title: 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.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Experimental Medicine, Rahway, New Jersey 07065, USA. gary_herman@merck.com
authors.forename: Gary A
authors.initials: GA
authors.lastname: Herman
authors.forename: Arthur
authors.initials: A
authors.lastname: Bergman
authors.forename: Catherine
authors.initials: C
authors.lastname: Stevens
authors.forename: Paul
authors.initials: P
authors.lastname: Kotey
authors.forename: Bingming
authors.initials: B
authors.lastname: Yi
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Bruno
authors.initials: B
authors.lastname: Dietrich
authors.forename: George
authors.initials: G
authors.lastname: Golor
authors.forename: Andreas
authors.initials: A
authors.lastname: Schrodter
authors.forename: Bart
authors.initials: B
authors.lastname: Keymeulen
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kipnes
authors.forename: Karen
authors.initials: K
authors.lastname: Snyder
authors.forename: Deborah
authors.initials: D
authors.lastname: Hilliard
authors.forename: Michael
authors.initials: M
authors.lastname: Tanen
authors.forename: Caroline
authors.initials: C
authors.lastname: Cilissen
authors.forename: Marina
authors.initials: M
authors.lastname: De Smet
authors.forename: Inge
authors.initials: I
authors.lastname: de Lepeleire
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Dyck
authors.forename: Amy Q
authors.initials: AQ
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Wesley
authors.initials: W
authors.lastname: Tanaka
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: 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
chemical_list: 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