This Article Full Text Full Text (PDF) All Versions of this Article: 109/8/966    most recent 01.CIR.0000116766.31036.03v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Salen, G. Search for Related Content PubMed PubMed Citation Articles by Salen, G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Related Collections Lipids Cardiovascular Pharmacology Primary prevention

(Circulation. 2004;109:966-971.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Ezetimibe Effectively Reduces Plasma Plant Sterols in Patients With Sitosterolemia

G. Salen, MD^*; K. von Bergmann, MD^*; D. Lütjohann, PhD; P. Kwiterovich, MD; J. Kane, MD, PhD; S.B. Patel, MD, PhD; T. Musliner, MD; P. Stein, MD; B. Musser, PhD, and the Multicenter Sitosterolemia Study Group

From the UMDNJ-New Jersey Medical School, Newark, NJ, and VA Medical Center, East Orange, NJ (G.S.); Department of Clinical Pharmacology, University of Bonn (K.V.B., D.L.), Bonn, Germany; Johns Hopkins University (P.K.), Baltimore, Md; University of California at San Francisco (J.K.), San Francisco, Calif; Medical University of South Carolina (S.B.P.), Charleston, SC; and Merck Research Laboratories (T.M., P.S., B.M.), Rahway, NJ.

Reprint requests to Dr Gerald Salen, University of Medicine and Dentistry of New Jersey, 185 S Orange Ave, MSB-H538, Newark, NJ 07103. E-mail SalenGe{at}UMDNJ.edu

Received April 22, 2003; de novo received September 30, 2003; accepted November 17, 2003.

Background— Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops.

Methods and Results— In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% (P<0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P<0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P<0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported.

Conclusions— Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.

Key Words: ezetimibe • sitosterolemia • cholesterol • coronary disease

This article has been cited by other articles:

				S. Helske, T. Miettinen, H. Gylling, M. Mayranpaa, J. Lommi, H. Turto, K. Werkkala, M. Kupari, and P. T. Kovanen Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves J. Lipid Res., July 1, 2008; 49(7): 1511 - 1518. [Abstract] [Full Text] [PDF]

				S Kidambi and S B Patel Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis J. Clin. Pathol., May 1, 2008; 61(5): 588 - 594. [Abstract] [Full Text] [PDF]

				J. K. Kruit, A. L. Drayer, V. W. Bloks, N. Blom, S. G. Olthof, P. J. J. Sauer, G. de Haan, I. P. Kema, E. Vellenga, and F. Kuipers Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia J. Biol. Chem., March 7, 2008; 283(10): 6281 - 6287. [Abstract] [Full Text] [PDF]

				V. Charlton-Menys and P. N. Durrington Human cholesterol metabolism and therapeutic molecules Exp Physiol, January 1, 2008; 93(1): 27 - 42. [Abstract] [Full Text] [PDF]

				M. A. Valasek, S. L. Clarke, and J. J. Repa Fenofibrate reduces intestinal cholesterol absorption via PPAR{alpha}-dependent modulation of NPC1L1 expression in mouse J. Lipid Res., December 1, 2007; 48(12): 2725 - 2735. [Abstract] [Full Text] [PDF]

				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]

				J. F. Oram and A. M. Vaughan ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease Circ. Res., November 10, 2006; 99(10): 1031 - 1043. [Abstract] [Full Text] [PDF]

				L. Bao, Y. Li, S.-X. Deng, D. Landry, and I. Tabas Sitosterol-containing Lipoproteins Trigger Free Sterol-induced Caspase-independent Death in ACAT-competent Macrophages J. Biol. Chem., November 3, 2006; 281(44): 33635 - 33649. [Abstract] [Full Text] [PDF]

				B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]

				E. Ikonen Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev, October 1, 2006; 86(4): 1237 - 1261. [Abstract] [Full Text] [PDF]

				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]

				R. P. Radermecker and A. J. Scheen Serum Plant Sterols and Atherosclerosis: Is There a Place for Statin-Ezetimibe Combination? J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1496 - 1497. [Full Text] [PDF]

				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]

				L. Yu, K. von Bergmann, D. Lutjohann, H. H. Hobbs, and J. C. Cohen Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 J. Lipid Res., August 1, 2005; 46(8): 1739 - 1744. [Abstract] [Full Text] [PDF]

				J. Lembcke, U. Ceglarek, G. M. Fiedler, S. Baumann, A. Leichtle, and J. Thiery Rapid quantification of free and esterified phytosterols in human serum using APPI-LC-MS/MS J. Lipid Res., January 1, 2005; 46(1): 21 - 26. [Abstract] [Full Text] [PDF]

				J. Wang, T. Joy, D. Mymin, J. Frohlich, and R. A. Hegele Phenotypic heterogeneity of sitosterolemia J. Lipid Res., December 1, 2004; 45(12): 2361 - 2367. [Abstract] [Full Text] [PDF]

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

				H. R. Davis Jr., L.-j. Zhu, L. M. Hoos, G. Tetzloff, M. Maguire, J. Liu, X. Yao, S. P. N. Iyer, M.-H. Lam, E. G. Lund, et al. Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis J. Biol. Chem., August 6, 2004; 279(32): 33586 - 33592. [Abstract] [Full Text] [PDF]