Body mass index-dependent therapeutic efficacy in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction: A systematic review and network meta-analysis

Objectives: Several pharmacological classes have demonstrated favorable impacts on cardiovascular outcomes in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF). Given the ubiquitous presence of obesity in HFmrEF and HFpEF, this study aimed to assess the cardiovascular benefits of principal heart failure drug classes according to body mass index (BMI) strata. Methods: A systematic search of the bibliographic databases (PubMed, Cochrane Library, and Embase) was conducted to identify randomized clinical trials published between January 2000 and January 2025, with no language restrictions. The study eligibility was restricted to peer-reviewed articles and randomized clinical trials. A systematic search of major electronic databases was conducted to identify studies comparing key drug classes, such as semaglutide, tirzepatide, finerenone, empagliflozin, dapagliflozin, and spironolactone. The primary endpoint was defined as a composite endpoint comprising cardiovascular death and heart failure hospitalizations. We employed Mendelian randomization to investigate the causal effects of glucagon-like peptide-1 receptor agonist activity on HFmrEF and HFpEF. The study protocol was prospectively registered with PROSPERO (registration ID: CRD420251022550). Results: Our search identified six eligible trials, encompassing a total of 33,524 patients for the pooled analysis, the majority of whom had HFpEF. In a network meta-analysis of patients with HFmrEF and a BMI ≥ 30 kg/m 2 , semaglutide was associated with a significant reduction in the hazard ratio compared with dapagliflozin (HR = 0.66, 95% credible interval [CI]: 0.44–0.99), spironolactone (HR = 0.61, 95% CI: 0.40–0.93), finerenone (HR = 0.61, 95% CI: 0.41–0.90), empagliflozin (HR = 0.57, 95% CI: 0.38–0.87), and placebo (HR = 0.49, 95% CI: 0.34–0.71), and achieved the highest P-score ranking. In patients with a BMI ≥ 35 kg/m 2 , semaglutide was associated with a statistically significant risk reduction compared to empagliflozin (HR = 0.62, 95% CI: 0.39-0.98) and achieved the highest P score. Empagliflozin was consistently identified as the preferred therapeutic option in both the BMI < 30 kg/m 2 or < 35 kg/m 2 subgroups, securing the highest P score rankings. Mendelian randomization analysis showed that glucagon-like peptide-1 action was associated with a decreased risk of HF in the HF and BMI > 25 kg/m 2 group, but not in the HF and all-BMI group. Conclusion: Semaglutide represents an effective therapeutic strategy for patients with HFpEF and concomitant obesity.