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

From the Guidelines

PSK9 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 use of PSK9 inhibitors, such as evolocumab and alirocumab, has been evaluated in several studies, including the FOURIER trial, which demonstrated a 15% relative risk reduction in the composite outcome of cardiovascular death, MI, stroke, hospitalization for angina, or revascularization in patients with prior ASCVD and an additional high-risk feature who were receiving maximum tolerated statin therapy 1. Key points to consider when prescribing PSK9 inhibitors include:

• They are primarily prescribed for patients with familial hypercholesterolemia, those with established atherosclerotic cardiovascular disease who need additional LDL lowering beyond statins, or patients who cannot tolerate statins.
• The two main PSK9 inhibitors available are alirocumab (Praluent) and evolocumab (Repatha), both administered as subcutaneous injections every 2-4 weeks.
• Alirocumab is typically dosed at 75-150 mg every two weeks, while evolocumab is given as 140 mg every two weeks or 420 mg monthly.
• PSK9 inhibitors can reduce LDL cholesterol by 50-70%, significantly more than statins alone, and have been shown to decrease ASCVD event rates by 15-20% 1.
• Side effects are generally mild and include injection site reactions and flu-like symptoms, making them valuable alternatives for statin-intolerant patients.

From the FDA Drug Label

PRALUENT is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor indicated: 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)

Psk9 inhibitor is used for several indications, including:

• 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.

From the Research

Psk9 Inhibitor Overview

• Psk9 inhibitors are a class of drugs used to lower low-density lipoprotein cholesterol (LDL-C) levels in the blood 3, 4, 5, 6, 7
• They work by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is involved in the regulation of LDL-C levels 3, 4, 5, 6, 7

Mechanism of Action

• Psk9 inhibitors increase the hepatic uptake of LDL-C, leading to a reduction in circulating LDL-C levels 3, 6
• They have been shown to achieve profound reductions in LDL-C (54%-74%) when added to statins 3
• Psk9 inhibitors also produce minimal side effects, with myopathy being rare in patients on these drugs 3

Clinical Applications

• Psk9 inhibitors are used in patients with heterozygous and homozygous familial hypercholesterolemia, as well as those with atherosclerotic cardiovascular disease who require additional LDL-C lowering 4, 5, 7
• They are also used in patients who are statin intolerant or not at goal levels with maximally tolerated statin therapy 3, 4, 5, 7
• Psk9 inhibitors have been shown to reduce major adverse cardiovascular events (MACE) in high-risk patients with LDL-C levels ≥70 mg/dL 3

Comparison with Other Lipid-Lowering Therapies

• Psk9 inhibitors have been compared to other lipid-lowering therapies, such as ezetimibe and statins, and have been shown to be more effective in reducing LDL-C levels 3, 5, 7
• They have also been compared to other novel lipid-lowering therapies, such as bempedoic acid and inclisiran, and have been shown to be effective in reducing LDL-C levels 5, 7