====== PCSK9 Inhibitors ======

PCSK9 inhibitors are advanced lipid-lowering therapies used in high-risk patients who require additional LDL reduction beyond [[cardio:lipids:start|statins]] and [[cardio:lipids:ezetimibe|ezetimibe]].

They significantly reduce LDL cholesterol and improve cardiovascular outcomes.

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===== Mechanism of Action =====

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

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===== Agents =====

==== Monoclonal Antibodies ====

  * [[cardio:lipids:alirocumab|Alirocumab]] (Praluent®)
  * [[cardio:lipids:evolocumab|Evolocumab]] (Repatha®)

Mechanism:
  * Bind circulating PCSK9
  * Prevent receptor degradation

Route:
  * Subcutaneous injection

Dosing:
  * Every 2–4 weeks

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==== Small Interfering RNA (siRNA) ====

  * [[cardio:lipids:inclisiran|Inclisiran]] (Leqvio®)

Mechanism:
  * Inhibits hepatic PCSK9 synthesis
  * Reduces circulating PCSK9 levels

Route:
  * Subcutaneous
  * Every 6 months (after loading)

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===== Indications =====

  * Very high-risk [[cardio:lipids:ascvd|ASCVD]]
  * Familial hypercholesterolemia
  * LDL not at goal despite:
      * Maximally tolerated [[cardio:lipids:start|statin]]
      * ± [[cardio:lipids:ezetimibe|ezetimibe]]

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

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===== LDL Reduction Magnitude =====

Approximate LDL Reduction:

  * 50–60% additional reduction beyond statin therapy

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

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===== Adverse Effects =====

Common:
  * Injection site reactions
  * Mild flu-like symptoms

Rare:
  * Hypersensitivity reactions

No significant myopathy signal.

No major hepatic toxicity.

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===== Clinical Strategy =====

Stepwise Lipid Escalation:

  * 1. [[cardio:lipids:start|High-Intensity Statin]]
  * 2. Add [[cardio:lipids:ezetimibe|Ezetimibe]]
  * 3. Add PCSK9 inhibitor if LDL remains above goal

PCSK9 inhibitors are additive, not replacements for statins.

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===== Comparison Within Class =====

Monoclonal Antibodies:
  * Faster onset
  * Biweekly/monthly dosing

[[cardio:lipids:inclisiran|Inclisiran]]:
  * Twice-yearly maintenance dosing
  * Hepatic synthesis inhibition
  * Slower steady-state effect

Clinical Role:
  * Ideal for adherence challenges
  * Very high-risk ASCVD patients

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===== High-Yield Pearls =====

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

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===== Related =====

  * [[cardio:lipids:start|Statins]]
  * [[cardio:lipids:ezetimibe|Ezetimibe]]
  * [[cardio:lipids:familial_hypercholesterolemia|Familial Hypercholesterolemia]]
  * [[cardio:intro:start|Cardiovascular Pharmacology]]