BI 10773 Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients.

• The composite of all events adjudicated: cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction, non-fatal stroke and hospitalization for unstable angina pectoris. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• To determine the incidence of microalbuminuria and the progression of microalbuminuria to macroalbuminuria from baseline to end of trial. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• To determine the incidence of silent MI [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]

• The composite of all events adjudicated: cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatalmyocardial infarctionI, non-fatal stroke and hospitalization for unstable angina pectoris. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• To determine the incidence of microalbuminuria and the progression of microalbuminuria to macroalbuminuria from baseline to end of trial. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• To determine the incidence of silent MI [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]

The aim of the present study is to investigate the safety of BI 10773 treatment in patients with Type 2 Diabetes Mellitus and high cardiovascular risk.

• Drug: BI 10773 low dose
  BI 10773 tablets once daily
• Drug: Placebo BI 10773 high dose
  Placebo tablets identical to BI 10773
• Drug: Placebo BI 10773 low dose
  Placebo tablets identical to BI 10773
• Drug: BI 10773 high dose
  BI 10773 tablets once daily

• Experimental: BI 10773 low dose
  BI 10773 tablets once daily
  Interventions:

  • Drug: BI 10773 low dose
  • Drug: Placebo BI 10773 high dose
• Experimental: BI 10773 high dose
  BI 10773 tablets once daily
  Interventions:

  • Drug: Placebo BI 10773 low dose
  • Drug: BI 10773 high dose
• Placebo Comparator: Placebo
  Placebo tablets matching BI 10773
  Interventions:

  • Drug: Placebo BI 10773 high dose
  • Drug: Placebo BI 10773 low dose

Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus prior to informed consent
2. Male or female patients on diet and exercise regimen who are drug naive or pre treated with any background therapy. Antidiabetic therapy has to be unchanged for 12 weeks prior to randomization.
3. Glycosylated haemoglobin (HbA1c) of >= 7.0% and <=10% for patients on background therapy or HbA1c >= 7.0% and <= 9.0% for drug naive patients
4. Age > 18 years
5. Body Mass index <= 45 at Visit 1
6. Signed and dated informed consent

7. At least one of the following criteria:

   • Confirmed history of myocardial infarction (> 2 months prior to informed consent)
   • Unstable angina (> 2 months prior informed consent) with documented multivessel coronary disease (at least two major coronary arteries in angiogram) or positive stress test (ST segment depression >= 2 mm or a positive nuclear perfusion scintigram)
   • Multivessel Percutaneous Coronary Intervention (PCI) > 2 months prior informed consent
   • Multivessel Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed consent or with recurrent angina following surgery
   • History of ischemic or hemorrhagic stroke (> 2 months prior to informed consent)
   • Peripheral occlusive arterial disease (previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or foot amputation due to circulatory insufficiency, angiographic or imaging detected (for example: ultrasound, Magnetic Resonance Imaging) significant vessel stenosis of major limb arteries)

Exclusion criteria:

1. Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
2. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase ALT or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening and/or run in.
3. Planned cardiac surgery or angioplasty within 3 months
4. Impaired renal function, defined as Glomerular Filtration Rate <30 ml/min (severe renal impairment, Modification of Diet in Renal Disease formula) during screening or run in.
5. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
6. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia)
7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
8. Contraindications to background therapy according to the local label
9. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
10. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except type 2 diabetes mellitus

11. Pre-menopausal women (last menstruation <+ 1 year prior to informed consent) who:

    • are nursing or pregnant or
    • are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method and vasectomised partner
12. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
13. Participation in another trial with an investigational drug within 30 days prior to informed consent
14. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial