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

• Published in: The journal of clinical endocrinology and metabolism 2007-11, Vol.92 (11), p.4165-4171
• Main Authors: El-Ouaghlidi, Andrea, Rehring, Erika, Holst, Jens J., Schweizer, Anja, Foley, James, Holmes, David, Nauck, Michael A.
• Format: Article
• Language: English
• Subjects: Adamantane - adverse effects; Adamantane - analogs & derivatives; Adult; Algorithms; Biological and medical sciences; C-Peptide - blood; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; Drug Interactions; Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; 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; Medical sciences; Nitriles - adverse effects; Pyrrolidines - adverse effects; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2006-1932

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 (≤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.