When would you prescribe Zetia (ezetimibe) to a patient?

When to Prescribe Zetia (Ezetimibe)

Prescribe ezetimibe primarily as add-on therapy to statins when patients fail to reach LDL-C targets on maximally tolerated statin therapy, particularly in high-risk and very high-risk cardiovascular disease patients. 1

Primary Indications for Ezetimibe

Secondary Prevention (Established ASCVD)

For patients with clinical atherosclerotic cardiovascular disease (ASCVD) on maximally tolerated statin therapy:

• Add ezetimibe when LDL-C remains ≥70 mg/dL in very high-risk patients (those with multiple major ASCVD events or one major event plus multiple high-risk conditions) 1
• This is a Class IIa recommendation (reasonable to prescribe) with Level B evidence from the 2018 AHA/ACC guidelines 1
• The 2022 BMJ guideline recommends ezetimibe as the preferred first add-on therapy before considering PCSK9 inhibitors, due to lower cost 1
• The 2020 European Heart Journal expert consensus strongly supports combination therapy with ezetimibe and statins for reducing LDL-C and cardiovascular events 1

Primary Prevention with Severe Hypercholesterolemia

For patients aged 20-75 years with LDL-C ≥190 mg/dL:

• Add ezetimibe when they achieve less than 50% reduction in LDL-C on maximally tolerated statin therapy and/or have LDL-C ≥100 mg/dL despite statin treatment 1
• This is a Class IIa recommendation with Level B evidence 1

Diabetes with High Cardiovascular Risk

For adults with diabetes and 10-year ASCVD risk ≥20%:

• Consider adding ezetimibe to maximally tolerated statin therapy to reduce LDL-C by 50% or more 1
• This is a Class IIb recommendation (may be reasonable) with Level C evidence 1

For patients with diabetes and established ASCVD considered very high-risk:

• Add ezetimibe if LDL-C ≥70 mg/dL on maximally tolerated statin dose (ezetimibe may be preferred over PCSK9 inhibitors due to lower cost) 1

Statin-Intolerant Patients

Ezetimibe should be the first-line alternative for patients who cannot tolerate statins 2:

• Use as monotherapy in patients who have documented intolerance to at least 2 different statins (including at least one at the lowest approved daily dose) 2
• The 2011 AHA/ACC guidelines classify this as Class IIb (may be considered) when patients do not tolerate or achieve target LDL-C with statins, bile acid sequestrants, and/or niacin 1

Expected Efficacy

Ezetimibe provides consistent LDL-C reduction:

• 15-20% reduction when used as monotherapy 3
• Additional 15-25% reduction when added to statin therapy 4
• The 2020 European expert panel found that ezetimibe added to stable rosuvastatin produced greater improvements in lipid profile with better LDL-C goal achievement compared to up-titration of rosuvastatin alone 1

Practical Prescribing Considerations

Dosing and administration:

• Standard dose is 10 mg once daily 5
• Can be taken with or without food 5
• When used with bile acid sequestrants, administer ezetimibe at least 2 hours before or 4 hours after the bile acid sequestrant 5

Safety profile:

• Adverse event profile similar to placebo when used as monotherapy or with statins 5, 3
• No clinically significant worsening of hypertriglyceridemia (unlike other GI-acting lipid medications) 3
• Monitor for cholelithiasis when combining with fenofibrate (both increase cholesterol excretion into bile) 5
• Monitor cyclosporine concentrations if used concomitantly, as both drug levels increase 5

Contraindications and precautions:

• Not recommended in moderate to severe hepatic impairment (Child-Pugh B or C) 5
• Co-administration with fibrates other than fenofibrate is not recommended 5
• When used with statins, refer to statin prescribing information for additional contraindications 5

Common Clinical Pitfall

The 2024 International Lipid Expert Panel emphasizes initiating combination therapy early (during hospitalization or first visit) in highest-risk patients, rather than sequential stepwise intensification 1. This approach increases the number of patients reaching LDL-C goals, reduces discontinuation risk, and minimizes side effects compared to up-titrating statin doses alone 1.