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

Abstract

Context: Dipeptidyl peptidase-4 inhibitors act by increasing plasma levels of glucagon-like pep- tide-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 a-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 (A) glucagon area under the concentration-time curve from time 0to 60 min (AUCo60min) during standard meal test. Beforethe 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 δAUCo60min 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 a-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. Copyright © 2009 by The Endocrine Society.