What is the mechanism of action of Zetia (ezetimibe)?

Mechanism of Action of Ezetimibe (Zetia)

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

Primary Mechanism

• Ezetimibe selectively inhibits the intestinal absorption of cholesterol by targeting the sterol transporter NPC1L1, which is involved in the uptake of both dietary and biliary cholesterol in the small intestine 1, 2
• The drug localizes at the brush border of the small intestine where it prevents cholesterol uptake into enterocytes, keeping cholesterol in the intestinal lumen for excretion 1, 2
• This mechanism is distinct from other cholesterol-lowering agents like statins (which inhibit cholesterol synthesis) or bile acid sequestrants (which bind bile acids) 3

Pharmacodynamic Effects

• Ezetimibe inhibits intestinal cholesterol absorption by approximately 54% compared to placebo in hypercholesterolemic patients 1, 2
• This inhibition leads to decreased delivery of intestinal cholesterol to the liver, causing:
  • Reduction of hepatic cholesterol stores
  • Upregulation of LDL receptors
  • Enhanced clearance of cholesterol from the bloodstream 1
• Ezetimibe reduces total cholesterol, LDL-C, apolipoprotein B, and non-HDL-C in patients with hyperlipidemia 1

Pharmacokinetics and Metabolism

• After oral administration, ezetimibe is rapidly absorbed and extensively conjugated (>80%) to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide) 1, 4
• Both ezetimibe and its glucuronide metabolite are active in inhibiting cholesterol absorption, with the glucuronide binding with higher affinity to NPC1L1 2
• Enterohepatic recirculation occurs, with the drug being excreted into bile and reabsorbed, ensuring repeated delivery to the intestinal site of action 1, 4
• This recycling contributes to the long elimination half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide 1, 4
• The long half-life allows for once-daily dosing 1

Selectivity and Safety Profile

• Ezetimibe selectively inhibits cholesterol absorption without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids 1, 2
• The drug has no clinically meaningful effect on plasma concentrations of fat-soluble vitamins A, D, and E 1
• Ezetimibe does not impair adrenocortical steroid hormone production 1
• Unlike other intestinally acting lipid-lowering agents, ezetimibe does not adversely affect triglyceride levels 5, 6

Clinical Applications

• Ezetimibe is used as monotherapy or in combination with statins for patients with primary hypercholesterolemia 3
• When used as monotherapy, ezetimibe typically reduces LDL-C by approximately 18% 3
• When added to statin therapy, ezetimibe provides an additional 25% reduction in LDL-C beyond what is achieved with the statin alone 3, 2
• Ezetimibe is also indicated for use in patients with homozygous familial hypercholesterolemia and homozygous sitosterolemia (phytosterolemia) 3

Unique Aspects of Mechanism

• Ezetimibe was the first medication in the novel class of selective cholesterol-absorption inhibitors 5
• The drug has minimal systemic exposure due to its localization at the intestinal wall and enterohepatic recirculation, which limits peripheral drug exposure 2, 4
• This targeted mechanism contributes to its favorable drug interaction profile, with few clinically significant interactions with other medications 4