Abstract
BACKGROUND: Steroidal mineralocorticoid receptor antagonists (MRAs) reduce morbidity in heart failure (HF) but frequently cause hyperkalemia, limiting long-term use. Non-steroidal MRAs such as finerenone offer improved receptor selectivity, but real-world comparative data remain scarce. METHODS: We used the TriNetX Global Collaborative Network to identify adults with type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and HF initiated on a non-steroidal (finerenone) or steroidal MRA (spironolactone, eplerenone) between January 2020 and December 2024. Propensity score matching (1:1) yielded 780 patients per cohort. Outcomes included hyperkalemia, arrhythmia, stroke, myocardial infarction (MI), and all-cause mortality. RESULTS: Non-steroidal MRAs were associated with significantly lower risks of hyperkalemia >5.5 mmol/L (16.0% vs 21.8%; HR 0.683, 95% CI 0.542-0.861; p=0.001) and severe hyperkalemia >6.0 mmol/L (7.6% vs 10.4%; HR 0.690, 95% CI 0.493-0.965; p=0.029). They were also linked to a lower arrhythmia incidence (31.2% vs 44.7%; HR 0.596, 95% CI 0.506-0.703; p<0.001), stroke (6.2% vs 9.9%; HR 0.606, 95% CI 0.422-0.869; p=0.006), and all-cause mortality (6.3% vs 16.5%; HR 0.359, 95% CI 0.258-0.499; p<0.001). MI was numerically lower (10.9% vs 13.5%; HR 0.762, 95% CI 0.572-1.014; p=0.061) but not statistically significant. CONCLUSION: In patients with T2DM, CKD, and HF, non-steroidal MRAs were associated with improved safety and cardiovascular outcomes compared with steroidal MRAs. However, the observational study design and, hence, the limitation in data that can be collected warrant cautious interpretation. Prospective randomized head-to-head trials are warranted before adaptation in clinical practice.