In a murine model of doxorubicin and trastuzumab-induced cardiotoxicity, semaglutide co-treatment significantly preserved left ventricular ejection fraction and fractional shortening (P<0.05).
Does semaglutide prevent cardiac dysfunction and myocardial injury in a murine model of sequential anthracycline-trastuzumab induced early cardiotoxicity?
Semaglutide demonstrates cardioprotective effects against sequential anthracycline and trastuzumab-induced cardiotoxicity in a preclinical murine model, preserving left ventricular function and reducing inflammation.
p-value: p=<0.05
Abstract Introduction Cardiotoxicity is a well-recognized adverse effect of sequential anthracycline and HER2-targeted therapies in cancer patients. While GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in diabetic individuals, their role in preventing chemotherapy-induced cardiotoxicity in non-diabetic settings remains unclear. Purpose To evaluate the cardioprotective effects of semaglutide in a murine model of short-term cardiotoxicity induced by sequential administration of doxorubicin and trastuzumab, using advanced echocardiographic parameters and biochemical profiling. Methods Female C57Bl/6 mice (6–7 weeks old) were randomized into four groups (n = 6/group): control, doxorubicin + trastuzumab (DOXO+TRAST), semaglutide alone, and DOXO+TRAST with semaglutide. Doxorubicin was administered intraperitoneally at 2.17 mg/kg/day for 5 consecutive days, followed by trastuzumab at 2.25 mg/kg/day for 5 days. Semaglutide (140 µg/kg/day s.c.) was co-administered throughout the 10-day protocol. Cardiac function was assessed by transthoracic echocardiography (Vevo 2100, 40 MHz) at baseline and day 10. Parameters included left ventricular ejection fraction (EF), fractional shortening (FS), and myocardial strain (radial and longitudinal) using speckle-tracking analysis. Systemic and cardio-renal biochemical markers (e.g., troponin, NT-proBNP, creatinine, inflammatory cytokines) were also evaluated. Immuneistochemical studies were performed in liver and heart of mice detecting tissue expression of MYD88, NLRP3, IL-1, IL-6, IL18. Results Mice treated with DOXO+TRAST exhibited a significant decline in EF (−20%), FS (−18%), and radial/longitudinal strain (−27% , -32%) versus controls (all p0.01), consistent with early cardiotoxicity. Semaglutide co-treatment significantly attenuated this decline (EF and FS preserved, p0.05 vs DOXO+TRAST), with partial recovery of longitudinal and radial strain. Biochemical analyses confirmed reduced myocardial injury and systemic inflammation in the semaglutide-treated group, with lower levels of cardiac troponin and pro-inflammatory cytokines. Renal parameters were also less affected. Tissue levels of NLRP3, MYD88, IL1, IL6,1L-18 were strongly reduced in SEMA+ DOXO/TR group vs DOXO/TRA group (p0.001) Conclusion In this short-term preclinical model of sequential anthracycline–trastuzumab cardiotoxicity, semaglutide preserved left ventricular function and reduced myocardial injury, as evidenced by both conventional and deformation imaging. These findings support the potential cardioprotective role of GLP-1 RAs in oncology settings, independent of glycemic status, and warrant further clinical investigation.
Maurea et al. (Thu,) conducted a other in Chemotherapy-induced cardiotoxicity (n=24). Semaglutide vs. Doxorubicin + trastuzumab (DOXO+TRAST) was evaluated on Left ventricular ejection fraction (EF) and fractional shortening (FS) (p=<0.05). In a murine model of doxorubicin and trastuzumab-induced cardiotoxicity, semaglutide co-treatment significantly preserved left ventricular ejection fraction and fractional shortening (P<0.05).