How does Zetia (ezetimibe) work?

How Ezetimibe (Zetia) Works

Ezetimibe works by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) protein in the brush border of the small intestine, which blocks intestinal absorption of cholesterol, resulting in decreased delivery of cholesterol to the liver and increased clearance of cholesterol from the blood. 1

Mechanism of Action in Detail

Ezetimibe targets a specific molecular pathway in cholesterol absorption:

1. Target Protein: Ezetimibe selectively binds to the NPC1L1 protein, which is responsible for cholesterol transport across the intestinal wall 2, 1

2. Site of Action: The medication localizes at the brush border of the small intestine where it:

   • Inhibits absorption of both dietary and biliary cholesterol
   • Does not affect absorption of fat-soluble vitamins, triglycerides, or bile acids 1

3. Metabolic Pathway:

   • After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide)
   • This glucuronide metabolite binds with higher affinity to NPC1L1 than the parent compound 3
   • Enterohepatic recirculation ensures repeated delivery to the intestinal site of action 1

Physiological Effects

Ezetimibe produces several downstream effects that contribute to its cholesterol-lowering properties:

• Hepatic Response: By reducing intestinal cholesterol absorption, ezetimibe:

  • Decreases the delivery of cholesterol to the liver
  • Reduces hepatic cholesterol stores
  • Triggers an increase in LDL receptors
  • Enhances clearance of LDL-cholesterol from the bloodstream 1

• Clinical Efficacy:

  • Monotherapy: Reduces LDL-cholesterol by approximately 18% 2
  • Combination therapy with statins: Provides an additional 25% reduction in LDL-cholesterol beyond statin effects alone 2
  • Inhibits cholesterol absorption by approximately 54% in hypercholesterolemic individuals 3

Pharmacokinetic Properties

• Absorption: After a 10mg dose, peak plasma concentrations are reached within 4-12 hours 1
• Distribution: Both ezetimibe and its glucuronide metabolite are highly bound (>90%) to plasma proteins 1
• Metabolism: Primarily metabolized in the small intestine and liver via glucuronide conjugation 1
• Elimination: Both ezetimibe and ezetimibe-glucuronide have a half-life of approximately 22 hours 1

Clinical Applications

Ezetimibe is FDA-approved for:

• Primary hyperlipidemia (as monotherapy or with statins)
• Mixed hyperlipidemia (in combination with fenofibrate)
• Homozygous familial hypercholesterolemia (with statins)
• Homozygous sitosterolemia 2

Advantages Over Other Intestinal Agents

Unlike other intestinally-acting lipid-lowering medications:

• Does not adversely affect triglyceride levels
• Has minimal systemic absorption
• Has few drug interactions 4
• Demonstrates a side effect profile similar to placebo 4

Understanding ezetimibe's unique mechanism of action explains why it works synergistically with statins - while statins reduce cholesterol synthesis in the liver, ezetimibe blocks intestinal cholesterol absorption, providing complementary pathways to reduce circulating cholesterol levels.