Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors

Derek Leong; Peter E. Wu

doi:10.1503/cmaj.190107

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.

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Footnotes

Competing interests: None declared.
This article has been peer reviewed.

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