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Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes

Department of Medicine (D.A.D., A.M.D., L.M.H.), University of Cincinnati and Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio 45267; Geriatric Research Education and Clinical Center (R.L.P.), Baltimore Veterans Affairs Medical Center and Division of Gerontology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Medicine (J.M.M., W.G.T., R.E.P.), University of Vermont, Burlington, Vermont 05401; Clinical Research and Development (M.L.S.), Novartis Pharmaceuticals, East Hanover, New Jersey 07936; Clinical Research and Development (Y.H., J.E.F.), Novartis Pharmaceuticals, Cambridge, Massachusetts 02139; and Pharmawrite (B.E.D.), Princeton New Jersey 08540

Address all correspondence and requests for reprints to: David D'Alessio, M.D., University of Cincinnati, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, ML 0547, Cincinnati, Ohio 45267. E-mail: dalessd{at}ucmail.uc.edu.

Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (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 because circulating levels of active GIP and GLP-1 are low in the postabsorptive state.

Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function.

Design: We conducted a randomized, double-blind, placebo-controlled trial.

Setting: The study was performed in General Clinical Research Centers at two University Hospitals.

Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2–7.5%.

Intervention: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout.

Major Outcome Measure: We measured 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 glycosylated hemoglobin 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.