When is Zetia (ezetimibe) recommended for lowering Low-Density Lipoprotein (LDL) cholesterol?

When Ezetimibe (Zetia) is Recommended for Lowering LDL Cholesterol

Ezetimibe is recommended as second-line therapy after maximally tolerated statin therapy when LDL-C targets are not achieved, particularly in high-risk and very high-risk patients with atherosclerotic cardiovascular disease (ASCVD). 1

Primary Indications Based on Risk Category

Very High-Risk Patients (Clinical ASCVD)

• Add ezetimibe when patients on maximally tolerated statin therapy have LDL-C ≥70 mg/dL. 1
• The American College of Cardiology gives this a Class IIa recommendation, meaning it is reasonable to add ezetimibe in this scenario. 2
• This applies to patients with established coronary disease, stroke, peripheral arterial disease, or other clinical manifestations of atherosclerosis. 1

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

• For patients aged 20-75 years with LDL-C ≥190 mg/dL who achieve <50% reduction on maximally tolerated statin therapy and/or have LDL-C ≥100 mg/dL, ezetimibe therapy is reasonable. 1
• This includes patients with heterozygous familial hypercholesterolemia (HeFH). 3
• The International Lipid Expert Panel recommends immediate addition of ezetimibe when baseline LDL-C levels are very high, providing an additional 15-25% reduction beyond statin monotherapy. 2

Diabetes with High ASCVD Risk

• For diabetic patients with <50% reduction in LDL-C on maximally tolerated statin therapy (and LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL), ezetimibe may be considered as the initial non-statin agent. 1
• This applies particularly to patients with 10-year ASCVD risk ≥7.5% or other high-risk features. 1

FDA-Approved Indications

The FDA has approved ezetimibe for the following specific uses: 3

• In combination with a statin (or alone when additional LDL-C lowering therapy is not possible) as adjunct to diet for primary hyperlipidemia including HeFH in adults
• In combination with a statin for pediatric patients ≥10 years with HeFH
• In combination with fenofibrate for mixed hyperlipidemia in adults
• In combination with a statin and other LDL-C lowering therapies for homozygous familial hypercholesterolemia (HoFH) in adults and pediatric patients ≥10 years
• As monotherapy for homozygous familial sitosterolemia in adults and pediatric patients ≥9 years

Treatment Algorithm

Step 1: Maximize Statin Therapy First

• Always initiate or optimize statin therapy before adding ezetimibe, unless statins are contraindicated or not tolerated. 1
• The European Society of Cardiology recommends starting with high-intensity statin therapy as the foundation. 2

Step 2: Add Ezetimibe When Targets Not Met

• If LDL-C remains above target on maximally tolerated statin, add ezetimibe 10 mg daily. 2, 1
• Ezetimibe provides an additional 15-25% reduction in LDL-C beyond statin monotherapy. 2, 4, 5, 6
• The IMPROVE-IT trial demonstrated that adding ezetimibe to statin therapy reduces cardiovascular events, with greatest benefit in high-risk patients. 2

Step 3: Consider PCSK9 Inhibitors if Still Not at Goal

• If LDL-C remains ≥70 mg/dL in very high-risk patients despite maximum statin plus ezetimibe, add a PCSK9 inhibitor. 2, 1
• Always try ezetimibe before PCSK9 inhibitors due to cost, convenience, and established safety profile. 1

Ezetimibe as Monotherapy

Ezetimibe can be used alone when additional LDL-C lowering therapy is not possible. 3 This includes:

• Statin-intolerant patients: Ezetimibe should be considered as first-line alternative medication for hyperlipidemia in patients unable to tolerate statins. 7
• Patients requiring modest LDL-C reductions: When 15-20% reduction is sufficient to reach goal. 4, 5, 6
• Patients with contraindications to statins: Though this is less common. 3

Key Advantages Supporting Its Use

• Preferred as initial non-statin therapy due to demonstrated safety, tolerability, convenience, and single-tablet daily dosing. 1
• No significant drug-drug interactions due to minimal effect on CYP450 enzymes. 8
• Adverse event profile similar to placebo when used as monotherapy or in combination with statins. 2, 3, 5, 6
• Does not worsen hypertriglyceridemia unlike bile acid sequestrants. 4
• Can be combined with fenofibrate for mixed hyperlipidemia. 3

Dosing and Administration

• Standard dose: 10 mg orally once daily, with or without food. 3
• Administer ≥2 hours before or ≥4 hours after bile acid sequestrants if using both agents. 3
• Assess LDL-C as early as 4 weeks after initiating therapy. 3

Important Monitoring and Safety Considerations

• Monitor liver enzymes as clinically indicated; consider withdrawal if ALT or AST ≥3× ULN persist. 3
• Watch for myopathy/rhabdomyolysis, especially when combined with statins or fibrates, though this is rare. 3
• When combined with a statin, refer to statin prescribing information for additional contraindications and monitoring requirements. 3

Common Pitfall to Avoid

Do not unnecessarily up-titrate statin doses when adding ezetimibe is more effective and better tolerated. 2 The combination of moderate-intensity statin plus ezetimibe often achieves greater LDL-C reduction with fewer adverse effects than high-intensity statin monotherapy.