Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2?
Information source: Baylor College of Medicine
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Type 2 Diabetes Mellitus
Intervention: Pioglitazone (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: Baylor College of Medicine
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.
Clinical Details
Official title: Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2?
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Serum and urine 6-keto-PGF1a Serum and urine 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
Minimum age: 21 Years.
Maximum age: N/A.
Gender(s): Both.
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.
Locations and Contacts
Baylor Clinics, Houston, Texas 77030, United States
Baylor College of Medicine, HOuston, Texas 77030, United States
Additional Information
Related publications: Ye Y, Lin Y, Perez-Polo JR, Uretsky BF, Ye Z, Tieu BC, Birnbaum Y. Phosphorylation of 5-lipoxygenase at ser523 by protein kinase A determines whether pioglitazone and atorvastatin induce proinflammatory leukotriene B4 or anti-inflammatory 15-epi-lipoxin a4 production. J Immunol. 2008 Sep 1;181(5):3515-23. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Huang MH, Perez-Polo JR, Uretsky BF. Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. Prostaglandins Other Lipid Mediat. 2007 Feb;83(1-2):89-98. Epub 2006 Nov 7. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, Huang MH, Uretsky BF, Perez-Polo JR. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006 Aug 29;114(9):929-35. Epub 2006 Aug 14.
Starting date: February 2010
Last updated: March 9, 2012
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