Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects.
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.
Herman
Gary A
GA
Merck Research Laboratories, RY34-A536, 126 East Lincoln Avenue, Rahway, NJ 07065-0900, USA. gary_herman@merck.com
Bergman
Arthur
A
Liu
Fang
F
Stevens
Cathy
C
Wang
Amy Q
AQ
Zeng
Wei
W
Chen
Li
L
Snyder
Karen
K
Hilliard
Deborah
D
Tanen
Michael
M
Tanaka
Wesley
W
Meehan
Alan G
AG
Lasseter
Kenneth
K
Dilzer
Stacy
S
Blum
Robert
R
Wagner
John A
JA
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine
D058892:Adenosine Deaminase Inhibitors; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D000068900:Sitagliptin Phosphate