Outpatient Discharge Therapy With Saxagliptin+MetforminXR vs GlipizideXL for Type 2 Diabetes With Severe Hyperglycemia

There is very little information regarding diabetes discharge regimens for patients with
recently diagnosed diabetes (<1 year duration) who present with severe hyperglycemia (blood
glucose 300-450 mg/dl) to the ED or other clinical settings and who do not need to be
admitted.

A combination of Saxagliptin+Metformin XR, could be a potential drug combination to be
tested as an initial treatment in these circumstances compared to Glipizide XL which was
shown to be effective in our previous study. We expect Saxagliptin to improve beta cell
function and decrease glucagon levels as was shown for the DPP-IV class medications and in
turn improve blood glucose levels, while Metformin XR may reduce insulin resistance and
hepatic glucose output. Such discharge therapy may help to prevent deterioration into acute
metabolic complications (DKA or hyperosmolar states) and avoid hospitalization. A high
proportion of patients may achieve glycemic targets without significant hypoglycemia as
measured by self glucose monitoring and objectively by continuous glucose monitoring system
(CGMS). Such an easy regimen may safely bridge the time gap until patients will be seen by
their providers.

Inclusion Criteria:

1. Target Population

1. Subjects recently diagnosed with T2DM (less than 1 year duration) who are either
drug naïve or who had not taken oral anti-diabetic agents or insulin for more
than 2 weeks.

2. FBG and or RBG > 300mg/dl and < 450mg/dl

2. Age and Sex

1. Men and women aged 18 to 75 years of age.

2. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks
after the last dose of study drug to minimize the risk of pregnancy.

WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 72 hours before the start of the investigational product.

Exclusion Criteria:

1. Sex and Reproductive Status

1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy
for the entire study period and for up to 4 weeks after the last dose of study
drug.

2. Women who are pregnant or breastfeeding.

3. Women with a positive pregnancy test.

4. Sexually active fertile men not using effective birth control if their partners
are WOCBP.

2. Target Disease Exceptions

1. Type 2 diabetes with weight less than 120 pounds

2. Type 1 diabetes

3. History of diabetic ketoacidosis or hyperosmolar nonketotic coma

3. Medical History and Concurrent Diseases

1. Age >75 years

2. History of congestive heart failure

3. Evidence of an impaired sensorium and/or dementia

4. Current history of alcohol or substance abuse

5. Patients with any acute or active chronic medical illness

4. Physical and Laboratory Test Findings

1. FBG and /or RGB < 300 mg/dl or >450 mg/dl

2. Unstable vitals signs (temperature >101 degrees Fahrenheit, systolic blood
pressure <90 or >180 mmhg, diastolic blood pressure <60 or >110 mmhg, heart rate
<60 or >120 beats/minute)

3. Electrolyte imbalances (serum bicarbonate level <20 mEq/L, serum sodium <125 or
>150 mEq/L, serum potassium <3.5 or >5.5 mEq/L), serum creatinine more than 1.5
in males and 1.4 in females, creatinine clearance less than 60ml/min, liver
enzymes 3 times above upper limit of normal range.

4. HbA1c > 12% (based on our previous study (4) patients with HbA1c of >12 had a
high rate of non-responders)

5. Liver enzymes 3 times above upper limit of normal range.

6. Allergies and Adverse Drug Reactions -Subjects with a history of any serious
hypersensitivity reaction to saxagliptin, glipizide or metformin XR.

5. Prohibited Treatments and/or Therapies

a)Treatment with systemic cytochrome P450 3A4 (CYP 3A4) inhibitors.

6. Other Exclusion Criteria

1. Prisoners or subjects who are involuntarily incarcerated.

2. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.