1. Frank Svec, MD, PhD Clinical Professor of Medicine Tulane University School of Medicine New Orleans, Louisiana Kevan Chambers Announcer Medscape Diabetes & Endocrinology Challenges in the Management of T2DM—Exploring the Role of GLP-1 Receptor Agonists: Southern Region

2. During today’s discussion, we will present 2 interactive questions You may also submit a question at any time during the program by using the “Ask a Question” box in the lower right- hand corner of your screen We hope to be able to answer at least some of your questions at the end of the program There will be a brief assessment at the end of the program asking about the changes that you might make in your practice, on the basis of your participation today. Your responses will help us to improve the content of this and future educational programs

3. Frank Svec, MD, PhD Clinical Professor of Medicine Tulane University School of Medicine New Orleans, Louisiana

4. Ralph A. DeFronzo, MD Professor of Medicine Chief of Diabetes Division University of Texas Health Science Center at San Antonio San Antonio, Texas Staff Physician Department of Medicine Audie L. Murphy Division South Texas Veterans Health Care System San Antonio, Texas

5. Program Goal Review the incidence and prevalence of type 2 diabetes mellitus (T2DM) Evaluate evidence-based guidelines for the management of diabetes Focus on the role of glucagon-like peptide (GLP)-1 receptor agonists to help you tailor therapies to your patients with T2DM

6. Age-Adjusted Percentage of US Adults With Diagnosed Diabetes Centers for Disease Control and Prevention: National Diabetes Surveillance System. http://www.cdc.gov/diabetes/statistics. 1994 1999 2008 Missing Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% ≥9.0%

7. a Centers for Disease Control and Prevention. 2008. b National Institute of Diabetes and Digestive and Kidney Diseases. 2008. Incidence of T2DM Approximately 20 million individuals with T2DM in the United States a Additional 4-5 million individuals with undiagnosed diabetes a 60 million individuals with prediabetes (ie, impaired glucose tolerance, impaired fasting glucose) b

8. Obesity Trends* Among US Adults *BMI ≥ 30 kg/m 2, or about 30 lb overweight for 5’4” person. Centers for Disease Control and Prevention. 2008. 19901999 2008 No Data <10% 10–14%15–19% 20–24%25–29%≥30%

9. In your region, what percentage of your patients are obese? A. ≤ 25% B. 26%-50% C. 51%-75% D. ≥ 76%

10. Initial Presentation 49-year-old man with a 1-year history of T2DM Waiter in the French Quarter; 2 meals/day; weight conscious Father died of coronary disease; older brother has coronary disease Initial glycated hemoglobin (A1c) 9.1%; BMI = 29.5 kg/m 2 Case 1 A1c today 8.1%; BMI = 28.8 kg/m 2 ; LDL = 87 mg/dL; HDL = 33 mg/dL Metformin 1000 mg twice daily and statin Is concerned about heart disease; wants to lose weight; nervous about insulin

11. Case Presentations, Continued Cannot exercise 2 meals/day; snacks; drinks on the weekend Does not check blood glucose values at home BMI = 33.2 kg/m 2 ; A1c 7.9%; LDL = 138 mg/dL; SCr = 1.6 mg/dL; blood pressure = 137/88 mm Hg ACE inhibitor/thiazide, sulfonylurea Case 2 67-year-old woman with a long history of T2DM Cared for at Charity Hospital before Hurricane Katrina; moved to Mississippi; back to New Orleans Old medical records lost On insulin? Lumbar disk disease and hypertension

12. Polling Question #1 Results

13. Rodgers G. http://www.nih.gov/news/radio/nov2009/20091110NDEP.htm T2DM Epidemic and Complications 4000 new cases of diabetes are diagnosed daily 800 deaths from individuals with T2DM daily 200 individuals with T2DM experience an amputation daily 50 individuals with T2DM develop blindness daily

14. a Lee ET, et al. Diabetes Care. 2002;25:49-54. b CDC. MMWR Morb Mortal Wkly Rep. 2004;53:941-944. c AHRQ. http://www.ahrq.gov/research/diabdisp.htm. Ethnic Disparities Highest incidence of diabetes among American Indians a High incidence of diabetes among Hispanics, Mexican Americans, and African Americans b,c Lowest incidence of diabetes among whites

15. a Lotufo PA, et al. Arch Intern Med. 2001;161:242-247. b National Institute of Diabetes and Digestive and Kidney Diseases. 2008. Diabetes and Cardiovascular Disease Increased incidence of atherosclerotic cardiovascular complications a Incidence of myocardial infarction and stroke increased a High cost of managing micro- and macrovascular complications b

16. Challenges to Diabetes Care Complications among undiagnosed individuals with diabetes Cost of medication Patient propensity to lose weight

17. What is your greatest obstacle to initiating therapy with GLP-1 receptor agonists? A. Not being up-to-date on current safety and efficacy evidence supporting use of these agents in T2DM B. Cost of medication/insurance/managed care issues C. They offer no advantages over current antidiabetic agents D. Unfamiliarity with placement of this class within treatment guidelines E. Patients’ fear of injections or other patient-related factors

18. Next Steps Reinforce positive results; his BMI went down Continue to reinforce the importance of diet and exercise GLP-1 agonist should be considered, given that his A1c is not at goal on metformin; he is worried about his heart, and wants to lose weight Need to check serum creatinine level and liver function Ask about history of pancreatitis Case 1 49-year-old man with 1-year history of T2DM; on metformin; A1c, 8.1%; scared of insulin, worried about heart disease, and wants to lose more weight

19. Exenatide Sustained A1c Reductions Over 82 Weeks 82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE. Time (week) Placebo-controlled Open-label extension Change in A1c (%) (All patients 10 mg BID) 8.3% 8.4% Mean Baseline A1c 82-Week ITT 82-Week Completer Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.

20. Durability of Exenatide: Weight

21. Effects of GLP-1 Agonists on Cardiovascular Risk Factors A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151) Triglycerides decreased 12% (P =.0003) Total cholesterol decreased 5% (P =.0007) LDL-C decreased 6% (P <.0001) HDL-C increased 24% (P <.0001) Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

22. Follow-up Warn him about the potential gastrointestinal side effects of GLP-1 agonists (nausea, vomiting) and that they generally abate over time Educate on the need to control glucose and weight Review cardiovascular risk parameters Test blood glucose twice daily – before breakfast, before dinner DPP-4 inhibitors are a possibility, but they offer modest glucose lowering and are weight neutral Case 1

23. Diabetes Algorithms and A1c Goal A1c Goal American Diabetes Association ≤ 7% American Association of Clinical Endocrinologists ≤ 6.5% European Association for the Study of Diabetes ≤ 6.5% Emerging Evidence/Expert Opinion ≤ 6%

24. American Diabetes Association American Diabetes Association. Diabetes Care. 2009;32(suppl1):S13-S61. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Lowering A1c to below or around 7% has been shown to reduce microvascular and macrovascular complications of T2DM

25. Lifestyle + MET + PIO + SFU STEP 1 At diagnosis: Lifestyle + MET STEP 2 STEP 3 Lifestyle + MET + Intensive Insulin OR If A1c ≥7% MET = metformin; PIO = pioglitazone; SFU = sulfonylurea *Validation based on clinical trials and clinical judgment Adapted from: Nathan DM, et al. Diabetes Care. 2009;32:193-203. Lifestyle + MET + Basal Insulin Lifestyle + MET + SFU Lifestyle + MET + Basal Insulin Tier 2: Less-well-validated therapies* Lifestyle + MET + PIO Lifestyle + MET + GLP-1 Agonist American Diabetes Association/European Association for the Study of Diabetes Tier 1: Well-validated core therapies*

26. American Association of Clinical Endocrinologists/American College of Endocrinology Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

27. Increased Hepatic Glucose Production Impaired Insulin Secretion Hyperglycemia Decreased Glucose Uptake TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylureas Thiazolidinediones Metformin  Metformin Thiazolidinediones _  Pathophysiologic Approach to Treatment of T2DM DeFronzo RA. Diabetes. 2009;58:773-795.

28. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. Consensus Statements for T2DM Consensus group of leading international endocrinologists and diabetologists with extensive clinical experience Recent medical literature and all currently approved classes of medications should be considered Common goal is to improve glucose control through individualization of therapy

29. Polling Question #2 Results

30. Schnabel CA, et al. Vasc Health Risk Manag. 2006;2:69-77. GLP-1 Receptor Agonists First-in-class exenatide approved in 2005 Augment insulin secretion Inhibit glucagon secretion Lower fasting glucose and improve postprandial glucose profile

31. Insulin secretion β-cell neogenesis β-cell apoptosis Glucagon secretion Glucose production Heart GI Tract Liver Muscle Drucker DJ. Cell Metab. 2006;3:153-165. Brain Appetite Cardioprotection Cardiac output Stomach Gastric emptying Neuroprotection Glucose Uptake _ + Stomach GLP-1 GLP-1 Actions in Peripheral Tissue

32. Side Effects: GLP-1 Receptor Agonists and DPP-4 Inhibitors GLP-1 Receptor AgonistsDPP-4 Inhibitors Side effects GastrointestinalWell tolerated Weight > 85% patients lose weight Weight neutral Administration Twice-daily injection Oral, once daily Other cardiac risk factors ↓ Triglycerides ↑ HDL ↓ Blood pressure Unknown Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.

33. MetforminThiazolidinediones Side effects Gastrointestinal Fluid retention, congestive heart failure, bone fractures Weight Weight neutral Weight gain Renal impairment Restricted > 1.4 mg/dL Seufert J, et al. Clin Ther. 2004;26:805-818. Side Effects: Metformin and Thiazolidinediones

34. Next Steps Case 2 67-year-old woman with a long history of T2DM; babysits grandchildren; on sulfonylurea; A1c, 7.9% Emphasize the importance of exercise and diet Serum creatinine is high, so cannot use metformin Insulin is a common next step and may be considered, but associated with weight gain and hypoglycemia GLP-1 agonists should be considered to help lower glucose levels and may be associated with mild improvements in blood pressure and lipid profile

35. Exenatide vs Insulin Glargine as Add-on Therapy in T2DM A1c Level (%) * * * * * * 0248121826 Change in Body Weight (kg) Heine RJ, et al. Ann Intern Med. 2005;143:559-569. Exenatide group (n = 275) Insulin glargine group (n = 260)

36. Mean (SE): *P <.005 SFU b MET + SFU c MET a * - 0.8 Change in A1c (%) 247 245 241 8.5 8.5 8.5 Baseline n 113 110 113 8.2 8.3 8.2 123 125 129 8.7 8.5 8.6 0.1 - 0.4 * - 0.8 * -0.5* - 0.9 * 0.1 0.2 - 0.6 * - 0.8 * Placebo BID Exenatide 5 μg BID Exenatide 10 μg BID MET = metformin; SFU = sulfonylurea a DeFronzo R, et al. Diabetes Care. 2005;28:1092-1100. b Buse JB, et al. Diabetes Care. 2004;27:2628-2635. c Kendall D, et al. Diabetes Care. 2005;28:1083-1091. Change in A1c Seen With Exenatide in Phase 3 Clinical Trials

37. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. Effects of Exenatide in Sulfonylurea- Treated Patients: Weight

38. Follow-up Illustrate the effects of binge alcohol consumption (hypoglycemia, pancreatitis risk) Another agent may help control hypertension A statin may help lower LDL Encourage home blood glucose monitoring DPP-4 inhibitors can be considered, but insulin may cause unwanted weight gain Case 2

39. Questions & Answers

40. Medullary Thyroid Cancer and Pancreatitis Liraglutide-induced medullary carcinoma is rare, but need to evaluate the patient’s risk Increase in incidence of pancreatitis in patients with T2DM, but unclear whether it is associated with use of exenatide Parks M, et al. N Engl J Med. 2010;362:774-777.

41. Differences in Glycemic Control Genetic variation on response to treatment commonly seen Further studies are needed

42. Challenges in the Management of T2DM—Exploring the Role of GLP-1 Receptor Agonists: Southern Region

43. Concluding Remarks Treatment of diabetes requires consideration of multiple risk factors Obesity/overweight is a prime factor in the development diabetes Glucose control is important and can be accomplished without worsening adiposity Discussion of side-effect profile of any medication ahead of time will enhance patient acceptance

44. Summary: T2DM Is 2 Diseases Microvascular complications Macrovascular complications Two distinct pathogenic sequences Two distinct clinical presentations

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