Supplementary Material for: Effects of Bardoxolone Methyl on Magnesium in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease

Background: Treatment with bardoxolone methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.