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

Dick De Zeeuw, Tadao Akizawa, Paul Audhya, George L. Bakris, Melanie Chin, Heidi Christ-Schmidt, Angie Goldsberry, Mark Houser, Melissa Krauth, Hiddo J. Lambers Heerspink, John J. McMurray, Colin J. Meyer, Hans Henrik Parving, Giuseppe Remuzzi, Robert D Toto, Nosratola D. Vaziri, Christoph Wanner, Janet Wittes, Danielle Wrolstad, Philip Raskin

Research output: Contribution to journalArticle

426 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 (US)
Pages (from-to)2492-2503
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number26
DOIs
StatePublished - 2013

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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

De Zeeuw, D., Akizawa, T., Audhya, P., Bakris, G. L., Chin, M., Christ-Schmidt, H., ... Raskin, P. (2013). Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. New England Journal of Medicine, 369(26), 2492-2503. https://doi.org/10.1056/NEJMoa1306033

Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. / De Zeeuw, Dick; Akizawa, Tadao; Audhya, Paul; Bakris, George L.; Chin, Melanie; Christ-Schmidt, Heidi; Goldsberry, Angie; Houser, Mark; Krauth, Melissa; Lambers Heerspink, Hiddo J.; McMurray, John J.; Meyer, Colin J.; Parving, Hans Henrik; Remuzzi, Giuseppe; Toto, Robert D; Vaziri, Nosratola D.; Wanner, Christoph; Wittes, Janet; Wrolstad, Danielle; Raskin, Philip.

In: New England Journal of Medicine, Vol. 369, No. 26, 2013, p. 2492-2503.

Research output: Contribution to journalArticle

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 & Raskin, P 2013, 'Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease', New England Journal of Medicine, vol. 369, no. 26, pp. 2492-2503. https://doi.org/10.1056/NEJMoa1306033
De Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. New England Journal of Medicine. 2013;369(26):2492-2503. https://doi.org/10.1056/NEJMoa1306033
De Zeeuw, Dick ; Akizawa, Tadao ; Audhya, Paul ; Bakris, George L. ; Chin, Melanie ; Christ-Schmidt, Heidi ; Goldsberry, Angie ; Houser, Mark ; Krauth, Melissa ; Lambers Heerspink, Hiddo J. ; McMurray, John J. ; Meyer, Colin J. ; Parving, Hans Henrik ; Remuzzi, Giuseppe ; Toto, Robert D ; Vaziri, Nosratola D. ; Wanner, Christoph ; Wittes, Janet ; Wrolstad, Danielle ; Raskin, Philip. / Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 26. pp. 2492-2503.
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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.",
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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

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 - Raskin, Philip

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.

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