Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus
Condition: Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Pioglitazone; Glimepiride
Intervention description: Up to 45 mg pioglitazone (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.; Up to 4 mg of glimepiride (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.
Intervention MeSH terms: Pioglitazone; Glimepiride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 547.0
Sex: All
Minimum age: 35 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus, Lipoatrophic; Dyslipidemia; Drug Therapy; Atherosclerosis

Summary:

      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.
    

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).