Comparative effectiveness of pharmacotherapy for heart failure with preserved ejection fraction: A systematic review...

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.

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.

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.

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.