658-P: Sustained Glucagon Effect on Cardiovascular Renal and Metabolic Disorders Mediated by a Long-Acting Glucagon Analog, HM15136, in Animal Disease Models

Abstract

Obesity is an increasing health problem worldwide, implicated with various metabolic disorders such as cardiovascular disease and chronic kidney disease (CKD). Previously, we showed that chronic treatment of HM15136, a long-acting GCG analog, led to robust body weight loss (BWL) in rodent obese models. Moreover, recent studies unveiled a novel role of GCG in vasodilation and inflammation. So, we hypothesized that HM15136 improve chronic metabolic disorders via direct action in addition to secondary effect to BWL. Here, we investigated potential therapeutic effect of HM15136 in animal models of cardiovascular renal and metabolic diseases. In DIO mice, BW, liver triglyceride (TG), and blood cholesterol (CHO) were measured, and all measurements were significantly reduced by HM15136 treatment (-37.5, -72.7, -78.4% vs. vehicle for BW, liver TG, blood CHO at day 17). Next, to explore therapeutic effect of HM15136 on cardiovascular renal diseases, spontaneously hypertensive rats, known model for hypertensive CKD, were used. Interestingly, abnormal elevation in blood pressure and renal function markers such as urine albumin/creatinine ratio (-23.6% vs. SHR vehicle at day 46) was meaningfully reduced by HM15136 treatment. In unilateral ureteral obstruction mice, known as acute kidney injury model, similar results were observed (-17.6%, -48.2% vs. vehicle for serum creatinine, kidney pro-collagen1α1 at day 12). Consistently, increase of vasodilation markers in rat aorta and inhibition of human primary podocyte apoptosis were confirmed, explaining underlying mechanism for these beneficial effects. Therefore, HM15136 could mitigate obesity and related complications especially hypertension and CKD. Hence, mechanistic study results highlight the essential role of direct GCG engagement in improvement of cardiovascular renal and metabolic diseases. Further studies are needed to assess a clinical relevance of these findings. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharmaceutical.