What is the proper use of Nexlezet?

Nexlezet: Proper Use for Cholesterol Management

Nexlezet is a fixed-dose combination of bempedoic acid and ezetimibe used to reduce cardiovascular risk in patients requiring additional LDL-C lowering beyond statin therapy, particularly valuable in statin-intolerant patients. 1

Indications and Patient Selection

Nexlezet should be considered for patients who fail to achieve LDL-C goals (<1.4 mmol/L or 55 mg/dL with ≥50% reduction) on maximally tolerated statin therapy. 2

Primary Target Populations:

• Statin-intolerant patients at high cardiovascular risk or with established cardiovascular disease 1
• Patients requiring additional LDL-C reduction after maximally tolerated statin therapy 2
• Patients with documented statin intolerance who have failed first-line non-statin therapies (ezetimibe alone) 3, 4

Treatment Algorithm:

1. First-line approach: Maximize statin therapy to the highest tolerated dose 2
2. Second-line: Add ezetimibe 10 mg daily as the initial non-statin agent 3, 4
3. Third-line: If LDL-C goals not achieved, add bempedoic acid or use the fixed-dose combination (Nexlezet) 2, 3

Dosing and Administration

The fixed-dose combination provides bempedoic acid 180 mg plus ezetimibe 10 mg once daily. 1

Key Dosing Considerations:

• Take once daily with or without food 1
• No dose adjustment needed based on patient characteristics 4
• When used with bile acid sequestrants: Take Nexlezet ≥2 hours before or ≥4 hours after the bile acid sequestrant 4

Mechanism and Expected Efficacy

Bempedoic acid inhibits ATP-citrate lyase in the cholesterol biosynthesis pathway, while ezetimibe blocks intestinal cholesterol absorption via NPC1L1 protein inhibition. 5, 4

LDL-C Reduction Expectations:

• Combination therapy (bempedoic acid + ezetimibe + statin): Achieves approximately 38% LDL-C reduction 3
• Ezetimibe component alone: Provides 17-18% additional LDL-C reduction when added to statin 3
• Bempedoic acid component: Contributes additional LDL-C lowering through hepatic cholesterol synthesis inhibition 5, 6

Cardiovascular Outcomes Evidence

The CLEAR Outcomes trial demonstrated that bempedoic acid significantly reduced major adverse cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization) in statin-intolerant patients. 1

Clinical Benefits:

• Proven cardiovascular risk reduction in statin-intolerant patients 1
• Low incidence of musculoskeletal adverse events compared to statins 1
• Favorable safety profile with no muscle activation of the prodrug 5, 6

Safety Profile and Monitoring

Bempedoic acid is activated only in liver and kidney cells, not in muscle or adipose tissue, resulting in minimal myotoxic potential. 5, 6

Common Adverse Effects:

• Ezetimibe component: Upper respiratory tract infection, muscle spasms, back pain, abdominal pain 3
• Bempedoic acid: Generally well tolerated with low muscle-related adverse events 1

Important Monitoring:

• Hepatic transaminases: Monitor based on statin monitoring guidelines when used with statins 4
• Avoid in pregnancy: Discontinue if pregnancy is recognized unless benefits outweigh risks 3
• Serum potassium: Not specifically required for this combination, but relevant if other potassium-affecting medications are used 4

Drug Interactions and Contraindications

Avoid concomitant use with simvastatin >20 mg daily or pravastatin >40 mg daily. 3

Key Interactions to Monitor:

• Cyclosporine and fibrates: Require monitoring when used with ezetimibe 3, 4
• Bile acid sequestrants: Timing adjustment required (see dosing section) 4

Clinical Positioning

Nexlezet is best positioned as combination therapy for patients who need substantial additional LDL-C lowering beyond statin therapy, particularly in those with statin intolerance. 6

Advantages Over Alternatives:

• Oral administration with once-daily dosing (vs. injectable PCSK9 inhibitors) 1
• Proven cardiovascular outcomes in statin-intolerant population 1
• Minimal muscle-related side effects due to tissue-specific activation 5, 6
• Combination convenience in a single tablet 3

Common Pitfalls to Avoid

• Do not use as first-line therapy: Always maximize statin therapy and add ezetimibe first before considering bempedoic acid 2, 3
• Do not expect statin-level efficacy: The combination achieves moderate LDL-C reductions; for more aggressive lowering, PCSK9 inhibitors may be needed 6
• Do not use during pregnancy: Safety data in humans is lacking 3
• Monitor for hepatotoxicity: Particularly when combined with statins 4