Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery
Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery
Background Endothelial dysfunction is one of the early events in atherosclerotic plaque
 development. It is characterized by an increased ratio of substances with vasoconstrictive,
 pro-thrombotic, and proliferative properties over substances with vasolidatory,
 antithrombogenic and antimitogenic properties. Endothelial dysfunction is also associated
 with high-risk patients with coronary artery disease. Hyperglycemia, obesity, hypertension
 and fat mass also impair the endothelium by increasing the expression of cytokines,
 inflammatory markers and vascular markers.

 Hypothesis Administration of dapagliflozin in addition to metformin background with clinical
 or subclinical cardiovascular atherosclerotic disease improves endothelial function when
 compared to those using glibenclamide in addition to metformin.

 Objectives Evaluate the effect of dapagliflozin vs glibenclamide on a metformin background on
 endothelial function in patients with clinical or subclinical cardiovascular atherosclerotic
 disease and poorly controlled diabetes.

 Enpoints Prymary Change in flow mediated dilation (FMD) and its related endpoint (FMD post
 reperfusion lesion) between the randomization visit and over 12 weeks of treatment.

 Secondary Change in plasma nitric oxide, isoprostane, ICAM-1, VCAM-1, ET-1, leptin,
 adiponectin, C-reactive protein, TNF- α, interleukin-6, interleukin-2, weight and body
 composition (% of fat mass and % free fat mass) at the randomization visit and over 12 weeks
 of treatment.

 3

 Design Randomized, parallel-group, comparative, prospective clinical study. The study is
 divided in two phases: Run-in and Randomization. In the former phase, which must have the
 maximum period of 16 weeks, patients will visit the outpatient to adjust metformin and blood
 pressure medications. After run-in phase, patients that fulfill inclusion criteria will
 perform an ambulatory blood pressure monitoring (ABPM) in order to asses BP; body composition
 will be assessed by dual x-ray absorptiometry (DXA); endothelial function as assessed by flow
 mediated dilation and vascular cytokines. Patients will by randomized to dapagliflozin or
 glibenclamide on a metformin background. After 12 weeks, the ABPM, DXA and endothelial
 function will be assessed.
Inclusion Criteria:

 (i) chronic coronary artery disease as shown by angiogram or subclinical artery disease
 diagnosed by the presence of carotid atherosclerotic plaque or carotid Intima-Media
 Thickness (cIMT) ≥ 1mm;

 (ii) T2DM using up to two oral hypoglycemic agents;

 (iii) inadequate glycemic control (HbA1c ≥ 7%);

 Exclusion Criteria:

 (i) HbA1c > 9%;

 (ii) contraindications to metformin use (Cr Clearance <60 ml/min, Cr> 1.5 mg/dL in men and>
 1.4 mg/dl in women, liver failure - AST or ALT> 3x upper normal limit or other conditions
 that might increase the risk of lactic acidosis);

 (vi) at the time of randomization, patient who is not on metformin XR 1500 mg/day
 monotherapy for at least 12 weeks;

 (vii) patients who spend more than 16 weeks to adjust metformin before randomization;

 (viii) BP ≥ 140 x 90 after 16 weeks of anti-hypertensive medication adjustment;

 (iii) hospitalization for unstable angina or acute myocardial infarction within 2 months
 prior to enrolment;

 (iv) acute stroke or transient ischemic attack (TIA) within two months prior to enrolment;

 (v) less than two months post coronary artery revascularization;

 (ix) patients with FMD <2% at the time of randomization;

 (x) triglycerides > 500 mg/dL;

 (xi) known allergy to any of the study drugs;

 (xii) patients with severe coronary artery disease and heart failure;

 (xiii) systemic vasculitis;

 (xiv) conditions that lead to systemic inflammation;

 (xv) patients using rosiglitazone;

 (xvi) polyuria, polydipsia, weight loss, or others clinical signs of volume depletion;

 (xvii) those who refuse to participate or sign the Statement of Informed Consent;

 (xviii) pregnancy or women during reproductive age;

 (xix) breastfeeding women;

 (xx) history of gastrointestinal disorders that may interfere with the absorption of study
 medication;

 (xxi) patients who are participating in other clinical studies or whose participation ended
 less than six months ago.