Lomitapide modifies high-density lipoprotein function in homozygous familial hypercholesterolaemia

Background Lomitapide reduces plasma low-density lipoprotein cholesterol (LDL-C) and is approved for the treatment of homozygous familial hypercholesterolemia (HoFH). This study aims to determine the effect of lomitapide on HDL and cholesterol efflux in a cohort of patients with HoFH. Patients and methods Analysis included plasma samples from 17 HoFH patients enrolled in the lomitapide phase 3 Aegerion clinical study (NCT00730236). Samples taken at baseline (pre-lomitapide) and weeks 56 and 66 (assumed steady-state on lomitapide) were analyzed for HDL-C levels and cholesterol efflux capacity (CEC) pathways via ABCA1, ABCG1, and SR-BI cholesterol uptake. Results Treatment with lomitapide is associated with a statistically significant decrease of both LDL-C and apo B when compared to baseline levels, p < 0.01. However, the reduction of Lp(a) appears only at a higher dose when compared to baseline (- 27% against values around - 55% for LDL-C and apo B). HDL-C shows a small 4.2% increase between the baseline and the treatment with a high dosage of lomitapide, while apo A-I displays an opposite small 3% decrease. Total efflux and ABCA1 mediated CEC decreased especially at higher dosage of lomitapide, with marked dose-dependent increase of SR-BI cholesterol uptake (+ 21.4% and + 64.3%, respectively, at a low and high dosages of lomitapide). However, ABCG1 did not change consistently. Conclusions Our report raises the hypothesis that lomitapide promotes lipidation of HDL particles independently of ABCA1 and ABCG1 through a process involving SR-BI pathway. This effect impairs the total efflux process suggesting that lomitapide drives the reverse cholesterol transport through SR-BI receptors in HoFH patients.