Comparing Tricor, Avandia, or Weight Loss to Lower Cardiovascular Risk Factors in People With High Triglycerides.
Comparison Fenofibrate, Rosiglitazone, or Weight Loss to Decrease Cardiovascular Risk in Insulin Resistant Dyslipidemic Individuals.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
It has been estimated that approximately ¼ of the US population has the Insulin Resistant Syndrome (IRS). The notion that insulin resistance and compensatory hyperinsulinemia lead to a cluster of abnormalities that increase CVD risk was first introduced in 1988, and central to the changes identified was a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. The atherogenic lipoprotein pattern associated with the IRS has grown to include enhanced postprandial lipemia and smaller and denser low-density lipoprotein (LDL) particles. In addition to being associated with insulin resistance and compensatory hyperinsulinemia, these changes in lipoprotein metabolism have been identified as increasing CVD risk. The power of the dyslipidemia associated with the IRS is reinforced by reports that the plasma TG/HDL-C concentration ratio is as powerful a predictor of CVD, if not more so, than the more conventional total plasma cholesterol/LDL-C concentration ratio, and evidence from the Copenhagen Male Study of the interaction between the plasma TG and HDL-C concentrations, "conventional" CVD risk factors, and CVD events. Specifically, these latter investigators were able to show in a prospective study (11) that CVD events were substantially attenuated in: 1) smokers; 2) patients with high blood pressure; 3) individuals with a high LDL-C concentration; and 4) subjects who were sedentary; as long as they were in the lowest 1/3rd of the population with the lowest TG/HDL-C concentration ratio and presumably insulin sensitive. Conversely, if they were in the tertile with the highest plasma TG/HDL-C concentration ratio, and presumably insulin resistant, they had a significant increase in CVD events in the absence of the four conventional CVD risk factors evaluated.
An obvious alternative therapeutic approach to decreasing CVD risk in patients with the IRS would be to administer a thiazolidinedione (TZD) compound in an effort to directly treat the basic defect of the syndrome. However, based upon our own results with rosiglitazone (ROSI) in several different patient populations, improvements in insulin sensitivity were not associated with a significant improvement in dyslipidemia. For example, in a recent study (unpublished) of ROSI-treated patients with type 2 diabetes, neither plasma TG (358 to 347 mg/dL) nor HDL-C (40 to 42 mg/dL) concentrations improved, and both total (215 to 239 mg/dL and LDL-C (118-142mg/dL) concentrations actually increased. Since the patients in this study became more insulin sensitive with treatment, and had lower daylong plasma glucose, insulin, and free fatty acid concentrations, the reason for the lack of a beneficial effect of ROSI on lipoprotein metabolism is not clear. On the other hand, given evidence of the importance of dyslipidemia in increasing CVD risk in insulin resistant individuals, it seems reasonable to question the notion that TZD compounds provide the most beneficial approach to decreasing CVD risk in the dyslipidemic patient with the IRS.
With this background in mind, we propose to initiate a study in which insulin resistant individuals with the dyslipidemia characteristic of the IRS will be randomized to treatment with fenofibrate,ROSI, or weight loss and the effect of these three treatments on CVD risk factors compared. It is postulated that although insulin resistance will improve to a greater degree with ROSI treatment, the atherogenic lipoprotein profile known to link IRS and CVD will only significantly improve following treatment with fenofibrate and effects of weight loss can effect both of these.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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California
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Stanford, California, United States, 94305
- Stanford University Medical Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Insulin Resistant Triglyceride 150 mg/dL or greater or triglyceride HDL-C ratio 3 or greater BMI 25-35
Exclusion Criteria:
Diabetes Mellitus History of gall stones History of CHF History of CAD Severe anemia,kidney, or liver disease
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Active Comparator: fenofibrate
160 mg daily for 12 weeks
|
Other Names:
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Active Comparator: rosiglitazone
4 mg/daily 4 weeks followed by 4 mg 2 x daily for 8 weeks
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Other Names:
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Active Comparator: calorie restricted diet
calorie restricted to achieve 0.5 kg weight loss/week x 12 weeks
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Pre- and Post-Intervention Triglyceride Levels
Time Frame: Baseline, 12 weeks
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Compare the change in mean triglyceride levels between groups after the interventions
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Baseline, 12 weeks
|
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Pre- and Post-Intervention LDL Cholesterol Levels
Time Frame: Baseline, 12 weeks
|
Compare the change in mean LDL Cholesterol levels between groups after the interventions
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Baseline, 12 weeks
|
|
Pre- and Post-Intervention HDL Cholesterol Levels
Time Frame: Baseline, 12 weeks
|
Compare the change in mean HDL Cholesterol levels between groups after the interventions
|
Baseline, 12 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Gerald M Reaven, MD, Stanford University
Publications and helpful links
General Publications
- Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595-607. doi: 10.2337/diab.37.12.1595.
- Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002 Jan 16;287(3):356-9. doi: 10.1001/jama.287.3.356.
- Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med. 1992 Jan;231(1):25-30. doi: 10.1111/j.1365-2796.1992.tb00494.x.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Body Weight
- Hyperinsulinism
- Body Weight Changes
- Lipid Metabolism Disorders
- Hyperlipidemias
- Dyslipidemias
- Weight Loss
- Insulin Resistance
- Hypertriglyceridemia
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites
- Hypolipidemic Agents
- Lipid Regulating Agents
- Rosiglitazone
- Fenofibrate
Other Study ID Numbers
- 79301
- SPO 28829
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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