Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2

Given the unmet needs for CVD risk reduction in patients with T2DM, the promising findings of
more effective glucose management and reductions in overall CVD events and hospitalization
for heart failure with SGLT-2 inhibition demonstrated in recent trials, and the capability of
cardiac MRI with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation,
the investigators propose to conduct a staged research program using adaptive study design to
investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial fibrosis and
inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2
diabetes.

A total of 60 subjects with >=18 years of age, type-2 diabetes history >=5 years and HbA1C
7-10% will be randomized at 1:1 to Dapagliflozin 10mg or matching placebo once daily for 1
year. All subjects will be followed every 3 months for clinical and laboratory evaluations
and assessments. All subjects will undergo CMRI at baseline and 1 year.

The primary myocardial fibrosis endpoint is change in extracellular volume fraction (ECV) as
assessed by T1-mapping over 12 months. ECV combines native and contrast-enhanced T1 mapping.
The change of the T1 relaxation rate (i.e., 1/T1) in blood between pre- and post-contrast
imaging is converted with the blood hematocrit into a reference for plasma T1, which serves
as reference for the T1 changes in tissue.

Inclusion Criteria:

1. Men and women at least 18 years of age

2. Subjects with type-2 diabetes history >=5 years

3. HbA1C 7-10% with glucose control medications including insulin, metformin or
sulfonylurea

4. Medically stable

5. Willing to participate and sign informed consent.

Exclusion Criteria:

1. Contraindication to MRI

2. Currently or within last three months treatment with a SGLT2 inhibitor

3. Currently taking GLP-1 receptor antagonist

4. GFR <60 mL/min/1.73 m2

5. Unstable or rapidly progressive renal disease

6. Hypotension with SBP <100 mmHg

7. Hypersensitivity to dapagliflozin or any excipients

8. Patients with severe hepatic impairment (Child-Pugh class C)

9. Patients with active hepatitis B or C infection

10. Any of the following CV/Vascular Diseases within 3 months prior to signing the consent
at enrollment, as assessed by the investigator:

1. Myocardial infarction

2. Cardiac surgery or revascularization (CABG/PTCA)

3. Unstable angina

4. HF New York Heart Association (NYHA) Class IV

5. Transient ischemic attack (TIA) or significant cerebrovascular disease

6. Unstable or previously undiagnosed arrhythmia

7. Established PAD

(18) Active bladder cancer (19) Recent episode of Diabetic ketoacidosis (DKA), frequent
episodes of DKA (20) High risk of fractures, amputations and fibrosis (21) Women of
child-bearing potential (ie, those who are not chemically or surgically sterilized or who
are not post-menopausal) who have a positive pregnancy test at enrollment or randomization,
OR women who are not willing to use a medically accepted method of contraception that is
considered reliable in the judgment of the investigator, from the time of signing the
informed consent until two weeks after the last dose of IP, OR women who are
breast-feeding.