title: Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.
abstract: BACKGROUND
  Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies.
  
  
  METHODS
  We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling.
  
  
  RESULTS
  Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance.
  
  
  CONCLUSIONS
  In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott). gerald.watts@uwa.edu.au.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Dick C
authors.initials: DC
authors.lastname: Chan
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Dent
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: Sally
authors.initials: S
authors.lastname: Burrows
authors.affiliation: From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott).
authors.forename: P Hugh
authors.initials: PH
authors.lastname: R Barrett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000069059:Atorvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; C577155:evolocumab
keywords: AMG 145; atorvastatin calcium; lipoproteins; metabolism