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

Study of Lipoprotein Subfractions, Inflammation, Oxidative Stress and Endothelial Function After Treatment With Simvastatin and Ezetimibe Administered Alone and in Combination in Hyperlipidemic Patients

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02304926

Enrollment

Registered

2014-12-02

Start date

2009-01-31

Completion date

2011-12-31

Last updated

2018-03-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dyslipidemia

Keywords

Dyslipidemia, Simvastatin, Ezetimibe, Lipid profile, Inflammation, Oxidative stress, Endothelial function

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.

Interventions

DRUGSimvastatin

simvastatin (40 mg/day) for 4 weeks

DRUGEzetimibe

ezetimibe (10 mg/day) for 4 weeks

DRUGSimvastatin + Ezetimibe

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Total Cholesterol Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Total cholesterol concentration was measured by enzymatic assay
Low-density Lipoprotein Cholesterol (LDLc) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Low-density lipoprotein cholesterol (LDLc) concentration was calculated using the method of Friedewald.
High-density Lipoprotein Cholesterol (HDLc) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	High-density lipoprotein cholesterol (HDLc) concentration was measured using a direct method
Triglycerides Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Triglyceride concentration were measured by enzymatic assay
Non-HDL Cholesterol Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Non-HDLc concentration was obtained by calculating the difference between total cholesterol and HDLc
Low Density Lipoprotein Size Before and After Simvastatin/Ezetimibe Administration	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.
Apolipoprotein B Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Levels of apolipoprotein B were determined by inmunonephelometry

Secondary

Measure	Time frame	Description
Leukocyte Rolling Flux Before and After Simvastatin/Ezetimibe Administration	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.
Leukocyte Adhesion Before and After Simvastatin/Ezetimibe Administration	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.
Leukocyte Rolling Velocity Before and After Simvastatin/Ezetimibe Administration	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.
Levels of High-sensitive C-reactive Protein (hsCRP) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Levels of high-sensitive C-reactive protein (hsCRP) were analysed by a latex-enhanced inmunonephelometric assay
Levels of Intercellular Adhesion Molecule 1 (ICAM-1) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	The intercellular adhesion molecule 1 (ICAM-1) was evaluated in serum by Luminex® 200™ system
Levels of E-selectin Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	E-selectin was evaluated in serum by Luminex® 200™ system
Levels of Vascular Cell Adhesion Molecule 1 (VCAM-1) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	The vascular cell adhesion molecule 1 (VCAM-1) was evaluated in serum by Luminex® 200™ system
Levels of Interleukin-6 (IL-6) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Levels of proinflammatory cytokines (interleukin-6 (IL-6)) were analysed with a Luminex® 200™ system
Levels of Tumor Necrosis Factor α (TNF-α) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Levels of proinflammatory cytokines (tumor necrosis factor α (TNF-α)) were analysed with a Luminex® 200™ system
Mitochondrial Oxygen (O2) Consumption Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Oxidative stress markers (mitochondrial oxygen (O2) consumption) was measured at baseline and after treatment by Clark electrode
Reactive Oxygen Species (ROS) Production Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Oxidative stress markers (Reactive oxygen species (ROS) production) was measured at baseline and after treatment by fluorometric techniques
Membrane Potential Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Oxidative stress markers (membrane potential) was measured at baseline and after treatment by fluorometric techniques
Levels of Glutathione (GSH) Before and After Simvastatin/Ezetimibe Administration	Baseline, 4 weeks and 8 weeks	Oxidative stress markers (levels of glutathione (GSH)) was measured at baseline and after treatment by fluorometric techniques

Participant flow

Participants by arm

Arm	Count
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	20
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	19
Total	39

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	2	1

Baseline characteristics

Characteristic	Simvastatin	Ezetimibe	Total
Age, Continuous	57.7 years STANDARD_DEVIATION 12.7	57.6 years STANDARD_DEVIATION 10.2	57.7 years STANDARD_DEVIATION 11.5
Body mass index	28.6 Kg/m2 STANDARD_DEVIATION 3.9	31.2 Kg/m2 STANDARD_DEVIATION 7.3	29.8 Kg/m2 STANDARD_DEVIATION 5.6
Diastolic blood pressure (mm Hg)	79 mm Hg STANDARD_DEVIATION 10	80 mm Hg STANDARD_DEVIATION 7	80 mm Hg STANDARD_DEVIATION 8
Sex: Female, Male Female	15 Participants	16 Participants	31 Participants
Sex: Female, Male Male	5 Participants	3 Participants	8 Participants
Systolic blood pressure	133 mm Hg STANDARD_DEVIATION 17	137 mm Hg STANDARD_DEVIATION 14	134 mm Hg STANDARD_DEVIATION 15

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 39	0 / 39
serious Total, serious adverse events	0 / 39	0 / 39