EFFICACY, SAFETY, AND DOSE-RESPONSE CHARACTERISTICS OF GLIPIZIDE GASTROINTESTINAL THERAPEUTIC SYSTEM ON GLYCEMIC CONTROL AND INSULIN-SECRETION IN NIDDM - RESULTS OF 2 MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED CLINICAL-TRIALS

OBJECTIVE - To investigate the efficacy, safety, and dose-response cha racteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosy lated hemoglobin (HbA(1c)), and insulin secretion to a liquid-mixed me al in NIDDM patients. RESEARCH DESIGN AND METHODS - Two prospective, r andomized, double-blind, placebo-controlled, multicenter clinical tria ls were performed in 22 sites and 347 patients with NIDDM (aged 59 +/- 0.6 years; BMI, 29 +/- 0.3 kg/m(2); 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 titra tion to a fixed dose, and 8-week maintenance phase at the assigned dos e. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizi de GITS were compared with placebo in 143 patients. In the second tria l, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with p lacebo in 204 patients. HbA(1c), 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 (Sustac al). RESULTS - All doses of glipizide GITS in both trials produced sig nificant reductions from placebo in FPG (range -57 to - 74 mg/dl) and HbA(1c) (range - 1.50 to -1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and r eduction in FPG and HbA(1c) 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 HbA(1c). PPG levels were significantly lower, and both postprandial insulin an d C-peptide levels significantly higher in patients treated with glipi zide GITS compared with placebo. The percent reduction in FPG was comp arable across patients with diverse demographic and clinical character istics, including those with entry FPG greater than or equal to 250 mg /dl, resulting in greater absolute decreases in FPG and HbA(1c) in pat ients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only ii patients in both studies discont inued therapy because of hypoglycemia. Glipizide GITS did not alter li pids levels or produce weight gain. CONCLUSIONS - The once-daily glipi zide GITS 1) lowered HbA(1c), FPG, and PPG over a dose range of 5-60 m g, 2) was maximally effective at 5 mg (using HbA(1c)) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) ma intained its effectiveness in poorly controlled patients (those with e ntry FPG greater than or equal to 250 mg/dl), 4) was safe and well tol erated in a wide variety of patients with NIDDM, and 5) did not produc e weight gain or adversely affect lipids.