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The Mechanism of Action of Ezetimibe (Zetia) on the Inhibition of Cholesterol Absorption


  • Ezetimibe (Zetia) is useful in treating LDL-C as either monotherapy, in combination with statins, in combination with fenofibrate, in patients with homozygous familial hypercholesterolemia on either atorvastatin or simvastatin and in patients with homozygous sitosterolemia.
  • Ezetimibe's inhibits cholesterol absorption by 54%, which contributes to the net 18-20% reductions in LDL-C seen in lipid profiles.
  • Its mechanism of action includes inhibiting the interaction between NPC1L1/cholesterol complex with clathrin/AP2, thereby preventing endocytosis of the NPC1L1/cholesterol complex into the enterocytes of the small intestine.  Therefore, there is a reduction in the amount of Apo-B48 containing lipoproteins available to go into circulation.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Donald S. Nuzum, PharmD, BCACP, CDE
Last Reviewed:
October 2015


  • Ezetimibe (Zetia) is the first cholesterol absorption inhibitor that can primarily reduce low density lipoprotein cholesterol (LDL-C), either as monotherapy, in combination with HMG CoA reductase inhibitor (statin) therapy, in combination with fenofibrate, or in patients with homozygous familial hypercholesterolemia on either atorvastatin or simvastatin and in patients with homozygous sitosterolemia.1-5  It has been especially useful in helping some patients with significant hyperlipidemia to get to their individualized LDL-C goals when max doses of statins have been tried.6  Ezetimibe's is able to inhibit cholesterol absorption by 54%, which contributes to the net 18-20% reductions in LDL-C seen in lipid profiles.7  It is important to note that this improvement in LDL-C is done without any compensatory increases in triglyceride concentrations, as seen with bile acid binding resins (or bile acid sequestrants such as cholestyramine, colesevelam) and without an increased risk for developing gallstones, as sometimes seen with fibrates (fenofibrate and gemfibrozil).8-10  


    How does cholesterol get absorbed into the body?
    It is first critical to understand the basic steps involved for both dietary and biliary cholesterol in the small intestine.11,12  Cholesterol absorption takes place in the small intestine and through a number of processes.13  Regardless of whether the free cholesterol came from dietary sources or from bile, it first binds to Niemann-Pick C1-like 1 (NPC1L1) protein located in the plasma membrane on the luminal side of the enterocyte in the small intestine.11-13  NPC1L1 and the bound cholesterol then bind to clathrin/AP2 so that the bound complex can undergo vesicular endocytosis within the enterocyte.14,15  Clathrin and AP2 are important for the formation of small vesicles that undergo endocytosis and are important to intracellular pathways (vesicular trafficking) that interact with the plasma membrane.  Without clathrin/AP2 activity the endocytosis (or delivery) of NPC1L1 and cholesterol would not occur.  

    Upon endocytosis of NPC1L1 and bound cholesterol, the cholesterol is released and the NPC1L1 is released to be returned back to the plasma membrane for additional cholesterol binding/absorption.15  The released cholesterol into the cytosol is then esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form cholesterol esters.16  The newly formed cholesterol esters then combine with triacylglycerol particles (from absorbed free fatty acids) through the facilitation by microsomal triacylglycerol transfer protein (MTP) to form ApoB-48 containing chylomicrons.16  The newly formed Apo-B48 containing chylomicrons will then taken up into the portal or lymphatic circulation for the liver and body to use.16 

    How does ezetimibe actually decrease cholesterol absorption from the intestine that results in these improvements in the lipid profile?
    Ezetimibe and its main metabolite, ezetimibe glucuronide, prevent the absorption of cholesterol by directly binding to a transmembrane loop for NPC1L1, thereby inhibiting its ability to bind with clathrin/AP2 that is required for its endocytosis.15  Since the NPC1L1 /cholesterol complex cannot be internalized, cholesterol cannot then be brought into the enterocyte to form the initial ApoB-48 containing chylomicrons that go into circulation.  This results in the net decreases of 18-20% in LDL-C on a patient's lipid profile.

    1. Bays HE, Moore PB, Drehobl MA et al.  Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.  Clin Ther  2001;23:1209-30.  
    2. Davidson MH, McGarry T, Bettis R et al.  Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.  J Am Coll Cardiol  2002;40:2125-34.  
    3. Ballantyne CM, Houri J, Notarbartolo A et al.  Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.  Circulation  2003;107:2409-15.  
    4. Ballantyne CM, Blazing MA, King TR et al.  Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.  Am J Cardiol  2004;93:1487-94.  
    5. Ezetimibe (Zetia┬«) product package insert.  Merck/Schering-Plough Pharmaceuticals.  North Wales, PA.  May 2009.
    6. Feldman T, Koren M, Insull W Jr et al.  Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Edcuation Program Adult Treatment Panel III low-density lipoprotein cholesterol goals.  Am J Cardiol  2004;93:1481-6.  
    7. Sudhop T, Lutjohann D, Kodal A et al.  Inhibition of intestinal cholesterol absorption by ezetimibe in humans.  Circulation  2002;106:1943-8.     
    8. Insull W Jr, Davidson MH, Demke DM et al.  The effects of colestipol tablets compared with colestipol granules on plasma cholesterol and other lipids in moderately hypercholesterolemic patients.  Atherosclerosis  1995;112:223-35. 
    9. Watanabe M, Houten SM, Wang L et al.  Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.  J Clin Invest  2004;113:1408-18.  
    10. McKenney JM, Farnier M, Lo KW et al.  Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia.  J Am Coll Cardiol  2006;47:1584-7.  
    11. Altmann SW, Davis HR Jr, Zhu LJ et al.  Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.  Science  2004;303:1201-4. 
    12. Davies JP, Scott C, Oishi K et al.  Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia.  J Biol Chem  2005;280:12710-20.  
    13. Sane AT, Sinnett D, Delvin E et al.  Localization and role of NPC1L1 in cholesterol absorption in human intestine.  J Lipid Res  2006;47:2112-20. 
    14. Chang TY, Chang C.  Ezetimibe blocks internalization of the NPC1L1/cholesterol complex.  Cell Metab  2008;7:469-71.  
    15. Wang J, Chu BB, Ge L et al.  Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption.  J Lipid Res  2009;[Epub ahead of print].  
    16. Choi BG, Badimon JJ, Moreno PR et al.  Lipoprotein metabolism and vascular biology.  In: Therapeutic Lipidology.  Davidson MH, Toth PP, Maki KC eds.  Human Press.  Totowa, NJ. 1-22.

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MESH Terms & Keywords

  • Ezetimibe, Zetia, Cholesterol Absorption