Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
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DOI：
10.1056/nejmoa1306033
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发表时间：
2013-12-26
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影响因子：
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通讯作者：
BEACON Trial Investigators
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作者：
de Zeeuw D;Akizawa T;Audhya P;Bakris GL;Chin M;Christ-Schmidt H;Goldsberry A;Houser M;Krauth M;Lambers Heerspink HJ;McMurray JJ;Meyer CJ;Parving HH;Remuzzi G;Toto RD;Vaziri ND;Wanner C;Wittes J;Wrolstad D;Chertow GM;BEACON Trial Investigators
尽管肾素-血管紧张素-醛固酮系统抑制剂可以减缓糖尿病肾病的进展，但残留风险很高。核1因子（红细胞衍生因子2）相关因子2激活剂是否能进一步降低这种风险尚不清楚。我们随机分配2185名2型糖尿病和4期慢性肾病患者（估计肾小球滤过率[GFR]，每分钟每1.73 m2体表面积15至<30 ml），每日剂量为20mg的甲基巴多隆或安慰剂。主要综合结局为终末期肾病（ESRD）或心血管原因死亡。根据独立数据和安全监测委员会的建议，主办方和指导委员会终止了试验；中位随访时间为9个月。1088名随机分配给甲基巴多洛酮组的患者中有69名（6%），1097名随机分配给安慰剂组的患者中有69名（6%）有主要的复合结局（甲基巴多洛酮组与安慰剂组的风险比为0.98；95%可信区间[CI]， 0.70 ~ 1.37; P = 0.92）。在巴多洛酮甲基组，43例患者发生ESRD， 27例患者死于心血管原因；在安慰剂组，51名患者发生ESRD， 19名患者死于心血管原因。巴多洛酮甲基组共有96例患者因心力衰竭住院或死于心力衰竭，而安慰剂组为55例（风险比为1.83；95% CI为1.32 ~ 2.55；P<0.001）。与安慰剂组相比，巴多洛酮甲基组估测的GFR、血压和尿白蛋白与肌酐比值显著增加，体重显著下降。在2型糖尿病和4期慢性肾病患者中，甲基巴多洛酮并没有降低ESRD或心血管原因死亡的风险。与安慰剂组相比，甲基巴多洛酮组的心血管事件发生率更高，这促使试验终止。（由Reata制药公司资助；BEACON ClinicalTrials.gov编号：NCT01351675）
Although inhibitors of the renin–angiotensin–aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)–related factor 2 activators further reduce this risk is unknown. We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m2 of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P = 0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.)