798-P: Potential Cardioprotective Effects of HM15275, a Novel, Long-Acting GLP-1/GIP/GCG Triple Agonist, in Animal Models of Hypertension

Introduction & Objective: Obesity is a major risk for development of cardiovascular disease (CVD). Both cardiac output and total blood volume are elevated in obesity, which eventually leads to cardiac hypertrophy and fibrosis. To date, therapeutic benefits of several incretin drugs were observed in cardiovascular outcomes trials. Based on these findings, the present study evaluates the cardioprotective effects of HM15275, a novel long-acting GLP-1/GIP/GCG triple agonist, in animal models of hypertension. Methods: Spontaneously hypertensive rat (SHR) was administered with HM15275 for 16 weeks. In angiotensin II (Ang II)-infused mice and AMLN mice, HM15275 was administered for 2 ~ 6 weeks, followed by the determination of cardiomyocytes size, and cardiac fibrosis (MT staining, collagen levels). To highlight CV benefits of HM15275, tirzepatide (TZP) was included as comparative control. Results: In SHR, cardiomyocytes cell size determined by WGA staining was significantly reduced by HM15275 treatment compared to TZP (-52.3% vs. TZP; p<0.001). In line with these results, both interstitial and perivascular fibrosis (% of extracellular collagen area using MT staining) were significantly improved by HM15275 treatment (-52.8% vs. TZP; p<0.001). In Ang II mice, the levels of pro-collagen-1α1 were significantly decreased by HM15275 in the heart (-40.5% vs. TZP; p<0.001). Moreover, cardiomyocyte enlargement caused by Ang II was significantly reduced by HM15275 treatment for 2 weeks. Similar benefits were also confirmed in AMLN mice. Conclusion: Collectively, the results showed that HM15275 could have more potent cardioprotective effects than TZP in hypertension mediated cardiac damage. Further mechanistic studies are needed to elucidate the MoA for the beneficial effects of HM15275. Disclosure S. Lee: None. J. Kim: None. E. Park: None. H. Kang: None. J.A. Kim: None. Y. Kim: None. S. Hong: None. S. Bae: None. S. Lee: None. I. Choi: None.