ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases

Abstract

Optimal management of low-density lipoprotein cholesterol (LDL-C) is a central tenet in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, significant residual cardiovascular risk remains despite achieving guideline-directed LDL-C levels, in part due to mixed hyperlipidemia with elevated fasting and non-fasting triglyceride-rich lipoprotein levels. Advances in human genetics have identified angiopoietin-like 3 (ANGPTL3) as a promising therapeutic target to lower cardiovascular risk. Evidence accrued from genetic epidemiological studies demonstrate that ANGPTL3 loss of function is strongly associated with lowering of circulating LDL-C, triglyceride-rich lipoproteins and concurrent risk reduction in development of coronary artery disease. Pharmacological inhibition of ANGPTL3 with monoclonal antibodies, antisense oligonucleotides and gene editing are in development with early studies showing their safety and efficacy in lowering in both, LDL-C and TGs, circumventing a key limitation of previous therapies. Monoclonal antibodies targeting ANGPTL3 are approved for clinical use in homozygous familial hypercholesteremia in USA and Europe. Although promising, future studies focusing on long-term beneficial effect in reducing cardiovascular events with inhibition of ANGPTL3 are warranted.