Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo 10mg tabs placebo matching dapagliflozin. |
Other: Placebo
Placebo
|
| Active Comparator: Active 10mg tabs of dapagliflozin |
Drug: dapagliflozin
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.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Extracellular volume fraction (ECV) [Approximately 12 Months]
Extracellular volume fraction (ECV) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. ECV combines native and contrast-enhanced T1 mapping. Ancova test with adjusted for baseline ECV will be used to compare change in ECV over 12 months between 2 treatment groups.
- Global myocardial longitudinal strain (GLS) [Approximately 12 Months]
Global myocardial longitudinal strain (GLS) 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 and strain rate from the bSSFP short-axis and long-axis cine images. Long-axis cine images will be further used to compute GLS. Ancova test with adjusted for baseline GLS will be used to compare change in GLS over 12 months between 2 treatment groups.
Secondary Outcome Measures
- 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
Other Outcome Measures
- Epicardial fat [Approximately 12 Months]
Change from baseline in Epicardial fat measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months Ancova test will be used for comparisons of epicardial fat between 2 different timepoints within each treatment group, at between 2 treatments at the same time point, and changes during the study.
- Fasting glucose [Approximately 12 Months]
Fasting glucose will be measured every 3 months for approximately 12 months.
- HbA1C [Approximately 12 Months]
Hemoglobin A1c (HbA1c) will be measured every 3 months for approximately 12 months.
- LDL particle size [Approximately 12 Months]
LDL particle size measured from plasma samples at Randomization and at approximately 12 Months
- hsCRP [Approximately 12 Months]
Inflammatory marker hsCRP at Screening, 6 months and at approximately 12 Months.
- Tumor necrosis factor (TNF)-α [Approximately 12 Months]
Inflammatory marker TNF-α measured from plasma samples at Randomization and at approximately 12 Months
- Iinterleukin (IL)-6 [Approximately 12 Months]
Inflammatory marker IL-6 measured from plasma samples at Randomization and at approximately 12 Months
Eligibility Criteria
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:
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Contraindication to MRI
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Currently or within last three months treatment with a SGLT2 inhibitor
-
Currently taking glucagon-like peptide (GLP)-1 receptor antagonist
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Glomerular filtration rate (GFR) <60 mL/min/1.73 m2
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Unstable or rapidly progressive renal disease
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Hypotension with systolic blood pressure (SBP) <100 mmHg
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Hypersensitivity to dapagliflozin or any excipients
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Patients with severe hepatic impairment (Child-Pugh class C)
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Patients with active hepatitis B or C infection
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Any of the following CV/Vascular Diseases within 3 months prior to signing the consent at enrollment, as assessed by the investigator:
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Myocardial infarction
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Cardiac surgery or revascularization (CABG/PTCA)
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Unstable angina
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Heart Failure - New York Heart Association (NYHA) Class IV
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Transient ischemic attack (TIA) or significant cerebrovascular disease
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Unstable or previously undiagnosed arrhythmia
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Washington | Seattle | Washington | United States | 98104 |
Sponsors and Collaborators
- University of Washington
- AstraZeneca
Investigators
- Principal Investigator: Xue-Qiao Zhao, MD, University of Washington
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- STUDY00004982
- ESR 17-13124