Cardiology Letters 2016, 25(2):91-98

Homozygous familial hypercholesterolaemia and its treatment

Šimurka P¹, Matejka M², Malinová J³

¹ Fakulta zdravotníctva, Trenčianska univerzita AD, Trenčín

² MEDMA, Ambulancia pre deti a dorast, Dunajská Lužná

³ Lekárská fakulta Univerzita Komenského v Bratislave, Slovenská republika

Homozygous familial hypercholesterolaemia (HoFH) is a life-threatening disease most commonly caused by loss-of-function mutations in both alleles of the LDL receptor gene. As a consequence of impaired LDL-receptor function, untreated total plasma cholesterol levels are typically greater than 13 mmol/l, resulting in premature and progressive atherosclerosis often leading to cardio-cerbrovascular disease before age 20 years and death before age 30 years. The condition is characterised by exceptionally high LDL cholesterol levels, cutaneous and tendon xanthomas, valvular and supravalvular stenosis and accelerated atherosclerosis, often leading to IM or TIA. Early initiation of aggressive treatment for these patients is, therefore, essential. The current standard of care for familial hypercholesterolaemia includes combined use of available lipidlowering drug therapies and apheresis. Patients with HoFH respond inadequately to conventional drug therapies, which generally reduce LDL cholesterol through upregulation of hepatic LDL receptors. Alternative therapeutic approaches have therefore been developed that target either ApoB synthesis, or the production of VLDL, the precursor of LDL. Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, the Consensus Panel on Familial Hy­ percholesterolaemia of the European Atherosclerosis Society (EAS) has critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Lomitapide, an orally administered inhibitor of the microsomal triglyceride transfer protein, inhibits the synthesis of chylomicrons and very low-density lipoprotein, thereby reducing plasma levels of low-density lipoprotein cholesterol (LDL-C). In a clinical trial in adults with HoFH, adjunctive treatment with oral lomitapide was associated with 40% reduction from baseline in mean plasma low-density lipoprotein cholesterol levels over a 26-week treatment period. Reductions were sustained for up to 78 weeks with continued treatment. Lomitapide is associated with a clinically manageable safety profile, with gastrointestinal effects being the most commonly reported adverse event. The study suggests that the risk-benefit ratio of lomitapide in HoFH patients, who are at high risk of cardio-cerebrovascular events and death at a young age, could be favourable. The significant progress in the treatment of such serious form of hypercholesterolaemia enables a change in the quality of life of the patient.

Keywords: hyperlipoproteinaemias; familial hypercholesterolaemia; homozygous familial hypercholes­ terolaemia; low-density lipoprotein cholesterol; PCSK9 inhibitors; microsomal triglyceride transfer protein; lomitapide; cardiovascular risk

Published: February 1, 2016  Show citation