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

J Clin Endocrinol Metab. 2006 Nov;91(11):4612-9. doi: 10.1210/jc.2006-1009. Epub 2006 Aug 15.


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.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Blood Glucose / drug effects*
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Double-Blind Method
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Gastric Inhibitory Polypeptide / blood*
  • Glucagon-Like Peptide 1 / blood
  • Glucose Tolerance Test / methods
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Middle Aged
  • Placebos
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Pyrazines / pharmacokinetics*
  • Pyrazines / therapeutic use
  • Sitagliptin Phosphate
  • Triazoles / administration & dosage
  • Triazoles / adverse effects
  • Triazoles / pharmacokinetics*
  • Triazoles / therapeutic use


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Placebos
  • Pyrazines
  • Triazoles
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Sitagliptin Phosphate