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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

Merck Research Laboratories (G.A.H., A.B., C.S., P.K., B.Y., P.Z., K.S., D.H., M.T., A.Q.W., W.Z., M.J.D., W.T., K.M.G., J.A.W.), Rahway, New Jersey 07065; 3ClinicalResearch AG (B.D., G.G.), 16761 Berlin, Germany; Focus Clinical Drug Development GmBH (A.S.), 41460 Neuss, Germany; Free University of Brussels (B.K.), Brussels, 1050 Belgium; Clinical Pharmacology Associates (K.C.L.), Miami, Florida 33142; Diabetes and Glandular Disease Research Associates (M.S.K.), San Antonio, Texas 78229; MSD-Europe (C.C., M.D.S., I.d.L., K.V.D.), 1180 Brussels, Belgium; and University of Copenhagen (J.J.H., C.F.D.), DK-2200 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Gary A. Herman, M.D., Merck Research Laboratories, Experimental Medicine, RY34-A4031, 126 East Lincoln Avenue, Rahway, New Jersey 07065. 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 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.

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