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.
OBJECTIVE
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.
El-Ouaghlidi
Andrea
A
Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany.
Rehring
Erika
E
Holst
Jens J
JJ
Schweizer
Anja
A
Foley
James
J
Holmes
David
D
Nauck
Michael A
MA
D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D000465:Algorithms; D002096:C-Peptide / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005746:Gastric Emptying / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors* / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors* / Q000097:blood; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000009:adverse effects*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007328:Insulin / Q000097:blood; D008297:Male; D009570:Nitriles / Q000009:adverse effects*; D011759:Pyrrolidines / Q000009:adverse effects*; D000077597:Vildagliptin
D002096:C-Peptide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane; D005905:Glyburide; D006854:Hydrocortisone