title: Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy.
abstract: BACKGROUND
  In patients with discordance between low-density lipoprotein (LDL) cholesterol and LDL particle (LDL-P) concentrations, cardiovascular risk more closely correlates with LDL-P.
  
  
  RESULTS
  We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase II, double-blind, placebo-controlled trial in patients (LDL cholesterol ≥100 mg/dL) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of LDL-P, very-low-density lipoprotein particles, and high-density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total LDL-P (-63.3% versus -1.0% with placebo) and large (-71.3% versus -21.8%) and small (-54.0% versus +17.8%) LDL-P subfractions and total very-low-density lipoprotein particle concentrations (-36.4% versus +33.4%; all P<0.01). Total high-density lipoprotein particles increased with alirocumab (+11.2% versus +1.4% with placebo; P<0.01). There were greater increases in large (44.6%) versus medium (17.7%) or small high-density lipoprotein particles (2.8%) with alirocumab. LDL-P size remained relatively unchanged in both groups; however, very-low-density and high-density lipoprotein particle sizes increased to a significantly greater extent with alirocumab.
  
  
  CONCLUSIONS
  Alirocumab significantly reduced LDL-C and LDL-P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant LDL-C and LDL-P concentrations.
  
  
  BACKGROUND
  URL: https://clinicaltrials.gov. Unique identifier: NCT01288443.
authors.affiliation: Jacksonville Center For Clinical Research, Jacksonville, FL (M.J.K.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Koren
authors.affiliation: The Christ Hospital Heart and Vascular Center/The Lindner Research Center, Cincinnati, OH (D.K.).
authors.forename: Dean
authors.initials: D
authors.lastname: Kereiakes
authors.affiliation: Alexion, Cheshire, CT (R.P.).
authors.forename: Ray
authors.initials: R
authors.lastname: Pourfarzib
authors.affiliation: LabCorp, Raleigh, NC (D.W.).
authors.forename: Deborah
authors.initials: D
authors.lastname: Winegar
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY (P.B., S.H.).
authors.forename: Poulabi
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY (P.B., S.H.).
authors.forename: Sara
authors.initials: S
authors.lastname: Hamon
authors.affiliation: Sanofi, Paris, France (C.H.).
authors.forename: Corinne
authors.initials: C
authors.lastname: Hanotin
authors.affiliation: Virginia Commonwealth University and National Clinical Research, Richmond, VA (J.M.M.K.).
authors.forename: James M
authors.initials: JM
authors.lastname: McKenney
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000069059:Atorvastatin / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D010316:Particle Size; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D015842:Serine Proteinase Inhibitors; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C571059:alirocumab
keywords: alirocumab; lipoprotein particle number; lipoprotein subfractions; nuclear magnetic resonance spectroscopy; proprotein convertase subtilisin/kexin type 9 inhibitor