Effect of Dapagliflozin on Inflammation and Endothelial Function

The insulin-resistant state of type 2 diabetes mellitus (T2DM) is largely mediated by
inflammatory pathways affecting skeletal muscle which is the primary site of whole body
insulin resistance. Nuclear factor kappa B (NFkappaB) regulates pro-inflammatory cytokines
which ultimately impair skeletal muscle insulin signaling and fatty acid oxidation; its
activity reflects overall inflammatory tone in skeletal muscle. Recent human studies confirm
that NFkappaB is elevated in the skeletal muscle of T2DM human subjects. Furthermore, the
same inflammatory processes and signaling impairments contribute to worsening endothelial
dysfunction, which is an independent predictor for future cardiovascular events in T2DM. In
addition, these SGLT-2 Inhibitors reduce body weight, visceral adiposity, systolic and
diastolic blood pressure, microalbuminuria, and oxidative stress. However, there are no
studies examining the effects of SGLT-2 inhibitor therapy on NFkappaB and other inflammatory
mediators in humans with T2DM. Moreover, no studies have examined the effect of SGLT-2
inhibitor therapy on endothelial function in this population. In the present study the
investigators will assess whether dapagliflozin treatment for 12 weeks reduces monocyte
inflammation and improves endothelial dysfunction in patients with type 2 diabetes on
metformin monotherapy.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures

2. Men and women, ages 21 to 70 years. i) Women of childbearing potential must be using
an acceptable method of contraception to avoid pregnancy throughout the study in such
a manner that the risk of pregnancy is minimized.

ii) Women must not be pregnant or breastfeeding.

3. Patients with Type 2 Diabetes Mellitus with the following parameters at study entry:
hemoglobin A1c ranging from 7.0% to 9.0% and a fasting blood glucose less than or
equal to 200 mg/dL.

4. Patients must be on a stable dose of Metformin therapy for 3 months; the dose of
metformin will not change for the duration of the study.

5. Patients are allowed, but not required, to be on statins, Angiotensin Converting
Enzyme (ACE) inhibitors, and angiotensin-receptor blockers at doses that have been
stable for at least the last 3 months prior to enrollment in the study. Doses will not
be changed for the duration of the study.

6. Patients must have a Body Mass Index between 27-35 kg/m2

7. Patients must have a stable body weight for three months prior to enrollment in the
study.

8. Patients must have a Creatinine Clearance greater than 60 mL/min (calculated by
Cockcroft-Gault formula).

9. Patients must have Hematocrit greater than or equal to 34%; Serum creatinine less
than1.5 mg/dl in men and 1.4 mg/dl in women and Creatinine Clearance greater than 60
ml/min; and serum aspartate aminotransferase (AST) less than 2.5 times upper limit of
normal, serum alanine transaminase (ALT) less than 2.5 times upper limit of normal,
serum alkaline phosphatase less than 2.5 times upper limit of normal.

Exclusion Criteria:

1. History of Type 1 diabetes mellitus

2. Women who are pregnant or breastfeeding

3. Patients receiving lipid-lowering medications other than statins within the last 3
months.

4. Patient receiving SGLT-2 inhibitors, incretin therapy, dipeptidyl peptidase 4 (DPP-4)
inhibitors, thiazolidinediones, insulin, sulfonylureas, alpha-glucosidase inhibitors,
corticosteroids, immunosuppressive therapy, thiazide or loop diuretics, or hormone
replacement therapy within the last 3 months .

5. Patient must stop treatment with nonsteroidal anti-inflammatory drugs (NSAID) and
antioxidant vitamin supplements at least one week prior to the start of the study

6. Patients with diabetic gastroparesis.

7. Patients with current tobacco use.

8. Patients with active malignancy.

9. Patients with history of urinary bladder cancer

10. Patients with a history of clinically significant heart disease, peripheral vascular
disease, or pulmonary disease will not be studied

11. Subjects with a history of any serious hypersensitivity reaction to dapagliflozin.

12. Prisoners, or subjects who are involuntarily incarcerated.

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

14. Patients with significant cardiac,hepatic or renal disease (Creatinine Clearance less
than 60 mL/min calculated by Cockcroft-Gault formula) will be excluded.