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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Simvastatin | Experimental | 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. |
|
| Ezetimibe | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Simvastatin | Drug | simvastatin (40 mg/day) for 4 weeks |
| |
| Ezetimibe |
| Measure | Description | Time Frame |
|---|---|---|
| Total Cholesterol Before and After Simvastatin/Ezetimibe Administration | Total cholesterol concentration was measured by enzymatic assay | Baseline, 4 weeks and 8 weeks |
| Low-density Lipoprotein Cholesterol (LDLc) Before and After Simvastatin/Ezetimibe Administration | Low-density lipoprotein cholesterol (LDLc) concentration was calculated using the method of Friedewald. | Baseline, 4 weeks and 8 weeks |
| High-density Lipoprotein Cholesterol (HDLc) Before and After Simvastatin/Ezetimibe Administration | High-density lipoprotein cholesterol (HDLc) concentration was measured using a direct method | Baseline, 4 weeks and 8 weeks |
| Triglycerides Before and After Simvastatin/Ezetimibe Administration | Triglyceride concentration were measured by enzymatic assay | Baseline, 4 weeks and 8 weeks |
| Non-HDL Cholesterol Before and After Simvastatin/Ezetimibe Administration | Non-HDLc concentration was obtained by calculating the difference between total cholesterol and HDLc | Baseline, 4 weeks and 8 weeks |
| Low Density Lipoprotein Size Before and After Simvastatin/Ezetimibe Administration | 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. | Baseline, 4 weeks and 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Levels of High-sensitive C-reactive Protein (hsCRP) Before and After Simvastatin/Ezetimibe Administration | Levels of high-sensitive C-reactive protein (hsCRP) were analysed by a latex-enhanced inmunonephelometric assay | Baseline, 4 weeks and 8 weeks |
| Levels of Interleukin-6 (IL-6) Before and After Simvastatin/Ezetimibe Administration |
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Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Antonio Hernández, MD, Phd | FISABIO - University Hospital Dr Peset | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20525999 | Background | Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. Eur Heart J. 2010 Jul;31(13):1633-9. doi: 10.1093/eurheartj/ehq181. Epub 2010 Jun 6. | |
| 21271793 | Background |
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| ID | Title | Description |
|---|---|---|
| FG000 | Simvastatin | 20 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. Simvastatin: simvastatin (40 mg/day) for 4 weeks Simvastatin + Ezetimibe: combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
| FG001 | Ezetimibe | 20 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. Ezetimibe: ezetimibe (10 mg/day) for 4 weeks Simvastatin + Ezetimibe: combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Simvastatin | 20 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. Simvastatin: simvastatin (40 mg/day) for 4 weeks Simvastatin + Ezetimibe: combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Cholesterol Before and After Simvastatin/Ezetimibe Administration | Total cholesterol concentration was measured by enzymatic assay | Posted | Mean | Standard Deviation | mg/dl | Baseline, 4 weeks and 8 weeks |
|
Adverse events were not collected
Adverse events were not collected
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Adverse Events Were Not Collected | Adverse events were not collected |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Antonio Hernández | FISABIO-University Hospital Dr Peset | 961622492 | hernandez_antmij@gva.es |
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| ID | Term |
|---|---|
| D050171 | Dyslipidemias |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D019821 | Simvastatin |
| D000069438 | Ezetimibe |
| D000069499 | Ezetimibe, Simvastatin Drug Combination |
| ID | Term |
|---|---|
| D008148 | Lovastatin |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| Drug |
ezetimibe (10 mg/day) for 4 weeks |
|
| Simvastatin + Ezetimibe | Drug | combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
|
| Apolipoprotein B Before and After Simvastatin/Ezetimibe Administration | Levels of apolipoprotein B were determined by inmunonephelometry | Baseline, 4 weeks and 8 weeks |
Levels of proinflammatory cytokines (interleukin-6 (IL-6)) were analysed with a Luminex® 200™ system |
| Baseline, 4 weeks and 8 weeks |
| Levels of Tumor Necrosis Factor α (TNF-α) Before and After Simvastatin/Ezetimibe Administration | Levels of proinflammatory cytokines (tumor necrosis factor α (TNF-α)) were analysed with a Luminex® 200™ system | Baseline, 4 weeks and 8 weeks |
| Mitochondrial Oxygen (O2) Consumption Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (mitochondrial oxygen (O2) consumption) was measured at baseline and after treatment by Clark electrode | Baseline, 4 weeks and 8 weeks |
| Reactive Oxygen Species (ROS) Production Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (Reactive oxygen species (ROS) production) was measured at baseline and after treatment by fluorometric techniques | Baseline, 4 weeks and 8 weeks |
| Membrane Potential Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (membrane potential) was measured at baseline and after treatment by fluorometric techniques | Baseline, 4 weeks and 8 weeks |
| Levels of Glutathione (GSH) Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (levels of glutathione (GSH)) was measured at baseline and after treatment by fluorometric techniques | Baseline, 4 weeks and 8 weeks |
| Leukocyte Rolling Flux Before and After Simvastatin/Ezetimibe Administration | 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. | Baseline, 4 weeks and 8 weeks |
| Leukocyte Adhesion Before and After Simvastatin/Ezetimibe Administration | 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. | Baseline, 4 weeks and 8 weeks |
| Leukocyte Rolling Velocity Before and After Simvastatin/Ezetimibe Administration | 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. | Baseline, 4 weeks and 8 weeks |
| Levels of Vascular Cell Adhesion Molecule 1 (VCAM-1) Before and After Simvastatin/Ezetimibe Administration | The vascular cell adhesion molecule 1 (VCAM-1) was evaluated in serum by Luminex® 200™ system | Baseline, 4 weeks and 8 weeks |
| Levels of Intercellular Adhesion Molecule 1 (ICAM-1) Before and After Simvastatin/Ezetimibe Administration | The intercellular adhesion molecule 1 (ICAM-1) was evaluated in serum by Luminex® 200™ system | Baseline, 4 weeks and 8 weeks |
| Levels of E-selectin Before and After Simvastatin/Ezetimibe Administration | E-selectin was evaluated in serum by Luminex® 200™ system | Baseline, 4 weeks and 8 weeks |
| Florentin M, Liberopoulos EN, Moutzouri E, Rizos CV, Tselepis AD, Elisaf MS. The effect of simvastatin alone versus simvastatin plus ezetimibe on the concentration of small dense low-density lipoprotein cholesterol in subjects with primary hypercholesterolemia. Curr Med Res Opin. 2011 Mar;27(3):685-92. doi: 10.1185/03007995.2010.546394. Epub 2011 Jan 27. |
| 15639688 | Background | Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson-Levonas AO, Sapre A, Donahue SR; Ezetimibe Study Group. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther. 2004 Nov;26(11):1758-73. doi: 10.1016/j.clinthera.2004.11.016. |
| BG001 | Ezetimibe | 20 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. Ezetimibe: ezetimibe (10 mg/day) for 4 weeks Simvastatin + Ezetimibe: combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Body mass index | Mean | Standard Deviation | Kg/m2 |
|
| Systolic blood pressure | Mean | Standard Deviation | mm Hg |
|
| Diastolic blood pressure (mm Hg) | Mean | Standard Deviation | mm Hg |
|
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. Ezetimibe: ezetimibe (10 mg/day) for 4 weeks Simvastatin + Ezetimibe: combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period |
|
|
|
| Primary | Low-density Lipoprotein Cholesterol (LDLc) Before and After Simvastatin/Ezetimibe Administration | Low-density lipoprotein cholesterol (LDLc) concentration was calculated using the method of Friedewald. | Posted | Mean | Standard Deviation | mg/dl | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Levels of High-sensitive C-reactive Protein (hsCRP) Before and After Simvastatin/Ezetimibe Administration | Levels of high-sensitive C-reactive protein (hsCRP) were analysed by a latex-enhanced inmunonephelometric assay | Posted | Mean | Standard Deviation | mg/l | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Levels of Interleukin-6 (IL-6) Before and After Simvastatin/Ezetimibe Administration | Levels of proinflammatory cytokines (interleukin-6 (IL-6)) were analysed with a Luminex® 200™ system | Posted | Mean | Standard Deviation | pg/ml | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Levels of Tumor Necrosis Factor α (TNF-α) Before and After Simvastatin/Ezetimibe Administration | Levels of proinflammatory cytokines (tumor necrosis factor α (TNF-α)) were analysed with a Luminex® 200™ system | Posted | Mean | Standard Deviation | pg/ml | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Primary | High-density Lipoprotein Cholesterol (HDLc) Before and After Simvastatin/Ezetimibe Administration | High-density lipoprotein cholesterol (HDLc) concentration was measured using a direct method | Posted | Mean | Standard Deviation | mg/dl | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Primary | Triglycerides Before and After Simvastatin/Ezetimibe Administration | Triglyceride concentration were measured by enzymatic assay | Posted | Median | Inter-Quartile Range | mg/dl | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Mitochondrial Oxygen (O2) Consumption Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (mitochondrial oxygen (O2) consumption) was measured at baseline and after treatment by Clark electrode | Posted | Mean | Standard Deviation | Nmol O2/min/million cells | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Reactive Oxygen Species (ROS) Production Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (Reactive oxygen species (ROS) production) was measured at baseline and after treatment by fluorometric techniques | Posted | Mean | Standard Deviation | Fluorescence Units | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Membrane Potential Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (membrane potential) was measured at baseline and after treatment by fluorometric techniques | Posted | Mean | Standard Deviation | Fluorescence Units | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Levels of Glutathione (GSH) Before and After Simvastatin/Ezetimibe Administration | Oxidative stress markers (levels of glutathione (GSH)) was measured at baseline and after treatment by fluorometric techniques | Posted | Mean | Standard Deviation | Fluorescence Units | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Leukocyte Rolling Flux Before and After Simvastatin/Ezetimibe Administration | 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. | Posted | Mean | Standard Deviation | polymorphonuclear cells/min | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Primary | Non-HDL Cholesterol Before and After Simvastatin/Ezetimibe Administration | Non-HDLc concentration was obtained by calculating the difference between total cholesterol and HDLc | Posted | Mean | Standard Deviation | mg/dl | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Primary | Low Density Lipoprotein Size Before and After Simvastatin/Ezetimibe Administration | 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. | Posted | Mean | Standard Deviation | Angström | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Leukocyte Adhesion Before and After Simvastatin/Ezetimibe Administration | 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. | Posted | Mean | Standard Deviation | polymorphonuclear cells/mm2 | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Leukocyte Rolling Velocity Before and After Simvastatin/Ezetimibe Administration | 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. | Posted | Mean | Standard Deviation | micrometer/second | Baseline, 4 weeks and 8 weeks |
|
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|
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| Primary | Apolipoprotein B Before and After Simvastatin/Ezetimibe Administration | Levels of apolipoprotein B were determined by inmunonephelometry | Posted | Mean | Standard Deviation | mg/dl | Baseline, 4 weeks and 8 weeks |
|
|
|
|
| Secondary | Levels of Vascular Cell Adhesion Molecule 1 (VCAM-1) Before and After Simvastatin/Ezetimibe Administration | The vascular cell adhesion molecule 1 (VCAM-1) was evaluated in serum by Luminex® 200™ system | Posted | Mean | Standard Deviation | ng/ml | Baseline, 4 weeks and 8 weeks |
|
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|
|
| Secondary | Levels of Intercellular Adhesion Molecule 1 (ICAM-1) Before and After Simvastatin/Ezetimibe Administration | The intercellular adhesion molecule 1 (ICAM-1) was evaluated in serum by Luminex® 200™ system | Posted | Mean | Standard Deviation | ng/ml | Baseline, 4 weeks and 8 weeks |
|
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|
|
| Secondary | Levels of E-selectin Before and After Simvastatin/Ezetimibe Administration | E-selectin was evaluated in serum by Luminex® 200™ system | Posted | Mean | Standard Deviation | ng/ml | Baseline, 4 weeks and 8 weeks |
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|
| 0 |
| 39 |
| 0 |
| 39 |
| EG001 | Adverse events were not collected | 0 | 39 | 0 | 39 |
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D001384 | Azetidines |
| D001385 | Azetines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
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