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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Yochai Birnbaum, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT01040819
First received: December 29, 2009
Last updated: March 9, 2012
Last verified: March 2012
  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?

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • 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
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01040819

Locations
United States, Texas
Baylor Clinics
Houston, Texas, United States, 77030
Baylor College of Medicine
HOuston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
  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
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Platelet Aggregation Inhibitors
Hematologic 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 August 26, 2014