Can ezetimibe 10 mg daily be safely combined with bempedoic acid 180 mg daily in an adult with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who is statin‑intolerant, and what monitoring (liver enzymes, renal function, uric acid, muscle symptoms) and contraindications should be considered?

Combination of Ezetimibe and Bempedoic Acid in Statin-Intolerant Patients

Direct Recommendation

Yes, ezetimibe 10 mg daily can be safely combined with bempedoic acid 180 mg daily in statin-intolerant adults with ASCVD or heterozygous familial hypercholesterolemia—this combination is FDA-approved specifically for this indication and achieves a robust 38% additional LDL-C reduction when added to maximally tolerated statin therapy (or as monotherapy in truly statin-intolerant patients). 1

FDA-Approved Indication and Dosing

• The fixed-dose combination (180 mg bempedoic acid/10 mg ezetimibe) is FDA-approved for adults with ASCVD or HeFH who require additional LDL-C lowering as an adjunct to diet and maximally tolerated statin therapy. 1

• Dosing is straightforward: one tablet orally once daily, with or without food. 1

• If bile acid sequestrants are used concurrently, administer the combination either 2 hours before or 4 hours after the bile acid sequestrant. 1

Efficacy Profile

• When combined with statin therapy, bempedoic acid plus ezetimibe produces a placebo-corrected incremental LDL-C reduction of 38%—substantially greater than either agent alone. 1

• Bempedoic acid monotherapy reduces LDL-C by approximately 17-18% when added to statins, or 24.5% as monotherapy in statin-intolerant patients. 1

• Ezetimibe alone typically reduces LDL-C by 15-20% when added to background therapy. 2

Contraindications

The only absolute contraindication is a history of 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. 3

Critical Monitoring Requirements

Uric Acid Monitoring

• Assess serum uric acid before initiating therapy and monitor for signs/symptoms of hyperuricemia during treatment. 1

• Bempedoic acid may increase serum uric acid (mean increase 0.8 mg/dL), with gout occurring in 1.5% vs. 0.4% with placebo in clinical trials. 1, 4

• Advise patients to contact their clinician if symptoms of hyperuricemia occur, and initiate urate-lowering drugs as appropriate. 1

Tendon-Related Monitoring

• Discontinue immediately if tendon rupture occurs (0.5% vs. 0% with placebo). 1

• Consider discontinuing if the patient experiences joint pain, swelling, or inflammation. 1

• Consider alternative therapy in patients with a history of tendon disorders or prior tendon rupture. 1

• Advise patients to rest at the first sign of tendinitis or tendon rupture and contact their provider immediately. 1

Liver Enzyme Monitoring

• Monitor for elevated liver enzymes, particularly when ezetimibe is combined with statins—persistent elevations in hepatic transaminases may occur. 3

• Elevated liver enzymes are listed as an adverse effect of the combination (anemia and elevated liver enzymes occur in both agents). 1

Muscle Symptom Monitoring

• Bempedoic acid is a prodrug activated by very-long-chain acyl-CoA synthetase-1, an enzyme present in liver but not skeletal muscle—this mechanism theoretically reduces muscle-related adverse effects. 1, 4, 5

• Clinical trials show no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. 4

• However, muscle spasms are reported as an adverse effect in clinical trials. 1

• The 2022 BMJ guideline recommends not automatically attributing muscle symptoms to ezetimibe without case-by-case investigation. 3

• Cases of myopathy and rhabdomyolysis have been reported when ezetimibe was used alone or with statins, though rare. 3

Renal Function Considerations

• While not explicitly required in the FDA labeling, clinical prudence suggests monitoring renal function given that both hyperuricemia and tendon complications may have renal implications. 1

Important Drug-Drug Interactions

• Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily when using bempedoic acid or the combination product. 1

• Avoid cyclosporine and fibrates when using the ezetimibe/bempedoic acid combination. 1

Common Adverse Effects

The most frequently reported adverse effects include: 1

• Upper respiratory tract infection
• Muscle spasms
• Hyperuricemia
• Back pain
• Abdominal pain or discomfort
• Bronchitis
• Pain in extremities
• Anemia
• Elevated liver enzymes
• Diarrhea, arthralgia, sinusitis, fatigue (with combination)

Additional Safety Signals from Clinical Trials

Small increases have been observed in: 1

• Atrial fibrillation (1.7% vs. 1.1%)
• Benign prostatic hyperplasia (1.3% vs. 0.1%)
• Elevation of creatine kinase levels (1.0% vs. 0.6%)

Pregnancy and Lactation

• Discontinue when pregnancy is recognized unless benefits outweigh potential fetal risks. 1

• No available data exist on use in pregnant women to evaluate drug-associated risks of major birth defects, miscarriage, or adverse maternal/fetal outcomes. 1

Cardiovascular Outcomes Evidence

• At the time of the 2022 ACC guidelines, cardiovascular outcomes data for bempedoic acid were pending from the CLEAR Outcomes trial (expected completion late 2022). 1

• The trial randomized 14,014 statin-intolerant patients with ASCVD or high risk to bempedoic acid vs. placebo, with primary endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization. 1

• Ezetimibe has proven cardiovascular benefit in the IMPROVE-IT trial, which demonstrated reduction in cardiovascular death, nonfatal MI, unstable angina, coronary revascularization, and nonfatal stroke when added to moderate-intensity statin. 2

Practical Implementation Considerations

• Cost and prior authorization requirements may represent barriers to implementation for both bempedoic acid and the fixed-dose combination. 1

• Pill burden is a consideration—the fixed-dose combination reduces this compared to separate agents. 1

• The combination is commercially available only as a branded product. 1

Clinical Pitfalls to Avoid

• Do not overlook baseline uric acid assessment—this is critical for monitoring hyperuricemia risk. 1

• Do not ignore tendon symptoms—immediate discontinuation is required for tendon rupture, and strong consideration for discontinuation with tendinitis. 1

• Do not exceed simvastatin 20 mg or pravastatin 40 mg daily when combining with bempedoic acid due to drug-drug interactions. 1

• Do not assume muscle symptoms are nocebo effects—investigate each case individually per BMJ guidance. 3