Background Patients with homozygous familial hypercholesterolemia (HoFH) respond inadequately to existing drugs. We conducted a phase 3 study to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with HoFH. Methods Twenty-nine subjects enrolled into a single-arm, open-label study and maintained current lipid lowering therapy from six weeks before baseline through at least week 26. Lomitapide dose was escalated based on safety and tolerability from 5 mg to a maximum of 60 mg/day. The primary endpoint was mean percent change from baseline in LDL-C at week 26, after which patients remained on lomitapide through week 78 for safety assessment. Findings Twenty-three subjects completed weeks 26 and 78. The median dose of lomitapide was 40 mg/day. LDL-C was reduced by 50% from baseline at week 26 (4·3 ± 2·5 mmol/L vs. 8·7 ± 2·9 mmol/L, p<0.0001). Eight subjects achieved LDL-C <2·6 mmol/L at this time point. LDL-C was reduced by 44% at week 56 and 38% at week 78 (p<0.0001 for both). Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase > 5× ULN that resolved after dose reduction or temporary interruption of lomitapide. No subject permanently discontinued treatment due to liver abnormalities. Liver fat content assessed by nuclear magnetic resonance spectroscopy (NMRS; n=20) was 1·0 ± 1·3 % at baseline, 8·6 ± 8·1% at week 26 and remained stable up to week 78 (8·3± 5·3%). Interpretation These data demonstrate that lomitapide had a robust and durable efficacy in lowering LDL-C in patients with HoFH with an acceptable safety and tolerability profile.

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Low density lipoprotein (LDL) oxidative modification in the vascular wall seems to be a key factor in atherosclerosis development. Oxidised LDLs might recruit monocytes and favour their transformation into foam cells through a receptor-mediated intake (scavenger pathway). Moreover oxidised LDLs show cytotoxic potential which is probably responsible for endothelial cell damage and macrophage degeneration in the atherosclerotic human plaque. Following the oxidation hypothesis of atherosclerosis the role of natural antioxidants, i.e. Vitamin C, Vitamin E and carotenoids, has been investigated in a large number of epidemiological, clinical and experimental studies. Animal studies indicate that dietary antioxidants may reduce atherosclerosis progression, and observational data in humans suggest that antioxidant vitamin ingestion is associated with reduced cardiovascular disease, but the results of randomised controlled trials are mainly disappointing. It has been suggested that natural antioxidants may be effective only in selected subgroups of patients with high levels of oxidative stress or depletion of natural antioxidant defence systems. The favourable effects shown by some studies relating antioxidant dietary intake and cardiovascular disease, may have been exerted by other chemicals present in foods. Flavonoids are the ideal candidates, since they are plentiful in foods containing antioxidant vitamins (i.e. fruits and vegetables) and are potent antioxidants. Tea and wine, rich in flavonoids, seem to have beneficial effects on multiple mechanisms involved in atherosclerosis. Future studies should probably select patients in a context of high-oxidative stress / low-antioxidant defence, to verify if antioxidants may really prove useful as therapeutic anti-atherosclerotic agents.

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