Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes.

Research output: Contribution to journalJournal articleResearchpeer-review

  • Gary A Herman
  • Arthur Bergman
  • Catherine Stevens
  • Paul Kotey
  • Bingming Yi
  • Peng Zhao
  • Bruno Dietrich
  • George Golor
  • Andreas Schrodter
  • Bart Keymeulen
  • Kenneth C Lasseter
  • Mark S Kipnes
  • Karen Snyder
  • Deborah Hilliard
  • Michael Tanen
  • Caroline Cilissen
  • Marina De Smet
  • Inge de Lepeleire
  • Kristien Van Dyck
  • Amy Q Wang
  • Wei Zeng
  • Michael J Davies
  • Wesley Tanaka
  • Keith M Gottesdiener
  • John A Wagner
CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. OBJECTIVE: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. DESIGN: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. SETTING: The study was conducted at six investigational sites. PATIENTS: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. INTERVENTIONS: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. MAIN OUTCOME MEASURES: Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics. RESULTS: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events. CONCLUSIONS: In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.
Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
Pages (from-to)4612-9
Number of pages7
Publication statusPublished - 2006

Bibliographical note

Keywords: Administration, Oral; Adult; Antigens, CD26; Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Enzyme Inhibitors; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Middle Aged; Placebos; Pyrazines; Triazoles

ID: 8417107