Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes

J Clin Endocrinol Metab. 2012 Oct;97(10):3799-806. doi: 10.1210/jc.2012-2332. Epub 2012 Aug 1.


Context: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes.

Objective: The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D).

Patients and methods: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter.

Main outcome measure: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165-195 of the test) was measured.

Results: During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curve(glucagon) 2.4±0.2 vs. 2.6±0.2 nmol/liter×minutes, P=0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5±1.0 pmol/liter with vildagliptin vs. 1.7±0.8 pmol/liter with placebo, P=NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was -3.4±1.0 mmol/mol (-0.32±0.09%; P=0.002)] from baseline of 57.9 mmol/mol (7.5%).

Conclusions: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D.

Trial registration: NCT01147276.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / administration & dosage
  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Adult
  • Blood Glucose / metabolism
  • Cross-Over Studies
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glucagon / blood*
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism
  • Glucose Clamp Technique
  • Humans
  • Hyperglycemia / drug therapy*
  • Hyperglycemia / metabolism*
  • Hypoglycemic Agents / administration & dosage
  • Insulin / administration & dosage
  • Male
  • Nitriles / administration & dosage*
  • Nitriles / adverse effects
  • Pyrrolidines / administration & dosage*
  • Pyrrolidines / adverse effects
  • Vildagliptin
  • Young Adult


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Insulin
  • Nitriles
  • Pyrrolidines
  • Glucagon
  • Vildagliptin
  • Adamantane

Associated data