How Zetia (Ezetimibe) Works
Zetia works by blocking cholesterol absorption in the small intestine through inhibition of the Niemann-Pick C1-Like 1 (NPC1L1) protein at the brush border of enterocytes, which prevents both dietary and biliary cholesterol from entering the bloodstream. 1
Molecular Mechanism of Action
Ezetimibe localizes specifically at the brush border of the small intestine and binds to the NPC1L1 sterol transporter, which is the molecular target responsible for intestinal cholesterol uptake. 1, 2 This binding action physically blocks the absorption of cholesterol and related plant sterols (phytosterols) from the intestinal lumen, keeping these compounds in the gut for fecal excretion rather than allowing them to enter enterocytes. 2, 3
The drug undergoes extensive first-pass glucuronidation in the small intestine and liver to form ezetimibe-glucuronide, which is also pharmacologically active and binds with even higher affinity to NPC1L1 than the parent compound. 3 This metabolite undergoes enterohepatic recirculation, ensuring repeated delivery to the intestinal site of action while maintaining limited peripheral exposure. 3
Downstream Effects on Cholesterol Metabolism
By blocking intestinal cholesterol absorption, ezetimibe decreases the delivery of cholesterol to the liver, which depletes hepatic cholesterol stores. 1 This depletion triggers a compensatory upregulation of hepatic LDL receptors through the sterol regulatory element binding protein 2 (SREBP2) pathway. 2 The increased number of LDL receptors on hepatocyte surfaces enhances clearance of LDL cholesterol from the bloodstream. 1
Clinical Efficacy
Ezetimibe inhibits intestinal cholesterol absorption by approximately 54% in hypercholesterolemic patients. 3 As monotherapy, it reduces LDL cholesterol by approximately 18-20%. 2, 4 When added to statin therapy, ezetimibe provides an additional 25% reduction in LDL cholesterol beyond what the statin achieves alone. 2, 4
Complementary Mechanism with Statins
The mechanisms of ezetimibe and statins are complementary and work through entirely different pathways. 2 While statins inhibit hepatic cholesterol synthesis by blocking HMG-CoA reductase, ezetimibe blocks intestinal cholesterol absorption. 2 Importantly, both drugs upregulate SREBP2, which increases LDL receptor expression but also increases PCSK9 expression—a protein that degrades LDL receptors. 2 This explains why combination therapy is particularly effective: the dual mechanism provides additive LDL-lowering while the shared PCSK9 upregulation represents a common limitation. 2
Selectivity and Safety Profile
Ezetimibe selectively inhibits cholesterol absorption without affecting the absorption of fat-soluble vitamins (A, D, E), triglycerides, or bile acids. 1, 5 The drug has no clinically meaningful effect on plasma concentrations of fat-soluble vitamins and does not impair adrenocortical steroid hormone production. 1 Unlike bile acid sequestrants, ezetimibe does not worsen hypertriglyceridemia. 6
Ezetimibe has minimal effects on cytochrome P450 enzymes, resulting in few drug-drug interactions. 3 The drug is highly protein-bound (>90%) and is eliminated with a half-life of approximately 22 hours for both ezetimibe and its glucuronide metabolite. 1
Cardiovascular Outcomes
The IMPROVE-IT trial demonstrated that ezetimibe added to moderate-intensity statin therapy significantly reduced major cardiovascular events by approximately 7% in patients with recent acute coronary syndrome, with the benefit proportional to the incremental LDL cholesterol lowering of 16 mg/dL. 2 The SHARP trial showed similar cardiovascular event reduction in patients with renal impairment. 2