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Effects of Simvastatin and Ezetimibe on Cardiovascular Risk Markers in Patients With Dyslipidemia

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ClinicalTrials.gov Identifier: NCT02304926
Recruitment Status : Completed
First Posted : December 2, 2014
Results First Posted : May 21, 2015
Last Update Posted : March 8, 2018
Sponsor:
Information provided by (Responsible Party):
Antonio Hernandez Mijares, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana

Brief Summary:
Coadministration of drugs is common in the pharmacologic treatment of dyslipidemia, with statins and ezetimibe generally constituting the medication of choice. By acting at different levels, the combination of these drugs allows the therapeutic objective to be achieved. However, it is not known how these drugs qualitatively affect the composition of lipoprotein subfractions, which differ in size and atherogenic potential. The investigators set out to evaluate this effect as well as their effects on inflammatory, oxidative stress and endothelial function parameters.

Condition or disease Intervention/treatment Phase
Dyslipidemia Drug: Simvastatin Drug: Ezetimibe Drug: Simvastatin + Ezetimibe Not Applicable

Detailed Description:
The study consisted of a randomised parallel trial and took place during a period of 2 months. A total of 42 hyperlipidemic patients were randomly assigned to one of 2 groups: one received simvastatin (40 mg/day) and the other received ezetimibe (10 mg/day) for 4 weeks, after which both groups were administered combined therapy for an additional 4-week period. Lipid profile, lipoprotein subfractions of LDL and HDL, inflammatory, oxidative stress and endothelial function parameters were evaluated.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Lipoprotein Subfractions, Inflammation, Oxidative Stress and Endothelial Function After Treatment With Simvastatin and Ezetimibe Administered Alone and in Combination in Hyperlipidemic Patients
Study Start Date : January 2009
Actual Primary Completion Date : December 2011
Actual Study Completion Date : December 2011

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Simvastatin
Hyperlipidemic patients received simvastatin (40 mg/day) for 4 weeks, after they were administered combined therapy (simvastatin, 40 mg/day plus ezetimibe,10 mg/day) for an additional 4-week period. Lipid profile, lipoprotein subfractions of LDL and HDL, inflammatory, oxidative stress and endothelial function parameters were evaluated.
Drug: Simvastatin
simvastatin (40 mg/day) for 4 weeks

Drug: Simvastatin + Ezetimibe
combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period

Experimental: Ezetimibe
Hyperlipidemic patients received ezetimibe (10 mg/day) for 4 weeks, after they were administered combined therapy (simvastatin, 40 mg/day plus ezetimibe,10 mg/day) for an additional 4-week period. Lipid profile, lipoprotein subfractions of LDL and HDL, inflammatory, oxidative stress and endothelial function parameters were evaluated.
Drug: Ezetimibe
ezetimibe (10 mg/day) for 4 weeks

Drug: Simvastatin + Ezetimibe
combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period




Primary Outcome Measures :
  1. Total Cholesterol Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Total cholesterol concentration was measured by enzymatic assay

  2. Low-density Lipoprotein Cholesterol (LDLc) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Low-density lipoprotein cholesterol (LDLc) concentration was calculated using the method of Friedewald.

  3. High-density Lipoprotein Cholesterol (HDLc) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    High-density lipoprotein cholesterol (HDLc) concentration was measured using a direct method

  4. Triglycerides Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Triglyceride concentration were measured by enzymatic assay

  5. Non-HDL Cholesterol Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Non-HDLc concentration was obtained by calculating the difference between total cholesterol and HDLc

  6. Low Density Lipoprotein Size Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    LDL subfractions were separated by high-resolution polyacrylamide gel tubes using the Lipoprint® system. The LDL electrophoretic profile allows 2 patterns to be defined: pattern A or large and buoyant LDL, and pattern non-A or small and dense LDL.

  7. Apolipoprotein B Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Levels of apolipoprotein B were determined by inmunonephelometry


Secondary Outcome Measures :
  1. Levels of High-sensitive C-reactive Protein (hsCRP) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Levels of high-sensitive C-reactive protein (hsCRP) were analysed by a latex-enhanced inmunonephelometric assay

  2. Levels of Interleukin-6 (IL-6) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Levels of proinflammatory cytokines (interleukin-6 (IL-6)) were analysed with a Luminex® 200™ system

  3. Levels of Tumor Necrosis Factor α (TNF-α) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Levels of proinflammatory cytokines (tumor necrosis factor α (TNF-α)) were analysed with a Luminex® 200™ system

  4. Mitochondrial Oxygen (O2) Consumption Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Oxidative stress markers (mitochondrial oxygen (O2) consumption) was measured at baseline and after treatment by Clark electrode

  5. Reactive Oxygen Species (ROS) Production Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Oxidative stress markers (Reactive oxygen species (ROS) production) was measured at baseline and after treatment by fluorometric techniques

  6. Membrane Potential Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Oxidative stress markers (membrane potential) was measured at baseline and after treatment by fluorometric techniques

  7. Levels of Glutathione (GSH) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Oxidative stress markers (levels of glutathione (GSH)) was measured at baseline and after treatment by fluorometric techniques

  8. Leukocyte Rolling Flux Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Interactions between leukocytes and human umbilical vein endothelial cells were evaluated by flow chamber microscopy. Leukocyte rolling was estimated as the number of leukocytes rolling over 100 μm2 of the endothelial monolayer during a 1-min period.

  9. Leukocyte Adhesion Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Interactions between leukocytes and human umbilical vein endothelial cells were evaluated by flow chamber microscopy. Adhesion was evaluated by counting the number of polymorphonuclear cells that maintained stable contact with human umbilical vein endothelial cells (HUVEC) for 30 seconds.

  10. Leukocyte Rolling Velocity Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    Interactions between leukocytes and human umbilical vein endothelial cells were evaluated by flow chamber microscopy.The rolling velocity in the field of focus was determined by measuring the time required by 20 consecutive leukocytes to cover a distance of 100 μm.

  11. Levels of Vascular Cell Adhesion Molecule 1 (VCAM-1) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    The vascular cell adhesion molecule 1 (VCAM-1) was evaluated in serum by Luminex® 200™ system

  12. Levels of Intercellular Adhesion Molecule 1 (ICAM-1) Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    The intercellular adhesion molecule 1 (ICAM-1) was evaluated in serum by Luminex® 200™ system

  13. Levels of E-selectin Before and After Simvastatin/Ezetimibe Administration [ Time Frame: Baseline, 4 weeks and 8 weeks ]
    E-selectin was evaluated in serum by Luminex® 200™ system



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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:

  • LDL cholesterol concentration of between 160-190 mg/dl in patients with less than 2 cardiovascular risk factors
  • LDL concentration of between 130-160 mg/dl in patients that presented 2 or more cardiovascular risk factors.

Cardiovascular risk factors were defined as: age (≥ 45 years in men and ≥55 years in women), a smoking habit, hypertension (≥140/90 mmHg), diabetes mellitus, a high-density lipoprotein (HDL) cholesterol concentration of ≤ 40mg/dl, and a family history of cardiovascular disease.

Exclusion Criteria:

  • Triglyceride concentration > 400 mg/dl
  • Diabetes Mellitus
  • Kidney, liver, or thyroid disease

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): NCT02304926


Sponsors and Collaborators
Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
Investigators
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Principal Investigator: Antonio Hernández, MD, Phd FISABIO - University Hospital Dr Peset
Publications:
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Responsible Party: Antonio Hernandez Mijares, MD, Phd, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
ClinicalTrials.gov Identifier: NCT02304926    
Other Study ID Numbers: SIM-EZE-2009-01
First Posted: December 2, 2014    Key Record Dates
Results First Posted: May 21, 2015
Last Update Posted: March 8, 2018
Last Verified: February 2018
Keywords provided by Antonio Hernandez Mijares, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana:
Dyslipidemia
Simvastatin
Ezetimibe
Lipid profile
Inflammation
Oxidative stress
Endothelial function
Additional relevant MeSH terms:
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Dyslipidemias
Lipid 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