Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus, Type 2, Congestive Heart Failure, Cardiopulmonary exercise testing, intracellular cardiomyocyte triglycerides, thiazolidinedione, rosiglitazone, nuclear magnetic resonance
Brief summary
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
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.
Interventions
DRUGrosiglitazone
6 months of treatment of blinded study drug
DRUGplacebo
blinded treatment with matching placebo
Sponsors
GlaxoSmithKline
Abbott RDx Cardiometabolic
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Oxygen Uptake (VO2) | 6 months | measurement of peak oxygen uptake (VO2peak) during treadmill exercise, in units of milliliters of oxygen per kilogram of fat-free mass per minute |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months | 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 (%) |
| Percentage of Patients Developing New or Worsening Peripheral Edema | 6 months | 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 |
Countries
United States
Participant flow
Recruitment details
recruitment 2/05-10/06
Participants by arm
| Arm | Count |
|---|---|
| Rosiglitazone 4mg oral tablet once daily titrated to 8mg oral tablet once daily | 74 |
| Placebo blinded placebo treatment matching 4mg placebo tablet oral once daily titrated to 8mg matching placebo tablet oral once daily | 76 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Withdrawal by Subject | 18 | 19 |
Baseline characteristics
| Characteristic | Placebo | Rosiglitazone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 74 Participants | 150 Participants |
| Age Continuous | 55.7 years STANDARD_DEVIATION 8.3 | 57.0 years STANDARD_DEVIATION 8.7 | 56.2 years STANDARD_DEVIATION 8.4 |
| Region of Enrollment United States | 76 participants | 74 participants | 150 participants |
| Sex: Female, Male Female | 30 Participants | 32 Participants | 62 Participants |
| Sex: Female, Male Male | 46 Participants | 42 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 74 | 0 / 76 |
| serious Total, serious adverse events | 3 / 74 | 2 / 76 |
Outcome results
Primary
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
Time frame: 6 months
Population: completed baseline and end-of-study cardiopulmonary exercise test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone | Peak Oxygen Uptake (VO2) | 26.1 ml O2 uptake/kg fat-free mass/minute | Standard Deviation 7 |
| Placebo | Peak Oxygen Uptake (VO2) | 27.6 ml O2 uptake/kg fat-free mass/minute | Standard Deviation 6.6 |
Comparison: powered to detect difference of at least 10% between groupsp-value: 0.26t-test, 2 sided
Secondary
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 (%)
Time frame: 6 months
Population: analysis limited to those with interpretable imaging data at baseline and end of study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone | Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months | 0.9 percentage of fat-to-water; % | Standard Deviation 0.49 |
| Placebo | Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months | 0.85 percentage of fat-to-water; % | Standard Deviation 0.5 |
Comparison: powered to detect at least 33% difference between groupsp-value: >0.05t-test, 2 sided
Secondary
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
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosiglitazone | Percentage of Patients Developing New or Worsening Peripheral Edema | 54 percentage of patients |
| Placebo | Percentage of Patients Developing New or Worsening Peripheral Edema | 33 percentage of patients |
Comparison: comparative incidencep-value: 0.03Chi-squared