Diabetes
Conditions
Keywords
Cardiovascular risk, biological markers
Brief summary
SPECIFIC AIMS 1. To determine whether pioglitazone will reduce levels of asymmetric dimethylarginine(ADMA) in patients with diabetes. 2. To determine whether nitric oxide(NOx) products are increased with pioglitazone treatment. 3. To determine whether pioglitazone reduces oxidative stress (F2-isoprostanes).
Detailed description
The primary purpose of this study is to determine whether treatment with pioglitazone can reduce serum levels of asymmetric dimethylarginine (ADMA) in patients with adult diabetes. Recent research has found that elevated serum ADMA is associated with increased cardiovascular events and mortality, particularly in people with diabetes (Boger 2005, Zoccali 2006, Ueda 2007). ADMA, by mediating nitric oxide (NO) availability, may trigger pro-atherogenic effects. High plasma concentration of this substance has been associated with intima-media thickening, left ventricular hypertrophy and all-cause and cardiovascular mortality in patients with end-stage renal disease, and associated with increased cardiovascular events in patients with diabetes (Kryzazanowska 2007). The result of higher levels of ADMA and reduced output of NO increases vasoconstriction, increases inflammation, and interferes with endothelial function. Preliminary studies indicate that pioglitazone may reduce ADMA levels, and thus lower cardiovascular risk.Thus, this protocol will test whether pioglitazone can reduce ADMA levels in adult patients with diabetes.
Interventions
DRUGPioglitazone then Placebo
Subjects will take the pioglitazone 30mg tablet daily for 3 months. This will be followed by a 4-week period during which subjects will not be taking either the study drug or placebo. During the final 12-week period the group will take a placebo.
DRUGPlacebo then Pioglitazone
Subjects will take the placebo for the first 12 weeks of the study. This will be followed by a 4-week period during which subjects will not be taking either the study drug or placebo. During the final 12-week period the group will take the pioglitazone 30mg tablet daily for 3 months.
Sponsors
Takeda Pharmaceuticals North America, Inc.
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Adults age 40--75 years-of-age, non-pregnant * Informed consent * History of type 2 Diabetes Mellitus * Stable weight for the last 3 months (no change greater than +5% of body weight) * ADMA \> 0.50 µM/L (mean of non-diabetic reference group) (Devangelio 2007) * On stable medical therapy for at least 3 months * A working telephone
Exclusion criteria
* Any history of known coronary heart disease, including a history of congestive heart failure, myocardial infarction, coronary re-vascularization, or stroke * Pregnancy * Chronic kidney disease, serum creatinine \>2.0mg/dl, chronic liver disease, or uncontrolled hypertension (\>160/100). * Current participation in a formal weight loss program or planning to start such a program during the next 3 months * Collagen vascular disease, infection, or other inflammatory condition * Electrocardiogram (EKG) evidence of ischemia or infarction * Macular edema (swelling of the back of the eye), recent excessive weight gain (over 5% of weight in 30 days), elevated liver function tests \> 2.5 X the upper limit, or history of osteoporosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Asymmetric Dimethylarginine (ADMA) Level | 3 months | Labs measured micro moles per liter of ADMA levels in participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NOx f2-isoprostanes | 3 months | Measured oxidative stress - NOx measured by chemiluminescence detection using the Sievers NOA 280i and f2-isoprostanes are isolated by thin layer chromatography and subjected to a highly sensitive and specific gas chromatography/mass spectroscopy method to measusre the oxidative stress |
Countries
United States
Participant flow
Recruitment details
medical clinic, 36 participants recruited
Pre-assignment details
After informed consent, a laboratory specimen will be obtained at the visit, including a pregnancy test (if indicated), and the screening ADMA level. This information will be used to determine study eligibility. Screened participants will be eligible if their ADMA \> 0.50 μM/L. If not eligible would be excluded from study.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone This is the analysis period during which participants took Pioglitazone. | 18 |
| Placebo The analysis period during which participant took the placebo. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Withdrawal by Subject | 0 | 2 |
| Second Intervention | Lost to Follow-up | 2 | 0 |
| Washout Period of 4 Weeks | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Pioglitazone | Placebo | 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 | 18 Participants | 18 Participants | 36 Participants |
| Age, Continuous | 52.2 years STANDARD_DEVIATION 1.89 | 55.7 years STANDARD_DEVIATION 2.42 | 54 years STANDARD_DEVIATION 1.56 |
| Region of Enrollment United States | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Asymmetric Dimethylarginine (ADMA) Level
Labs measured micro moles per liter of ADMA levels in participants.
Time frame: 3 months
Population: Recruited 36 participants per randomization.1st analysis is serum Asymmetric Dimethylarginine ADMA at 12 weeks b/w groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Asymmetric Dimethylarginine (ADMA) Level | .80 umol/L |
| Placebo | Asymmetric Dimethylarginine (ADMA) Level | .75 umol/L |
Comparison: A twosample comparison of mean treatment differences conducted using a pre-determined significance level of alpha level \<0.05. 2 a comparison of means for NOx levels at 12 weeks b/w groups. 3 on the change F2-isoprostanes at 12 weeks b/w groups.p-value: 0.37t-test, 2 sided
Secondary
NOx f2-isoprostanes
Measured oxidative stress - NOx measured by chemiluminescence detection using the Sievers NOA 280i and f2-isoprostanes are isolated by thin layer chromatography and subjected to a highly sensitive and specific gas chromatography/mass spectroscopy method to measusre the oxidative stress
Time frame: 3 months
Population: 36 adults with diabetes enrolled in the study, and 31 completed the 7-month protocol. Adherence with medication was 93% during the trial according to pill counts at the final visit. Participants were allowed to take their other regular medications during the trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | NOx f2-isoprostanes | -1.4 Oxidative stress | Standard Error 1.4 |
| Placebo | NOx f2-isoprostanes | -1 Oxidative stress | Standard Error 2.6 |