What are Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors?

From the Guidelines

PCSK9 inhibitors should be used as adjunctive therapy for individuals with ASCVD or familial hypercholesterolemia who are receiving maximum tolerated statin therapy but require additional lowering of LDL cholesterol, as they have been shown to reduce LDL cholesterol by 36-59% and decrease ASCVD event rates by 15-20% 1. The primary mechanism of action of PCSK9 inhibitors, such as evolocumab and alirocumab, is to block the PCSK9 protein, which normally breaks down LDL receptors in the liver, allowing for a significant reduction in LDL cholesterol levels 1. Key points to consider when prescribing PCSK9 inhibitors include:

• They are typically administered as subcutaneous injections every 2-4 weeks 1
• Evolocumab is usually given as 140mg every 2 weeks or 420mg monthly, while alirocumab is given as 75-150mg every 2 weeks 1
• Patients should be taught proper injection technique for self-administration and the medications require refrigeration before use 1
• Side effects are generally mild and include injection site reactions, flu-like symptoms, and rarely, allergic reactions 1
• The FOURIER trial demonstrated a 15% relative risk reduction in the composite outcome of cardiovascular death, MI, stroke, hospitalization for angina, or revascularization with evolocumab therapy 1
• The ODYSSEY OUTCOMES trial showed a 20% reduction in the combined endpoint of cardiovascular death, MI, or stroke with alirocumab therapy 1

From the FDA Drug Label

To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease (1) As adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C. (1) As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C (1) As an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 8 years and older with HeFH to reduce LDL-C. (1) To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease (1)

PCSK9 Inhibitors are indicated for:

• Reducing the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
• Reducing LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
• Reducing LDL-C in adult patients with homozygous familial hypercholesterolemia (HoFH).
• Reducing LDL-C in pediatric patients aged 8 years and older with HeFH 2, 3, 2.

From the Research

Overview of PCSK9 Inhibitors

• PCSK9 inhibitors are a class of drugs that have emerged as a significant therapeutic target for further lowering of low-density lipoprotein cholesterol (LDL-C) when used in combination with statins 4, 5.
• They have been shown to reduce LDL-C levels by up to 60% and are relatively safe, with the exception of injection site reactions 4, 6.
• PCSK9 inhibitors, such as alirocumab and evolocumab, have been approved by the US Food and Drug Administration and have demonstrated significant reductions in ASCVD events when used in combination with statin therapy compared to statin alone 4, 7.

Efficacy and Safety of PCSK9 Inhibitors

• Multiple phase II and III studies have demonstrated the efficacy and safety of PCSK9 inhibitors in patients with atherosclerotic cardiovascular disease (ASCVD) 4, 5.
• A systematic review and meta-analysis of 32 randomized controlled trials found that PCSK9 monoclonal antibodies significantly improved LDL-C and other lipid profiles, and reduced the risk of major cardiovascular events (MACEs) 6.
• The reduction in MACEs was observed in White but not in Asian subjects, and no significant reduction of all-cause mortality was found 6.

Clinical Practice Guidelines and Future Directions

• Current clinical practice guidelines recommend PCSK9-directed therapies for higher-risk patients with established ASCVD and those with familial hypercholesterolemia 7, 8.
• The cost-effectiveness of PCSK9 inhibitors is limited to secondary prevention in high-risk patients, and additional research is needed to explore the role of PCSK9 inhibitors in other populations, including primary prevention and patients unable to tolerate statins 4, 8.
• Emerging PCSK9-directed therapies, such as small interfering RNA (siRNA) therapies and oral therapies, are in development and may offer new treatment options for patients with ASCVD 8.