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

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.