Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride

Study Overview
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Brief Summary
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The purpose of this study is to determine if rosiglitazone treatment improves integrated cardiovascular performance in patients at risk for congestive heart failure. A second aim of this study is to determine if treatment with rosiglitazone decreases intracellular (ectopic) triglyceride (TG) deposition in cardiomyocytes using nuclear magnetic resonance (NMR) techniques, and how changes in intra-myocardial lipid content relate to changes in cardiac structure and function.

Detailed Description
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Cardiovascular disease (CVD), including congestive heart failure (CHF), accounts for over 75% of deaths among patients with diabetes. Thus, it is imperative to rigorously evaluate existing and emerging hypoglycemic therapies with regard to their cardiovascular consequences. The thiazolidinedione (TZD) class of drugs, alone or in combination with other oral hypoglycemic medications or with insulin, has emerged as a safe and effective treatment of hyperglycemia in type 2 diabetes. Both in vitro and in vivo studies have revealed favorable pleiotropic effects of TZD on myocyte and ventricular structure and function. However, approximately 10% of patients taking TZDs develop peripheral edema and some patients have developed heart failure decompensation on the drug. These observations have led to a Food and Drug Administration (FDA) warning regarding the use of TZDs in patients with or at high risk of developing congestive heart failure (CHF). The exact effects of TZDs on integrated cardiovascular performance remain unclear. The primary hypothesis of this study is that TZD treatment improves integrated cardiovascular performance in patients at risk for CHF by improving both central (i.e. cardiac output) and peripheral (i.e. vascular resistance) function. Recently, we have developed a sensitive, reproducible noninvasive assay to measure intra-cardiomyocyte fat, which varies widely in amount between individuals. The relationship between the amount of cardiomyocyte triglyceride accumulation and LV mass and function remains unclear. TZDs have been previously shown to be associated with decreases in the TG content of the liver and muscle. The secondary hypothesis being tested in this study is that TZD treatment improves cardiac function by decreasing intra-cardiac myocyte triglyceride content. Comparisons: Peak oxygen uptake (VO2) during cardiopulmonary exercise testing in individuals randomized to rosiglitazone, compared to those on placebo. Amount of intra-myocardial triglycerides using NMR techniques in in individuals randomized to rosiglitazone, compared to those on placebo.

Official Title
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Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: rosiglitazone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: type 2 diabetes mellitus (prior clinical diagnosis and current use of hypoglycemic medical therapy or by new diagnosis according to ADA criteria) with at least one of the following: prior diagnosis of cardiovascular disease (CAD, MI, revascularization, CVA/TIA, carotid or peripheral arterial disease) at least one additional CVD risk factor (smoking, hypertension, hypercholesterolemia, albuminuria, family history of premature CAD, or documented hsCRP>3) Exclusion Criteria: treatment with a TZD within prior 6 months documented intolerance to TZD history or evidence of CHF AST/ALT>3X upper limits of normal creatinine >2.5

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rosiglitazone<br>4mg titrated to 8mg daily | Drug: rosiglitazone<br>* 6 months of treatment of blinded study drug<br>* Other names: Avandia;|
| Placebo Comparator: Placebo<br>blinded matching placebo treatment | Drug: placebo<br>* blinded treatment with matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Oxygen Uptake (VO2) | measurement of peak oxygen uptake (VO2peak) during treadmill exercise, in units of milliliters of oxygen per kilogram of fat-free mass per minute | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months | proton magnetic resonance spectroscopy determination of intra-myocardial triglyceride content at baseline and after 6 months, with triglyceride quantified analyzing fat and water signals assuming monoexponential signal decay and expressed as a percentage of fat-to-water (%) | 6 months | 
| Percentage of Patients Developing New or Worsening Peripheral Edema | clinical evaluation of peripheral edema by physical exam at each study visit by a cardiologist using standard clinical severity scale 0-4, with new/worsening edema defined as any edema in patients with none at baseline, OR increase in severity by 2 or more points in patients with edema at baseline | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Congestive Heart Failure, Cardiopulmonary exercise testing, intracellular cardiomyocyte triglycerides, thiazolidinedione, rosiglitazone, nuclear magnetic resonance