Mechanism of Action of Ezetimibe
Ezetimibe is a cholesterol absorption inhibitor that selectively inhibits the intestinal absorption of cholesterol and related phytosterols by targeting the Niemann-Pick C1-Like 1 (NPC1L1) protein at the brush border of the small intestine. 1
Detailed Mechanism
Ezetimibe works through a specific mechanism that differentiates it from other lipid-lowering medications:
- Target site: Localizes at the brush border of the small intestine 2
- Molecular target: Inhibits the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1) protein 1
- Absorption effects: Blocks the absorption of:
- Dietary cholesterol
- Biliary cholesterol (reabsorption of cholesterol derived from intestinal cell breakdown)
- Phytosterols 1
Physiological Effects
The inhibition of intestinal cholesterol absorption by ezetimibe leads to a cascade of effects:
- Decreases delivery of intestinal cholesterol to the liver
- Reduces hepatic cholesterol stores
- Increases LDL receptor expression in the liver
- Enhances clearance of cholesterol from the blood 1
Clinical Impact on Lipid Parameters
When used as monotherapy, ezetimibe 10 mg daily produces:
- 15-20% reduction in LDL cholesterol
- 2.5-5% increase in HDL cholesterol
- No adverse effects on triglyceride levels 3, 4
Pharmacological Characteristics
- Dosage: Standard dose is 10 mg once daily 1
- Metabolism: Primarily metabolized in the small intestine and liver via glucuronide conjugation
- Half-life: Approximately 22 hours for both ezetimibe and its active metabolite (ezetimibe-glucuronide) 1
- Excretion: Primarily eliminated in feces (78%) with minimal urinary excretion (11%) 1
Therapeutic Applications
Ezetimibe is indicated for:
- Combination therapy: As an adjunct to statin therapy when LDL-C goals are not achieved with statins alone 2
- Monotherapy: For patients who are statin-intolerant or for whom statins are contraindicated 5
- Specific conditions: Effective in homozygous and heterozygous familial hypercholesterolemia and sitosterolemia 4
Synergistic Effects with Other Lipid-Lowering Therapies
Ezetimibe's mechanism complements statin therapy:
- Statins inhibit cholesterol synthesis in the liver
- Ezetimibe inhibits cholesterol absorption in the intestine
- When combined, they provide complementary and synergistic effects on LDL-C reduction 5
- Adding ezetimibe 10 mg to any statin produces an additional 18% LDL-C reduction beyond statin monotherapy 6
Ezetimibe represents a distinct class of lipid-lowering agents with a unique mechanism that specifically targets intestinal cholesterol absorption, making it a valuable option in the management of hypercholesterolemia, either alone or in combination with other lipid-lowering therapies.