Comparative effectiveness of pharmacotherapy for heart failure with preserved ejection fraction: A systematic review and network meta‐analysis

AIM: Heart failure with preserved ejection fraction (HFpEF) presents a therapeutic challenge, characterised by a paucity of validated treatments. Emerging data suggest that targeting adiposity is central to HFpEF pathogenesis. We conducted an updated network meta-analysis to compare the efficacy of emerging and established HFpEF therapies. MATERIALS AND METHODS: We systematically searched PubMed, Embase and Cochrane Library from inception to April 2025 for randomised controlled trials enrolling patients with HFpEF and evaluating pharmacotherapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists (MRAs), digoxin, angiotensin receptor-neprilysin inhibitor, sodium-glucose transporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), nitrates and nitrites. The primary outcome was a composite of cardiovascular death and heart failure (HF) hospitalisation. The secondary outcomes included cardiovascular death, all-cause mortality, worsening HF events, change in the 6-min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and N-terminal pro-B-type natriuretic peptide levels. A frequentist random-effects NMA was conducted. RESULTS: Thirty-nine trials with 78 treatment arms and 48 235 patients were enrolled. Compared with placebo, GLP-1 RAs (HR: 0.73, 95% CI 0.61-0.88) and SGLT2is (HR: 0.79, 95% CI 0.70-0.90; P-score: 0.807) significantly reduced the risk of cardiovascular death and HF hospitalisation. GLP-1 RAs showed the highest probability of ranking first (P-score: 0.871). GLP-1 RAs elicited the greatest improvement in functional outcomes, including the 6MWT (mean difference: +17.60 m, 95% CI 8.53-26.67) and KCCQ-CSS (mean difference: +7.38 points, 95% CI 5.51-9.26). No statistically significant differences in cardiovascular death or all-cause mortality were observed among the treatments. CONCLUSIONS: In patients with HFpEF, GLP-1RA, SGLT2i and MRA significantly reduced the risk of cardiovascular death and HF hospitalisation, while GLP-1RA additionally improved the functional and quality-of-life outcomes. GLP-1RA and SGLT2i significantly reduced HF morbidity, and GLP-1RA uniquely improved functional status, positioning adiposity modulation as a central therapeutic target in HFpEF.