Effect of Pioglitazone on Oxidative Load, Inflammatory End-Points and Vascular Reactivity in Obese Non-Diabetic Patients: A Dose Ranging Study

Study Overview
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Brief Summary
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Pioglitazone decreases oxidative load, inflammatory end points and improves vascular reactivity in obese patients in a dose dependent manner and that this effect is independent of its glucose lowering effects.

Detailed Description
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This is a single center, open labeled study. A total of 24 obese patients will be recruited to participate in this study. The study will have three groups of 8 patients each. Subjects will be enrolled into each group by alternate recruitment. Subjects in group one will receive 15mg of pioglitazone; subjects in group two will receive 30 mg of pioglitazone; subjects in group three will receive placebo. All subjects will receive Pioglitazone or placebo for 6 weeks, followed by a 6-week observation period off Pioglitazone/placebo. At baseline, and at week 1, week 2, week 4, week 6 and month 3 all patients will have blood drawn for TBARS, ortho and meta-tyrosine, 9-HODE and 13-HODE, NF, Ikb, TNF-a, ICAM-1, VCAM-1, PAI-1, AP-1, EGR-1, MMP-2, MMP-9, TIMP, CRP-1, E-Selectin, P-Selectin, Asymmetric dimethylarginine (ADMA), PAPP-A, SAA, MCP-1, IL-6, ROS generation, insulin levels, and CRP. Post-ischemic dilation of the brachial artery will be used as an index of endothelium-mediated vasodilation. All subjects will have an oral glucose tolerance test (GTT) with 75gm of glucose at Day 0 and at Day 42. Vascular reactivity will be assessed at 0, 6, and at 12 weeks.

Official Title
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Effect of Pioglitazone on Oxidative Load, Inflammatory End-Points and Vascular Reactivity in Obese Non-Diabetic Patients: A Dose Ranging Study

Conditions
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Inflammation

Intervention / Treatment
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* Drug: Pioglitazone 15mg
* Drug: pioglitazone 30mg
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Obese (BMI>=30) Age: 20 to 65 years of age inclusive Without established clinical coronary artery disease (documented history or myocardial infarction, typical angina and an exercise ECG positive for ischemia or angiographic evidence of CAD) Good health as evidence by History and Physical exam Female subjects must be: Postmenopausal for at least one year or Surgically incapable of childbearing (i.e. have had a hysterectomy or tubal ligation) or, if capable of childbearing a subject, must be practicing an acceptable method of contraception. • Subject will be available for duration of the study and willing to comply with all study requirements. Exclusion Criteria: • Diabetes Mellitus Allergy or sensitivity to Pioglitazone Current use of Insulin therapy. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous four weeks Hepatic disease (transaminase > 3 times normal) Renal impairment (Creatinine clearance < 50 mL/min) History of drug or alcohol abuse COPD Participation in any other concurrent clinical trial Any other life-threatening, non-cardiac disease Use of an investigational agent or therapeutic regimen within 30 days of study Pregnancy or nursing

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone 15mg<br>8 patient will receive this drug | Drug: Pioglitazone 15mg<br> <br> |
| Experimental: pioglitazone 30mg<br>8 patients will get this drug | Drug: pioglitazone 30mg<br> <br> |
| Placebo Comparator: Placebo<br>8 patient will get this drug | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammation | Percent change in NFkb at baseline and after 1, 2, 4, 6, and 12 weeks of pioglitazone therapy. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| inflammation | TBARS (Thiobarbituric acid reactive substances), ortho and meta-tyrosine, 9-HODE and 13-HODE (hydroxyoctadecadieonic acid derivatives), Cellular/nuclear fractions and DNA binding activity of Nuclear Factor kb, Ikb (inhibitory kappa B), TNF-a(Tumor necrosis factor a), ICAM-1 (Intracellular adhesion molecule 1), VCAM-1(Vascular adhesion molecule 1), PAI-1 (Plasminogen Activator Inhibitor -1) and CRP (C-Reactive protein) and %change in vascular reactivity. | 12 weeks |