Semaglutide and Linagliptin Shift Myocardial Metabolism from Fatty Acid Oxidation to Glucose in Ischemic Swine

Coronary artery disease (CAD) remains the leading cause of global morbidity and mortality, often exacerbated by metabolic syndrome. Traditional therapies for conditions like Type 2 Diabetes Mellitus have shown limited efficacy in reducing major adverse cardiovascular events. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4is), have demonstrated cardioprotective effects beyond mere glycemic control. This study investigates the specific metabolic alterations induced by these agents in the ischemic myocardium, addressing a critical gap in understanding their direct cardiac mechanisms.

Researchers induced metabolic syndrome in Yorkshire swine via a high-fat diet over 6 weeks, followed by surgical placement of an ameroid constrictor on the left circumflex artery to model progressive coronary artery disease. Animals were randomized into three cohorts (n = 8/cohort): high-fat diet semaglutide, high-fat diet linagliptin, or no drug control. Treatments were administered daily for 5 weeks. Cardiac tissue from the most ischemic myocardial regions was then harvested and subjected to comprehensive proteomic and metabolomic profiling, supplemented by immunoblotting and histology for corroboration.

Semaglutide treatment significantly altered myocardial metabolism, leading to upregulation of fatty acid biosynthesis, the pentose phosphate pathway, and starch and sucrose metabolism. Concurrently, semaglutide downregulated fatty acid beta-oxidation. Linagliptin treatment produced a similar, though less pronounced, metabolic profile, also notably downregulating fatty acid oxidation. Multiomic pathway analysis consistently suggested increased flux into the citrate cycle in both high-fat diet semaglutide and high-fat diet linagliptin cohorts, providing further evidence of enhanced glucose metabolism. Statistical significance for these metabolic shifts was defined as log2(fold change) ≥0.7 or ≤-0.7 and P ≤.05. These findings indicate a clear shift in substrate utilization.

Both semaglutide and linagliptin promoted a metabolic switch from fatty acid oxidation towards increased glucose metabolism in the ischemic myocardium of swine with metabolic syndrome.