Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus

The purpose of this study was to determine the efficacy of pioglitazone, once daily (QD), compared to glimepiride on atherosclerotic disease measured by intravascular ultrasound.

Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral tissue cells to circulating insulin (ie, insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (ie, insulin deficiency due to beta-cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 21 million people have diabetes, with type 2 diabetes occurring in approximately 90% to 95% of cases. The goal of treating type 2 diabetes is to control blood glucose and thereby prevent long-term complications. Adequate glycemic control is paramount in attempting to avert chronic complications, including blindness; renal dysfunction resulting in dialysis or renal transplantation; neuropathy; non-traumatic amputations; and macrovascular complications, including myocardial ischemia and myocardial infarction, stroke, and peripheral arterial disease. Intensive glucose management in the early stages of diabetes may help forestall such complications.

Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal by binding to nuclear receptors known as peroxisome proliferator-activated receptors. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis), with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin without predisposing patients to hypoglycemia. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue.

This study was designed to compare the effects of pioglitazone compared to glimepiride on progression of atherosclerotic disease, as measured by intravascular ultrasound.

Eligibility Criteria:
Inclusion Criteria:

* Females of childbearing potential who were sexually active agreed to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
* Had a diagnosis of type 2 diabetes mellitus
* Have received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise.
* naïve to or was not currently taking antidiabetic therapy, or were currently treated with monotherapy or combination therapy.
* Had a glycosylated hemoglobin level greater than or equal to 6.0% and less than 9% at screening if taking antidiabetic medication or greater than or equal to 6.5% and less than 10% at screening if naive to or not taking antidiabetic medication.
* Angiographic criteria:

  * Entire Coronary Circulation: must have angiographic evidence of coronary heart disease as defined by at least 1 lesion in a native coronary artery that has greater than or equal to 20% reduction in lumen diameter by angiographic visual estimation.
  * Left Main Coronary Artery: must not have greater than 50% reduction in lumen diameter by visual angiographic estimation.
  * Target Coronary Artery:

    * The target vessel, which includes the main artery and all of its side branches, had not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery.
    * The target vessel, which includes the main artery and all of its side branches, was not currently a candidate for intervention or a likely candidate for intervention over the next 72 weeks.
    * The target vessel was not a bypass graft.
    * The target vessel was not infarct related.
* Had previous coronary artery bypass surgery at least six weeks prior to the qualifying intravascular ultrasound are eligible provided they are stable and meet all other entry criteria.
* Had an intravascular ultrasound tape deemed to be of acceptable intravascular ultrasound image quality and demonstrated adherence to the intravascular ultrasound interrogation protocol, as determined by the intravascular ultrasound Core Laboratory™ assessment.

Exclusion Criteria:

* Had type I diabetes mellitus.
* Had participated in another investigational study, or participated in an investigational study 30 days prior to the start of this study, or who were scheduled to participate in an investigational study during the time frame of this study.
* Male subjects who had a serum creatinine level greater than or equal to 2.0 mg/dL (greater than or equal to 177 µmol/L) (greater than or equal to 1.5 mg/dL; \[greater than or equal to 133 µmol /L\] if taking metformin) and female subjects who have serum creatinine greater than or equal to 1.8 mg/dL \[greater than or equal to 159 µmol /L\] (greater than or equal to 1.4 mg/dL \[greater than or equal to 124 µmol /L\] if taking metformin).
* Had unexplained microscopic hematuria greater than +1, confirmed by repeat testing.
* Had a history of drug abuse or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years.
* Had clinical cardiac failure as defined by New York Heart Association class III or IV, or known left ventricular dysfunction measured as left ventricular ejection fraction less than 40%, or by current use of diuretics or angiotensin converting enzyme inhibitors for treatment of heart failure.
* Had an alanine transaminase level of greater than 2.5 times the upper limit of normal active liver disease, or jaundice.
* Had a body mass index greater than 48 kg/m2 as calculated by weight (kg)/height (m2) or weight (pounds)/height (inches) 2 x 703.
* Was required to take or intended to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including:

  * Chronically used oral glucocorticoids (eg, prednisone, cortisone, hydrocortisone, dexamethasone)
  * Niacin greater than100 mg a day, including niacin-containing products such as Advicor®
  * Chronically used steroid-joint injections
  * Thiazolidinediones
  * Sulfonylureas
  * Metformin/sulfonylurea combination
  * Other oral antidiabetic medications (eg, nateglinide \[Starlix®\], acarbose \[Precose®\]) with the exception of metformin
* Had known or suspected malignancy or recurrence of malignancy within the past 5 years, with the exception of basal cell carcinoma and Stage 1 squamous cell carcinoma of the skin.
* Had any disease where, in the opinion of the investigator (or designee), survival is expected to be less than 72 weeks.
* Clinical status was unstable (ie, requiring vasopressors or intravenous inotropes, intra-aortic balloon pump, hypotension \[systolic blood pressure less than 90 mm Hg\]).
* Prior to the screening visit, was scheduled for a staged cardiac intervention (percutaneous coronary intervention), peripheral vascular intervention, or coronary artery bypass graft surgery following the screening angiography.
* In the opinion of the investigator (or designee) had clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study.
* Had persistent, uncontrolled hypertension (ie, sitting systolic blood pressure greater than 160 mm Hg or sitting diastolic blood pressure greater than 100 mm Hg) at randomization.
* Males who had hemoglobin less than 10.5 g/dL (less than 105 g/L) and female subjects who had hemoglobin less than 10.0 g/dL (less than 100 g/L).
* Had a triglyceride level greater than 500 mg/dL (greater than 5.6 mmol/L).