Beyond the Statins: Overview of Ezetimibe and Bempedoic Acid

February 8, 2021

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Ezetimibe (Zetia®- approved October-2002)
Mechanism: works by blocking NCP1L1 (Niemann-Pick C1-Like 1), which blocks intestinal absorption of cholesterol and phytosterols. It is effective in absence of dietary cholesterol because it blocks absorption of cholesterol in the bile.
It lowers LDL by 18%, and triglycerides by 8%, and raises HDL by 1-5% by itself.  When combined with statins it lowers LDL 25%, triglycerides by 14%, and raises HDL by 3%.
Prescribers Note: 
Most clinicians will try to get a statin on board even if the patient complains of muscle pain.  Even giving Atorvastatin 5mg 3 or 4 times a week greatly improves the lipid profile over that of ezetimibe (Zetia®) alone. Ezetimibe may be helpful for avoiding high doses of statins, and therefore possibly decreasing risk of myopathy in patients who do not meet cholesterol goals on low-dose statin therapy alone.
Warnings/Precautions/Adverse Effects:
Well tolerated.  May see increase in liver transaminases when combined with statins.
Pregnancy Category-C
Bempedoic Acid (Nexletol®-approved 2020)
Mechanism: the first ATPcitrate lyase (ACL) inhibitor, indicated for use as adjunct to diet and maximally tolerated statin therapy.  This enzyme is “upstream” from HMG reductase, the enzyme that statins block. First oral, once daily, non-statin in 20 years since ezetimibe.
Lowered LDL-C by 17% on background therapy.
Dose: 180mg once daily, with or without food.

  • Simvastatin: Avoid concomitant use with simvastatin greater than 20 mg.
  • Pravastatin: Avoid concomitant use with pravastatin greater than 40 mg
    • Practice Point: other statins such as rosuvastatin and atorvastatin do not seem to be affected by bempedoic acid and may be a more rational choice.

Warning: may increase blood uric acid levels.  Hyperuricemia may occur early in treatment and persist throughout treatment and may lead to the development of gout.

  • Practice Point: Check the profile for allopurinol, febuxostat or colchicine which indicate potential for gout flares.  Be sure to contact the prescriber and patient.

Tendinopathies: bempedoic acid increases the risk for tendon rupture, especially in the rotator cuff, biceps, and Achilles tendons.

  • Practice point: Check patient profile for the following that can increase the risk of tendon rupture: patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders.

Pennsylvania Medicaid Formulary requires: “Is being prescribed the ACL inhibitor by or in consultation with an appropriate specialist (e.g., cardiologist, endocrinologist, or other provider specializing in lipid disorders.”

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Do not consider Bempedoic acid to be as safe as the PCSK-9 inhibitors (alirocumab (Praluent®), evolocumab (Repatha®).  The potential for gout as well as tendinopathies makes it necessary for the prescriber and pharmacist to provide a more intense patient counseling effort.
This is especially important for patients with commercial insurance or Medicare-D plans where the prescriber might not need to be a specialist as required for the state Medicaid plans, such as Pennsylvania’s. 
Nexletol (bempedoic acid) and Nexlizet (bempedoic acid + ezetimibe) are being detailed to family practice offices as well as the specialists. 
Make sure you are monitoring the uric acid levels, as bempedoic acid might precipitate a gout attack.  Most recommendations say check uric acid (and get it under control) before prescribing bempedoic acid.
Have a Great Day on the Bench!!