Thiazolidinedione Intervention With Vitamin D Evaluation
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: pioglitazone; rosiglitazone; placebo; Vitamin D; Placebo
Intervention description: Pioglitazone30 mg and 45 mg tablets are over-encapsulated with Swedish orange size DB-AA capsule shell.; Rosiglitazone 4 mg and 8 mg tablets are over-encapsulated with Swedish orange size DB-AA capsule shell.; Placebo to match is Swedish orange size DB-AA capsule filled with white to off-white non-active powder blend.; Vitamin D factor intervention; Vitamin D factor intervention
Intervention MeSH terms: Vitamin D; Pioglitazone; Rosiglitazone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1332.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Cardiovascular Outcomes

Summary:

      This study will answer two separate questions.

      The first question is to test the cardiovascular effects of long-term treatment with
      rosiglitazone or pioglitazone when used as part of standard of care compared to similar
      standard of care without rosiglitazone or pioglitazone in patients with type 2 diabetes who
      have a history of or are at risk for cardiovascular disease.

      The second question will compare the effects of long-term supplementation of vitamin D on
      death and cancer
    

Eligibility criteria:

        Inclusion Criteria:

          -  Men or women with: a) newly detected type 2 diabetes based on a fasting plasma glucose
             greater than or equal to 7.0 mmol/l (126 mg/dL) or a 2 hour plasma glucose (FPG)
             greater than or equal to 11.1 mmol/l (200 mg/dL) on an oral glucose tolerance test, or
             b) a history of type 2 diabetes

          -  Hemoglobin A1c (A1C) 6.5-9.5% inclusive (for assays with upper limit of normal of 6%)
             within one month of screening

          -  Age ≥ 50 years and evidence of vascular disease defined as ≥1of:

               -  prior myocardial infarction

               -  prior stroke

               -  coronary, carotid or peripheral artery revascularization ≥ 4 years earlier

               -  previous documented myocardial ischemia on either an exercise stress test or on
                  any cardiac imaging, or previous unstable angina with ECG changes or cardiac
                  enzyme elevation OR

          -  Age ≥ 55 years and evidence of subclinical vascular disease defined as ≥1 of:

               -  microalbuminuria or proteinuria

               -  history of treated or untreated hypertension with left ventricular hypertrophy by
                  electrocardiogram (ECG) or echocardiogram

                    -  50% stenosis on any imaging of coronary, carotid or lower extremity arteries

               -  ankle/brachial index <0.9 OR

          -  Age ≥ 60 years and at least 2 of the following cardiovascular disease risk factors:

               -  current tobacco use

               -  LDL-c ≥3.4 mmol/L (130 mg/dL) or on a lipid lowering medication

               -  HDL-c < 1.0 mmol/L (40 mg/dL) for men and < 1.3 mmol/L (50 mg/dL) for women or
                  triglycerides ≥ 2.3 mmol/L (200 mg/dL)

               -  BP lowering medication use or untreated SBP ≥ 140 mmHg or DBP ≥ 95 mmHg

               -  Waist to hip ratio > 1.0 for men and > 0.8 for women

          -  On no insulin and on less than or equal to 2 anti-diabetes drugs where at least one
             drug is at or below the half-maximal dose (as indicated in the MOP) with stable dosing
             for 10 weeks prior to screening

        Exclusion Criteria:

          -  Type 1 diabetes

          -  Current need for insulin treatment

          -  Symptomatic hyperglycemia requiring immediate therapy in the judgment of the physician

          -  An acute cardiovascular event within 30 days prior to randomization

          -  Symptomatic heart failure (i.e. New York Heart Association class II or higher) or any
             episode of previous pulmonary edema or known ejection fraction < 0.4 or current use of
             loop diuretics

          -  Any fracture within the past 1 year

          -  Currently planned coronary, carotid or peripheral artery revascularization or cardiac
             valve surgery

          -  Coronary, carotid or peripheral artery revascularization within the 4 years prior to
             screening in the absence of angina, MI, or stroke in the intervening period

          -  End stage renal disease requiring renal replacement therapy

          -  Receiving drug therapy to treat liver disease

          -  A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or
             adequately treated cervical carcinoma in situ) in the past 3 years or current
             treatment for the active cancer (other than prophylactic)

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 2.5 times
             the upper limit of normal

          -  A prior heart transplant or awaiting a heart transplant

          -  Previous or current hypercalcemia, hyperparathyroidism, osteomalacia or other
             contraindication for vitamin D therapy

          -  Regular use of or indication for greater than 400IU of vitamin D daily

          -  Clinically or medically unstable with expected survival < 1 year

          -  Unwillingness to permit sites to contact their primary physicians to communicate
             information about the study and the participant's data

          -  Any other factor likely to limit protocol compliance or reporting of adverse events

          -  Inability to discontinue a TZD (if taking one) in the judgement of the
             physician/investigator

          -  Contraindications to or history of hypersensitivity to the investigational products

          -  History of renal stones within the past 2 years

          -  Participation in another clinical trial of an investigational agent