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What about microsomal triglyceride transfer protein (MTP) inhibition? MTP is required for the transport of lipids to ApoB to produce containing lipoproteins. An inhibitor of MTP (originally BMS 201038, now AEGR-733, lomitapide) had been tested in the past in a small trial of patients with homozygote FH. At a dose of 1 mg, patients who received this drug showed reductions in total cholesterol of >58%, LDL-C of 50.9%, VLDL of 78.7%, and triglycerides of 65.4%, all compared with baseline.
Side effects of treatment included transient diarrhea and increases in amino transferase and fat in the liver. The main limitation of this small study was the large variability in the liver function test levels and hepatic fat content.
At the European Atherosclerosis Society (EAS) meetings in May 2012 an abstract presented results of a phase III evaluation of lomitapide in patients with FH. Of 29 patients enrolled, 23 patients completed the study at a median dose of 40 mg/day. LDL-C levels were reduced by 40% from baseline at week 26 and this reduction was maintained through week 56. Lomitapide was generally well-tolerated, with gastrointestinal symptoms being the most common adverse events. Four patients had confirmed elevations in transaminases of 5-11 times ULN, but these resolved with dose reductions or temporary suspension of the study drug. There were no changes in bilirubin or alkaline phosphatase. Liver fat content, assessed by NMR, was 0.9 at baseline, increased to 9 at week 26, and fell back to 7.3 at week 56 - meaning that liver fat did level off throughout the study, and no patients discontinued treatment due to liver function abnormalities.
[42] Wetterau JR, et al. Biocem Biophys Acta. 1997;1345:136-150.
[37] Cuchel M, et al. NEJM. 2007;356:148-156.