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

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GLP-1 Agonists and DPP-4 Inhibitors How do they work? Part 5

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.

GLP-1 Regulates Central Feeding Behavior Intracerebroventricular injection of GLP-1 causes a dose-response decrease in food intake in rats. As shown in the insert in the upper right, GLP-1 receptors are abundant in the paraventricuar nucleus of the hypothalamus and the central nucleus of the amygdala. Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69-72.

Change in Body Weight Over 24 Weeks: Sitagliptin Monotherapy Studies In a 24-week study, sitagliptin was shown to have no effect on body weight in patients with T2DM. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;2(12):2632-2637.

Sitagliptin + Pioglitazone Are Weight Neutral Compared to Pioglitazone Alone in T2DM In a 24-week study, sitagliptin did not blunt the weight gain observed with pioglitazone treatment in patients with T2DM. Rosenstock J, Brazg R, Andryuk PJ, et al; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):1556-1568.