What are the benefits of high Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) levels?

From the Guidelines

High PCSK9 levels are associated with increased risk of cardiovascular disease, and there are no known benefits to having high PCSK9 levels. The primary concern with high PCSK9 levels is their role in promoting the degradation of LDL receptors in the liver, leading to increased LDL cholesterol in the bloodstream, which is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) 1.

Key Points to Consider

• PCSK9 inhibitors like evolocumab and alirocumab are used to lower LDL cholesterol in patients with high cardiovascular risk or familial hypercholesterolemia by blocking PCSK9 and allowing more LDL receptors to remain on liver cells, thus removing more LDL cholesterol from the bloodstream 1.
• The standard dosing for evolocumab is 140 mg every 2 weeks or 420 mg monthly by subcutaneous injection, while alirocumab is typically given as 75-150 mg every 2 weeks by subcutaneous injection 1.
• The evidence on the effect of PCSK9 inhibition on ASCVD outcomes is from studies of treatment with the monoclonal antibodies alirocumab and evolocumab, which have demonstrated significant reductions in major adverse cardiovascular events by 15–20% in the FOURIER and ODYSSEY OUTCOMES trials 1.

Recommendations for Patient Groups

• Patients with ASCVD, by definition at very high risk, who have substantially elevated LDL-C levels despite maximally tolerated statin with or without ezetimibe therapy, and thus are considered at particularly high risk of an adverse prognosis, should be considered for PCSK9 inhibitor therapy 1.
• Patients with ASCVD and at very high risk who do not tolerate appropriate doses of at least three statins and thus have elevated LDL-C levels should also be considered for PCSK9 inhibitor therapy 1.
• Familial hypercholesterolaemia patients without clinically diagnosed ASCVD, at high or very high cardiovascular risk, and with substantially elevated LDL-C levels despite maximally tolerated statin plus ezetimibe therapy, should be considered for PCSK9 inhibitor therapy 1.

Recent Guidelines

• The 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk recommends considering a PCSK9 inhibitor in patients who are unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens and have persistent <50% LDL-C reduction or LDL-C ≥ 70 mg/dL (or non–HDL-C ≥ 100 mg/dL) 1.
• A PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy, and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes 1.

From the Research

Benefits of PCSK9 Inhibitors

• PCSK9 inhibitors, such as alirocumab and evolocumab, have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients at high cardiovascular risk 2, 3, 4, 5, 6
• These inhibitors have been found to be effective in reducing the risk of major cardiovascular events (MACEs), especially in secondary preventive patients 2, 6
• PCSK9 inhibitors have also been shown to be safe, with the most common adverse event being injection site reactions 2, 6

Efficacy of PCSK9 Inhibitors

• A study found that a recommended dose of 140 mg of evolocumab every 2 weeks was likely to produce a relatively stronger effect than 150 mg of alirocumab every 2 weeks in terms of the absolute change and percent change in LDL-C levels 2
• Another study found that PCSK9 inhibitors decreased LDL-C levels by -49.59% compared to placebo in patients with familial hypercholesterolemia 6
• PCSK9 inhibitors have also been found to reduce the levels of lipoprotein(a), triglycerides, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B, and increase the levels of high-density lipoprotein cholesterol and apolipoprotein A1 6

Safety of PCSK9 Inhibitors

• PCSK9 inhibitors have been found to be well-tolerated, with the most common adverse event being injection site reactions 2, 6
• A study found that PCSK9 inhibitors did not alter the treatment-emergent adverse event (TEAE) and neuronal events compared to placebo in patients with familial hypercholesterolemia 6
• Another study found that PCSK9 inhibitors were associated with a lower risk of MACEs, especially in secondary preventive patients, but the effect on all-cause mortality remains uncertain 2