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

Study Overview
=================
Brief Summary
-----------------
There is an unmet need for Cardiovascular Disease (CVD) risk reduction in patients with Type 2 Diabetes. In recent trials there has been promising findings of more effective glucose management and reductions in overall CVD events and hospitalization for heart failure with SGLT-2 inhibition. Using the capability of cardiac MRI with T1- and T2-mapping in assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a clinical trial to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial strain, fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes. Over approximately 12 months subjects will have 6 clinical visits at the investigators research clinic. During this time subjects will be randomized to receive either active 10mg dapagliflozin or a matching placebo. 2 MRI scans at one of the two University of Washington research imaging centers will take place. One at randomization and the second scan will occur approximately 12 months after the first scan.

Detailed Description
-----------------
Given the unmet needs for CVD risk reduction in patients with Type 2 Diabetes Mellitus (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 (CMRI) 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 strain, 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 strain endpoint includes global myocardial longitudinal strain (GLS). 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.

Official Title
-----------------
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

Conditions
-----------------
Type 2 Diabetes Mellitus, Myocardial Fibrosis, Myocardial Inflammation

Intervention / Treatment
-----------------
* Drug: dapagliflozin
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women at least 18 years of age Subjects with type-2 diabetes history >=5 years HbA1C 7-10% with glucose control medications including insulin, metformin or sulfonylurea Medically stable Willing to participate and sign informed consent. Exclusion Criteria: Contraindication to MRI Currently or within last three months treatment with a SGLT2 inhibitor Currently taking glucagon-like peptide (GLP)-1 receptor antagonist Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 Unstable or rapidly progressive renal disease Hypotension with systolic blood pressure (SBP) <100 mmHg Hypersensitivity to dapagliflozin or any excipients Patients with severe hepatic impairment (Child-Pugh class C) Patients with active hepatitis B or C infection Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator: Myocardial infarction Cardiac surgery or revascularization (CABG/PTCA) Unstable angina Heart Failure - New York Heart Association (NYHA) Class IV Transient ischemic attack (TIA) or significant cerebrovascular disease Unstable or previously undiagnosed arrhythmia Established peripheral artery disease (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 study drug, OR women who are breast-feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind and placebo controlled cardiac MRI study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>10mg tabs placebo matching dapagliflozin. | Other: Placebo<br>* Placebo<br>|
| Active Comparator: Active<br>10mg tabs of dapagliflozin | Drug: dapagliflozin<br>* Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study.<br>* Other names: Forxiga;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extracellular Volume Fraction (ECV) | Cardiac MRI using T1-mapping is capable of quantifying myocardial extracellular volume (ECV), a surrogate of fibrosis, with excellent inter- and intra-observer variability. Cardiac fibrosis was assessed by cardiac MRI T1 mapping to calculate ECV at two timepoints, baseline and at approximately 1 year. ECV combines native and contrast-enhanced T1 mapping. Extracellular Volume (ECV) maps were generated offline using MATLAB software. ECV was calculated from native and post-contrast T1 values for blood and myocardial tissue, the partition coefficient lambda (λ), and hematocrit using the following formulas: ECV = λ(1-hematocrit); λ = (1/T1 myocardium post-contrast-1/T1 myocardium-native)/(1/T1 blood post-contrast-1/T1 blood-native). | Approximately 12 Months | 
| Global Myocardial Strain | Global myocardial strain measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain from the Balanced Steady State Free Precession (bSSFP) short-axis and long-axis cine images. Long-axis cine images will be further used to compute global myocardial strain. Ancova test with adjusted for baseline global myocardial strain will be used to compare change in global myocardial strain over 12 months between 2 treatment groups. Global myocardial strain reported as longitudinal, radial, and circumferential at baseline and 1 year. | Approximately 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T2 Relaxation Time | Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months | Approximately 12 Months |