Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events in patients with type 2 diabetes and obesity[1, 2], but the mechanisms underlying these benefits remain incompletely defined. Although GLP-1RAs improve vascular function[3] and alter circulating lipid species associated with cardiovascular risk [4-6], whether these effects extend to diseased coronary vessels and occur independently of weight loss is unknown. Here, we show that weight-neutral semaglutide administration in two complementary cardiometabolic HFpEF models - a porcine model of metabolic syndrome with coronary artery disease and the ZSF-1 obese HFpEF rat - improves coronary and aortic endothelium-dependent vasodilation, attenuates coronary vascular remodeling and fibrosis, increases myocardial microvascular density, and remodels the plasma lipidome through reductions in ceramides and diacylglycerols together with enrichment of long-chain polyunsaturated triacylglycerols. These findings identify direct vascular and metabolic actions of semaglutide that are independent of weight loss.
