PCSK9 inhibitors and LDL receptor recycling
PCSK9 inhibitors block PCSK9, a liver-made protein that sends LDL receptors to be destroyed, so the receptors are recycled to the cell surface and more LDL is cleared.
Remember
PCSK9 inhibitors block PCSK9, so LDL receptors are saved from destruction and recycled, which lets the liver clear more LDL.
Memory aid
PCSK9 is a shredder for LDL receptors, and alirocumab jams the shredder.
PCSK9 destroys LDL receptors like a shredder, and blocking it stops the shredding, so the receptors are recycled.
Liver cells (hepatocytes) mainly clear LDL cholesterol from the blood with LDL receptors. Each receptor grabs an LDL particle, pulls it into the cell and normally returns to the cell surface to be used again.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein made by the liver. It binds the receptor and steers it to the lysosomes, the cell's waste-disposal compartments, where the receptor is destroyed instead of being reused. With fewer receptors, LDL cholesterol is higher.
PCSK9 inhibitors are monoclonal antibodies (laboratory-made antibodies aimed at one specific protein), namely alirocumab and evolocumab. They bind free PCSK9, so the receptors survive, return to the liver cell surface and clear more LDL. The antibody binds PCSK9, not LDL particles.
A statin is a drug that lowers the cholesterol made inside liver cells, and that raises the number of receptors. A PCSK9 inhibitor protects those receptors from destruction, so the two work at different steps and add together, giving around 50 to 60% extra LDL reduction.
The idea came from human genetics. Many people with unusually low LDL carry loss-of-function PCSK9 mutations and have a reduced lifetime risk of coronary disease. Loss of function here means less PCSK9 activity, and so less receptor destruction. The antibodies copy the effect of those mutations.
These drugs are costly, so NICE restricts them to people with familial hypercholesterolaemia (an inherited condition in which LDL is raised from birth; in the heterozygous form, with one faulty gene copy, it is about twice normal) or established cardiovascular disease who fail to reach their target on standard therapy.
Key facts
- Target
- PCSK9 is a protein made by the liver that sends LDL receptors to be destroyed.
- Drugs
- alirocumab and evolocumab are monoclonal antibodies against PCSK9, given by subcutaneous injection.
- Size of effect
- LDL reduction is around 50 to 60% on top of a statin.
- Genetic clue
- many people with unusually low LDL carry loss-of-function PCSK9 mutations and have a reduced lifetime risk of coronary disease.
- UK use
- NICE restricts these drugs to familial hypercholesterolaemia or established cardiovascular disease when standard therapy fails to reach target.
- Inclisiran
- a related subcutaneous drug that is a small interfering RNA (a short piece of genetic material that switches off production of one protein), not an antibody, and it reduces PCSK9 production.
Exam traps
- Inclisiran also ends with more LDL receptors being recycled and is given by subcutaneous injection, but it is a small interfering RNA that reduces PCSK9 production, not a monoclonal antibody.
- The antibody binds the protein PCSK9, not the LDL particles. LDL is cleared faster because more receptors survive to take it up.
- Increased degradation of the receptors is what PCSK9 itself does, which makes it a reversal. A PCSK9 inhibitor blocks that process, so degradation falls.
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