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PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: does reality match the hype?
  1. Savvas Hadjiphilippou1,
  2. Kausik K Ray2
  1. 1 Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK
  2. 2 Department of Primary Care and Public Health, Imperial College, London, UK
  1. Correspondence to Professor Kausik K Ray, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College, Reynolds Bldg, St. Dunstan’s Rd, London W6 8RP, UK; k.ray{at}


Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12–26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.

  • Cardiac risk factors and prevention
  • Lipoproteins and hyperlipidemia
  • Coronary artery disease
  • Genetics
  • Pharmacology

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  • Contributors Both authors conceived and contributed equally to this study.

  • Funding This review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests KKR reports personal fees from Aegerion, grants and personal fees from Amgen, grants and personal fees from Sanofi/Regeneron, grants and personal fees from Pfizer, personal fees from Astra Zeneca, personal fees from Cerenis, personal fees from ISIS Pharma, personal fees from Medco, personal fees from Resverlogix, personal fees from Kowa, personal fees from Novartis, personal fees from Cipla, personal fees from Lilly, personal fees from Algorithm, personal fees from Takeda, personal fees from Boehringer Ingelheim, personal fees from MSD and personal fees from Abbvie, outside the submitted work.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Correction notice This article has been corected since it was published Online First. Figures 3, 4 and 5 have been re-ordered.