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
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
复制标题
格列吡嗪胃肠道治疗系统对 NIDDM 血糖控制和胰岛素分泌的功效、安全性和剂量反应特征：两项多中心、随机、安慰剂对照临床试验的结果
作者：
D. Simonson;I. Kourides;M. Feinglos;H. Shamoon;C. Fischette
目的研究格列吡嗪缓释制剂经胃肠道治疗系统（GITS）对2型糖尿病（NIDDM）患者餐后血糖、糖化血红蛋白（HbA 1c）及胰岛素分泌的影响。研究设计和方法在22个地点进行了两项前瞻性、随机、双盲、安慰剂对照、多中心临床试验，研究了347例NIDDM患者（年龄59 ± 0.6岁; BMI，29 ± 0.3 kg/m2;已知糖尿病病程，8 ± 0.4年）。每项临床试验的持续时间为16周，包括1周洗脱期、3周单盲安慰剂期、4周滴定至固定剂量期和8周指定剂量维持期。在第一项试验中，在143例患者中比较了格列吡嗪GITS 5、20、40或60 mg每日一次给药与安慰剂。在第二项试验中，在204例患者中比较了格列吡嗪GITS 5、10、15或20 mg剂量与安慰剂。在整个研究期间定期测定HbA 1c、空腹血糖（FPG）、胰岛素、C肽和格列吡嗪水平。还在混合餐（Sustacal）后1小时和2小时测定餐后血糖（PPG）、胰岛素和C肽。结果：两项试验中所有剂量的格列吡嗪GITS均使FPG（范围为−57至−74 mg/dl）和HbA 1c（范围为−1.50至−1.82%）较安慰剂显著降低。药效学分析表明，在5-60 mg剂量范围内，格列吡嗪血药浓度与FPG和HbA 1c降低之间存在显著相关性，FPG在20 mg剂量下达到最大疗效，HbA 1c在5 mg剂量下达到最大疗效。格列吡嗪GITS组患者的PPG水平显著低于安慰剂组，餐后胰岛素和C肽水平显著高于安慰剂组。具有不同人口统计学和临床特征的患者（包括入组FPG ≥ 250 mg/dl的患者）的FPG下降百分比相当，导致最严重高血糖患者的FPG和HbA 1c绝对下降幅度更大。尽管强制调整至随机分配的剂量，但两项研究中只有11名患者因低血糖而停止治疗。格列吡嗪GITS不会改变血脂水平或导致体重增加。结论：每日一次格列吡嗪GITS 1）在5-60 mg剂量范围内降低HbA 1c、FPG和PPG，2）5 mg时最有效（使用HbA 1c）或20 mg（使用FPG）基于药代动力学和药效学关系，3）在控制不佳的患者中保持其有效性（入组FPG ≥ 250 mg/dl者），4）在各种NIDDM患者中安全且耐受性良好，5）不会导致体重增加或对血脂产生不良影响。
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.
影响因子：
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作者：
R. Klein;B. Klein;S. Moss;K. Cruickshanks
通讯作者：
R. Klein;B. Klein;S. Moss;K. Cruickshanks
影响因子：
16.2
作者：
R. DeFronzo;D. Simonson
通讯作者：
R. DeFronzo;D. Simonson
磺酰脲类药物对人类胰岛功能的急性和慢性影响。
影响因子：
16.2
作者：
Pfeifer,MA;Halter,JB;Judzewitsch,RG;Beard,JC;Best,JD;Ward,WK;PorteJr,D
通讯作者：
PorteJr,D