Effects of Ezetimibe, Simvastatin, and Vytorin on Reducing L5 a Subfraction of LDL in Patients With Metabolic Syndrome. (Merck-123)

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ClinicalTrials.gov Identifier: NCT00988364

Recruitment Status : Completed

First Posted : October 2, 2009

Last Update Posted : July 25, 2022

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Sponsor:

Collaborator:

Merck Sharp & Dohme LLC

Information provided by (Responsible Party):

Chu-Huang Chen, Baylor College of Medicine

Study Description

Brief Summary:

The purpose of this study is:

To identify the common factor for L5 prevalence in patients with Metabolic Syndrome.
To determine whether Ezetimibe, Simvastatin, and Vytorin can correct the L5- promoting factor and reduce L5 in Metabolic Syndrome patients.

Condition or disease	Intervention/treatment	Phase
Metabolic Syndrome	Drug: Simvastatin Drug: Vytorin Drug: Placebo Drug: Ezetimibe	Phase 4

Detailed Description:

Epidemiological evidence indicates that metabolic syndrome (MS) is a strong predisposing condition for atherosclerosis. Elevation of plasma low-density lipoprotein (LDL) cholesterol(LDL-C) concentration is the most important risk factor for atherosclerosis; however, LDL-C elevation is not a criterion for metabolic syndrome, raising the question of LDL's role in the syndrome's association with atherosclerosis. L5, a highly electronegative and mildly oxidized LDL subfraction that we recently isolated from hypercholesterolemic human plasma, may provide a key to answering this question. In cultured vascular endothelial cells (EC), L5 inhibits proliferation and induces apoptosis and monocyte-EC adhesion. In our preliminary studies, L5 could also be detected in patients with MS without elevated LDL-C. Because other LDL subfractions were harmless to EC, the presence of MS-L5 prompted us to hypothesize that the atherogenic role of LDL is not solely determined by plasma LDL-C concentration, but more importantly, by its composition. The proposed study is designed to test this hypothesis. The first question we will address is what lipid factor determines the prevalence of L5 in MS.

Subsequently, we will examine whether treatment with selected medicines can effectively reduce L5 in MS patients by correcting the factor favorable for L5 formation.

We are in the process of identifying the active components of L5 to fully characterize the atherogenic role of L5 in MS,. In the current proposal, we focus our interest on the efficacy of Ezetimibe, Simvastatin, and Vytorin in reducing L5 from the plasma of MS patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	24 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Double (Participant, Care Provider)
Primary Purpose:	Treatment
Official Title:	Effects of Ezetimibe, Simvastatin, and Vytorin on Reducing L5 in Patients With Metabolic Syndrome
Study Start Date :	March 2007
Actual Primary Completion Date :	February 2008
Actual Study Completion Date :	February 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cholesterol Medicines Metabolic Syndrome

Drug Information available for: Simvastatin Ezetimibe

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Ezetimibe Randomly chosen participants will receive ezetimibe 10mg daily for 3 months.	Drug: Ezetimibe Ezetimibe 10mg daily for 3 months. Other Name: Zetia
Active Comparator: Simvastatin Randomly chosen participants will receive Simvastatin 20mg daily for 3 months.	Drug: Simvastatin Simvastatin 20mg daily for 3 months. Other Name: Zocor
Active Comparator: Vytorin Randomly chosen participants will receive Vytorin 20/10mg daily for 3 months.	Drug: Vytorin Vytorin 20/10mg daily for 3 months. Other Name: Ezetimibe/Simvastatin
Placebo Comparator: Placebo Randomly chosen participants will receive Placebo tab 1 daily for 3 months.	Drug: Placebo Placebo one tablet daily times 3 months. Other Name: Control

Outcome Measures

Primary Outcome Measures :

To identify the common factor for L5 prevalence in Metabolic Syndrome patients. [ Time Frame: 3 months ]
Patient's blood samples will be collected at the corresponding time points. L5 will be purified by ultracentrifugation, FPLC. Quantification analysis will indicate the L5 concentration, lipoprotein distribution profile in each participant."

Secondary Outcome Measures :

To determine whether Ezetimibe, Simvastatin, and Vytorin can correct the L5- promoting factor and reduce L5 in Metabolic Syndrome. [ Time Frame: 3 months ]
Patient's blood samples will be collected at each corresponding time point for L5 purification. L5 quantification and characterization will be investigated with chemical analysis, proteomics and in-vitro cell signaling analysis. Final data analysis will determine total L5 concentration, lipid/lipoprotein profile difference before and after treatment, and its cell signaling impact in endothelial/smooth muscle cell model.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Participants who meet 3 or more of the 5 criteria specified in the ATPIII guidelines will be recruited.
The 5 criteria are:
1. abdominal obesity (men>40 inches, women >35 inches);
2. TG> 150mg/dL;
3. low HDL-C (men < 40mg/dL, women < 50 mg/dL);
4. high blood pressure (>or=130/>or=85 mmHg);
5. fasting glucose > or = 110mg/dL.
People with different ethnic backgrounds will be included.

Exclusion Criteria:

symptomatic coronary artery disease
peripheral vascular disease
cerebral ischemia (stroke)
smoking
hypothyroidism
kidney diseases
consumption of antioxidation supplements/drugs or use of lipid-lowering drugs in the last 3 months
women who are pregnant, nursing, or planning to become pregnant

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00988364

Locations

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United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030

Sponsors and Collaborators

Baylor College of Medicine

Merck Sharp & Dohme LLC

Investigators

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Principal Investigator:	Chu-Huang Chen, M.D., Ph.D.	Baylor College of Medicine
Study Director:	Christie Ballantyne, M.D.	Baylor College of Medicine

More Information

Publications:

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Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP; Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003 May 20;107(19):2409-15. doi: 10.1161/01.CIR.0000068312.21969.C8. Epub 2003 Apr 28.

Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, Sharrett AR. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004 Feb 24;109(7):837-42. doi: 10.1161/01.CIR.0000116763.91992.F1. Epub 2004 Feb 2.

Chan DC, Watts GF, Barrett PH, Mamo JC, Redgrave TG. Markers of triglyceride-rich lipoprotein remnant metabolism in visceral obesity. Clin Chem. 2002 Feb;48(2):278-83.

Chen CH, Jiang T, Yang JH, Jiang W, Lu J, Marathe GK, Pownall HJ, Ballantyne CM, McIntyre TM, Henry PD, Yang CY. Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation. 2003 Apr 29;107(16):2102-8. doi: 10.1161/01.CIR.0000065220.70220.F7. Epub 2003 Apr 14.

Chen CH, Pace PW, Karakoc ND, Lu J, Chen HH, Henry PD, Pownall HJ Foreyt JP, Ballantyne CM, Yang CY. Effective reduction of novel atherogenic LDL subfraction by atorvastatin in patients with hypercholesteremia. J AM Coll Cardiol. 2004:43(suppl A):486A (Abstract)

Chappey B, Myara I, Benoit MO, Maziere C, Maziere JC, Moatti N. Characteristics of ten charge-differing subfractions isolated from human native low-density lipoproteins (LDL). No evidence of peroxidative modifications. Biochim Biophys Acta. 1995 Dec 7;1259(3):261-70. doi: 10.1016/0005-2760(95)00172-7.

De Castellarnau C, Sanchez-Quesada JL, Benitez S, Rosa R, Caveda L, Vila L, Ordonez-Llanos J. Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells. Arterioscler Thromb Vasc Biol. 2000 Oct;20(10):2281-7. doi: 10.1161/01.atv.20.10.2281.

Demuth K, Myara I, Chappey B, Vedie B, Pech-Amsellem MA, Haberland ME, Moatti N. A cytotoxic electronegative LDL subfraction is present in human plasma. Arterioscler Thromb Vasc Biol. 1996 Jun;16(6):773-83. doi: 10.1161/01.atv.16.6.773.

Kleinman Y, Krul ES, Burnes M, Aronson W, Pfleger B, Schonfeld G. Lipolysis of LDL with phospholipase A2 alters the expression of selected apoB-100 epitopes and the interaction of LDL with cells. J Lipid Res. 1988 Jun;29(6):729-43.

La Belle M, Blanche PJ, Krauss RM. Charge properties of low density lipoprotein subclasses. J Lipid Res. 1997 Apr;38(4):690-700.

Lee SJ, Campos H, Moye LA, Sacks FM. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):853-8. doi: 10.1161/01.ATV.0000066131.01313.EB. Epub 2003 Mar 13.

Libby P. Inflammation in atherosclerosis. Nature. 2002 Dec 19-26;420(6917):868-74. doi: 10.1038/nature01323.

Sanchez-Quesada JL, Benitez S, Ordonez-Llanos J. Electronegative low-density lipoprotein. Curr Opin Lipidol. 2004 Jun;15(3):329-35. doi: 10.1097/00041433-200406000-00014.

Sevanian A, Bittolo-Bon G, Cazzolato G, Hodis H, Hwang J, Zamburlini A, Maiorino M, Ursini F. LDL- is a lipid hydroperoxide-enriched circulating lipoprotein. J Lipid Res. 1997 Mar;38(3):419-28.

Steinberg D. Lewis A. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation. 1997 Feb 18;95(4):1062-71. doi: 10.1161/01.cir.95.4.1062. No abstract available.

Simons L, Tonkon M, Masana L, Maccubbin D, Shah A, Lee M, Gumbiner B. Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome. Curr Med Res Opin. 2004 Sep;20(9):1437-45. doi: 10.1185/030079904x2321.

van Heek M, Austin TM, Farley C, Cook JA, Tetzloff GG, Davis HR. Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters. Diabetes. 2001 Jun;50(6):1330-5. doi: 10.2337/diabetes.50.6.1330.

Yang CY, Raya JL, Chen HH, Chen CH, Abe Y, Pownall HJ, Taylor AA, Smith CV. Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. Arterioscler Thromb Vasc Biol. 2003 Jun 1;23(6):1083-90. doi: 10.1161/01.ATV.0000071350.78872.C4. Epub 2003 Apr 10.

Yang CY, Chen HH, Huang MT, Raya JL, Yang JH, Chen CH, Gaubatz JW, Pownall HJ, Taylor AA, Ballantyne CM, Jenniskens FA, Smith CV. Pro-apoptotic low-density lipoprotein subfractions in type II diabetes. Atherosclerosis. 2007 Aug;193(2):283-91. doi: 10.1016/j.atherosclerosis.2006.08.059. Epub 2006 Oct 9.

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Responsible Party:	Chu-Huang Chen, Principal Investigator, Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT00988364
Other Study ID Numbers:	H-20169 MK0653A ( Other Grant/Funding Number: Merck )
First Posted:	October 2, 2009 Key Record Dates
Last Update Posted:	July 25, 2022
Last Verified:	July 2022

Keywords provided by Chu-Huang Chen, Baylor College of Medicine:


Metabolic Syndrome LDL subfraction L5 The reduction of LDL in patients with Metabolic Syndrome The prevalence of L5 in patients with Metabolic Syndrome The reduction of L5 in patients with Metabolic Syndrome

Additional relevant MeSH terms:

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Metabolic Syndrome Syndrome Disease Pathologic Processes Insulin Resistance Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases Simvastatin	Ezetimibe Ezetimibe, Simvastatin Drug Combination Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors

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