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
Overview
- Phase
- Phase 4
- Intervention
- Placebo
- Conditions
- Type 2 Diabetes Mellitus
- Sponsor
- University of Washington
- Enrollment
- 62
- Locations
- 1
- Primary Endpoint
- Extracellular Volume Fraction (ECV)
- Status
- Completed
- Last Updated
- 2 years ago
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.
Investigators
Francis Kim
Professor: School of Medicine
University of Washington
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:
Arms & Interventions
Placebo
10mg tabs placebo matching dapagliflozin.
Intervention: Placebo
Active
10mg tabs of dapagliflozin
Intervention: dapagliflozin
Outcomes
Primary Outcomes
Extracellular Volume Fraction (ECV)
Time Frame: Approximately 12 Months
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).
Global Myocardial Strain
Time Frame: Approximately 12 Months
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.
Secondary Outcomes
- T2 Relaxation Time(Approximately 12 Months)