title: Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects.
abstract: BACKGROUND
  Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.
  
  
  METHODS
  We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).
  
  
  RESULTS
  Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.
  
  
  CONCLUSIONS
  These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00990808.
  
  
  BACKGROUND
  Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Gissette
authors.initials: G
authors.lastname: Reyes-Soffer
authors.forename: Patricia
authors.initials: P
authors.lastname: Jumes
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dunbar
authors.forename: Emil M
authors.initials: EM
authors.lastname: deGoma
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Baer
authors.forename: Wahida
authors.initials: W
authors.lastname: Karmally
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Donovan
authors.forename: Hashmi
authors.initials: H
authors.lastname: Rafeek
authors.forename: Laura
authors.initials: L
authors.lastname: Pollan
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tohyama
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Stephen
authors.initials: S
authors.lastname: Holleran
authors.forename: Joseph
authors.initials: J
authors.lastname: Obunike
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lassman
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D053299:Apolipoprotein B-100 / Q000097:blood*; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: C569471:APOB protein, human; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D008077:Lipoproteins, LDL; D023303:Oxazolidinones; D011758:Pyrroles; D014280:Triglycerides; C032607:low density lipoprotein triglyceride; D000069059:Atorvastatin; C530884:anacetrapib