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Preclinical and clinical studies have identified favourable actions of GLP-1R agonists on cardiovascular outcomes.GLP-1R agonist-induced cardioprotection is likely mediated via indirect mechanisms.The optimization of cardiac energy metabolism may explain GLP-1R agonist-induced cardioprotection in diabetic patients.Glucagon-like peptide-1 receptor (GLP-1R) agonists are frequently used to improve glycemia in patients with type 2 diabetes (T2D). Recent data from cardiovascular outcomes trials for the GLP-1R agonists, liraglutide and semaglutide, have also demonstrated significant reductions in death rates from cardiovascular causes in patients with T2D. As cardiovascular death is the number one cause of death in patients with T2D, understanding the mechanisms by which GLP-1R agonists such as liraglutide and semaglutide improve cardiac function is essential. Yet despite strong evidence from preclinical and clinical studies supporting the cardioprotective actions of GLP-1R agonists, the precise mechanism(s) by which this drug-class for T2D may produce these beneficial actions remains enigmatic. Negligible GLP-1R expression in ventricular cardiac myocytes suggests that GLP-1R agonist-induced cardioprotection is likely partially attributed to indirect actions on peripheral tissues other than the heart. Because insulin increases glucose oxidation, whereas glucagon increases fatty acid oxidation in the heart, GLP-1R agonist-induced increases and decreases in insulin and glucagon secretion, respectively, may modify cardiac energy metabolism in T2D patients. This may represent a potential mechanism for GLP-1R agonist-induced cardioprotection in T2D, as increases in fatty acid oxidation and decreases in glucose oxidation are frequently observed in the hearts of animals and human subjects with T2D.