Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2492-2503 |
| Number of pages | 12 |
| Journal | New England Journal of Medicine |
| Volume | 369 |
| Issue number | 26 |
| DOIs | |
| State | Published - 2013 |
ASJC Scopus subject areas
- General Medicine
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In: New England Journal of Medicine, Vol. 369, No. 26, 2013, p. 2492-2503.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease
AU - De Zeeuw, Dick
AU - Akizawa, Tadao
AU - Audhya, Paul
AU - Bakris, George L.
AU - Chin, Melanie
AU - Christ-Schmidt, Heidi
AU - Goldsberry, Angie
AU - Houser, Mark
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AU - Lambers Heerspink, Hiddo J.
AU - McMurray, John J.
AU - Meyer, Colin J.
AU - Parving, Hans Henrik
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AU - Toto, Robert D.
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AU - Newman, J.
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AU - Parker, J.
AU - Parnes, E.
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AU - Pergola, P.
AU - Perlman, A.
AU - Perry, R. G.
AU - Petrillo, R.
AU - Prabhakar, S.
AU - Purighalla, R. S.
AU - Quesada-Suarez, L.
AU - Rabiei, A.
AU - Raskin, P.
AU - Rastogi, A.
AU - Reisin, E.
AU - Rekhi, A.
AU - Rivera-Colon, L.
AU - Rizk, D.
AU - Rodelas, R.
AU - Roer, D.
AU - Rosas, S.
AU - Ross, D. L.
AU - Rovner, S.
AU - Sackel, H.
AU - Sader, S.
AU - Santos, P.
AU - Schmidt, R.
AU - Shafik, S.
AU - Shakeel, M.
AU - Sharon, Z.
AU - Silva, A. L.
AU - Silva, A.
AU - Singh, B.
AU - Smith, M.
AU - Solomon, R.
AU - Soman, S.
AU - Spinowitz, B.
AU - Sprague, S. M.
AU - Spry, L.
AU - Stonesifer, L.
AU - Streja, D.
AU - Suchinda, P.
AU - Sun, C.
AU - Thakar, C. V.
AU - Trespalacios, F.
AU - Tumlin, J. A.
AU - Van Buren, P.
AU - Vernace, M.
AU - Vicks, S.
AU - Warren, M.
AU - Weiss, D.
AU - Welker, J.
AU - Winston, J. A.
AU - Wombolt, D. G.
AU - Wood, M.
AU - Wu, M.
AU - Wynne, A.
AU - Yu, H.
AU - Zabaneh, R. I.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84890946148&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890946148&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1306033
DO - 10.1056/NEJMoa1306033
M3 - Article
C2 - 24206459
AN - SCOPUS:84890946148
SN - 0028-4793
VL - 369
SP - 2492
EP - 2503
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 26
ER -