GLP1 Agonists and DPP4 Inhibitors How do they

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

DPP-4 Inhibition and Plasma Levels GLP-1 • DPP-4 inhibition of 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

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

Exendin-4: A GLP-1 R Agonist

Exenatide Restores First-Phase Insulin Secretion in Type 2 Diabetes

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 A 1 C=7. 5%; FPG=9. 1 m. M Study Design: Exenatide*(n=36) vs glargine (n=33) Treatment goal = A 1 C ≤ 7. 0% Actual A 1 C=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.

C-Peptide Secretion During Hyperglycemic Clamp After 1 Year of Exenatide (10 µg BID-15 µg TID) vs Glargine Insulin Therapy to Reduce A 1 C <7. 0%

Effect of Exenatide vs Glargine on Postmeal Blood Glucose Excursion

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

Summary of Combined Exenatide (30 Weeks) Pivotal Studies (N=1446): Effect on Fasting Plasma Glucose Concentration Change in FPG From Baseline (mg/d. L) 5 Exenatide 5 µg BID (n=480) 0 Exenatide 10 µg BID (n=483) Placebo (n=483) -5 1. De. Fronzo 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. P<. 0001

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