Incretin-based therapies and altered myocardial metabolism in a swine model of ischemic heart disease in the setting of metabolic syndrome.
basic_science · Level V
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- Record sourced from PubMed, PMID 42386418.
- Also identified by DOI 10.1016/j.surg.2026.110369.
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Abstract
Coronary artery disease is the leading cause of morbidity and mortality worldwide. Incretin-based therapies, including dipeptidyl peptidase-4 inhibitors (eg, linagliptin) and glucagon-like peptide-1 receptor agonists (eg, semaglutide), have gathered interest for potential cardioprotective effects beyond glycemic control. This study examines how incretin mimetics alter myocardial metabolism in a large animal model of coronary artery disease with metabolic syndrome. Metabolic syndrome was induced in Yorkshire swine through administration of a high-fat diet over a 6-week period. Swine then underwent surgical placement of an ameroid constrictor on the left circumflex artery to model progressive coronary artery disease. Animals were randomized to receive daily treatment with high-fat diet semaglutide, high-fat diet linagliptin, or no drug (n = 8/cohort). After 5 weeks of treatment, cardiac tissue was harvested. The most ischemic myocardial regions were subjected to comprehensive proteomic and metabolomic profiling. Integrated multiomic data were analyzed, with statistical significance defined as log<sub>2</sub>(fold change) ≥0.7 or ≤-0.7 and P ≤.05. Immunoblotting and histology were performed to supplement and corroborate multiomics. Semaglutide treatment was associated with upregulation of fatty acid biosynthesis, pentose phosphate pathway, and starch and sucrose metabolism, and downregulation of fatty acid beta-oxidation. Linagliptin treatment resulted in a similar but less pronounced metabolic profile, notable for downregulation of fatty acid oxidation. Multiomic pathway analysis also suggested increased flux into the citrate cycle in both high-fat diet semaglutide and high-fat diet linagliptin cohorts, further supporting increased glucose metabolism. Glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 inhibitor linagliptin are associated with reduced fatty acid oxidation and increased glucose metabolism in a swine model of coronary artery disease with metabolic syndrome.