What is the current status and pharmacology of Proprotein Convertase Subtilisin/Kexin Type 9 (PSCK9) inhibitors, such as alirocumab (Alirocumab) and evolocumab (Evolocumab), in the management of high cardiovascular risk or familial hypercholesterolemia?

PCSK9 Inhibitors: Pharmacology, Clinical Trials, and Current Status

PCSK9 inhibitors are recommended as an additional therapeutic option for patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) who cannot achieve LDL-C targets despite maximally tolerated statin plus ezetimibe therapy. 1, 2

Pharmacology

PCSK9 inhibitors are monoclonal antibodies that target and inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that regulates LDL receptor recycling. By blocking PCSK9:

• They prevent PCSK9-mediated degradation of LDL receptors
• Increase the number of LDL receptors on hepatocyte surfaces
• Enhance clearance of LDL-C from circulation
• Result in substantial reductions in LDL-C levels

Currently approved PCSK9 inhibitors include:

1. Alirocumab (Praluent):

   • Administered subcutaneously every 2 weeks (75mg or 150mg) or every 4 weeks (300mg)
   • Reduces LDL-C by 40-67% 1, 3

2. Evolocumab (Repatha):

   • Administered subcutaneously every 2 weeks (140mg) or every 4 weeks (420mg)
   • Reduces LDL-C by 32-71% 3

Both medications require some level of LDL receptor activity to be effective, with minimal efficacy in patients with negative/negative LDLR mutations with receptor activity below 2% 1.

Clinical Indications

According to FDA labeling, PCSK9 inhibitors are indicated for:

Alirocumab 4:

• Reducing risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease
• As adjunct to diet, alone or with other LDL-C-lowering therapies in adults with primary hyperlipidemia, including HeFH
• As adjunct to other LDL-C-lowering therapies in adult patients with HoFH
• As adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 8 years and older with HeFH

Evolocumab 5:

• Reducing risk of major adverse cardiovascular events in adults with established cardiovascular disease
• As adjunct to diet, alone or with other LDL-C-lowering therapies in adults with primary hyperlipidemia, including HeFH
• As adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH
• As adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 10 years and older with HoFH

Clinical Trial Evidence

PCSK9 inhibitors have demonstrated significant efficacy in multiple clinical trials:

• LDL-C reduction: Both alirocumab and evolocumab consistently demonstrate substantial LDL-C reductions (40-71%) across various patient populations 3, 6
• Cardiovascular outcomes: Both medications have shown significant reductions in major cardiovascular events (MACE):
  • Alirocumab: 11% reduction in MACE (RR 0.89; 95% CI 0.83-0.95) 6
  • Evolocumab: 14% reduction in MACE (RR 0.86; 95% CI 0.80-0.92) 6
• Other lipid parameters: Significant improvements in HDL-C (4.5-12% increase), lipoprotein(a), triglycerides, total cholesterol, and apolipoprotein B 3, 7

Current Clinical Status and Recommendations

Current guidelines recommend PCSK9 inhibitors in specific clinical scenarios:

1. For ASCVD patients:

   • When LDL-C targets (<1.8 mmol/L or <70 mg/dL) cannot be achieved despite maximally tolerated statin plus ezetimibe therapy 2

2. For HeFH patients without ASCVD:

   • When LDL-C remains >4.5 mmol/L (>180 mg/dL) despite maximally tolerated statin plus ezetimibe therapy 1, 2
   • When LDL-C remains >3.6 mmol/L (>140 mg/dL) with additional risk factors (diabetes with target organ damage, lipoprotein(a) >50 mg/dL, major risk factors like smoking or marked hypertension, premature ASCVD in first-degree relatives) 1

3. For HoFH patients:

   • As an adjunct therapy in patients with or without apheresis 1
   • Not recommended in patients with negative/negative LDLR mutations with LDL receptor activity below 2% 1

Safety Profile

PCSK9 inhibitors have demonstrated favorable safety profiles in clinical trials:

• Common adverse events: Injection site reactions (significantly higher than placebo, RR 1.54; 95% CI 1.38-1.71) 6
• Neurological effects: No significant increase in cognitive adverse events, even with very low LDL-C levels 1, 7
• Metabolic effects: No significant changes in glycated hemoglobin or increased risk of diabetes in short-term studies, though Mendelian randomization studies suggest potential long-term risk 1
• Very low LDL-C levels: No increase in adverse events including muscle symptoms, liver enzyme elevation, or hemorrhagic stroke with very low LDL-C levels 1

Practical Considerations

• Cost: PCSK9 inhibitors are expensive (>$12,000 per year), limiting their widespread use 8
• Monitoring: LDL-C response can be assessed as early as 4 weeks after initiation 1
• Administration: Subcutaneous injection into thigh, abdomen, or upper arm, with rotation of injection sites 4
• Patient selection: Most appropriate for high-risk patients who cannot achieve LDL-C targets with conventional therapy 9

Remaining Knowledge Gaps

Several important questions remain unanswered 1:

• Long-term safety of very low LDL-C levels
• Impact on cardiovascular mortality and disability
• Long-term evaluation of type 2 diabetes risk
• Effects on plaque composition and stability
• Cost-effectiveness in various patient populations

PCSK9 inhibitors represent a significant advance in lipid management, particularly for high-risk patients unable to achieve LDL-C targets with conventional therapy, but their high cost and limited long-term safety data currently restrict their widespread use.