Skip Navigation

European Heart Journal 2003 24(8):729-741; doi:10.1016/S0195-668X(02)00807-2
Copyright © 2003 by the European Society of Cardiology.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in EHJ
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (115)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Knopp, R.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Knopp, R.H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Regular Articles

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia

R.H. Knoppa,*, H. Gitterb, T. Truittc, H. Baysd, C.V. Manione, L.J. Lipkaf, A.P. LeBeautf, R. Sureshf, B. Yangf and E.P. Veltrif for the Ezetimibe Study Group

a Division of Metabolism, Endocrinology & Nutrition, Northwest Lipid Research Clinic, 325 Ninth Avenue, Room 465, Box 359720, Seattle, WA 98104, USA
b Jersey Research Foundation, Inc., Linwood, NJ, USA
c Health Advance Institute, Melbourne, FL, USA
d L-MARC Research Center, Louisville, KY, USA
e Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
f Schering-Plough Research Institute, Kenilworth, NJ, USA

* Corresponding author. Tel.: +1-206-341-4413; fax: +1-206-731-8536
E-mail address: rhknopp{at}u.washington.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A: >The Ezetimibe...
 References
 
Aims This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10mg/day in patients with primary hypercholesterolemia.

Methods and results Following dietary stabilization, a 2–12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥3.36mmol/l (130mg/dl) to ≤6.47mmol/l (250mg/dl) and triglycerides ≤3.95mmol/l (350mg/dl) were randomized 3:1 to receive ezetimibe 10mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo . Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein2-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo.

Conclusions Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.

Key Words: Ezetimibe • Efficacy • Hypercholesterolaemia • Safety • Selective cholesterol absorption inhibitor

 


   Acknowledgments
 
The authors wish to thank Arlene Reiss for her assistance in the preparation of this manuscript.


   Footnotes
 
{dagger} Deceased. Back


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A: >The Ezetimibe...
 References
 

  1. 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.[Abstract/Free Full Text]
  2. van Heek M, Farley C, Compton DS et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol. 2000;129:1748–1754.[CrossRef][ISI][Medline]
  3. van Heek M, Farley C, Compton D et al. The potent cholesterol absorption inhibitor, ezetimibe, is glucuronidated in the intestine, localizes to the intestine, and circulates enterohepatically. [Abstract]Atherosclerosis. 2000;151:155.
  4. Zhu Y, Statkevich P, Kosoglou T et al. The effect of gender on the pharmacokinetics of SCH 58235, a cholesterol absorption inhibitor. [Abstract]AAPS PharmSci. 1999;1:S-24 [AAPS Annual Meeting Supplement. Available at http://www.aapspharmaceutica.com/scientificjournals/pharmsci/am_ abstracts/1999/1623.htm].
  5. 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;23:1209–1230.[CrossRef][ISI][Medline]
  6. Zhu Y, Statkevich P, Kosoglou T et al. Effect of ezetimibe (SCH 58235) on the activity of drug metabolizing enzymes in vivo. [Abstract]Clin Pharmacol Ther. 2000;67:152–1230.
  7. Kosoglou T, Statkevich P, Bauer KS et al. Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of digoxin. AAPS PharmSci. 2001;3(3):.
  8. Statkevich P, Reyderman L, Kosoglou T et al. Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of glipizide. [Abstract]Clin Pharmacol Ther. 2001;69:P67.
  9. Keung ACF, Kosoglou T, Statkevich P et al. Ezetimibe does not affect the pharmacokinetics of oral contraceptives. [Abstract]Clin Pharmacol Ther. 2001;69:P5–1230.[CrossRef]
  10. Bauer KS, Kosoglou T, Statkevich P et al. Ezetimibe does not affect the pharmacokinetics or pharmacodynamics of warfarin. [Abstract]Clin Pharmacol Ther. 2001;69:P5.[CrossRef]
  11. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023.[CrossRef][ISI][Medline]
  12. New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston: Little Brown; 1964. 114pp.
  13. Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
  14. Harris WS, Held SJ, Dujovne CA. Comparison of two scoring systems used to monitor diets in outpatient clinical trials. J Cardiovasc Risk. 1995;2:359–365.[CrossRef][Medline]
  15. Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J. 2001;3(Suppl E):E11–E16.
  16. Dujovne CA, Ettinger MP, McNeer JF et al. Ezetimibe, a selective cholesterol absorption inhibitor, improves plasma lipids in hypercholesterolemic patients. Circulation. 2001;104(Suppl):II-176.
  17. Data on file. Schering-Plough Research Institute. New Jersey: Kenilworth; 2002..
  18. Davidson MH, Dillon MA, Gordon B et al. Colesevelam hydrochloride (Cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159:1893–1900.[Abstract/Free Full Text]
  19. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251:365–374.[Abstract]
  20. Probstfield JL, Statland BE, Gorman L et al. Alterations in human serum alkaline phosphatase and its isoenzymes by hypolipidemic agents: colestipol and clofibrate. Metabolism. 1983;32:818–821.[CrossRef][ISI][Medline]
  21. Tolman KG. Defining patient risks from expanded preventive therapies. Am J Cardiol. 2000;85(12A):15E–19E.[CrossRef][ISI][Medline]
  22. van Heek M, Farley C, Compton DS et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol. 2001;134:409–417.[CrossRef][ISI][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?

Related articles in EHJ:

Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia
James Shepherd
EHJ 2003 24: 685-689. [Extract] [Full Text]  



This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
A. B. Weinglass, M. Kohler, U. Schulte, J. Liu, E. O. Nketiah, A. Thomas, W. Schmalhofer, B. Williams, W. Bildl, D. R. McMasters, et al.
Extracellular loop C of NPC1L1 is important for binding to ezetimibe
PNAS, August 12, 2008; 105(32): 11140 - 11145.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Fahmi, C. Yang, S. Esmail, H. H. Hobbs, and J. C. Cohen
Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes
Hum. Mol. Genet., July 15, 2008; 17(14): 2101 - 2107.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
K. Narushima, T. Takada, Y. Yamanashi, and H. Suzuki
Niemann-Pick C1-Like 1 Mediates {alpha}-Tocopherol Transport
Mol. Pharmacol., July 1, 2008; 74(1): 42 - 49.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
J Armitage
Commentary on NICE technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia
Heart, May 1, 2008; 94(5): 643 - 645.
[Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. B. Weinglass, M. G. Kohler, E. O. Nketiah, J. Liu, W. Schmalhofer, A. Thomas, B. Williams, L. Beers, L. Smith, M. Hafey, et al.
Madin-Darby Canine Kidney II Cells: A Pharmacologically Validated System for NPC1L1-Mediated Cholesterol Uptake
Mol. Pharmacol., April 1, 2008; 73(4): 1072 - 1084.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
B. M. Psaty and T. Lumley
Surrogate End Points and FDA Approval: A Tale of 2 Lipid-Altering Drugs
JAMA, March 26, 2008; 299(12): 1474 - 1476.
[Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
V. G. Saougos, A. P. Tambaki, M. Kalogirou, M. Kostapanos, I. F. Gazi, R. L. Wolfert, M. Elisaf, and A. D. Tselepis
Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2
Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2236 - 2243.
[Abstract] [Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
J. S Sampalis, S. Bissonnette, R. Habib, S. Boukas, and for the Ezetrol Add-On Investigators
Reduction in Estimated Risk for Coronary Artery Disease After Use of Ezetimibe with a Statin
Ann. Pharmacother., September 1, 2007; 41(9): 1345 - 1351.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
B. E. Hawes, K. A. O'Neill, X. Yao, J. H. Crona, H. R. Davis Jr., M. P. Graziano, and S. W. Altmann
In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs
Mol. Pharmacol., January 1, 2007; 71(1): 19 - 29.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. J. Clarenbach, M. Reber, D. Lutjohann, K. von Bergmann, and T. Sudhop
The lipid-lowering effect of ezetimibe in pure vegetarians
J. Lipid Res., December 1, 2006; 47(12): 2820 - 2824.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
I. Staprans, X.-M. Pan, J. H. Rapp, A. H. Moser, and K. R. Feingold
Ezetimibe inhibits the incorporation of dietary oxidized cholesterol into lipoproteins
J. Lipid Res., November 1, 2006; 47(11): 2575 - 2580.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. Oswald, S. Westrup, M. Grube, H. K. Kroemer, W. Weitschies, and W. Siegmund
Disposition and Sterol-Lowering Effect of Ezetimibe in Multidrug Resistance-Associated Protein 2-Deficient Rats
J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1293 - 1299.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
J. M. McKenney, M. Farnier, K.-W. Lo, H. E. Bays, I. Perevozkaya, G. Carlson, M. J. Davies, Y. B. Mitchel, and B. Gumbiner
Safety and Efficacy of Long-Term Co-Administration of Fenofibrate and Ezetimibe in Patients With Mixed Hyperlipidemia
J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1584 - 1587.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
A. J. Bergman, J. Burke, P. Larson, A. O. Johnson-Levonas, L. Reyderman, P. Statkevich, T. Kosoglou, H. E. Greenberg, W. K. Kraft, G. Frick, et al.
Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects.
J. Clin. Pharmacol., March 1, 2006; 46(3): 321 - 327.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
A. J. Bergman, J. Burke, P. Larson, A. O. Johnson-Levonas, L. Reyderman, P. Statkevich, S. E. Maxwell, T. Kosoglou, G. Murphy, K. Gottesdiener, et al.
Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients.
J. Clin. Pharmacol., March 1, 2006; 46(3): 328 - 336.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
L. Jakulj, M. D. Trip, T. Sudhop, K. von Bergmann, J. J. P. Kastelein, and M. N. Vissers
Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels
J. Lipid Res., December 1, 2005; 46(12): 2692 - 2698.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Garcia-Calvo, J. Lisnock, H. G. Bull, B. E. Hawes, D. A. Burnett, M. P. Braun, J. H. Crona, H. R. Davis Jr., D. C. Dean, P. A. Detmers, et al.
The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)
PNAS, June 7, 2005; 102(23): 8132 - 8137.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
M. Farnier, M. W. Freeman, G. Macdonell, I. Perevozskaya, M. J. Davies, Y. B. Mitchel, B. Gumbiner, and for the Ezetimibe Study Group
Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia
Eur. Heart J., May 1, 2005; 26(9): 897 - 905.
[Abstract] [Full Text] [PDF]

Home page
 DTBHome page
{blacktriangledown}Ezetimibe - a new cholesterol-lowering drug
DTB, September 1, 2004; 42(9): 65 - 67.
[Abstract] [Full Text] [PDF]

Home page
 British Journal of Diabetes & Vascular DiseaseHome page
A. Rees
Review: Ezetimibe -- clinical and pharmacological profile
The British Journal of Diabetes & Vascular Disease, May 1, 2004; 4(3): 163 - 171.
[Abstract] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
L. Berglund and D. Hyson
Cholesterol Absorption and the Metabolic Syndrome: A New Look at an Old Area
Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1314 - 1316.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in EHJ
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (115)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Knopp, R.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Knopp, R.H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?