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Clinical Trial
. 2025 Apr 11;30(1):266.
doi: 10.1186/s40001-025-02439-0.

Lomitapide modifies high-density lipoprotein function in homozygous familial hypercholesterolaemia

Anouar Hafiane  1 , Annalisa Ronca  2 , Matteo Incerti  2 , Alessandra Rossi  2 , Matteo Manfredini  3 , Elda Favari  4
Affiliations
Clinical Trial

Lomitapide modifies high-density lipoprotein function in homozygous familial hypercholesterolaemia

Anouar Hafiane et al. Eur J Med Res. .

Abstract

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.

Keywords: Apo B; Cholesterol efflux capacity; HDL cholesterol; Homozygous familial hypercholesterolaemia; LDL cholesterol; Lomitapide.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All the investigation of the current study was performed under the approval of the ethic committee of University of Parma as well as the Declaration of Helsinki. Patients’ recruitment has been done by the Phase 3, Aegerion clinical study of lomitapide in patients with HoFH (NCT00730236). Consent for publication: All the authors approved the final manuscript and the submission to this journal. Competing interest: All authors have no conflicts to disclose that are relevant to this publication.

Figures

Fig. 1
Fig. 1
Dot plots of the parameters investigated before (pre) and after (post) treatment with lomitapide. Median values in red
Fig. 2
Fig. 2
Graphical abstract. The effect of treatment with lomitapide on high-density lipoprotein (HDL) functionality of serum from patients with homozygous familial hypercholesterolaemia (HoFH)
Fig. 3
Fig. 3
Schematic representation lomitapide of effect on reverse cholesterol transport in HoFH patients. (1) Total efflux and ABCA1 mediated CEC decreased especially after the introduction of high dose lomitapide (2) ABCG1 mediated CEC was not changed (3). Cholesterol uptake through SR–BI is markedly increased by lomitapide (4). Plasma HDL-C levels increased by 4.2% after the introduction of high doses of lomitapide, while plasma apoA–I levels decreased by 3% under the same conditions
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