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 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.).

Figure 1. Kaplan–Meier Plots of the Time to the First Event of the Primary Outcome and Its Components

Panel A shows the time to the first occurrence of the primary composite outcome (end-stage renal disease [ESRD] or death from cardiovascular causes) among patients in the bardoxolone methyl group and those in the placebo group. Panel B shows the time to death from cardiovascular causes in the two study groups, and Panel C the time to the development of ESRD in the two groups.

Figure 2. Kaplan–Meier Plots of the Time to the First Event of the Discrete Secondary Outcomes

Panel A shows the time to the first event of heart failure, defined as death due to heart failure or hospitalization for heart failure, among patients in the bardoxolone methyl group and those in the placebo group. Panel B shows the time to the first event of the secondary composite outcome (nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes) in the two study groups. The first event was nonfatal myocardial infarction in 17 patients in the bardoxolone methyl group and 11 in the placebo group, nonfatal stroke in 12 patients in the bardoxolone methyl group and 8 in the placebo group, hospitalization for heart failure in 91 patients in the bardoxolone methyl group and 54 in the placebo group, and death from cardiovascular causes in 19 patients in the bardoxolone methyl group and 13 in the placebo group.

Figure 3. Estimated Glomerular Filtration Rate (GFR), Body Weight, and Urinary Albumin-to-Creatinine Ratio

The urinary albumin-to-creatinine ratio is based on measurement of albumin in milligrams and creatinine in grams. For the estimated GFR and body weight, I bars indicate ±1 SE; for the urinary albumin-to-creatinine ratio, I bars indicate the antilog of the standard error for log urinary albumin-to-creatinine ratio.