The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion

J Clin Endocrinol Metab. 2007 Nov;92(11):4165-71. doi: 10.1210/jc.2006-1932. Epub 2007 Aug 14.

Abstract

Background/aims: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test.

Methods: There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA.

Results: Glibenclamide provoked hypoglycemia (<or=1.9 mm), but this was not accentuated by the simultaneous administration of vildagliptin (P = 0.25). The integrated incremental responses of total GLP-1 were reduced by vildagliptin by 72% (with glibenclamide) and 48% (without glibenclamide) (effect of vildagliptin: P < 0.0001; glibenclamide: P = 0.31; interaction: P = 0.26). Similarly, integrated incremental responses of total GIP were reduced by vildagliptin by 26 and 21%, with and without glibenclamide, respectively (vildagliptin: P = 0.017; glibenclamide: P = 0.44; interaction: P = 0.69).

Conclusions: Sulfonylurea-induced hypoglycemia after the oral administration of glibenclamide is not accentuated by the coadministration of vildagliptin. This may be explained by a negative feedback regulation of GLP-1 and GIP secretion that limits the degree to which the active incretin levels are enhanced.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Adult
  • Algorithms
  • C-Peptide / blood
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects*
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay
  • Gastric Emptying / drug effects
  • Gastric Inhibitory Polypeptide / antagonists & inhibitors*
  • Gastric Inhibitory Polypeptide / blood
  • Glucagon / blood
  • Glucagon-Like Peptide 1 / antagonists & inhibitors*
  • Glucagon-Like Peptide 1 / blood
  • Glucose / pharmacology*
  • Glyburide / adverse effects*
  • Humans
  • Hydrocortisone / blood
  • Hypoglycemia / blood
  • Hypoglycemia / chemically induced*
  • Hypoglycemic Agents / adverse effects*
  • Insulin / blood
  • Male
  • Nitriles / adverse effects*
  • Pyrrolidines / adverse effects*
  • Vildagliptin

Substances

  • C-Peptide
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Insulin
  • Nitriles
  • Pyrrolidines
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Vildagliptin
  • Glucose
  • Adamantane
  • Glyburide
  • Hydrocortisone