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J Clin Endocrinol Metab. 2006 Nov;91(11):4612-9. Epub 2006 Aug 15.

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.

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1
Merck Research Laboratories, Experimental Medicine, Rahway, New Jersey 07065, USA. gary_herman@merck.com

Abstract

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.

PMID:
16912128
DOI:
10.1210/jc.2006-1009
[Indexed for MEDLINE]
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