A Study to Determine Acute (After First Dose) and Chronic (After 28 Days) Effects of the SGLT-2 Inhibitor Empagliflozin (BI 10773) on Pre and Postprandial Glucose Homeostasis in Patients With Impaired Glucose Tolerance and Type 2 Diabetes Mellitus.

In patients with poorly controlled diabetes, up-regulation of distinct glucose transporters including SLGT2 results in increased renal tubular glucose reabsorption. An orally available, potent and selective SGLT2 inhibitor such as BI 10773 lowers both the saturation threshold and the transport maximum of glucose levels with low risk of hypoglycaemia, and negative energy balance with potential weight reduction.

The effect of BI 10773-mediated urinary glucose and calory loss on endogenous glucose production (EGP) is unknown. Under normal circumstances, ingestion of a mixed meal leads to a protracted suppression of endogenous glucose production. Such effect is known to be impaired in patients with diabetes, whose postprandial EGP is inappropriately elevated and contributes to the hyperglycaemia.

Inclusion criteria:

1a Male and female patients diagnosed with impaired glucose tolerance (IGT) according to the current American Diabetes Association (ADA) guidelines as a two-hour glucose levels of 140 to 199 mg/dl (7.8 mmol/l to 11.1 mmol/l) on the 75-g oral glucose tolerance test (OGTT), with an OGTT performed at the time of the screening visit (Visit 1), or

1b Male and female patients diagnosed with type 2 diabetes mellitus (T2DM) prior to informed consent, on diet and exercise regimen who are drug-naïve, defined as absence of any oral antidiabetic therapy or insulin for 12 weeks prior to the planned Day 1 of the trial, or,

1. c Male and female patients diagnosed with type 2 diabetes mellitus prior to informed consent, who are pre-treated with metformin (only immediate release formulations permitted) background therapy, on a stable dose of metformin of at least 1500 mg per day, unchanged for at least 12 weeks prior to the planned Day 1 in the trial.

2. HbA1c (haemoglobin glycosylated A1c) at Visit 1 (screening):

   1. For patients diagnosed of IGT: HbA1c < 6.5%
   2. For patients diagnosed of T2DM: HbA1c = > 6.5 % and < = 10.5 %
3. Age = 18 at Visit 1.
4. BMI = > 20 and < = 40 Kg/m2 (Body Mass Index) at Visit 1.
5. For patients who are under current antihypertensive treatment, this must be stable (with no changes in dosage) within 4 weeks prior to the planned Day 1 (Visit 4) in the trial.
6. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practises (GCP) and local legislation.

Exclusion criteria:

1. Acute coronary syndrome (non-STEMI [ST elevation myocardial infarction], STEMI, unstable AP [angina pectoris]), stroke or Transient Ischemic Attack (TIA) within 6 months prior to informed consent.
2. 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).
3. Any other antidiabetic drug within 12 weeks prior to starting the open-label active treatment (Visit 4) except those defined as background via inclusion criterion 1c.
4. Indication of liver disease, defined by serum levels of either Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in phase.
5. Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) < 60 ml/min (moderate and severe renal impairment) as determined during screening and/or run-in phase.
6. Medical history of insufficient bladder emptying (i.e. neurogenic bladder disorders).
7. Patients with an Haemoglobin (Hb) < 11.5 g/dl (for males) and Hb < 10.5 g/dl (for females) at Visit 1.
8. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption within the last 5 years.
9. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.
10. For patients on metformin background therapy, the investigator must check for potential exclusion criteria according to local metformin label.
11. Treatment with anti-obesity drugs 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.
12. 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 T2DM. However, the use of inhaled steroids (e.g., for asthma, Chronic Obstructive Pulmonary Disease [COPD]) is not an exclusion as these do not cause systemic steroid action.
13. Alcohol or drug abuse (according to investigators judgment) 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.
14. Intake of an investigational drug in another trial Participation in another trial within 30 days prior to intake of study medication in this trial.

15. 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.

16. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial.