Inhibition of hepatic microsomal triglyceride transfer protein - a novel therapeutic option for treatment of homozygous familial hypercholesterolemia.

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.