What is the indication for Zetia (ezetimibe)?

Indications for Zetia (Ezetimibe)

Zetia (ezetimibe) is indicated as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, either alone or in combination with statin therapy when additional LDL-C lowering is needed. 1

FDA-Approved Indications

Ezetimibe has several specific FDA-approved indications:

1. Primary Hyperlipidemia:

   • In combination with a statin, or alone when additional LDL-C lowering therapy is not possible, to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 2
   • In combination with a statin to reduce elevated LDL-C in pediatric patients 10 years and older with HeFH 2

2. Mixed Hyperlipidemia:

   • In combination with fenofibrate to reduce elevated LDL-C in adults with mixed hyperlipidemia 2

3. Homozygous Familial Hypercholesterolemia (HoFH):

   • In combination with a statin and other LDL-C lowering therapies to reduce elevated LDL-C levels in adults and pediatric patients 10 years and older with HoFH 2

4. Homozygous Familial Sitosterolemia:

   • As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and pediatric patients 9 years and older 2

Mechanism of Action

Ezetimibe works by:

• Inhibiting the Niemann-Pick C1 Like 1 (NPC1L1) protein in the small intestine 1
• Reducing cholesterol absorption in the small intestine without affecting absorption of fat-soluble vitamins, triglycerides, or bile acids 3
• This mechanism is complementary to statins, which inhibit cholesterol synthesis in the liver

Efficacy

Ezetimibe provides:

• 18% reduction in LDL-C as monotherapy 1
• 25% additional reduction in LDL-C when combined with statin therapy 1
• Inhibits cholesterol absorption by approximately 54% in hypercholesterolemic individuals 3

Dosing

• Standard dose: 10 mg orally once daily, with or without food 2
• When used with bile acid sequestrants, administer ezetimibe either ≥2 hours before or ≥4 hours after the bile acid sequestrant 2

Clinical Considerations

When to Consider Ezetimibe

1. Add-on to statin therapy when:

   • Patients have not achieved LDL-C goal on maximally tolerated statin therapy 1
   • Very high-risk patients with LDL-C remaining ≥70 mg/dL on statin therapy 1

2. Monotherapy when:

   • Patients need modest reductions in LDL-C (15-20%) 4
   • Patients are intolerant to statins or other lipid-lowering medications 4

3. Special populations:

   • Patients with homozygous familial sitosterolemia 1
   • Patients with homozygous or heterozygous familial hypercholesterolemia 2

Safety Profile

Ezetimibe is generally well-tolerated with:

• Adverse effects similar to placebo when used as monotherapy 1
• Common adverse effects include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, and fatigue 2
• Minimal drug interactions due to limited systemic absorption and elimination primarily through glucuronidation rather than CYP450 metabolism 5

Monitoring

• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe 2
• Monitor liver enzymes when used in combination with statins 2
• Watch for signs of myopathy or rhabdomyolysis, especially when combined with statins 2

Clinical Outcomes

Ezetimibe has demonstrated cardiovascular outcome benefits in clinical trials:

• IMPROVE-IT trial showed that adding ezetimibe to moderate-intensity statin therapy in patients with recent acute coronary syndrome reduced the primary composite endpoint of cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke 1
• SHARP trial demonstrated that simvastatin plus ezetimibe reduced the primary endpoint of first major ASCVD event compared to placebo in patients with chronic kidney disease 1

In summary, ezetimibe is a valuable option for LDL-C reduction, either as monotherapy in patients who need modest LDL-C lowering or cannot tolerate statins, or as an add-on therapy to statins when additional LDL-C reduction is needed to achieve treatment goals.