Glucagon-like peptide-1 receptor agonists and outcomes in heart failure with preserved ejection fraction and obesity: a real-world systematic review and meta-analysis of observational studies

Background Heart failure with preserved ejection fraction (HFpEF) and obesity represent a common clinical phenotype associated with functional limitations, increased morbidity and mortality, and recurrent hospitalizations. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have demonstrated clinically meaningful benefits in randomized clinical trials, including weight reduction, improved quality of life, and a lower risk of worsening heart failure in patients with HFpEF and obesity. In this context, evaluating the impact of GLP-1 RA therapy in real-world settings is crucial, where patient characteristics and routine clinical practice may differ from controlled trials. Methods We performed a systematic review and meta-analysis of observational studies evaluating GLP-1 RA therapy in adult patients with HFpEF and obesity. Eligible studies included patients with a clinical diagnosis of HFpEF and body mass index (BMI) ≥30 kg/m², compared GLP-1 RA therapy with non–GLP-1 RA control groups, and reported adjusted hazard ratios (aHR) for mortality and/or worsening heart failure. The primary outcome was all-cause mortality. The secondary outcome was worsening heart failure, defined as hospitalization or emergency department visit for decompensated heart failure. Pooled adjusted HRs were calculated using random-effects models. Study quality was assessed using the ROBINS-I tool. Results Five observational studies comprising 17,066 patiens (8,476 GLP-1 RA users and 8,590 control) were included. Mean age was 65 years and mean BMI was 36.6 kg/m². Semaglutide was the predominant GLP-1 RA evaluated across the included studies. GLP-1 RA therapy was associated with a significant reduction in all-cause mortality (pooled adjusted HR 0.78, 95% CI 0.69–0.88; p<0.0001; I²=46%). Additionally, GLP-1 RA use was associated with a lower risk of worsening heart failure (pooled adjusted HR 0.77, 95% CI 0.75–0.80; p<0.0001; I²=0%). Conclusions In this meta-analysis of real-world evidence, GLP-1 receptor agonist therapy was associated with lower mortality and a reduced risk of worsening heart failure in patients with HFpEF and obesity. These findings are consistent with results from randomized clinical trials and extend their observations to broader, less selected populations encountered in routine clinical practice.