Efficacy of Exenatide-LAR and Dapagliflozin in Overweight/Obese, Insulin Treated Patients With Type 2 Diabetes

This is a single center prospective, randomized, placebo-controlled trial in
overweight/obese patients with insulin treated uncontrolled type 2 diabetes

Eligible subjects willing to participate in the study will be randomized to one of 3
treatment groups:

Group 1: Insulin titration + behavioral therapy Basal insulin titration upto 12 weeks with 2
U increment every 3 days (Fasting glucose goal <110) based on self-monitored blood glucose.

After 12 weeks, patients with HbA1c >8% will switch to a basal bolus regimen. Basal insulin
dose will be reduced by one-third or one-half at the investigator's discretion and replaced
with 3 doses of prandial insulin(lispro/novorapid) to maintain the same total insulin dose.
Thereafter, basal insulin will be titrated as before and prandial insulin titration will be
based on self-monitored pre-meal glucose.

Group 2: Exenatide-LAR 2mg q week x 24 weeks + Dapagliflozin placebo x 52 weeks + behavioral
therapy. Daily insulin dose will be reduced by 20%.

Group 3: Exenatide-LAR 2mg q week x 24 weeks plus Dapagliflozin 5mg QD x 2 weeks followed by
10mg QD x22 weeks + behavioral therapy. Daily insulin dose will be reduced by 20%.

Behavioral therapy will be delivered by registered dietitians and will include the BMIQ
program -a web based medical weight loss program designed by Dr Aronne.

All procedures in the study are standard of care except DEXA and blood biomarkers which will
be done for research purposes. Further details of the study design and procedures are in the
attached protocol.

Inclusion Criteria:

- Diagnosis of Type 2 diabetes, BMI ≥27kg/m^2, Hemoglobin A1C 8-12%, English speaking,
provided written consent, on a stable dose of metformin and/or glitazone and/or
alpha-glucosidase inhibitors for greater or equal to 8 weeks

Exclusion Criteria:

- History of type 1 diabetes, fasting c-peptide <.8 ng/ml, eGFR <60 ml/min/1.73 m^2,
urine albumin-to-creatinine ratio greater or equal to 300 mg/g, AST/ALT greater or
equal to 2.5 upper limits of normal, history of infectious liver disease (HBV, HCV),
creatine kinase greater or equal to 3 times the upper limits of normal, unstable or
serious cardiovascular, renal, or hepatic disease, symptoms of severely uncontrolled
diabetes, history of more than 1 episode of severe/major hypoglycemia within 6
months, active/history of bladder cancer, female patients who are pregnant or
intending to become pregnant, women who are breastfeeding, personal/family history of
medullary thyroid cancer or MEN2, fasting triglyceride levels > 500 mg/dl, history of
confirmed pancreatitis, known hypersensitivity or allergy to exenatide or
dapagliflozin, are currently enrolled in or discontinued within last 30 days from
another study, have any other condition that precludes the patient from following and
completing the protocol, history of diabetic ketoacidosis, anti-diabetes medication
other than those listed in the inclusion criteria within 8 weeks of screening,
history of previous bariatric surgery or planned bariatric surgery during the course
of the study, clinically significant abnormal free T4/TSH requiring initiation or
adjustment of thyroid treatment