Human Angiopoietin-like Protein 3/ANGPTL3 Antibodies: Adding to the Armamentarium in the Management of Dyslipidemia

Cardiovascular (CV) disease remains the leading cause of death in the United States. In addition to lifestyle modifications, current guidelines primarily focus on lowering low-density lipoprotein cholesterol (LDL-C) to reduce atherosclerotic CV disease risk. However, despite aggressive management, a degree of residual risk remains, suggesting that focusing on lowering LDL-C alone may be inadequate and that other lipid parameters may need to be targeted. In patients who remain at high risk despite current pharmacologic options either because of inadequate response, elevated levels of other lipoproteins, or those who have genetic variants predisposing them to atherosclerotic CV disease, additional treatment strategies continue to be sought. One such group is the homozygous familial hypercholesterolemia population, especially those patients carrying the null low-density lipoprotein receptor mutation as they often fail to derive the same benefit from traditional LDL-C lower strategies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitors that work by upregulating the LDL receptor. Emerging data also suggest that patients with increased levels of triglyceride-rich lipoproteins are also at increased risk as elevated levels are proposed to have a role in various pathways promoting atherogenesis. Angiopoietin-life protein 3 (ANGLTPL3) has recently become a target of interest because of the discovery that inhibiting its action leads to reductions in lipid parameters. Although the mechanism of action of ANGLTPL3 inhibitors is independent of the LDL receptor, their ability to significantly lower triglycerides and LDL-C make them an attractive option particularly in patients with homozygous familial hypercholesterolemia and hypertriglyceridemia. The efficacy and safety of 2 ANGLTPL3 inhibitor agents have been evaluated in clinical trials. In this review, the lipid lowering, metabolic effects, and safety are reported. Ongoing trials assessing CV outcomes as well as long-term safety data are still needed to provide a more definitive role for these agents in the overall management in these populations.