Comparative effectiveness of mineralocorticoid receptor antagonists in cardiorenal and metabolic disease

Introduction Mineralocorticoid receptor antagonists (MRAs) are foundational in cardiorenal therapy, yet head-to-head comparisons across specific clinical phenotypes are scarce. This real-world study evaluates the comparative effectiveness and safety of various MRAs in patients with heart failure (HF), chronic kidney disease (CKD), and diabetes mellitus (DM). Methods Utilizing the TriNetX global health research network, we identified adults initiating spironolactone, eplerenone, or finerenone (the latter in conjunction with SGLT2 inhibitors). Patients were stratified into five cohorts: HFrEF, HFpEF, CKD, DM, and non-DM. Pairwise 1:1 propensity score matching was employed to ensure balanced comparisons between the steroidal and non-steroidal MRA groups. Results The totals of patients initiating MRAs concurrently with SGLT2 inhibitors after January 1, 2022, were 1,270 for HFrEF, 2,084 for HFpEF, 11,984 in CKD, 14,328 in DM, and 2,546 in non-DM. In the heart failure cohorts, finerenone was associated with a significant reduction in HF events compared to steroidal MRAs (HFrEF: HR=0.75, 95% CI: 0.67-0.85; HFpEF: HR=0.62, 95% CI: 0.56-0.68; p<0.001 for both) , though no significant differences were observed in overall survival (HFrEF: p = 0.313; HFpEF: p=0.309). Finerenone also showed a trend toward increased hyperkalemia risk in these patients (HFrEF: HR=1.42, p=0.103; HFpEF: HR=1.41, p=0.057). Conversely, in the CKD and DM cohorts, finerenone demonstrated comprehensive superiority. In CKD, it significantly reduced the risk of death (HR = 0.38, 95% CI: 0.32-0.45, p<0.001) and adapted-MACE (HR=0.45, 95% CI: 0.39-0.52, p<0.001) , with similar mortality benefits observed in DM (HR=0.43, p < 0.001) and non-DM (HR=0.31, p < 0.001) groups. Regarding safety, finerenone was associated with a lower risk of acute kidney injury across CKD (HR=0.59) , DM (HR=0.72) , and non-DM (HR=0.41) phenotypes (p<0.001 for all) , and a significantly reduced risk of hyperkalemia in CKD (HR=0.82, p = 0.004) and non-DM patients (HR=0.37, p = 0.001). Conclusion While finerenone appears superior for cardiorenal protection in CKD and metabolic phenotypes, steroidal MRAs maintain a favorable efficacy-safety balance in heart failure. These hypothesis-generating findings support a phenotype-driven, individualized approach to MRA selection, pending confirmation from prospective clinical trials.