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

When Zetia (Ezetimibe) 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 by Clinical Scenario

Patients with Clinical ASCVD (Secondary Prevention)

• Add ezetimibe when LDL-C remains ≥70 mg/dL despite maximally tolerated statin therapy 1
• This represents the most common and evidence-based indication for ezetimibe use 2
• The IMPROVE-IT trial demonstrated cardiovascular event reduction when ezetimibe was added to statin therapy, with greatest benefit in high-risk patients 2

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

• For patients 20-75 years with LDL-C ≥190 mg/dL who achieve <50% reduction in LDL-C on maximally tolerated statin therapy and/or have LDL-C ≥100 mg/dL, ezetimibe therapy is reasonable 1
• The International Lipid Expert Panel recommends immediate addition of ezetimibe when baseline LDL-C levels are very high 2

Diabetes with Elevated Cardiovascular Risk

• For patients with diabetes who have <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 high-risk features 1

Familial Hypercholesterolemia

• FDA-approved in combination with a statin for adults with heterozygous familial hypercholesterolemia (HeFH) 3
• FDA-approved in combination with a statin for pediatric patients 10 years of age and older with HeFH 3
• FDA-approved in combination with a statin and other LDL-C lowering therapies for adults and pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH) 3

Treatment Algorithm

Step 1: Maximize Statin Therapy First

• Always initiate or optimize statin therapy before adding ezetimibe 1
• Ensure the patient is on maximally tolerated statin dose 2, 1

Step 2: Add Ezetimibe as Second-Line

• Ezetimibe is preferred as the initial non-statin therapy due to demonstrated safety, tolerability, convenience, and single-tablet daily dosing 1
• Add ezetimibe as second-line therapy before considering PCSK9 inhibitors in very high-risk patients 1
• Provides an additional 15-25% reduction in LDL-C beyond statin monotherapy 2, 4, 5

Step 3: Consider PCSK9 Inhibitors if Needed

• If LDL-C remains elevated despite maximum statin plus ezetimibe, add a PCSK9 inhibitor (evolocumab or alirocumab), which can provide an additional 50-60% reduction in LDL-C 2

Monotherapy Indications

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

• Statin-intolerant patients who cannot tolerate any statin 6, 7
• Patients requiring modest LDL-C reductions (15-20% reduction) 4, 8
• As monotherapy, ezetimibe reduces LDL-C by 15-25% 1, 4

Special Populations

Mixed Hyperlipidemia

• FDA-approved in combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia 3

Homozygous Familial Sitosterolemia

• FDA-approved as an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and pediatric patients 9 years of age and older 3

Dosing and Administration

• Standard dose: 10 mg orally once daily, with or without food 3
• Administer ezetimibe either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant 3
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe 3

Key Advantages Over Alternative Non-Statin Therapies

• Single-tablet daily dosing improves adherence 1
• Adverse event profile similar to placebo 3, 4, 8
• Does not worsen hypertriglyceridemia, unlike bile acid sequestrants 4
• No significant drug-drug interactions 4, 7
• Combination therapy reduces adverse effects compared to up-titrating statin doses to achieve similar LDL reductions 2

Common Pitfall to Avoid

Do not unnecessarily up-titrate statin doses when adding ezetimibe is more effective and better tolerated 2. The addition of ezetimibe to a statin produces an LDL-C reduction of similar magnitude to a three-fold increase in statin dose 7, but with fewer side effects.