Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, 6-Ketoprostaglandin F1 alpha, 15-epi-lipoxin A4, Thiazolidinediones, Pioglitazone
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.
Interventions
DRUGPioglitazone
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.
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma 15-epi-lipoxin A4 | 2 months | Plasma 15-epi-LXA4 levels |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 | 13 |
| 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. | 12 |
| Total | 25 |
Baseline characteristics
| Characteristic | Pioglitazone 30 mg/d | Pioglitazone 15 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 13 Participants | 25 Participants |
| Age, Continuous | 58 years STANDARD_DEVIATION 6 | 54 years STANDARD_DEVIATION 4 | 56 years STANDARD_DEVIATION 5 |
| Region of Enrollment United States | 12 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Plasma 15-epi-lipoxin A4
Plasma 15-epi-LXA4 levels
Time frame: 2 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 15 mg | Plasma 15-epi-lipoxin A4 | 1.05 ng/ml | Standard Error 0.08 |
| Pioglitazone 30 mg/d | Plasma 15-epi-lipoxin A4 | 1.08 ng/ml | Standard Error 0.12 |