Treatment of Homozygous Familial Hypercholesterolemia: Challenges and Latest Development

Abstract

Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder of lipoprotein metabolism. Patients can be heterozygous (HeFH) with one mutated allele, homozygous (HoFH) with two identical mutations, or compound heterozygous with different mutations in each allele. HoFH is the more severe form of the disease and is associated with extremely elevated levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C). These lipid abnormalities are associated with accelerated atherosclerosis and cardiovascular disease (CVD) and an increased risk of cardiac events and early death. The prevalence of HoFH has been estimated to be 1 in 1 million; however, this is likely an underestimation as the disease is substantially underdiagnosed and undertreated. Early diagnosis and treatment are important to reduce CVD events. Aggressive therapy with conventional agents such as statins and ezetimibe produce substantial reductions in LDL-C, but patients rarely reach target goals. Apheresis should be considered in all patients with HoFH, although LDL-C levels rapidly rebound to baseline levels. Three recently introduced novel agents (mipomersen, lomitapide, and evolocumab)-each with a unique mechanism of action-have increased therapeutic options in this difficult-to-treat population. When added to standard therapy, these agents produce significant additional LDL-C lowering and can potentially improve clinical outcomes.