Does ezetimibe (EZETIMIBE) alone decrease cardiovascular events in patients with elevated Low-Density Lipoprotein (LDL) cholesterol levels?

Ezetimibe Alone for Cardiovascular Event Reduction

Ezetimibe alone is not recommended as first-line therapy for cardiovascular event reduction, as it has not demonstrated significant cardiovascular benefit when used as monotherapy. 1

Evidence on Ezetimibe Monotherapy and CV Events

Current Guidelines Position

• The 2022 BMJ clinical practice guideline indicates that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, but this evidence primarily applies to combination therapy rather than monotherapy 1
• When adding a lipid-lowering drug is indicated, the guideline panel suggests ezetimibe in preference to PCSK9 inhibitors, but this is in the context of add-on therapy, not monotherapy 1

Evidence for Ezetimibe's CV Effects

• The American Heart Association/American College of Cardiology statement notes that convincing evidence of reduced cardiovascular events with ezetimibe has been slow to emerge 1
• The primary evidence for ezetimibe's cardiovascular benefit comes from two key trials:
  • SHARP (Study of Heart and Renal Protection) - showed ezetimibe plus simvastatin versus double placebo reduced CV events in patients with renal impairment 1
  • IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) - demonstrated that ezetimibe plus simvastatin significantly reduced major cardiovascular events by ~7% compared to simvastatin alone 1, 2

Important Distinction

• Both major trials (SHARP and IMPROVE-IT) tested ezetimibe in combination with statins, not as monotherapy 1, 2
• There is no large randomized controlled trial demonstrating cardiovascular benefit of ezetimibe monotherapy 3

Mechanism and LDL-Lowering Effect

• Ezetimibe blocks intestinal cholesterol absorption by interfering with Niemann Pick C1-like receptor 1 (NPC1L1) 1
• As monotherapy, ezetimibe reduces LDL cholesterol by approximately 15-20% 1, 4, 5
• When added to statins, it provides an additional 25% reduction in LDL cholesterol 1
• Ezetimibe has been shown to reduce oxidized LDL cholesterol, which is a predictor of adverse cardiovascular events 6

Clinical Application and Recommendations

Appropriate Use of Ezetimibe

• Ezetimibe is most appropriate as:
  1. Add-on therapy to statins when LDL targets are not achieved with maximum tolerated statin therapy 1
  2. Alternative therapy in patients who are statin-intolerant 1, 4, 5

Risk Stratification Approach

• For patients at very high or high cardiovascular risk who cannot tolerate statins, lipid-lowering therapy with ezetimibe is recommended 1
• For patients at low cardiovascular risk, lipid-lowering drugs including ezetimibe are not recommended 1

Practical Considerations

• Ezetimibe is generally well-tolerated with a side-effect profile similar to placebo 1, 4, 5
• It can be taken with or without food, and should be taken either ≥2 hours before or ≥4 hours after bile acid sequestrants if used in combination 1
• Ezetimibe is not recommended in patients with moderate/severe hepatic impairment 1

Common Pitfalls and Caveats

• Assuming ezetimibe monotherapy has proven cardiovascular benefit - the evidence primarily supports its use in combination with statins
• Using ezetimibe as first-line therapy instead of statins - statins remain the first-line therapy for cardiovascular risk reduction
• Expecting large LDL reductions with ezetimibe alone - it provides modest LDL reduction (15-20%) compared to high-intensity statins (≥50%)
• Overlooking the need for consistent therapy - adherence is crucial for any lipid-lowering medication to be effective 7