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

NCT01040819 | Completed Phase 4 Results

• 1 other identifier: H-24253
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

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.

Conditions

Type 2 Diabetes Mellitus

Keywords

Diabetes Mellitus; 6-Ketoprostaglandin F1 alpha; 15-epi-lipoxin A4; Thiazolidinediones; Pioglitazone

Outcome Measures

Primary Outcomes (1)

• Plasma 15-epi-lipoxin A4

  Plasma 15-epi-LXA4 levels

  2 months

Study Arms (2)

Pioglitazone 15 mg

EXPERIMENTAL

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

Pioglitazone 30 mg/d

EXPERIMENTAL

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

Interventions

Pioglitazone DRUG

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.

Also known as: Actos

Pioglitazone 15 mg; Pioglitazone 30 mg/d

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Men and women \> 21 years old with type 2 diabetes Mellitus and otherwise stable medical conditions

You may not qualify if:

• 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

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (2)

Baylor Clinics

Houston, Texas, 77030, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (3)

• 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. doi: 10.4049/jimmunol.181.5.3515.

  PMID: 18714024 BACKGROUND

• 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. doi: 10.1016/j.prostaglandins.2006.10.003. Epub 2006 Nov 7.

  PMID: 17259075 BACKGROUND

• 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. doi: 10.1161/CIRCULATIONAHA.106.629907. Epub 2006 Aug 14.

  PMID: 16908763 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Yochai Birnbaum
• Organization: Baylor College of Medicine

ybirnbau@bcm.edu

713-798-0273

Study Officials

• Yochai Birnbaum, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: December 29, 2009
• First Posted: December 30, 2009
• Study Start: February 1, 2010
• Primary Completion: October 1, 2011
• Study Completion: December 1, 2011
• Last Updated: June 22, 2016
• Results First Posted: June 22, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)