Clinical Updates in Type 2 Diabetes

Clinical Updates in Type 2 Diabetes An Evolving Role for Combinations of Injectable Antihyperglycemic Therapies

Faculty

John L. Leahy, MD Professor, Department of Medicine Co-Director, Division of Endocrinology, Diabetes and Metabolism University of Vermont Larner College of Medicine Burlington, Vermont University of Vermont Research Facility Colchester, Vermont

Dr. Jack Leahy is the Sarah Nichols Gruenig Green & Gold Professor of Diabetes Research, and Co-Chief of the Division of Endocrinology, Diabetes and Metabolism, at the University of Vermont Larner College of Medicine in Burlington.

Dr. Leahy’s research interests include the molecular and pathophysiological basis for the pancreatic β-cell dysfunction in type 2 diabetes, the use of animal and cell systems to investigate the β-cell signaling and fuel metabolism basis for successful β-cell compensation for metabolic stresses, and how these systems fail, resulting in type 2 diabetes. Dr. Leahy is currently the principal investigator in studies examining the molecular mechanisms of β-cell compensation and failure.

Dr. Leahy has authored and coauthored many book chapters and articles, the latter of which have appeared in such peer-reviewed journals as Diabetes, The Journal of Clinical Investigation, and The New England Journal of Medicine. In addition, he coedited 2 books on clinical care for people with diabetes, and was Editor-in-Chief of the journal volume entitled Insulin Therapy and Your Practice: Strategies for Improving Patient Outcomes, published by the American Diabetes Association.

After earning his medical degree at the Medical College of Virginia in Richmond, Dr. Leahy completed his internship, residency, and chief residency in medicine, and then his clinical fellowship in endocrinology and his fellowship in research at the same institution. He is board certified in internal medicine and in endocrinology and metabolism.

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Javier Morales, MD, FACP, FACE Associate Clinical Professor of Medicine Donald and Barbara Zucker School of Medicine at Hofstra Northwell Hempstead, New York Vice President Advanced Internal Medicine Group, PC East Hills, New York

Dr. Javier Morales is in private practice with the Advanced Internal Medicine Group in Great Neck, New York.

After having graduated from the University of Medicine and Dentistry of New Jersey—New Jersey Medical School in Newark, he completed residencies at Memorial Sloan-Kettering Cancer Center and North Shore University Hospital, where he served as Chief Medical Resident. He serves on multiple committees at St. Francis Hospital in Roslyn, New York. In addition to coauthoring several publications, he has served as principal investigator for a number of studies and clinical trials.

Active in the educational sector, Dr. Morales has presented at many continuing education symposiums both nationally and internationally. He further serves as clinical instructor for several nurse practitioner programs and physician assistant programs, in addition to the internal medicine residency program at North Shore University Hospital and Winthrop University Hospital, where he is an Associate Clinical Professor of Medicine.

In addition to being an avid musician and percussionist, Dr. Morales is fluent in Spanish, Italian, and Portuguese. A fellow of the Interamerican College of Physicians and Surgeons, he is also a member of the American Medical Association, American College of Physicians, American Society of Clinical Pathologists, National Hispanic Medical Association, Nassau County Medical Society, American Academy of Family Physicians, and the American Association of Clinical Endocrinologists.

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Preamble

Target Audience The educational design of this activity addresses the needs of primary care providers and other clinicians involved in the ongoing management of patients with type 2 diabetes mellitus (T2DM).

Statement of Need/Program Overview Despite recent signs of success in slowing the United States’ epidemic of type 2 diabetes mellitus (T2DM), many patients are not consistently meeting recommended targets for blood glucose levels.1,2 Poorly controlled T2DM continues to place tremendous burdens on affected individuals, their families, and health care systems.3-5 Over the two last decades, a better pathophysiologic understanding of the disease has spurred the development of new and expanding classes of antihyperglycemic medications.6-8 These include new long-acting basal insulin analogs with reduced hypoglycemia risks and several pleiotropic agonists of glucagon-like peptide-1 (GLP-1) receptors.9,10 These advances have naturally led to studies evaluating outcomes when T2DM is treated with multidrug regimens comprising agents from both injectable medication classes.11 In fact, two fixed-dose combination formulations are now available in the United States.12-14 With overall goals of improving glycemic control and reducing long-term risks among the diverse patient populations, this multimedia eHealth Source™ activity focuses on the mechanistic rationale, the clinical trial data for efficacy and safety, and the practical considerations for combining basal insulin analogs and GLP-1 receptor agonists to better manage T2DM antihyperglycemic medication classes.

References 1.

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Gregg EW. The changing tides of the type 2 diabetes epidemic—smooth sailing or troubled waters ahead? Kelly West Award Lecture 2016. Diabetes Care. 2017;40(10):1289-1297.

2. Carls G, et al. Achievement of glycated hemoglobin goals in the US remains unchanged through 2014. Diabetes Ther.

2017;8(4):863-873.

3. Liu J, et al. The burden of severe hypoglycemia in type 2 diabetes. Curr Med Res Opin. 2017:1-19.

4. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes. 2008;26(2):77-82.

5. Chawla A, et al. Microvascular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab. 2016;20(4):546-551.

6. American Diabetes Association. Standards of Medical Care in Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S1-S135.

7. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.

8. Garber AJ, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2017 Executive Summary. Endocr Pract.

2017;23(2):207-238.

9. Ratner RE, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab. 2013;15(2):175-184.

10. Trujillo JM, et al. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2015;6(1): 19-28.

11. Eng C, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228-2234.

12. Valentine V, et al. Rationale for, initiation and titration of the basal insulin/GLP-1RA fixed-ratio combination products, IDegLira and iGlarLixi, for the management of type 2 diabetes. Diabetes Ther. 2017;8(4):739-752.

13. Linjawi S, et al. The efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial. Diabetes Ther.

2017;8(1):101-114.

14. Rosenstock J, et al. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: The LixiLan-O randomized trial. Diabetes Care. 2016;39(11):2026-2035.

Educational Objectives After completing this activity, the participant should be better able to: • Describe the clinical rationale for combining insulin and incretin-based agents in the treatment of patients with T2DM • Discuss the clinical profiles and prescribing considerations for combinations of injectable antihyperglycemic agents in the management of T2DM • Intensify antihyperglycemic regimens with injectable combination medications based on progress toward individualized glycemic targets, risks of hypoglycemia, and other patient-specific parameters • Educate patients with T2DM to motivate lifestyle modifications, reduce hypoglycemia risks, and enhance treatment adherence

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

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Physician Credit Designation Global Education Group designates this activity for a maximum of 1.5 AMA PRA Category 1 Credits™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Instructions to Receive Credit To receive CME credit, participants should direct their Web browsers to http://www.ExchangeCME.com/ T2DMeHealth17. Participants will have two attempts to obtain a passing grade of 70% on the posttest and be eligible to obtain CME credit

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: John L. Leahy, MD Honoraria: Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk Inc.; sanofi-aventis U.S. LLC. Javier Morales, MD, FACP, FACE Consultant/Independent Contractor: Abbott Laboratories; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk Inc. Honoraria: Abbott Laboratories; Eli Lilly and Company; Novo Nordisk Inc. Speakers Bureau: Abbott Laboratories; Eli Lilly and Company; Janssen Pharmaceuticals, Inc. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Ashley Marostica, RN, MSN

Nothing to disclose

Andrea Funk

Nothing to disclose

Laura Gilsdorf

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

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Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Integritas do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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Type 2 Diabetes and Injectable Antihyperglycemic Agents More than 30 million Americans have a diabetes disorder, and almost 85 million adults in the United States have prediabetes.1-3 Approximately 90% of the identified cases are type 2 diabetes mellitus (T2DM).1-3 Because the risk of developing this diabetes disorder is higher when patients are older, overweight or obese, or of certain racial or ethnic backgrounds, the incidence of T2DM will very likely continue to increase as the general population ages and high-risk cohorts expand.1,4 This trend will undoubtedly present challenges for clinicians and health care systems: a growing volume of T2DM cases will need to be diagnosed, after which patients require a comprehensive management plan based on their individual medical, psychosocial, and educational needs. Primary care providers (PCPs) are expected to assume much of the responsibility for identifying and longitudinally treating the growing and heterogeneous population of patients with T2DM.5 Both annually updated guidelines from either the American Diabetes Association (ADA) or the American Association of Clinical Endocrinologists (AACE) support intensifying antihyperglycemic regimens as often as every 3 months until patients reach individualized glycemic targets.6,7 Each of these societies also stress the importance of minimizing treatment-related adverse events (eg, hypoglycemia), offer advice on reducing patients’ risks of long-term cardiovascular complications, and review the clinical profiles of various antihyperglycemic classes that can be added-on to the most commonly used first-line agent, metformin.6,7 While the ADA does not specifically highlight preferred options among the second-line antihyperglycemic classes, the AACE has created a suggested hierarchy of medications based on efficacy and safety, which clinicians can consider when metformin alone fails to get patients to agreed-upon glycemic goals (Figure 1.1).

6,7 This multiformat eHealth Source™ activity reviews the rationale and latest clinical trial evidence for injectable antihyperglycemic medications in T2DM management, with a focus on potential benefits, risks, and prescribing considerations when basal insulin analogs and agonists of glucagon-like peptide 1 (GLP-1) receptors are combined in individualized treatment regimens.

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A Multidimensional Pathophysiology in T2DM Development T2DM typically evolves insidiously over many years.8,9 The pathophysiology of the disease is multidimensional (Video 1). Numerous cardiometabolic pathways that normally govern glucose homeostasis become dysregulated, promoting the development and progression of persistent hyperglycemia.10 Abnormal pancreatic islet cell function is a defining feature of T2DM. Initially, aberrantly elevated blood glucose levels, especially after meals, reduce insulin sensitivity in tissues throughout the body.11,12 The consequently higher demand for insulin from pancreatic β cells increases their workload and the associated risk for cellular degeneration, both of which have been detected as much as a decade before patients meet the diagnostic criteria for T2DM.11,12 In patients with prediabetes or early-stage disease, insulin secretion by β cells is generally normal or increased in absolute terms, but remains inadequate as various organs and tissues become increasingly insensitive to the effects of the

VIDEO 1: Pathophysiology of T2DM John L. Leahy, MD

circulating hormone.13 Eventually, β cells can no 8

longer produce enough insulin to compensate for its reduced effects. Clinically, these changes are first revealed by prolonged periods of postprandial hyperglycemia, which are followed by persistently elevated fasting plasma glucose (FPG) concentrations. Over time, the increased burden of insulin resistance takes its toll and β-cell failure becomes more prevalent, leading to a lowered capacity for insulin secretion and continued rises in blood glucose levels.

In addition to β-cell loss, pancreatic α cells secrete more glucagon, a peptide hormone that promotes the conversion of hepatically stored glycogen into glucose that is then released into the bloodstream.10 Thus, the liver overproduces glucose under basal conditions, and postprandial insulin release fails to generate the usual suppression of hepatic glucose production.10,12 Patients with T2DM also show deficiencies in signaling by incretin hormones, important mediators of physiologic processes that control postprandial rises in blood glucose levels.10,14-16 Muscles become increasingly insulin resistant, such that they remove less circulating glucose from the bloodstream.10 Fat cells—particularly those associated with visceral adiposity—also play pathogenic roles in T2DM. Insulin resistance in these cells decreases their ability to store energy as fat, leading to increased lipolysis, rises in free fatty-acid plasma concentrations, and stimulation of gluconeogenesis.10 Dysfunctional fat cells also produce proinflammatory adipocytokines, and do not secrete enough signaling factors that normally sensitize other tissues to insulin.10 Additionally, in the diabetic kidney, the normally adaptive recapture of glucose that has been filtered out of the bloodstream becomes counterproductive.10 Despite the general state of hyperglycemia, the kidneys continue to reabsorb glucose from renal tubules. In fact, some evidence suggests that the renal reabsorptive capacity for glucose actually increases in T2DM partly owing to the increased expression and activities of transmembrane proteins that return glucose to the bloodstream from the glomerular filtrate.10 Over the last few decades, a deeper understanding of T2DM pathophysiology has revealed the interconnected processes driving disease development and progression, while increasingly supporting the use of rational combinations of antihyperglycemic medications to address multiple underlying disease mechanisms. Additionally, this research has led to the creation of new antihyperglycemic medications with novel mechanisms of action, and aided in the development of new options in established drug classes with improved safety profiles.

Injectable Antihyperglycemic Agents for T2DM GLP-1 Receptor Agonists The incretin system was originally hypothesized based on observations of higher levels of pancreatic insulin release when glucose is administered orally vs intravenously—ie, the incretin effect.17 Subsequent research identified peptide hormones—eg, GLP-1 and gastric inhibitory polypeptide—that are quickly released into the bloodstream by gastrointestinal L cells and K cells, respectively, after nutrients are consumed.18 These hormones travel to the pancreas, where they stimulate glucose-dependent insulin release from β cells.17,19 Additionally, there is an growing body of evidence showing that the incretins are markedly pleiotropic (Video 2). For instance, in the presence of glucose, GLP-1 suppresses glucagon release from pancreatic α cells, resulting in the inhibition of hepatic glucose production.18 Other effects of GLP-1 include slowing the rate of gastric emptying, which creates a feeling of fullness, while also spreading out the intestinal absorption of ingested carbohydrates, fat, and protein over time to help blunt postprandial spikes in blood glucose levels.20

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Other studies have shown that GLP-1 may increase insulin biosynthesis, reduce endogenous insulin resistance, and induce satiety when its receptors are activated in certain areas of the central nervous system (CNS).10,21-23 In summary, 4 major glucoregulatory effects of GLP-1 support the idea that activating this signaling pathway is an attractive option to reduce hyperglycemia in patients with T2DM: 1) glucosedependent augmentation of insulin secretion from pancreatic β cells; 2) glucose-dependent inhibition of glucagon secretion from pancreatic α cells, VIDEO 2: Physiologic Effects of GLP-1 leading to less hepatic glucose production; 3) Javier Morales, MD slowing of gastric emptying and nutrient uptake into the bloodstream after food is ingested; and 4) promotion of satiety and reduction in appetite in part via activation of central neural circuits. Of note, patients with T2DM may show decrements in incretin hormone secretion, yet physiologic responses to GLP-1 receptor activation remain intact. Furthermore, endogenous GLP-1 is usually degraded quickly to a biologically inactive peptide by the relatively ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4).24 To circumvent this enzymatic degradation and enhance GLP-1 signaling, some patients with T2DM are prescribed oral medications that inhibit the activity of DPP-4, thereby prolonging the effects of the native GLP-1 hormone.24 However, although various DPP-4 inhibitors are approved to improve glycemic control in patients with T2DM, their glucose-lowering effects are relatively modest compared with other antihyperglycemic classes.25 Moreover, inhibiting endogenous GLP-1 degradation to maintain physiologic levels of the circulating hormone does not appear to markedly activate CNS receptors, which is supported by the weight-neutral effects of DPP-4 inhibitors in clinical trials.25 Alternatively, patients can be treated with injectable agonists of GLP-1 receptors. These synthetic peptides are designed to resist DPP-4–mediated cleavage and are administered at dosages that result in supraphysiologic levels of the hormone analogs, leading to .prolonged GLP-1 receptor activation throughout the body.24,26 This includes CNS networks involved in satiation, which contribute clinically to reductions in patients’ body weight when these agents are prescribed for T2DM. 24,27,28

As of August 2017, six injectable GLP-1 receptor agonists have been approved by the US Food and Drug Administration (FDA) as adjuncts to diet and exercise to improve glycemic control in adults with T2DM: dulaglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, and albiglutide (note that the manufacturer of albiglutide will

VIDEO 3: FDA-Approved GLP-1 Receptor Agonists Javier Morales, MD 10

discontinue producing the medication by July 2018) (Video 3).29-34 Additionally, at least 1 more injectable GLP-1 receptor agonist (semaglutide) is expected to receive regulatory approval in late 2017â&#x20AC;&#x201D; in October 2018, the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 16-0 in favor of approving of semaglutide once-weekly to improve glycemic control in adults with T2DM.35,36 The approved medications are often classified into short-acting (half-life <12 hours) and long-acting agents (half-life â&#x2030;Ľ12 hours) (Table 1.1).

29-34 Both GLP-1 receptor agonist subclasses can robustly reduce fasting and postprandial hyperglycemia.

However, short-acting agents are thought to have particularly strong effects on postprandial glucose excursions.37 On the other hand, long-acting formulations mitigate postprandial hyperglycemia while also producing sustained reductions in FPG levels, which together result in larger decreases in glycated hemoglobin (A1c) values compared with the short-acting GLP-1 receptor agonists.37

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Clinical trials with each approved GLP-1 receptor agonist have also shown treatment-related weight loss, an important clinical outcome for patients who are often overweight or obese.38 Hypoglycemia risks are relatively low, in part because GLP-1–induced insulin secretion and inhibition of glucagon release are glucosedependent. Thus, these effects and the associated reduction in hepatic glucose production fade after nutrients have been ingested and circulating glucose levels begin to fall.18,21,39 Cardiometabolic benefits of GLP-1 receptor agonists in recent meta-analyses include a small lowering of systolic blood pressure (average between –2 and –5 mm Hg across agents) and lower circulating lipid levels (up to –6 mg/dL for low-density lipoprotein cholesterol, –26.5 mg/dL for triglycerides with liraglutide 1.8 mg once daily).40,41 Current evidence from FDA-mandated studies designed specifically to assess long-term cardiovascular safety demonstrates that 2 drugs from this antihyperglycemic class (liraglutide and semaglutide) can decrease risks of major adverse cardiovascular events.42,43 The most common adverse events with GLP-1 receptor agonists are gastrointestinal (ie, nausea, vomiting, and diarrhea).29-34 However, these side effects are often transient after therapy is initiated, and can potentially be avoided via proper dose titration and patient education on recommendations related to meal size, eating pace, and drug administration relative to meal timing.29-34 These trial data and real-word clinical experience with these injectable agents reveal the class to be highly effective at reducing hyperglycemia with a relatively positive profile regarding physiologic effects and safety issues.

Basal Insulin Analogs The other frequently prescribed injectable antihyperglycemic class comprises the insulins. Most patients with T2DM will eventually require some form of insulin replacement therapy. Insulin should be considered immediately to lower glucose levels quickly when newly diagnosed cases present with extreme hyperglycemia or clear signs of glucotoxicity.6,7 Examples include patients with FPG levels consistently >300 mg/dL, A1c values >10%, ketonuria, or other symptomatic issues, such as polyuria, polydipsia, or substantial weight loss.6 Advantages of insulin therapy for T2DM include its nearly universal efficacy for reducing hyperglycemia and the theoretical option to titrate the dosage up indefinitely until FPG levels reach recommended targets (often safety issues override doing this clinically).6 Moreover, clinical trials have shown that, when properly used, insulin replacement therapy can reduce long-term microvascular risks in patients with T2DM by improving glycemic control.6 On the other hand, relatively high risks for hypoglycemia and weight gain, and the potential to eventually need up to 4 injections daily can leave both patients and providers reluctant to initiate insulin.6 Therefore, it is important that providers frame these issues relative to the likely deleterious consequences of uncontrolled hyperglycemia. And even before insulin therapy is needed, it should not be described as an undesirable option if other approaches fail or used as a threat to patients about the ramifications of poor adherence to current treatment regimens.6 Both ADA and AACE guidelines include algorithms outlining preferred approaches to initiating and titrating basal insulin therapy (visit the Clinical Resource Center for this activity).6,7 Key recommendations found in both guidelines include individualizing glycemic targets based on a full medical and psychosocial picture of each patient, taking steps to reduce hypoglycemia and weight gain, discontinuing sulfonylureas (or at least reducing doses) when adding insulin (and/or a GLP-1 receptor agonist), and titrating doses stepwise to achieve the desired efficacy and safety outcomes.6,7 The last 2 decades have seen an increase in the number of available basal insulin medications (Table 1.2). Long-acting basal insulin analogs produce less hypoglycemia compared with neutral protamine Hagedorn (NPH) insulin.6,44 Furthermore, recent clinical 12

studies have shown newer ultra-long-acting options (eg, insulin degludec and insulin glargine 300) display reduced pharmacodynamic variability over 24 hours and lower rates of overall, nocturnal, and severe hypoglycemia compared with older long-acting basal insulin analogs.6,44-47

Key Clinical Highlights • T2DM development and progression are driven by multiple pathophysiologic processes, highlighting the need for appropriately intensified and mechanistically diverse treatment regimens • A better understanding of T2DM pathophysiology has supported the development of novel antihyperglycemic classes, such as GLP-1 receptor agonists • Newer basal insulin analogs with improved clinical profiles (eg, less pharmacodynamic variability, reduced hypoglycemia risks) are available to treat patients with T2DM

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CDC. Diabetes at a Glance 2016: Working to Reverse the US Epidemic. Atlanta, GA: National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention; 2016. https://www.cdc.gov/chronicdisease/ resources/publications/aag/pdf/2016/diabetes-aag.pdf.

Dabelea D, et al. Incidence of diabetes in youth in the United States. JAMA. 2007;297(24):2716-2724.

CDC. Diabetes Report Card 2012. 2012. http://www.cdc.gov/diabetes/pubs/pdf/DiabetesReportCard.pdf.

Seidu S, et al. Integrated primary care: is this the solution to the diabetes epidemic? Diabet Med. 2017;34(6):748-750.

American Diabetes Association. Standards of Medical Care in Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S1-S135.

Garber AJ, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2017 Executive Summary. Endocr Pract.

2017;23(2):207-238.

Berends LM, Ozanne SE. Early determinants of type-2 diabetes. Best Pract Res Clin Endocrinol Metab. 2012;26(5):569-580.

Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet. 2012;380(9841):601-610.

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Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev. 2007;28(3):253-283.

Freeman JS. Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.

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Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6): 819-837.

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Klonoff DC, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275-286.

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Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.

Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19): 1834-1844.

Marso SP, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;376(9):891-892.

Wysham C, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA. 2017;318(1):45-56.

Ritzel R, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab. 2015;17(9): 859-867.

Heise T, et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14(9):859-864.

US Department of Health and Human Services. Drugs@FDA: FDA approved drug products. https:// www.accessdata.fda.gov/scripts/cder/daf/. Accessed August 21, 2017.

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Rationale and Evidence for Combining GLP-1 Receptor Agonists and Basal Insulin Analogs Over the last decade, published reviews from expert diabetologists and a number of randomized controlled studies have explored theoretical advantages, multiparameter clinical efficacy, and potential safety concerns associated with treating type 2 diabetes mellitus (T2DM) by coadministering a basal insulin analog and an incretin-based agentâ&#x20AC;&#x201D;in particular, a glucagon-like peptide-1 (GLP-1) receptor agonist.1-7 The available evidence largely supports using both injectable medication classes as a rational approach when metformin and either a basal insulin analog or a GLP-1 receptor agonist alone fail to get patients to individualized glycemic targets.1-7 In fact, in late 2016, two fixed-ratio, two-drug combination formulations were approved by the US Food and Drug Administration (FDA) to treat adult patients with T2DM: insulin degludec with liraglutide coadministered as IDegLira and insulin glargine plus lixisenatide injected together as iGlarLixi.8-10

Rationale for Combining Basal Insulin Analogs and GLP-1 Receptor Agonists The potential benefits of concomitantly treating T2DM with both injectable antihyperglycemic classes were initially predicted based on the complementary physiologic activities of the GLP-1 hormone and long-acting insulin analogs. For example, basal insulin is very effective at reducing fasting plasma glucose (FPG) levels and nocturnal hyperglycemia, in large part owing to sustained inhibition of hepatic glucose production.11 All of the available GLP-1 receptor agonists can also markedly improve FPG concentrations.12,13 Further, because the pancreatic activities of GLP-1 receptor agonists are glucose-dependent, these medications are particularly effective at controlling glycemic excursions after meals, with the strongest postprandial effects observed with agents injected at least once daily (subsequently discussed in more detail).14-17 Thus, adding a GLP-1 receptor agonist can benefit patients who achieve FPG targets with basal insulin (with or without metformin), but fail to reach overall A1c goals.18 In many cases, GLP-1 receptor agonist/basal insulin combinations may be preferred to basal/bolus insulin regimens; using the incretin-based agent instead of prandial insulin can lessen management burdens for patients and prescribersâ&#x20AC;&#x201D;for example, curtailing the need for patient education about monitoring carbohydrate intake and blood glucose levels, or in some cases reducing the number of daily injections).1,19 16

Combining these classes may also maximize pancreatic β-cell survival in patients with T2DM. Administering exogenous insulin likely allows β cells to “rest” despite an increasing demand for insulin as T2DM progresses.20 Other studies suggest that GLP-1 receptor agonists also prevent β-cell failure, potentially by inhibiting T2DM-mediated proapoptotic signaling.17,21,22 In one preclinical β-cell model, incubations with an insulin analog and a GLP-1 receptor agonist resulted in an 80% reduction in the number of apoptotic cells after the samples were exposed to harmful cytokines and fatty acids, suggesting that these medications have synergistic effects on β-cell survivial.23 Additional studies are needed to confirm the clinical relevance of these findings by reproducing these outcomes in patients with either new-onset or more established T2DM. Finally, treatment-related side effects can be mitigated by combining GLP-1 receptor agonists and basal insulin analogs instead of intensifying therapy by up-titrating the dosage of one agent—often a basal insulin medication—to obtain adequate efficacy. American Diabetes Association (ADA) guidelines note that, among the second-line postmetformin options, basal insulin analogs are most likely to subject patients to hypoglycemia.18 Adding a GLP-1 receptor agonist can reduce the daily basal insulin dosage needed to consistently maintain a near-euglycemic state, thereby lowering the risk of hypoglycemia.24 Additionally, unlike insulin replacement therapy, GLP-1 receptor agonists generally result in weight loss and ameliorate insulin-induced weight gain in injectable combination regimens.18,25,26 On the other side, gastrointestinal adverse events associated with GLP-1 receptor agonists were less frequent in some studies when both injectable medications were administered vs the incretin-based medications alone.4,24

Clinical Options for Combining Basal Insulin Analogs and GLP-1 Receptor Agonists As of September 2017, dulaglutide was the only GLP-1 receptor agonist specifically approved by the FDA for use in combination with either basal insulin analogs or prandial insulin injections.27-32 The FDA also supports coadministration of albiglutide, exenatide twice daily, liraglutide, or lixisenatide with a basal insulin analog (but not prandial insulin injections), whereas no studies reviewed by the FDA have addressed the use of exenatide once weekly with either basal or prandial insulin.27-32 Even so, optimally individualizing T2DM management based on clinical presentations, patient preferences, and reimbursement options will likely require clinicians to consider the full range of potential insulin/GLP-1 receptor agonist combinations. The peer-reviewed literature includes numerous T2DM trials conducted with different injectable drug regimens, study designs, patient cohorts, and comparators. A metaanalysis published in April 2017 identified 26 highquality studies that met predefined inclusion VIDEO 4: GLP-1 Receptor Agonist and Basal criteria (a 2014 meta-analysis from Lancet included Insulin Combination Products 15 studies).7,33 In the vast majority of these trials, John L. Leahy, MD

17

basal insulin/GLP-1 receptor agonist combinations produced significantly better A1c outcomes than various other injectable comparators, often with reductions in final body weight and without notably increasing hypoglycemia risks (Figure 2.1).7,33 As noted previously, similar results have been observed in trials evaluating the 2 fixed-dose combination formulations containing a GLP-1 receptor agonist and a basal insulin analog (Video 4).4,6,34-37

Clinical Trials With IDegLira (Insulin Degludec Plus Liraglutide) IDegLiraâ&#x20AC;&#x201D;a fixed-dose combination of the basal analog insulin degludec and the GLP-1 receptor agonist liraglutideâ&#x20AC;&#x201D;has been approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM inadequately controlled by basal insulin (>50 units daily) or liraglutide.10 Of the two combination formulations, more phase 3 studies with IDegLira have been completed (the DUAL studies), many of which have summarized results published in peer-reviewed journals and/or presented at major

18

medical conferences.5,6,24,35,37-39 For example, the 26-week DUAL I trial evaluated insulin-naĂŻve adults with uncontrolled T2DM despite treatment with oral antihyperglycemic agents.24 Study subjects were randomized to daily injections of IDegLira, insulin degludec, or liraglutide 1.8 mg. IDegLira (with a maximum of 50 units) and insulin degludec were titrated up until patients achieved target prebreakfast plasma glucose levels. A subsequent analysis of the DUAL I extension trial categorized patients into quartiles based on baseline A1c values; each subgroup treated with IDegLira finished with a mean A1c level â&#x2030;¤7.0%, including patients with A1c values >9.0% at baseline.40 In addition to significantly greater efficacy compared with either monotherapy, IDegLira was less likely to cause hypoglycemia compared with insulin degludec alone, and fewer gastrointestinal adverse events vs liraglutide alone.40 The efficacy results of many of the DUAL studies are summarized in Table 2.1 (DUAL VI is discussed in a subsequent section, whereas DUAL VIII does not have reported results as of October 2017).5,6,38-40 It is important to note that the IDegLira combination formulation carries the warnings, contraindications, and potential for adverse reactions associated with each of the component medications, which should be assessed for and communicated to patients before initiating therapy.10

Clinical Trials With iGlarLixi (Insulin Glargine and Lixisenatide) The other fixed-dose combination formulation containing a basal insulin analog and a GLP-1 receptor agonist is iGlarLixi, which has been approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM inadequately controlled by basal insulin (>60 units daily) or lixisenatide.9 Two phase 3 studies have been published with iGlarLixi: LixiLan-O compared iGlarLixi with either insulin glargine

19

or lixisenatide as add-ons to metformin in patients with T2DM not controlled on oral agents, whereas LixiLanL examined the combination drug vs both individual components in cases of T2DM not controlled with basal insulin and ≤2 oral antihyperglycemic agents.4,34 In LixiLan-O, iGlarLixi more effectively reduced A1c levels than either single component, and the addition of the short-acting GLP-1 receptor agonist prevented the weight gain observed with insulin glargine alone (Figure 2.2). Compared with those in the iGlarLixi-treated group, patients randomized to insulin glargine experienced similar rates of symptomatic hypoglycemia (22% vs 24%, respectively), whereas those treated with lixisenatide more frequently reported gastrointestinal side effects (22% vs 37%, respectively).4 Initiating iGlarLixi, like IDegLira, requires assessment and patient education about the warnings, contraindications, and potential for adverse reactions associated with each of the component medications before initiating therapy.

Key Clinical Highlights • Basal insulin analogs and GLP-1 receptor agonists have complementary physiologic effects as antihyperglycemic therapies, supporting coadministration of these agents to treat T2DM • Combining a GLP-1 receptor agonist with a basal insulin analog can reduce certain safety and tolerability risks associated with the use of either injectable agent alone • The FDA has approved the fixed-dose combination formulations insulin degludec/liraglutide (IDegLira) and insulin glargine/lixisenatide (iGlarLixi) for adults with T2DM that is inadequately controlled by either of the component medications

20

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Anderson SL, Trujillo JM. Basal insulin use with GLP-1 receptor agonists. Diabetes Spectr. 2016;29(3):152-160.

Giorgino F, et al. Treatment intensification in patients with inadequate glycemic control on basal insulin: rationale and clinical evidence for the use of short-acting and other glucagon-like peptide-1 receptor agonists. Diabetes Metab Res Rev. 2016;32(6):497-511.

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Mathieu C, et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes Obes Metab. 2014;16(7):636-644.

Rosenstock J, et al. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLanO randomized trial. Diabetes Care. 2016;39(11):2026-2035.

Buse JB, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira).

Diabetes Care. 2014;37(11):2926-2933.

Linjawi S, et al. The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical Ttrial. Diabetes Ther.

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Valentine V, et al. Rationale for, initiation and titration of the basal insulin/GLP-1RA fixed-ratio combination products, IDegLira and iGlarLixi, for the management of type 2 diabetes. Diabetes Ther. 2017;8(4):739-752.

Soliqua (insulin glargine 100 units/mL and lixisenatide 33 Âľg/mL) [prescribing information]. Initial US approval 2016.

Bridgewater, NJ: sanofi-aventis U.S. LLC; 2017.

Xultophy (insulin degludec 100 units/mL and liraglutide 3.6 mg/mL) [prescribing information]. Initial US approval 2016.

Bagsvaerd, Denmark: Novo Nordisk A/S; 2016.

Moore MC, et al. Comparison of insulins detemir and glargine: effects on glucose disposal, hepatic glucose release and the central nervous system. Diabetes Obes Metab. 2011;13(9):832-840.

Buse JB, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallelgroup, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.

Pratley RE, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2(4):289-297.

Uccellatore A, et al. Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists.

Diabetes Ther. 2015;6(3):239-256.

Holst JJ, Vilsbøll T. Combining GLP-1 receptor agonists with insulin: therapeutic rationales and clinical findings. Diabetes Obes Metab. 2013;15(1):3-14.

Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.

Diabetes Care. 2015;38(1):140-149.

Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12): 728-742.

American Diabetes Association. Standards of Medical Care in Diabetes--2017. Diabetes Care. 2017;40(suppl 1):S1-S135.

Garber AJ, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm â&#x20AC;&#x201D; 2017 executive summary. Endocr Pract.

2017;23(2):207-238.

Brown RJ, Rother KI. Effects of beta-cell rest on beta-cell function: a review of clinical and preclinical data. Pediatr Diabetes. 2008;9(3 Pt 2):14-22.

Natalicchio A, et al. Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway. Diabetologia. 2013;56(11):2456-2466.

Natalicchio A, et al. Exendin-4 prevents c-Jun N-terminal protein kinase activation by tumor necrosis factor-alpha (TNFalpha) and inhibits TNFalpha-induced apoptosis in insulin-secreting cells. Endocrinology. 2010;151(5):2019-2029.

Tews D, et al. Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues. Horm Metab Res. 2008;40(3): 172-180.

Gough SC, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulinnaive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2(11):885-893.

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Sun F, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res. 2015;2015:157201.

Potts JE, et al. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: a systematic review and mixed treatment comparison meta-analysis. PLoS One. 2015;10(6):e0126769.

Byetta (exenatide twice daily) [prescribing information]. Initial US approval 2005. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.

Trulicity (dulaglutide) [prescribing information]. Initial US approval 2014. Indianapolis, IN: Eli Lilly and Company; 2017.

Victoza (liraglutide) [prescribing information]. Initial US approval 2010. Bagsvaerd, Denmark: Novo Nordisk A/S; 2017.

Bydureon (exenatide extended-release) [prescribing information]. Initial US approval 2012. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

Adlyxin (lixisenatide) [prescribing information]. Initial US approval 2016. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2016.

Tanzeum (abiglutide) [prescribing information]. Initial US approval 2014. Wilmington, DE: GlaxoSmithKline LLC; 2017.

Maiorino MI, et al. Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2017;40(4):614-624.

Aroda VR, et al. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial. Diabetes Care.

2016;39(11):1972-1980.

Buse JB, et al. IDegLira, a novel fixed ratio combination of insulin degludec and liraglutide, is efficacious and safe in subjects with type 2 diabetes: a large, randomized phase 3 trial. Paper presented at: 73rd Scientific Sessions of the American Diabetes Association; June 21-25, 2013, 2013; Chicago, IL. Abstract OR/0065.

Harris SB, et al. Safety and efficacy of IDegLira titrated once weekly versus twice weekly in patients with type 2 diabetes uncontrolled on oral antidiabetic drugs: DUAL VI randomized clinical trial. Diabetes Obes Metab. 2017;19(6):858-865.

Lingvay I, et al. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA. 2016;315(9):898-907.

Rodbard HW, et al. Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naive people with type 2 diabetes: the DUAL IV trial. Diabet Med. 2017;34(2): 189-196.

Billings LK, et al. Efficacy and safety of insulin degludec/liraglutide (IDegLira) vs. basal-bolus (BB) therapy in patients with type 2 diabetes (T2D): DUAL VII trial. Paper presented at: 77th Scientific Sessions of the American Diabetes Association; June 9-13, 2017; San Diego, CA. Abstract 124-LB. Rodbard HW, et al. Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes. Diabetes Obes Metab. 2016;18(1):40-48.

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Intensifying Injectable Antihyperglycemic Regimens for T2DM Contrary to many dire predictions about the seemingly unrelenting growth of the type 2 diabetes mellitus (T2DM) epidemic in the United States, the most recent epidemiologic data demonstrate potential plateaus in disease incidence and prevalence in the last few years.1,2 Although the improved outlook reinforces the benefits of increased focus on lifestyle management for at-risk cohorts and the positive effects of other public health initiatives, it is important to remember that diabetes disorders are still a top 10 cause of death among Americans.1,2 Current estimates of the direct and indirect costs of T2DM are also massive, with inpatient hospital care accounting for the largest component of diabetes-related expenditures.3-6 Many medical, psychosocial, and economic burdens of T2DM could be mitigated if more patients achieved individualized glycated hemoglobin (A1c) targets concordant with guideline recommendations without facing more frequent treatment-related hypoglycemia.3,4 However, data from the US National Health and Nutrition Examination Survey show that only half of patients with diagnosed T2DM meet the American Diabetes Associationâ&#x20AC;&#x2122;s A1c goal of <7.0%, while A1c values are >9.0% in approximately 1 in 6 cases.3,4,7 Long-term outcomes for patients with T2DM depend on how consistently blood glucose levels are maintained in the appropriate range. Patients with poorly controlled T2DM are more likely to experience a diverse range of disease-related complications. For example, the degree and duration of hyperglycemia correlate with the risks for various microvascular maladies, such as diabetic renal diseaseâ&#x20AC;&#x201D;the most common cause of kidney failure in the United States.8,9 T2DMâ&#x20AC;&#x2122;s other microvascular manifestations include diabetic retinopathy, which contributes to new-onset blindness in approximately 10,000 Americans each year.10 Diabetic neuropathies are also common and often functionally debilitating, potentially affecting both peripheral and autonomic nerves.8 Diabetes-related nerve damage has been detected in up to half of patients with T2DM, with most cases initially presenting as pain and/or numbness in the feet and legs, although the digestive system, urinary tract, blood vessels, and heart can also be affected.8 T2DM also increases the risks of macrovascular complications, including acute coronary syndromes, myocardial infarction, stable or unstable angina, and stroke, to name a few.3,8 Research into the underlying pathophysiologic mechanisms has linked persistent hyperglycemia to chronic inflammation, higher levels of

23

oxidative stress, increased platelet aggregation, and other damaging processes in arterial walls, which can result in the formation of atherosclerotic lesions.8 Interestingly, patients with T2DM who have any of the common microvascular manifestations described above are more likely to experience poor macrovascular outcomes, suggesting that shared or interconnected pathophysiologic processes underlie many T2DMrelated morbidities.9 Additionally, many of the most common coexisting conditions found in patients with T2DM are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD).3 For example, approximately half of the people with T2DM are hypertensive, which quadruples the risk of poor ASCVD outcomes in this cohort.11,12 These data highlight the essential need to assess patients with T2DM at least annually for cardiovascular risk factors, including hypertension, dyslipidemia, smoking status, family history of ASCVD, and albuminuria.3 Moreover, these and other comorbidities should be aggressively managed and proactively considered when glycemic goals are individualized and treatment regimens are intensified.5 Encouragingly, increased knowledge about disease pathophysiology and the perpetually advancing course of T2DM has pushed many clinicians to embrace the need for individualized treatment goals and progressively intensified treatment regimens, while concurrently supporting the development of new antihyperglycemic drug classes and an overall expansion of the therapeutic armamentarium.3,5 This progress is reflected in observational studies that show declining risks of various complications among patients with T2DM, with gains that exceed results observed for the US population as a whole (Figure 3.1).13 To continue pushing for better patient outcomes in the absence of an absolute cure, clinicians must commit to reviewing and adhering to frequently updated clinical practice guidelines, remain open to altering their usual approaches to patient management based on newly published evidence, and encourage patients to actively participate in constructing comprehensive treatment plans and then tailoring regimens when the need arises.3,4

24

Individualizing T2DM Treatment With GLP-1 Receptor and Basal Insulin Analogs In the absence of contraindications or unacceptable tolerability issues, metformin is generally accepted as the first-line medication of choice for newly diagnosed T2DM.3,4 This consensus recommendation reflects metformin’s long history of efficacy and safety, relatively low cost, and published evidence linking metformin to modest weight loss and lower long-term risks of cardiovascular complications and mortality.3,4,14 However, to sustain adequate glycemic control as T2DM progresses, almost all patients require antihyperglycemic regimens that advance beyond recommended lifestyle modifications and maximally dosed metformin alone.

3,4 In fact, discussions of the potential benefits and risks of initiating therapy with multiple medications are warranted when untreated patients present with markedly elevated A1c levels. In the 2017 version of their comprehensive Standards in Medical Care in Diabetes, the American Diabetes Association (ADA) states that initial 2-drug regimens (ie, metformin plus a second agent) should be considered when A1c values are ≥9.0% in newly diagnosed T2DM cases or in other patients not currently taking antihyperglycemic medications.3 The ADA also makes the point that combinations of injectable therapies are appropriate initial regimens when A1c values are ≥10.0%, fasting plasma glucose levels are ≥300 mg/dL, or the patient is markedly symptomatic.3 The glycemic control algorithm published by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) is more aggressive, noting that two-drug regimens are the preferred initial choice when patients enter treatment with A1c values ≥7.5%.4,15 Among the numerous possible combinations of antihyperglycemic classes and individual agents available to treat T2DM, many recent clinical trials and other peer-reviewed publications have focused on the potential benefits of coadministering glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulin analogs.16,17 These efforts largely reflect the promise of simultaneously harnessing the robust glucose-lowering effects of both medication classes, while also taking advantage of safety profiles and secondary benefits observed in clinical trials with GLP-1 receptor agonists. In real-world practice, GLP-1 receptor agonist/basal insulin combination regimens will usually be only considered in patients for whom regimens containing an agent from 1 of the 2 injectable antihyperglycemic classes have failed to provide adequate glycemic control. This is also reflected in the prescribing information sheets for the 2 fixed-dose GLP-1 receptor agonist/basal insulin analog combination formulations approved by the US Food and Drug Administration (FDA) (Table 3.1).

If the clinician and patient agree that combining a GLP-1 receptor agonist and a basal insulin analog is the most attractive next step to achieve adequate glycemic control, the next step is to determine which particular combination is the best choice for that individual. This decision should be made based on published efficacy and safety evidence for the various combinations, patient preferences, previous assessment of treatment adherence, and consideration of unique aspects in the clinical profiles of the individual agents, information from regulatory agencies, and managed care constraints. For example, options for a given patient may at times be narrowed by insurance formularies or, in the case of albiglutide, the manufacturer’s decision to discontinue production within the next 9 months. Furthermore, as discussed in Chapter 2, the FDA’s specific indications differ on using the various GLP-1 receptor agonists with either basal or prandial insulin products, although this inconsistency primarily reflects whether data have been submitted for formal FDA review, rather than efficacy or safety concerns when “off-label” combinations are prescribed.

Clinicians can also consider the published results of numerous head-to-head trials with GLP-1 receptor agonists, many of which have revealed efficacy and/or tolerability differences.20,21 Major themes emerging 25

from these trials included the greater A1c reductions with long-acting GLP-1 receptor agonists (except albiglutide) vs the short-acting options exenatide twice-daily or lixisenatide.20,21 Similarly, certain basal insulin analogs have demonstrated less pharmacodynamic variability and lower risks of overall and nocturnal hypoglycemia relative to other options from the class.22-24 All of these factors need to be integrated into clinical decisions as the injectable therapies are combined during regimen intensification for patients with T2DM.

Considerations Based on Safety and Tolerability The most common tolerability issues reported by patients starting treatment with a GLP-1 receptor agonist are gastrointestinalâ&#x20AC;&#x201D;notably, nausea, vomiting, and diarrhea.25-30 In clinical trials, each of the available agents produced higher rates of these adverse events versus comparators, but the shortacting drugs appear to be somewhat more likely to cause gastrointestinal distress, especially nausea (Video 5).26,30 Alternatively, the FDA-defined contraindications for the use of GLP-1 receptor agonists in patients with multiple endocrine neoplasia syndrome type 2, or a personal or family

VIDEO 5:Â Adverse Events with GLP-1 Receptor Agonists â&#x20AC;¨ John L. Leahy, MD 26

history of medullary thyroid carcinoma currently apply only to the long-acting medications, including the insulin combination formulation with liraglutide (IDegLira).18,25,27-29 Warnings for patients with impaired renal function also vary. All GLP-1 receptor agonists should be used with caution in patients with renal impairment or renal transplant—especially when initiating treatment or escalating doses—because nausea/vomitinginduced hypovolemia can worsen renal function.25-30 However, both exenatide formulations are primarily cleared via the kidneys, and therefore have more strictly defined restrictions in people with impaired renal function: neither should be used in patients with creatinine clearance rates ≤30 mL/min or end-stage renal disease.25,26 Other parameters that shape the selection of individual agents for injectable combination regimens include the somewhat related considerations of cardiovascular and hypoglycemia risks. Indeed, the most common cause of diabetes-related morbidity and mortality is ASCVD, which encompasses acute coronary syndromes, previous myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, and peripheral arterial disease with atherosclerotic etiology.3 In fact, patients with diabetes are more than twice as likely to die from a cardiovascular cause than individuals without diabetes (Figure 3.2).31 Cardiovascular complications also account for more direct and indirect diabetes-related costs than any other factor.3 There is considerable evidence demonstrating that managing variables known to affect cardiovascular event rates can prevent or slow the development of ASCVD in patients with diabetes, especially when multiple risk factors are simultaneously addressed.32,33 Many beneficial cardiometabolic effects of the GLP-1 hormone and the synthetic receptor agonists used to treat T2DM were discussed in Chapter 1. Importantly, the FDA has mandated that all new diabetes drugs be examined in large-scale outcome trials designed to assess cardiovascular safety. Among the results of these studies reported to date, lixisenatide and exenatide once weekly did not significantly increase the risk of major adverse cardiovascular events, although no significant cardioprotective benefits were noted for the patient groups treated with either GLP-1 receptor agonist.34,35 More promisingly, the GLP-1 receptor agonist– treated patients in both the LEADER trial with liraglutide and the SUSTAIN-6 trial with semaglutide showed significantly lower rates of the primary endpoint (composite of cardiovascular-related death, nonfatal myocardial infarction, and nonfatal stroke) compared with the placebo arms (Figure 3.3).36,37 Risks for cardiovascular problems and other poor outcomes can also be reduced by limiting patients’ exposure to hypoglycemia. Not surprisingly, aggressively intensifying antihyperglycemic regimens to drive large reductions in A1c levels may increase the chances that blood glucose levels will drop into hypoglycemic ranges.38 Both severe and more mild episodes of hypoglycemia have been increasingly recognized for their

27

negative cardiovascular effects, contributing to blood coagulation abnormalities, systemic inflammation, endothelial dysfunction, and sympathoadrenal responses with increased noradrenaline release.39 In the seminal ADVANCE trial, mortality rates in patients who experienced severe episodes of hypoglycemia were more than double those in other study subjects (Video 6).40

Initiating Combination Therapy With GLP-1 Receptor Agonists and Basal Insulin Analogs

VIDEO 6:Â Negative Consequences of Hypoglycemiaâ&#x20AC;¨ Javier Morales, MD

As discussed above, the eventual choice of injectable drugs to be coadministered will often include either a GLP-1 receptor agonist or a basal insulin analog that was part of the previous inadequately effective or intolerable treatment regimen. However, in some cases, ongoing discussions about the characteristics of particular options from each medication class or a desire to turn to the IDegLira or iGlarLixi fixed-dose combination formulations may lead to discontinuing the previous injectable medication and then intensifying therapy with 2 agents that are new to the patient. In either case, patients previously on metformin should continue to use the medication with the GLP-1 receptor agonist/basal insulin combinations, whereas other oral agents may be discontinued based on their efficacy and safety in combination with the injectable antihyperglycemics and in the individual patient.3 For example, in light of the high hypoglycemia 28

risks, there is strong support for discontinuing or reducing the dosage of sulfonylureas when basal insulin is added to the treatment plan.3,4 Another issue emerges from the general idea that adding a GLP-1 receptor agonist can reduce the daily insulin doses needed to maintain adequate glycemic control, thereby reducing the risk of hypoglycemia. As noted by many experts, however, there are practical concerns about hypoglycemia when a medication known to markedly decrease FPG values is added to an insulin-based regimen that has already significantly reduced T2DM-related hyperglycemia but failed to get the patient to the target levels for A1c or FPG. This issue should be considered when long-acting GLP-1 receptor agonistsâ&#x20AC;&#x201D;medications that are very effective at inhibiting glucagon release and downstream hepatic glucose productionâ&#x20AC;&#x201D;are added to insulin-based regimens in patients who are somewhat close to recommended A1c targets. Study protocols used in a few clinical trials examining long-acting GLP-1 receptor agonists have demonstrated that this problem can be avoided; clinicians initiating the injectable incretin-based agent reduced the patients' daily insulin doses by 20% when baseline A1c values were â&#x2030;¤8.0%, although the basal insulin may need to be titrated back up after 3 or 4 doses of the long-acting GLP-1 receptor agonist to maximize the efficacy of the regimen and achieve steady-state pharmacokinetics.41

Managing Postprandial Hyperglycemia Blunting postmeal excursions in blood glucose levels has been increasingly recognized as an important management goal for patients with T2DM.42 In fact, as T2DM therapy pushes aberrantly elevated blood glucose levels down toward threshold values that define sufficient glycemic control, postprandial hyperglycemia makes increasingly larger contributions to overall A1c values.43 The most recent guidelines from the ADA highlight adding a GLP-1 receptor agonist as an appropriate option alongside introducing a bolus rapid-acting insulin injection before the largest meal of the day, or transitioning to premixed insulin containing both basal and prandial components injected before breakfast and dinner.3 Interestingly, however, their most recent position statement on individualizing T2DM management specifically notes the growing pool of evidence favoring the use of GLP-1 receptor agonists over mealtime insulin to control postprandial spikes in blood glucose levels.5 AACE/ACE guidelines include the addition of GLP-1 receptor agonist or prandial insulin injections as the first-line options for intensifying treatment to target prandial control.4 Selecting a specific GLP-1 receptor agonist to increase postprandial glycemic control in T2DM requires consideration of the relative effects of the options on postprandial versus fasting hyperglycemia.44 Although all GLP-1 receptor agonists reduce postmeal spikes in blood glucose levels, the short-acting agents are often cited for particularly strong postprandial effects. Nevertheless, clinical trials have shown postprandial benefits with a number of GLP-1 receptor agonists added to basal insulin therapy.45-47 Often the patients receiving the GLP-1 receptor agonist as an add-on to basal insulin achieved similar improvements in postprandial hyperglycemia compared with those treated with basal and bolus insulin regimens.45,46 Subjects in the GLP-1 receptor agonist arms also benefited from significantly larger FPG reductions, lost weight, and experienced fewer episodes of hypoglycemia, whereas gastrointestinal side effects were more prevalent.45-47

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Encouraging Shared Decision-Making and Maximizing Treatment Adherence Many national societies, including the ADA and the AACE, are increasingly emphasizing shared clinical decision-making as a key component of patient-centered health care and a cornerstone of comprehensively managing chronic diseases.4,5 In T2DM, this approach requires clinicians to elicit goals, preferences, potential barriers, and fears from patients who have been educated on the disease, their individualized glycemic goals, and available antihyperglycemic options, including expected outcomes and relative risks.48 To support patients’ participation in these decisions, they must be given relevant information in a form that that reflects their health literacy, medical status, and psychosocial profile.48 Clinicians must also foster patients’ aptitude and desire to voice their questions, aspirations, concerns, and ultimately preferred path forward.48 These conversations are most likely to flourish in empathic, nonjudgmental environments, in which the patient and clinician can openly converse about addressing problems that may arise when an individual is living with T2DM and related illnesses.

The plainly evident need for open and ongoing bidirectional dialogue highlights the promise of the longitudinal clinician-patient relationships that frequently develop in primary care.49,50 On the other hand, time limitations that are increasingly endemic to primary care practices present a significant hurdle to fostering these relationships and allowing the conversational depth needed to uncover all of the most helpful information, especially for issues that patients are reluctant to discuss or unaware of VIDEO 7: Fostering Shared Clinical their clinical importance. In these situations, the Decision-Making required dialogue can occur over the course of Javier Morales, MD multiple appointments (Video 7).

When prescribing GLP-1 receptor agonist/basal insulin analog combinations, core topics for which patient engagement can be especially helpful to optimize self-management include the chronic and progressive nature of T2DM, benefits of consistent glucose control, potential side effects of each medication in the regimen, perhaps most critically, signs and symptoms of hypoglycemia and how to address these episodes quickly. Many experts advocate teaching the “Rule of 15” as easily executed response to signs and symptoms of a hypoglycemic episode (Figure 3.4).3 There are 3 steps to this rule: 1) consume 15-20 g of simple carbohydrates; 2) wait 15 minutes; and 3) repeat steps 1 and 2 if glucose levels remain below 70 mg/ dL.3 Educating patients on these issues can improve factors that negatively influence treatment outcomes, such as feelings of fear or hopelessness owing to a limited understanding of the disease and its treatments.

Patient misconceptions regarding treatment risks and injection phobia can create additional hurdles to the initiation of injectable therapies. Moreover, concerns regarding hypoglycemia can cause patients to reduce or omit doses, particularly after nocturnal episodes.

Numerous studies have shown that adherence is essential to positive patient outcomes in T2DM.3,51 For example, 1 study found that failure to adhere to antihyperglycemic regimens resulted in a 2.5-fold increase in 30

the risk of diabetes-related hospitalization.52 Racial/ethnic barriers related to language, religion, and health beliefs may impair patient-physician communication, reduce treatment acceptance, and negatively affect treatment adherence. Inviting patients to help shape their own management plans not surprisingly enhances adherence to those regimens, especially when intensified treatment results in increased activity, weight loss, and feelings of self-control over health outcomes.5

Key Clinical Highlights • Potentially devastating consequences of poorly controlled hyperglycemia in patients with T2DM include a diverse range of microvascular and macrovascular complications • Individualizing a GLP-1 receptor agonist/basal insulin combination regimen should reflect relevant clinical trial data in T2DM, a comprehensive picture of the individual’s medical status, patient preferences, and the clinical benefits and other characteristics associated with the individual injectable agents • When basal insulin therapy achieves acceptable FPG levels but postprandial glycemic excursions remain problematic, adding a GLP-1 receptor agonist can be as effective as prandial insulin boluses while facilitating weight loss and reducing hypoglycemia risks • Patient-centered communication based on active caregiver listening combined with shared clinical decision-making incorporating patients’ preferences, health literacy, and other potential barriers to care helps clinicians navigate psychosocial complications, optimize medical and quality of life outcomes, and promote treatment adherence in patients with T2DM

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Type 2 Diabetes Clinical Resource Centerâ&#x201E;˘

Guidelines Standards of Medical Care in Diabetesâ&#x20AC;&#x201D;2017.

The ADAâ&#x20AC;&#x2122;s Standards of Care provide clinicians, patients, researchers, payers, and other interested individuals with the components of good diabetes management, general treatment goals, and tools to evaluate the quality of care. Importantly, these recommendations should be adjusted based on individual preferences, comorbidities, and other patient-related factors.

American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135.

http://care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf

AACE/ACE Comprehensive Diabetes Management Algorithm 2017.

The AACE/ACE algorithm provides recommendations on evaluating the whole patient, outlines potential risks and complications, and highlights evidence-based treatment approaches for diabetes. The document contains sections on lifestyle changes, considerations for obese individuals, prediabetes, glycemic goals, antihyperglycemic therapies, treatment algorithms, modifications for atherosclerotic cardiovascular disease risk factors, and overall principles of diabetes management.

Garber AJ, et al. Endocr Pract. 2017;23(2):207-238.

https://www.aace.com/files/aace_algorithm_slides.pptx

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Patient and Caregiver Resources Diabetes HealthSense Created as part of the National Diabetes Education Program, Diabetes HealthSense includes easily accessible resources that can help patients live well and meet their goalsâ&#x20AC;&#x201D;whether they have diabetes or are at risk for the disease. http://ndep.nih.gov/resources/diabetes-healthsense/

Decision Aids for T2DM To facilitate shared decision making, these examples of medication choice decision aids from the Mayo Clinic are organized into 7 issues that may be of interest to patients with T2DM. A video demonstrating the use of these cards can be found at: www.youtube.com/watch?v=SYTPqceFgSw. http://shareddecisions.mayoclinic.org/files/2011/08/Diabetes-brochure.pdf

Suggested Readings Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial.

Aroda VR, et al. Diabetes Care. 2016;39(11):1972-1980.

http://care.diabetesjournals.org/content/early/2016/09/09/dc16-1495.full-text.pdf

Pharmacology, physiology, and mechanisms of incretin hormone action.

Campbell JE, Drucker DJ. Cell Metab. 2013;17(6):819-837.

http://www.cell.com/cell-metabolism/pdf/S1550-4131(13)00150-2.pdf

From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.

Defronzo RA. Diabetes. 2009;58(4):773-795.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661582/pdf/zdb773.pdf

Minimizing hypoglycemia in diabetes.

International Hypoglycemia Study Group. Diabetes Care. 2015;38(8):1583-1591.

http://care.diabetesjournals.org/content/38/8/1583.full.pdf+html

Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.

Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.

http://care.diabetesjournals.org/content/38/1/140.full.pdf+html

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Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial.

Lingvay I, et al. JAMA. 2016;315(9):898-907; requires registration for a free personal account.

https://jamanetwork.com/journals/jama/fullarticle/2497908

The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial.

Linjawi S, et al. Diabetes Ther. 2017;8(1):101-114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306117/pdf/13300_2016_Article_218.pdf

Liraglutide and renal outcomes in type 2 diabetes.

Mann JFE, et al. N Engl J Med. 2017;377(9):839-848.

http://www.nejm.org/doi/full/10.1056/NEJMoa1616011

Liraglutide and cardiovascular outcomes in type 2 diabetes.

Marso SP, et al. N Engl J Med. 2016;375(4): 311-322.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1603827

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.

Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1607141

Efficacy and safety of degludec versus glargine in type 2 diabetes.

Marso SP, et al. N Engl J Med. 2017;377(8):723-732.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1615692

Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.

Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1509225

Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes.

Rodbard HW, et al. Diabetes Obes Metab. 2016;18(1):40-48.

http://onlinelibrary.wiley.com/doi/10.1111/dom.12574/epdf

Benefits of LixiLan,, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan,-O randomized trial.

Rosenstock J, et al. Diabetes Care. 2016;39(11):2026-2035.

http://care.diabetesjournals.org/content/39/11/2026.full-text.pdf

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Type 2 diabetes patients reach target glycemic control faster using IDegLira than either insulin degludec or liraglutide given alone.

Vilsbøll T, et al. Clin Drug Investig. 2016;36(4):293-303.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801992/pdf/40261_2016_Article_376.pdf

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CME Posttest To receive CME credit, participants should direct their Web browsers to http://www.ExchangeCME.com/ T2DMeHealth17. Participants will have two attempts to obtain a passing grade of 70% on the posttest and be eligible to obtain CME credit.

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