Does Pioglitazone Increase the Production of 15-EPI-Lipoxin A4?

Study Overview
=================
Brief 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.

Detailed Description
-----------------
Type-2 diabetes mellitus is a public health concern. According to the World health organization (WHO), diabetes mellitus affects more than 180 million people worldwide. Type 2 diabetes mellitus accounts for 80-95% of diabetes cases in developed countries and a higher proportion in developing countries (IDF 2006). 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. Several studies have suggested that PIO decreases serum markers of inflammation including C-reactive protein (CRP). 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.

Official Title
-----------------
Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2?

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Pioglitazone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Men and women > 21 years old with type 2 diabetes Mellitus and otherwise stable medical conditions Exclusion Criteria: Serum creatinine >= 1.5 mg/dl and/or renal failure NYHA class III or IV heart failure Known intolerance to TZD Current use of NSAID, COX-2 inhibitors, steroids (oral, topical and inhalation) or immunosuppressive therapy Aspirin > 162 mg/d Recent myocardial infarction, ACS, or stroke <=3 months) Significant comorbid conditions such as: cancer (not cured), end stage renal disease, severe obstructive lung disease, cirrhosis, etc) Recent (<1 month) infection Recent CABG or PCI (<3 months) Use of prostaglandin analogs (i.e., iloprost) Active inflammatory disease Current use of TZD Pregnancy 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.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone 15 mg<br>Patients will receive PIO 15 mg/d for two months. Serum and urine samples for 6-keto-PGF1a and 15-epi-lipoxin A4 will be taken at baseline, one month and 2 months. | Drug: Pioglitazone<br>* 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.<br>* Other names: Actos;|
| Experimental: Pioglitazone 30 mg/d<br>Patients will receive PIO 15 mg/d for one month. Then, dose will be increased to 30 mg/d for an additional month. Serum and urine samples for 6-keto-PGF1a and 15-epi-lipoxin A4 will be taken at baseline, one month and 2 months. | Drug: Pioglitazone<br>* 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.<br>* Other names: Actos;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma 15-epi-lipoxin A4 | Plasma 15-epi-LXA4 levels | 2 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes Mellitus, 6-Ketoprostaglandin F1 alpha, 15-epi-lipoxin A4, Thiazolidinediones, Pioglitazone