Abstract
<h3>Lead Author's Financial Disclosures</h3> D.B. has received consulting fees from Amryt. <h3>Study Funding</h3> Amryt Pharma. <h3>Background/Synopsis</h3> Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) secondary to bi-allelic pathogenic mutations affecting key proteins in the LDL receptor pathway. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that acts independently of the LDL receptor and is licenced for the treatment of adult patients with HoFH. To date, there are few prospective cardiovascular outcomes data for HoFH patients receiving lomitapide. <h3>Objective/Purpose</h3> To evaluate the effect of lomitapide use on carotid intima-media thickness (CIMT) in patients with HoFH. <h3>Methods</h3> Thirteen HoFH patients (mean+/-SD age 29.3+/-12.5 years) in seven global centers were treated in accordance with the lomitapide product label and local clinical practice. Patients underwent routine laboratory testing, including lipid and liver panels. CIMT imaging was recorded to monitor atherosclerotic cardiovascular disease (ASCVD) according to local protocols. <h3>Results</h3> Lomitapide resulted in marked decreases in LDL-C (mean+/-SD: 76.5+/-11.7%; range 56.8-93.9% at the lowest point). Notably, eight patients achieved LDL-C levels below the European Atherosclerosis Society target of <100mg/dL, and three patients achieved LDL-C <70mg/dL at least once. Over a mean follow-up of 3.9+/-2.3 years between measurements, CIMT regressed in 7 cases. The remaining patients demonstrated no progression (Supplementary Table). In two patients where assessments of plaque area were available, modest regression or stabilisation in CIMT (0.82mm to 0.65mm over 24 months [20.7% reduction]; 0.56mm to 0.57mm over 26 months [1.8% increase]) was accompanied by clinically significant regression of plaque area (147.1mm2 to 120.5mm2 [18.1% reduction]; 64.0 mm2to 42.1 mm2 [34.7% reduction]. Calculation of vascular age in n=9 patients indicated mean improvement of -18.8+/-32.6 years (range -60 to +30 years). Elevations in ALT/AST enzyme levels >3x upper limit of normal were evident in 6/13 patients. In all cases, these elevations either resolved without intervention or were managed with brief, transient reductions in lomitapide dose. <h3>Conclusions</h3> Lomitapide dramatically reduces LDL-C levels in patients with HoFH, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk.
Published Version
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