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PCSK9 Inhibitor Mechanism — EECC MCQ

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ModerateCoronary Artery DiseasePCSK9 Inhibitor MechanismEECC

A 50-year-old woman with familial hypercholesterolaemia on maximal statin and ezetimibe has LDL-C 3.8 mmol/L. She is started on evolocumab 140 mg fortnightly. What is the mechanism of PCSK9 inhibitors?

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Correct answer: D — PCSK9 normally binds LDL receptors on hepatocytes and promotes their degradation; PCSK9 inhibitors prevent this binding, increasing LDL receptor recycling to the cell surface and enhancing LDL-C clearance from plasma

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease produced by hepatocytes. Normally, PCSK9 binds to LDL receptors (LDLR) on the hepatocyte surface, directing them to lysosomal degradation rather than recycling to the cell surface. This reduces LDLR density and decreases LDL-C clearance. PCSK9 monoclonal antibodies (evolocumab, alirocumab) bind circulating PCSK9, preventing its interaction with LDLR. This results in: (1) increased LDLR recycling; (2) higher LDLR surface density; (3) enhanced LDL-C clearance from plasma. The FOURIER (evolocumab) and ODYSSEY OUTCOMES (alirocumab) trials demonstrated ~60% LDL-C reduction and significant MACE reduction when added to statin therapy. The mechanism is complementary to statins (which upregulate LDLR synthesis) and synergistic.

Reference: ESC/EAS (2019/2025): Dyslipidaemia Guidelines; FOURIER/ODYSSEY Trials