Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: How Do They Exert Their Metabolic Actions? Part 5

Summary of Exenatide (30 Weeks) Pivotal Studies (N=1446): Effect on Postprandial Glucose Exenatide treatment (5 µg bid and 10 µg bid) for 30 weeks caused a dose-response effect to reduce the postmeal plasma glucose excursion, while causing only a modest reduction in FPG.   1. DeFronzo R, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005 May;28(5):1092-100. 2. Buse J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004 Nov;27(11):2628-35. 3. Kendall, DM et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005 May;28(5):1083-91.

Change in FPG From Baseline (mg/dL) Summary of Combined Exenatide (30 Weeks) Pivotal Studies (N=1446): Effect on Fasting Plasma Glucose Concentration 5 Change in FPG From Baseline (mg/dL) P<.0001 Exenatide 5 µg BID (n=480) 10 µg BID (n=483) Placebo (n=483) -5 Exenatide treatment (5 µg bid and 10 µg bid) for 30 weeks caused a modest reduction in FPG compared to patients with T2DM treated with placebo. 1. DeFronzo R, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005 May;28(5):1092-100. 2. Buse J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004 Nov;27(11):2628-35. 3. Kendall, DM et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005 May;28(5):1083-91. 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. P<.0001

Actions of DPP-4 Inhibitors and GLP-1 Receptor Agonists in Regulating Glucose Homeostasis Differences between the effect of DPP-4 inhibitors and GLP-1 receptor agonists (exenatide) are related to differences in the plasma GLP-1 levels achieved with the two therapies. DPP-4 inhibitors cause a physiologic rise in the plasma GLP-1 concentration (to 10-15 pmol/L), whereas exenatide causes a pharmacologic rise in the plasma GLP-1 concentration (50-60 pmol/L). Satiety, weight loss, and delayed gastric emptying only are observed with pharmacologic levels of GLP-1, i.e., as seen with exenatide.

Overview Discuss normal GLP-1 physiology Examine the actions of DPP-4 inhibitors and GLP-1R agonists Review the tissue-specific differences in the mechanisms of action of GLP-1 analogs, DPP-4 inhibitors, and GLP-1R agonists

Summary of Pharmacologic Incretin Actions on Different Target Tissues Heart Brain Neuroprotection Stomach Appetite Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver See slide # 4 – emphasize pancreatic effects with this slide Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):154-165. GI Tract Insulin Secretion β-Cell Neogenesis β-Cell Apoptosis Glucagon Secretion Glucose Production + Glucose Uptake Muscle Drucker DJ. Cell Metab. 2006;3:153-165.

Summary of Pharmacologic Incretin Actions on Different Target Tissues Heart Brain Neuroprotection Stomach Appetite Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver See slide #4 – emphasize gastric emptying   Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):154-165. GI Tract Insulin Secretion β-Cell Neogenesis β-Cell Apoptosis Glucagon Secretion Glucose Production + Glucose Uptake Muscle Drucker DJ, Cell Metab. 2006;3:153-165.

Effect of GLP-1 (7-36)amide SC on Gastric Emptying Subcutaneous injection of GLP-1 reduces the postmeal plasma glucose concentration, stimulates insulin secretion, and delays gastric emptying of a liquid meal.   Nauck MA, Wollschläger D, Werner J, et al. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia. 1996;39(12):1546-1553.

Vildagliptin and other DPP-4 inhibitors do not delay gastric emptying. DPP-4 Inhibition With Vildagliptin Has No Effect on Gastric Emptying in Human Subjects Vildagliptin and other DPP-4 inhibitors do not delay gastric emptying.   Vella A, Bock G, Giesler PD, et al. Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes. 2007;56(5):1475-1480.

Exenatide Increases Gastric Half-Emptying Time (T50) for Solid Meal (Tc-Labeled Eggs) Exenatide causes a dose-response inhibition of gastric emptying of a solid meal.   Linnebjerg H, Park S, Kothare P, et al. Effects of exenatide on gastric emptying and postprandial glucose in type 2 diabetes. Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Abstract 116-OR.

Summary of Pharmacologic Incretin Actions on Different Target Tissues Heart Brain Neuroprotection Stomach Appetite Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver See slide #4 – emphasize brain, satiety, weight loss.   Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):154-165. GI Tract Insulin Secretion β-Cell Neogenesis β-Cell Apoptosis Glucagon Secretion Glucose Production + Glucose Uptake Muscle Drucker DJ. Cell Metab. 2006;3:153-165.