PCSK9 Inhibitors: How They Lower LDL Cholesterol
PCSK9 inhibitors are an important new class of drug employed in the treatment of high cholesterol. Until now, statins have been regarded as the cornerstone of cholesterol treatment. However, statins in some patients are ineffective at reaching the recommended goals. I am referring to the familial types of hypercholesterolaemia in which patients often fail to reach their goal with statin therapy alone.
Patients like these often never reached their target cholesterol levels. With the introduction of PCSK9 inhibitors, like evolocumab and alirocumab, this has changed because these drugs provide an additional 50 to 60% lowering of the serum LDL over statin therapy alone.
How PCSK9 inhibitors work
Let us take a look at how these amazing drugs work. Normally, LDL receptors on the surface of liver cells remove LDL cholesterol from the blood. Once an LDL particle enters the liver cell, the receptor can return to the cell surface and capture another particle. However, PCSK9 interferes with this recycling process. When PCSK9 binds to an LDL receptor, it directs the receptor toward destruction inside the cell. As a result, fewer LDL receptors remain available to clear cholesterol from the bloodstream.
PCSK9 is mainly produced by liver cells, although smaller quantities are produced in the small intestine, kidneys, and brain as well. From these sites, PCSK9 molecules enter the bloodstream and travel to the liver, where they act on the LDL receptors, rendering them ineffective.
Statins, the traditional backbones of cholesterol management, inhibit the production of cholesterol by inhibiting the HMG-CoA reductase enzyme, which is central to the production of cholesterol in the body. This essentially lowers the level of cholesterol in the blood. A lower cholesterol, however, also triggers the liver cells to produce more LDL receptors on their surface, and this can enhance the clearance of cholesterol from the circulation.
Unfortunately, statins also stimulate the production of PCSK9, causing its levels to rise. This increased level of circulating PCSK9, as described above, reduces the number of LDL receptors available for cholesterol clearance. This, in effect, counteracts the increase in LDL receptors produced by statin therapy, causing cholesterol levels to remain high despite increased doses of statins.
PCSK9 inhibitors, by inactivating PCSK9, remove this limitation, so newly formed LDL receptors produced by the actions of statins remain active and continue to clear cholesterol from the blood.
But not all PCSK9 inhibitors work the same way. Evolocumab (Repatha) and Alirocumab (Praluent) bind circulating PCSK9, preventing it from directing LDL receptors toward destruction. They typically reduce LDL cholesterol by approximately 50–60%.
Inclisiran (Leqvio) works differently. Rather than binding circulating PCSK9, it reduces PCSK9 production within liver cells. It generally lowers LDL cholesterol by approximately 50%.
The newest development in PCSK9 inhibition is enlicitide (Lipfendra), the first oral PCSK9 inhibitor, approved by the FDA in July 2026.
Unlike the injectable monoclonal antibodies, enlicitide is a small, specially designed cyclic peptide that can be taken as a once-daily tablet. Once absorbed into the bloodstream, it binds directly to circulating PCSK9, preventing PCSK9 from attaching to LDL receptors on liver cells. This protects the receptors from premature destruction, allowing them to be recycled and continue removing LDL cholesterol from the blood.
Clinical trials have demonstrated LDL cholesterol reductions of approximately 55–60%, comparable to those achieved with injectable PCSK9 antibodies. This represents an important advancement for patients who require additional cholesterol-lowering but prefer oral medication to injections.
PCSK9 acts as a brake in the system, and PCSK9 inhibitors remove the brake. The clearance of cholesterol by statins, in the presence of PCSK9 inhibitors, can proceed unimpeded and is therefore more effective.
Unfortunately, PCSK9 inhibitors depend on the presence of LDL receptors to be effective.
They are particularly effective in patients with heterozygous familial hypercholesterolemia, who generally retain some functioning LDL receptors.
However, their effectiveness may be considerably reduced in patients with homozygous familial hypercholesterolemia, especially those whose genetic mutations leave them with little or no functioning LDL receptors. Since PCSK9 inhibitors work by preventing the destruction of LDL receptors, their effectiveness depends on the presence of receptors that can still function. In patients with virtually no functional LDL receptors, these drugs may provide little or no benefit.
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