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

Phase 4

Completed

• Conditions: Type 2 Diabetes Mellitus; Myocardial Fibrosis; Myocardial Inflammation
• Interventions: Other: Placebo; Drug: dapagliflozin

• Registration Number: NCT03782259
• Lead Sponsor: University of Washington

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.

Study Timeline

• Study First Submitted: 2018-10-24
• Study First Submitted QC: 2018-12-18
• Study First Posted: 2018-12-20
• Study Start: 2019-02-26
• Primary Completion: 2022-11-16
• Study Completion: 2022-11-16
• Results First Submitted: 2023-10-26
• Status Verified: 2023-12
• Results First Submitted QC: 2023-12-11
• Last Update Submitted: 2023-12-11
• Results First Posted: 2023-12-29
• Last Update Posted: 2023-12-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

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 glucagon-like peptide (GLP)-1 receptor antagonist

4. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2

5. Unstable or rapidly progressive renal disease

6. Hypotension with systolic blood pressure (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. Heart Failure - New York Heart Association (NYHA) Class IV
    5. Transient ischemic attack (TIA) or significant cerebrovascular disease
    6. Unstable or previously undiagnosed arrhythmia
    7. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	10mg tabs placebo matching dapagliflozin.
Active	dapagliflozin	10mg tabs of dapagliflozin

Primary Outcome Measures

Name	Time	Method
Extracellular Volume Fraction (ECV)	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	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 Outcome Measures

Name	Time	Method
T2 Relaxation Time	Approximately 12 Months	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

Trial Locations

Locations (1)

University of Washington; 🇺🇸 Seattle, Washington, United States