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

Study Overview
=================
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.

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.

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

Conditions
-----------------
Dyslipidemia

Intervention / Treatment
-----------------
* Drug: Simvastatin
* Drug: Ezetimibe
* Drug: Simvastatin + Ezetimibe


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>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<br>* simvastatin (40 mg/day) for 4 weeks<br>Drug: Simvastatin + Ezetimibe<br>* combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period<br>|
| Experimental: Ezetimibe<br>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<br>* ezetimibe (10 mg/day) for 4 weeks<br>Drug: Simvastatin + Ezetimibe<br>* combined therapy simvastatin (40 mg/day) + ezetimibe (10 mg/day) for 4-week period<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 
| Apolipoprotein B Before and After Simvastatin/Ezetimibe Administration | Levels of apolipoprotein B were determined by inmunonephelometry | Baseline, 4 weeks and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dyslipidemia, Simvastatin, Ezetimibe, Lipid profile, Inflammation, Oxidative stress, Endothelial function