Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease

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Research output: Contribution to journalArticle

432 Citations (Scopus)

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 languageEnglish
Pages (from-to)2492-2503
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number26
DOIs
Publication statusPublished - Jan 1 2013
Externally publishedYes

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Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Placebos
Chronic Kidney Failure
Glomerular Filtration Rate
Cause of Death
GATA1 Transcription Factor
Heart Failure
Clinical Trials Data Monitoring Committees
Confidence Intervals
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Body Surface Area
Diabetic Nephropathies
Renin-Angiotensin System
Albumins
Creatinine
Body Weight
Blood Pressure
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. / Unknown.

In: New England Journal of Medicine, Vol. 369, No. 26, 01.01.2013, p. 2492-2503.

Research output: Contribution to journalArticle

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title = "Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease",
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.",
author = "Unknown and {De Zeeuw}, Dick and Tadao Akizawa and Paul Audhya and Bakris, {George L.} and Melanie Chin and Heidi Christ-Schmidt and Angie Goldsberry and Mark Houser and Melissa Krauth and {Lambers Heerspink}, {Hiddo J.} and McMurray, {John J.} and Meyer, {Colin J.} and Parving, {Hans Henrik} and Giuseppe Remuzzi and Toto, {Robert D.} and Vaziri, {Nosratola D.} and Christoph Wanner and Janet Wittes and Danielle Wrolstad and Chertow, {Glenn M.} and B. Toto and P. McCullough and P. Ivanovich and M. Ketteler and J. Lachin and J. McGill and R. Agarwal and S. Anker and Arenillas, {J. F.} and J. Januzzi and A. Jardine and S. Kasner and B. Kissela and D. Kolansky and J. Mann and R. Thadhani and {Champion de Crespigny}, P. and Chan, {D. T.} and E. D'Almeida and I. Fraser and N. Gray and S. Holt and A. Irish and N. Isbel and P. Kerr and D. Packham and R. Phoon and C. Pollock and S. Roger and M. Wu",
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T1 - Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease

AU - Unknown

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

AU - Krauth, Melissa

AU - Lambers Heerspink, Hiddo J.

AU - McMurray, John J.

AU - Meyer, Colin J.

AU - Parving, Hans Henrik

AU - Remuzzi, Giuseppe

AU - Toto, Robert D.

AU - Vaziri, Nosratola D.

AU - Wanner, Christoph

AU - Wittes, Janet

AU - Wrolstad, Danielle

AU - Chertow, Glenn M.

AU - Toto, B.

AU - McCullough, P.

AU - Ivanovich, P.

AU - Ketteler, M.

AU - Lachin, J.

AU - McGill, J.

AU - Agarwal, R.

AU - Anker, S.

AU - Arenillas, J. F.

AU - Januzzi, J.

AU - Jardine, A.

AU - Kasner, S.

AU - Kissela, B.

AU - Kolansky, D.

AU - Mann, J.

AU - Thadhani, R.

AU - Champion de Crespigny, P.

AU - Chan, D. T.

AU - D'Almeida, E.

AU - Fraser, I.

AU - Gray, N.

AU - Holt, S.

AU - Irish, A.

AU - Isbel, N.

AU - Kerr, P.

AU - Packham, D.

AU - Phoon, R.

AU - Pollock, C.

AU - Roger, S.

AU - Wu, M.

PY - 2013/1/1

Y1 - 2013/1/1

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.

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DO - 10.1056/NEJMoa1306033

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EP - 2503

JO - New England Journal of Medicine

JF - New England Journal of Medicine

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