Introduction: Cardiotoxicity remains a major limitation in the use of anthracyclines and anti-HER2 agents, such as doxorubicin and trastuzumab, particularly when administered sequentially. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, have demonstrated cardioprotective and anti-inflammatory properties beyond glycemic control. However, their potential role in mitigating chemotherapy-induced cardiac injury in non-diabetic settings has not been explored. We investigated the effects of semaglutide in non-diabetic murine models subjected to sequential treatment with doxorubicin followed by trastuzumab over 10 days. Methods: Mice were randomized to receive semaglutide or vehicle. Cardiac function was assessed by echocardiography, including left ventricular ejection fraction (LVEF), longitudinal strain, and radial strain. Histological analyses evaluated myocardial fibrosis and hypertrophy. IHC analysis were performed in myocardial, hepatic and renal tissues. Circulating cardiac injury and inflammation biomarkers, including troponins, IL-1β, IL-6, IL-8, CCL12, and high-sensitivity C-reactive protein (hsCRP), were quantified. Results: Sequential exposure to doxorubicin and trastuzumab induced significant cardiac dysfunction, characterized by a reduction in LVEF and strain parameters, increased myocardial fibrosis and hypertrophy, and elevated circulating troponins and inflammatory cytokines. Conclusion: Semaglutide treatment significantly attenuated these changes, preserving LVEF, longitudinal and radial strain, and reducing histological evidence of fibrosis and cardiomyocyte hypertrophy. Moreover, semaglutide markedly decreased systemic concentrations of troponins and inflammatory mediators, including IL-1β, IL-6, IL-8, CCL12, and hsCRP.
Associazione Nazionale Medici Cardiologi Ospedalieri
