Iomitapide (Lojuxta). Use only in homozygous familial hypercholesterolaemia, with caution.

Patients with rare homozygous familial hypercholesterolaemia are at risk of dying at a very young age. When liver transplantation is not feasible, treatment is based on regular LDL apheresis sessions, a burdensome and inconvenient procedure, and on high-dose statins in combination with ezetimibe. Lomitapide acts by inhibiting the synthesis of LDL constituents. It has been granted EU marketing authorisation as adjunctive therapy for homozygous familial hypercholesterolaemia. Clinical evaluation of lomitapide is based on a non-comparative trial in 29 adults. When added to standard therapy, lomitapide led to about a 40% reduction in absolute LDL cholesterol levels. Longer follow-up is needed to determine whether this is sufficient to prevent cardiovascular complications. Seven of the 13 patients under-going LDL apheresis were able to increase the interval between sessions or stop them altogether. Nearly all patients treated with lomitapide experienced gastrointestinal adverse effects, including diarrhoea, nausea, vomiting and dyspepsia. Lomitapide was associated with hepatic abnormalities in about one-third of patients in the short-term. It remains to be seen whether the hepatic steatosis observed in some patients progresses to fibrosis or cirrhosis with long-term use. Lomitapide is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 and also inhibits P-glycoprotein, hence a risk of multiple pharmacokinetic interactions. In particular, lomitapide increases the plasma concentrations of statins, and their toxicity. Lomitapide was teratogenic in experimental animals. In practice, lomitapide should be strictly reserved for patients with homozygous familial hypercholesterolaemia. Clinical evaluation must continue in these rare patients at high risk of early death.