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Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease
Dick de Zeeuw1, Tadao Akizawa, Paul Audhya
1From the University of Groningen, Groningen, the Netherlands (D.Z., H.J.L.H.); Showa University School of Medicine, Tokyo (T.A.); Reata Pharmaceuticals, Irving, TX (P.A., M.C., A.G., M.K., C.J.M.); University of Chicago (G.L.B.) and AbbVie Pharmaceuticals (M.H.) - both in Chicago; Statistics Collaborative, Washington, DC (H.C.-S., J.W., D.W.); University of Glasgow, Glasgow, United Kingdom (J.J.M.); Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.); Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy (G.R.); University of Texas Southwestern Medical Center, Dallas (R.D.T.); University of California, Irvine (N.D.V.); University of Würzburg, Würzburg, Germany (C.W.); and Stanford University, Palo Alto, CA (G.M.C.).
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.).
Insights
Bardoxolone methyl did not reduce the risk of end-stage renal disease or cardiovascular death in patients with type 2 diabetes and advanced chronic kidney disease. The trial was stopped early due to increased heart failure events in the bardoxolone methyl group.
Area of Science:
- Nephrology
- Cardiology
- Endocrinology
Background:
- Diabetic kidney disease (DKD) progression remains a significant risk despite renin-angiotensin-aldosterone system inhibitors.
- The potential benefit of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) activators in reducing residual risk in DKD is not well-established.
Purpose of the Study:
- To evaluate the efficacy of bardoxolone methyl, an Nrf2 activator, in reducing the risk of end-stage renal disease (ESRD) or cardiovascular death in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease.
- To assess the safety profile of bardoxolone methyl in this patient population.
Main Methods:
- A randomized, placebo-controlled trial involving 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (eGFR 15–30 ml/min/1.73 m²).
- Patients received either 20 mg of bardoxolone methyl daily or a placebo.
- The primary composite outcome was ESRD or death from cardiovascular causes. The trial was terminated early based on data and safety monitoring committee recommendations.
Main Results:
- The primary composite outcome occurred in 6% of patients in both the bardoxolone methyl and placebo groups (hazard ratio, 0.98; 95% CI, 0.70 to 1.37; P=0.92).
- Bardoxolone methyl treatment was associated with a significantly higher rate of hospitalization for or death from heart failure (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001).
- Bardoxolone methyl led to significant increases in estimated GFR, blood pressure, and urinary albumin-to-creatinine ratio, and a decrease in body weight compared to placebo.
Conclusions:
- Bardoxolone methyl did not demonstrate a reduction in the risk of ESRD or cardiovascular death in patients with type 2 diabetes and stage 4 chronic kidney disease.
- The trial's early termination was prompted by an increased incidence of cardiovascular events, particularly heart failure, in the bardoxolone methyl group.
- Nrf2 activation with bardoxolone methyl in this high-risk population did not provide the anticipated clinical benefit and raised safety concerns.
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