion counseling if indicated. Diabetes- tity and consistency of data are convinc- specific testing should include A1C, Insulin Physiology ing and support the recommendation to thyroid-stimulating hormone, creatinine, Early pregnancy is a time of insulin sensi- – – optimize glycemic control prior to con- and urinary albumin to creatinine ratio; tivity, lower glucose levels, and lower in- , ception, with A1C 6.5% (48 mmol/mol) review of the medication list for potentially sulin requirements in women with type 1 associated with the lowest risk of congen- teratogenic drugs, i.e., ACE inhibitors (8), diabetes. The situation rapidly reverses as ital anomalies (3,4). angiotensin receptor blockers (8), and insulin resistance increases exponentially There are opportunities to educate all statins (9,10); and referral for a compre- during the second and early third trimes- women and adolescents of reproductive hensive eye exam. Women with preexist- ters and levels off toward the end of the age with diabetes about the risks of ing diabetic retinopathy will need close third trimester. In women with normal unplanned pregnancies and improved monitoring during pregnancy to ensure pancreatic function, insulin production is maternal and fetal outcomes with preg- that retinopathy does not progress. sufficient to meet the challenge of this nancy planning (5). Effective preconcep- physiological insulin resistance and to tion counseling could avert substantial GLYCEMIC TARGETS IN maintain normal glucose levels. However, health and associated cost burdens in PREGNANCY in women with GDM or preexisting dia- offspring (6). Family planning should be betes, hyperglycemia occurs if treatment discussed, and effective contraception Recommendations is not adjusted appropriately. should be prescribed and used until a c Fasting and postprandial self- woman is prepared and ready to become monitoring of blood glucose are recom- Glucose Monitoring pregnant. mended in both gestational diabetes Reflecting this physiology, fasting and To minimize the occurrence of compli- mellitus and preexisting diabetes in postprandial monitoring of blood glucose cations, beginning at the onset of puberty pregnancy to achieve glycemic con- is recommended to achieve metabolic con- or at diagnosis, all women with diabetes trol. Some women with preexisting trol in pregnant women with diabetes. Pre- of childbearing potential should receive diabetes should also test blood glu- prandial testing is also recommended for education about 1) the risks of malforma- cose preprandially. B women with preexisting diabetes using in- tions associated with unplanned pregnan- c Due to increased red blood cell turn- sulin pumps or basal-bolus therapy, so that cies and poor metabolic control and over, A1C is slightly lower in normal premeal rapid-acting insulin dosage can be 2) the use of effective contraception at pregnancy than in normal nonpreg- adjusted. Postprandial monitoring is associ- all times when preventing a pregnancy. nant women. The A1C target in preg- ated with better glycemic control and lower Preconception counseling using develop- nancy is 6–6.5% (42–48 mmol/mol); risk of preeclampsia (11–13). There are no mentally appropriate educational tools ,6% (42 mmol/mol) may be opti- adequately powered randomized trials enables adolescent girls to make well- mal if this can be achieved without comparing different fasting and postmeal informed decisions (5). Preconception significant hypoglycemia, but the glycemic targets in diabetes in pregnancy. counseling resources tailored for adoles- targetmayberelaxedto,7% Similar to the targets recommended cents are available at no cost through the (53 mmol/mol) if necessary to pre- by the American College of Obstetri- American Diabetes Association (ADA) (7). vent hypoglycemia. B cians and Gynecologists (14), the ADA- recommended targets for women with Preconception Testing Pregnancy in women with normal glucose type 1 or type 2 diabetes (the same as metabolism is characterized by fasting for GDM; described below) are as follows: Recommendation levels of blood glucose that are lower c Women with preexisting type 1 or than in the nonpregnant state due to ○ Fasting ,95 mg/dL (5.3 mmol/L) and type 2 diabetes who are planning insulin-independent glucose uptake by either pregnancy or who have become the fetus and placenta and by postpran- ○ One-hour postprandial ,140 mg/dL pregnant should be counseled on dial hyperglycemia and carbohydrate in- (7.8 mmol/L) or the risk of development and/or tolerance as a result of diabetogenic ○ Two-hour postprandial ,120 mg/dL progression of diabetic retinopathy. placental hormones. In patients with pre- (6.7 mmol/L) Dilated eye examinations should oc- existing diabetes, glycemic targets are cur before pregnancy or in the first usually achieved through a combination These values represent optimal control if trimester, and then patients should of insulin administration and medical nu- they can be achieved safely. In practice, it be monitored every trimester and trition therapy. Because glycemic targets may be challenging for women with type 1 for 1-year postpartum as indicated in pregnancy are stricter than in nonpreg- diabetes to achieve these targets without by the degree of retinopathy and nant individuals, it is important that hypoglycemia, particularly women with a as recommended by the eye care women with diabetes eat consistent history of recurrent hypoglycemia or hypo- provider. B amounts of carbohydrates to match glycemia unawareness. care.diabetesjournals.org Management of Diabetes in Pregnancy S139

If women cannot achieve these targets plasma glucose ,95 mg/dL [5.3 mmol/L]) used, but both cross the placenta to without significant hypoglycemia, the ADA who meet glucose goals after a week of the fetus, with metformin likely cross- suggests less stringent targets based on clin- medical nutrition therapy can safely per- ing to a greater extent than glyburide. ical experience and individualization of care. form self-monitoring of blood glucose All oral agents lack long-term safety every other day, rather than daily (26). A1C in Pregnancy data. A Observational studies show the lowest c Metformin, when used to treat Medical Nutrition Therapy rates of adverse fetal outcomes in association polycystic ovary syndrome and in- Medical nutrition therapy for GDM is an with A1C ,6–6.5% (42–48 mmol/mol) duce ovulation, need not be con- individualized nutrition plan developed early in gestation (4,15–17). Clinical trials tinued once pregnancy has been between the woman and a registered di- have not evaluated the risks and benefits confirmed. A etitian familiar with the management of of achieving these targets, and treatment GDM (27,28). The food plan should pro- goals should account for the risk of ma- GDM is characterized by increased risk of vide adequate calorie intake to promote ternal hypoglycemia in setting an individ- macrosomia and birth complications and fetal/neonatal and maternal health, ualized target of ,6% (42 mmol/mol) an increased risk of maternal type 2 diabe- achieve glycemic goals, and promote ap- to ,7% (53 mmol/mol). Due to physio- tes after pregnancy. The association of propriate gestational weight gain. There logical increases in red blood cell turn- macrosomia and birth complications with is no definitive research that identifies a over, A1C levels fall during normal oral glucose tolerance test (OGTT) results is specific optimal calorie intake for women pregnancy (18,19). Additionally, as A1C continuous with no clear inflection points with GDM or suggests that their calorie represents an integrated measure of glu- (20). In other words, risks increase with needs are different from those of pregnant cose, it may not fully capture postprandial progressive hyperglycemia. Therefore, all women without GDM. The food plan should hyperglycemia, which drives macrosomia. women should be tested as outlined in bebasedonanutritionassessmentwith Thus, although A1C may be useful, it Section 2 “Classification and Diagnosis of guidance from the Dietary Reference Intakes should be used as a secondary measure Diabetes.” Although there is some het- (DRI). The DRI for all pregnant women of glycemic control in pregnancy, after erogeneity, many randomized controlled recommends a minimum of 175 g of carbo- self-monitoring of blood glucose. trials suggest that the risk of GDM may be hydrate, a minimum of 71 g of protein, and Inthesecondandthirdtrimesters, reduced by diet, exercise, and lifestyle 28 g of fiber. As is true for all nutrition A1C ,6% (42 mmol/mol) has the lowest counseling, particularly when interven- therapy in patients with diabetes, the risk of large-for-gestational-age infants, tions are started during the first or early amount and type of carbohydrate will im- whereas other adverse outcomes in- in the second trimester (21–23). pact glucose levels, especially postmeal crease with A1C $6.5% (48 mmol/mol). excursions. Lifestyle Management Taking all of this into account, a target of After diagnosis, treatment starts with Pharmacologic Therapy 6–6.5% (42–48 mmol/mol) is recom- medical nutrition therapy, physical activ- Women with greater initial degrees of hy- mended but ,6% (42 mmol/mol) may ity, and weight management depending perglycemia may require earlier initiation be optimal as pregnancy progresses. on pregestational weight, as outlined in of pharmacologic therapy. Treatment has These levels should be achieved without the section below on preexisting type 2 been demonstrated to improve perinatal hypoglycemia, which, in addition to the diabetes, and glucose monitoring aiming outcomes in two large randomized stud- usual adverse sequelae, may increase for the targets recommended by the Fifth ies as summarized in a U.S. Preventive the risk of low birth weight. Given the International Workshop-Conference on Services Task Force review (29). Insulin alteration in red blood cell kinetics during Gestational Diabetes Mellitus (24): is the first-line agent recommended for pregnancy and physiological changes in treatment of GDM in the U.S. While indi- glycemic parameters, A1C levels may ○ Fasting ,95 mg/dL (5.3 mmol/L) and vidual randomized controlled trials sup- need to be monitored more frequently either port the efficacy and short-term safety than usual (e.g., monthly). ○ One-hour postprandial ,140 mg/dL of metformin (30,31) and glyburide (32) MANAGEMENT OF GESTATIONAL (7.8 mmol/L) or for the treatment of GDM, both agents DIABETES MELLITUS ○ Two-hour postprandial ,120 mg/dL cross the placenta. There is not agree- (6.7 mmol/L) ment regarding the comparative advan- Recommendations tages and disadvantages of the two oral c Lifestyle change is an essential com- Depending on the population, studies sug- agents; the most recent systematic re- ponent of management of gesta- gest that 70–85% of women diagnosed view of randomized controlled trials com- tional diabetes mellitus and may with GDM under Carpenter-Coustan or paring metformin and glyburide for GDM suffice for the treatment of many National Diabetes Data Group (NDDG) cri- found no clear differences in maternal or women. Medications should be teria can control GDM with lifestyle mod- neonatal outcomes (33). A more recent added if needed to achieve glyce- ification alone; it is anticipated that this randomized controlled trial demon- mic targets. A proportion will be even higher if the lower strated that glyburide and metformin c Insulin is the preferred medication for International Association of the Diabetes are comparable oral treatments for treating hyperglycemia in gestational and Pregnancy Study Groups (IADPSG) GDM regarding glucose control and ad- diabetes mellitus as it does not cross (25) diagnostic thresholds are used. A reverse effects. In this study, they were the placenta to a measurable extent. cent randomized controlled trial suggests combined, with data demonstrating a Metformin and glyburide may be that women with mild GDM (fasting high efficacy rate with a significantly S140 Management of Diabetes in Pregnancy Diabetes Care Volume 41, Supplement 1, January 2018

reduced need for insulin, with a possible this approach would reduce morbidity, and type 2 diabetes in pregnancy advantage for metformin over glyburide save lives, and lower health care costs (49). because it does not cross the pla- as first-line therapy (34). However, more centa, and because oral agents are definitive studies are required in this area. Type 1 Diabetes generally insufficient to overcome Long-term safety data are not available Women with type 1 diabetes have an in- the insulin resistance in type 2 dia- for any oral agent (35). creased risk of hypoglycemia in the first betesandareineffectiveintype1di- trimester and, like all women, have al- Sulfonylureas E abetes. tered counterregulatory response in Concentrations of glyburide in umbilical cord pregnancy that may decrease hypoglyce- plasma are approximately 70% of maternal The physiology of pregnancy necessitates mia awareness. Education for patients levels (36). Glyburide was associated with frequent titration of insulin to match and family members about the preven- a higher rate of neonatal hypoglycemia changing requirements and underscores tion, recognition, and treatment of hypo- and macrosomia than insulin or metfor- the importance of daily and frequent self- glycemia is important before, during, and min in a 2015 systematic review (37). fi monitoring of blood glucose. In the rst after pregnancy to help to prevent and Metformin trimester, there is often a decrease in manage the risks of hypoglycemia. Insulin Metformin was associated with a lower risk total daily insulin requirements, and resistance drops rapidly with delivery of of neonatal hypoglycemia and less maternal women, particularly those with type 1 di- the placenta. Women become very insu- weight gain than insulin in 2015 systematic abetes, may experience increased hypo- lin sensitive immediately following deliv- reviews (37–39); however, metformin glycemia. In the second trimester, rapidly ery and may initially require much less may slightly increase the risk of prematu- increasing insulin resistance requires insulin than in the prepartum period. rity. Furthermore, nearly half of patients weekly or biweekly increases in insulin Pregnancy is a ketogenic state, and with GDM who were initially treated with dose to achieve glycemic targets. In women with type 1 diabetes, and to a lesser metformin in a randomized trial needed general, a smaller proportion of the total extent those with type 2 diabetes, are at risk insulin in order to achieve acceptable glu- daily dose should be given as basal insulin for diabetic ketoacidosis at lower blood glu- , . cose control (30). Umbilical cord blood ( 50%) and a greater proportion ( 50%) cose levels than in the nonpregnant state. levels of metformin are higher than simul- as prandial insulin. Late in the third tri- Women with preexisting diabetes, espe- taneous maternal levels (40,41). None of mester, there is often a leveling off or cially type 1 diabetes, need ketone strips these studies or meta-analyses evaluated small decrease in insulin requirements. at home and education on diabetic ketoaci- long-term outcomes in the offspring. Pa- Due to the complexity of insulin manage- dosis prevention and detection. In addition, tients treated with oral agents should be ment in pregnancy, referral to a specialized rapid implementation of tight glycemic con- informed that they cross the placenta, center offering team-based care (with trol in the setting of retinopathy is associ- and although no adverse effects on the team members including high-risk obste- ated with worsening of retinopathy (50). fetus have been demonstrated, long-term trician, endocrinologist, or other provider studies are lacking. experienced in managing pregnancy in Type 2 Diabetes Randomized, double-blind, controlled women with preexisting diabetes, dietitian, Type2diabetesisoftenassociatedwith trials comparing metformin with other nurse, and social worker, as needed) is rec- obesity. Recommended weight gain during – therapies for ovulation induction in ommended if this resource is available. pregnancy for overweight women is 15 25 – women with polycystic ovary syndrome None of the currently available insulin lb and for obese women is 10 20 lb (51). have not demonstrated benefitinprevent- preparations have been demonstrated to Glycemic control is often easier to achieve ing spontaneous abortion or GDM (42), cross the placenta. in women with type 2 diabetes than in and there is no evidence-based need to thosewithtype1diabetesbutcanrequire continue metformin in such patients once Preeclampsia and Aspirin much higher doses of insulin, sometimes pregnancy has been confirmed (43–45). necessitating concentrated insulin formula- Recommendation tions. As in type 1 diabetes, insulin require- Insulin c Women with type 1 or type 2 dia- ments drop dramatically after delivery. The Insulin may be required to treat hypergly- betes should be prescribed low- risk for associated hypertension and other cemia, and its use should follow the dose aspirin 60–150 mg/day (usual comorbidities may be as high or higher with guidelines below. Both multiple daily in- dose 81 mg/day) from the end of type 2 diabetes as with type 1 diabetes, sulin injections and continuous subcuta- the first trimester until the baby is even if diabetes is better controlled and of neous insulin infusion are reasonable born in order to lower the risk of shorter apparent duration, with pregnancy alternatives, and neither has been shown preeclampsia. A loss appearing to be more prevalent in the to be superior during pregnancy (46). third trimester in women with type 2 dia- Diabetes in pregnancy is associated with fi MANAGEMENT OF PREEXISTING betes compared with the rst trimester in an increased risk of preeclampsia (47). women with type 1 diabetes (52,53). TYPE 1 DIABETES AND TYPE 2 Based upon the results of clinical trials, DIABETES IN PREGNANCY the U.S. Preventive Services Task Force PREGNANCY AND DRUG Insulin Use recommends the use of low-dose aspirin CONSIDERATIONS (81 mg/day) as a preventive medication Recommendation Recommendations after 12 weeks of gestation in women c Insulin is the preferred agent for man- c In pregnant patients with diabetes who are at high risk for preeclampsia (48). agement of both type 1 diabetes and chronic hypertension, blood Acost-benefit analysis has concluded that care.diabetesjournals.org Management of Diabetes in Pregnancy S141

Gestational Diabetes Mellitus history of GDM and prediabetes, only 5–6 pressure targets of 120–160/80– Initial Testing women need to be treated with either 105 mmHg are suggested in the Because GDM may represent preexisting intervention to prevent one case of dia- interest of optimizing long-term ma- undiagnosed type 2 or even type 1 diabe- betes over 3 years (64). In these women, ternal health and minimizing impaired tes, women with GDM should be tested lifestyle intervention and metformin re- fetal growth. E for persistent diabetes or prediabetes at duced progression to diabetes by 35% c Potentially teratogenic medications 4–12 weeks postpartum with a 75-g OGTT and 40%, respectively, over 10 years com- (i.e., ACE inhibitors, angiotensin re- using nonpregnancy criteria as outlined in pared with placebo (65). If the pregnancy ceptor blockers, statins) should be Section 2 “Classification and Diagnosis of has motivated the adoption of a healthier avoided in sexually active women of Diabetes.” diet, building on these gains to support childbearing age who are not using weight loss is recommended in the post- reliable contraception. B Postpartum Follow-up partum period. The OGTT is recommended over A1C at In normal pregnancy, blood pressure is the time of the 4- to 12-week postpartum Preexisting Type 1 and Type 2 Diabetes lower than in the nonpregnant state. visit because A1C may be persistently im- Insulin sensitivity increases with delivery In a pregnancy complicated by diabetes pacted (lowered) by the increased red of the placenta and then returns to pre- and chronic hypertension, target goals blood cell turnover related to pregnancy pregnancy levels over the following for systolic blood pressure 120–160 or blood loss at delivery and because the 1–2 weeks. In women taking insulin, par- mmHg and diastolic blood pressure 80– OGTT is more sensitive at detecting glu- ticular attention should be directed to hy- 105 mmHg are reasonable (54). Lower cose intolerance, including both predia- poglycemia prevention in the setting of blood pressure levels may be associ- betes and diabetes. Reproductive-aged breastfeeding and erratic sleep and eat- ated with impaired fetal growth. In a women with prediabetes may develop ing schedules. 2015 study targeting diastolic blood pres- type 2 diabetes by the time of their next Contraception sure of 100 mmHg versus 85 mmHg in pregnancy and will need preconception A major barrier to effective preconception pregnant women, only 6% of whom had evaluation. Because GDM is associated care is the fact that the majority of pregnan- GDM at enrollment, there was no dif- with an increased lifetime maternal risk cies are unplanned. Planning pregnancy is ference in pregnancy loss, neonatal care, for diabetes estimated at 50–70% after critical in women with preexisting diabetes or other neonatal outcomes, although 15–25 years (60,61), women should also due to the need for preconception glycemic women in the less intensive treatment be tested every 1–3 years thereafter if the control and preventive health services. group had a higher rate of uncontrolled 4- to 12-week 75-g OGTT is normal, with Therefore, all women with diabetes of child- hypertension (55). frequency of testing depending on other bearing potential should have family plan- During pregnancy, treatment with ACE risk factors including family history, pre- ning options reviewed at regular intervals. inhibitors and angiotensin receptor block- pregnancy BMI, and need for insulin or This applies to women in the immediate ers is contraindicated because they may oral glucose-lowering medication during postpartum period. Women with diabetes cause fetal renal dysplasia, oligohydram- pregnancy. Ongoing evaluation may be have the same contraception options and nios, and intrauterine growth restriction performed with any recommended glyce- recommendations as those without diabe- (8). Antihypertensive drugs known to be mic test (e.g., A1C, fasting plasma glu- tes. The risk of an unplanned pregnancy effective and safe in pregnancy include cose, or 75-g OGTT using nonpregnant outweighs the risk of any given contracep- methyldopa, labetalol, diltiazem, cloni- thresholds). dine, and prazosin. Chronic diuretic use tion option. Gestational Diabetes Mellitus and Type 2 during pregnancy is not recommended References as it has been associated with restricted Diabetes WomenwithahistoryofGDMhavea 1. Holmes VA, Young IS, Patterson CC, et al.; Di- maternal plasma volume, which may re- greatly increased risk of conversion to abetes and Pre-eclampsia Intervention Trial Study duce uteroplacental perfusion (56). On Group. Optimal glycemic control, pre-eclampsia, type 2 diabetes over time and not solely the basis of available evidence, statins and gestational hypertension in women with type 1 within the 4- to 12-week postpartum time should also be avoided in pregnancy (57). diabetes in the Diabetes and Pre-eclampsia Inter- frame (60). In the prospective Nurses’ vention Trial. Diabetes Care 2011;34:1683–1688 Health Study II, subsequent diabetes risk 2. Dabelea D, Hanson RL, Lindsay RS, et al. Intra- POSTPARTUM CARE after a history of GDM was significantly uterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant Postpartum care should include psy- lower in women who followed healthy sibships. Diabetes 2000;49:2208–2211 chosocial assessment and support for eating patterns (62). Adjusting for BMI 3. Guerin A, Nisenbaum R, Ray JG. Use of mater- self-care. moderately, but not completely, attenua- nal GHb concentration to estimate the risk of con- ted this association. Interpregnancy or post- genital anomalies in the offspring of women with Lactation partum weight gain is associated with prepregnancy diabetes. Diabetes Care 2007;30: 1920–1925 In light of the immediate nutritional and increased risk of adverse pregnancy out- 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- immunological benefits of breastfeeding comes in subsequent pregnancies (63) and conceptional A1C and risk of serious adverse preg- for the baby, all women including those earlier progression to type 2 diabetes. nancy outcome in 933 women with type 1 diabetes. with diabetes should be supported in at- Both metformin and intensive lifestyle Diabetes Care 2009;32:1046–1048 5. Charron-Prochownik D, Sereika SM, Becker D, tempts to breastfeed. Breastfeeding may intervention prevent or delay progression et al. Long-term effects of the booster-enhanced also confer longer-term metabolic benefits to diabetes in women with prediabetes READY-Girls preconception counseling program to both mother (58) and offspring (59). and a history of GDM. Of women with a on intentions and behaviors for family planning S142 Management of Diabetes in Pregnancy Diabetes Care Volume 41, Supplement 1, January 2018

in teens with diabetes. Diabetes Care 2013;36: by lifestyle intervention: the Finnish Gestational 37. Balsells M, Garc´ıa-Patterson A, SolaI,Roqu` e´ 3870–3874 Diabetes Prevention Study (RADIEL): a random- M, Gich I, Corcoy R. Glibenclamide, metformin, 6. Peterson C, Grosse SD, Li R, et al. Preventable ized controlled trial. Diabetes Care 2015 and insulin for the treatment of gestational dia- health and cost burden of adverse birth outcomes 23. Wang C, Wei Y, Zhang X, et al. A randomized betes: a systematic review and meta-analysis. associated with pregestational diabetes in the clinical trial of exercise during pregnancy to pre- BMJ 2015;350:h102 United States. Am J Obstet Gynecol 2015;212: vent gestational diabetes mellitus and improve 38. Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu 74.e1–74.e9 pregnancy outcome in overweight and obese Z-N, Su S-W. Comparative efficacy and safety of 7. Charron-Prochownik D, Downs J. Diabetes and pregnant women. Am J Obstet Gynecol 2017; OADs in management of GDM: network meta- Reproductive Health for Girls. Alexandria, VA, 216:340–351 analysis of randomized controlled trials. J Clin En- American Diabetes Association, 2016 24. Metzger BE, Buchanan TA, Coustan DR, et al. docrinol Metab 2015;100:2071–2080 8. Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Summary and recommendations of the Fifth Interna- 39. Camelo Castillo W, Boggess K, Sturmer¨ T, Simonetti GD. Pregnancy outcome following expo- tional Workshop-Conference on Gestational Diabetes Brookhart MA, Benjamin DK Jr, Jonsson Funk M. sure to angiotensin-converting enzyme inhibitors Mellitus. Diabetes Care 2007;30(Suppl. 2):S251– Association of adverse pregnancy outcomes or angiotensin receptor antagonists: a systematic S260 with glyburide vs insulin in women with ges- review. Hypertension 2012;60:444–450 25. Mayo K, Melamed N, Vandenberghe H, tational diabetes. JAMA Pediatr 2015;169:452– 9. Taguchi N, Rubin ET, Hosokawa A, et al. Pre- Berger H. The impact of adoption of the Interna- 458 natal exposure to HMG-CoA reductase inhibitors: tional Association of Diabetes in Pregnancy Study 40. Vanky E, Zahlsen K, Spigset O, Carlsen SM. effects on fetal and neonatal outcomes. Reprod Group criteria for the screening and diagnosis of Placental passage of metformin in women with Toxicol 2008;26:175–177 gestational diabetes. Am J Obstet Gynecol 2015; polycystic ovary syndrome. Fertil Steril 2005;83: 10. Bateman BT, Hernandez-Diaz S, Fischer MA, 212:224.e1–224.e9 1575–1578 et al. Statins and congenital malformations: co- 26. Mendez-Figueroa H, Schuster M, Maggio L, 41. Charles B, Norris R, Xiao X, Hague W. Popula- hort study. BMJ 2015;350:h1035 Pedroza C, Chauhan SP, Paglia MJ. Gestational dition pharmacokinetics of metformin in late preg- 11. Manderson JG, Patterson CC, Hadden DR, abetes mellitus and frequency of blood glucose nancy. Ther Drug Monit 2006;28:67–72 Traub AI, Ennis C, McCance DR. Preprandial versus monitoring: a randomized controlled trial. Obstet 42. Vanky E, Stridsklev S, Heimstad R, et al. Met- postprandial blood glucose monitoring in type 1 Gynecol 2017;130:163–170 formin versus placebo from first trimester to diabetic pregnancy: a randomized controlled clin- 27. Han S, Crowther CA, Middleton P, Heatley E. delivery in polycystic ovary syndrome: a random- ical trial. Am J Obstet Gynecol 2003;189:507–512 Different types of dietary advice for women with ized, controlled multicenter study. J Clin Endocri- 12. de Veciana M, Major CA, Morgan MA, et al. gestational diabetes mellitus. Cochrane Database nol Metab 2010;95:E448–E455 Postprandial versus preprandial blood glucose Syst Rev 2013;3:CD009275 43. Legro RS, Barnhart HX, Schlaff WD, et al.; Co- monitoring in women with gestational diabetes 28. Viana LV, Gross JL, Azevedo MJ. Dietary in- operative Multicenter Reproductive Medicine mellitus requiring insulin therapy. N Engl J Med tervention in patients with gestational diabetes Network. Clomiphene, metformin, or both for in- 1995;333:1237–1241 mellitus: a systematic review and meta-analysis fertility in the polycystic ovary syndrome. N Engl J 13. Jovanovic-Peterson L, Peterson CM, Reed GF, of randomized clinical trials on maternal and new- Med 2007;356:551–566 et al. Maternal postprandial glucose levels and born outcomes. Diabetes Care 2014;37:3345– 44. Palomba S, Orio F Jr, Falbo A, et al. Prospec- infant birth weight: the Diabetes in Early Pregnancy 3355 tive parallel randomized, double-blind, double- Study. The National Institute of Child Health and 29. Hartling L, Dryden DM, Guthrie A, Muise M, dummy controlled clinical trial comparing clomiphene Human Development–Diabetes in Early Pregnancy Vandermeer B, Donovan L. Benefits and harms of citrate and metformin as the first-line treatment for Study. Am J Obstet Gynecol 1991;164:103–111 treating gestational diabetes mellitus: a system- ovulation induction in nonobese anovulatory 14. Committee on Practice Bulletins–Obstetrics. atic review and meta-analysis for the U.S. Preven- women with polycystic ovary syndrome. J Clin En- Practice Bulletin No. 137: Gestational diabetes tive Services Task Force and the National docrinol Metab 2005;90:4068–4074 mellitus. Obstet Gynecol 2013;122:406–416 Institutes of Health Office of Medical Applications 45. Palomba S, Orio F Jr, Nardo LG, et al. Metfor- 15. Nielsen GL, Møller M, Sørensen HT. HbA1c in of Research. Ann Intern Med 2013;159:123–129 min administration versus laparoscopic ovarian early diabetic pregnancy and pregnancy out- 30. Rowan JA, Hague WM, Gao W, Battin MR, diathermy in clomiphene citrate-resistant women comes: a Danish population-based cohort study Moore MP; MiG Trial Investigators. Metformin with polycystic ovary syndrome: a prospective of 573 pregnancies in women with type 1 diabe- versus insulin for the treatment of gestational di- parallel randomized double-blind placebo- tes. Diabetes Care 2006;29:2612–2616 abetes. N Engl J Med 2008;358:2003–2015 controlled trial. J Clin Endocrinol Metab 2004; 16. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic 31. Gui J, Liu Q, Feng L. Metformin vs insulin in 89:4801–4809 control during early pregnancy and fetal malfor- the management of gestational diabetes: a meta- 46. Farrar D, Tuffnell DJ, West J, West HM. Con- mations in women with type I diabetes mellitus. analysis. PLoS One 2013;8:e64585 tinuous subcutaneous insulin infusion versus Diabetologia 2000;43:79–82 32. Langer O, Conway DL, Berkus MD, Xenakis multiple daily injections of insulin for pregnant 17. Maresh MJA, Holmes VA, Patterson CC, et al.; EM-J, Gonzales O. A comparison of glyburide women with diabetes. Cochrane Database Syst Diabetes and Pre-eclampsia Intervention Trial and insulin in women with gestational diabetes Rev 2016;6:CD005542 Study Group. Glycemic targets in the second and mellitus. N Engl J Med 2000;343:1134–1138 47. Duckitt K, Harrington D. Risk factors for pre- third trimester of pregnancy for women with 33. Brown J, Martis R, Hughes B, Rowan J, eclampsia at antenatal booking: systematic re- type 1 diabetes. Diabetes Care 2015;38:34–42 Crowther CA. Oral anti-diabetic pharmacological view of controlled studies. BMJ 2005;330:565 18. Nielsen LR, Ekbom P, Damm P, et al. HbA1c therapies for the treatment of women with ges- 48. Henderson JT, Whitlock EP, O’Conner E, levels are significantly lower in early and late preg- tational diabetes. Cochrane Database Syst Rev Senger CA, Thompson JH, Rowland MG. Low- nancy. Diabetes Care 2004;27:1200–1201 2017;1:CD011967 dose aspirin for the prevention of morbidity and 19. Mosca A, Paleari R, Dalfra` MG, et al. Refer- 34. Nachum Z, Zafran N, Salim R, et al. Glyburide mortality from preeclampsia: a systematic evi- ence intervals for hemoglobin A1c in pregnant versus metformin and their combination for the dence review for the U.S. Preventive Services women: data from an Italian multicenter study. treatment of gestational diabetes mellitus: a ran- Task Force [article online], 2014. Rockville, MD: Clin Chem 2006;52:1138–1143 domized controlled study. Diabetes Care 2017;40: Agency for Healthcare Research and Quality. 20. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO 332–337 Available from http://www.ncbi.nlm.nih.gov/ Study Cooperative Research Group. Hyperglyce- 35. Coustan DR. Pharmacological management books/NBK196392/. Accessed 25 September mia and adverse pregnancy outcomes. N Engl J of gestational diabetes: an overview. Diabetes 2017 Med 2008;358:1991–2002 Care 2007;30(Suppl. 2):S206–S208 49. Werner EF, Hauspurg AK, Rouse DJ. A cost- 21. Bain E, Crane M, Tieu J, Han S, Crowther CA, 36. Hebert MF, Ma X, Naraharisetti SB, et al.; benefit analysis of low-dose aspirin prophylaxis Middleton P. Diet and exercise interventions for Obstetric-Fetal Pharmacology Research Unit Net- for the prevention of preeclampsia in the preventing gestational diabetes mellitus. Co- work. Are we optimizing gestational diabetes United States. Obstet Gynecol 2015;126:1242– chrane Database Syst Rev 2015;4:CD010443 treatment with glyburide? The pharmacologic ba- 1250 22. Koivusalo SB, Ron¨ o¨ K, Klemetti MM, et al. sis for better clinical practice. Clin Pharmacol Ther 50. Chew EY, Mills JL, Metzger BE, et al. Meta- Gestational diabetes mellitus can be prevented 2009;85:607–614 bolic control and progression of retinopathy: The care.diabetesjournals.org Management of Diabetes in Pregnancy S143

Diabetes in Early Pregnancy Study. Diabetes Care 56. Sibai BM. Treatment of hypertension in 62. Tobias DK, Hu FB, Chavarro J, Rosner B, 1995;18:631–637 pregnant women. N Engl J Med 1996;335:257–265 Mozaffarian D, Zhang C. Healthful dietary patterns 51. Institute of Medicine and National Research 57. Kazmin A, Garcia-Bournissen F, Koren G. Risks and type 2 diabetes mellitus risk among women Council. Weight Gain during Pregnancy: Reex- of statin use during pregnancy: a systematic with a history of gestational diabetes mellitus. amining the Guidelines. Washington, DC, The Na- review. J Obstet Gynaecol Can 2007;29:906– Arch Intern Med 2012;172:1566–1572 tional Academies Press, 2009 908 63. Villamor E, Cnattingius S. Interpregnancy 52. Clausen TD, Mathiesen E, Ekbom P, Hellmuth 58. Stuebe AM, Rich-Edwards JW, Willett WC, weight change and risk of adverse pregnancy out- E, Mandrup-Poulsen T, Damm P. Poor pregnancy Manson JE, Michels KB. Duration of lactation comes: a population-based study. Lancet 2006; outcome in women with type 2 diabetes. Diabetes and incidence of type 2 diabetes. JAMA 2005; 368:1164–1170 Care 2005;28:323–328 294:2601–2610 64. Ratner RE, Christophi CA, Metzger BE, et al.; 53. Cundy T, Gamble G, Neale L, et al. Differing 59. PereiraPF, Alfenas R de CG, Araujo´ RMA. Does Diabetes Prevention Program Research Group. causes of pregnancy loss in type 1 and type 2 di- breastfeeding inﬂuence the risk of developing di- Prevention of diabetes in women with a history abetes. Diabetes Care 2007;30:2603–2607 abetes mellitus in children? A review of current of gestational diabetes: effects of metformin and 54. American College of Obstetricians and Gyne- evidence. J Pediatr (Rio J) 2014;90:7–15 lifestyle interventions. J Clin Endocrinol Metab cologists; Task Force on Hypertension in Preg- 60. Kim C, Newton KM, Knopp RH. Gestational 2008;93:4774–4779 nancy. Hypertension in pregnancy. Report of the diabetes and the incidence of type 2 diabetes: a 65. Aroda VR, Christophi CA, Edelstein SL, et al.; American College of Obstetricians and Gynecolo- systematic review. Diabetes Care 2002;25:1862– Diabetes Prevention Program Research Group. gists’ Task Force on Hypertension in Pregnancy. 1868 The effect of lifestyle intervention and metformin Obstet Gynecol 2013;122:1122–1131 61. Sutherland HW, Stowers JM, Pearson DWM on preventing or delaying diabetes among women 55. Magee LA, von Dadelszen P, Rey E, et al. Less- (Eds.). Carbohydrate Metabolism in Pregnancy with and without gestational diabetes: the Diabetes tight versus tight control of hypertension in preg- and the Newborn IV. Edinburgh, Churchill Living- Prevention Program Outcomes Study 10-year follow- nancy. N Engl J Med 2015;372:407–417 stone, 1984 up. J Clin Endocrinol Metab 2015;100:1646–1653 S144 Diabetes Care Volume 41, Supplement 1, January 2018

14. Diabetes Care in the Hospital: American Diabetes Association Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S144–S151 | https://doi.org/10.2337/dc18-S014

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 short- est 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

Recommendation c Peform an A1C on all patients with diabetes or hyperglycemia (blood glucose .140 mg/dL) admitted to the hospital if not performed in the prior 3months.B

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 established protocols for structured patient care and structured order sets, which include computerized physician order entry (CPOE). Suggested citation: American Diabetes As- Considerations on Admission sociation. 14. Diabetes care in the hospital: Initial orders should state the type of diabetes (i.e., type 1 or type 2 diabetes) or no previous Standards of Medical Care in Diabetesd2018. history of diabetes. Because inpatient insulin use (5) and discharge orders (6) can be more Diabetes Care 2018;41(Suppl. 1):S144–S151 effective if based on an A1C level on admission (7), perform an A1C test on all patients © 2017 by the American Diabetes Association. with diabetes or hyperglycemia admitted to the hospital if the test has not been Readers may use this article as long as the work is properly cited, the use is educational and not performed in the prior 3 months. In addition, diabetes self-management knowledge for proﬁt, and the work is not altered. More infor- and behaviors should be assessed on admission and diabetes self-management edu- mation is available at http://www.diabetesjournals cation (DSME) should be provided, if appropriate. DSME should include appropriate .org/content/license. care.diabetesjournals.org Diabetes Care in the Hospital S145

skills needed after discharge, such as tak- therapy is started, a target glucose range hyperglycemia starting at a threshold ing antihyperglycemic medications, mon- of 140–180 mg/dL (7.8–10.0 mmol/L) is $180 mg/dL (10.0 mmol/L). Once itoring glucose, and recognizing and recommended for the majority of critically insulin therapy is started, a target treating hypoglycemia (2). ill and noncritically ill patients (2). More glucose range of 140–180 mg/dL stringent goals, such as ,140 mg/dL Physician Order Entry (7.8–10.0 mmol/L) is recommended (7.8 mmol/L), may be appropriate for se- for the majority of critically ill pa- Recommendation lected patients, as long as this can be tients and noncritically ill patients. A c Insulin should be administered using achieved without significant hypoglyce- c More stringent goals, such as 110– validated written or computerized mia. Conversely, higher glucose ranges 140 mg/dL (6.1–7.8 mmol/L), may protocols that allow for predefined may be acceptable in terminally ill pa- be appropriate for selected pa- adjustments in the insulin dosage tients, in patients with severe comorbid- tients, if this can be achieved with- basedonglycemicfluctuations. E ities, and in inpatient care settings where out significant hypoglycemia. C frequentglucosemonitoringorclosenurs- The National Academy of Medicine rec- ing supervision is not feasible. Standard Definition of Glucose ommends CPOE to prevent medication- Clinical judgment combined with on- Abnormalities related errors and to increase efficiency going assessment of the patient’s clinical Hyperglycemia in hospitalized patients is de- in medication administration (8). A Co- status, including changes in the trajectory fined as blood glucose levels .140 mg/dL chrane review of randomized controlled of glucose measures, illness severity, nu- (7.8 mmol/L) (2,16). Blood glucose levels trials using computerized advice to im- tritional status, or concomitant medica- that are persistently above this level prove glucose control in the hospital tions that might affect glucose levels may require alterations in diet or a change found significant improvement in the per- (e.g., glucocorticoids), should be incorpo- in medications that cause hypergly- centage of time patients spent in the rated into the day-to-day decisions re- cemia. An admission A1C value $6.5% target glucose range, lower mean blood garding insulin doses (2). glucose levels, and no increase in hypo- (48 mmol/mol) suggests that diabetes glycemia (9). Thus, where feasible, there preceded hospitalization (see Section BEDSIDE BLOOD GLUCOSE should be structured order sets that 2 “Classification and Diagnosis of Diabe- MONITORING provide computerized advice for glucose tes”) (2,16). The hypoglycemia alert value control. Electronic insulin order templates in hospitalized patients is defined as Indications also improve mean glucose levels without blood glucose #70 mg/dL (3.9 mmol/L) In the patient who is eating meals, glu- increasing hypoglycemia in patients with (17) and clinically significant hypoglyce- cose monitoring should be performed type 2 diabetes, so structured insulin or- mia as glucose values ,54 mg/dL (3.0 before meals. In the patient who is not der sets should be incorporated into the mmol/L). Severe hypoglycemia is defined eating, glucose monitoring is advised ev- CPOE (10). as that associated with severe cognitive ery 4–6 h (2). More frequent blood glu- impairment regardless of blood glucose cose testing ranging from every 30 min to Diabetes Care Providers in the Hospital level (17). every 2 h is required for patients receiving intravenous insulin. Safety standards Appropriately trained specialists or spe- Moderate Versus Tight Glycemic should be established for blood glucose cialty teams may reduce length of stay, Control monitoring that prohibit the sharing of improve glycemic control, and improve A meta-analysis of over 26 studies, includ- fingerstick lancing devices, lancets, and outcomes, but studies are few (11,12). A ing the Normoglycemia in Intensive Care needles (21). call to action outlined the studies needed Evaluation–Survival Using Glucose Algo- to evaluate these outcomes (13). Details rithm Regulation (NICE-SUGAR) study, Point-of-Care Meters of team formation are available from the showed increased rates of severe hypo- Point-of-care (POC) meters have limitations Society of Hospital Medicine and the Joint glycemia (defined in the analysis as blood for measuring blood glucose. Although the Commission standards for programs. glucose ,40 mg/dL [2.2 mmol/L]) and U.S. Food and Drug Administration (FDA) Quality Assurance Standards mortality in tightly versus moderately has standards for blood glucose meters Even the best orders may not be carried controlled cohorts (18). Recent random- used by lay persons, there have been ques- out in a way that improves quality, nor are ized controlled studies and meta-analyses tions about the appropriateness of these they automatically updated when new ev- in surgical patients have also reported criteria, especially in the hospital and for fi idence arises. To this end, the Joint Com- that targeting moderate perioperative lower blood glucose readings (22). Signi - , mission has an accreditation program for blood glucose levels to 180 mg/dL (10 cant discrepancies between capillary, ve- the hospital care of diabetes (14), and the mmol/L) is associated with lower rates nous, and arterial plasma samples have Society of Hospital Medicine has a work- of mortality and stroke compared with been observed in patients with low or . book for program development (15). a liberal target glucose 200 mg/dL high hemoglobin concentrations and (11.1 mmol/L), whereas no significant ad- with hypoperfusion. Any glucose result GLYCEMIC TARGETS ditional benefitwasfoundwithmore that does not correlate with the pa- IN HOSPITALIZED PATIENTS strict glycemic control (,140 mg/dl [7.8 tient’s clinical status should be confirmed mmol/L]) (19,20). Insulin therapy should through conventional laboratory glucose Recommendations be initiated for treatment of persistent tests. The FDA established a separate cat- c Insulin therapy should be initi- hyperglycemia starting at a threshold egory for POC glucose meters for use in ated for treatment of persistent $180 mg/dL (10.0 mmol/L). Once insulin health care settings and has released S146 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018

guidance on in-hospital use with stricter shown to be the best method for achiev- Type 1 Diabetes standards (23). Before choosing a device ing glycemic targets. Intravenous insulin For patients with type 1 diabetes, dosing for in-hospital use, consider the device’s infusions should be administered based insulin based solely on premeal glucose approval status and accuracy. on validated written or computerized levels does not account for basal insulin protocols that allow for predefined ad- requirements or caloric intake, increasing Continuous Glucose Monitoring justments in the infusion rate, account- both hypoglycemia and hyperglycemia Continuous glucose monitoring (CGM) ing for glycemic fluctuations and insulin risks and potentially leading to diabetic provides frequent measurements of in- dose (2). ketoacidosis (DKA). Typically, basal insulin terstitial glucose levels, as well as direc- dosing schemes are based on body tion and magnitude of glucose trends, Noncritical Care Setting weight, with some evidence that patients which may have an advantage over Outside of critical care units, scheduled with renal insufficiency should be treat- POC glucose testing in detecting and re- insulin regimens are recommended to ed with lower doses (34). An insulin ducing the incidence of hypoglycemia manage hyperglycemia in patients regimen with basal and correction com- (24). Several inpatient studies have with diabetes. Regimens using insulin ponents is necessary for all hospitalized shown that CGM use did not improve glu- analogs and human insulin result in sim- patients with type 1 diabetes, with the cose control but detected a greater num- ilar glycemic control in the hospital set- addition of nutritional insulin if the pa- ber of hypoglycemic events than POC ting (30). tient is eating. testing (25). However, a recent review The use of subcutaneous rapid- or has recommended against using CGM short-acting insulin before meals or ev- Transitioning Intravenous to Subcutaneous Insulin in adults in a hospital setting until ery 4–6 h if no meals are given or if the When discontinuing intravenous insulin, more safety and efficacy data become patient is receiving continuous enteral/ a transition protocol is associated with available (25). parenteral nutrition is indicated to correct less morbidity and lower costs of care hyperglycemia (2). Basal insulin or a basal ANTIHYPERGLYCEMIC AGENTS (35) and is therefore recommended. A pa- plus bolus correction insulin regimen is IN HOSPITALIZED PATIENTS tient with type 1 or type 2 diabetes being the preferred treatment for noncritically transitioned to outpatient subcutane- Recommendations ill patients with poor oral intake or those ous insulin should receive subcutaneous c A basal plus bolus correction insulin who are taking nothing by mouth (NPO). basal insulin 2–4 h before the intravenous regimen, with the addition of nutri- An insulin regimen with basal, nutritional, insulin is discontinued. Converting to tional insulin in patients who have and correction components is the pre- basal insulin at 60–80% of the daily infusion good nutritional intake, is the preferred treatment for noncritically ill hos- dose has been shown to be effective ferred treatment for noncritically ill pitalized patients with good nutritional (2,35,36). For patients continuing regi- patients. A intake. mens with concentrated insulin in the in- c Sole use of sliding scale insulin in If the patient is eating, insulin injec- patient setting, it is important to ensure the inpatient hospital setting is tions should align with meals. In such in- the correct dosing by utilizing an individ- strongly discouraged. A stances, POC glucose testing should be ual pen and cartridge for each patient, performed immediately before meals. If meticulous pharmacist supervision of In most instances in the hospital setting, oral intake is poor, a safer procedure is to the dose administered, or other means insulin is the preferred treatment for glyce- administer the rapid-acting insulin imme- (37,38). mic control (2). However, in certain circum- diately after the patient eats or to count stances, it may be appropriate to continue the carbohydrates and cover the amount Noninsulin Therapies home regimens including oral antihyper- ingested (30). Thesafetyandefficacy of noninsulin anti- glycemic medications (26). If oral medica- Arandomizedcontrolledtrialhas hyperglycemic therapies in the hospital tions are held in the hospital, there should shown that basal-bolus treatment im- setting is an area of active research. A be a protocol for resuming them 1– proved glycemic control and reduced hos- few recent randomized pilot trials in gen- 2 days before discharge. Insulin pens pital complications compared with sliding eral medicine and surgery patients re- are the subject of an FDA warning be- scale insulin in general surgery patients ported that a dipeptidyl peptidase 4 cause of potential blood-borne diseases, with type 2 diabetes (31). Prolonged inhibitor alone or in combination with and care should be taken to follow the sole use of sliding scale insulin in the in- basal insulin was well tolerated and re- label insert “For single patient use only.” patient hospital setting is strongly dis- sulted in similar glucose control and fre- Recent reports, however, have indicated couraged (2,13). quency of hypoglycemia compared with a that the inpatient use of insulin pens ap- While there is evidence for using pre- basal-bolus regimen (39–41). However, a pears to be safe and may be associated mixed insulin formulations in the outpa- recent FDA bulletin states that providers with improved nurse satisfaction com- tient setting (32), a recent inpatient study should consider discontinuing saxagliptin pared with the use of insulin vials and of 70/30 NPH/regular insulin versus and alogliptin in people who develop syringes (27–29). basal-bolus therapy showed comparable heart failure (42). A review of antihyperglycemic control but significantly in- glycemic medications concluded that Insulin Therapy creased hypoglycemia in the group re- glucagon-like peptide 1 receptor agonists Critical Care Setting ceiving premixed insulin (33). Therefore, show promise in the inpatient setting In the critical care setting, continuous premixed insulin regimens are not rou- (43); however, proof of safety and effi- intravenous insulin infusion has been tinely recommended for in-hospital use. cacy awaits the results of randomized care.diabetesjournals.org Diabetes Care in the Hospital S147

controlled trials (44). Moreover, the gas- treating hypoglycemia for each patient. MEDICAL NUTRITION THERAPY trointestinal symptoms associated with An American Diabetes Association (ADA) IN THE HOSPITAL the glucagon-like peptide 1 receptor ago- consensus report suggested that a pa- The goals of medical nutrition therapy in nists may be problematic in the inpatient tient’s overall treatment regimen be re- the hospital are to provide adequate cal- setting. viewed when a blood glucose value ories to meet metabolic demands, opti- Regarding the sodium–glucose trans- of #70 mg/dL (3.9 mmol/L) is identified mize glycemic control, address personal porter 2 (SGLT2) inhibitors, the FDA because such readings often predict im- food preferences, and facilitate creation includes warnings about DKA and uro- minent severe hypoglycemia (2). of a discharge plan. The ADA does not sepsis (45), urinary tract infections, and Episodes of hypoglycemia in the hospi- endorse any single meal plan or specified kidney injury (46) on the drug labels. A tal should be documented in the medical percentages of macronutrients. Current recent review suggested SGLT2 inhibi- record and tracked (2). nutrition recommendations advise indi- tors be avoided in severe illness, when vidualization based on treatment goals, ketone bodies are present, and during Triggering Events physiological parameters, and medication prolonged fasting and surgical proce- Iatrogenic hypoglycemia triggers may in- use. Consistent carbohydrate meal plans dures (3). Until safety and effectiveness clude sudden reduction of corticosteroid are preferred by many hospitals as they are established, SGLT2 inhibitors cannot dose, reduced oral intake, emesis, new facilitate matching the prandial insulin be recommended for routine in-hospital NPO status, inappropriate timing of short- dose to the amount of carbohydrate con- use. acting insulin in relation to meals, reduced sumed (51). Regarding enteral nutritional infusion rate of intravenous dextrose, un- fi HYPOGLYCEMIA therapy, diabetes-speci c formulas ap- expected interruption of oral, enteral, or pear to be superior to standard formulas Recommendations parenteral feedings, and altered ability of in controlling postprandial glucose, A1C, c A hypoglycemia management pro- the patient to report symptoms (3). and the insulin response (52). tocol should be adopted and imple- Predictors of Hypoglycemia When the nutritional issues in the hos- mented by each hospital or hospital In one study, 84% of patients with an ep- pital are complex, a registered dietitian, system. A plan for preventing and isode of severe hypoglycemia (,40 mg/dL knowledgeable and skilled in medical nu- treating hypoglycemia should be [2.2 mmol/L]) had a prior episode of hy- trition therapy, can serve as an individual established for each patient. Epi- poglycemia (,70 mg/dL [3.9 mmol/L]) inpatient team member. That person sodes of hypoglycemia in the hospi- during the same admission (47). In an- should be responsible for integrating in- ’ tal should be documented in the other study of hypoglycemic episodes formation about the patient s clinical con- E medical record and tracked. (,50 mg/dL [2.8 mmol/L]), 78% of pa- dition, meal planning, and lifestyle habits c The treatment regimen should be tients were using basal insulin, with the and for establishing realistic treatment reviewed and changed as neces- incidence of hypoglycemia peaking be- goals after discharge. Orders should also sary to prevent further hypoglyce- indicate that the meal delivery and nutri- tween midnight and 6 A.M. Despite recog- mia when a blood glucose value is nition of hypoglycemia, 75% of patients tional insulin coverage should be coordi- # C 70 mg/dL (3.9 mmol/L). did not have their dose of basal insulin nated, as their variability often creates changed before the next insulin adminis- the possibility of hyperglycemic and hy- Patients with or without diabetes may ex- tration (48). poglycemic events. perience hypoglycemia in the hospital setting. While hypoglycemia is associated Prevention SELF-MANAGEMENT IN THE with increased mortality, hypoglycemia Common preventable sources of iatro- HOSPITAL may be a marker of underlying disease genic hypoglycemia are improper pre- Diabetes self-management in the hospital rather than the cause of increased mor- scribing of hypoglycemic medications, may be appropriate for select youth and tality. However, until it is proven not to be inappropriate management of the first adult patients (53,54). Candidates include causal, it is prudent to avoid hypoglyce- episode of hypoglycemia, and nutrition– patients who successfully conduct self- mia. Despite the preventable nature of insulin mismatch, often related to an management of diabetes at home, have many inpatient episodes of hypoglyce- unexpected interruption of nutrition. Stud- the cognitive and physical skills needed to mia, institutions are more likely to have ies of “bundled” preventative therapies successfully self-administer insulin, and nursing protocols for hypoglycemia treat- including proactive surveillance of gly- perform self-monitoring of blood glucose. ment than for its prevention when both cemic outliers and an interdisciplinary In addition, they should have adequate are needed. data-driven approach to glycemic man- oral intake, be proficient in carbohydrate A hypoglycemia prevention and management showed that hypoglycemic epi- estimation, use multiple daily insulin in- agement protocol should be adopted and sodes in the hospital could be prevented. jections or continuous subcutaneous in- implemented by each hospital or hospital Compared with baseline, two such stud- sulin infusion (CSII) pump therapy, have system. There should be a standardized ies found that hypoglycemic events fell stable insulin requirements, and un- hospital-wide, nurse-initiated hypogly- by 56% to 80% (49,50). The Joint Commis- derstand sick-day management. If self- cemia treatment protocol to immedi- sion recommends that all hypoglycemic management is to be used, a protocol should ately address blood glucose levels of episodes be evaluated for a root cause include a requirement that the patient, #70 mg/dL (3.9 mmol/L), as well as in- and the episodes be aggregated and re- nursing staff, and physician agree that pa- dividualized plans for preventing and viewed to address systemic issues. tient self-management is appropriate. If S148 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018

CSII is to be used, hospital policy and pro- Correctional insulin coverage should be mg/dL (4.4–10.0 mmol/L). cedures delineating guidelines for CSII added as needed before each feeding. 2. Perform a preoperative risk assessment therapy, including the changing of infu- For patients receiving continuous periph- for patients at high risk for ischemic sion sites, are advised (55). eral or central parenteral nutrition, regu- heart disease and those with autono- STANDARDS FOR SPECIAL lar insulin may be added to the solution, mic neuropathy or renal failure. . SITUATIONS particularly if 20 units of correctional 3. Withhold metformin the day of surgery. insulin have been required in the past 4. Withhold any other oral hypoglycemic Enteral/Parenteral Feedings 24 h. A starting dose of 1 unit of human agents the morning of surgery or pro- For patients receiving enteral or paren- regular insulin for every 10 g dextrose has cedure and give half of NPH dose or teral feedings who require insulin, insulin been recommended (57), to be adjusted 60–80% doses of a long-acting analog should be divided into basal, nutritional, daily in the solution. Correctional insulin or pump basal insulin. and correctional components. This is par- should be administered subcutaneously. 5. Monitor blood glucose at least every ticularly important for people with type 1 For full enteral/parenteral feeding guid- 4–6 h while NPO and dose with short- diabetes to ensure that they continue to ance, the reader is encouraged to consult acting insulin as needed. receive basal insulin even if the feedings review articles (2,58) and see Table 14.1. are discontinued. One may use the pa- A review found that perioperative gly- tient’s preadmission basal insulin dose Glucocorticoid Therapy cemic control tighter than 80–180 mg/dL or a percentage of the total daily dose Glucocorticoid type and duration of action (4.4–10.0 mmol/L) did not improve out- of insulin when the patient is being fed must be considered in determining insulin comes and was associated with more hy- (usually 30 to 50% of the total daily dose treatment regimens. Once-a-day, short- poglycemia (62); therefore, in general, of insulin) to estimate basal insulin re- acting glucocorticoids such as prednisone tighter glycemic targets are not advised. quirements. However, if no basal insulin peak in about 4 to 8 h (59), so cover- A recent study reported that, compared was used, consider using 5 units of NPH/ age with intermediate-acting (NPH) insulin with the usual insulin dose, on average a detemir insulin subcutaneously every may be sufﬁcient. For long-acting gluco- ;25% reduction in the insulin dose given 12 h or 10 units of insulin glargine every corticoids such as dexamethasoneor mul- the evening before surgery was more 24 h (56). For patients receiving continu- tidose or continuous glucocorticoid use, likely to achieve perioperative blood glu- ous tube feedings, the total daily nutri- long-acting insulin may be used (26,58). cose levels in the target range with de- tional component may be calculated as For higher doses of glucocorticoids, increased risk for hypoglycemia (63). 1 unit of insulin for every 10–15 g carbo- creasing doses of prandial and supplemen- In noncardiac general surgery pa- hydrate per day or as a percentage of the tal insulin may be needed in addition to tients, basal insulin plus premeal regular total daily dose of insulin when the pa- basal insulin (60). Whatever orders are or short-acting insulin (basal-bolus) cov- tient is being fed (usually 50 to 70% of started, adjustments based on antici- erage has been associated with improved the total daily dose of insulin). Correc- pated changes in glucocorticoid dosing glycemic control and lower rates of peri- tional insulin should also be administered and POC glucose test results are critical. operative complications compared with subcutaneously every 6 h using human the traditional sliding scale regimen (reg- Perioperative Care regular insulin or every 4 h using a rapid- ular or short-acting insulin coverage only Many standards for perioperative care acting insulin such as lispro, aspart, or gluli- with no basal dosing) (31,64). sine. For patients receiving enteral bolus lack a robust evidence base. However, feedings, approximately 1 unit of regu- the following approach (61) may be con- Diabetic Ketoacidosis and lar human insulin or rapid-acting insulin sidered: Hyperosmolar Hyperglycemic State should be given per 10–15 g carbohydrate 1. Target glucose range for the peri- There is considerable variability in the subcutaneously before each feeding. operative period should be 80–180 presentation of DKA and hyperosmolar

Table 14.1—Insulin dosing for enteral/parenteral feedings Situation Basal/nutritional Correctional Continuous enteral feedings Continue prior basal or, if none, calculate from TDD or SQ regular insulin every 6 h or rapid-acting insulin consider 5 units NPH/detemir every 12 h or 10 units every 4 h for hyperglycemia glargine/degludec 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 Continue prior basal or, if none, calculate from TDD or SQ regular insulin every 6 h or rapid-acting insulin consider 5 units NPH/detemir every 12 h or 10 units every 4 h for hyperglycemia glargine/degludec daily Nutritional: give regular insulin or rapid-acting insulin SQ before each feeding, starting with 1 unit per 10–15 g of carbohydrate; adjust daily Parenteral feedings Add regular insulin to TPN IV solution, starting with 1 unit SQ regular insulin every 6 h or rapid-acting insulin per 10 g of carbohydrate; adjust daily every 4 h for hyperglycemia IV, intravenous; SQ, subcutaneous; TDD, total daily dose; TPN, total parenteral nutrition. care.diabetesjournals.org Diabetes Care in the Hospital S149

hyperglycemic state, ranging from eugly- be discharged to varied settings, including + Discharge summaries should be trans cemia or mild hyperglycemia and acidosis home (with or without visiting nurse ser- mitted to the primary physician as soon to severe hyperglycemia, dehydration, vices), assisted living, rehabilitation, or as possible after discharge. and coma; therefore, treatment individu- skilled nursing facilities. For the patient + Appointment-keeping behavior is en- alization based on a careful clinical and whoisdischargedtohomeortoassistedliv- hanced when the inpatient team sched- laboratory assessment is needed (65). ing, the optimal program will need to con- ules outpatient medical follow-up prior Management goals include restoration sider diabetes type and severity, effects of to discharge. of circulatory volume and tissue perfu- the patient’s illness on blood glucose levels, sion, resolution of hyperglycemia, and and the patient’scapacitiesanddesires. It is recommended that the following correction of electrolyte imbalance and An outpatient follow-up visit with the areas of knowledge be reviewed and ad- ketosis. It is also important to treat any primary care provider, endocrinologist, or dressed prior to hospital discharge: correctable underlying cause of DKA such diabetes educator within 1 month of dis- as sepsis. charge is advised for all patients having + Identificationofthehealthcarepro- In critically ill and mentally obtunded hyperglycemia in the hospital. If glycemic vider who will provide diabetes care patients with DKA or hyperosmolar hy- medications are changed or glucose con- after discharge. perglycemic state, continuous intra- trol is not optimal at discharge, an earlier + Level of understanding related to the venous insulin is the standard of care. appointment (in 1–2weeks)ispreferred, diabetes diagnosis, self-monitoring of However, there is no significant differ- and frequent contact may be needed to blood glucose, explanation of home ence in outcomes for intravenous regular avoid hyperglycemia and hypoglycemia. blood glucose goals, and when to call insulin versus subcutaneous rapid-acting A recent discharge algorithm for glycemic the provider. analogs when combined with aggressive medication adjustment based on admis- + Definition, recognition, treatment, fluid management for treating mild or sion A1C found that the average A1C in and prevention of hyperglycemia and moderate DKA (66). Patients with uncom- patients with diabetes after discharge hypoglycemia. plicated DKA may sometimes be treated was significantly improved (6). Therefore, + Information on consistent nutrition with subcutaneous insulin in the emer- if an A1C from the prior 3 months is un- habits. gency department or step-down units available, measuring the A1C in all patients + If relevant, when and how to take (67), an approach that may be safer and with diabetes or hyperglycemia admitted blood glucose–lowering medications, more cost-effective than treatment with to the hospital is recommended. including insulin administration. intravenous insulin (68). If subcutaneous Clear communication with outpatient + Sick-day management. administration is used, it is important to providers either directly or via hospital + Proper use and disposal of needles provide adequate fluid replacement, discharge summaries facilitates safe transi- and syringes. nurse training, frequent bedside testing, tions to outpatient care. Providing informa- infection treatment if warranted, and ap- tion regarding the cause of hyperglycemia It is important that patients be pro- propriate follow-up to avoid recurrent (or the plan for determining the cause), re- vided with appropriate durable medical DKA. Several studies have shown that lated complications and comorbidities, and equipment, medications, supplies (e.g., the use of bicarbonate in patients with recommended treatments can assist out- insulin pens), and prescriptions along with DKA made no difference in resolution of patient providers as they assume ongoing appropriate education at the time of dis- acidosis or time to discharge, and its use is care. charge in order to avoid a potentially dan- generally not recommended (69). For fur- The Agency for Healthcare Research gerous hiatus in care. ther information regarding treatment, re- and Quality (AHRQ) recommends that, fer to recent in-depth reviews (3,70). at a minimum, discharge plans include the PREVENTING ADMISSIONS AND following (72): READMISSIONS Preventing Hypoglycemic Admissions TRANSITION FROM THE ACUTE in Older Adults CARE SETTING Medication Reconciliation Insulin-treated patients 80 years of age or ’ Recommendation + The patient s medications must be older are more than twice as likely to visit c There should be a structured dis- cross-checked to ensure that no chronic the emergency department and nearly charge plan tailored to the individ- medications were stopped and to en- five times as likely to be admitted for ual patient with diabetes. B sure the safety of new prescriptions. insulin-related hypoglycemia than those + Prescriptions for new or changed med 45–64 years of age (73). However, older A structured discharge plan tailored to the ication should be filled and reviewed adults with type 2 diabetes in long-term individual patient may reduce length of with the patient and family at or before care facilities taking either oral antihyper- hospital stay and readmission rates and in- discharge. glycemic agents or basal insulin have sim- crease patient satisfaction (71). Therefore, Structured Discharge Communication ilar glycemic control (74), suggesting that there should be a structured discharge oral therapy may be used in place of in- plan tailored to each patient. Discharge + Information on medication changes, sulin to lower the risk of hypoglycemia for planning should begin at admission and pending tests and studies, and follow- some patients. In addition, many older be updated as patient needs change. up needs must be accurately and adults with diabetes are overtreated (75), Transition from the acute care setting is promptly communicated to outpa- with half of those maintaining an A1C ,7% a risky time for all patients. Inpatients may tient physicians. being treated with insulin or a sulfonylurea, S150 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018

which are associated with hypoglycemia. To unknown diabetes in the ICU. Crit Care Med recommendations from an ASHP Foundation ex- further lower the risk of hypoglycemia- 2015;43:e541–e550 pert consensus panel. Am J Health Syst Pharm Preventing Medica- – related admissions in older adults, providers 8. Institute of Medicine. 2013;70:1404 1413 tion Errors. Aspden P, Wolcott J, Bootman JL, 22. Boyd JC, Bruns DE. Quality specifications for may, on an individual basis, relax A1C tar- Cronenwett LR, Eds. Washington, DC, The Na- glucose meters: assessment by simulation model- gets to ,8% or ,8.5% in patients with tional Academies Press, 2007 ing of errors in insulin dose. Clin Chem 2001;47: shortened life expectancies and signifi- 9. Gillaizeau F, Chan E, Trinquart L, et al. Comput- 209–214 cant comorbidities (refer to Section erized advice on drug dosage to improve prescrib- 23. U.S. Food and Drug Administration. Blood Glu- “ ” ing practice. Cochrane Database Syst Rev 2013; cose Monitoring Test Systems for Prescription 11 Older Adults for detailed criteria). 11:CD002894 Point-of-Care Use: Guidance for Industry and Food 10. Wexler DJ, Shrader P, Burns SM, Cagliero E. and Drug Administration Staff [Internet], 2016. Preventing Readmissions Effectiveness of a computerized insulin order Available from https://www.fda.gov/downloads/ In patients with diabetes, the readmission template in general medical inpatients with medicaldevices/deviceregulationandguidance/ rate is between 14 and 20% (76). Risk type 2 diabetes: a cluster randomized trial. Diabe- guidancedocuments/ucm380325.pdf. Accessed – factors for readmission include lower so- tes Care 2010;33:2181 2183 21 November 2016 11. Wang YJ, Seggelke S, Hawkins RM, et al. Im- 24. Wallia A, Umpierrez GE, Rushakoff RJ, et al.; cioeconomic status, certain racial/ethnic pact of glucose management team on outcomes DTS Continuous Glucose Monitoring in the Hospi- minority groups, comorbidities, urgent of hospitalizaron in patients with type 2 diabetes tal Panel. Consensus statement on inpatient use admission, and recent prior hospitaliza- admitted to the medical service. Endocr Pract of continuous glucose monitoring. J Diabetes Sci tion (76). Of interest, 30% of patients 2016;22:1401–1405 Technol 2017;11:1036–1044 with two or more hospital stays account 12. Garg R, Schuman B, Bader A, et al. Effect of 25. Gomez AM, Umpierrez GE. Continuous glu- preoperative diabetes management on glycemic cose monitoring in insulin-treated patients in for over 50% of hospitalizations and their control and clinical outcomes after elective sur- non-ICU settings. J Diabetes Sci Technol 2014;8: accompanying hospital costs (77). While gery. Ann Surg. 25 May 2017 [Epub ahead of 930–936 there is no standard to prevent readmis- print]. https://doi.org/10.1097/SLA.0000000 26. Maynard G, Wesorick DH, O’Malley C, sions, several successful strategies have 000002323 Inzucchi SE; Society of Hospital Medicine Glycemic 13. Draznin B, Gilden J, Golden SH, et al.; PRIDE Control Task Force. Subcutaneous insulin order been reported, including an intervention investigators. Pathways to quality inpatient man- sets and protocols: effective design and im- program targeting ketosis-prone patients agement of hyperglycemia and diabetes: a call to plementation strategies. J Hosp Med 2008; with type 1 diabetes (78), initiating insulin action. Diabetes Care 2013;36:1807–1814 3(Suppl.):29–41 treatment in patients with admission 14. Arnold P, Scheurer D, Dake AW, et al. Hospital 27. Brown KE, Hertig JB. Determining current in- A1C .9% (79), and a transitional care Guidelines for Diabetes Management and the sulin pen use practices and errors in the inpatient Joint Commission-American Diabetes Association setting. Jt Comm J Qual Patient Saf 2016;42:568– model (80). For people with diabetic kid- Inpatient Diabetes Certification. Am J Med Sci 575 ney disease, patient-centered medical 2016;351:333–341 28. Horne J, Bond R, Sarangarm P. Comparison of home collaboratives may decrease risk- 15. Society of Hospital Medicine. Clinical Tools | inpatient glycemic control with insulin vials versus adjusted readmission rates (81). Glycemic Control Implementation Toolkit [Inter- insulin pens in general medicine patients. Hosp net]. Available from: http://www.hospitalmedicine Pharm 2015;50:514–521 .org/Web/Quality_Innovation/Implementation_ 29. Veronesi G, Poerio CS, Braus A, et al. De- References Toolkits/Glycemic_Control/Web/Quality___ terminants of nurse satisfaction using insulin 1. Clement S, Braithwaite SS, Magee MF, et al.; Innovation/Implementation_Toolkit/Glycemic/ pen devices with safety needles: an exploratory Diabetes in Hospitals Writing Committee. Man- Clinical_Tools/Clinical_Tools.aspx. Accessed factor analysis. Clin Diabetes Endocrinol 2015;1: agement of diabetes and hyperglycemia in hospi- 25 August 2015 15 tals [published corrections appear in Diabetes 16. Umpierrez GE, Hellman R, Korytkowski MT, 30. Bueno E, Benitez A, Rufinelli JV, et al. Basal- Care 2004;27:856 and Diabetes Care 2004;27: et al.; Endocrine Society. Management of hyper- bolus regimen with insulin analogues versus human 1255]. Diabetes Care 2004;27:553–591 glycemia in hospitalized patients in non-critical insulin in medical patients with type 2 diabetes: a 2. Moghissi ES, Korytkowski MT, DiNardo M, care setting: an Endocrine Society clinical prac- randomized controlled trial in Latin America. En- et al.; American Association of Clinical Endocrinol- tice guideline. J Clin Endocrinol Metab 2012;97: docr Pract 2015;21:807–813 ogists; American Diabetes Association. American 16–38 31. Umpierrez GE, Smiley D, Jacobs S, et al. Ran- Association of Clinical Endocrinologists and Amer- 17. International Hypoglycaemia Study Group. domized study of basal-bolus insulin therapy in the ican Diabetes Association consensus statement Glucose concentrations of less than 3.0 mmol/L inpatient management of patients with type 2 on inpatient glycemic control. Diabetes Care (54 mg/dL) should be reported in clinical trials: a diabetes undergoing general surgery (RABBIT 2 2009;32:1119–1131 joint position statement of the American Diabetes surgery). Diabetes Care 2011;34:256–261 3. Umpierrez G, Korytkowski M. Diabetic Association and the European Association for the 32. Giugliano D, Chiodini P, Maiorino MI, emergenciesdketoacidosis, hyperglycaemic hy- Study of Diabetes. Diabetes Care 2017;40:155– Bellastella G, Esposito K. Intensification of insulin perosmolar state and hypoglycaemia. Nat Rev En- 157 therapy with basal-bolus or premixed insulin reg- docrinol 2016;12:222–232 18. NICE-SUGAR Study Investigators, Finfer S, imens in type 2 diabetes: a systematic review and 4. Bogun M, Inzucchi SE. Inpatient management Chittock DR, et al. Intensive versus conventional meta-analysis of randomized controlled trials. En- of diabetes and hyperglycemia. Clin Ther 2013;35: glucose control in critically ill patients. N Engl J docrine 2016;51:417–428 724–733 Med 2009;360:1283–1297 33. Bellido V, Suarez L, Rodriguez MG, et al. Com- 5. Pasquel FJ, Gomez-Huelgas R, Anzola I, et al. 19. Sathya B, Davis R, Taveira T, Whitlatch H, Wu parison of basal-bolus and premixed insulin regi- Predictive value of admission hemoglobin A1c on W-C. Intensity of peri-operative glycemic control mens in hospitalized patients with type 2 diabetes. inpatient glycemic control and response to insulin and postoperative outcomes in patients with di- Diabetes Care 2015;38:2211–2216 therapy in medicine and surgery patients with abetes: a meta-analysis. Diabetes Res Clin Pract 34. Baldwin D, Zander J, Munoz C, et al. A ran- type 2 diabetes. Diabetes Care 2015;38:e202– 2013;102:8–15 domized trial of two weight-based doses of insulin e203 20. Umpierrez G, Cardona S, Pasquel F, et al. Ran- glargine and glulisine in hospitalized subjects with 6.UmpierrezGE,ReyesD,SmileyD,etal.Hospi- domized controlled trial of intensive versus con- type 2 diabetes and renal insufficiency. Diabetes tal discharge algorithm based on admission HbA1c servative glucose control in patients undergoing Care 2012;35:1970–1974 for the management of patients with type 2 di- coronary artery bypass graft surgery: GLUCO- 35. Schmeltz LR, DeSantis AJ, Thiyagarajan V, abetes. Diabetes Care 2014;37:2934–2939 CABG trial. Diabetes Care 2015;38:1665–1672 et al. Reduction of surgical mortality and morbid- 7. Carpenter DL, Gregg SR, Xu K, Buchman TG, 21. Cobaugh DJ, Maynard G, Cooper L, et al. En- ity in diabetic patients undergoing cardiac surgery Coopersmith CM. Prevalence and impact of hancing insulin-use safety in hospitals: practical with a combined intravenous and subcutaneous care.diabetesjournals.org Diabetes Care in the Hospital S151

insulin glucose management strategy. Diabetes systems approach to inpatient glycemic manage- 66. Andrade-Castellanos CA, Colunga-Lozano LE, Care 2007;30:823–828 ment. Endocr Pract 2015;21:355–367 Delgado-Figueroa N, Gonzalez-Padilla DA. Subcu- 36. Shomali ME, Herr DL, Hill PC, Pehlivanova M, 50. Milligan PE, Bocox MC, Pratt E, Hoehner CM, taneous rapid-acting insulin analogues for dia- Sharretts JM, Magee MF. Conversion from intra- Krettek JE, Dunagan WC. Multifaceted approach betic ketoacidosis. Cochrane Database Syst Rev venous insulin to subcutaneous insulin after car- to reducing occurrence of severe hypoglycemia 2016;1:CD011281 diovascular surgery: transition to target study. in a large healthcare system. Am J Health Syst 67. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy Diabetes Technol Ther 2011;13:121–126 Pharm 2015;72:1631–1641 MB, Stentz FB. Thirty years of personal experience 37. Tripathy PR, Lansang MC. U-500 regular in- 51. Curll M, Dinardo M, Noschese M, Korytkowski in hyperglycemic crises: diabetic ketoacidosis and sulin use in hospitalized patients. Endocr Pract MT. Menu selection, glycaemic control and satis- hyperglycemic hyperosmolar state. J Clin Endocri- 2015;21:54–58 faction with standard and patient-controlled con- nol Metab 2008;93:1541–1552 38. Lansang MC, Umpierrez GE. Inpatient hyper- sistent carbohydrate meal plans in hospitalised 68. Umpierrez GE, Latif K, Stoever J, et al. Efficacy glycemia management: a practical review for pri- patients with diabetes. Qual Saf Health Care of subcutaneous insulin lispro versus continuous mary medical and surgical teams. Cleve Clin J Med 2010;19:355–359 intravenous regular insulin for the treatment of 2016;83(Suppl. 1):S34–S43 52. Ojo O, Brooke J. Evaluation of the role of patients with diabetic ketoacidosis. Am J Med 39. Umpierrez GE, Gianchandani R, Smiley D, enteral nutrition in managing patients with diabe- 2004;117:291–296 et al. Safety and efficacy of sitagliptin therapy tes: a systematic review. Nutrients 2014;6:5142– 69. Duhon B, Attridge RL, Franco-Martinez AC, for the inpatient management of general medi- 5152 Maxwell PR, Hughes DW. Intravenous sodium bi- cine and surgery patients with type 2 diabetes: a 53. MabreyME, Setji TL. Patient self-management carbonate therapy in severely acidotic diabetic pilot, randomized, controlled study. Diabetes Care of diabetes care in the inpatient setting: pro. J ketoacidosis. Ann Pharmacother 2013;47:970– 2013;36:3430–3435 Diabetes Sci Technol 2015;9:1152–1154 975 40. Pasquel FJ, Gianchandani R, Rubin DJ, et al. 54. Shah AD, Rushakoff RJ. Patient self- 70. Gosmanov AR, Gosmanova EO, Kitabchi AE. Efficacy of sitagliptin for the hospital management management of diabetes care in the inpatient setting: Hyperglycemic crises: diabetic ketoacidosis (DKA), of general medicine and surgery patients with con. J Diabetes Sci Technol 2015;9:1155–1157 and hyperglycemic hyperosmolar state (HHS). In type 2 diabetes (Sita-Hospital): a multicentre, pro- 55. Houlden RL, Moore S. In-hospital management Endotext [Internet]. Available from http://www spective, open-label, non-inferiority randomised of adults using insulin pump therapy. Can J Diabetes .ncbi.nlm.nih.gov/books/NBK279052/. Accessed trial. Lancet Diabetes Endocrinol 2017;5:125–133 2014;38:126–133 7 October 2016 41. Garg R, Schuman B, Hurwitz S, Metzger C, 56. Umpierrez GE. Basal versus sliding-scale reg- 71. Shepperd S, Lannin NA, Clemson LM, Bhandari S. Safety and efficacy of saxagliptin for ular insulin in hospitalized patients with hypergly- McCluskey A, Cameron ID, Barras SL. Discharge glycemic control in non-critically ill hospitalized cemia during enteral nutrition therapy. Diabetes planning from hospital to home. Cochrane Data- patients. BMJ Open Diabetes Res Care 2017;5: Care 2009;32:751–753 base Syst Rev 1996;1:CD000313 e000394 57. Pichardo-Lowden AR, Fan CY, Gabbay RA. 72. Agency for Healthcare Research and Quality. 42. U.S. Food and Drug Administration. FDA Drug Management of hyperglycemia in the non- Readmission and adverse events after hospital Safety Communication: FDA adds warnings about intensive care patient: featuring subcutaneous discharge [Internet], 2017. Available from http:// heart failure risk to labels of type 2 diabetes med- insulin protocols. Endocr Pract 2011;17:249–260 psnet.ahrq.gov/primer.aspx?primerID511. Ac- icines containing saxagliptin and alogliptin [Inter- 58. Corsino L, Dhatariya K, Umpierrez G. Manage- cessed 18 October 2017 net], 2016. Available from http://www.fda.gov/ ment of diabetes and hyperglycemia in hospital- 73. Bansal N, Dhaliwal R, Weinstock RS. Manage- Drugs/DrugSafety/ucm486096.htm. Accessed ized patients. In Endotext [Internet]. Available ment of diabetes in the elderly. Med Clin North 7 October 2016 from http://www.ncbi.nlm.nih.gov/books/NBK2 Am 2015;99:351–377 43. Mendez CE, Umpierrez GE. Pharmacotherapy 79093/. Accessed 21 November 2016 74. Pasquel FJ, Powell W, Peng L, et al. A ran- for hyperglycemia in noncritically ill hospitalized 59. Kwon S, Hermayer KL. Glucocorticoid- domized controlled trial comparing treatment patients. Diabetes Spectr 2014;27:180–188 induced hyperglycemia. Am J Med Sci 2013;345: with oral agents and basal insulin in elderly pa- 44. Umpierrez GE, Korytkowski M. Is incretin- 274–277 tients with type 2 diabetes in long-term care based therapy ready for the care of hospitalized 60. Brady V, Thosani S, Zhou S, Bassett R, Busaidy facilities. BMJ Open Diabetes Res Care 2015;3: patients with type 2 diabetes?: Insulin therapy has NL, Lavis V. Safe and effective dosing of basal- e000104 proven itself and is considered the mainstay of bolus insulin in patients receiving high-dose ste- 75. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, treatment. Diabetes Care 2013;36:2112–2117 roids for hyper-cyclophosphamide, doxorubicin, Steinman MA. Potential overtreatment of diabe- 45. U.S. Food and Drug Administration. FDA Drug vincristine, and dexamethasone chemotherapy. tes mellitus in older adults with tight glycemic con- Safety Communication: FDA revises labels of Diabetes Technol Ther 2014;16:874–879 trol. JAMA Intern Med 2015;175:356–362 SGLT2 inhibitors for diabetes to include warnings 61. Smiley DD, Umpierrez GE. Perioperative glu- 76. Rubin DJ. Hospital readmission of patients about too much acid in the blood and serious cose control in the diabetic or nondiabetic pa- with diabetes. Curr Diab Rep 2015;15:17 urinary tract infections [Internet], 2015. Available tient. South Med J 2006;99:580–589 77. Jiang HJ, Stryer D, Friedman B, Andrews R. from http://www.fda.gov/Drugs/DrugSafety/ 62. Buchleitner AM, Mart´ınez-Alonso M, Multiple hospitalizations for patients with diabe- ucm475463.htm. Accessed 7 October 2016 Hernandez´ M, Sola` I, Mauricio D. Perioperative tes. Diabetes Care 2003;26:1421–1426 46. U.S. Food and Drug Administration. FDA glycaemic control for diabetic patients undergo- 78. Maldonado MR, D’Amico S, Rodriguez L, Iyer strengthens kidney warnings for diabetes med- ing surgery. Cochrane Database Syst Rev 2012;9: D, Balasubramanyam A. Improved outcomes in icines canagliflozin (Invokana, Invokamet) and CD007315 indigent patients with ketosis-prone diabetes: ef- dapagliflozin (Farxiga, Xigduo XR) [Internet], 63. Demma LJ, Carlson KT, Duggan EW, Morrow fect of a dedicated diabetes treatment unit. En- 2016. Available from http://www.fda.gov/drugs/ JG 3rd, Umpierrez G. Effect of basal insulin dosage docr Pract 2003;9:26–32 drugsafety/drugsafetypodcasts/ucm507785.htm. on blood glucose concentration in ambulatory 79. Wu EQ, Zhou S, Yu A, et al. Outcomes associ- Accessed 7 October 2016 surgery patients with type 2 diabetes. J Clin ated with post-discharge insulin continuity in US 47. Dendy JA, Chockalingam V, Tirumalasetty NN, Anesth 2017;36:184–188 patients with type 2 diabetes mellitus initiating et al. Identifying risk factors for severe hypoglyce- 64. Umpierrez GE, Smiley D, Hermayer K, et al. insulin in the hospital. Hosp Pract (1995) 2012; mia in hospitalized patients with diabetes. Endocr Randomized study comparing a basal-bolus with 40:40–48 Pract 2014;20:1051–1056 a basal plus correction insulin regimen for the 80. Hirschman KB, Bixby MB. Transitions in care 48. Ulmer BJ, Kara A, Mariash CN. Temporal oc- hospital management of medical and surgical pa- from the hospital to home for patients with di- currences and recurrence patterns of hypoglyce- tients with type 2 diabetes: basal plus trial. Di- abetes. Diabetes Spectr 2014;27:192–195 mia during hospitalization. Endocr Pract 2015;21: abetes Care 2013;36:2169–2174 81. Tuttle KR, Bakris GL, Bilous RW, et al. Di- 501–507 65. Kitabchi AE, Umpierrez GE, Miles JM, Fisher abetic kidney disease: a report from an ADA 49. Maynard G, Kulasa K, Ramos P, et al. Impact JN. Hyperglycemic crises in adult patients with Consensus Conference. Diabetes Care 2014;37: of a hypoglycemia reduction bundle and a diabetes. Diabetes Care 2009;32:1335–1343 2864–2883 S152 Diabetes Care Volume 41, Supplement 1, January 2018

15. Diabetes Advocacy: Standards American Diabetes Association of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S152–S153 | https://doi.org/10.2337/dc18-S015

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, policy makers, and others about the inter- section of diabetes medicine and the law.

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

Diabetes Care in the School Setting (1) First publication: 1998 (revised 2015) A sizeable portion of a child’s day is spent in school, so close communication with and cooperation of school personnel are essential to optimize diabetes manage- Suggested citation: American Diabetes Associa- ment, safety, and academic opportunities. See the ADA position statement “Diabe- tion. 15. Diabetes advocacy: Standards of Med- ” ical Care in Diabetesd2018. Diabetes Care tes Care in the School Setting (http://care.diabetesjournals.org/content/38/10/ 2018;41(Suppl. 1):S152–S153 1958.full). © 2017 by the American Diabetes Association. Readers may use this article as long as the work Care of Young Children With Diabetes in the Child Care Setting (2) First publication: 2014 is properly cited, the use is educational and not for proﬁt, and the work is not altered. More infor- Very young children (aged ,6 years) with diabetes have legal protections and can mation is available at http://www.diabetesjournals be safely cared for by child care providers with appropriate training, access to .org/content/license. care.diabetesjournals.org Diabetes Advocacy S153

resources, and a system of communication Driving” (http://care.diabetesjournals that nearly 80,000 inmates have diabe- with parents and the child’sdiabetespro- .org/content/37/Supplement_1/S97). tes, correctional institutions should have vider. See the ADA position statement written policies and procedures for the “Care of Young Children With Diabetes in Diabetes and Employment (4) management of diabetes and for the train- the Child Care Setting” (http://care First publication: 1984 (revised 2009) ing of medical and correctional staff in .diabetesjournals.org/content/37/10/ Anypersonwithdiabetes, whether insulin diabetes care practices. See the ADA 2834). treated or noninsulin treated, should be el- position statement “Diabetes Manage- igible for any employment for which he or ment in Correctional Institutions” (http:// Diabetes and Driving (3) she is otherwise qualified. Employment de- care.diabetesjournals.org/content/37/ First publication: 2012 cisions should never be based on gener- Supplement_1/S104). Peoplewithdiabeteswhowishtooperate alizations or stereotypes regarding the motorvehiclesaresubjecttoagreatvari- effects of diabetes. When questions References ety of licensing requirements applied by ariseaboutthemedicalfitness of a person 1. Jackson CC, Albanese-O’Neill A, Butler KL, both state and federal jurisdictions, which with diabetes for a particular job, a health et al. Diabetes care in the school setting: a position statement of the American Diabetes mayleadtolossofemploymentorsignif- care professional with expertise in treating Association. Diabetes Care 2015;38:1958– icant restrictions on a person’s license. diabetes should perform an individualized 1963 Presence of a medical condition that can assessment. See the ADA position state- 2. Siminerio LM, Albanese-O’Neill A, Chiang JL, lead to significantly impaired conscious- ment “Diabetes and Employment” (http:// et al. Care of young children with diabetes in the ness or cognition may lead to drivers being care.diabetesjournals.org/content/37/ child care setting: a position statement of the fi American Diabetes Association. Diabetes Care evaluated for their tness to drive. People Supplement_1/S112). 2014;37:2834–2842 with diabetes should be individually as- 3. American Diabetes Association. Diabetes and sessed by a health care professional knowl- Diabetes Management in Correctional driving. Diabetes Care 2014;37:(Suppl. 1):S97–S103 edgeable in diabetes if license restrictions Institutions (5) 4. American Diabetes Association. Diabetes and are being considered, and patients should First publication: 1989 (revised 2008) employment. Diabetes Care 2014;37(Suppl. 1): S112–S117 be counseled about detecting and avoid- People with diabetes in correctional fa- 5. American Diabetes Association. Diabetes ing hypoglycemia while driving. See the cilities should receive care that meets management in correctional institutions. Diabe- ADA position statement “Diabetes and national standards. Because it is estimated tes Care 2014;37(Suppl. 1):S104–S111 S154 Diabetes Care Volume 41, Supplement 1, January 2018

Professional Practice Committee, American College of d

PROFESSIONAL PRACTICE COMMITTEE DISCLOSURES Cardiology Designated Representatives, and American Diabetes Association Staff Disclosures Diabetes Care 2018;41(Suppl. 1):S154–S155 | https://doi.org/10.2337/dc18-SDIS01

The following financial or other conflicts of interest cover the period 12 months before December 2017 Other research Member Employment Research grant support Rita R. Kalyani, MD, MHS, FACP (Chair) Johns Hopkins University, Baltimore, MD None None Christopher P. Cannon, MD Brigham and Women’s Hospital, Amgen, Arisaph, Boehringer Ingelheim, None Boston, MA Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Takeda Andrea L. Cherrington, MD, MPH University of Alabama, Birmingham, AL None None Donald R. Coustan, MD The Warren Alpert Medical School of Brown None None University, Providence, RI Ian H. de Boer, MD, MS University of Washington, Seattle, WA Research grant from ADA Medtronic, Abbott Hope Feldman, CRNP, FNP-BC Abbottsford-Falls Family Practice & None None Counseling, Philadelphia, PA Judith Fradkin, MD National Institute of Diabetes and Digestive None None and Kidney Diseases, Bethesda, MD David Maahs, MD, PhD Stanford University, School of Medicine, Medtronic, Dexcom, Roche, Insulet, None Stanford, CA Bigfoot Melinda Maryniuk, MEd, RD, CDE Joslin Diabetes Center, Boston, MA None None Medha N. Munshi, MD Beth Israel Deaconess Medical Center, None Common Harvard Medical School, Boston, MA Sensing Joshua J. Neumiller, PharmD, Washington State University, Spokane, WA CDE, FASCP None None Guillermo E. Umpierrez, MD, CDE, Emory University, Atlanta, GA Sanofi, Novo Nordisk, Merck, Boehringer None FACE, FACP Ingelheim, AstraZeneca

Sandeep Das, MD, MPH^ University of Texas Southwestern Medical None None Center Mikhail Kosiborod, MD^ University of Missouri-Kansas City School of None None Medicine

William T. Cefalu, MD (Staff)† American Diabetes Association, Arlington, VA Sanoﬁ*# None Erika Gebel Berg, PhD (Staff) American Diabetes Association, Arlington, VA None None Tamara Darsow, PhD (Staff) American Diabetes Association, Arlington, VA None None Matthew P. Petersen (Staff) American Diabetes Association, Arlington, VA None None Sacha Uelmen, RDN, CDE (Staff) American Diabetes Association, Arlington, VA None None care.diabetesjournals.org Disclosures S155

Speakers’ bureau/ Member honoraria Ownershipinterest Consultant/advisoryboard Other R.R.K. None None None None C.P.C. None None Alnylam, Amarin, Amgen, Arisaph, None AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi, Takeda A.L.C. AstraZeneca (Women Connection Health None Coinvestigator, drug study by Merck Scientists Board) (Volunteer Chief Medical Sharp & Dohme; Officer) Site investigator, drug study by Boehringer Ingelheim D.R.C. None None None None I.H.d.B. None None Boehringer Ingelheim, None Janssen, Ironwood H.F. None None None Member, American Diabetes Association Primary Care Advisory Group; Member, Diabetes Spectrum Editorial Board J.F. None None None None D.M. None None Insulet, Helmsely Charitable Trust Editorial Boards, The Journal of Pediatrics and Diabetes Technology & Therapeutics; Associate Editor, Diabetic Medicine; and Secretary- General, International Society for Pediatric and Adolescent Diabetes M.M. None None None None M.N.M. Novo Nordisk, None Sanofi None Sanofi,EliLilly J.J.N. None None None Editor in Chief, Diabetes Spectrum G.E.U. None None Sanofi Member, Endocrine Society Council Member, American Association of Clinical Endocrinologists Board of Directors Editor in Chief, BMJ Open Diabetes Research & Care S.D.^ None None Roche Diagnostic None M.K.^ None None AstraZeneca, Sanofi, GlaxoSmithKline, None Amgen, Boehringer Ingelheim, Novo Nordisk, Merck (Diabetes), Eisai, ZS Pharma, Glytec, Janssen, Intarcia, Novartis W.T.C.† None None Sanofi, Intarcia, Adocia Former Editor in Chief, Diabetes Care E.G.B. None None None None T.D. None None None None M.P.P. None None None None S.U. None None None None Âmerican College of Cardiologyddesignated representative (Section 9); *$$10,000 per year from company to individual; #grant or contract is to university or other employer; †prior to joining ADA, no active disclosures. S156 Diabetes Care Volume 41, Supplement 1, January 2018

Index

A1C testing bile acid sequestrants, S79, S81 Cholesterol Treatment Trialists’ Collaboration, in African Americans, S15, S58 blood pressure control. see hypertension S93 in children, adolescents, S58, S128 bromocriptine, S79, S81 cholesteryl ester transfer protein (CETP) inhibi- clinical trials, S59–S60 tors, S93, S94 CVD and, S59–S60 canagliflozin, S79, S81, S99–S100, S108 Chronic Care Model, S8–S10, S28 diagnostic, S14–S15 cancer, S32 CKD. see kidney disease glycemic targets and, S60–S61 CANVAS Program, S99–S100, S108 classification, S4, S13–S14 goals, S58–S59 CANVAS-R trial, S100 cognitive impairment/dementia, S32, S95, S120 hemoglobinopathies in, S15 capsaicin, S113 colesevelam, S79, S81 limitations, S57 carbamazepine, S113 community health workers (CHWs), S10 mean glucose and, S57–S58 carbohydrates, S40–S42 comorbidities evaluation, assessment microvascular complications and, S59 cardiac autonomic neuropathy, S112 anxiety disorders, S34 in older adults, S121 cardiovascular disease autoimmune diseases, S32 prediabetes screening, S16 A1C testing and, S59–S60 cancer, S32 in pregnancy, S139 antiplatelet agents, S95–S96 cognitive impairment/dementia, S32 recommendations, S57 assessment of, S86 depression, S34–S35 red blood cell turnover, S15 asymptomatic patients, screening, disordered eating behaviors, S35 acarbose, S79, S81 S96–S99 fatty liver disease, S33 ACCORD BP trial, S87, S88 atherosclerotic, S5, S75, S86 fractures, S33 ACCORD MIND trial, S120 cardiac testing, S96–S99 hearing impairment, S33 ACCORD trial, S32–S33, S59–S61, S94, S108 children, adolescents, S129–S131 HIV, S33–S34 ACE inhibitors, S89, S91, S109, S141 coronary heart disease, S96–S101 hyperglycemia/hypoglycemia, S32–S33 acute kidney injury (AKI), S89, S106–S107 heart failure, S99 medical evaluation, S29–S32 ADAG study, S57–S58, S61–S62 hypertension/blood pressure control, nutrition therapy, S33 ADA Statements, S1 S86–S91 obstructive sleep apnea, S34 adolescents. see children and adolescents lifestyle management, S99 pancreatitis, S33 ADVANCE BP trial, S87, S88 lipid management, S5, S91–S95 patient-centered collaborative care, ADVANCE trial, S59–S61 medications, clinical trials, S97–S100 S28–S29 advocacy position statements, S152–S153 prevention of, S53 periodontal disease, S34 Affordable Care Act, S9, S133 primary prevention, S93 psychosocial/emotional disorders, S34, age in A1C testing, S15, S20 revisions summary, S5 S45–S46 a-glucosidase inhibitors, S79, S81 risk stratification, S92–S93 recommendations, S28 AIM-HIGH trial, S94 secondary prevention, S93 revisions summary, S4 albiglutide, S80, S81 statins, S33, S91–S95 serious mental illness, S35 alcohol, S40, S42–S43, S70, S88, S94, S111 type 1 diabetes, S93 statins, S33 Alli (orlistat), S68 celiac disease, S129 testosterone levels, S34 alogliptin, S79, S81, S97–S99 CGM. see continuous glucose monitoring (CGM) Consensus Reports, S1 amylin mimetics, S74, S80, S81 Charcot neuroarthropathy, S114 continuous glucose monitoring (CGM) anacetrapib, S94 children and adolescents children, adolescents, S128 angiotensin receptor blockers, S89, S91, A1C testing in, S58, S128 described, S56–S57 S109, S141 autoimmune diseases, S128–S129 flash, S56 antihyperglycemic therapy, S5, S67, S75–S76, celiac disease, S129 hospital care, S146 S96–S100, S146–S147 comorbidities, S133 hybrid closed-loop systems, S57 antihypertensive medications, S89–S91, continuous glucose monitoring, S128 recommendations, S55 S109, S141 CVD risk factor management, S129–S131 revisions summary, S4–S5 antiplatelet agents, S95–S96 DSMES, S127 type 1 diabetes, S73–S74 Antithrombotic Trialists’ Collaboration, S95 dyslipidemia in, S130 continuous subcutaneous insulin infusion (CSII), anti-VEGF, S109–S111 glycemic control, S128 S74, S147–S148 anxiety disorders, S34 hypertension in, S129–S130 contraception, S141 ASCVD. see cardiovascular disease hypoglycemia, S61–S62 Contrave (naltrexone/bupropion), S69 aspart, S80, S82 kidney disease, S131 coronary heart disease, S96–S101 ASPIRE trial, S57 lifestyle management, S132 correctional facilities, S153 aspirin resistance, S96 mature minor rule, S127 cost-effectiveness model, S52–S53 aspirin therapy, S95–S96, S140 neuropathy, S131 costs atherosclerotic cardiovascular disease. see pediatric to adult care transition, S133 of medications, S81–S82 cardiovascular disease pharmacologic therapy, S132–S133 reduction strategies, system-level, S9 atorvastatin, S92 physical activity/exercise, S43–S44, S52 cystic fibrosis–related diabetes screening, S24 autoimmune diseases, S32, S128–S129 prediabetes screening, S4, S5, S16, autonomic neuropathy, S44, S111–S113 S19, S20 dapagliflozin, S79, S81 psychosocial issues, S127–S128 DASH diet, S41 balance training, S43 retinopathy, S131 DAWN2 study, S45–S46 INDEX bariatric surgery, S67–S70 school, child care, S127, S152–S153 degludec, S80, S82 BARI 2D trial, S112 smoking cessation, S130–S131 depression, S34–S35, S127–S128 b-blockers, S96 thyroid disease, S129 detemir, S80, S82, S148 Belviq (lorcaserin), S68 type 1 diabetes, S126–S131 Diabetes Control and Complications Trial biguanides, S79, S81 type 2 diabetes, S19, S20, S131–S133 (DCCT), S59, S74, S108, S120, S128 care.diabetesjournals.org Index S157

diabetes distress, S35, S45–S46, S128 classification, S13 HPS2-THRIVE trial, S94 Diabetes Prevention Program, S52–S53 contraception, S141 hyperbaric oxygen therapy, S114 Diabetes Prevention Recognition Program, S52 definition, S20–S21 hyperglycemia, S9–S10, S32, S60 diabetes self-management education and diagnosis, S21–S22 hyperkalemia, S89 support (DSMES), S8, S38–S39, S53, S127 management of, S139–S140 hyperosmolar hyperglycemic state, S148–S149 diabetic retinopathy, S44, S109–S111 nutrition in, S139 hypertension Diabetic Retinopathy Study, S110, S111 pharmacologic therapy, S139–S140 antihypertensive medications, S89–S91, diagnosis physical activity and, S44 S109, S141 ADA risk test, S18 postpartum care, S141 in children, adolescents, S129–S130 community screening, S20 prevalence of, S137 clinical trials, S87 confirmation of, S15 testing recommendations, S20 kidney disease and, S108–S109 monogenic syndromes, S22–S25 type 2 diabetes and, S141 lifestyle management, S88–S89 one-step strategy, S21, S22 glargine, S80, S82, S148 meta-analyses of trials, S87 revisions summary, S4 glimepiride, S79, S81 in older adults, S120, S121 testing interval, S20 glipizide, S10, S79, S81 in pregnancy, S87 tests, criteria, S14, S15 GLP-1 agonists resistant, S89–S90 two-step strategy, S21, S22 characterization, S69, S74, S76 screening, diagnosis, S87 disordered eating behaviors, S35 in CKD, S108 treatment, individualization of, S87–S88 dopamine-2 agonists, S79, S81 clinical trials, S97–S98, S100 treatment goals, S87 DPP-4 inhibitors costs of, S81–S82 treatment recommendations, S90 characterization, S83 older adults, S122 treatment strategies, S88–S91 clinical trials, S97–S99 pharmacology, S79–S80 hypertriglyceridemia, S94 costs, S81 stopping therapy, S83 hypoglycemia hospital care, S146–S147 glucagon, S62 anxiety disorders and, S34 older adults, S122 glulisine, S80, S82 assessment of, S32–S33 pharmacology, S76, S79 glyburide, S79, S81, S140 children/older adults, S61–S62 driving, S153 glycemic management. see also A1C testing classification of, S61 dulaglutide, S80, S81 control, assessment of, S55 cognitive decline/impairment, S61 duloxetine, S112 intercurrent illness, S62 food insecurity and, S9–S10 physical activity and, S44 glucagon, S62 e-cigarettes, S44–S45 recommendations, S55, S60 hospital care, S147 EDIC study, S59 revisions summary, S4–S5 iatrogenic, S147 ELIXA trial, S97–S98, S100 self-monitoring of blood glucose (SMBG), mortality, S61 empagliflozin, S79, S81, S97–S98, S100, S108 S55–S56, S60 nocturnal, S57 EMPA-REG OUTCOME, S97–S99, S108 in older adults, S120, S123 employment, S153 HAPO study, S21 physical activity and, S44 – end-of-life care, S122 S124 hearing impairment, S33 predictors of, S147 eplerenone, S109 hemoglobinopathies, S15 prevention, S62, S147 erectile dysfunction, S113 hepatitis B, S29, S32 recommendations, S61 ETDRS trial, S110, S111 herbal supplements, S40, S42 symptoms of, S61 evidence-grading system (ADA), S2 HIV, S33–S34 treatment, S62 – EXAMINE, S97 S99 homelessness, S10 triggering events, S147 exenatide, exenatide ER, S79, S81, hospital care hypoglycemia unawareness, S34, S57, S61, S62 – S97 S98, S100 admission, S144–S145 – exercise/physical activity, S43 S44, S52, admission/readmission prevention, – immune-mediated diabetes, S17 S66 S67 S149–S150 – immunizations, S29–S30 EXSCEL trial, S97 S98, S100 antihyperglycemic agents, S146–S147 eye disease, S44, S109–S111 IMPROVE-IT trial, S93 critical care units, S146 incretin-based therapies, S69, S74, S76, S81, ezetimide, S92, S93 – delivery standards, S144 S145 S97–S98 diabetes care providers, S145 influenza, S29, S32 fats (dietary), S40, S42 – diabetes self-management, S147 S148 insulin therapy fatty liver disease, S33 discharge planning, S149 basal, S82 fenofibrate, S94 – DKA, S148 S149 bolus, S82–S83 fibrate, S94 – DPP-4 inhibitors, S146 S147 carbohydrate intake and, S42 finerenone, S109 enteral/parenteral feedings, S148 combination injectable, S83 flash CGM device, S56 glucocorticoid therapy, S148 concentrated preparations, S83 flexibility training, S43 fi glucose abnormalities de nitions, S145 correctional, in hospital care, S148 fluvastatin, S92 – glucose monitoring, bedside, S145 S146 costs, S82 food insecurity, S9–S10 vs. glycemic control, moderate tight, S145 CSII/CGM, S74 foot care, S5, S113–S114 glycemic targets, S145 food insecurity patients, S10 FOURIER trial, S93 hyperosmolar hyperglycemic state, in GDM, S140 FPG testing, S14 – S148 S149 hospital care, S146, S148 fractures, S33 hypoglycemia, S147 inhaled, S83 insulin therapy, S146, S148 older adults, S122–S123 gabapentin, S113 medical nutrition therapy, S147 pharmacology, S80 gastrointestinal neuropathies, S112 medication reconciliation, S149 premixed, S83 gastroparesis, S113 perioperative care, S148 SMBG, S55–S56, S60 see GDM. gestational diabetes mellitus physician order entry, S145 type 1 diabetes, S73–S74 generalized anxiety disorder, S34 posttransplantation diabetes therapy, S25 type 2 diabetes, S76, S78, S82–S83 genitourinary disturbances, S112 quality assurance standards, S145 gestational diabetes mellitus. see also revisions summary, S6 pregnancy HOT trial, S87, S88 jail, S153 S158 Index Diabetes Care Volume 41, Supplement 1, January 2018

kidney disease medical nutrition therapy (MNT), S29, S38–S43, diet, physical activity, behavioral therapy, acute kidney injury, S89, S106–S107 S52, S91, S107–S108, S139, S147. see also S43–S44, S52, S66–S67 albuminuria assessment, S106 nutrition therapy medications, S67–S69 children, adolescents, S131 Medicare, S39 metabolic surgery, S67–S70 complications of, S107 medications. see also specific drugs and drug prediabetes screening, S16 diagnosis of, S106 classes prediabetes testing recommendations, eGFR assessment, S106 cardiovascular outcomes trials, S77–S81 S4, S5 epidemiology, S106 combination therapy, S75–S81, S83, S93 recommendations, S65, S66 glucose-lowering medications, S108 compliance, S8–S9 treatment options, S66 glycemic control, S108 concomitant, S67 obstructive sleep apnea, S34 hypertension and, S108–S109 costs, S81–S82 older adults interventions, S107–S109 CVOTs, S97–S100 A1C in, S121 nutrition therapy, S107–S108 diabetes screening, S20 admission/readmission prevention, physical activity and, S44 efficacy, safety assessment, S67 S149–S150 proteins, dietary, S42 obesity management, S67–S69 alert strategy, S123 recommendations, S105–S106 pharmacology, S79–S80 aspirin use in, S96 revisions summary, S5 recommendations, S53 assisted living facilities, S123 screening, S105 type 1 diabetes, S73–S75 cognitive impairment/dementia, S32, S95, stages, S106, S107 type 2 diabetes, S75–S83 S120 surveillance, S107 Mediterranean diet, S33, S41, S42 CVD primary prevention, S93 treatment, S105–S106 meglitinides (glinides), S79, S81 hypertension in, S120, S121 Kumamoto Study, S59 metformin hypoglycemia, S61–S62 A1C guidelines, S4 hypoglycemia in, S120, S123 in CKD, S108 insulin therapy, S122–S123 language barriers, S10 coronary heart disease, S96 LTC facilities, S123 laropiprant, S94 costs, S81 nutrition, S123 – LEADER trial, S97 S98, S100, S108 CVD risk reduction agents with, S100– palliative, end-of-life care, S122–S124 lifestyle management S101 pharmacologic therapies, S122–S123 cardiovascular disease, S99 in GDM, S140 recommendations, S119 children, adolescents, S132 pharmacology, S79 revisions summary, S5 – cost-effectiveness model, S52 S53 type 1 diabetes, S74 statins, S33, S91–S95 – DSMES, S8, S38 S39, S53 type 2 diabetes, S53, S75–S78 treatment goals, S60, S120–S122 gestational diabetes mellitus, S139 metoclopramide, S113 orlistat (Alli), S68 – hypertension, S88 S89 micronutrients, in MNT, S40, S42 orlistat (Xenical), S68 lipids, S91 microvascular complications, S5. see also orthostatic hypotension, S113 – nutrition therapy, S39 S43, S52 specific conditions physical activity/exercise, S43–S44, miglitol, S79, S81 – S52, S66–S67 palliative, end-of-life care, S122 S124 mineralocorticoid receptor antagonists, psychosocial issues, S34, S45–S46 pancreas, pancreatic islet transplantation, S33, S91, S109 S74–S75 recommendations, S38 mobile apps, S52 revisions summary, S4 pancreatitis, S33 modified plate method, S42 – – smoking cessation, S44–S45 patient-centered care, S7 S8, S28 S29 technology platforms, S52 Patient-Centered Medical Home, S8 – weight, S41, S52, S66–S67, S88 nateglinide, S79, S81 PCSK9 inhibitors, S92 S95 linagliptin, S79, S81 National Diabetes Education Program, S8 pediatric to adult care transition, S133 lipase inhibitors, S68 National Quality Strategy, S9 periodontal disease, S34 lipid management neonatal diabetes screening, S22–S23 peripheral arterial disease, S114 – in children and adolescents, S130 nephropathy. see kidney disease peripheral neuropathy, S44, S111 S113 see specific hypertriglyceridemia, S94 neuropathic pain, S112–S113 pharmacotherapy. medications; medications by name lifestyle modifications, S91 neuropathy, S44, S111–S113, S131 revisions summary, S5 new-onset diabetes after transplantation phentermine (Lomaira), S68 – statins, S33, S91–S95 (NODAT), S24–S25 photocoagulation surgery, S109 S111 – therapy, monitoring, S91 niacin, S94 physical activity/exercise, S43 S44, S52, – liraglutide (Saxenda), S69, S80, S81, S82, NPH, S80, S82, S83, S148 S66 S67 S97–S98, S108 nutrition therapy pioglitazone, S79, S81 lispro, S80, S82 alcohol, S40, S42–S43, S88 pitavastatin, S92 lixisenatide, S80, S81, S82, S97–S98, S100 carbohydrates, S40–S42 plant-based diets, S41 Lomaira (phentermine), S68 comorbidities, S33 plasma glucose testing, S15 Look AHEAD trial, S66, S99 DASH diet, S41 pneumococcal pneumonia, S29, S32 – lorcaserin (Belviq), S68 fats (dietary), S40, S42 point-of-care (POC) meters, S145 S146 loss of protective sensation (LOPS), S111, in GDM, S139 population health S113–S114 herbal supplements, S40, S42 care delivery systems, S8 – lovastatin, S92 hospital care, S147 Chronic Care Model, S8 S10, S28 kidney disease, S107–S108 community support, S10 fi lifestyle management, S39–S43, S52 de ned, S7 – maturity-onset diabetes/young (MODY), Mediterranean diet, S33, S41, S42 food insecurity, S9 S10 – S23 S24 older adults, S123 homelessness, S10 – – meal planning, S39 S43, S52, S88, S107 S108 proteins, S40, S42 language barriers, S10 medical evaluation patient-centered care, S7–S8 immunizations, S29–S30 recommendations, S7 pre-exercise, S44 obesity management revisions summary, S4 recommendations, S29 assessment, S65–S66 social context, determinants, S9 referrals, S32, S46, S109 diabetes screening, S20 system-level improvement strategies, S8 care.diabetesjournals.org Index S159

posttransplantation diabetes screening, S24–S25 SAVOR-TIMI 53, S97–S99 children and adolescents, S126–S131 pramlintide, S77, S80, S81 saxagliptin, S79, S81, S97–S98 classification, S13–S14 pravastatin, S92 Saxenda (liraglutide), S69, S80–S82, S97–S98, CVD/A1C and, S59 prediabetes S108 diagnosis (see diagnosis) described, S16 schizophrenia, S35 disordered eating behaviors in, S35 increased risk categories, S17 school, child care, S127, S152–S153 idiopathic, testing for, S17 screening, S4, S15–S16 scientific reviews, S2 insulin therapy, S73–S74 screening in asymptomatic adults, S16, SEARCH study, S130 medications, S73–S75 S19–S20 self-monitoring of blood glucose (SMBG), pathophysiology, S14 serious mental illness, S35 S55–S56, S60 physical activity/exercise, S43–S44 pregabalin, S112 semaglutide, S97–S98, S100, S108 predictors, S14 pregnancy. see also gestational diabetes mellitus SGLT2 inhibitors retinopathy and, S110 A1C in, S139 characterization, S74 risk testing, S17 antihypertensive medications, S90–S91, S141 clinical trials, S97–S100 stages of, S14 glucose monitoring, S138–S139 costs, S81 surgical treatment, S74–S75 glycemic targets in, S138 hospital care, S147 testing recommendations, S16–S17 hypertension in, S87 kidney disease, S106–S108 type 2 diabetes insulin physiology, S138 older adults, S122 age as risk factor, S20 lactation, S141 pharmacology, S76, S79 BMI as risk factor, S20 medications contraindicated, S91, stopping therapy, S83 children and adolescents, S19, S20, S131–S133 S140–S141 shoes, S114 classification, S13–S14 postpartum care, S141 simvastatin, S92–S94 CVD/A1C and, S59 preconception counseling, testing, sitagliptin, S79, S81, S97–S99 described, S19 S137–S138 smoking cessation, S44–S45, S130–S131 diagnosis (see diagnosis) preeclampsia, aspirin and, S140 sodium, S40, S42, S88, S107–S108 DKA in, S19 preexisting diabetes, S140 spironolactone, S91, S109 ethnicity as risk factor, S20 prevalence of diabetes in, S137 SPRINT trial, S87, S88 hypertriglyceridemia, S94 retinopathy and, S110 SSRIs, S68 medications, S75–S83 revisions summary, S5–S6 Standards of Care statements, S1, S3 pathophysiology, S14 prison, S153 statins, S33, S91–S95 physical activity/exercise, S43–S44 Professional Practice Committee (PPC), S3 sulfonylureas prevention/delay, S4, S51–S53 proteins, S40, S42 costs, S81 proteins, dietary, S42 psychosis, S35 food insecurity patients, S10 retinopathy and, S110 psychosocial/emotional disorders, S34, S45–S46 in GDM, S140 risk-based screening, S19 P2Y12 receptor antagonists, S96 older adults, S122 screening in asymptomatic adults, S16, pharmacology, S79 S19–S20 Qsymia (phentermine/topiramate), S68 stopping therapy, S83 screening in dental practices, S20 type 2 diabetes, S76 serious mental illness, S35 SUSTAIN-6, S97–S98, S100, S108 testing recommendations, S17–S19 race/ethnicity in A1C testing, S15, S20 sweeteners (nonnutritive), S41, S43 weight management, S41, S52 ranibizumab, S109–S111 REMOVAL trial, S74 repaglinide, S79, S81 tai chi, S43 UK Prospective Diabetes Study (UKPDS), S59, S96 retinal photography, S109, S110 tapentadol, S112–S113 retinopathy, S44, S109–S111, S131 TECOS, S97–S99 VADT trial, S59, S60 REVEAL trial, S94 testosterone levels, S34 venlafaxine, S113 risk management thiazolidinediones, S76, S79, S81, S83, S122 – calculator, S92 S93 thyroid disease, S129 weight management, S41, S52, S66–S67, S88 revisions summary, S5 tobacco, S44–S45 statins based on, S92 tramadol, S113 Xenical (orlistat), S68 stratification, S92 tricyclic antidepressants, S113 rosiglitazone, S79, S81 2-h PG testing, S14 rosuvastatin, S92, S95 type 1 diabetes yoga, S43