Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.

BACKGROUND: Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking. METHODS: Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. RESULTS: SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both<0.03); reduced perivascular and interstitial fibrosis (both<0.03); and apoptosis (=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (=0.005), coupled with downstream increases in eNOS (endothelial NO synthase;=0.014). CONCLUSIONS: This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.