title: A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab.
abstract: BACKGROUND
  The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of cholesterol-lowering medications that provide significant reductions in lipids but at a large cost relative to statins. With 2 such drugs now on the market, alirocumab and evolocumab, comparing the evidence base for these drugs is necessary for informed decision making.
  
  
  OBJECTIVE
  To compare the benefits and harms of the PCSK9 inhibitors alirocumab and evolocumab.
  
  
  METHODS
  The databases Ovid MEDLINE, Cochrane Library, SCOPUS, and ClinicalTrials.gov were used to search for randomized controlled trials of alirocumab or evolocumab with any relevant comparator reporting health outcomes, lipid outcomes, or harms through September 2015, and information was requested from manufacturers. Results were reviewed according to standard review methods.
  
  
  RESULTS
  The database searches revealed 17 fair- and good-quality trials; however, none had primary health outcomes or directly compared PCSK9 inhibitors. Alirocumab (75 mg to 150 mg subcutaneously every 2 weeks) resulted in significantly greater reductions in low-density lipoprotein cholesterol (LDL-C; -8% to -67%) at 12-24 weeks in patients with (a) heterozygous familial hypercholesterolemia and (b) patients at high or varied cardiovascular (CV) risk who were not at LDL-C goals with statin therapy. The highest strength evidence was for patients with high CV risk not at LDL-C goals. Alirocumab also resulted in high-density lipoprotein cholesterol (HDL-C) increases of 6%-12%. Low- and moderate-strength evidence for adjudicated CV events at 52-78 weeks for a priori analyses indicated no benefit. Low- and moderate-strength evidence also found no differences in harms except possibly slightly more injection-site reactions. Evolocumab (120 mg subcutaneously every 2 weeks to 420 mg every 4 weeks) resulted in significantly greater reductions in LDL-C (-32% to -71%) at 12-52 weeks in patients with heterozygous or homozygous familial hypercholesterolemia, patients intolerant of statins, and patients with varied CV risk not at LDL-C goal with statin therapy. The highest strength evidence was for heterozygous familial hypercholesterolemia and patients not at LDL-C goals. Moderate-strength evidence showed HDL-C increases in the range of 4.5%-6.8%. Harms were not different between groups, except possibly slightly greater overall adverse event reporting. Evidence on adjudicated CV outcomes was insufficient to draw conclusions because of sparseness of events, study limitations, and inability to assess consistency of findings.
  
  
  CONCLUSIONS
  Alirocumab and evolocumab have evidence of large improvements in lipid levels. The strength of the evidence is greater for alirocumab than evolocumab in patients with high CV risk who were not at LDL-C target goals, while evidence for evolocumab is stronger in patients with heterogeneous familial hypercholesterolemia and patients with varied CV risk who were not at LDL-C target goals. Evidence on adjudicated CV outcomes for a priori analyses is unable to show benefit for alirocumab and is insufficient to draw conclusions for evolocumab. Important questions remain about the comparative effects on long-term health outcomes.
  
  
  BACKGROUND
  This project was funded by The Drug Effectiveness Review Project. Project participants reviewed the manuscript but had no role in conducting the work or writing the manuscript. Any comments received from the participants during the course of the review were taken at the discretion of the authors independently. All authors had access to the data and a role in writing the manuscript. McDonagh, Peterson, and Holzhammer declare no conflict of interest or financial interest in any therapy discussed in this article. Fazio declares receiving compensation from Sanofi for a presentation on his science to a group of their advisors and has served as a consultant to MSD, BASF, NHP, Sanofi, Ionis Pharmaceuticals, and Kowa. Study concept and design were primarily contributed by McDonagh, along with Peterson and Holzhammer, with assistance from Fazio. Holzhammer took the lead in data collection, with assistance from McDonagh and Peterson. Data interpretation was performed by McDonagh, Peterson, and Fazio. The manuscript was written by McDonagh, Peterson, and Fazio, with assistance from Holzhammer, and revised by all the authors.
authors.affiliation: 1 The Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon.
authors.forename: Marian
authors.initials: M
authors.lastname: McDonagh
authors.affiliation: 1 The Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon.
authors.forename: Kim
authors.initials: K
authors.lastname: Peterson
authors.affiliation: 1 The Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon.
authors.forename: Brittany
authors.initials: B
authors.lastname: Holzhammer
authors.affiliation: 2 Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab; C571059:alirocumab