Echocardiographic Evidence for Valvular Toxicity of Benfluorex: A Double-Blind Randomised Trial in Patients with Type 2 Diabetes Mellitus

ObjectivesREGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. MethodsDouble-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA1c. Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. ResultsAt baseline, patients were 59.1±10.5 years old with HbA1c 8.3±0.8%, and DM duration 7.1±6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30±0.80 to 7.77±1.31 versus pioglitazone: from 8.30±0.80 to 7.45±1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p ConclusionAfter 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug. Trial registrationwww.controlled-trials.com ISRCTN 27354239. isrctn27354239

REGULATE试验旨在对比苯氟雷司（benfluorex）与吡格列酮（pioglitazone）在2型糖尿病（type 2 diabetes mellitus, DM）患者中的疗效与安全性。
本试验为双盲、平行组、国际化随机化非劣效性试验。196家参与中心中超过半数为基层医疗中心。纳入合格受试者为接受磺酰脲类药物治疗但血糖控制不佳的2型糖尿病患者，共随机入组846例，接受为期1年的研究干预治疗。其中423例被分配至苯氟雷司组（每日剂量150~450mg），423例被分配至吡格列酮组（每日剂量30~45mg）。本试验主要疗效终点为糖化血红蛋白（HbA1c）水平。安全性评估包括对心脏及瓣膜状态的盲法超声心动图评估。
基线时，受试者平均年龄为59.1±10.5岁，糖化血红蛋白水平为8.3±0.8%，糖尿病病程为7.1±6.0年。试验期间，两组患者的平均糖化血红蛋白水平均显著降低：苯氟雷司组从8.30±0.80%降至7.77±1.31%，吡格列酮组从8.30±0.80%降至7.45±1.30%。吡格列酮组末次糖化血红蛋白水平显著低于苯氟雷司组（P值原文缺失）。
经1年药物暴露治疗后，本研究结果显示苯氟雷司组瓣膜反流发生率升高2.97倍，为该药物的瓣膜毒性提供了循证依据。
试验注册信息：www.controlled-trials.com ISRCTN 27354239，即isrctn27354239