1. GLP-1 Agonists and DPP-4 Inhibitors How do they work? Part 4

2. DPP-4 Inhibition and Plasma Levels of GLP-1 DPP-4 inhibition prevents the degradation of active GLP-1 but does not increase GLP-1 secretion nor prevent the kidney from rapidly clearing GLP-1 DPP-4 inhibition also acutely decreases L-cell secretion of GLP-1, most likely via negative feedback inhibition of the L-cell. During a meal, total GLP-1 decreases but active GLP-1 (7-36) increases

3. DPP-4 Inhibition and Plasma Levels of GLP-1 DPP-4 inhibition prevents the degradation of active GLP-1 but does not increase GLP-1 secretion nor prevent the kidney from rapidly clearing GLP-1

4. Exendin-4: A GLP-1R Agonist

5. Exenatide Restores First-Phase Insulin Secretion in Type 2 Diabetes

6. Effect of Exenatide Versus Glargine Insulin on Insulin Secretion in Type 2 Diabetes Subjects:55 type 2 diabetes Age=58 years; BMI=30.5 kg/m 2 Diabetes duration=4.8 years A1C=7.5%; FPG=9.1 mM Study Design:Exenatide*(n=36) vs glargine (n=33) Treatment goal = A1C ≤7.0% Actual A1C=6.8±0.1% ∆ Body wt (kg)=+1.0 glargine vs -3.6 exenatide Study Duration:1 Year *5-10 µg BID up to 15-20 µg TID.

7. C-Peptide Secretion During Hyperglycemic Clamp After 1 Year of Exenatide (10 µg BID-15 µg TID) vs Glargine Insulin Therapy to Reduce A1C <7.0%

8. Effect of Exenatide vs Glargine on Postmeal Blood Glucose Excursion

9. Summary of Exenatide (30 Weeks) Pivotal Studies (N=1446): Effect on Postprandial Glucose

10. Summary of Combined Exenatide (30 Weeks) Pivotal Studies (N=1446): Effect on Fasting Plasma Glucose Concentration P<.0001 5 Change in FPG From Baseline (mg/dL) P<.0001 Exenatide 5 µg BID (n=480) Exenatide 10 µg BID (n=483) 0 Placebo (n=483) -5 1. DeFronzo R, et al. Diabetes Care. 2005 May;28(5):1092-100. 2. Buse J, et al. Diabetes Care. 2004 Nov;27(11):2628-35. 3. Kendall, DM et al. Diabetes Care. 2005 May;28(5):1083-91.

11. Actions of DPP-4 Inhibitors and GLP-1 Receptor Agonists in Regulating Glucose Homeostasis