Sex differences in efficacy and safety of lomitapide in real-world HoFH patients
In a post-hoc analysis of the Pan-European Lomitapide Study among 75 homozygous familial hypercholesterolemia (HoFH) patients, lomitapide led to comparable LDL-c reductions in men and women, but women reported more gastrointestinal adverse events.
This summary is based on the publication of Pavanello C, Suppressa P, Castiglione S, et al. - Sex-related differences in response to lomitapide in HoFH: A subanalysis of the Pan-European Lomitapide retrospective observational study. Atherosclerosis. 2025 Feb;401:119089. doi: 10.1016/j.atherosclerosis.2024.119089
Introduction and methods
Background
Homozygous familial hypercholesterolemia (HoFH) is a hereditary lipid metabolism disorder characterized by severely elevated LDL-c levels and increased risk of premature ASCVD [1]. Men and women are affected equally [2]. Lomitapide, an oral, selective inhibitor of microsomal triglyceride transfer protein, reduced LDL-c levels by 60% in a real-world setting, although responses varied [3]. Possibly, sex differences play a role in the effect of drug therapies and CV outcomes in patients with HoFH.
Aim of the study
The authors analyzed sex disparities in the effectiveness and safety of lomitapide and the rate of MACE.
Methods
This was a post-hoc analysis of the Pan-European Lomitapide Study, a multicenter, observational, retrospective, uncontrolled study in which 75 HoFH patients from 9 European countries received lomitapide for ≥1 month [3]. Median follow-up duration was 19 months (IQR: 11–41).
Outcomes
Main outcomes were the percentage LDL-c change at 3, 6, 12, and 24 months and reported adverse events during treatment.
Main results
Efficacy
• Baseline patient characteristics, including lipid levels and CVD risk factors, were comparable between men (n=37) and women (n=38).
• Although LDL-c decreases were numerically larger in women, there were no significant differences in the mean percentage LDL-c change between sexes at 3, 12, and 24 months. At 6 months, women exhibited a trend towards greater median LDL-c reduction compared with men (–53.0%; IQR: –66.9% to –24.3% vs. –32.9%; IQR: –51.5% to –20.3%; P=0.051).
• LDL-c levels were numerically, albeit not significantly, lower in women than men at all follow-up time points (all P>0.05).
• Furthermore, the annual mean ± SD LDL-c reduction did not differ between women (–4.83% ± 7.02%) and men ( –4.03% ± 9.74%; P=0.526).
• There were no differences in the median lomitapide doses at any time point between sexes, nor in the intensity of concomitant lipid-lowering therapies.
• During follow-up, 6 women and 3 men experienced an ASCVD event, but ASCVD event–free survival did not differ between the 2 groups (P=0.363).
Safety
• Gastrointestinal disturbances, such as diarrhea, nausea, and abdominal pain, were the most frequently reported adverse events, and they occurred more often in women than men (78 vs. 32 events; P=0.0002).
• Most gastrointestinal adverse events were mild to moderate in severity.
• Elevated levels of liver transaminases (>3x upper limit of normal) were observed in 22 women (58%) and 16 men (43%) (P=0.368).
Conclusion
In this post-hoc analysis of the observational, retrospective, uncontrolled Pan-European Lomitapide Study among 75 HoFH patients, lomitapide treatment resulted in comparable LDL-c reductions and ASCVD event–free survival in men and women. The rate of gastrointestinal adverse events was higher in women than men.
References
- R.A. Hegele, et al., Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement, Lancet Diabetes Endocrinol. 8 (1) (2020) 50–67.
- J. Mulder, et al., Sex differences in diagnosis, treatment, and cardiovascular outcomes in homozygous familial hypercholesterolemia, JAMA Cardiol. 9 (4) (2024) 313–322.
- L. D’Erasmo, et al., Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-European retrospective observational study, Eur J Prev Cardiol. 29 (5) (2022) 832–841.