Abstract Body (Do not enter title and authors here): Background: Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with limited therapeutic options for improving long-term cardiovascular outcomes. Semaglutide, a GLP-1 agonist, has shown promising effects in improving cardiovascular function and metabolic control. However, its overall efficacy in patients with heart failure has not yet been established.
Methods: We conducted searches of PubMed, Embase, Scopus, and Web of Science through February 21, 2025, identifying randomized controlled trials (RCTs) and cohort studies comparing semaglutide with placebo in patients with HF. The main outcomes were variation from baseline in 6-minute walk distance traveled (6MWD), C-reactive protein (CRP) concentration, amino-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration, body weight, waist circumference, adjudicated HF event (hospitalization or urgent visit), cardiac mortality, all-cause mortality, serious adverse events (SAEs), and cardiac events. Relative risks (RR), mean differences (MD), and hazard ratios (HR) with their 95% confidence intervals (CI) were calculated using a random-effects model. Heterogeneity was assessed with the I² statistic.
Results: Four RCTs and two cohort studies were included, with a total population of 6,479 patients with HF, of whom 3,200 (49.39%) received semaglutide and 3,279 (50.61%) received placebo. Treatment with semaglutide was associated with a significant increase in 6MWD (RR: 16.60; 95%CI: 10.58 to 22.62; p < 0.00001), a reduction in CRP (RR:0.59; 95%CI: 0.49 to 0.70; p<0.00001) and NT-proBNP (RR:0.81; 95%CI: 0.74 to 0.89; p<0.00001), a decrease in body weight (MD:-6.11; 95%CI: -11.41 to -0.82; p=0.02) and waist circumference (MD:-7.43; 95%CI: -9.26 to -5.60; p<0.00001). In addition, lower adjudicated HF events (RR:0.69; 95%CI: 0.50 to 0.97; p=0.03), SAEs (RR:0.77; 95%CI: 0.66 to 0.91; p=0.001), cardiac events (RR:0.54; 95%CI: 0.32 to 0.92; p=0.02), all-cause mortality (RR:0.80; 95%CI: 0.67 to 0.95; p=0.01) and cardiac mortality (HR:0.72; 95%CI: 0.60 to 0.86; p=0.0003).
Conclusion: This meta-analysis is one of the first to approach the potential of semaglutide in patients with HF. Semaglutide significantly improves functional capacity and metabolic parameters while reducing cardiac events, SAEs, and mortality. These findings suggest that semaglutide may represent a promising therapeutic option in this population and further research is warranted to confirm these results.