ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis

Abstract

Purpose of review: Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors.

Recent findings: ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid-based therapies will shape the future of the lipid arena. ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction.

Keywords: ANGPTL3; Atherosclerosis; Endothelial lipase; LDL-C; Lipoprotein lipase; Residual cardiovascular risk; Triglycerides.

Fig. 1

Strategies to reduce residual CV risk have recently been focused on lowering TG levels. ANGPTL3 inhibitors have the benefit of reducing both LDL-C and TGs, and are thus indicated in both familial and mixed hypercholesterolemia, whereby target LDL-C is not achieved despite optimal LLT. Both ANGPTL3 and APOC inhibition are equally effective in reducing TG levels; however, there may be greater efficacy of TG reduction with the APOC-III inhibitors. Inhibition of ANGPTL3 has the benefit of greater LDL-C lowering and would thus be indicated in FH patients and those with mixed dyslipidemia. Adapted by permission from Springer Nature from: Ward NC et al. BioDrugs. 2022;36(2):121–135) [•]. ANGPTL3, angiopoietin-like 3; APOC-III, apolipoprotein C-III; FCS, familial chylomicronemia syndrome; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; HC, hypercholesterolemia; LLT, lipid-lowering therapy; TG, triglycerides