Vildagliptin Reduces Glucagon during Hyperglycemia and Sustains Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes

Abstract

Abstract 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 curveglucagon 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.