What is the role of bempedoic acid (Esperion's Nexletol) in primary prevention of hyperlipidemia?

From the Guidelines

Bempedoic acid is a recommended option for primary prevention of hyperlipidemia, particularly in patients who cannot tolerate statins or require additional LDL lowering, as it has been shown to reduce the primary composite outcome by 30% compared to placebo. The use of bempedoic acid in primary prevention is supported by the findings of the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid or Placebo (CLEAR Outcomes) trial, as reported in the 2025 standards of care in diabetes 1. Key points to consider when using bempedoic acid for primary prevention include:

• It can be used as monotherapy or in combination with other lipid-lowering medications, such as ezetimibe, which results in an additional 19% reduction in LDL cholesterol 1.
• The standard dose is 180 mg taken orally once daily, with or without food.
• Bempedoic acid works by inhibiting ATP citrate lyase, an enzyme involved in cholesterol synthesis upstream from HMG-CoA reductase, resulting in LDL reductions of approximately 15-25% 1.
• Common side effects include upper respiratory tract infections, muscle pain, and elevated uric acid levels, though muscle-related adverse effects appear less frequent than with statins.
• Laboratory monitoring should include baseline liver function tests, with periodic monitoring thereafter.
• Bempedoic acid should be avoided in patients with severe renal impairment, end-stage renal disease, or active liver disease. The CLEAR Outcomes trial demonstrated that bempedoic acid reduces cardiovascular events in statin-intolerant patients with or at high risk for cardiovascular disease, making it particularly useful for patients who cannot tolerate statins but need primary prevention of cardiovascular events 1.

From the FDA Drug Label

12 CLINICAL PHARMACOLOGY

1. 1 Mechanism of Action Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers LDL-C by inhibition of cholesterol synthesis in the liver.
2. 2 Pharmacodynamics Administration of bempedoic acid alone, or in combination with other lipid modifying agents, decreases LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in patients with hyperlipidemia.

The role of bempedoic acid (Esperion's Nexletol) in primary prevention of hyperlipidemia is not explicitly stated in the provided drug label. The label discusses the mechanism of action and pharmacodynamics of bempedoic acid in patients with hyperlipidemia, but it does not provide information on its use in primary prevention.

• Key points:
  • Bempedoic acid lowers LDL-C by inhibiting cholesterol synthesis in the liver.
  • It decreases LDL-C, non-HDL-C, apo B, and TC in patients with hyperlipidemia.
• Clinical decision: Due to the lack of direct information on primary prevention, a conservative clinical decision would be to not recommend bempedoic acid for primary prevention of hyperlipidemia based solely on the provided drug label 2.

From the Research

Role of Bempedoic Acid in Primary Prevention of Hyperlipidemia

• Bempedoic acid is a novel, first-in-class molecule that inhibits cholesterol biosynthesis in the same mechanistic pathway as statins 3.
• It is approved for use in secondary prevention, and in primary prevention, its approval is limited to individuals with heterozygous familial hypercholesterolemia (FH) 4.
• Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia 3.
• The National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone 3.

Mechanism and Efficacy

• Bempedoic acid works by inhibiting the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway, leading to a reduction in LDL-C levels 5.
• Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin 5.
• Bempedoic acid also reduced inflammatory markers like hs-CRP 5.
• The fixed drug combination of bempedoic acid and ezetimibe showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients 5.

Safety and Tolerability

• Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle, resulting in a lower prevalence of musculoskeletal-related adverse events 3.
• Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe 3.
• Overall safety of bempedoic acid seems to be comparable to placebo, except for increased serum uric acid and tendon rupture 6.