A patient with familial hypercholesterolaemia (FH) has a defective LDL receptor. LDL particles are not cleared, leading to hypercholesterolaemia. PCSK9 inhibitors lower LDL by:

• A Directly inhibiting HMG-CoA reductase like statins
• B Stimulating VLDL secretion to shift cholesterol to the LDL-R independent pathway
• C Inhibiting NPC1L1 to reduce intestinal cholesterol absorption
• D Preventing PCSK9-mediated degradation of LDL receptors, increasing LDL-R recycling to the hepatocyte surface ✓

Explanation

PCSK9 (proprotein convertase subtilisin/kexin type 9) normally binds to LDL-R on the hepatocyte surface and directs it to lysosomal degradation after LDL endocytosis; anti-PCSK9 monoclonal antibodies (evolocumab, alirocumab) block this interaction, allowing LDL-R to recycle to the cell surface and bind more LDL, dramatically lowering LDL-C. Statins inhibit HMG-CoA reductase. Ezetimibe inhibits NPC1L1. VLDL secretion is not the mechanism.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.