Pioglitazone and Serum Asymmetric Dimethylarginine (ADMA) in Patients With Diabetes

Study Overview
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Brief Summary
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SPECIFIC AIMS To determine whether pioglitazone will reduce levels of asymmetric dimethylarginine(ADMA) in patients with diabetes. To determine whether nitric oxide(NOx) products are increased with pioglitazone treatment. To determine whether pioglitazone reduces oxidative stress (F2-isoprostanes).

Detailed Description
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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.

Official Title
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Pioglitazone and Serum Asymmetric Dimethylarginine (ADMA) in Patients With Diabetes

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Pioglitazone then Placebo
* Drug: Placebo then Pioglitazone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone then Placebo<br>18 volunteers that are Diabetic adults, 40-75 years that have higher ADMA levels as well as increased inflammation will take Pioglitazone for the first 12 week period of the study and then take the placebo for the final 12 weeks of the study. | Drug: Pioglitazone then Placebo<br>* 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.<br>* Other names: Actos, Glustin, Zactos;|
| Experimental: Placebo then Pioglitazone<br>18 (other half of participants) volunteers that are Diabetic adults, 40-75 years that have higher ADMA levels as well as increased inflammation will take the placebo for the first 12 week period of the study and then take the Pioglitazone for the final 12 weeks of the study. | Drug: Placebo then Pioglitazone<br>* 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.<br>* Other names: Actos, Glustin, Zactos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asymmetric Dimethylarginine (ADMA) Level | Labs measured micro moles per liter of ADMA levels in participants. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular risk, biological markers