title: Microsomal transfer protein inhibition in humans.
abstract: OBJECTIVE
  Microsomal triglyceride transfer protein (MTP) is a key protein in the secretion of apolipoprotein B-containing lipoproteins. Its pharmacological inhibition is associated with a decrease in LDL cholesterol (LDL-C) and triglycerides. However, the clinical use of MTP inhibitors has been uncertain because of the gastrointestinal adverse events and the increase in liver fat content observed during their administration.
  
  
  RESULTS
  Lomitapide, a systemic MTP inhibitor, significantly reduces LDL-C in homozygous familial hypercholesterolemia (hoFH) when administered concurrently with other lipid-lowering therapies, including apheresis. Its lipid-lowering effect is additive to that of existing drugs. In the presence of an up-titration regiment and low-fat diet, lomitapide is generally well tolerated and liver fat accumulation stabilizes after the initial increase. Elevation of alanine aminotranferase levels greater than 3 times the upper limit of normal can be managed successfully with temporary dose reduction. Drug-drug interaction studies show that concomitant treatment of lomitapide with other lipid-lowering drugs is generally safe. Based on these findings, lomitapide was recently approved for the treatment of hoFH as add-on therapy.
  
  
  CONCLUSIONS
  MTP inhibition is a valuable therapeutic approach for hoFH. Long-term safety consequences of liver fat accumulation will need to be assessed.
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. mcuchel@mail.med.upenn.edu
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000627:therapeutic use*; D001781:Blood Component Removal; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D018752:Diet, Fat-Restricted; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; C473731:BMS201038; D001562:Benzimidazoles; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D000410:Alanine Transaminase