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

• Published in: The journal of clinical endocrinology and metabolism Vol. 91; no. 11; pp. 4612 - 4619
• Main Authors: Herman, Gary A., Bergman, Arthur, Stevens, Catherine, Kotey, Paul, Yi, Bingming, Zhao, Peng, Dietrich, Bruno, Golor, George, Schrodter, Andreas, Keymeulen, Bart, Lasseter, Kenneth C., Kipnes, Mark S., Snyder, Karen, Hilliard, Deborah, Tanen, Michael, Cilissen, Caroline, De Smet, Marina, de Lepeleire, Inge, Van Dyck, Kristien, Wang, Amy Q., Zeng, Wei, Davies, Michael J., Tanaka, Wesley, Holst, Jens J., Deacon, Carolyn F., Gottesdiener, Keith M., Wagner, John A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.11.2006; Copyright by The Endocrine Society
• Subjects: Administration, Oral; Adult; Area Under Curve; Biological and medical sciences; Blood Glucose - drug effects; Cross-Over Studies; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Gastric Inhibitory Polypeptide - blood; Glucagon-Like Peptide 1 - blood; Glucose Tolerance Test - methods; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Male; Medical sciences; Middle Aged; Placebos; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Pyrazines - therapeutic use; Sitagliptin Phosphate; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics; Triazoles - therapeutic use; Vertebrates: endocrinology; Endocrinopathy; Type 2 diabetes; Human; Single dose; Oral administration; Metabolic diseases; Glucose tolerance test; Inhibitor; Glucose; Endocrinology; Glycemia
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2006-1009

Context: 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. Design: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. Setting: The study was conducted at six investigational sites. Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. Interventions: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. Main Outcome Measures: 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.