27 - Inhibition of ANGPTL3 as a Target for Treating Dyslipidemias

Abstract

Angiopoietin-like protein 3 (ANGPTL3) is a secretory hepatokine that can broadly regulate lipid and lipoprotein metabolism. Carriers of loss-of-function variants in ANGPTL3 have lower plasma levels of triglyceride and low-density lipoprotein (LDL) cholesterol, as well as reduced risk of atherosclerotic cardiovascular disease (ASCVD). Hence, inhibition of ANGPTL3 may offer a new strategy for universally correcting atherogenic dyslipidemia in patients at high risk of ASCVD and cardiometabolic disease. Such patients include those with familial hypercholesterolemia, mixed hyperlipidemia, insulin resistance and diabetes, hepatic steatosis, and severe hypertriglyceridemia syndromes. The mechanism of action of ANGPTL3 inhibition involves a combination of reduced production and increased catabolism of triglyceride-rich lipoprotein and LDL particles. ANGPTL3 may be inactivated with a monoclonal antibody or with nucleic acids targeted at mRNA, such as antisense oligonucleotide and RNA interference therapies. Early clinical trials have demonstrated that ANGPTL3 inhibitors can safely and effectively lower plasma triglyceride and LDL cholesterol levels by up to 70% and 50%, respectively. The precise role of these new agents in clinical practice awaits confirmation of their long-term safety and cost-effectiveness from ongoing and future studies.