When should ezetimibe be prescribed to patients with primary hyperlipidemia, particularly those with a history of statin intolerance or inadequate cholesterol reduction with statin therapy alone?

When to Prescribe Ezetimibe

Ezetimibe should be added to maximally tolerated statin therapy when LDL-C remains ≥70 mg/dL in patients with atherosclerotic cardiovascular disease (ASCVD), or when LDL-C remains ≥100 mg/dL in patients with severe primary hypercholesterolemia (LDL-C ≥190 mg/dL) despite statin therapy. 1

Primary Indications for Ezetimibe

Patients with Clinical ASCVD (Secondary Prevention)

• Add ezetimibe when LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin therapy 1
• This applies to patients with history of acute coronary syndrome, myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease 1
• The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy in patients with recent acute coronary syndrome reduced cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, and nonfatal stroke over 6 years of follow-up 1
• Ezetimibe provides an additional 25% incremental LDL-C reduction when combined with statin therapy 1

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

• Add ezetimibe when patients achieve <50% LDL-C reduction on maximally tolerated statin therapy and/or LDL-C remains ≥100 mg/dL (≥2.6 mmol/L) 1
• This is particularly important for patients with heterozygous familial hypercholesterolemia 1
• The goal is to achieve ≥50% LDL-C reduction from baseline using high-intensity statin or maximal tolerated statin intensity first 1
• When LDL-C remains >100 mg/dL despite maximal statin therapy, ezetimibe addition is reasonable as it is well-tolerated and available as a generic 1

Patients with Diabetes Mellitus

• Consider adding ezetimibe in diabetic patients with 10-year ASCVD risk ≥20% when LDL-C reduction of 50% or more is not achieved with maximally tolerated statin therapy 1
• Start with moderate-intensity statin in all diabetic patients aged 40-75 years regardless of ASCVD risk 1
• Escalate to high-intensity statin in diabetic patients with multiple ASCVD risk factors 1

Primary Prevention in High-Risk Patients

• Add ezetimibe when maximum tolerated statin dose does not achieve non-HDL cholesterol reduction >40% of baseline after 3 months 1
• The European Society of Cardiology recommends adding ezetimibe when LDL goals are not achieved with maximum tolerated statin dose, with goals ranging from 55 mg/dL (1.4 mmol/L) for very high-risk patients to 116 mg/dL (3.0 mmol/L) for low-risk patients 1

Statin Intolerance

• Ezetimibe monotherapy is indicated when additional LDL-C lowering therapy is not possible due to statin intolerance 1, 2
• As monotherapy, ezetimibe reduces LDL-C by approximately 18% 1
• Ezetimibe has a favorable safety profile with adverse effects similar to placebo when used as monotherapy 3, 4, 5
• Common adverse effects include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremities 1, 2

Practical Prescribing Considerations

Dosing and Administration

• Dose: 10 mg orally once daily, with or without food 1, 2
• Administer ezetimibe ≥2 hours before or ≥4 hours after bile acid sequestrants if used in combination 1, 2
• Assess LDL-C as early as 4 weeks after initiating therapy 2

Monitoring Requirements

• Perform liver enzyme testing as clinically indicated, particularly when combined with statin therapy 1, 2
• Consider withdrawal if ALT or AST elevations ≥3× upper limit of normal persist 2
• Monitor for myopathy symptoms, especially when combined with statins or fibrates 1, 2

Contraindications and Precautions

• Contraindicated in patients with hypersensitivity to ezetimibe 1, 2
• Not recommended in patients with moderate to severe hepatic impairment 1
• Avoid use during pregnancy and lactation due to lack of safety data 1
• Be aware of drug interactions with cyclosporine, fibrates, and bile acid sequestrants 1

Common Clinical Pitfalls

• Do not delay adding ezetimibe in ASCVD patients with persistently elevated LDL-C ≥70 mg/dL on statin therapy – the IMPROVE-IT trial demonstrated clear cardiovascular benefit 1
• Do not overlook ezetimibe as first-line add-on therapy before considering more expensive PCSK9 inhibitors – ezetimibe is well-tolerated, effective, and available as a generic 1
• Do not assume all patients will tolerate maximum statin doses – ezetimibe provides an effective alternative for achieving LDL-C goals in statin-intolerant patients 2, 6
• Do not forget to assess response at 4 weeks – early reassessment allows timely escalation if goals are not met 2