A total of 40 patients will be followed for 1 year. Active treatment with Metformin 1000 mg administered twice daily and Sitagliptin 100mg once daily will be compared to treatment with Metformin 1000 mg twice daily and Sitagliptin/Placebo 100mg once daily. The study participants will receive follow-up phone calls at two, four weeks and intermittently after randomization, and make clinic visits at baseline, 6 weeks and every three months for the duration of the study.

Inclusion criteria:

1. Patients with type 2 diabetes aged 30-75 inclusive

2. Taking either no diabetes medication OR taking 1 or 2 oral anti-diabetic agents

3. A1c between 6.0 % and 9.0 % inclusive

Exclusion Criteria:

1. Current use of insulin therapy

2. Involvement in any other study requiring drug therapy

3. History of active liver or renal disease

4. History of uncontrolled hypertension or serious cardiac arrhythmias

5. HIV, Hepatitis B/C or tuberculosis infection

6. Any major illness with a life expectancy of <5 years or that may interfere with the patient's participation in the study

7. Excessive alcohol consumption

8. Pregnancy or unwillingness to use reliable contraception.

Basic entry criteria for study participants includes:  (1) Relatives of people with T1DM with insulin antibodies (mIAA) and at least one other diabetes autoantibody present and  (2) have a normal blood glucose levels during and oral glucose tolerance test performed within 7 weeks prior to randomization. This study will provide a information of the effects of oral insulin therapy in subjects with different T1DM risk profiles and will give us an idea of whether or not this treatment is  effective.

1. Have a proband with T1DM.
2. If the proband is a sibling or a child, the study participant must be 3 - 45 years of age.  If the proband is a second or third degree relative (i.e. Niece, Nephew, Aunt, Uncle, Grandchild, Cousin), the study participant must be 3-20 years of age.
3. Willing to sign Informed Consent Form.
4. OGTT performed within 7 weeks prior to randomization in which: 
   a)  fasting plasma glucose < 110 mg/dL (6.1 mmol/l), and
   b)  2 hour plasma glucose < 140 mg/dL (7.8 mmol/l)
5. mIAA confirmed positive within the previous six months.
6. Two samples with at least one autoantibody other than mIAA positive within the previous six months.

Angela Roode (Research Nurse)
Hospital for Sick Children        
Phone: 416-813-5858  or  Toll-free 1-866-699-1899
E-mail: angela.roode@sickkids.ca

Natasha Razack (Project Manager)
Hospital for Sick Children      
Phone: 416-813-5858  or  toll-free 1-866-699-1899
E-mail: natasha.razack@sickkids.ca

Start:  September 2005

Inclusion Criteria:

1. Age range of 35-75yrs. 

2. Visual acuity of 20/40) or better.  

3. Type 2 diabetes (and healthy age-matched controls)

Exclusion Criteria:

1. Distance refractive error > ±6.00DS & / or ±2.50DC.

2. Any other eye disease or disorder including lenticular opacity or ocular surgery.

3. Habitual smoking.

4. Lung disease.

5. Proliferative diabetic retinopathy.

At each visit, retinal vessel images will be acquired while the patient is breathing air and then elevated oxygen through a breathing mask. Completion of the study requires six study visits, each lasting approximately 90 minutes.

• Six study visits, each lasting approximately 90 minutes (Healthy controls will attend for 2 visits).
• Food and beverage diary recorded on the day before each visit. 
• Avoid caffeine and nasal decongestants, and will be asked to fast for 8hrs (i.e. over night) prior to visit. 
• Patients will be asked to wear a breathing mask to permit the delivery of air and elevated oxygen.
• Images of retinal vessels will be non-invasively acquired at each visit.
• Blood tests to measure cholesterol, blood glucose and cytokines will also be taken.

1. Have elevated blood cholesterol
2. Have been prescribed Lipitor by their doctor
3. Have visual acuity of 20/20 or better
4. Are 20 years of age or older

Exclusion Criteria:

1. Refractive error >+/- 6.00 DS and/or +/- 2.50 DC
2. Any eye disease
3. History of eye surgery
4. Current smokers (or those who have ceased smoking for < 6 months)
5. Acute liver disease
6. Nursing or pregnant women
7. Systemic disease including respiratory disorders, and heart or cardiovascular disease

1. To determine whether treatment with Avandamet, in addition to a healthy living lifestyle program, will prevent the development of Type 2 diabetes in subjects with impaired glucose tolerance (IGT).

2. To determine whether treatment with Avandamet, in addition to a healthy living lifestyle program, will improve risk factors for cardiovascular disease and diabetes.

CANOE is a randomized, double-blind controlled trial to determine whether Avandamet will decrease the development of diabetes in individuals with IGT (a condition indicating high diabetes risk).  A total of 200 patients will be followed for an average follow up of 4 years (range 3 – 5 years).  Active treatment with Avandamet (Metformin 500 mg / Avandia 2 mg) administered twice daily will be compared to matched placebo.  All study participants will receive a lifestyle intervention program based on the latest evidence-based guidelines recommended by the Canadian Diabetes Association.  The study participants will receive a follow-up phone call two weeks after randomization and make clinic visits every two months thereafter for the first year.  They will then be seen every six months for the duration of the study.  The primary outcome is the development of new onset diabetes.  Secondary outcomes include markers of diabetes and cardiovascular risk.

Inclusion Criteria:

• Residents of Ontario age 18-75 years (for Native Canadians) or 30-75 years (for other ethnic groups).

• IGT on glucose tolerance testing.

Exclusion Criteria:

• Current use of Metformin or Rosiglitazone

• Prior use of medication to treat diabetes with the exception of during gestational diabetes

• Use of drugs known to worsen glucose tolerance (e.g. systemic glucocorticoids, thiazide diuretics, or niacin)

• History of diabetes, except gestational diabetes

• Active liver or kidney disease or anemia

• Any major illness with a life expectancy of <5 years or that may interfere with the patient's participation in the study

• Involvement in any other study requiring drug therapy

• History of congestive heart failure or current congestive heart failure

• Excessive alcohol consumption

• Pregnancy or unwillingness to use reliable contraception.

Prospective cohort design.  Screening, baseline, repeat assessments will assess metabolic & immunologic status over time.  Relatives of people with type 1 diabetes will be screened to determine if they are at risk for the development of type 1 diabetes.  Screening involves a blood  test for diabetes related antibodies. If  antibodies are not present, individuals under 18 will be offered to be screened again on a  yearly  basis  to discover if they develop the antibodies in question.  If antibodies are present, further testing will be offered to determine individuals' risk of developing diabetes at a baseline risk assessment visit.  Antibody-positive subjects will be followed every 6 months to learn how their immune response changes and if they are developing diabetes.

Inclusion Criteria:

• Willing to give informed  consent
• 1 to 45 years
• Have a blood relative with T1D (primarily 1st degree, but those  <=20 with 2nd or 3rd degree relatives are eligible)
• DPT-1 (predecessor trial) subjects will be entered into appropriate phase of study

Exclusion Criteria:

• History of insulin treatment or oral hypoglycemic agents
• Have diabetes (1997 ADA criteria)
• Have known severe active diseases
• Unable to comply with protocol

Natasha Razack (Project Manager)
Hospital for Sick Children
PhoneL 416-813-5858 or toll-free 1-866-699-1899
Email: natasha.razack@sickkids.ca