title: The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis.
abstract: OBJECTIVE
  We performed a network meta-analysis of randomized controlled trials (RCTs) in patients with primary hypercholesterolaemia to compare the impact of proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) inhibitors with placebo and ezetimibe on lipid levels and outcomes.
  
  
  RESULTS
  MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched for RCTs assessing PCSK9 inhibitors vs. other therapies in patients with primary hypercholesterolaemia. Network meta-analysis with both a frequentist approach and a Bayesian framework was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo. Odds ratios with 95% confidence intervals (OR [95% CIs]) were generated with random-effects models to compare outcomes. Our meta-analysis included 17 RCTs with 13 083 patients that were randomized to PCSK9 inhibitors (n = 8250), placebo (n = 3957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n = 30). The mean age was 59 ± 10, 52% were male, 34% had coronary artery disease, 51% had hypertension, 19% had diabetes mellitus, baseline LDL of 122 ± 36 mg/dL, total cholesterol of 199 ± 39 mg/dL, and HDL of 51 ± 14 mg/dL. inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (P < 0.001) and 36.1% relative to ezetimibe (P < 0.001). Proprotein convertase subtilisin-kexin type 9 serine protease inhibitors reduced the incidence of all-cause mortality [OR 0.43 (95% CI 0.22-0.82), P = 0.01] but was associated with an increased incidence of neurocognitive adverse events [OR 2.34 (95% CI 1.11-4.93), I(2) = 4%, P = 0.02] when compared with placebo.
  
  
  CONCLUSIONS
  Proprotein convertase subtilisin-kexin type 9 serine protease inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo but had a higher rate of neurocognitive adverse events. Thus, PCSK9 inhibitor therapy may serve as an alternative for patients with statin intolerance and for those who do not respond to other lipid reduction therapy.
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lipinski
authors.affiliation: University of Bristol, School of Clinical Sciences, Bristol Royal Infirmary, Bristol, UK.
authors.forename: Umberto
authors.initials: U
authors.lastname: Benedetto
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: Ricardo O
authors.initials: RO
authors.lastname: Escarcega
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi-Zoccai
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: Thibault
authors.initials: T
authors.lastname: Lhermusier
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: Nevin C
authors.initials: NC
authors.lastname: Baker
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Torguson
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA.
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.affiliation: Medstar Cardiovascular Research Network, Medstar Heart and Vascular Institute, Medstar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA ron.waksman@medstar.net.
authors.forename: Ron
authors.initials: R
authors.lastname: Waksman
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D000091362:PCSK9 Inhibitors; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D000071449:Proprotein Convertase 9
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Hypercholesterolemia; Lipid levels; Outcomes; PCSK9 inhibitors