Familial Hypercholesterolemia: Therapeutic Advances

Familial hypercholesterolemia (FH), the most common and severe form of hypercholesterolemia, is an autosomal co-dominant disease characterized by an increased plasma low density lipoprotein (LDL) -cholesterol and premature atherosclerosis. The most common cause of FH is the mutations either in LDL receptor, apolipoprotein B (ApoB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Management of FH is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis concomitant with lipid-lowering therapy is the treatment of choice for homozygous FH, preferably with LDL-C levels greater than 200 mg/dl (greater than300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against ApoB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. Anti-PCSK9 monoclonal antibodies showed encouraging results and are currently being evaluated in phase III clinical trials. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society. The aim of this short review is to describe the new frontier of PCSK9 inhibition.