Efficacy, Safety, and Dose-Response Characteristics of Glipizide Gastrointestinal Therapeutic System on Glycemic Control and Insulin Secretion in NIDDM: Results of two multicenter, randomized, placebo-controlled clinical trials

Abstract

OBJECTIVE To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients. RESEARCH DESIGN AND METHODS Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 ± 0.6 years; BMI, 29 ± 0.3 kg/m2; known diabetes duration, 8 ± 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal). RESULTS All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range −57 to −74 mg/dl) and HbA1c (range −1.50 to −1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5–60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG ≥ 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain. CONCLUSIONS The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5–60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG ≥ 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids.