Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the
low-density lipoprotein (
LDL)-receptor gene (LDLR). Patients with homozygous FH (
hoFH) have inherited a mutated LDLR gene from both parents, and therefore all their
LDL-receptors are incapable of functioning normally. In
hoFH, serum
LDL levels often exceed 13 mmol/L and tendon and cutaneous xanthomata appear early (under 10 years of age). If untreated, this extremely severe form of
hypercholesterolemia may cause death in childhood or in early adulthood. Based on recent data, it can be estimated that the prevalence of
hoFH is about 1:500,000 or even 1:400,000. Until now, the treatment of
hoFH has been based on high-dose
statin treatment combined with
LDL apheresis. Since the
LDL cholesterol-lowering effect of
statins is weak in this disease, and
apheresis is a cumbersome treatment and not available at all centers, alternative novel
pharmaceutical therapies are needed.
Lomitapide is a newly introduced
drug, capable of effectively decreasing serum
LDL cholesterol concentration in
hoFH. It inhibits the
microsomal triglyceride transfer protein (
MTTP). By inhibiting in hepatocytes the transfer of
triglycerides into
very low density lipoprotein particles, the
drug blocks their assembly and secretion into the circulating blood. Since the
very low density lipoprotein particles are precursors of
LDL particles in the circulation, the reduced secretion of the former results in lower plasma concentration of the latter. The greatest concern in
lomitapide treatment has been the increase in liver fat, which can be, however, counteracted by strictly adhering to a
low-fat diet.
Lomitapide is a welcome addition to the meager selection of drugs currently available for the treatment of refractory
hypercholesterolemia in
hoFH patients.