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.
BACKGROUND
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.


METHODS
This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study.


METHODS
The study was conducted at six investigational sites.


METHODS
The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents.


METHODS
Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo.


METHODS
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.
Herman
Gary A
GA
Merck Research Laboratories, Experimental Medicine, Rahway, New Jersey 07065, USA. gary_herman@merck.com
Bergman
Arthur
A
Stevens
Catherine
C
Kotey
Paul
P
Yi
Bingming
B
Zhao
Peng
P
Dietrich
Bruno
B
Golor
George
G
Schrodter
Andreas
A
Keymeulen
Bart
B
Lasseter
Kenneth C
KC
Kipnes
Mark S
MS
Snyder
Karen
K
Hilliard
Deborah
D
Tanen
Michael
M
Cilissen
Caroline
C
De Smet
Marina
M
de Lepeleire
Inge
I
Van Dyck
Kristien
K
Wang
Amy Q
AQ
Zeng
Wei
W
Davies
Michael J
MJ
Tanaka
Wesley
W
Holst
Jens J
JJ
Deacon
Carolyn F
CF
Gottesdiener
Keith M
KM
Wagner
John A
JA
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood*; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010919:Placebos; D011719:Pyrazines; D014230:Triazoles; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate