Dyslipidemia is a well-established risk factor for cardiovascular disease. Although an efficacy has been demonstrated for several drugs including HMGCR inhibitor and PCSK9 inhibitor, overall outcome was still in doubt due to heterogeneity of this disease. Thus, targeting multiple pathways may provide promising efficacy in broad patient population. Previously, we showed that a long-acting GLP-1/GIP/Glucagon triple agonist, HM15211, not only provided efficient weight loss, but also improved lipid profiles in DIO mice. Of note, unlike current drugs possessing a single target, HM15211 could affect multiple pathways in lipid metabolism, suggesting HM15211 as a potential therapeutic option for dyslipidemia. Here, we investigated the effect of HM15211 on dyslipidemia and its mode of action (MoA). In high fructose-fed hamsters, HM15211 showed greater LDL lowering (-69.3% vs. Veh.) than evolocumab, PCSK9 Ab (-17.9% vs. Veh.). To elucidate the responsible MoA, HepG2 cells were treated with HM15211, and significantly increased LDLR expression (4.1-fold for HM15211, 2.3-fold for evolocumab vs. CTL) was observed. Consistently, the amount of LDL uptake (3.6-fold for HM15211, 2.8-fold for evolocumab vs. CTL) indicated enhanced LDL clearance by HM15211 via increasing LDLR expression even greater than evolocumab. To further identify the HM15211 target, the activity status of HMGCR, the key enzyme for cholesterol synthesis, was evaluated. Surprisingly, HM15211 progressively induced phosphorylation and degradation of HMGCR, thereby inhibiting its enzymatic activity. In case of free fatty acid (FFA) metabolism, HM15211 led to a favorable gene expression signature associated with β-oxidation and enhanced β-oxidation. Increased ApoA1 may explain, at least in part, the increase of HDL by HM15211.
In conclusion, we propose that by targeting multiple steps essential for LDL and FFA metabolism, HM15211 could provide therapeutic benefits for dyslipidemia patients.
J. Choi: None. H. Jo: None. J. Kim: None. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.