title: Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  This study sought to examine the efficacy and safety of mipomersen for reducing atherogenic lipids and lipoproteins in patients with hypercholesterolemia.
  
  
  BACKGROUND
  Many patients on lipid-lowering therapies remain unable to achieve target low-density lipoprotein (LDL) cholesterol levels. Mipomersen, an antisense oligonucleotide inhibitor of apolipoprotein B, reduces LDL cholesterol and atherogenic lipoproteins.
  
  
  METHODS
  This randomized, double-blind, multicenter study enrolled 158 patients with baseline LDL cholesterol levels ≥100 mg/dl with, or at high risk for, coronary heart disease who were receiving maximally tolerated lipid-lowering therapy. Patients received weekly subcutaneous mipomersen 200 mg (n = 105) or placebo (n = 52) for 26 weeks, with a 24-week follow-up period. Randomization was stratified by type 2 diabetes status.
  
  
  RESULTS
  Sixty mipomersen and 44 placebo patients completed treatment. Mean baseline LDL cholesterol levels were 122.7 and 122.6 mg/dl in the placebo and mipomersen patients, respectively. Mipomersen reduced LDL cholesterol by -36.9% compared with placebo at -4.5% (p < 0.001). Target LDL cholesterol <100 mg/dl was attained in 76% of mipomersen and 38% of placebo patients. Mipomersen also significantly reduced apolipoprotein B (-38%) and lipoprotein(a) (-24%) (p < 0.001). Common adverse events included injection site reactions (78% with mipomersen, 31% with placebo) and flu-like symptoms (34% with mipomersen, 21% with placebo). Elevations in transaminases and liver fat also occurred in some patients, and these levels returned toward baseline after treatment cessation.
  
  
  CONCLUSIONS
  Mipomersen significantly reduced LDL cholesterol, apolipoprotein B, and lipoprotein(a) in patients with hypercholesterolemia with, or at risk for, coronary heart disease not controlled by existing therapies. (Safety and Efficacy of Mipomersen [ISIS 301012] as Add-On Therapy in High Risk Hypercholesterolemic Patients; NCT00770146).
authors.affiliation: Long Beach Memorial Medical Center, Long Beach, California; University of California, Irvine, Irvine, California. Electronic address: gthomas1@memorialcare.org.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Thomas
authors.forename: William C
authors.initials: WC
authors.lastname: Cromwell
authors.forename: Shariq
authors.initials: S
authors.lastname: Ali
authors.forename: Wai
authors.initials: W
authors.lastname: Chin
authors.forename: JoAnn D
authors.initials: JD
authors.lastname: Flaim
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors*; D050197:Atherosclerosis / Q000517:prevention & control*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D009841:Oligonucleotides; C524142:mipomersen
keywords: AE; ALT; CHD; FH; FLS; HDL; ISR; LDL; Lp(a); T2DM; VLDL; adverse event(s); alanine aminotransferase; antisense oligonucleotides; apoB; apolipoprotein B; cholesterol inhibitors; coronary heart disease; familial hypercholesterolemia; flu-like symptoms; high-density lipoprotein; hypolipidemic agents; injection site reaction; lipid-regulating agents; lipoprotein(a); low-density lipoprotein; type 2 diabetes mellitus; very-low-density lipoprotein