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Practice

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors

Derek Leong and Peter E. Wu
CMAJ August 12, 2019 191 (32) E894; DOI: https://doi.org/10.1503/cmaj.190107
Derek Leong
Department of Pharmacy (Leong) and Division of General Internal Medicine (Wu), University Health Network; Division of Clinical Pharmacology and Toxicology (Wu), Department of Medicine, University of Toronto, Toronto, Ont.
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Peter E. Wu
Department of Pharmacy (Leong) and Division of General Internal Medicine (Wu), University Health Network; Division of Clinical Pharmacology and Toxicology (Wu), Department of Medicine, University of Toronto, Toronto, Ont.
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Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a new class of low-density lipoprotein (LDL-C)–lowering medications

PCSK9 is a protease that degrades hepatic LDL-C receptors. Evolocumab and alirocumab are fully human monoclonal antibodies administered as subcutaneous injections that inhibit PCSK9, preserving receptor availability to clear circulating LDL-C.1,2

PCSK9 inhibitors have been shown to improve cardiovascular outcomes

In randomized, placebo-controlled trials of patients with atherosclerotic cardiovascular disease and LDL-C ≥ 1.8 mmol/L despite maximal statin therapy with or without ezetimibe, evolocumab and alirocumab both reduced major cardiovascular events with an absolute risk reduction of 1.5% (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.79–0.92, p < 0.001; number needed to treat: 67) after 2.2 years of follow-up and 1.6% (HR 0.85, 95% CI 0.78–0.93, p < 0.001; number needed to treat: 63) after 2.8 years of follow-up, respectively. 1,2 These benefits were driven primarily by reduced morbidity.

PCSK9 inhibitors are recommended as add-on therapy in patients at very high risk

The 2018 American dyslipidemia guideline recommends adding PCSK9 inhibitors in patients at very high risk (multiple cardiovascular events or 1 cardiovascular event plus risk factors) with LDL-C ≥ 1.8 mmol/L despite maximal statin therapy with or without ezetimibe.3 PCSK9 inhibitors are also recommended in patients with severe hypercholesterolemia (LDL-C ≥ 4.9 mmol/L) above target despite maximal statin therapy and ezetimibe.3

PCSK9 inhibitors are well tolerated, but long-term safety data are lacking

Mild, self-limiting injection-site reactions are the most common adverse effect; no clinically important drug interactions have been reported.1,2

The price of PCSK9 inhibitors limits their cost-effectiveness

Economic evaluations of evolocumab and alirocumab incorporating data on clinical outcomes1,2 conclude that these medications are not cost-effective at current pricing, even with a $100 000 threshold quality-adjusted life-year cost.3–5 Their annual cost is more than $15 000 in the United States and approximately $7500 in Canada.4,5 Substantial price reductions (e.g., to about $2000/yr) are needed in order for them to be cost-effective.4,5 Provincial coverage varies and is generally limited to patients at high risk.

CMAJ invites submissions to “Five things to know about …” Submit manuscripts online at http://mc.manuscriptcentral.com/cmaj

Footnotes

  • Competing interests: None declared.

  • This article has been peer reviewed.

References

  1. ↵
    1. Sabatine MS,
    2. Giugliano RP,
    3. Keech AC,
    4. et al.
    FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Schwartz GG,
    2. Steg PG,
    3. Szarek M,
    4. et al.
    ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.
    OpenUrlCrossRef
  3. ↵
    1. Grundy SM,
    2. Stone NJ,
    3. Bailey AL,
    4. et al
    . 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines [published erratum in Circulation 2019;139:e1182–6]. Circulation 2019;139:e1082–143.
    OpenUrl
  4. ↵
    1. Kazi DS,
    2. Penko J,
    3. Coxson PG,
    4. et al
    . Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY outcomes trial. Ann Intern Med 20192019;170:221–9.
    OpenUrl
  5. ↵
    1. Lee TC,
    2. Kaouache M,
    3. Grover SA
    . Evaluation of the cost-effectiveness of evolocumab in the FOURIER study: a Canadian analysis. CMAJ Open 2018;6:E162–7.
    OpenUrl
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Canadian Medical Association Journal: 191 (32)
CMAJ
Vol. 191, Issue 32
12 Aug 2019
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Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors
Derek Leong, Peter E. Wu
CMAJ Aug 2019, 191 (32) E894; DOI: 10.1503/cmaj.190107

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Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors
Derek Leong, Peter E. Wu
CMAJ Aug 2019, 191 (32) E894; DOI: 10.1503/cmaj.190107
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  • Article
    • Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a new class of low-density lipoprotein (LDL-C)–lowering medications
    • PCSK9 inhibitors have been shown to improve cardiovascular outcomes
    • PCSK9 inhibitors are recommended as add-on therapy in patients at very high risk
    • PCSK9 inhibitors are well tolerated, but long-term safety data are lacking
    • The price of PCSK9 inhibitors limits their cost-effectiveness
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