What are PCSK9 Inhibitors and how do they work?

Official answer

by Drugs.com

The PCSK9 inhibitors are used for the treatment of high-risk patients with elevated cholesterol, especially when statins aren't adequate. They work by blocking PCSK9, leaving more receptors available to capture your "bad" cholesterol (LDL) for break down and removal from the blood.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitors include the following medications:

Praluent (evolocumab)

Repatha (alirocumab)

Leqvio (inclisiran)

About 1 in 5 patients on statins cannot lower their cholesterol enough, sometimes due to a serious genetic defect called familial hypercholesterolemia (FH). In addition, some patients stop their statin treatment due to side effects, like intolerable or dangerous muscle aches, muscle or liver damage from statins, elevated blood sugar, or other side effects.

FDA Approved Uses

Praleunt and Repatha are FDA-approved to be used:

in combination with maximally tolerated doses of statins to further lower the hardest-to-treat elevated cholesterol levels for adult patients with heterozygous familial hypercholesterolemia (HeFH) or heart disease, who require additional lowering of LDL-cholesterol.

as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).

for cardiovascular risk reduction, which means they may help you avoid a heart attack or stroke.

in conjunction with other LDL-lowering agents when used for Homozygous Familial Hypercholesterolemia (HoFH), a dangerous and rare form of high LDL that is passed down through families.

Leqvio is FDA-approved to be used:

in combination with diet and a statin (another type of cholesterol-lowering medicine) for the treatment of adults with heart disease when the maximum dose of the statin does not lower cholesterol levels enough.

in combination with diet and a statin for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH), an inherited condition that causes high levels of LDL-C, when the maximum dose of the statin does not lower cholesterol levels enough.

What about statins?

By now you've heard of statins, also known as HMG-CoA reductase inhibitors. Statins have been the cornerstone of treatment to help regulate cholesterol production for over 3 decades. Available since the late 1980's, statins include well-known blockbusters like:

atorvastatin (Lipitor)

simvastatin (Zocor)

rosuvastatin (Crestor)

pravastatin

fluvastatin

Statins work so well because they block an enzyme involved in the production of cholesterol in the liver and boost the number of low density lipoprotein (LDL) receptors to help clear the body of LDL (also known as "bad cholesterol"). But not all people can tolerate them and they may not lower cholesterol levels enough in some patients.

How do the PCSK9 inhibitors work?

The PCSK9 inhibitors are a class of injectable drugs approved in 2015 that have been shown to dramatically lower LDL cholesterol levels -- by up to 60% in some reports -- when combined with a statin.

Praluent and Repatha may be used alone (with diet) OR as an add-on drug (with drugs like a statin) plus diet. These 2 agents can reduce the risk of heart attack, stroke, and other heart complications in adults with heart disease.

Leqvio is only indicated by the FDA to be used in combination with a statin and diet at this time, and it is not known if it will lower the risk of cardiovascular morbidity and mortality.

Mechanism of Action

Although all three drugs inhibit a protein called PCSK9 (proprotein convertase subtilisin kexin 9), they work by different mechanisms.

Repatha and Praluent are monoclonal antibodies that bind to PCSK9 in the liver and prevent it from binding to LDL receptors.

Leqvio blocks the PCSK9 protein by interfering with the translation of PCSK9 messenger RNA. It inhibits the intracellular synthesis of PCSK9.

It's important to block PCSK9 because it inactivates the needed receptors on the liver cell surface that transport LDL into the liver for metabolism (break down). Lower levels of LDL is better for the heart, and can help to protect against heart disease, heart attacks and stroke.

Ultimately, these agents all have the same action, and that is to free LDL receptors on liver cells to allow LDL (bad cholesterol) to be removed from the blood. In short - by blocking PCSK9, more receptors are available to capture your "bad" cholesterol for break down and removal from the blood.

This is not all the information you need to know about PCSK9 inhibitor for safe and effective use and does not take the place of your doctor’s directions. Review the full product information and discuss this information and any questions you have with your doctor or other health care provider.

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