How does bempedoic acid work?

Mechanism of Action of Bempedoic Acid

Bempedoic acid works by inhibiting 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 that improve LDL clearance from the bloodstream. 1

Unique Pharmacological Properties

Bempedoic acid has several distinctive characteristics that differentiate it from other lipid-lowering medications:

• Prodrug activation: Bempedoic acid is administered as a prodrug that requires activation by very-long-chain acyl-CoA synthetase-1 (ACSVL1) to form ETC-1002-CoA 2
• Liver-selective action: The activating enzyme ACSVL1 is expressed primarily in the liver but not in skeletal muscle 2
• Reduced muscle-related side effects: This liver-selective activation provides a potential advantage for patients with statin-associated muscle symptoms 1

Mechanism in Detail

1. Inhibition of cholesterol synthesis pathway:

   • Bempedoic acid inhibits ATP-citrate lyase, which is upstream of HMG-CoA reductase (the target of statins) 1
   • This inhibition reduces acetyl-CoA availability for cholesterol synthesis 1

2. Metabolic activation:

   • Bempedoic acid requires conversion to its CoA thioester form (ETC-1002-CoA) to become active 2
   • This conversion occurs via ACSVL1, which is primarily expressed in liver cells 1

3. Downstream effects:

   • Reduced hepatic cholesterol synthesis leads to upregulation of LDL receptors 1
   • Increased LDL receptor expression enhances clearance of LDL from the bloodstream 1

Clinical Effects on Lipid Parameters

Bempedoic acid demonstrates several beneficial effects on lipid parameters:

• LDL-C reduction: Monotherapy reduces LDL-C by approximately 15-25% 1
• Additional LDL-C lowering: When added to statin therapy, provides an additional 15-18% reduction in LDL-C 1
• Combination therapy: When combined with ezetimibe, can provide up to 38% additional LDL-C reduction 1
• Anti-inflammatory effects: Reduces high-sensitivity C-reactive protein (hs-CRP) by approximately 20% 3

Clinical Applications

Bempedoic acid is particularly valuable in specific patient populations:

• Statin-intolerant patients: Due to its liver-selective activation, it avoids the muscle-related side effects common with statins 1
• Patients needing additional LDL-C lowering: Used as adjunctive therapy when statins alone are insufficient 4
• Combination therapy: Available in fixed-dose combination with ezetimibe for enhanced LDL-C reduction 1

Important Considerations

• FDA approval: Indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) requiring additional LDL-C lowering 1
• Safety monitoring: Patients should be monitored for potential side effects including gout (due to increased uric acid), tendon rupture, and elevated creatinine levels 5
• Cardiovascular outcomes: The CLEAR Outcomes trial has demonstrated cardiovascular risk reduction in high-risk patients who were statin-intolerant 5

Bempedoic acid represents an important addition to the lipid-lowering armamentarium, particularly for patients who cannot tolerate statins or who require additional LDL-C reduction beyond what can be achieved with statins alone.