Network meta-analysis of pharmacotherapies shows GLP-1 RAs and SGLT2is reduce composite cardiovascular death and hospitalization in HFpEFNew drugs may lower heart failure risk and improve walking distance for patients with preserved ejection fraction

This study utilized a network meta-analysis approach to assess the comparative effectiveness of multiple pharmacotherapies for heart failure with preserved ejection fraction (HFpEF). The analysis included a total sample of 48,235 patients. The interventions examined encompassed angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists (MRAs), digoxin, angiotensin receptor-neprilysin inhibitors, sodium-glucose transporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and nitrates and nitrites. The primary comparator was placebo. The primary outcome measured was the composite of cardiovascular death and heart failure hospitalization. Secondary outcomes included cardiovascular death, all-cause mortality, worsening heart failure events, change in the 6-minute walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), and N-terminal pro-B-type natriuretic peptide levels.

Regarding the primary outcome, the network meta-analysis found that GLP-1 RAs significantly reduced the risk of the composite endpoint of cardiovascular death and HF hospitalization, with a hazard ratio of 0.73 (95% CI 0.61-0.88). Similarly, SGLT2is significantly reduced this risk, with a hazard ratio of 0.79 (95% CI 0.70-0.90). In contrast, no statistically significant differences were observed among the treatments regarding cardiovascular death or all-cause mortality alone.

When evaluating functional and symptomatic outcomes, GLP-1 RAs elicited the greatest improvement in the 6-minute walk test (6MWT) distance, with a mean difference of +17.60 meters (95% CI 8.53-26.67). Furthermore, GLP-1 RAs showed the most substantial improvement in the KCCQ-CSS, with a mean difference of +7.38 points (95% CI 5.51-9.26). These findings suggest a potential benefit of GLP-1 RAs in enhancing physical performance and patient-reported quality of life in this population.

Safety and tolerability data were not reported in the source evidence provided for this analysis. Consequently, specific adverse event rates, serious adverse events, discontinuation rates, and general tolerability profiles could not be detailed. This lack of reported safety data represents a significant gap in the current evidence base for these specific agents within the context of this network meta-analysis.

The study design, being a network meta-analysis, allows for the simultaneous comparison of multiple interventions, even if not all were tested in the same randomized controlled trials. However, the absence of reported safety data limits the ability to fully weigh the risk-benefit profile of GLP-1 RAs and SGLT2is against other standard therapies. The results indicate that while these agents offer significant benefits in reducing hospitalization and cardiovascular death, their impact on mortality remains statistically indistinguishable from placebo in this specific analysis. Additionally, the lack of reported safety information prevents clinicians from making fully informed decisions regarding potential side effects or discontinuation risks.

These results highlight the potential role of GLP-1 RAs and SGLT2is in the management of HFpEF, particularly for improving functional capacity and reducing hospitalization rates. However, the absence of mortality benefit in the statistical analysis and the lack of safety reporting necessitate cautious interpretation. Clinicians should consider these findings alongside existing guidelines and emerging data, acknowledging that the current evidence does not yet support definitive statements regarding mortality reduction or specific safety profiles for these newer agents in HFpEF.