PCSK9 inhibitors are advanced lipid-lowering therapies used in high-risk patients who require additional LDL reduction beyond statins and ezetimibe.

They significantly reduce LDL cholesterol and improve cardiovascular outcomes.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) regulates LDL receptor degradation.

Normal Physiology:

• PCSK9 binds LDL receptors
• Promotes receptor degradation
• ↓ LDL receptor recycling
• ↑ Circulating LDL levels

PCSK9 Inhibition:

• Blocks PCSK9 activity
• Preserves LDL receptors
• ↑ LDL receptor recycling
• ↑ LDL clearance

Net Effect:

• Profound LDL reduction (50–60%)
• Reduced ASCVD events

• Alirocumab (Praluent®)
• Evolocumab (Repatha®)

Mechanism:

• Bind circulating PCSK9
• Prevent receptor degradation

Route:

• Subcutaneous injection

Dosing:

• Every 2–4 weeks

• Inclisiran (Leqvio®)

Mechanism:

• Inhibits hepatic PCSK9 synthesis
• Reduces circulating PCSK9 levels

Route:

• Subcutaneous
• Every 6 months (after loading)

• Very high-risk ASCVD
• Familial hypercholesterolemia
• LDL not at goal despite:
  • Maximally tolerated statin
  • ± ezetimibe

Used in secondary prevention and select high-risk primary prevention.

Approximate LDL Reduction:

• 50–60% additional reduction beyond statin therapy

Often lowers LDL to <55 mg/dL in very high-risk patients.

Common:

• Injection site reactions
• Mild flu-like symptoms

Rare:

• Hypersensitivity reactions

No significant myopathy signal.

No major hepatic toxicity.

Stepwise Lipid Escalation:

• 1. High-Intensity Statin
• 2. Add Ezetimibe
• 3. Add PCSK9 inhibitor if LDL remains above goal

PCSK9 inhibitors are additive, not replacements for statins.

Monoclonal Antibodies:

• Faster onset
• Biweekly/monthly dosing

Inclisiran:

• Twice-yearly maintenance dosing
• Hepatic synthesis inhibition
• Slower steady-state effect

Clinical Role:

• Ideal for adherence challenges
• Very high-risk ASCVD patients

• 50–60% LDL reduction
• Proven ASCVD outcome benefit
• Injectable therapy
• Used after statin + ezetimibe
• Expensive; insurance approval often required

• Statins
• Ezetimibe
• Familial Hypercholesterolemia
• Cardiovascular Pharmacology