Breaking barriers: Innovative therapies for managing homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal recessive disorder characterized by variants in genes involved in the regulation of low-density lipoprotein cholesterol (LDL-C) metabolism. The genetic basis of HoFH is complex, with biallelic variants in the low-density lipoprotein receptor (LDLR) gene being the most prevalent. Early diagnosis and appropriate lipid-lowering therapy (LLT) are essential for patients with HoFH to prevent the premature onset of atherosclerotic cardiovascular disease (ASCVD). Effective and timely reduction of LDL-C levels is crucial for the success of LLT. Nevertheless, the majority of patients with HoFH exhibit resistance to conventional LLT due to insufficient or absent activity of LDL-R, rendering the management of HoFH challenging. Recent advancements have introduced novel pharmacological agents for treating HoFH (e.g. evolocumab, alirocumab, inclisiran and bempedoic acid), including cholesterol-lowering strategies that function independently of LDL-R such as lomitapide and evinacumab offering significant promise for managing this condition. However, disparities in the treatment of HoFH persist across different regions and countries. In this context, the review provides a comprehensive overview of established treatment modalities and emerging therapeutic agents for individuals with HoFH.