Factoring in ANGPTL3 When LDL Is Refractory

Patients with familial hypercholesterolemia (FH), who experience severely elevated low-density lipoprotein (LDL) cholesterol from birth and face a high risk of premature cardiovascular disease, have been instrumental in driving significant advancements in lipid-lowering therapies. A notable example is the development of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor class of drugs. Inhibition of PCSK9, which promotes the degradation of LDL receptors, can lead to substantial reductions in LDL cholesterol levels, typically by 60%, and a corresponding decrease in cardiovascular risk, with benefits linked to achieving very low absolute LDL cholesterol levels.

Despite these therapeutic breakthroughs, some patients, particularly those with homozygous FH, continue to have extremely high LDL cholesterol levels, maintaining a high residual risk for cardiovascular events. Emerging research focuses on angiopoietin-like 3 (ANGPTL3), a protein that acts as an inhibitor of both lipoprotein lipase and endothelial lipase, thereby increasing circulating triglyceride and LDL cholesterol levels. Evinacumab, a monoclonal antibody designed to neutralize ANGPTL3, has demonstrated impressive reductions in LDL cholesterol (nearly 50%) in patients with homozygous FH, including those with genetic mutations that render their LDL receptors nonfunctional. This discovery and the efficacy of ANGPTL3 inhibition mark a significant new therapeutic pathway for individuals with refractory hypercholesterolemia, including the challenging cases of homozygous FH.

Patients with familial hypercholesterolemia (FH), who experience severely elevated low-density lipoprotein (LDL) cholesterol from birth and face a high risk of premature cardiovascular disease, have been instrumental in driving significant advancements in lipid-lowering therapies. A notable example is the development of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor class of drugs. Inhibition of PCSK9, which promotes the degradation of LDL receptors, can lead to substantial reductions in LDL cholesterol levels, typically by 60%, and a corresponding decrease in cardiovascular risk, with benefits linked to achieving very low absolute LDL cholesterol levels.

Despite these therapeutic breakthroughs, some patients, particularly those with homozygous FH, continue to have extremely high LDL cholesterol levels, maintaining a high residual risk for cardiovascular events. Emerging research focuses on angiopoietin-like 3 (ANGPTL3), a protein that acts as an inhibitor of both lipoprotein lipase and endothelial lipase, thereby increasing circulating triglyceride and LDL cholesterol levels. Evinacumab, a monoclonal antibody designed to neutralize ANGPTL3, has demonstrated impressive reductions in LDL cholesterol (nearly 50%) in patients with homozygous FH, including those with genetic mutations that render their LDL receptors nonfunctional. This discovery and the efficacy of ANGPTL3 inhibition mark a significant new therapeutic pathway for individuals with refractory hypercholesterolemia, including the challenging cases of homozygous FH.