Effect of Dapagliflozin on Inflammation and Endothelial Function
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 2; Inflammation
Intervention: Dapagliflozin; Placebo
Intervention description: Patients with Type 2 diabetes will be randomized to receive dapagliflozin 5 mg daily for 2 weeks followed by10 mg daily for 10 weeks by mouth or matching placebo for 12 weeks. All subjects will receive measurements of fasting plasma glucose, Free Fatty Acids, inflammatory markers and adipocytokines, monocyte inflammation, as well as ultrasound assessment of flow-mediated dilatation (FMD) of the brachial artery at baseline and after 12 weeks of drug treatment with either dapagliflozin or placebo.; Patients with Type 2 diabetes will be randomized to receive dapagliflozin 5 mg daily for 2 weeks followed by10 mg daily for 10 weeks by mouth or matching placebo for 12 weeks. All subjects will receive measurements of fasting plasma glucose, Free Fatty Acids, inflammatory markers and adipocytokines, monocyte inflammation, as well as ultrasound assessment of flow-mediated dilatation (FMD) of the brachial artery at baseline and after 12 weeks of drug treatment with either dapagliflozin or placebo.
Intervention MeSH terms: Dapagliflozin
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 17.0
Sex: All
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      Sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce hyperglycemia and improve
      peripheral insulin sensitivity by ameliorating glucotoxicity. Insulin resistance in type 2
      diabetes (T2DM) is associated with endothelial dysfunction and vascular inflammation. Thus
      strategies to improve insulin sensitivity and lower glucotoxicity may improve endothelial
      inflammation and vascular inflammation. However, the effects of these agents on vascular
      inflammation and endothelial function is not known in patients with type 2 diabetes although
      anti-inflammatory properties have been demonstrated in various animal models. In the present
      study the investigators will assess if dapagliflozin treatment for 12 weeks decreases
      monocyte inflammation and improves endothelial function in patients with type 2 diabetes on
      metformin monotherapy.
    

Eligibility criteria:

        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.