Treatment with the DPP-4 inhibitor Vildagliptin improves fasting islet-cell function in subjects with Type 2 diabetes.

Author(s): D'Alessio DA, Denney AM, Hermiller LM, Prigeon RL, Martin JM, Tharp WG, Saylan ML, He Y, Dunning BE, Foley JE, Pratley RE

Affiliation(s): Department of Medicine, University of Cincinnati, and Cincinnati VA Medical Center, Cincinnati, OH; Geriatric Research Education and Clinical Center (GRECC), Baltimore Veterans Affairs Medical Center and Division of Gerontology, University of Maryland School of Medicine, Baltimore, MD; Department of Medicine, University of Vermont, Burlington, VT; Clinical Research & Development, Novartis Pharmaceuticals, East Hanover, NJ; Clinical Research & Development, Novartis Pharmaceuticals, Cambridge MA; Pharmawrite, Princeton New Jersey.

Publication date & source: 2008-10-28, J Clin Endocrinol Metab., [Epub ahead of print]

Publication type:

Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin, and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect since circulating levels of active GIP and GLP-1 are low in the postabsorptive state. Objective: To examine the effects of DPP-4 inhibition on fasting islet function. Design: A randomized, double-blind placebo controlled trial. Setting: General Clinical Research Centers at two University Hospitals. Subjects: Forty-one subjects with T2DM treated with metformin or diet, having good glycemic control with HbA1c values of 6.2-7.5%. Intervention: Treatment with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2 week washout. Major Outcome measure: Insulin secretion in response to IV glucose and arginine before and after treatment, and after drug washout. Results: There were small and comparable reductions in HbA1c in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; p < 0.05) and increased the slope of the C-peptide response to glucose (33%; p = 0.023). Conclusion: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.