Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: How Do They Exert Their Metabolic Actions? Part 3

Effect of Vilagliptin on Plasma Glucagon Levels During Mixed Meal Patients with T2DM manifest a paradoxical rise or lack of suppression of glucagon in response to a mixed meal. Vildagliptin, 100 mg orally, markedly inhibits the plasma glucagon response to a meal.   Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249-1255.

Effect of Vildagliptin on Plasma Insulin and C-Peptide Concentrations During Mixed Meal After a single dose of vildagliptin, 100 mg orally, meal-stimulated plasma insulin and C-peptide concentrations increased significantly. These changes in plasma insulin and glucagon concentrations, as depicted here and in the previous slide (Effect of Vilagliptin on Plasma Glucagon Levels During Mixed Meal), were associated with a significant reduction in postmeal plasma glucose concentration.   Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249-1255.

Effect of Vildagliptin on Endogenous (Hepatic) Glucose Production During Mixed Meal The increase in plasma insulin response in concert with the decline in plasma glucagon response following vildagliptin leads to an enhanced suppression of HGP during the meal.   Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249-1255.

Vildagliptin Does Not Increase Tissue Glucose Uptake After Mixed Meal Increased tissue (muscle) glucose uptake does not contribute to the reduced postprandial rise in plasma glucose concentration seen after a meal when vildagliptin is administered 30 minutes prior. This is explained by a reduced plasma glucose concentration (decreased mass action effect of hyperglycemia to augment tissue glucose uptake) that offsets the increased plasma insulin response, which otherwise would augment muscle glucose uptake. Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249-1255.

Vildagliptin: Comparison With Metformin In a 1-year study, the reduction in A1C with vildagliptin is comparable to that observed with metformin in drug-naive patients.   Rosenstock J, Baron MA, Dejager S, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):217-223.

Vildagliptin Compared to Rosiglitazone in Drug-Naive Patients In a 1-year study, the reduction in A1C with vildagliptin is comparable to that observed with rosiglitazone, irrespective of the starting A1C, in drug-naïve patients with T2DM.   Rosenstock J, Baron MA, Dejager S, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):217-223.

Vildagliptin Added to Metfromin in Patients With Type 2 Diabetes When added to metformin, vildagliptin produces a dose-response additive effect to reduce A1C.   Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30(4):890-895.

Vildagliptin Provides Sustained Improvement of -Cell Function Vildagliptin treatment for 1 year in patients with T2DM treated with metformin enhanced insulin secretion (left), the OGIS index of insulin sensitivity (middle), and the adaptation index (equivalent to the insulin secretion/insulin resistance or disposition index). The latter provides an index of beta-cell function that relates the insulin secretory response during the oral glucose tolerance test (OGTT) to the severity of insulin resistance.   Adapted from Ahrén B, Pacini G, Foley JE, et al. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care. 2005; 28(8):1936-1940.

Vildagliptin: Pooled Analysis of Clinical Data Adverse Event Profiles Vildagliptin 100 mg Daily (n=1530) Metformin ≤2g Daily (n=252) Rosiglitazone 8 mg Daily (n=267) Placebo (n=255) Any 63.6 75.4 64.0 60.0 Nasopharyngitis 7.6 9.5 7.5 7.1 Headache 5.2 5.9 Dizziness 5.8 6.0 4.1 4.3 Upper respiratory tract infection 4.6 3.0 2.7 Diarrhea 3.1 26.2 2.6 Nausea 2.9 10.3 0.7 3.9 Abdominal Pain 1.2 Vildagliptin has an excellent safety profile.   1. Nathwani A. Reduction in blood pressure in patients treated with vildagliptin as monotherapy or in combination with metformin for type 2 diabetes. Diabetes. 2006;55(suppl 1):A474-P. 2. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, Shao Q, Dejager S. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2009 Feb;11(2):157-66. 3. Ahrén B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert. Opin Emerg Drugs. 2008 Dec;13(4):593-607. 1. Nathwani A. Diabetes. 2006;55(suppl1):A474-P. 2. Ferrannini E, et al. Diabetes Obes Metab. 2009 Feb;11(2):157-66. 3. Ahrén B. Expert Opin Emerg Drugs. 2008 Dec;13(4):593-607.

Plasma Levels of Bioactive Intact GLP-1 (9-36)amide After Sitagliptin Administration in T2DM DPP-4 inhibition with sitagliptin, 25 mg, causes a near maximal increase in active GLP-1 (9-36) amide in patients with T2DM. However, these levels are significantly less than those observed with subcutaneous injection of GLP-1 or exenatide (see slide 15).   Adapted from Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619.

Sitagliptin Reduces Glucose AUC After a Glucose Load Sitagliptin, 25 mg, causes a near-maximal reduction in the postprandial plasma glucose excursion.   Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619.

Sitagliptin Once Daily Improves Both Fasting and Postmeal Glucose Concentration Sitagliptin, 100 mg once daily, reduces both the fasting and postprandial plasma glucose concentrations. 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;29(12):2632-2637.

Sitagliptin Monotherapy and Coadministration With Metformin Sitagliptin monotherapy and metformin monotherapy produce similar reductions in A1C in patients with T2DM and, when given in combination, provide an additive effect to reduce A1C.   Aschner P, Kipnes M, Lunceford J, et al. Sitagliptin monotherapy improved glycaemic control in patients with type 2 diabetes. Presented at: EASD 42nd Annual Meeting; September 14-17, 2006; Copenhagen, Denmark. Abstract 0005.

Sitagliptin: Proportion of Patients Achieving A1C Goals Sitagliptin monotherapy and metformin monotherapy allow a similar percentage of participants with T2DM to achieve an A1C <7.0% and have an additive effect to reduce A1C to <7.0%.   Aschner P, Kipnes M, Lunceford J, et al. Sitagliptin monotherapy improved glycaemic control in patients with type 2 diabetes. Presented at: EASD 42nd Annual Meeting; September 14-17, 2006; Copenhagen, Denmark. Abstract 0005.

Sitagliptin: Active-Comparator (Glipizide) Add-on to Metformin The addition of sitagliptin to metformin produces a similar decrease in A1C as the addition of glipizide to metformin over a 1-year period.   Nauck MA, Meininger G, Sheng D, et al; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9(2):194-205. 16

Sitagliptin: Effect on Baseline A1C The addition of sitagliptin to metformin produces a similar decrease in A1C, irrespective of the starting baseline A1C, as does the addition of glipizide to metformin over a 1-year period.   Stein P. Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.