GLP1 receptor agonism attenuates anthracycline and HER2 targeted therapy induced cardiac dysfunction and systemic inflammation in non-diabetic models

Background Sequential administration of anthracyclines and HER2-targeted agents represents a highly effective therapeutic strategy in breast cancer but is frequently complicated by cumulative cardiotoxicity, limiting treatment durability and long-term cardiovascular outcomes. Inflammation-driven myocardial injury and multi-organ stress responses are increasingly recognised as central mechanisms in cancer therapy–related cardiac dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert pleiotropic cardiovascular and anti-inflammatory effects independent of glucose lowering, yet their role in preventing chemotherapy-induced cardiac injury in non-diabetic settings remains largely unexplored. Methods Non-diabetic murine models were exposed to sequential doxorubicin followed by trastuzumab over a 10-day protocol. Animals were randomised to receive the GLP-1 receptor agonist semaglutide or vehicle. Cardiac function was serially assessed by echocardiography, including left ventricular ejection fraction and myocardial strain parameters. Histopathological analyses evaluated myocardial fibrosis and cardiomyocyte hypertrophy. Immunohistochemical profiling was performed in cardiac, hepatic, and renal tissues. Circulating biomarkers of myocardial injury and systemic inflammation, including troponins, IL-1β, IL-6, IL-8, CCL12, and high-sensitivity C-reactive protein, were quantified. Results Sequential anthracycline and HER2 blockade induced marked cardiac dysfunction, characterised by significant impairment of systolic performance and myocardial deformation, accompanied by increased myocardial fibrosis, cardiomyocyte hypertrophy, and elevated circulating markers of cardiac injury and inflammation. Semaglutide administration significantly preserved left ventricular ejection fraction and strain parameters and substantially attenuated structural myocardial remodelling. These functional benefits were paralleled by a robust reduction in circulating troponins and pro-inflammatory cytokines. In addition, semaglutide mitigated inflammatory signalling across cardiac, hepatic, and renal tissues, indicating a broader cardio-renal protective profile. Conclusions GLP-1 receptor agonism confers significant protection against chemotherapy-induced cardiac dysfunction and systemic inflammatory injury in non-diabetic preclinical models exposed to anthracycline and HER2-targeted therapy. These findings support a novel, glucose-independent role for GLP-1RAs in cardio-oncology, with potential implications for integrated strategies aimed at preserving cardiovascular and multi-organ health during intensive anticancer treatment. Further translational studies are warranted to define their clinical relevance in patients at high risk of cancer therapy–related cardiac dysfunction.