Mechanism of Action of Ezetimibe
Ezetimibe reduces blood cholesterol by selectively blocking the intestinal absorption of cholesterol through inhibition of the Niemann-Pick C1-Like 1 (NPC1L1) sterol transporter located at the brush border of the small intestine. 1
Molecular Target and Site of Action
Ezetimibe localizes at the brush border of the small intestine where it specifically targets the NPC1L1 protein, which is the molecular transporter responsible for facilitating the intestinal uptake of cholesterol and phytosterols. 1, 2
The drug blocks the passage of both dietary cholesterol and biliary cholesterol (cholesterol secreted in bile and reabsorbed) across the intestinal wall, preventing their absorption into enterocytes. 3, 4
This mechanism is fundamentally distinct from statins (which inhibit cholesterol synthesis in the liver) and bile acid sequestrants (which bind bile acids in the intestinal lumen). 5, 6
Downstream Hepatic Effects
By blocking intestinal cholesterol absorption, ezetimibe decreases the delivery of intestinal cholesterol to the liver via chylomicrons. 1, 7
This depletion of hepatic cholesterol stores triggers a compensatory upregulation of hepatic LDL receptors. 1
The increased LDL receptor expression results in enhanced clearance of LDL cholesterol from the bloodstream. 1
Clinical Lipid-Lowering Effects
As monotherapy, ezetimibe typically reduces LDL-C by approximately 18-20%. 5, 6, 3
When added to ongoing statin therapy, ezetimibe provides an additional 25% reduction in LDL-C beyond the statin effect alone. 6, 4
Ezetimibe also modestly increases HDL cholesterol by 2.5-5% and reduces triglycerides by approximately 14% when combined with statins. 3, 4
Selectivity and Specificity
Ezetimibe selectively inhibits cholesterol absorption without affecting the absorption of fat-soluble vitamins (A, D, E), triglycerides, or bile acids. 5, 1, 3
The drug also blocks absorption of phytosterols (plant sterols), making it useful in treating homozygous sitosterolemia. 5, 6, 2
Ezetimibe does not impair adrenocortical steroid hormone production. 1
Clinical Caveat
- While ezetimibe effectively lowers LDL-C through this mechanism, the cardiovascular benefit is proportional to the degree of LDL-C reduction achieved, as demonstrated in the IMPROVE-IT trial where adding ezetimibe to simvastatin reduced major cardiovascular events by approximately 7% commensurate with an incremental LDL-C reduction of 16 mg/dL. 5