The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded rapidly for the management of diabetes and obesity. However, beyond glycemic control, GLP-1RAs have demonstrated consistent cardiometabolic benefits, including reductions in major adverse cardiovascular events, mediated through anti-inflammatory, endothelial, and metabolic mechanisms. Cardiac surgery induces a profound physiological stress response characterized by systemic inflammation, ischemia-reperfusion injury, endothelial dysfunction, and metabolic derangements. Despite this strong mechanistic overlap, the role of GLP-1RAs in the perioperative cardiac surgical setting remains incompletely understood. This review endeavors to synthesize current mechanistic and clinical evidence and evaluate the potential role of GLP-1RAs in enhancing myocardial resilience during cardiac surgery. GLP-1 signaling targets multiple pathways implicated in perioperative myocardial injury. GLP-1RAs reduce epicardial adipose tissue activity and inflammatory cytokine signaling associated with postoperative atrial fibrillation. In ischemia-reperfusion injury, GLP-1 signaling reduces oxidative stress, inflammation, and cardiomyocyte cell death. Additionally, these agents improve endothelial function through nitric oxide-mediated vasodilation and modulation of mitogen-activated protein kinases signaling, suggesting a role in mitigating cardiopulmonary bypass-associated microvascular dysfunction. GLP-1RAs also enhance perioperative metabolic stability by improving glycemic control and reducing insulin requirements. However, perioperative use is complicated by the associated risk of delayed gastric emptying and aspiration risk. GLP-1RAs demonstrate strong biological plausibility for improving myocardial resilience during cardiac surgery. However, clinical evidence in surgical patients remains limited, and definitive benefit has not been fully established. Prospective, cardiac-surgery-specific studies are needed to determine whether mechanistic advantages translate into measurable improvements perioperatively and in the long term.
