What is the recommended dosage and use of Ezetimibe (ezetimibe) for treating primary hypercholesterolemia?

Ezetimibe for Primary Hypercholesterolemia

The recommended dosage of ezetimibe is 10 mg orally once daily, with or without food, either as monotherapy when statins are not tolerated or in combination with a statin to achieve additional LDL-C lowering in patients with primary hypercholesterolemia. 1

FDA-Approved Indications and Dosing

Ezetimibe 10 mg daily is FDA-approved for primary hypercholesterolemia in the following scenarios: 1

• In combination with a statin as adjunct to diet to reduce elevated LDL-C in adults with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH) 1
• As monotherapy when additional LDL-C lowering therapy is not possible (e.g., statin intolerance or contraindication) 1
• In combination with fenofibrate for mixed hyperlipidemia 1

Administration details: 1

• Take 10 mg once daily, with or without food 1
• If a dose is missed, take as soon as possible but do not double the next dose 1
• When used with bile acid sequestrants, administer ezetimibe at least 2 hours before or 4 hours after the sequestrant 1
• Assess LDL-C as early as 4 weeks after initiation 1

Guideline-Based Treatment Algorithm

For Severe Primary Hypercholesterolemia (LDL-C ≥190 mg/dL)

Step 1: Initiate maximally tolerated statin therapy with goal of ≥50% LDL-C reduction 2

Step 2: Add ezetimibe 10 mg daily if: 2

• LDL-C reduction is <50% on maximally tolerated statin, AND/OR
• LDL-C remains ≥100 mg/dL despite maximally tolerated statin 2

This recommendation is Class IIa (reasonable to use) with Level B evidence 2

Step 3: Consider bile acid sequestrant if: 2

• LDL-C reduction remains <50% on maximally tolerated statin plus ezetimibe, AND
• Fasting triglycerides ≤300 mg/dL 2

Step 4: Consider PCSK9 inhibitor if: 2

• For heterozygous FH patients age 30-75 years with LDL-C ≥100 mg/dL on maximally tolerated statin plus ezetimibe 2
• For patients with baseline LDL-C ≥220 mg/dL and on-treatment LDL-C ≥130 mg/dL on maximally tolerated statin plus ezetimibe 2

For Diabetes Mellitus

Ezetimibe should be added to statin therapy in diabetic patients with: 2

• Multiple ASCVD risk factors requiring high-intensity statin therapy 2
• Persistent LDL-C elevation despite maximally tolerated statin 2

For Established ASCVD (Secondary Prevention)

Add ezetimibe 10 mg daily to maximally tolerated statin when: 3, 4

• LDL-C remains ≥70 mg/dL or non-HDL-C ≥100 mg/dL 3
• Additional >25% LDL-C reduction is needed 3

Mechanism and Expected Efficacy

Ezetimibe inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein at the intestinal brush border, reducing cholesterol absorption by approximately 54%. 3, 5

Expected LDL-C reductions: 2, 3, 1

• Monotherapy: 18-20% reduction 2, 3, 1, 5
• Added to ongoing statin: Additional 25% incremental reduction 2, 3, 1
• Initiated concurrently with statin: Combined reductions of 46-61% depending on statin dose 1, 6

Additional lipid effects: 1, 5

• Increases HDL-C by 2.5-5% 5
• Reduces total cholesterol, apolipoprotein B, and non-HDL-C 1
• Does not adversely affect triglycerides 5

Cardiovascular Outcomes Evidence

Two major trials demonstrate cardiovascular benefit: 2, 3

IMPROVE-IT trial: Addition of ezetimibe to moderate-intensity statin (simvastatin 40 mg) in post-acute coronary syndrome patients reduced the composite endpoint of CV death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke over median 6-year follow-up 2, 3, 4

SHARP trial: Simvastatin plus ezetimibe reduced major ASCVD events compared to placebo in chronic kidney disease patients over median 4.9-year follow-up 2, 3

Safety Profile and Monitoring

Common adverse effects (similar to placebo in monotherapy): 2, 1

• Nasopharyngitis, upper respiratory tract infection 2
• Diarrhea, arthralgia 2
• When combined with statins: myalgia, arthralgia 2

Important safety considerations: 3, 1

• Hepatic monitoring: Perform liver enzyme testing as clinically indicated; consider withdrawal if ALT or AST ≥3× ULN persist 3, 1
• Myopathy/rhabdomyolysis risk: Discontinue if myopathy suspected, particularly when combined with statins or fibrates 3, 1
• Contraindicated: In patients with hypersensitivity to ezetimibe (anaphylaxis, angioedema, rash, urticaria reported) 1

Drug interactions requiring attention: 2, 3

• Cyclosporine: Monitor cyclosporine concentrations as ezetimibe increases exposure of both drugs 3
• Bile acid sequestrants: Separate administration by ≥2 hours before or ≥4 hours after sequestrant 3, 1
• Fibrates: Use with caution; increased myopathy risk 2

Timing of Administration

Ezetimibe can be administered at any time of day with equivalent efficacy. Morning administration is noninferior to evening administration with respect to LDL-C lowering ability 7. This flexibility distinguishes ezetimibe from statins, which are traditionally dosed in the evening 7.

Common Pitfalls to Avoid

Do not use ezetimibe as first-line monotherapy when statins are tolerated—statins remain the foundation of lipid-lowering therapy with proven cardiovascular outcomes 2

Do not add niacin instead of ezetimibe to statin therapy—the AIM-HIGH trial showed niacin added to simvastatin plus ezetimibe improved lipid profiles but did not reduce cardiovascular events and increased adverse effects 2, 4

Do not assume ezetimibe is ineffective without adequate statin optimization first—maximize statin intensity before adding ezetimibe 2

Do not overlook medication adherence before intensifying therapy—non-adherence is a common reason for failure to achieve lipid goals 4

Verify patient is not taking bile acid sequestrants at the same time as ezetimibe, as this reduces ezetimibe absorption 3, 1