Ezetimibe: Clinical Overview
Indications
Ezetimibe 10 mg daily is FDA-approved as adjunctive therapy to diet for reducing LDL-C in adults with primary hyperlipidemia, either in combination with a statin or as monotherapy when additional LDL-C lowering is not possible. 1
Specific FDA-Approved Indications:
- Primary hyperlipidemia (including heterozygous familial hypercholesterolemia) in adults: Use with a statin or alone when additional LDL-C lowering therapy is not possible 1
- Heterozygous familial hypercholesterolemia in pediatric patients ≥10 years: Use in combination with a statin 1
- Mixed hyperlipidemia in adults: Use in combination with fenofibrate 1
- Homozygous familial hypercholesterolemia in adults and pediatric patients ≥10 years: Use with a statin and other LDL-C lowering therapies 1
- Homozygous familial sitosterolemia in adults and pediatric patients ≥9 years: As adjunct to diet for reducing elevated sitosterol and campesterol levels 1
Evidence-Based Clinical Application:
For secondary prevention (established ASCVD), initiate high-intensity statin plus ezetimibe concurrently to maximize LDL-C reduction and cardiovascular risk reduction. 2 This approach avoids the therapeutic inertia commonly seen with stepwise titration. 3
For primary prevention with moderate-to-high ASCVD risk, initiate moderate-to-high intensity statin and add ezetimibe if LDL-C remains >70 mg/dL or if the patient doesn't achieve ≥50% LDL-C reduction. 2
The IMPROVE-IT trial definitively demonstrated that ezetimibe added to moderate-intensity statin (simvastatin 40 mg) reduced the composite endpoint of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke over 6 years in 18,144 patients with recent acute coronary syndrome. 3, 2 High-risk patients derived the greatest absolute benefit, with those achieving LDL-C <30 mg/dL having the lowest cardiovascular event rates. 2
Dosage and Administration
Administer ezetimibe 10 mg orally once daily, with or without food. 1
Key Dosing Considerations:
- Timing with bile acid sequestrants: Administer ezetimibe either ≥2 hours before or ≥4 hours after a bile acid sequestrant to avoid binding interactions 1
- LDL-C assessment: Assess LDL-C as early as 4 weeks after initiating ezetimibe 1
- No dose adjustment needed for renal impairment or mild hepatic impairment 1
Expected Lipid Effects:
- Monotherapy: Reduces LDL-C by approximately 15-20% and increases HDL-C by 2.5-5% 4, 5
- Combination with statin: Provides an additional 21-25% LDL-C reduction beyond statin alone 3, 6
- In the IMPROVE-IT trial, ezetimibe added to simvastatin 40 mg achieved a mean LDL-C of 53.2 mg/dL versus 69.9 mg/dL with statin alone (24% additional reduction) 3
The I-ROSETTE trial demonstrated that all fixed-dose combinations of ezetimibe/rosuvastatin achieved >50% LDL-C reduction from baseline, superior to rosuvastatin monotherapy. 3
Mechanism of Action
Ezetimibe inhibits cholesterol absorption by blocking the NPC1L1 protein at the brush border of the small intestine, reducing absorption of both dietary and biliary cholesterol by approximately 54%. 7, 6, 8
- Does not affect absorption of fat-soluble vitamins, triglycerides, or bile acids 4
- Undergoes enterohepatic recirculation, ensuring repeated delivery to the intestinal site of action with limited peripheral exposure 6
- Minimal systemic absorption results in few drug interactions 4
Adverse Effects
Common Adverse Effects (≥2% incidence):
Ezetimibe monotherapy: Upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremities, fatigue, and influenza 1
Ezetimibe with statin: Nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea 9, 1
The overall safety profile is comparable to placebo in large cardiovascular outcomes trials. 9, 7
Serious but Rare Adverse Effects:
- Myopathy and rhabdomyolysis: Can occur with ezetimibe alone or in combination with statins 9, 1 Most post-marketing reports of rhabdomyolysis occurred in patients taking concomitant statins or fibrates 1
- Elevated hepatic transaminases: May occur when combined with statins 9, 1
Important Safety Clarifications:
Ezetimibe does not increase the risk of hemorrhagic stroke, cancer, bleeding-related adverse events, or noncardiovascular mortality. 7 The IMPROVE-IT and SHARP trials definitively demonstrated no increased bleeding risk. 7
Ezetimibe does not cause pulmonary toxicity or interstitial lung disease. 9 If respiratory symptoms develop, investigate other etiologies rather than attributing them to ezetimibe. 9
Ezetimibe does not cause gingivitis or other oral health complications. 7 The medication can be safely continued in patients who develop gingivitis. 7
Contraindications
Ezetimibe is contraindicated in patients with hypersensitivity to ezetimibe or any excipient. 1
When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe is contraindicated in patients for whom those agents are contraindicated. 1 Refer to the prescribing information of the combination agent for specific contraindications. 1
Warnings and Precautions
Hepatic Considerations:
Do not use ezetimibe in patients with moderate to severe hepatic impairment. 7, 1
Perform liver enzyme testing as clinically indicated and consider withdrawing ezetimibe if ALT or AST elevations ≥3× ULN persist. 1 Increases in serum transaminases have been reported, particularly when combined with statins. 1
Skeletal Muscle Monitoring:
If myopathy is suspected, discontinue ezetimibe and other concomitant medications as appropriate. 1 However, do not automatically attribute muscle symptoms to ezetimibe without case-by-case investigation to determine the true cause. 7
Combination Therapy Considerations:
When using ezetimibe with statins, fenofibrate, or other LDL-C lowering therapies, refer to the prescribing information of those products for their specific warnings and precautions. 1
The ACTE trial demonstrated that adding ezetimibe 10 mg to stable rosuvastatin 5 or 10 mg produced greater LDL-C improvements than up-titrating the rosuvastatin dose, with better tolerability. 3 Similarly, a randomized trial in non-ST elevation ACS showed that rosuvastatin 10 mg/ezetimibe 10 mg was superior to rosuvastatin 20 mg with lower incidence of drug-related adverse events. 3
Monitoring Recommendations
Assess LDL-C as early as 4 weeks after initiating ezetimibe to evaluate therapeutic response. 1
Monitor liver enzymes as clinically indicated, particularly when ezetimibe is combined with a statin. 1 Consider withdrawal if persistent elevations ≥3× ULN occur. 1
Evaluate for muscle-related symptoms (pain, weakness, tenderness), especially when combined with statins or fibrates, though the incidence is comparable to statin monotherapy. 3, 7
No routine monitoring of creatine kinase is required unless myopathy is clinically suspected. 1