Drugs · Oct 29, 2026

Comparative Effects of Pharmacological Treatment on Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials

By Zhang J, Wang Y, Li J et al.

BACKGROUND: The comparative efficacy and safety of the new drugs (including sodium-glucose cotransporter-2 inhibitors [SGLT-2Is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], non-steroidal mineralocorticoid receptor antagonists [nsMRAs], and soluble guanylate cyclase stimulators [sGCs]) for heart failure with mildly reduced or preserved (HFmrEF/HFpEF) ejection fraction remains largely unclear. We conducted a systematic review and network meta-analysis to evaluate their comparative effects on HFmrEF/HFpEF, aiming to provide evidence-based guidance for treatment selection. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were comprehensively searched. We included randomized controlled trials that compared nsMRA, sGC, SGLT-2I, and GLP-1RA with placebo for patients with HFmrEF/HFpEF. Primary efficacy outcomes were cardiovascular (CV) death, hospitalization for heart failure (HF hospitalization), and all-cause mortality, while primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). The main analysis was conducted to compare the effects on HFmrEF/HFpEF between individual drugs. A frequentist network meta-analysis with random-effects models was used to calculate risk ratios (RRs) for dichotomous outcomes and standardized mean differences (SMDs) for continuous outcomes. RESULTS: A total of 20 randomized controlled trials (RCTs, including 10 drugs from 35 publications) were included for analyses, but none provided head-to-head direct comparisons. No significant differences among all the individual drugs were found in risks of CV death or all-cause mortality. Compared with exenatide, low or moderate certainty evidence showed that dapagliflozin (RR 0.57, 95% CI 0.36-0.91), empagliflozin (RR 0.54, 95% CI 0.34-0.86), and semaglutide (RR 0.43, 95% CI 0.20-0.91) were related to decreased risk of HF hospitalization. No significant differences in the risk of SAEs were found among the individual drugs. Compared with empagliflozin, very low certainty evidence showed that tirzepatide (RR 1.17, 95% CI 1.04-1.32) was related to increased risk of AEs. When comparing the four drug classes (nsMRA, sGC, SGLT-2I, and GLP-1RA), no significant differences in efficacy outcomes were found, while SGLT-2I (RR 0.87, 95% CI 0.78-0.96) was associated with a decreased risk of AEs compared with GLP-1RA. CONCLUSIONS: No significant differences among the individual SGLT-2I, GLP-1RA, nsMRA, and sGC drugs were found in risks of CV death, all-cause mortality or SAEs in patients with HFmrEF/HFpEF. Further evidence is needed to support these comparative effects and update guidance on medication choice for HFmrEF/HFpEF. REGISTRATION: PROSPERO identifier number CRD420251143542.

doi.org/10.1007/s40265-026-02409-8PubMed 42955666Interventions