Bempedoic acid is a small‑molecule lipid‑lowering agent that inhibits ATP‑citrate lyase, an enzyme upstream of HMG‑CoA reductase in the cholesterol biosynthesis pathway. It is used primarily to reduce low‑density lipoprotein cholesterol (LDL‑C) in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional LDL‑C lowering beyond statin therapy.
Chemical Information
| Property | Data |
|---|---|
| IUPAC name | 8‑[(4‑hydroxy‑3‑pyridyl)methyl]‑9‑oxo‑7‑oxo‑2‑propyl‑2,8‑dihydro‑3H‑thieno[2,3‑d]pyrimidine‑6‑carboxylic acid |
| CAS Registry Number | 1119923‑99‑5 |
| Molecular formula | C₂₁H₂₀O₅ |
| Molecular weight | 344.37 g mol⁻¹ |
| Structural class | Pro‑drug; activated in the liver to its CoA thioester form (bempedoic acid‑CoA) |
Mechanism of Action
- Pro‑drug activation – Bempedoic acid is taken up by the liver and converted by very‑long‑chain acyl‑CoA synthetase‑1 (ACSVL1) to the pharmacologically active bempedoic acid‑CoA.
- Enzyme inhibition – Bempedoic acid‑CoA competitively inhibits ATP‑citrate lyase (ACL), decreasing conversion of citrate to acetyl‑CoA, a precursor for cholesterol and fatty‑acid synthesis.
- LDL‑C reduction – Reduced hepatic cholesterol synthesis up‑regulates LDL receptors, enhancing plasma LDL‑C clearance.
Because the activating enzyme is highly expressed in liver but minimally in skeletal muscle, bempedoic acid does not appear to cause the myopathic adverse effects associated with statins.
Clinical Use
| Indication | Typical Dose | Route of Administration |
|---|---|---|
| Adjunct to maximally tolerated statin therapy, or as monotherapy when statins are contraindicated, for LDL‑C lowering in adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) | 180 mg tablet taken orally once daily, with or without food | Oral |
Brand name: Nexletol (U.S. FDA) and Nexdia (Europe).
The drug received United States Food and Drug Administration (FDA) approval in February 2020 and European Medicines Agency (EMA) approval in July 2020.
Efficacy
- In phase III trials (CLEAR Harmony, CLEAR Wisdom, and CLEAR Tranquility), bempedoic acid added to statins reduced LDL‑C by ≈18 % versus placebo (average reduction 15–20 %).
- In patients intolerant to statins, monotherapy produced LDL‑C reductions of ≈21 %.
- Secondary analysis indicated modest reductions in non‑HDL‑C and apoB levels.
- Cardiovascular outcomes data are limited; the ongoing CLEAR Outcomes trial (expected results 2028) aims to assess major adverse cardiovascular events (MACE) with long‑term therapy.
Safety Profile
| Common adverse events (≥5 % incidence) | Notable laboratory abnormalities |
|---|---|
| Upper respiratory tract infection, nasopharyngitis, arthralgia, hyperuricemia, constipation | Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) |
| Gout – incidence higher in patients with baseline hyperuricemia | Increases in serum creatinine reported rarely |
- Contraindications: Known hypersensitivity to bempedoic acid or any component of the formulation.
- Precautions: Monitor liver enzymes; assess serum uric acid in patients with gout history. Use with caution in severe hepatic impairment (Child‑Pugh C) due to lack of dedicated studies.
Drug‑drug interactions are limited; however, concomitant use with statins may modestly increase statin plasma concentrations, warranting review of statin dosing to avoid myopathy.
Pharmacokinetics
- Absorption: Peak plasma concentrations achieved within 3–4 hours; food has minimal effect on exposure.
- Distribution: Volume of distribution ≈ 30 L; plasma protein binding ≈ 99 %.
- Metabolism: Minimal hepatic metabolism; primary route is conversion to the active CoA thioester.
- Elimination: Approximately 70 % excreted unchanged in the urine; terminal half‑life ≈ 21 hours, supporting once‑daily dosing.
Regulatory Status
| Region | Approval Status | Notable Regulatory Notes |
|---|---|---|
| United States | FDA‑approved (Nexletol) for LDL‑C reduction adjunct to statins or as monotherapy | Approved under the Prescription Drug User Fee Act (PDUFA) pathway |
| European Union | EMA‑approved (Nexdia) for the same indications | Conditional marketing authorization granted, subject to post‑marketing studies |
| Canada | Health Canada approved (Bempedoic acid) in 2020 | Same dosing and indication as U.S. |
| Japan | Not yet approved (as of 2026) | Ongoing clinical development reported |
Research and Development
- Combination therapy: Fixed‑dose combination tablets of bempedoic acid with ezetimibe (Nexlizet) have been approved, providing an additive LDL‑C‑lowering effect (~35 % reduction versus placebo).
- Cardiovascular outcomes: The CLEAR Outcomes trial (NCT03837184) is a prospective, randomized, placebo‑controlled study enrolling ≈ 14 000 participants to evaluate MACE over a median follow‑up of 3–5 years. Results are pending.
Summary
Bempedoic acid is an orally administered, liver‑targeted ACL inhibitor approved for adjunctive LDL‑C reduction in adults with high cardiovascular risk, especially when statin therapy alone is insufficient or not tolerated. Its pharmacologic profile offers LDL‑C lowering comparable to modest‑dose statins while avoiding muscle‑related side effects, though it can raise serum uric acid and liver enzymes. Ongoing outcome trials aim to define its role in reducing cardiovascular events.
