Semaglutide reduced the risk of HF events by 16% (RR 0.84, 95% CI 0.74-0.95; ARR 0.62%, 95% CI 0.19%-1.00%; NNT 161, 95% CI 100-526), and by 31% in those without baseline HF (RR 0.69, 95% CI 0.55-0.88; ARR 1.25%, 95% CI 0.48%-1.82%; NNT 80, 95% CI 55-208).<h4>Conclusion</h4>GLP-1 receptor agonists have limited absolute benefit for preventing HF events in patients with type 2 diabetes and/or obesity, including in those without baseline HF.<h4>Systematic review registration</h4>PROSPERO: CRD420251074882. This evidence concerns the gene GLP1R and obesity due to melanocortin 4 receptor deficiency.