GLP-1-Based therapies for obesity-related heart failure with preserved ejection fraction: an umbrella review incorporating broader heart failure and cardiometabolic evidence

Background The cardiometabolic phenotype of obesity-related heart failure with preserved ejection fraction (HFpEF) is increasing in clinical prevalence. Existing systematic reviews and meta-analyses have primarily summarized efficacy estimates for glucagon-like peptide-1 (GLP-1)-based therapies, but the credibility and independence of these syntheses remain uncertain because methodological limitations and overlap in primary trials have not been systematically evaluated. This umbrella review therefore appraised the methodological quality, overlap, consistency, and robustness of the existing review-level evidence rather than generating another efficacy synthesis. Methods We conducted an umbrella review of systematic reviews, meta-analyses, and network meta-analyses evaluating GLP-1-based regimens in obesity-related HFpEF and adjacent cardiometabolic populations. PubMed, Embase, Web of Science, and the Cochrane Library were searched over the preceding decade. The systematic review or meta-analysis was the unit of analysis. Methodological quality was assessed with AMSTAR 2, and overlap of primary studies across reviews was quantified using the corrected covered area (CCA). No de novo meta-analysis was performed; primary trials were examined only to assess overlap and calculate the CCA. Review-level findings were synthesized according to effect direction, consistency, precision, sample size, methodological quality, clinical relevance, and overlap. Results Seventeen systematic reviews underwent qualitative profiling, of which 11 reported quantitative estimates relevant to the core review-level synthesis. For heart failure hospitalization, the review by Diallo et al. reported HR 0.78 (95% CI 0.73–0.84; n = 25,440). For the composite of cardiovascular death and heart failure hospitalization, Diallo et al. reported HR 0.84 (95% CI 0.78–0.89), Ahmed HM et al. reported HR 0.76 (95% CI 0.64–0.90), and Ahmed M et al. reported RR 0.73 (95% CI 0.57–0.93). Existing reviews also consistently suggested improvements in functional status. The review by Gera et al. reported OR 0.85 (95% CI 0.77–0.93; n = 85,373) for stroke, whereas findings for cardiovascular and all-cause mortality remained inconsistent. Evidence for major adverse cardiovascular events was limited; the review by Gonzales-Uribe et al. reported HR 0.71 (95% CI 0.60–0.86). AMSTAR 2 classified six reviews as having low overall methodological confidence and five as having critically low overall methodological confidence. The CCA was 13.2%, indicating high overlap. All HR, RR, and OR values were estimates reported by included reviews and were not recalculated or quantitatively combined in this umbrella review. Conclusions At the level of existing evidence syntheses, GLP-1-based therapies appear most consistently associated with fewer heart failure hospitalizations and improved functional capacity in obesity-related HFpEF. However, the review-level evidence does not establish a consistent mortality benefit or support GLP-1-based therapy as a universal mortality-modifying treatment for HFpEF. These agents are better interpreted as emerging metabolic-functional therapies whose apparent benefits must be considered in light of methodological limitations and high overlap among reviews.