Sex-related differences in response to lomitapide in HoFH: A subanalysis of the Pan-European Lomitapide retrospective observational study

Background and aims: Homozygous familial hypercholesterolemia (HoFH) is a hereditary lipid metabolism disorder characterized by severe elevation of low-density lipoprotein cholesterol (LDL-C) and heightened risk of premature atherosclerotic cardiovascular disease (ASCVD). Lomitapide, an inhibitor of microsomal triglyceride transfer protein, has shown promise in reducing LDL-C levels, albeit with variable response in real-world settings. Sex-based differences in treatment efficacy and safety remain unclear. Methods and Results: This post-hoc analysis of the Pan-European Lomitapide Study investigated sex-specific disparities in the efficacy and safety of lomitapide in HoFH patients (N=38 women and N=37 men). Data were collected from HoFH patients receiving lomitapide across Europe. Clinical characteristics, lipid profile, and adverse events were compared between women and men. Results indicate comparable baseline characteristics and cardiovascular risk factors between sexes. While LDL-C reduction was comparable at each time point between the two groups, women exhibited a trend towards greater reduction compared to men, particularly evident at 6 months (−53.0% vs −32.9% p=0.051). Annual LDL-C reduction did not differ between sexes (−4.83% ± 7.02 vs −4.03% ± 9.74 p=0.526). No differences in the median lomitapide dose or the intensity of concomitant lipid lowering therapies were observed between sexes. Notably, gastrointestinal disturbances were more prevalent in women (78 events in women vs 32 in men, p=0.0002), although most adverse events were manageable. Event-free survival curves for ASCVD did not significantly differ between sexes (p=0.363). Conclusions: Lomitapide demonstrates comparable efficacy in reducing LDL-C levels in men and women with HoFH, with potential sex-specific variations in tolerability.