The New England Journal of Medicine, 2013, Vol.369(26), pp.2492-2503
Background 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. Methods 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 m 2 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. Results 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. Conclusions 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 .) Among patients with type 2 diabetes and stage 4 chronic kidney disease, bardoxolone methyl, as compared with placebo, did not reduce the risk of end-stage renal disease or cardiovascular death. Cardiovascular events in the bardoxolone group prompted trial termination. Type 2 diabetes mellitus is the most important cause of progressive chronic kidney disease in the developed and developing worlds. Various therapeutic approaches to slow progression, including restriction of dietary protein, glycemic control, and control of hypertension, have yielded mixed results.1–3 Several randomized clinical trials have shown that inhibitors of the renin–angiotensin–aldosterone system significantly reduce the risk of progression,4–6 although the residual risk remains high.7 None of the new agents tested during the past decade have proved effective in late-stage clinical trials.8–12 Oxidative stress and impaired antioxidant capacity intensify with the progression of chronic kidney disease.13 In . . .