Lomitapide response in a cohort of patients with homozygous familial hypercholesterolemia and the potential influence of MTTP gene variants

TL;DR

This study examines how patients with a rare cholesterol disorder respond to a specific drug and how genetic differences might affect treatment outcomes.

Contribution

The study identifies specific MTTP gene variants potentially linked to greater response to lomitapide treatment in patients with homozygous familial hypercholesterolemia.

Findings

Lomitapide treatment significantly reduced LDL cholesterol levels in all patients with homozygous familial hypercholesterolemia.

Certain MTTP gene variants were more common in patients with greater than 50% LDL-C reduction.

The study found a trend suggesting more MTTP gene variants per patient in those with greater LDL-C reduction.

Abstract

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism caused by pathogenic variants in both alleles of key low-density lipoprotein receptor (LDLR)-mediated pathway genes, resulting in very high LDL cholesterol (LDL-C) levels from birth. The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide, is an effective treatment for lowering LDL-C in HoFH that acts independently of LDLR. This study investigated the response to lomitapide treatment and the potential impact of MTTP gene variants in a cohort of patients with HoFH.

Data were extracted from medical records of patients diagnosed with HoFH and receiving treatment with lomitapide in addition to background statin + ezetimibe + PCSK9 inhibitor therapy. Data on LDL-C levels before and after lomitapide treatment were collected from patient medical histories. Genetic sequencing of all exonic and intronic flanking regions of the MTTP gene was carried out for all patients with genomic DNA isolated from whole blood.

A total of 13 patients with a diagnosis of HoFH were identified (mean ± standard deviation age, 47.3 ± 17.3 years). The median (range) dose of lomitapide was 20 mg/day (10 to 60 mg/day). Median (range) baseline LDL-C (before lomitapide) was 240 mg/dL (162 to 478 mg/dL). Following lomitapide treatment the median (range) LDL-C level was 119 mg/dL (56 to 305 mg/dL), and all patients reported a reduction in LDL-C with lomitapide. A total of 151 MTTP gene variants were identified encompassing 50 distinct variants. There was a trend for more variants per patient with LDL-C reduction > 50% vs. patients with LDL-C reduction ≤ 50% (difference, 8.5; 95% confidence interval [CI] − 1.2, 18.1; P = 0.08). Several MTTP gene variants (rs17533489, rs79194015, rs745075, rs41275715, rs1491246, and rs17533517) previously identified as potentially associated with a greater response to lomitapide treatment were significantly more common in patients with a reduction in LDL-C > 50% than those with a reduction in LDL-C ≤ 50% (difference, 3.9; 95% CI 3.3, 4.5; P < 0.001).

This study builds upon previous findings by our group suggesting that variants in the MTTP gene may influence response to lomitapide. This study further presented a number of variants that may be uniquely associated with higher or lower response to lomitapide treatment.

The online version contains supplementary material available at 10.1186/s13023-025-04033-3.

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