What are the primary indications for ezetimibe (Low-Density Lipoprotein Cholesterol (LDL-C) lowering medication)?

Principal Indications for Ezetimibe

Ezetimibe is primarily indicated as a second-line therapy in combination with statins when LDL-C goals are not achieved with maximally tolerated statin therapy alone, or as monotherapy when statins cannot be tolerated. 1, 2

Primary Indications

In Adults:

• Combination therapy with statins:

  • For patients who fail to achieve LDL-C goals on maximally tolerated statin therapy 2
  • For very high-risk patients with atherosclerotic cardiovascular disease (ASCVD) 2
  • For patients with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 1

• Monotherapy:

  • When additional LDL-C lowering is needed but statin therapy is not possible (statin intolerance) 1, 3
  • As an alternative to statins in patients who cannot tolerate them 2

• Other specific indications:

  • In combination with fenofibrate for mixed hyperlipidemia 1
  • In combination with statins for homozygous familial hypercholesterolemia (HoFH) 1
  • For reduction of elevated sitosterol and campesterol levels in homozygous familial sitosterolemia 1

In Pediatric Patients:

• In combination with statins for HeFH in patients 10 years and older 1
• For homozygous familial sitosterolemia in patients 9 years and older 1

Efficacy and Mechanism of Action

Ezetimibe works by inhibiting the Niemann-Pick C1 like 1 (NPC1L1) protein in the small intestine, reducing cholesterol absorption 2. As monotherapy, it reduces LDL-C by approximately 18%, and when added to statins, it provides an additional 25% reduction in LDL-C 2, 4.

Treatment Approach and Algorithms

For Secondary Prevention (Patients with ASCVD):

1. Start with maximally tolerated high-intensity statin therapy
2. If LDL-C goal (<1.4 mmol/L or 55 mg/dL and ≥50% reduction from baseline) is not achieved, add ezetimibe 2
3. If goals still not met, consider adding PCSK9 inhibitors 2

For Primary Prevention:

1. Start with appropriate intensity statin based on risk assessment
2. If LDL-C goals are not achieved, add ezetimibe 2
3. For patients with familial hypercholesterolemia who don't reach goals, consider further therapies 1

For Statin-Intolerant Patients:

1. Ezetimibe can be used as first-line therapy 1, 3
2. Consider combination with bempedoic acid if further LDL-C reduction is needed 2, 3

Important Considerations and Caveats

• Ezetimibe should be administered either ≥2 hours before or ≥4 hours after bile acid sequestrants if used in combination 1
• While ezetimibe effectively lowers LDL-C, earlier studies showed limited effects on carotid intima-media thickness compared to statins 2, 5
• The IMPROVE-IT trial demonstrated that adding ezetimibe to statin therapy in patients with recent acute coronary syndrome reduced cardiovascular events 2
• Real-world data suggests that only about 26% of patients with ASCVD or HeFH achieve LDL-C goals <70 mg/dL when adding or switching to ezetimibe 6
• Ezetimibe is generally well-tolerated with a safety profile similar to placebo when used as monotherapy 4
• Common adverse effects include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza 1

Ezetimibe represents an important option in lipid management, particularly for patients who cannot achieve LDL-C goals with statins alone or cannot tolerate statins, but should be used as part of a comprehensive approach to cardiovascular risk reduction.