非甾体类盐皮质激素受体拮抗剂在糖尿病肾病治疗中的研究进展

Research Progress of Non-Steroidal Mineralocorticoid Receptor Antagonists in the Treatment of Diabetic Kidney Disease

摘要: 糖尿病肾病(DKD)是终末期肾病的主要病因。现有治疗手段如肾素–血管紧张素系统抑制剂(RASi)与钠–葡萄糖耦联转运体2抑制剂(SGLT2i)虽然能延缓疾病进展，但患者仍然存在比较高的心肾残余风险，这说明还有别的致病通路没有被充分干预。盐皮质激素受体(MR)过度激活在DKD发病过程中起着关键作用，它会直接推动炎症反应、纤维化进程以及心肾组织损伤。传统的甾体类MR拮抗剂(MRA)虽然有效，但由于存在性激素相关不良反应以及高钾血症的风险，在临床上使用起来限制比较多。以非奈利酮为代表的非甾体类MRA，凭借其独特的分子结构设计，对MR的选择性更高，组织分布也更均衡，脱靶效应明显减少。Ⅲ期临床研究FIDELIO-DKD和FIGARO-DKD以及它们的事后汇总分析FIDELITY的结果显示，在RASi ± SGLT2i治疗基础上加用非奈利酮，可以使肾脏复合终点风险降低18%到23%，心血管复合终点风险降低13%到14%，而且安全性方面是可以监测和管理的。本文对非甾体类MRA的药理学特点、现有的临床研究证据、安全性问题以及它在DKD综合治疗中的定位进行了系统梳理，同时对“RASi + SGLT2i + ns-MRA”三联疗法的循证依据和临床实施框架进行了讨论，也对未来的研究方向作了展望。

Abstract: Diabetic kidney disease (DKD) is a leading cause of end‑stage kidney disease. Although current therapeutic approaches, such as renin‑angiotensin system inhibitors (RASi) and sodium‑glucose cotransporter‑2 inhibitors (SGLT2i), can slow disease progression, patients still face a considerable residual cardiorenal risk, suggesting that other pathogenic pathways remain inadequately addressed. Excessive activation of the mineralocorticoid receptor (MR) plays a pivotal role in the pathogenesis of DKD by directly promoting inflammation, fibrosis, and cardiorenal tissue injury. Traditional steroidal MR antagonists (MRAs) are effective, but their clinical use is substantially limited by sex‑hormone‑related adverse effects and the risk of hyperkalemia. Non‑steroidal MRAs, represented by finerenone, offer higher selectivity for MR and more balanced tissue distribution owing to their unique molecular design, with significantly reduced off‑target effects. Results from the phase III clinical trials FIDELIO‑DKD and FIGARO‑DKD, as well as their prespecified pooled analysis FIDELITY, have shown that adding finerenone to background therapy with RASi ± SGLT2i reduces the risk of the renal composite endpoint by 18%~23% and the cardiovascular composite endpoint by 13%~14%, with a manageable and monitorable safety profile. This article systematically reviews the pharmacological characteristics of non‑steroidal MRAs, the available clinical evidence, safety considerations, and their positioning in the comprehensive management of DKD. It also discusses the evidence base and clinical implementation framework for the triple therapy combination “RASi + SGLT2i + ns‑MRA,” and outlines future research directions.