Ezetimibe: A novel cholesterol-lowering agent that highlights novel physiologic pathways
- Shailendra B. Patel BM, ChB, DPhil
- … show all 1 hide
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Ezetimibe is a US Food and Drug Administration-approved novel drug that targets the absorption of cholesterol in the intestine. The identification of this drug has also led to the elucidation of the dietary cholesterol receptor. Ezetimibe is efficacious as a plasma cholesterol-lowering agent as monotherapy, but its greatest utility seems to be as a combination with a low-dose statin, where it results in cholesterol lowering that is equivalent to using maximum-dose statins. It has a very favorable side-effect profile, as well as a lack of drug-drug interactions. In addition, it prevents the absorption of noncholesterol sterols, such as plant sterols. In clinical studies, it has been shown to be highly efficacious in lowering plant sterols in a rare genetic disorder, sitosterolemia. Both the disease, as well as this therapeutic agent, have led to the concept that ezetimibe may be also useful in dissecting the role of these noncholesterol sterols in the pathogenesis of atherosclerosis.
- Phillips LS, Branch WT, Cook CB, et al.: Clinical inertia. Ann Intern Med 2001, 135:825–834. Excellent review of clinical issues affecting the management of chronic but common disorders that are seen and managed, but where optimal management is likely to greatly improve healthcare outcomes.
- Miettinen TA, Puska P, Gylling H, et al.: Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med 1995, 333:1308–1312. CrossRef
- Van Heek M, France CF, Compton DS, et al.: In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther 1997, 283:157–163.
- Lipka LJ: Ezetimibe: a first-in-class, novel cholesterol absorption inhibitor. Cardiovasc Drug Rev 2003, 21:293–312. CrossRef
- Hernandez M, Montenegro J, Steiner M, et al.: Intestinal absorption of cholesterol is mediated by a saturable, inhibitable transporter [in process citation]. Biochim Biophys Acta 2000, 1486:232–242.
- Davis HR Jr., Compton DS, Hoos L, Tetzloff G: Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol 2001, 21:2032–2038. Study that shows that the use of this single agent in the ApoE mouse prevents the development of atherosclerosis and shows that targeting of intestinal cholesterol alone can affect this process.
- Zaks A, Dodds DR: Enzymatic glucuronidation of a novel cholesterol absorption inhibitor, Sch 58235. Appl Biochem Biotechnol 1998, 73:205–214.
- Ghosal A, Hapangama N, Yuan Y, et al.: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos 2004, 32:314–320. CrossRef
- Patrick JE, Kosoglou T, Stauber KL, et al.: Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos 2002, 30:430–437. CrossRef
- Altmann SW, Davis HR Jr., Zhu LJ, et al.: Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004, 303:1201–1204. A key paper that identified the likely target for ezetimibe and at the same time allowed new concepts of how intestinal cholesterol transport may take place. CrossRef
- Klett EL, Patel SB: Biomedicine. Will the real cholesterol transporter please stand up. Science 2004, 303:1149–1150. A review of the paper above, as well as a review summarizing the molecular pathways involved in dietary cholesterol transport. CrossRef
- Dujovne CA, Ettinger MP, McNeer JF, et al.: Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002, 90:1092–1097. CrossRef
- Knopp RH, Gitter H, Truitt T, et al.: Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003, 24:729–741. CrossRef
- Bosner MS, Ostlund RE Jr., Osofisan O, et al.: Assessment of percent cholesterol absorption in humans with stable isotopes. J Lipid Res 1993, 34:1047–1053.
- Dietschy JM: Theoretical considerations of what regulates lowdensity-lipoprotein and high-density-lipoprotein cholesterol. Am J Clin Nutr 1997, 65:1581S-1589S. An excellent treatise on whole body cholesterol metabolism and a must-read for all who want to understand the key pathways and how many of the current drugs are likely to have their therapeutic effect and how future targets may also be effective.
- Sudhop T, Lutjohann D, Kodal A, et al.: Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002, 106:1943–1948. An up to date study of not only the effects of ezetimibe on cholesterol absorption in humans, but how plasma plant sterols are also reduced by this drug. CrossRef
- Davidson MH, McGarry T, Bettis R, et al.: Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002, 40:2125–2134. CrossRef
- Gagne C, Gaudet D, Bruckert E: Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002, 105:2469–2475. A study involving probably the most difficult to treat plasma cholesterol, homozygous FH, and how the combination of ezetimibe and a statin is effective. CrossRef
- Gagne C, Bays HE, Weiss SR, et al.: Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002, 90:1084–1091. CrossRef
- Kerzner B, Corbelli J, Sharp S, et al.: Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003, 91:418–424. CrossRef
- Melani L, Mills R, Hassman D, et al.: Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003, 24:717–728. CrossRef
- Jurado J, Seip R, Thompson PD: Effectiveness of ezetimibe in clinical practice. Am J Cardiol 2004, 93:641–643. CrossRef
- Fux R, Morike K, Gundel UF, et al.: Ezetimibe and statin-associated myopathy. Ann Intern Med 2004, 140:671–672.
- Lu K, Lee M, Patel SB: Dietary cholesterol absorption; more than just bile. Trends Endocrinol Metab 2001, 12:314–320. A short review of dietary sterol physiology in humans and a description of the rare human disease sitosterolemia. CrossRef
- Salen G, Von Bergmann K, Lutjohann D, et al.: Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 2004, 109:966–971. A placebo-controlled study that showed the effectiveness of ezetimibe in reducing plant sterol levels. CrossRef
- Klett EL, Patel S: Genetic defenses against noncholesterol sterols. Curr Opin Lipidol 2003, 14:341–345. A review of the connection between dietary sterols and atherosclerosis and a summary of evidence that noncholesterol sterols may be the link between diet and atherosclerosis risk. CrossRef
- Ezetimibe: A novel cholesterol-lowering agent that highlights novel physiologic pathways
Current Cardiology Reports
Volume 6, Issue 6 , pp 439-442
- Cover Date
- Print ISSN
- Online ISSN
- Current Medicine Group
- Additional Links
- Author Affiliations
- 1. Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, 114 Doughty Street, STR 541, 29403, Charleston, SC, USA