What is the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)?

From the Guidelines

PCSK9 plays a crucial role in regulating LDL cholesterol levels by binding to LDL receptors on liver cells, and its inhibition has been shown to significantly reduce LDL cholesterol levels and cardiovascular events in high-risk patients. The enzyme works by causing the degradation of LDL receptors, resulting in fewer receptors available to remove LDL cholesterol from the blood, leading to higher LDL cholesterol levels 1. PCSK9 inhibitors, such as evolocumab and alirocumab, block this enzyme, allowing more LDL receptors to remain active on liver cells, which increases the removal of LDL cholesterol from the bloodstream.

Key points about PCSK9 and its inhibition include:

• PCSK9 inhibitors can lower LDL cholesterol by 36-59% when added to maximally tolerated doses of statin therapy 1
• The FOURIER trial demonstrated that evolocumab reduced LDL cholesterol by 59% from a median of 92 to 30 mg/dL in patients with prior ASCVD and an additional high-risk feature 1
• PCSK9 inhibitors are typically prescribed for patients with familial hypercholesterolemia or those with atherosclerotic cardiovascular disease who cannot achieve target LDL levels with statins alone
• The medications are administered as subcutaneous injections every 2-4 weeks, and side effects are generally mild, including injection site reactions and flu-like symptoms, with a low risk of serious adverse events.

In terms of clinical practice, the use of PCSK9 inhibitors as adjunctive therapy for patients with ASCVD or familial hypercholesterolemia who are receiving maximally tolerated statin therapy but require additional lowering of LDL cholesterol is supported by the evidence 1. This approach can help reduce cardiovascular events in high-risk patients, and the benefits of PCSK9 inhibition on LDL cholesterol levels and cardiovascular outcomes have been consistently demonstrated in clinical trials 1.

From the FDA Drug Label

PCSK9 binds to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

The role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is to bind to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes, promoting LDLR degradation within the liver. This process regulates the number of LDLRs available to clear LDL from the blood, thereby affecting LDL-C levels 2.

From the Research

Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

• PCSK9 is an enzyme that plays a crucial role in lipoprotein metabolism 3
• It is involved in the degradation of LDL receptors, which leads to an increase in LDL cholesterol levels 3, 4
• Rare gain-of-function mutations in PCSK9 can lead to high LDL cholesterol levels and premature coronary heart disease, while loss-of-function variants can lead to low LDL cholesterol levels and a reduced incidence of coronary heart disease 3

PCSK9 Inhibition as a Therapeutic Target

• PCSK9 inhibition is a rational therapeutic target for lowering LDL cholesterol levels 3, 5, 4
• Several approaches are being pursued to inhibit PCSK9, including monoclonal antibodies 3, 5, 6, 7
• PCSK9 inhibitors have been shown to produce an additional 50-60% decrease in LDL cholesterol levels when used in combination with statin therapy 3, 5, 4

Clinical Evidence for PCSK9 Inhibitors

• Multiple phase II and III studies have demonstrated that PCSK9 inhibitors, such as alirocumab and evolocumab, reduce LDL cholesterol levels by up to 60% and are relatively safe 5, 6, 7
• Two randomized controlled clinical trials have demonstrated that both alirocumab and evolocumab reduce atherosclerotic cardiovascular disease events when used in combination with statin therapy compared to statin alone 5, 7
• The 2018 Cholesterol Guideline incorporated PCSK9 inhibitors into the treatment algorithm for select secondary prevention patients unable to achieve an LDL cholesterol level below 70 mg/dL despite maximally tolerated statin plus ezetimibe 5