Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH
Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH.
Diabetes Care. 2018 Dec;41(12):2603-2609. doi: 10.2337/dc18-0755.
To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.
A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.
The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3-5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, < 0.001, and the incidence for ≥10 × ULN was 0.31% vs. 0.06%, < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63).
Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.
评估 fasiglifam（一种新型 G 蛋白偶联受体 40（GPR40）激动剂）在 2 型糖尿病患者中的心血管（CV）安全性。
一项 3 期多中心随机双盲安慰剂对照双臂试验旨在将 5000 名 2 型糖尿病高危 CV 患者随机分为 fasiglifam 组或安慰剂组。试验的主要目的是排除 fasiglifam 治疗组与安慰剂组相比，CV 复合事件的危害比（HR）单侧 97.5%置信限的上限非劣效性边界>1.3。主要终点是首次发生任何主要不良 CV 事件复合事件（CV 死亡、非致死性心肌梗死、非致死性卒中和不稳定型心绞痛住院）的时间。
该研究纳入了 3207 名参与者，但由于肝安全性问题而终止。fasiglifam 组观察到肝酶升高（AST/ALT≥3-5×正常值上限[ULN]）的发生率增加。与安慰剂相比，fasiglifam 组 ALT 或 AST≥3×ULN 的发生率为 2.1%比 0.5%，<0.001，≥10×ULN 的发生率为 0.31%比 0.06%，<0.001。12 个月时，fasiglifam 组和安慰剂组各有 40 例（2.5%）发生主要 CV 复合结局（HR 1.05；95%CI 0.67，1.63）。
由于担心药物引起的肝损伤，fasiglifam 的开发被终止。美国食品和药物管理局要求进行 CV 结局试验，这支持了 fasiglifam 临床项目的终止。
