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This study compares the effects of Exenatide and Sitagliptin on glucose control, insulin secretion, gastric emptying, and caloric intake in patients with type 2 diabetes. Exenatide showed superior outcomes in reducing postprandial glucose levels.

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  1. Disclosure/Disclaimer All material is intended for your medical education purposes only

  2. Effects Of Exenatide Versus Sitagliptin On Postprandial Glucose, Insulin and Glucagon Secretion, Gastric Emptying, And Caloric Intake: A Randomized, Cross-Over Study Ralph A. DeFronzo1; Ted Okerson2; Prabhakar Viswanathan2; Xuesong Guan2; John H. Holcombe3; Leigh MacConell2 1Division of Diabetes, University of Texas Health Science Center, San Antonio, TX, USA; 2Amylin Pharmaceuticals, Inc., San Diego, CA, USA; 3Eli Lilly and Company, Indianapolis, IN, USA

  3. Introduction • This study provides the first head-to-head comparison of incretin-based therapies developed to treat T2DM1: • The GLP-1 receptor agonist, exenatide • The dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin • Exenatide binds directly to the GLP-1 receptor and is at least equipotent, if not more potent, than GLP‑12,3 in: • Stimulation of glucose-dependent secretion of insulin • Restoration of first-phase and second-phase insulin secretion • Suppression of inappropriately elevated postprandial glucagon secretion • Slowing of gastric emptying • Reduction in food intake • Promotion of β-cell proliferation and islet neogenesis from precursor cells in both in vitro and in vivo models of diabetes1

  4. Introduction • The DPP-4 inhibitor sitagliptin inhibits the proteolytic cleavage of GLP-1 in the circulation by binding to and reducing the activity of the DPP-4 enzyme by approximately 80%, increasing the concentration of endogenous GLP-1 by approximately 2-fold, thereby: • Reducing plasma glucagon and increasing insulin and C-peptide concentrations, and increasing β-cell mass and function1

  5. Exenatide vs Sitagliptin MOA Study: Study Design • Primary endpoint: comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations in patients with T2D Study Termination Randomization Crossover Treatment Period 1 Treatment Period 2 Exenatide 5 µg BID Exenatide 10 µg BID Exenatide 5 µg BID Exenatide 10 µg BID Sequence A Placebo Lead-in Sequence B Sitagliptin 100 mg QAM Sitagliptin 100 mg QAM 1 week 2 weeks 2 weeks Standard Meal Test Standard Meal Test Standard Meal Test MET background;MOA indicates mechanism of action; QAM, once per day in the morning DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  6. Demographic and Baseline Characteristics Patients with T2D; MET background; Mean ± SD, unless otherwise indicated; BMI indicates body mass index DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  7. Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1 Baseline Exenatide Sitagliptin 75 75 63.8 50 50 2-h Postprandial Plasma GLP-1 (pM) 2-h Plasma Exenatide (pM) 25 25 15.1 7.9 7.2 0 0 Plasma GLP-1 Plasma Exenatide Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE 2-wk post-treatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  8. Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin Baseline Exenatide Sitagliptin Primary Endpoint PPG (mg/dL) Standard Meal Time (min) Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001 DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  9. Reductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin Exenatide Sitagliptin Baseline End of Period 1 End of Period 2 2-hr PPG (mg/dL) • After Period 1, patients were switched to the other therapy Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32 Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  10. Improvement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin Geometric Mean Baseline Insulinogenic Index2: 0.4 P = 0.02 1.0 0.9 0.8 0.82 0.82 Insulinogenic Index1 0.7 0.6 0.55 0.55 0.5 0.4 Exenatide Sitagliptin Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  11. Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than Sitagliptin Baseline Exenatide Sitagliptin Plasma Glucagon (pg/mL) Time (min) Standard Meal Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  12. Exenatide Slowed Gastric Emptying Compared to Sitagliptin Baseline Exenatide Sitagliptin Plasma Acetaminophen (µg/mL) Time (min) Standard Meal Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  13. Exenatide Reduced Mean Caloric Intake Mean Baseline Caloric Intake2: 1071 kcal P = 0.0227 300 200 +130 +130 100 Δ Caloric Intake From Baseline (kcal)1 0 - 134 - 134 -100 -200 Exenatide Sitagliptin -300 • Changes in median caloric intake showed similar trends (exenatide, -138 kcal; sitagliptin, 63 kcal) Patients with T2D; Evaluable ad lib cohort, n = 25 for both treatment groups; LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

  14. Exenatide vs Sitagliptin: Safety Both exenatide and sitagliptin were generally well tolerated1 • Overall incidence of AEs was low2 Mild-to-moderate nausea and vomiting were the most frequently reported events1 • Nausea: exenatide, 34%; sitagliptin, 12% • Vomiting: exenatide, 24%; sitagliptin, 3% Study withdrawals due to AEs1 • 2 patients on exenatide (nausea and moderate hypoglycemia symptoms) • 1 patient on sitagliptin (dizziness) No major hypoglycemic events were reported1 Patients with type 2 diabetes; ITT population, N = 95; AE indicates adverse event 1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952; 2. Data on file, Amylin Pharmaceuticals, Inc.

  15. Exenatide vs Sitagliptin MOA Study: Conclusions 2-hr PPG concentration was significantly reduced with exenatide compared with sitagliptin Compared with sitagliptin treatment, exenatide treatment led to Greater reductions in PPG concentrations over time Postprandial glucose excursions Postprandial glucagon levels Improved insulinogenic index Delayed gastric emptying Decreased caloric intake Changes in FPG concentrations were comparable with exenatide and sitagliptin Both exenatide and sitagliptin were generally well tolerated DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

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