Does Pioglitazone Increase the Production of 15-EPI-Lipoxin A4?
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Pioglitazone
Intervention description: Patients will receive PIO 15 mg/d for one month, then 55 patients continue with the same dose for one additional month, and in 55 patients the dose will be increased to 30 mg/d for an additional one month. Other non-diabetes drugs should not be changed. Other hypoglycemic agents, including insulin may be adjusted, if clinically indicated. NSAID, COX2 inhibitors, aspirin >162 mg/d, steroids and prostaglandin analogs will be prohibited.
Intervention MeSH terms: Pioglitazone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 25.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: Diabetes Mellitus; 6-Ketoprostaglandin F1 alpha; 15-epi-lipoxin A4; Thiazolidinediones; Pioglitazone

Summary:

      Type-2 diabetes mellitus is a public health concern. Patients with type 2 diabetes mellitus
      are at high risk of developing cardiovascular complications. Diabetic patients are two to
      four-times more likely to develope cardiovascular disease. The mortality of diabetic patients
      with cardiovascular disease is much higher than in non-diabetic matched patients with
      cardiovascular disease. Recently, it has become apparent that not all anti-diabetic drugs
      have the same effect on the progression of atherosclerosis and on cardiovascular outcomes.
      There is a great need to understand the potential protective mechanisms of the various
      anti-diabetic drugs in order to decrease their risk for cardiovascular morbidity and
      mortality. In addition to increasing insulin sensitivity, Pioglitazone (PIO) has
      anti-inflammatory properties. However, the underlying mechanisms of these anti-inflammatory
      (and probably anti-atherosclerotic) effects of PIO are unknown. We have shown in the rat that
      3-day pretreatment with PIO increases myocardial cyclooxygenase-2 (COX2) activity and levels
      of both 6-keto-PGF1a, the stable metabolite of prostacyclin (PGI2) and 15-epi-lipoxin A4, a
      lipid mediator with a strong anti-inflammatory properties. Prostacyclin inhibits platelet
      aggregation and causes vasodilatation. Increased levels of 6-keto-PGF1a and 15-epi-lipoxin A4
      may thus be the explanation for the anti-inflammatory and anti-atherosclerosis effects of
      PIO. Several clinical studies have shown that COX2 inhibition is associated with increased
      cardiovascular events. Thus, augmenting COX2 activity and the production of prostacyclin and
      15-epi-lipoxin A4 may have potential favorable effects. The purpose of the study is to test
      whether PIO therapy is associated with an increase in serum and/or urine levels of
      6-keto-PGF1a and 15-epi-lipoxin A4 in patients with diabetes mellitus type 2.
    

Eligibility criteria:

        Inclusion Criteria:

        1. Men and women > 21 years old with type 2 diabetes Mellitus and otherwise stable medical
        conditions

        Exclusion Criteria:

          1. Serum creatinine >= 1.5 mg/dl and/or renal failure

          2. NYHA class III or IV heart failure

          3. Known intolerance to TZD

          4. Current use of NSAID, COX-2 inhibitors, steroids (oral, topical and inhalation) or
             immunosuppressive therapy

          5. Aspirin > 162 mg/d

          6. Recent myocardial infarction, ACS, or stroke <=3 months)

          7. Significant comorbid conditions such as: cancer (not cured), end stage renal disease,
             severe obstructive lung disease, cirrhosis, etc)

          8. Recent (<1 month) infection

          9. Recent CABG or PCI (<3 months)

         10. Use of prostaglandin analogs (i.e., iloprost)

         11. Active inflammatory disease

         12. Current use of TZD

         13. Pregnancy

         14. Osteoporosis or high risk for bone fracture. Use of other antihyperglycemic agents is
             not an exclusion criterion. HbA1c and glucose levels will not restrict enrollment.