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Effects of Pioglitazone on Endothelial Progenitor Cells in Type 2 Diabetic Patients With Vascular Complications - The SPLENDOR Study.

Phase 4
40 Years
70 Years
Not Enrolling
Diabetes Mellitus

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Trial Information

Effects of Pioglitazone on Endothelial Progenitor Cells in Type 2 Diabetic Patients With Vascular Complications - The SPLENDOR Study.

Diabetes is one of the most common chronic diseases worldwide, affecting nearly 200 million
people, almost all suffering from Type 2 Diabetes. It is the fourth leading cause of death
in developed countries due to the negative impact of the disease on the cardiovascular
system. Treatment, aimed to the reduction of this intrinsic cardiovascular risk, is based on
tight control of glucose and all coexisting metabolic abnormalities as well as of
biomarkers of inflammation and atherogenesis.

Macrovascular complications account for the vast majority of morbidity and mortality in
diabetic patients, and there is growing evidence that pathophysiologic mechanisms other than
hyperglycemia are responsible. The condition of the vascular endothelium in particular has
been shown to effect the health and disease of the cardiovascular system.

The number and function of endothelial progenitor cells correlate inversely with
cardiovascular risk factors and may be a surrogate biologic marker for vascular function and
cumulative cardiovascular risk.

Pioglitazone is an orally active thiazolidinedione derivative. It is a ligand for peroxisome
proliferator-activated receptor-gamma activation that alters transcription of various genes
regulating carbohydrate and lipid metabolism.

Inclusion Criteria:

- Females must be non-pregnant, non-lactating and post-menopausal.

- A glycosylated hemoglobin level greater than 7.5% and less than 10%.

- Has an age of onset of Type 2 Diabetes greater than 35 years of age.

- Is on metformin monotherapy up to the maximum tolerated daily dose.

- Has a normal or only slightly impaired renal function (a modification of diet in
renal disease estimated glomerular filtration rate greater than 60 ml/min/1.73m2.

- Antihypertensives, statins and any other hypolipidemic medications have been
initiated at least three months prior to enrollment; no dose modifications are
allowed during the study.

- Has one or more cardiovascular comorbidities as follows:

- stable angina pectoris

- previous (greater than three months) transient ischemic attack, cerebrovascular
accident or carotid atherosclerosis as assessed by bilateral carotid artery

- peripheral vascular complications documented by a history of claudication or
rest pain, ultrasonography or angiography.

- and/or two or more of the following major cardiovascular risk factors:

- hypertension (blood pressure >130/80 mmHg or treatment)

- dyslipidemia (low-density lipoprotein-cholesterol >100 mg/dl or treatment and/or
high-density lipoprotein-cholesterol <40 mg/dl in men and <45 mg/dl in women or

- smoking (>10 cigarettes/day)

Exclusion Criteria:

- Has Type 1 Diabetes.

- Is on insulin therapy.

- Is severely obese defined as a body mass index greater than or equal to 40mg/m2

- Has diabetic retinopathy.

- Has evidence of hepatic dysfunction including liver transaminase greater than three
times the upper limit of normal.

- Is unable to remain on a stable dose of the following class of medications 30 days
prior to randomization and throughout the six months of the study:

- antihypertensives

- statins

- other hypolipidemic and antiplatelet drugs

- Has a history of alcohol or other drug abuse.

- Has had a new diagnosis of cancer or recurrent cancer within five years of screening.

- Has a need for chronic (greater than two weeks) immunosuppressive therapy.

- Has had heart failure based on the New York Heart Association Functional Class I
through IV.

- Is required to take or intends to continue taking any disallowed medication, any
prescription medication, herbal treatment or over-the counter medication that may
interfere with evaluation of the study medication, including:

- Other antidiabetic drugs (except metformin)

- Fibrates

- Rifampicin

- Glibenclamide interacting drugs, including nonsteroidal anti-inflammatory agents

- Other drugs that are highly protein bound, including:

- sulphonamides

- chloramphenicol

- probenecid

- monoamine oxidase inhibitors

- fluoroquinolones antibiotics

- oral miconazole

- Has participated in another clinical study within the past three months.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Increase from Baseline in the number of Endothelial Progenitor Cells (CD34+KDR+).

Outcome Time Frame:

Baseline and Final Visit.

Safety Issue:


Principal Investigator

Medical Director

Investigator Role:

Study Director

Investigator Affiliation:

Takeda Italia Farmaceutici S.p.A.


Italy: Ministry of Health

Study ID:




Start Date:

March 2009

Completion Date:

May 2011

Related Keywords:

  • Diabetes Mellitus
  • Glucose Metabolism Disorder
  • Dysmetabolic Syndrome
  • Type II Diabetes
  • Diabetes Mellitus, Lipoatrophic
  • Dyslipidemia
  • Drug Therapy
  • Diabetes Mellitus
  • Diabetes Mellitus, Type 2