II. Mechanism

  1. PCSK9 Inhibitors are monoclonal antibodies
    1. Inhibit PCSK9 (Proprotein Convertase subtilisin/kexin type 9)
    2. Antibodies bind PCSK9 and prevent their binding to LDL receptors
    3. Results in lowering of LDL Cholesterol
  2. PCSK9 binds to LDL receptors on hepatocytes
    1. Promotes LDL receptor degradation on binding
    2. Prevents LDL Cholesterol clearance from circulation
    3. Raises serum LDL Cholesterol levels

III. Indications

  1. Severe familial Hypercholesterolemia (e.g. LDL Cholesterol >190 mg/dl)

IV. Background

  1. Available in U.S. as of 2015

VI. Efficacy

  1. See disadvantages below
  2. Lower LDL Cholesterol up to 60%
  3. Repatha added to Statin for 2 years prevents one more CV event per 74 treated ($2,000,000 per CV event prevented)
    1. Alkhalil (2017) JAMA 317(16):1690-1691 +PMID: 28444271 [PubMed]

VII. Disadvantages

  1. Very expensive agents (>$10,000 per year in 2022)
    1. Contrast with Statins which cost $250 per year
    2. Statin alone for 5 years prevents one more fatal CV event per 39 treated ($48,000 per fatal CV event prevented)
  2. New, with only short-term data
    1. Unknown longterm safety
    2. Unknown mortality reduction (contrast with proven Statin efficacy)

VIII. References

  1. (2015) Presc Lett 22(9): 50-1
  2. (2022) Non-StatinLipid Lowering Agents, Presc Lett, #380202
  3. (2022) Med Lett Drug Ther 64(1659): 145-52
  4. Robinson (2015) N Engl J Med 372(16):1489-99 +PMID:25773378 [PubMed]
  5. Stroes (2014) J Am Coll Cardiol 63(23):2541-8 [PubMed]

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