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.

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.

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