What is the recommended dosing regimen of bempedoic acid 180 mg and ezetimibe 10 mg for hyperlipidemia in patients who need additional LDL‑cholesterol lowering beyond maximally tolerated statin therapy or are statin‑intolerant?

Bempedoic Acid and Ezetimibe Dosing for Hyperlipidemia

The recommended dosing regimen is one tablet of the fixed-dose combination (bempedoic acid 180 mg / ezetimibe 10 mg) taken orally once daily, with or without food, as an adjunct to diet and maximally tolerated statin therapy. 1

Dosing Administration

• Take one tablet (180 mg bempedoic acid / 10 mg ezetimibe) once daily, with or without food. 1
• When co-administered with a bile-acid sequestrant, take the combination ≥2 hours before or ≥4 hours after the sequestrant to avoid binding interactions. 1
• No dose adjustments are required based on LDL-C response; the dose remains fixed at 180 mg/10 mg daily. 2

Clinical Decision Algorithm

If Patient Is NOT Currently on Ezetimibe:

• Prescribe the fixed-dose combination (Nexlizet) as a single tablet once daily rather than bempedoic acid alone (Nexletol), because the combination yields approximately 38% LDL-C reduction versus 15-25% with bempedoic acid monotherapy. 3
• This approach consolidates two agents into one tablet, improving adherence and avoiding the loss of an additional 15-20% LDL-C reduction that ezetimibe provides. 3

If Patient Is Already on Ezetimibe 10 mg Daily:

• Add bempedoic acid 180 mg (Nexletol) to the existing ezetimibe regimen rather than switching to the fixed-dose combination. 3
• This achieves the same therapeutic effect while maintaining the patient's current ezetimibe prescription. 3

Expected LDL-C Lowering Efficacy

• The fixed-dose combination (180 mg/10 mg) produces approximately 38% placebo-corrected LDL-C reduction when added to maximally tolerated statin therapy. 1, 4
• In statin-intolerant patients, the combination achieves a 35-38% total LDL-C reduction. 3, 5
• Bempedoic acid monotherapy lowers LDL-C by approximately 17-18% when added to statins, and by approximately 24.5% as monotherapy in truly statin-intolerant patients. 1
• Ezetimibe alone reduces LDL-C by approximately 15-20%. 3

Mandatory Baseline and Monitoring Requirements

Uric Acid Monitoring:

• Measure serum uric acid before initiating therapy and monitor periodically for hyperuricemia symptoms during treatment. 1
• Bempedoic acid raises serum uric acid by a mean of approximately 0.8 mg/dL; gout occurred in 1.5% of treated patients versus 0.4% with placebo. 1
• Instruct patients to report hyperuricemia symptoms (joint pain, swelling) promptly; initiate urate-lowering therapy as needed. 1

Tendon Monitoring:

• Tendon rupture occurred in 0.5% of patients receiving the combination versus 0% with placebo; discontinue immediately if rupture occurs. 1
• For joint pain, swelling, or inflammation suggestive of tendinitis, strongly consider discontinuing therapy. 1
• Patients with a prior history of tendon disorders or rupture should be offered alternative lipid-lowering strategies (PCSK9 inhibitors). 1

Liver Enzyme Monitoring:

• Monitor hepatic transaminases periodically, especially when ezetimibe is combined with statins, because persistent elevations have been reported. 1

Muscle Symptom Monitoring:

• Bempedoic acid is a prodrug activated in the liver (via very-long-chain acyl-CoA synthetase-1) and not in skeletal muscle, theoretically reducing muscle-related adverse effects. 1
• Muscle spasms have been reported as an adverse effect; monitor and educate patients accordingly. 1

Critical Drug-Drug Interactions

• Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily when using bempedoic acid or the fixed-dose combination. 1
• Do not co-administer cyclosporine or fibrates with the ezetimibe + bempedoic acid combination. 1

Contraindications

• The only absolute contraindication is documented hypersensitivity to ezetimibe. 1
• Bempedoic acid has no listed contraindications in the FDA labeling. 1
• Do not use ezetimibe in patients with moderate-to-severe hepatic impairment. 1

Common Adverse Effects (Incidence ≥1%)

• Upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal discomfort, bronchitis, pain in extremities, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, and fatigue. 1
• Atrial fibrillation occurred in 1.7% of treated patients versus 1.1% with placebo. 1
• Benign prostatic hyperplasia: 1.3% versus 0.1% (treatment versus placebo). 1
• Elevated creatine kinase levels: 1.0% versus 0.6% (treatment versus placebo). 1

Pregnancy and Lactation

• Discontinue the combination when pregnancy is recognized unless the anticipated maternal benefit outweighs potential fetal risk. 1
• No human data are available regarding major birth defects, miscarriage, or other adverse maternal/fetal outcomes. 1

Cardiovascular Outcomes Evidence

• The CLEAR Outcomes trial (14,014 statin-intolerant patients) demonstrated a 13% reduction in major adverse cardiovascular events (cardiovascular death, non-fatal MI, non-fatal stroke, or coronary revascularization) with bempedoic acid. 1, 2
• In the primary-prevention subgroup, bempedoic acid achieved a 32% relative risk reduction with a number-needed-to-treat of 43. 2
• Non-fatal myocardial infarction was reduced by 23% and coronary revascularization by 19%. 2

Cost and Access Considerations

• Both the fixed-dose combination and bempedoic acid alone are branded medications that typically require prior authorization. 1
• Patient-assistance programs and copay-card options are available to improve access. 1
• The fixed-dose combination reduces pill burden compared with taking the two agents separately. 1

Critical Pitfalls to Avoid

• Do not prescribe bempedoic acid alone (Nexletol) when the patient is not already on ezetimibe, as this forfeits an additional 15-20% LDL-C reduction; start with the fixed-dose combination (Nexlizet) instead. 3
• Do not overlook baseline serum uric-acid measurement before initiating therapy. 1
• Do not exceed simvastatin 20 mg or pravastatin 40 mg daily when the combination is used, to avoid drug-interaction-related toxicity. 1
• Do not ignore tendon symptoms; immediate discontinuation is required for rupture, and strong consideration for discontinuation with tendinitis. 1