What is the role of Nexletol (bempedoic acid) in managing low-density lipoprotein (LDL) cholesterol levels?

Role of Nexletol (Bempedoic Acid) in Managing LDL Cholesterol Levels

Bempedoic acid (Nexletol) is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional LDL-C lowering, providing approximately 15-25% additional LDL-C reduction. 1

Mechanism of Action and Unique Properties

• Inhibits ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway
• Requires activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), which is primarily expressed in the liver but not in skeletal muscle 2, 3
• This liver-selective activation provides a potential advantage for patients with statin-associated muscle symptoms 2

Clinical Efficacy

• Monotherapy: Reduces LDL-C by approximately 15-25% 2, 4
• Added to statin therapy: Provides additional 15-18% reduction in LDL-C 1, 2
• Combination with ezetimibe: Can provide up to 38% additional LDL-C reduction 1, 2
• Also reduces non-HDL cholesterol, apolipoprotein B, total cholesterol, and high-sensitivity C-reactive protein 3, 5

Place in Therapy

According to current guidelines, bempedoic acid should be considered in the following scenarios:

1. For patients with established ASCVD who have not achieved ≥50% LDL-C reduction and LDL-C <70 mg/dL on maximally tolerated statin therapy 1

2. After consideration of ezetimibe or PCSK9 inhibitors in the treatment algorithm:

   • Ezetimibe is typically considered first
   • PCSK9 inhibitors (evolocumab, alirocumab) are often considered next due to their proven cardiovascular outcomes benefit
   • Bempedoic acid may be considered when these options are insufficient or not tolerated 1

3. For statin-intolerant patients who cannot achieve LDL-C goals with other non-statin therapies 1, 2, 6

Advantages and Limitations

Advantages:

• Once-daily oral administration 3, 5
• Lower risk of muscle-related adverse effects compared to statins due to liver-selective activation 2, 6
• Available as monotherapy or in fixed-dose combination with ezetimibe 1, 2

Limitations:

• Less potent LDL-C reduction compared to PCSK9 inhibitors 1
• No completed cardiovascular outcomes trials yet (CLEAR Outcomes trial results pending) 1, 7
• Higher cost than generic statins and ezetimibe 1

Safety Considerations

• Hyperuricemia and gout: Monitor uric acid levels in patients with history of gout 1
• Tendon rupture: Use with caution in patients with history of tendon disorders; discontinue immediately if tendon rupture occurs 1
• Other adverse effects: Upper respiratory tract infection, muscle spasms, back pain, abdominal pain, and elevated liver enzymes 1
• No dosage adjustment needed for mild-to-moderate renal or hepatic impairment 3

Clinical Decision Algorithm

1. First-line therapy: Maximally tolerated high-intensity statin therapy
2. If LDL-C goal not achieved: Add ezetimibe
3. If further LDL-C lowering needed:
   • For very high-risk ASCVD patients: Consider PCSK9 inhibitor (evolocumab or alirocumab)
   • For statin-intolerant patients: Consider bempedoic acid (with or without ezetimibe)
   • For patients requiring moderate additional LDL-C lowering: Consider bempedoic acid

Practical Considerations

• Bempedoic acid is particularly valuable for:
  • Patients with documented statin intolerance
  • Patients who prefer oral therapy over injectable PCSK9 inhibitors
  • Patients who need moderate additional LDL-C lowering beyond statin and ezetimibe
• Prior authorization may be required by insurance
• Patient assistance programs are available for eligible patients

In summary, bempedoic acid represents an important addition to the lipid-lowering armamentarium, particularly for patients who cannot tolerate statins or who require additional LDL-C lowering beyond what can be achieved with statins and ezetimibe.