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

From Merck Research Laboratories, Rahway, New Jersey (Dr Herman, Dr Liu, Ms Stevens, Ms Snyder, Ms Hilliard, Mr Tanen, Dr Tanaka, Dr Meehan, Dr Wagner); Merck Research Laboratories, West Point, Pennsylvania (Dr Bergman, Dr Wang, Mr Zeng, Dr Chen); SFBC International, Miami, Florida (Dr Lasseter, Ms Dilzer); and Buffalo Clinical Research Center, Buffalo, New York (Dr Blum).

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 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.

Key Words: Incretins • DPP-4 • MK-0431 • obesity • glycemic efficacy

Address for reprints: Gary A. Herman, Merck Research Laboratories, RY34-A536, 126 East Lincoln Avenue, Rahway, NJ 07065-0900; phone: (732) 594-1893; fax: (732) 594-5405; e-mail: gary_herman{at}merck.com.

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				A. J. Bergman, J. Cote, B. Yi, T. Marbury, S. K. Swan, W. Smith, K. Gottesdiener, J. Wagner, and G. A. Herman Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor Diabetes Care, July 1, 2007; 30(7): 1862 - 1864. [Full Text] [PDF]