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

2. 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 May;28(5):
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 Nov;27(11):
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 May;28(5):

3. 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 May;28(5):
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 Nov;27(11):
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 May;28(5):
1. DeFronzo R, et al. Diabetes Care May;28(5): Buse J, et al. Diabetes Care Nov;27(11): Kendall, DM et al. Diabetes Care May;28(5):
P<.0001

4. 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 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.

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

6. 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):
GI Tract
Insulin Secretion
β-Cell Neogenesis
β-Cell Apoptosis
Glucagon Secretion
Glucose
Production +
Glucose
Uptake
Muscle
Drucker DJ. Cell Metab. 2006;3:

7. 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):
GI Tract
Insulin Secretion
β-Cell Neogenesis
β-Cell Apoptosis
Glucagon Secretion
Glucose
Production +
Glucose
Uptake
Muscle
Drucker DJ, Cell Metab. 2006;3:

8. 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):

9. 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):

10. 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.

11. 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):
GI Tract
Insulin Secretion
β-Cell Neogenesis
β-Cell Apoptosis
Glucagon Secretion
Glucose
Production +
Glucose
Uptake
Muscle
Drucker DJ. Cell Metab. 2006;3: