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.

背景：在一项跨国3期临床试验「慢性肾病与2型糖尿病患者巴多索隆甲酯（bardoxolone methyl）评估试验（BEACON）」中，接受巴多索隆甲酯（Bard）治疗的患者估算肾小球滤过率出现升高，同时血清镁水平伴随降低。本研究对多项试验的数据进行分析，以明确巴多索隆甲酯所致镁水平降低的特征。
方法：BEACON试验将2185名2型糖尿病（T2DM）合并4期慢性肾病（CKD）的患者按1:1随机分组，分别接受每日一次20mg巴多索隆甲酯或安慰剂治疗。在另一项开放标签研究中，研究人员对连续56天每日接受20mg巴多索隆甲酯治疗的3b-4期慢性肾病合并2型糖尿病患者的24小时尿液样本及舌下上皮细胞样本中的镁水平进行了分析。
结果：BEACON试验中，相较于安慰剂组患者，巴多索隆甲酯组患者的血清镁水平较基线出现显著降低（降幅0.17 mEq/L，95%置信区间：–0.18至–0.60 mEq/L；p < 0.001）。另一项研究显示，巴多索隆甲酯治疗后患者的细胞内镁及尿镁水平无明显变化。
结论：巴多索隆甲酯治疗可显著降低血清镁水平，但该变化与细胞内镁及尿镁水平的改变无关，提示血清镁水平降低并非由肾脏镁流失或全身镁耗竭所致。值得注意的是，巴多索隆甲酯所致血清镁水平降低与QT间期不良反应并无关联。