Angiopoietin-like 3 Protein Inhibition: A New Frontier in Lipid Lowering Treatment

Angiopoietin-like 3 protein (ANGPTL3) is an inhibitor of both lipoprotein lipase and endothelial lipase in humans. Population studies indicate a relationship between loss of function mutations in ANGPTL3 and favorable reductions in triglycerides and non-HDL cholesterol. In addition, loss of function mutations are associated with a reduced risk of coronary artery disease. While ANGPTL3\u27s role in human lipid metabolism has yet to be fully clarified, it is unlikely that ANGPTL3 impacts cholesterol uptake via the LDL-receptor, unlike the proprotein convertase subtilisin/kexin9 inhibitors. In contrast to other forms of lipid-lowering therapy, ANGPTL3 inhibition may improve insulin sensitivity. The promise of this new therapy, particularly its independence from the LDL-receptor, has prompted the creation of a monoclonal antibody inhibitor; evinacumab. Evinacumab has shown favorable lipid-lowering action in both human and mouse models. Efficacy trials are currently ongoing and will be completed in the near future. In addition, ANGPTL3 inhibition via an antisense oligonucleotide was performed in healthy human subjects, which resulted in a dose-dependent reduction in circulating ANGPTL3 levels and an anti-atherogenic lipid profile. When tested in mouse models, administration of the antisense oligonucleotide caused a reduction in progression of atherosclerosis. Further investigation is required to evaluate the efficacy, safety and net benefit of clinical ANGPTL3 inhibition before it can be accepted into clinical practice