BACKGROUND Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. METHODS The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. RESULTS A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm3 in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33×10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. CONCLUSIONS Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.

中文翻译：

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盐皮质激素受体拮抗作用可防止 2 型糖尿病和慢性肾病患者的主动脉斑块进展并减少左心室质量和纤维化：MAGMA 试验。


背景 持续的盐皮质激素受体激活是 2 型糖尿病和慢性肾病的病理反应。虽然盐皮质激素受体拮抗剂有助于减少心血管并发症，但缺乏这些作用在人类中的直接机制途径。方法 MAGMA 试验 （盐皮质激素受体拮抗动脉粥样硬化临床评估） 是一项随机、双盲、安慰剂对照试验，针对接受最大耐受肾素-血管紧张素系统阻断的慢性肾病 （未接受透析） 的高危 2 型糖尿病患者。主要终点是 12 个月时使用 3T 磁共振成像的胸主动脉壁体积的变化，以绝对值或百分比值 （ΔTWV 或 ΔPWV） 表示。次要终点是左心室 （LV） 质量的变化;左心室纤维化，以心肌天然 T1 的变化来衡量;以及 24 小时动态和中央主动脉血压。第三终点包括使用基于适配体的测定法的 7596 种血浆蛋白的血浆蛋白质组学变化。结果 共有 79 例患者被随机分配至安慰剂组 （n=42） 或每日 25 mg 螺内酯组 （n=37）。在修改意向治疗后，包括研究终点的可用基线数据，完成试验方案的患者被纳入最终分析。在 12 个月的随访中，安慰剂组 PWV 的平均变化为 7.1±10.7%，螺内酯组为 0.87±10.0% （P=0.028），ΔTWV 为安慰剂组 1.2±1.7 cm3，螺内酯组为 0.037±1.9 cm3 （P=0.022）。安慰剂组 LV 质量变化为 3.1±8.4 g，螺内酯组 -5.8±8.4 g （P = 0.001）。 安慰剂组和螺内酯组之间 LV T1 值的变化存在显著差异 （安慰剂组为 26.0±41.9 ms，而螺内酯组为 -10.1±36.3 ms;P=6.33×10-4）。介导分析显示，螺内酯对胸主动脉壁体积和心肌质量的影响在调整动态和中央血压后仍然显着。蛋白质组学分析揭示了螺内酯对涉及氧化应激、炎症和白细胞活化的途径的主导作用。结论 在心血管风险升高的中重度慢性肾病糖尿病患者中，螺内酯治疗阻止了主动脉壁体积的进展，导致 LV 质量消退和天然 T1 的有利改变，表明左心室纤维化得到改善。注册网址：https://www.clinicaltrials.gov;唯一标识符：NCT02169089。