Semaglutide augments vascular proliferation and cardiac performance in a large animal model of ischemic cardiomyopathy

The search for effective adjuncts to procedural revascularization for patients with coronary artery disease (CAD) has revealed, after several successful outcomes trials, the substantial potential of glucagon-like peptide 1 (GLP-1) analogs such as semaglutide. Because this potential has not been mechanistically illuminated in the setting of CAD and metabolic syndrome, we used a large animal model to evaluate the cardiac consequences of GLP-1 receptor (GLP-1R) agonism. Sixteen Yorkshire swine, after provision of a high-fat diet for 5 wk to induce metabolic syndrome, underwent ameroid constrictor-mediated induction of focal CAD. Animals were then either randomized to receive semaglutide (SEM, <i>n</i> = 8, 4 males, 4 females) or no drug (CON, <i>n</i> = 8, 4 males, 4 females) for 5 wk, followed by a terminal sternotomy for left ventricular pressure-volume catheterization, coronary collateral characterization, and myocardial resection and sectioning. Coronary arterioles from the peri-ischemic myocardium were mounted and suffused to assess vasoactivity, and molecular changes within the most ischemic territory were assayed using immunoblotting, immunofluorescence, and proteomics. Treated animals exhibited enhanced left ventricular filling, end diastolic volume, stroke volume, and cardiac index (all <i>P</i> < 0.05); increased arteriolar density (<i>P</i> < 0.001); improved microvascular endothelium-dependent vasodilation (<i>P</i> < 0.01); and, as indicated by increases in fibroblast growth factor, angiostatin, endostatin, and endothelial nitric oxide synthase (eNOS) (all <i>P</i> < 0.01) augmented vascular remodeling and endothelial function. In a large animal model that recapitulates the clinical comorbidities of CAD, improved left ventricular arteriolar density, vascular reactivity, and performance throughout the cardiac cycle position semaglutide as a highly promising addition to the adjunctive armamentarium against CAD.<b>NEW & NOTEWORTHY</b> In a clinically relevant swine model of chronic ischemic cardiomyopathy, oral semaglutide improved ventricular performance, likely through enhanced coronary collateralization. This benefit holds particular promise for patients with obesity and type 2 diabetes-populations already eligible for GLP-1 analog therapy. These findings support the initiation of randomized clinical trials of early GLP-1R agonist use at the time of CAD diagnosis to assess long-term outcomes and potential incorporation into standard ischemic heart disease management.