University Hospitals (S.R., M.D., J.-E.D., A.V.-M., H.C., A.D., L.R.-N., A.F., G.P.), Cleveland, OH.
Case Western Reserve University (S.R., M.D., J.-E.D., A.V.-M., L.R.-N., J.E.-G., M.C., C.C.), Cleveland, OH.
Circulation. 2024 Aug 27;150(9):663-676. doi: 10.1161/CIRCULATIONAHA.123.067620. Epub 2024 Aug 12.
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.
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.
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 (=0.028), and ΔTWV was 1.2±1.7 cm in the placebo group and 0.037±1.9 cm in the spironolactone group (=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 (=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; =6.33×10). 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.
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.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.
持续的盐皮质激素受体激活是 2 型糖尿病和慢性肾脏病的病理反应。虽然盐皮质激素受体拮抗剂有益于减少心血管并发症，但在人类中缺乏这些作用的直接机制途径。
MAGMA 试验（矿物质皮质激素受体拮抗剂在动脉粥样硬化中的临床评估）是一项在接受最大耐受肾素-血管紧张素系统阻断剂治疗的高危 2 型糖尿病合并慢性肾脏病（未接受透析）患者中进行的随机、双盲、安慰剂对照试验。主要终点是使用 3T 磁共振成像在 12 个月时测量胸主动脉壁体积的变化，以绝对值或百分比值（ΔTWV 或 ΔPWV）表示。次要终点包括左心室（LV）质量的变化；心肌固有 T1 变化表示 LV 纤维化的变化；24 小时动态和中心主动脉血压的变化。三级终点包括使用基于适配子的测定法测量 7596 种血浆蛋白中的血浆蛋白质组学变化。
共有 79 名患者被随机分配至安慰剂组（n=42）或每日 25 毫克螺内酯组（n=37）。经过改良的意向治疗，包括研究终点的基线数据，完成试验方案的患者被纳入最终分析。在 12 个月的随访中，安慰剂组的 PWV 平均变化为 7.1±10.7%，螺内酯组为 0.87±10.0%（=0.028），TWV 平均变化为 1.2±1.7cm 安慰剂组和 0.037±1.9cm 螺内酯组（=0.022）。安慰剂组 LV 质量增加 3.1±8.4g，螺内酯组减少 5.8±8.4g（=0.001）。LV T1 值的变化在安慰剂组和螺内酯组之间有显著差异（安慰剂组 26.0±41.9ms 与螺内酯组 -10.1±36.3ms；=6.33×10）。中介分析显示，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心血压后仍然显著。蛋白质组学分析显示，螺内酯对涉及氧化应激、炎症和白细胞激活的途径有明显影响。
在患有中度至重度慢性肾脏病且心血管风险升高的 2 型糖尿病患者中，螺内酯治疗可预防主动脉壁体积的进展，并导致 LV 质量的回归和心肌固有 T1 的有利变化，表明左心室纤维化得到改善。
