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Effects of Ezetimibe Add-On to Statin Therapy on Adipokine Production in Obese and Metabolic Syndrome Patients With Atherosclerosis

Primary Purpose

Metabolic Syndrome, Obesity, Coronary Artery Disease

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Ezetimibe
Sponsored by
Canadian Collaborative Research Network
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metabolic Syndrome focused on measuring Ezetimibe, Statin, Low- density lipoprotein cholesterol, Adipokine, Adiponectin, C-reactive protein, Coronary artery disease, Metabolic Syndrome, Obesity

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients on statin therapy (no dose change within past 4 weeks) with LDL-c > 2mmol/l

  • Presence of atherosclerosis (CHD* and/or cerebrovascular disease** and/ or peripheral arterial disease (PAD)***) plus at least one of the following:

    1. Metabolic Syndrome (according to modified NCEP ATP III criteria, using waist circumference cut-offs of 80 cm for women and 90 cm for men in all subjects of Asian origin and cut-offs of 88 cm for women and 102 cm for men in all Caucasian subjects)

    2. Obesity (BMI > 30 Kg/m2 or waist circumference of > 102 for men and > 88 for women. For subjects of Asian origin the cutoff values should be 25, 90 and 80 respectively)

      • CHD defined as (any one of the following): previous myocardial infarction; coronary angiography demonstrating at least 50% diameter stenosis in an epicardial coronary artery or its major branch; previous percutaneous transluminal coronary angioplasty (PTCA) with or without stent implantation (atherectomy included) or previous coronary artery bypass grafting (CABG)

        • Cerebrovascular disease defined as (any one of the following): prior ischemic stroke, documented TIA, or flow-limiting stenosis in extracranial artery documented by Doppler or angiography.

          • PAD defined as (any one of the following): prior peripheral arterial revascularization (PTA or surgery), amputation, or documented intermittent claudication with ABI < 0.9

Exclusion Criteria:

  • Women who are pregnant, breast feeding, or not using a reliable method of contraception
  • Clinical signs of congestive heart failure or measured left ventricular ejection fraction <40%
  • Hemodynamically significant valvular heart disease or hypertrophic obstructive cardiomyopathy
  • Renal dysfunction (creatinine > 1.8 x ULN)
  • Hepatic disease (liver function test >1.5 x ULN [upper limit normal])
  • Other significant laboratory abnormalities that the investigator feels may compromise the patient's safety by participation in the study
  • History of systemic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematous), myositis/myopathic process, or cancer)
  • HIV
  • Use of steroids or chemotherapy drugs within the past year or chronic use of nonsteroidal anti-inflammatory drugs besides aspirin (use for > 2 weeks within the past year);
  • Known hypersensitivity to Ezetimibe
  • Participation in another clinical study concurrently or within the 30-day phase prior to screening for entry into the present study
  • Unwilling to provide written informed consent for study participant and/or
  • Unreliability as a study participant as based on the investigator's prior knowledge of the patient, such as the inability or willingness to participate in or complete the study or the presence of concurrent physical or psychological disorders that may make it impractical for the patient to participate in or complete the study.

Sites / Locations

  • Partners Research

Outcomes

Primary Outcome Measures

Change in adiponectin levels

Secondary Outcome Measures

Change in CRP, PAI-1, Il-6, TNF-α, resistin, leptin levels and serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, Triglycerides).

Full Information

First Posted
June 8, 2007
Last Updated
November 24, 2010
Sponsor
Canadian Collaborative Research Network
Collaborators
Schering-Plough
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1. Study Identification

Unique Protocol Identification Number
NCT00485121
Brief Title
Effects of Ezetimibe Add-On to Statin Therapy on Adipokine Production in Obese and Metabolic Syndrome Patients With Atherosclerosis
Official Title
Effects of Ezetimibe Add-On to Statin Therapy on Adipokine Production in Obese and Metabolic Syndrome Patients With Atherosclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2008
Overall Recruitment Status
Completed
Study Start Date
April 2007 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
April 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Canadian Collaborative Research Network
Collaborators
Schering-Plough

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to investigate the effects of adding ezetimibe to statin therapy on levels of inflammatory markers and adipokines in patients with atherosclerosis disease and features of the metabolic syndrome,whose LDL-c remains above target (> 2.0 mmol/L) despite statin monotherapy. We hypothesize that the addition of Ezetimibe (10mg per day for 12 weeks) to ongoing statin therapy in patients with atherosclerosis and features of the metabolic syndrome will favourably modify levels of inflammatory biomarkers and adipokines.
Detailed Description
Atherosclerotic cardiovascular disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment and prevention. While there has been a trend over the last half century showing a general decline in the age-adjusted death rates of heart disease and stroke, the increasing epidemic of obesity, followed closely by insulin resistance and type 2 diabetes will likely slow the decline and promise to reverse this trend. Obesity mediates increased cardiovascular disease risks through multiple pathways. Adipose tissue is no longer viewed as a passive repository for triacylglycerol storage and a source of free fatty acids (FFAs). It is recognized as a rich source of proinflammatory mediators, many of which are cytokines, growth factors and hormones that directly contribute to the proinflammatory milieu mediating vascular injury, insulin resistance and ultimately impacting on cardiovascular health. These proinflammatory adipocytokines, or adipokines include tumor necrosis factor- α (TNF α), interleukin-6 (IL-6), leptin, plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, resistin and more recently C-reactive protein (CRP). On the other hand, nitric oxide (NO) and another adipokine called adiponectin confer protection against inflammation and obesity-linked insulin resistance. The evolving role of augmented adipokine production in obese and insulin resistant states in cardiovascular disease risk opens new avenues for therapeutic interventions. Treatment of the metabolic syndrome will need to embrace new strategies to reduce the burden of proinflammatory adipokines. Lifestyle intervention remains the cornerstone therapy, but considerations should also be given to a number of drugs that can decrease the inflammatory adipokines. Ezetimibe selectively inhibits the absorption of biliary and dietary cholesterol and phytosterols at the intestinal brush border. When added to or coadministered with a statin, ezetimibe produces significant incremental LDL-C, apolipoprotein (apo) B, and triglyceride (TG) reductions, beneficial effects on high-density lipoprotein cholesterol (HDL-C) compared to statin monotherapy, and is well tolerated with a low incidence of side effects. It was previously demonstrated that in a 12 week trial that the addition of ezetimibe to simvastatin resulted in significant incremental reductions in CRP compared to simvastatin monotherapy. The outlined study protocol investigates the effects of adding ezetimibe to statin therapy on levels of inflammatory markers and adipokines in patients with atherosclerosis and features of the metabolic syndrome, whose LDL-c remains above target (> 2.0 mmol/L) despite statin monotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metabolic Syndrome, Obesity, Coronary Artery Disease
Keywords
Ezetimibe, Statin, Low- density lipoprotein cholesterol, Adipokine, Adiponectin, C-reactive protein, Coronary artery disease, Metabolic Syndrome, Obesity

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Ezetimibe
Primary Outcome Measure Information:
Title
Change in adiponectin levels
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Change in CRP, PAI-1, Il-6, TNF-α, resistin, leptin levels and serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, Triglycerides).
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients on statin therapy (no dose change within past 4 weeks) with LDL-c > 2mmol/l Presence of atherosclerosis (CHD* and/or cerebrovascular disease** and/ or peripheral arterial disease (PAD)***) plus at least one of the following: Metabolic Syndrome (according to modified NCEP ATP III criteria, using waist circumference cut-offs of 80 cm for women and 90 cm for men in all subjects of Asian origin and cut-offs of 88 cm for women and 102 cm for men in all Caucasian subjects) Obesity (BMI > 30 Kg/m2 or waist circumference of > 102 for men and > 88 for women. For subjects of Asian origin the cutoff values should be 25, 90 and 80 respectively) CHD defined as (any one of the following): previous myocardial infarction; coronary angiography demonstrating at least 50% diameter stenosis in an epicardial coronary artery or its major branch; previous percutaneous transluminal coronary angioplasty (PTCA) with or without stent implantation (atherectomy included) or previous coronary artery bypass grafting (CABG) Cerebrovascular disease defined as (any one of the following): prior ischemic stroke, documented TIA, or flow-limiting stenosis in extracranial artery documented by Doppler or angiography. PAD defined as (any one of the following): prior peripheral arterial revascularization (PTA or surgery), amputation, or documented intermittent claudication with ABI < 0.9 Exclusion Criteria: Women who are pregnant, breast feeding, or not using a reliable method of contraception Clinical signs of congestive heart failure or measured left ventricular ejection fraction <40% Hemodynamically significant valvular heart disease or hypertrophic obstructive cardiomyopathy Renal dysfunction (creatinine > 1.8 x ULN) Hepatic disease (liver function test >1.5 x ULN [upper limit normal]) Other significant laboratory abnormalities that the investigator feels may compromise the patient's safety by participation in the study History of systemic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematous), myositis/myopathic process, or cancer) HIV Use of steroids or chemotherapy drugs within the past year or chronic use of nonsteroidal anti-inflammatory drugs besides aspirin (use for > 2 weeks within the past year); Known hypersensitivity to Ezetimibe Participation in another clinical study concurrently or within the 30-day phase prior to screening for entry into the present study Unwilling to provide written informed consent for study participant and/or Unreliability as a study participant as based on the investigator's prior knowledge of the patient, such as the inability or willingness to participate in or complete the study or the presence of concurrent physical or psychological disorders that may make it impractical for the patient to participate in or complete the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Milan K Gupta, MD
Organizational Affiliation
Partners Research
Official's Role
Principal Investigator
Facility Information:
Facility Name
Partners Research
City
Brampton
State/Province
Ontario
ZIP/Postal Code
L6V 1B4
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

Effects of Ezetimibe Add-On to Statin Therapy on Adipokine Production in Obese and Metabolic Syndrome Patients With Atherosclerosis

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