Bempedoic Acid

Bempedoic acid acts as a prodrug that requires intracellular activation to exert its cholesterol-lowering effects. It achieves this by inhibiting adenosine triphosphate-citrate lyase (ACL), a crucial enzyme involved in cholesterol biosynthesis. By targeting ACL, bempedoic acid disrupts the production of mevalonate, a precursor molecule essential for cholesterol synthesis. This inhibition occurs upstream of HMG-CoA reductase, the target of statin therapies. Consequently, bempedoic acid reduces the cellular production of LDL cholesterol (LDL-C), leading to an upregulation of LDL receptors and increased clearance of LDL-C from the bloodstream. Its unique formulation as a hepatocyte-only-activated prodrug ensures its action primarily within hepatocytes, minimizing the risk of myopathy compared to statin therapy.

The efficacy of bempedoic acid has been demonstrated in various patient populations:

  • In high-risk ASCVD patients on maximally tolerated statin therapy (CLEAR Harmony and Wisdom trials)
  • In statin-intolerant patients (CLEAR Serenity, Tranquility, and Outcomes trials)

Across these trials, bempedoic acid consistently reduced LDL-C levels when compared to placebo. Notably, the CLEAR Outcomes trial also evaluated cardiovascular outcomes beyond LDL-C reduction, showing a reduction in the incidence of major adverse cardiovascular events (MACE).

Additionally, a phase III trial demonstrated the effectiveness of combination therapy with bempedoic acid and ezetimibe in further reducing LDL-C levels.

Bempedoic acid received FDA approval in 2020 as an adjunct to diet and maximally tolerated statin therapy for individuals with HeFH or established ASCVD requiring additional LDL-C reduction.

Subsequently, the FDA expanded indications for bempedoic acid and combination therapy with ezetimibe for primary hyperlipidemia. This expansion removed the prerequisite for patients to be on maximally tolerated statin therapy.

The 2022 AHA/ACC guidelines recommend the use of bempedoic acid in specific patient populations, including those with clinical ASCVD who are unable to achieve target LDL-C levels despite standard therapy, as well as those with statin intolerance. Bempedoic acid is typically prescribed as a fixed dose of 180 mg orally once daily, or in combination with ezetimibe.

Bempedoic acid has demonstrated a favorable safety profile in clinical trials, with rare adverse effects observed compared to placebo.

These adverse effects include increased blood uric acid levels, gout, decreased glomerular filtration rate, and elevated hepatic enzyme levels. Additionally, bempedoic acid is associated with cholelithiasis and is relatively contraindicated in patients with comorbid gout.

However, real-world clinical experience with bempedoic acid is still limited, warranting ongoing monitoring of its safety profile.

The long-term cost-effectiveness of bempedoic acid in the United States is still being evaluated.

Studies have assessed its cost-effectiveness in combination with statin therapy, producing varying results. Notably, its net cost per quality-adjusted life year (QALY) gained has not consistently met commonly cited thresholds of cost-effectiveness.

Recommendations from organizations such as the Institute for Clinical and Economic Review suggest price benchmarks for bempedoic acid to improve its cost-effectiveness, highlighting the need for potential pricing adjustments.

© The AtheroPrev Team (2024)

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