What are PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitors, such as alirocumab (Alirocumab) and evolocumab (Evolocumab), and what are their side effects?

PCSK9 Inhibitors: Mechanism and Side Effects

What Are PCSK9 Inhibitors?

PCSK9 inhibitors (alirocumab and evolocumab) are fully humanized monoclonal antibodies that bind to PCSK9 enzyme, preventing it from degrading LDL receptors on hepatocytes, thereby increasing LDL receptor availability and dramatically lowering LDL cholesterol by 50-70%. 1, 2

Mechanism of Action

• PCSK9 normally binds to LDL receptors (LDLR) on hepatocyte surfaces and promotes their degradation within the liver 1
• By inhibiting PCSK9 binding to LDLR, these antibodies increase the number of LDL receptors available to clear LDL from circulation, thereby lowering LDL-C levels 1
• Both alirocumab and evolocumab are administered subcutaneously, with alirocumab dosed at 75-150 mg every 2 weeks and evolocumab at 140 mg every 2 weeks or 420 mg monthly 3
• Maximal suppression of free PCSK9 occurs within 4-8 hours after administration, with steady state reached after 2-3 doses 1

Clinical Efficacy

• PCSK9 inhibitors reduce LDL-C by 50-65% when added to statin therapy, achieving mean LDL-C levels of approximately 30-35 mg/dL 3, 4, 5
• The FOURIER trial demonstrated that evolocumab reduced major cardiovascular events by 15-20% (HR 0.85, p<0.001) in 27,564 high-risk patients with prior ASCVD on maximally tolerated statin therapy 3, 6, 5
• The ODYSSEY Outcomes trial showed alirocumab reduced LDL-C by 57% and adverse cardiovascular events by 15% 5
• Both agents demonstrate cardiovascular benefit primarily in secondary prevention patients with established ASCVD, particularly those with multiple major ASCVD events 4, 7

Side Effects Profile

Common and Mild Side Effects

The most common side effect is injection site reactions, occurring in less than 5% of patients, which are predominantly very mild in intensity with no cumulative effect over time. 3

• Injection site reactions occurred at a rate of 1.54 times higher than placebo (95% CI 1.38-1.71), but were mainly of very mild intensity 3, 7
• Nasopharyngitis and upper respiratory infections are among the most frequently reported adverse effects, though generally mild 6
• Overall adverse event rates are similar between PCSK9 inhibitors and standard of care (statin with or without ezetimibe) 3

Serious Adverse Events - Reassuring Safety Data

Large-scale trials including ODYSSEY, PROFICIO, FOURIER, and IMPROVE-IT showed no increase in severe muscle symptoms, liver enzyme elevation, cognitive adverse events, or hemorrhagic stroke with PCSK9 inhibitors, even at very low LDL-C levels below 25 mg/dL. 3

• The EBBINGHAUS trial specifically evaluated cognitive function in 1,204 patients using validated neuropsychological testing and showed no cognitive detriment, even in patients achieving LDL-C levels <25 mg/dL 3
• Muscle symptoms occurred at lower rates with PCSK9 inhibitors compared to standard of care (4.7% vs. 8.5% annualized event rates) 3
• No increase in hemorrhagic stroke risk was observed with PCSK9 inhibitor therapy 3
• No clinically significant drug-drug interactions have been identified with evolocumab 6

Diabetes Risk - Nuanced Consideration

Clinical trial data showed no excess risk for new-onset diabetes in the short term (2.8% vs. 4.0% with standard of care), and very low LDL-C levels did not affect glycated hemoglobin or fasting glucose in diabetic patients. 3

However, there is an important caveat:

• Mendelian randomization studies indicate a potential increase in lifetime risk for type 2 diabetes with PCSK9 loss-of-function variants, requiring longer observation periods to fully assess this risk 3
• In patients with diabetes treated with insulin, alirocumab showed no change in glycated hemoglobin or fasting plasma glucose during treatment 3

Long-Term Safety Considerations

To date, there are exposure data for up to 4 years of PCSK9 inhibitor treatment, predominantly in patients on concomitant statin therapy, with no new safety signals emerging. 3

• Long-term safety remains to be fully established, particularly regarding very low LDL-C levels maintained over extended periods 3
• Long-term evaluation is especially warranted in older patients (>75 years) 3
• Ongoing gaps in knowledge include long-term impact on disability, cardiovascular mortality, and sustained effects of very low LDL-C levels on plaque composition 3

Special Populations

• No dose adjustment is needed for patients with mild or moderate renal or hepatic impairment 1
• No data are available in patients with severe renal or hepatic impairment 1
• No overall differences in safety or effectiveness were observed in patients ≥65 years or ≥75 years of age 1
• PCSK9 inhibitors are not recommended in homozygous familial hypercholesterolemia patients with negative/negative LDLR mutations (LDL receptor activity <2%), as some receptor activity is required for efficacy 3

Monitoring Recommendations

• LDL-C response should be assessed 4 weeks after initiating PCSK9 inhibitor therapy 3, 4
• Before considering PCSK9 inhibitors, ensure patient adherence to maximally tolerated statin and ezetimibe therapy 4