This study aims to elucidate the impact of SGLT2 inhibition on peripheral vascular function, renal function, fluid volume, neurohormonal activation and inflammatory/fibrotic pathways in patients with T2D at high cardiovascular risk and non-T2D patients.

In light of EMPA-REG OUTCOME, CANVAS Program and DECLARE trials, we aim to elucidate the impact of SGLT2 inhibition on peripheral vascular function while also exploring the effects of this therapy on renal function, fluid volume, neurohormonal activation and inflammatory/fibrotic pathways in patients with T2D at high cardiovascular risk to best replicate the patient populations in recent cardiovascular outcome trials (CVOT), who are also participating in ongoing CVOTs such as VERTIS (ertugliflozin), as well as non-T2D patients in other ongoing trials examining cardiorenal effects of these therapies. We will test the hypothesis that in a high- risk population, regardless of T2D status, SGLT2 inhibition will improve markers of arterial stiffness (decreases in pulse wave velocity and augmentation index) in the study cohort - a surrogate marker of cardiovascular risk independent of glucose lowering. In addition, dapagliflozin will improve endothelial function ("flow-mediated vasodilatation" - FMD) and increase natriuresis (fractional excretion of sodium or FENa+), thereby reducing blood pressure, without inducing renal vasoconstriction or activation of the sympathetic nervous system (SNS). Based on extensive experimental literature, we also hypothesize that SGLT2 inhibition will suppress levels of pro-inflammatory/fibrotic mediators (see below) that have been linked with progression of cardiovascular and renal disease. The systematic understanding of the effects of SGLT2 inhibitors in the setting of patients at high cardiovascular risk will enable the design of rational physiology-based strategies to decrease the burden of cardiorenal disease, which could have important clinical and research implications. Data from DAPA-SWEET will also be valuable to better understand the results of trials that include patients using SGLT2 inhibitors as primary prevention strategies, such as in DECLARE TIMI-58.

Inclusion Criteria:

1. eGFR ≥30 ml/min/1.73m2
2. In patients with type 2 diabetes, HbA1c <12.0%
3. Body Mass Index (BMI) 18.5-45.0 kg/m2
4. Blood pressure < or = 160/100 at screening (sitting)
5. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days
6. Stable diuretic dose for at least 14 days prior to baseline study Visit
7. High cardiovascular risk: an age of 50 years or more with at least one cardiovascular coexisting condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage 3 or greater, or chronic heart failure of New York Heart Association class II or III) OR an age of 60 years or more with at least one cardiovascular risk factor, as determined by the investigator (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index [the ratio of the systolic blood pressure at the ankle to the systolic blood pressure in the arm] of less than 0.9).

Exclusion Criteria:

1. Type 1 Diabetes
2. Iodine intolerance
3. Hypersensitivity or allergy to dapagliflozin
4. Use of an SGLT2 inhibitor within 30 days
5. Leukocyte and/or nitrite positive urinalysis that is untreated
6. Severe hypoglycaemia within 1 month prior to screening
7. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months
8. Clinically significant valvular disease in the opinion of the investigator
9. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction
10. Bariatric surgery or other surgeries that induce chronic malabsorption within 1 year;
11. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
12. Treatment with systemic corticosteroids
13. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells
14. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control
15. Participation in another trial with an investigational drug within 30 days of informed consent
16. Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement
17. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening
18. Medical history of cancer or treatment for cancer in the last five years prior to screening, aside from uncomplicated basal cell or squamous cell carcinoma;
19. Unstable or rapidly progressive renal disease as per investigator judgement
20. Intolerance or sensitivity to SGLT2 inhibitors

Double-blind study