Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP‐4 Inhibitor Sitagliptin in Middle‐Aged Obese Subjects

Abstract

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.

Identification and Characterization of Prokaryotic Dipeptidyl-peptidase 5 from Porphyromonas gingivalis

“…3). Furthermore, in accordance with no preference for Pro, inhibitor analysis using P32/98 (39), sitagliptin (40), and vildagliptin (41), potent inhibitors of human DPP4, demonstrated that neither had an effect on Lys-Ala-MCA hydrolysis by PGN_0756, whereas these compounds completely abrogated the activity of P. gingivalis DPP4 toward Lys-Ala-and Gly-Pro-MCA (Fig. 4).…”

Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor

“…ANCOVA models containing creatinine clearance as a continuous or categorical variable and covariates of age, sex, and weight were both used for analysis of pharmacokinetic parameter data. Based on the apparent wide therapeutic index of sitagliptin (2,5,6), an increase in plasma sitagliptin exposure (i.e., AUC 0 -ϱ ) of less than twofold was not considered clinically meaningful.…”

The Incretin System and Type 2 Diabetes

“…45 This results in at least a two-fold increase in post-meal levels of endogenous GLP-1 compared with placebo. [45][46][47] The greatest HbA 1c reductions reported with sitagliptin have been observed when it has been used in combination with metformin in previously OAD-naïve patients (placebo-adjusted reductions of -0.83 and -1.57% for sitagliptin 100mg…”