Comparative clinical outcomes and safety of finerenone, SGLT2 inhibitors, RAS inhibitors and ARNI in heart failure with preserved or mildly reduced ejection fraction: a systematic review and network meta-analysis

Background: Although pharmacological therapies for heart failure have advanced, direct comparative evidence on the clinical outcomes and safety of finerenone versus other agents remains limited in HFpEF or HFmrEF. Objective: A network meta-analysis was conducted to compare clinical outcomes and safety among finerenone, sodium-glucose cotransporter 2 inhibitors (SGLT2i), renin-angiotensin system inhibitors (RASi) and angiotensin receptor-neprilysin inhibitors (ARNI) in patients with HFpEF or HFmrEF. Methods: A comprehensive systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science from database inception to 3 January 2026. Randomized controlled trials (RCTs) were included, and a network meta-analysis was performed to evaluate cardiovascular (CV) death, worsening heart failure (HF) events, composite renal outcomes, all-cause mortality, total HF hospitalizations, and adverse events. Results: A total of 27 RCTs involving 65,929 patients were included. Compared with placebo, finerenone was associated with lower risk of CV death (OR = 0.89, 95% CI 0.82-0.95) and worsening HF events (OR = 0.75, 95% CI 0.71-0.79), but higher risk of composite renal outcomes (OR = 1.42, 95% CI 1.10-1.84). No significant differences in CV death or all-cause mortality. In indirect comparisons, finerenone was associated with lower risk of worsening HF events versus canagliflozin (OR = 2.12, 95% CI 1.13-3.98) and RASi (OR = 1.21, 95% CI 1.03-1.42). Sotagliflozin (OR = 0.61, 95% CI 0.50-0.74) and empagliflozin (OR = 0.83, 95% CI 0.69-0.99) were associated with lower risk of total HF hospitalizations. Relative to finerenone, canagliflozin (OR = 1.53, 95% CI 1.25-1.88) and RASi (OR = 1.31, 95% CI 1.10-1.57) were associated with higher risk of adverse events. Conclusion: Compared with placebo, finerenone was associated with lower risk of CV death and worsening HF events. As most comparisons between interventions were indirect, sotagliflozin and empagliflozin were associated with lower risk of total HF hospitalizations relative to finerenone, whereas ARNI and empagliflozin were associated with lower risk of composite renal outcomes, and canagliflozin and RASi with higher risk of adverse events. No significant differences were observed between interventions for CV death or all-cause mortality.