title: Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients.
  
  
  BACKGROUND
  Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects.
  
  
  METHODS
  We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs).
  
  
  RESULTS
  Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose.
  
  
  CONCLUSIONS
  PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Arsenault
authors.forename: Weihang
authors.initials: W
authors.lastname: Bao
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Davaine
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.forename: Francine
authors.initials: F
authors.lastname: Petrides
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: David A
authors.initials: DA
authors.lastname: DeMicco
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D011758:Pyrroles / Q000008:administration & dosage*; D012697:Serine Endopeptidases / Q000097:blood*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases