Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2?
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Type 2 Diabetes Mellitus |
Drug: Pioglitazone |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2? |
- Serum and urine 6-keto-PGF1a Serum and urine 15-epi-lipoxin A4 [ Time Frame: 2 months ] [ Designated as safety issue: No ]
| Enrollment: | 25 |
| Study Start Date: | February 2010 |
| Study Completion Date: | December 2011 |
| Primary Completion Date: | October 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Pioglitazone 15 mg
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
Patients will receive PIO 15 mg/d for one month, then 55 patients will 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. While on PIO, other non-diabetes drugs should not be changed, unless emergency. 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. At baseline, and after 1, and 2 months of treatment the following samples will be taken: 1. Serum for lipid profile, ALT, AST, CK, creatinine, BUN, glucose, HbA1c (the biochemistry laboratory at UTMB) 2. Serum for 6-keto-PGF1a and 15-epi-lipoxin A4 3. Serum for hs-CRP 4. Urine for creatinine, 6-keto-PGF1a and 15-epi-lipoxin A4
|
|
Experimental: Pioglitazone 30 mg/d
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
Patients will receive PIO 15 mg/d for one month, then 55 patients will 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. While on PIO, other non-diabetes drugs should not be changed, unless emergency. 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. At baseline, and after 1, and 2 months of treatment the following samples will be taken: 1. Serum for lipid profile, ALT, AST, CK, creatinine, BUN, glucose, HbA1c (the biochemistry laboratory at UTMB) 2. Serum for 6-keto-PGF1a and 15-epi-lipoxin A4 3. Serum for hs-CRP 4. Urine for creatinine, 6-keto-PGF1a and 15-epi-lipoxin A4
|
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.
Eligibility| Ages Eligible for Study: | 21 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations More Information
Publications:
| Responsible Party: | Yochai Birnbaum, Professor of Medicine, Baylor College of Medicine |
| ClinicalTrials.gov Identifier: | NCT01040819 History of Changes |
| Other Study ID Numbers: | H-24253 |
| Study First Received: | December 29, 2009 |
| Last Updated: | March 9, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Baylor College of Medicine:
|
Diabetes Mellitus 6-Ketoprostaglandin F1 alpha 15-epi-lipoxin A4 Thiazolidinediones Pioglitazone |
Additional relevant MeSH terms:
|
Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Epoprostenol Tezosentan Lipoxin A4 Pioglitazone Platelet Aggregation Inhibitors Hematologic Agents Therapeutic Uses Pharmacologic Actions |
Antihypertensive Agents Cardiovascular Agents Vasodilator Agents Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Central Nervous System Agents Hypoglycemic Agents |
ClinicalTrials.gov processed this record on May 16, 2013