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

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.

Study Overview

• Status: Completed
• Conditions: Dyslipidemia
• Intervention / Treatment: Drug: Simvastatin; Drug: Simvastatin + Ezetimibe; Drug: Ezetimibe

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
• Investigators: Principal Investigator: Antonio Hernández, MD, Phd, FISABIO - University Hospital Dr Peset

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: November 25, 2014
• First Submitted That Met QC Criteria: November 26, 2014
• First Posted (Estimate): December 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 8, 2018
• Last Update Submitted That Met QC Criteria: February 6, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Oxidative stress; Inflammation; Dyslipidemia; Endothelial function; Simvastatin; Lipid profile; Ezetimibe
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Ezetimibe; Ezetimibe, Simvastatin Drug Combination
• Other Study ID Numbers: SIM-EZE-2009-01