Evidence-based validation of cardiovascular benefits from novel MRAs in type 2 diabetes: A meta-analysis of over 30,000 patients.

To evaluate the clinical efficacy and explore the potential mechanisms of novel mineralocorticoid receptor antagonists (MRAs) in reducing the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCTs), including relevant subgroup analyses, of steroidal MRAs (eplerenone, canrenone) and non-steroidal MRAs (finerenone, esaxerenone) in T2DM patients were identified through systematic searches of English and Chinese databases. Meta-analysis was performed to assess clinical outcomes, and network pharmacology was used to explore underlying molecular mechanisms. 18 RCTs (including relevant subgroup analyses) involving 30,103 participants were included. MRAs significantly reduced MACE risk (OR = 0.81, 95 % CI: 0.75-0.86; P < 0.00001). MRAs also significantly decreased cardiovascular mortality (OR = 0.86, 95 % CI: 0.77-0.97; P = 0.01) and hospitalization for heart failure (OR = 0.77, 95 % CI: 0.68-0.87; P < 0.0001). Network pharmacology identified that steroidal MRAs mainly act via IL-17 and relaxin signaling pathways, targeting MAPK10, GSK3B, PTGS2, NOS2, and MMP1. Non-steroidal MRAs primarily modulate Ras and relaxin pathways, involving targets such as EGFR and PIK3C. This study provides high-certainty evidence supporting MRAs in reducing MACE and heart failure hospitalization, and moderate-certainty evidence for benefits on cardiovascular mortality. Cardioprotective effects may involve Ras, IL-17, and relaxin signaling.