What is the mechanism of action of bempedoic acid in a patient with cardiovascular disease taking pravastatin and ezetimibe?

Mechanism of Action of Bempedoic Acid

Bempedoic acid inhibits ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway, resulting in decreased hepatic cholesterol synthesis and upregulation of LDL receptors for enhanced LDL-C clearance. 1, 2

Primary Mechanism

• Bempedoic acid blocks ATP-citrate lyase (ACL), a cytoplasmic enzyme that generates acetyl coenzyme A for de novo synthesis of fatty acids and cholesterol. 1

• ACL sits two steps upstream from HMG-CoA reductase (the target of statins) in the cholesterol biosynthesis pathway, providing a complementary mechanism when combined with statins like pravastatin. 2, 3

• Inhibition of ACL decreases hepatic cholesterol synthesis, which triggers upregulation of LDL receptors on liver cells, thereby increasing LDL-C clearance from the bloodstream. 1, 2

Prodrug Activation: The Muscle-Sparing Advantage

• Bempedoic acid is administered as a prodrug that requires activation by very-long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme expressed primarily in the liver but absent in skeletal muscle cells. 1, 2

• This hepatic-specific activation explains why bempedoic acid does not cause muscle-related adverse effects, unlike statins—the drug simply cannot be activated in muscle tissue. 1, 3

• The active metabolite, ESP15228, contributes minimally to overall clinical activity based on systemic exposure and relative potency. 2

Complementary Action with Pravastatin and Ezetimibe

• When combined with pravastatin (a statin targeting HMG-CoA reductase), bempedoic acid provides additive LDL-C lowering by blocking an upstream step in the same cholesterol synthesis pathway. 1

• When combined with ezetimibe (which blocks intestinal cholesterol absorption via NPC1L1), bempedoic acid addresses a completely different mechanism—hepatic cholesterol synthesis—resulting in synergistic LDL-C reduction of approximately 38%. 1

• This triple combination (statin + ezetimibe + bempedoic acid) targets three distinct pathways: hepatic cholesterol synthesis at two points (ACL and HMG-CoA reductase) plus intestinal absorption. 1

Important Pharmacokinetic Considerations

• Bempedoic acid reaches steady-state after 7 days of once-daily dosing, with a half-life of 21 hours, supporting once-daily administration. 2

• The drug undergoes primarily hepatic metabolism via acyl glucuronide formation, with less than 2% renal clearance of unchanged drug. 2

• Plasma protein binding exceeds 99%, and the drug does not partition into blood cells. 2

Critical Drug Interaction with Pravastatin

• Avoid combining bempedoic acid with pravastatin doses exceeding 40 mg daily due to increased pravastatin exposure risk. 4

• If your patient is on pravastatin >40 mg, reduce the pravastatin dose to ≤40 mg before adding bempedoic acid. 4