Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease
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 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. 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. Copyright © 2013 Massachusetts Medical Society.
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; Toto, B; McCullough, P; Ivanovich, P; Ketteler, M; Lachin, J; McGill, J; Agarwal, R; Anker, S; Arenillas, JF; Januzzi, J; Jardine, A; Kasner, S; Kissela, B; Kolansky, D; Mann, J; Thadhani, R; Champion de Crespigny, P; Chan, DT; D'Almeida, E; Fraser, I; Gray, N; Holt, S; Irish, A; Isbel, N; Kerr, P; Packham, D; Phoon, R; Pollock, C; Roger, S; Suranyi, M; Walker, R; Wittert, G; Yue, D; Balcke, P; Prager, R; Schernthaner, G; Sunder-Plassmann, G; Jadoul, M; Krzesinski, JM; Peeters, P; Van der Niepen, P; Van Gaal, L; Van Vlem, B; Warling, X; Chow, S; Cournoyer, S; Dumas, R; Jolly, S; Levin, A; McMahon, A; Mehta, H; Ooi, TC; Perkins, D; Roy, L; Sapir, D; Tam, P; Bartaskova, D; Hemzsky, L; Kubina, D; Szabo, M; Tesar, V; Combe, C; Faller, B; Fauvel, JP; Halimi, JM; Hourmant, M; Le Meur, Y; Urena-Torres, P; Zaoui, P; Al-Sarraf, S; Burst, V; Degenhardt, S; Kempe, HP; Kleophas, W; Kosch, C; Krumme, B; Kuhlmann, M; Pistrosch, F; Rambausek, M
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