What Drugs are PCSK9 Inhibitors?

October 8, 2025 •

4 min read

PCSK9 inhibitors can significantly lower "bad" low-density lipoprotein (LDL) cholesterol by 50% to 70%, offering a powerful treatment option for patients who cannot achieve their target levels with statins alone. These advanced medications target a specific protein in the liver to increase cholesterol clearance from the bloodstream. This guide explores the different drugs that are PCSK9 inhibitors, their mechanisms, and their role in modern cardiovascular care.

Quick Summary

PCSK9 inhibitors are injectable medications like evolocumab (Repatha), alirocumab (Praluent), and inclisiran (Leqvio) that effectively reduce LDL cholesterol, often used when statins are insufficient. They function by blocking a protein that interferes with the liver's ability to clear cholesterol from the blood.

Key Points

Drug Examples: The main PCSK9 inhibitor drugs available are evolocumab (Repatha), alirocumab (Praluent), and inclisiran (Leqvio).
Two Mechanisms: Evolocumab and alirocumab are monoclonal antibodies that bind to the PCSK9 protein, while inclisiran is an siRNA that prevents its production.
Administration: All PCSK9 inhibitors are administered via subcutaneous injection, with varying frequencies from bi-weekly to twice yearly.
Primary Candidates: These medications are typically used for high-risk patients with familial hypercholesterolemia, established cardiovascular disease, or statin intolerance.
High Efficacy: PCSK9 inhibitors are highly effective, capable of lowering LDL cholesterol by a significant margin (50-70%).
Complementary to Statins: They are often used in combination with statins for enhanced lipid lowering, working via a different pathway.
Cost and Access: PCSK9 inhibitors are more expensive than statins, and access often depends on meeting specific insurance and clinical criteria.

The Role of PCSK9 in Cholesterol Metabolism

To understand what drugs are PCSK9 inhibitors, it is essential to first understand the role of the PCSK9 protein. Your liver plays a critical role in regulating cholesterol levels by producing LDL receptors (LDLRs) on the surface of its cells. These receptors act like a vacuum, binding to and clearing LDL cholesterol from the bloodstream. After capturing LDL, the receptors are typically recycled back to the liver cell's surface to continue their work.

However, the PCSK9 protein, which is also produced by the liver, disrupts this process. It binds to the LDLRs, preventing them from being recycled and instead directing them for destruction within the liver cells. More PCSK9 means fewer LDLRs on the cell surface, resulting in higher levels of circulating LDL cholesterol. Inherited genetic conditions with high PCSK9 levels lead to very high LDL cholesterol and premature cardiovascular disease, while mutations with low PCSK9 levels have the opposite effect.

How PCSK9 Inhibitors Block the Protein

PCSK9 inhibitors are designed to counteract the function of the PCSK9 protein, thereby increasing the number of available LDLRs on the liver cell surface to remove more LDL from the blood. The drugs achieve this through two distinct mechanisms: monoclonal antibodies and small interfering RNA (siRNA) technology.

Monoclonal Antibody Inhibitors

This class of PCSK9 inhibitors consists of human-made antibodies that are administered by subcutaneous injection, typically every two or four weeks. They work by binding directly to the PCSK9 protein circulating in the bloodstream, blocking it from attaching to LDLRs on liver cells. The two primary monoclonal antibody PCSK9 inhibitors are:

Evolocumab (Repatha): First approved by the FDA in 2015, evolocumab is indicated for adults with atherosclerotic cardiovascular disease, familial hypercholesterolemia (FH), and other forms of hyperlipidemia to reduce LDL-C. It is administered via self-injection every two weeks or monthly.
Alirocumab (Praluent): Also approved in 2015, alirocumab is used to reduce the risk of heart attack, stroke, and unstable angina in adults with established cardiovascular disease. It is also indicated for patients with hyperlipidemia and FH and is administered every two or four weeks.

Small Interfering RNA (siRNA) Inhibitors

This newer class of PCSK9 inhibitor works differently from monoclonal antibodies. Instead of binding to the PCSK9 protein itself, small interfering RNA (siRNA) drugs target the messenger RNA (mRNA) inside liver cells that carries the instructions to produce the PCSK9 protein. By destroying the mRNA, they prevent the synthesis of PCSK9 entirely. The most prominent siRNA PCSK9 inhibitor is:

Inclisiran (Leqvio): Approved by the FDA in 2021, inclisiran offers a much less frequent dosing schedule. After an initial dose, a second is given at three months, and subsequent doses are only required every six months, with administration performed by a healthcare professional.

PCSK9 Inhibitors vs. Statins: A Comparison

PCSK9 inhibitors are often used in combination with statins or as an alternative for patients who cannot tolerate them. The table below highlights key differences between these two drug classes.


Feature	PCSK9 Inhibitors	Statins
Mechanism of Action	Block the PCSK9 protein or its production to prevent LDL receptor degradation.	Block the enzyme HMG-CoA reductase to reduce cholesterol production in the liver.
Administration	Subcutaneous injection every 2 weeks, monthly, or twice yearly.	Oral pill, typically taken daily.
Primary Use	Generally used in high-risk patients when statins are insufficient or not tolerated.	First-line treatment for high cholesterol for most patients.
Efficacy	Can lower LDL cholesterol by 50-70%, with a greater effect than statins for some.	Can lower LDL cholesterol by 20-50% depending on the statin's intensity.
Side Effects	Injection site reactions, flu-like symptoms, and nasopharyngitis are common.	Muscle pain, myopathy, and potential liver enzyme elevations are possible.
Cost	Significantly more expensive, often requiring insurance approval and manufacturer programs.	Widely available as low-cost generics.

Who is a Candidate for PCSK9 Inhibitors?

PCSK9 inhibitors are potent and are typically reserved for specific, high-risk patient populations. A healthcare provider may consider these medications if you have:

Atherosclerotic Cardiovascular Disease (ASCVD): This includes a history of heart attack, stroke, or peripheral arterial disease, especially if LDL cholesterol remains high despite maximum tolerated statin therapy.
Familial Hypercholesterolemia (FH): This genetic condition results in severely high cholesterol levels from an early age. PCSK9 inhibitors are a crucial component of treatment for both heterozygous (HeFH) and homozygous (HoFH) forms.
Statin Intolerance: For patients who experience severe side effects from statins that prevent their continued use, a PCSK9 inhibitor may be a suitable alternative.

Considerations for Using PCSK9 Inhibitors

While highly effective, PCSK9 inhibitors come with certain considerations. The most common side effects are generally mild and localized to the injection site, but patients should be aware of potential allergic reactions. The high cost of these medications means that access is often managed by insurance companies, and patients may need to follow specific criteria for coverage.

Conclusion

In conclusion, the primary FDA-approved drugs that are PCSK9 inhibitors are evolocumab (Repatha), alirocumab (Praluent), and inclisiran (Leqvio). These medications represent a significant advancement in the fight against high LDL cholesterol, offering powerful new options for high-risk patients who need additional lipid-lowering therapy beyond standard statins. They work by boosting the liver's ability to clear cholesterol from the blood, thereby reducing the risk of cardiovascular events like heart attack and stroke. As with any potent medication, a thorough discussion with a healthcare provider is necessary to determine if a PCSK9 inhibitor is the right choice for a patient's specific health needs and risk profile. For more information, please consult authoritative medical resources like the National Institutes of Health.

Frequently Asked Questions

Repatha (evolocumab) and Praluent (alirocumab) are monoclonal antibodies that bind to and inactivate the PCSK9 protein circulating in the blood. In contrast, Leqvio (inclisiran) is a small interfering RNA (siRNA) that works inside liver cells to block the production of the PCSK9 protein itself. Both achieve the goal of increasing LDL receptor availability but through different mechanisms.

No, PCSK9 inhibitors are not available as oral pills. They are administered via subcutaneous injection, either by a patient at home (for Repatha and Praluent) or by a healthcare provider in the office (for Leqvio).

PCSK9 inhibitors are primarily reserved for patients who cannot tolerate statins due to side effects or for those with high cholesterol that is not sufficiently lowered by statins and other therapies. While they can be used alone, they are often used in combination with statins to achieve the best results.

The most common side effects often include injection site reactions such as redness, pain, or bruising, as well as nasopharyngitis (inflammation of the nose and throat) or flu-like symptoms. Severe allergic reactions are possible but rare.

The injection frequency varies depending on the drug. Repatha (evolocumab) is typically injected every two weeks or monthly. Praluent (alirocumab) is injected every two weeks or monthly. Leqvio (inclisiran) is injected initially, again at three months, and then every six months.

Yes, PCSK9 inhibitors are significantly more expensive than statins. As brand-name-only medications, they may require prior authorization from insurance providers, and patients may need to enroll in manufacturer-sponsored savings programs to manage costs.

PCSK9 inhibitors are highly effective at lowering LDL-C levels. Studies have shown that adding them to statin therapy can reduce LDL cholesterol by an additional 50-60%. Clinical trials have also demonstrated their ability to reduce major cardiovascular events.