PCSK9 Inhibitors in Disease Treatment

Introduction to PCSK9 Inhibitors

The European Society of Cardiology recommends PCSK9 inhibitors for patients with atherosclerotic cardiovascular disease (ASCVD) or at very high cardiovascular risk who have not achieved target LDL-C levels despite maximally tolerated statin therapy and ezetimibe 1, 2

PCSK9 inhibitors are monoclonal antibodies that prevent degradation of LDL receptors, allowing for continued recycling of these receptors to the hepatocyte surface and resulting in significant LDL-C reduction 3, 4
These agents reduce LDL-C by 50-65%, with mean LDL-C levels of approximately 0.9 mmol/L (35 mg/dL) achievable when added to maximal statin therapy 3, 4
Beyond LDL-C reduction, PCSK9 inhibitors improve other lipid parameters, including Lp(a) which is reduced by up to 25% 4, 5

In patients with clinical ASCVD who are judged to be at very high risk and are on maximally tolerated LDL-C lowering therapy with LDL-C ≥70 mg/dL (≥1.8 mmol/L), adding a PCSK9 inhibitor is reasonable 2, 6
The European Society of Cardiology recommends PCSK9 inhibitors for very high-risk patients who do not achieve their LDL-C goal on maximum tolerated statin dose and ezetimibe 6, 7
For patients with ASCVD, PCSK9 inhibitors should be considered after optimizing statin therapy and adding ezetimibe 1, 2

Alirocumab 150 mg biweekly and evolocumab 140 mg biweekly or 420 mg every 4 weeks have comparable LDL-lowering efficacy 3, 4

PCSK9 inhibitors appear well tolerated in trials up to 78 weeks in duration 4, 5
Common side effects include injection site reactions, which are relatively infrequent and mild 4
A small, non-significant increase in neurocognitive events has been reported for alirocumab and evolocumab 4, 5
No excess adverse events have emerged in patients with very low LDL-C levels (<0.65 mmol/L or <25 mg/dL) over 78 weeks of treatment 4, 5

Preliminary data suggest that PCSK9 inhibitors reduce cardiovascular events over 1 to 1.5 years 4, 5
The FOURIER trial demonstrated that the addition of evolocumab to statin therapy significantly reduced cardiovascular morbidity and mortality in patients with prevalent atherosclerotic CVD 8, 9
A meta-analysis of phase 2 and 3 trials found reduced total mortality with alirocumab and evolocumab in trials ranging from 12 to 78 weeks 4, 5

The American College of Cardiology recommends high-intensity statin therapy as first-line therapy to achieve >50% reduction in LDL-C 1, 2
If LDL-C goal is not achieved after 4-6 weeks with maximally tolerated statin dose, the American College of Cardiology recommends adding ezetimibe as second-line therapy 1, 2
The American College of Cardiology recommends considering PCSK9 inhibitor as third-line therapy if LDL-C remains elevated despite maximally tolerated statin plus ezetimibe 2, 6