An Investigation Into The Anti-hypertensive And Potential Anti-inflammatory Actions Of Dapagliflozin

Study Overview
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Brief Summary
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This is a single center, prospective, randomized, placebo -controlled, parallel design and double blind study to evaluate oxidative stress, inflammation and hypertension markers and mediators before and after treatment with dapagliflozin.

Detailed Description
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Two groups of 26 patients each (total 52 patients) with type 2 diabetes on oral agents will be included in the study. One group will be randomized to dapagliflozin (a dose of 5 mg daily will be titrated to 10 mg daily during the first week) while the other will be placebo. The patients will be treated for 12 weeks. Only half the patients (equal numbers in both groups) will be tested for the secondary endpoints related to postprandial and single dose induced changes. The primary endpoint of the study is to detect a significant difference in the percent change in fasting Nuclear factor-k B (NFκB) activation (DNA binding activity) in mononuclear cells (MNC) before and after dapagliflozin use (0 week vs. 12 weeks) as compared to placebo.

Official Title
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An Investigation Into The Anti-hypertensive And Potential Anti-inflammatory Actions Of Dapagliflozin

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 20-80 years inclusive. Type 2 diabetes BMI ≥30 kg/m2 Subjects on statins, ACE inhibitors, ARBs, thiazolidinediones and -antioxidants will be allowed as long as they are on stable doses of these -compounds and the dosage in not changed during the course of study. -Patients will be evenly distributed between the 2 groups based on statins, -ARBs, TZDs and ACE inhibitors use. HbA1c ≤ 8.0% Exclusion Criteria: Use of GLP-1 agonists or DPP-IV or SGLT-2 inhibitors therapy in the last 3 -months. Risk for pancreatitis, i.e., history of gallstones, alcohol abuse, and -hypertriglyceridemia. Coronary event or procedure (myocardial infarction, unstable angina, coronary -artery bypass, surgery or coronary angioplasty) in the previous 3 months. Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver -function defined as: aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or -alanine aminotransferase (ALT) >3x ULN Total bilirubin >2.0 mg/dL (34.2 µmol/L) Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody (liver function tests more than 3 times the upper limit of normal) Renal impairment (serum eGFR <60 ml/min) Any other life-threatening, non-cardiac disease Uncontrolled hypertension (BP > 160/100 mm of Hg) Congestive Heart Failure class III or IV. Use of an investigational agent or therapeutic regimen within 30 days of study Participation in any other concurrent clinical trial pregnant or breastfeeding patients Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients will be treated for 12 weeks with placebo once daily | Drug: Placebo<br> <br> |
| Active Comparator: Dapagliflozin<br>10 mg daily for the 12 weeks | Drug: dapagliflozin<br>* SGLT-2 inhibitor for the treatment of type 2 diabetes<br>* Other names: Farxiga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | nuclear factor kappa-light-chain-enhancer of activated B cells measurement through Transcription factor assay | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Expression of Inflammatory Mediators | p47phox in mononuclear cells through real time polymerase chain reaction | 12 Weeks | 
| Changes in Expression of Inflammatory Mediators | Suppressor Of Cytokine Signaling 3 measurement in Mononuclear cells through real time polymerase chain reaction | 12 weeks | 
| Changes in Expression of Inflammatory Mediators | Interleukin 1 Beta measurement in mononuclear cells through real time polymerase chain reaction | 12 weeks | 
| Changes in Expression of Inflammatory Mediators | c-Jun N-terminal kinase 1 measurement in Mononuclear cells through real time polymerase chain reaction | 12 weeks | 
| Changes in Expression of Inflammatory Mediators | Toll-like receptor 4 measurement in mononuclear cells through real time polymerase chain reaction | 12 weeks | 
| Changes in Expression of Inflammatory Mediators | Tumor necrosis factor alpha measurement in mononuclear through real time polymerase chain reaction | 12 weeks |