1872-LB: Therapeutic Potential of HM15275, a Novel Long-Acting GLP-1/GIP/GCG Triple Agonist, in Animal Models of Heart Failure

Introduction & Objective: Obesity significantly increases the risk of cardiovascular death and is a leading cause of heart failure with preserved ejection fraction (HFpEF). Considering these outcomes, the purpose of this study is to evaluate whether HM15275, a novel long-acting GLP-1/GIP/GCG triple agonist, could alleviate heart failure (HF)-related symptoms in various animal models of HF. Methods: To investigate therapeutic effects of HM15275 in HF animal models, we used the monocrotaline (MCT)-induced HF rat model to induce HF caused by pulmonary arterial hypertension (PAH), which is one of the major contributing factors to HF. Second, isoproterenol (ISO)-induced HF mouse model was used to induce HF with cardiac dilation and ventricular dysfunction through the increase in cardiac hypercontractility. Finally, we used a high fat diet (HFD) + nitrol-arginine methyl ester (L-NAME) mouse model of HFpEF, induced by obesity and hypertension. HM15275 was administrated for 2 to 5 weeks after model induction. Semaglutide (SMG) and tirzepatide (TZP) were used as comparative control. Results: In three HF animal models, HM15275 significantly improved cardiac hypertrophy (-66.5% in MCT-induced HF model, -12.6% in ISO-induced HF model, -28.8% in HFD + L-NAME model) compared to other incretin drugs, SMG and TZP. Interestingly, HM15275 significantly improved exercise capacity (+313.9%) and arterial oxygen saturation (+13.8%) and reduced myocardial fibrosis and cardiomyocytes size compared to SMG and TZP in MCT-induced HF rat model. Also, in HFD + L-NAME mouse model, HM15275 remarkably changed multiple biomarkers of cardiovascular risk, including body weight, blood glucose, levels of lipids, and physical limitations. Conclusion: HM15275 significantly improved exercise intolerance, cardiac hypertrophy, and fibrosis in HF murine models, compared to SMG and TZP, supporting that it could be a novel therapeutic option for HF patients. Disclosure B. Ye: None. W. Kim: None. S. Lee: None. J.A. Kim: None. E. Kim: None. S. Bae: None. S. Lee: None. I. Choi: None.