Vildagliptin Enhances Islet Responsiveness to Both Hyper- and Hypoglycemia in Patients with Type 2 Diabetes

Context: Dipeptidyl peptidase-4 inhibitors act by increasing plasma levels of glucagon-like peptide-1 and suppressing excessive glucagon secretion in patients with type 2 diabetes. However, their effects on the glucagon response to hypoglycemia are not established. Objective: The aim of the study was to assess effects of the dipeptidyl peptidase-4 inhibitor vildagliptin on alpha-cell response to hyper- and hypoglycemia. Design: We conducted a single-center, randomized, double-blind, placebo-controlled, two-period crossover study of 28-d treatment, with a 4-wk between-period washout. Patients: We studied drug-naive patients with type 2 diabetes and baseline glycosylated hemoglobin of 7.5% or less. Intervention: Participants received vildagliptin (100 mg/d) or placebo as outpatients. Primary Outcome Measure(s): We measured the following: 1) change in plasma glucagon levels during hypoglycemic (2.5 mM glucose) clamp; and 2) incremental (Delta) glucagon area under the concentration-time curve from time 0 to 60 min (AUC(0-60min)) during standard meal test. Before the study, it was hypothesized that vildagliptin would suppress glucagon secretion during meal tests and enhance the glucagon response to hypoglycemia. Results: The mean change in glucagon during hypoglycemic clamp was 46.7 +/- 6.9 ng/liter with vildagliptin treatment and 33.9 +/- 6.7 ng/liter with placebo; the between-treatment difference was 12.8 +/- 7.0 ng/liter (P = 0.039), representing a 38% increase with vildagliptin. In contrast, the mean glucagon Delta AUC(0-60min) during meal test with vildagliptin was 512 +/- 163 ng/liter . min vs. 861 +/- 130 ng/liter . min with placebo; the between-treatment difference was -349 +/- 158 ng/liter . min (P = 0.019), representing a 41% decrease with vildagliptin. Conclusions: Vildagliptin enhances alpha-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia. These effects likely contribute to the efficacy of vildagliptin to improve glycemic control as well as to its low hypoglycemic potential. (J Clin Endocrinol Metab 94: 1236-1243, 2009)