INTRODUCTION AND AIMS: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in seven studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed a post-hoc analysis of BEACON to characterize changes in kidney function induced by bardoxolone methyl.
METHODS: Patients in BEACON (n=2185) were randomized 1:1 to receive once-daily bardoxolone methyl (20 mg) or placebo. Estimated GFR was calculated using serum creatinine and the Modification of Diet in Renal Disease (MDRD) Study equation and assessed every 4 weeks through Week 12, followed by assessments every 8 weeks thereafter. We performed a time-to-event analysis for a surrogate endpoint for kidney failure: confirmed ≥30% decline from baseline in eGFR. Confirmation of each eGFR decline event was based on ≥ 30% decline from baseline in eGFR occurring at two or more visits. All BEACON patients were included in the analysis and patients who did not experience an event were censored.
RESULTS: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Patients randomized to bardoxolone methyl were significantly less likely to experience a ≥ 30% decline from baseline in eGFR (hazard ratio 0.44 [95% CI 0.27 to 0.72]; p=0.001), and more than twice as many patients randomized to placebo experienced an event (55 versus 22 in patients randomized to bardoxolone methyl).
CONCLUSIONS: Bardoxolone methyl increased eGFR and significantly decreased the likelihood of ≥ 30% decline in eGFR, which is a validated surrogate for progression to kidney failure in clinical trials of CKD. Thus, the improvements in eGFR with bardoxolone methyl may translate to delays in the onset of kidney failure in patients with CKD.
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