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This version published online on August 15, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1009
A more recent version of this article appeared on November 1, 2006
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*Compound via MeSH
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*Diabetes

Submitted on May 10, 2006
Accepted on August 3, 2006

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

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, Jens J. Holst, Carolyn F. Deacon, Keith M. Gottesdiener, and John A. Wagner

Merck Research Laboratories, Rahway, NJ, 3 Clinical Research AG, Berlin, Germany, Focus Clinical Drug Development GmBH, Neuss, Germany, Free University of Brussels, Brussels, Belgium, Clinical Pharmacology Associates, Miami, FL, Diabetes & Glandular Disease Research Associates, San Antonio, TX, MSD-Europe, Brussels, Belgium, University of Copenhagen, Copenhagen, Denmark

* To whom correspondence should be addressed. E-mail: gary_herman{at}merck.com.

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 following an oral glucose tolerance test (OGTT) were evaluated.

Objective: To examine the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of sitagliptin.

Design: A randomized, double-blind, placebo-controlled, 3-period, single-dose crossover study.

Setting: Six investigational sites.

Patients: 58 patients with type 2 diabetes not on antihyperglycemic agents.

Interventions: Sitagliptin 25 mg, sitagliptin 200 mg, or placebo.

Main Outcome Measures: Plasma DPP-4 activity; post-OGTT glucose excursion, active and total incretin GIP levels and insulin, C-peptide, and glucagon concentrations; sitagliptin PK.

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 following OGTTs administered at 2 and 24 h following single oral 25-mg 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 following single oral doses was associated with inhibition of plasma DPP-4 activity of ≥80%, corresponding to a plasma sitagliptin concentration of ≥100 nM, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher following an OGTT.
Key words: incretins • DPP-IV • MK-0431 • dipeptidyl peptidase-IV




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