ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model1

Copyright © 2020 Hurt-Camejo. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This article is available online at https://www.jlr. org The current focus of therapeutic intervention to reduce atherosclerotic cardiovascular disease (ACVD) risk is lowering plasma LDL-C to below 70 mg/dl using primarily statins. However, many patients on statins remain at high ASCVD risk (1). Monoclonal antibodies against PCSK9, in addition to statins, can further reduce LDL-C. Also, Mendelian randomization reports show that moderately elevated triglyceride-rich lipoproteins and remnant cholesterol increase ASCVD risk independently of LDL-C levels (2). This supports the use of drug combinations targeting complementary pathways explored in the study by Pouwer and collaborators (3) reported in this issue of the Journal of Lipid Research. This also suggests that simultaneous therapeutic reduction in plasma triglycerides associated with apoB-containing lipoproteins could have a greater atheroprotective effect (4). The consensus documents from the European Society of Atherosclerosis (EAS) and the International Society of Atherosclerosis (ISA) support the central role of apoB lipoproteins as a cause of ASCVD (1). The study by Pouwer et al. (3) in a preclinical mouse model and the human Mendelian randomization findings indicate that the contribution of LDL-C to the development of ASCVD is determined not only by the absolute LDL-C level but also by the cumulative time exposure of the arterial wall to apoB lipoproteins (1). Pouwer et al. (3) report results from a study comparing double and triple combination treatments with the hypolipidemic drugs alirocumab and evinacumab, a human PCSK9 and an ANGPTL3 monoclonal antibody, respectively, combined with atorvastatin. In this interesting study, the effects on plasma lipoprotein levels and their impact on atherosclerosis progression and regression were evaluated in apoE*3Leiden.CETP mice, a well-established humanized model characterized by elevated triglycerides and VLDL-C remnant lipoproteins. This is the first mouse study using a combination of drugs currently in humans and in clinical development for treatment of dyslipidemias and reduction of atherosclerotic cardiovascular risk. Alirocumab is a monoclonal antibody to PCSK9 that reduces LDL-C plasma levels by ≥51% and the risk of recurrent ischemic cardiovascular events in patients with acute coronary syndrome when administered with statins (5). Evinacumab (REGN1500), under clinical development, is a monoclonal antibody against ANGPTL3, a circulating protein secreted by the liver that regulates the hydrolysis of VLDL triglycerides (TGs) and HDL phospholipids by lipoprotein lipase and endothelial lipase, respectively (6). In mice, inactivation of PCSK9 increases hepatic LDL receptors (LDL-Rs), consequently reducing circulating LDL levels (7). On the other hand, ANGPTL3 inactivation increases TG-rich VLDL hydrolysis, thus generating remnants apoB lipoproteins and their conversion into LDL particles rapidly cleared from circulation with or without direct involvement of hepatic LDL-R (8). The mice in this study received a Western-type diet containing 0.30% cholesterol and 15% saturated fat for 13 weeks that enhanced hyperlipidemia and accelerated atherosclerosis. The animals received the diet with different drug combinations for 25 weeks in the following groups: 1) control without any hypolipidemic drug, 2) atorvastatin as monotherapy, 3) atorvastatin with alirocumab, 4) atorvastatin with evinacumab, or 5) triple treatment with atorvastatin, alirocumab, and evinacumab. All drugs reduced total cholesterol (TC), nonHDL-C, and TGs with the triple treatment achieving the highest reduction at the end of the study. No changes in HDL-C were observed in any treatment. This study confirmed that alirocumab and evinacumab, targeting different biochemical pathways together with a statin, caused an additive reduction of apoB-containing lipoproteins. Atorvastatin alone induced a 27% reduction, while the combination of atorvastatin with alirocumab or ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model