Patients with heart failure with preserved ejection fraction (HFpEF) often have an unfavorable cardiometabolic profile, and obesity-related HFpEF has become a well-recognized HFpEF sub-phenotype. Targeting this unfavorable cardiometabolic profile may therefore represent a rational treatment strategy. The glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide has been shown to induce significant weight loss and to improve cardiovascular outcomes. In this study, we investigated the cardiometabolic effects of semaglutide in a representative mouse model of HFpEF and compared it to the effects of weight loss by caloric restriction.