Inflamed epicardial fat (EAT) accumulation around the myocardium and coronaries is a risk factor for cardiovascular disease. Glucagon-like peptide receptor-agonists 1 improves the insulin response and reduces EAT thickness. We aimed to demonstrate the effect of semaglutide on proinflammatory epicardial adipogenesis with paracrine effects on cardiomyocytes. Biopsies or isolated stromal cells from subcutaneous adipose tissue and EAT of 67 patients undergoing open-heart surgery were studied by real-time quantitative polymerase chain reaction, proteomics, and metabolic assays. Adipogenesis assay and paracrine effect over atrial cardiomyocytes determined that semaglutide treatment modulates proinflammatory adiposity markers FABP4 and sPLA2 in epicardial adipogenesis with a paracrine effect in atrial cardiomyocytes.