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

NCT03782259 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: STUDY00004982ESR 17-13124
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus; Myocardial Fibrosis; Myocardial Inflammation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• T2 Relaxation Time

  Approximately 12 Months

Other Outcomes (3)

• Fasting Glucose

  Approximately 12 Months

• HbA1C

  Approximately 12 Months

• hsCRP

  Approximately 12 Months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

10mg tabs placebo matching dapagliflozin.

Other: Placebo

Active

ACTIVE COMPARATOR

10mg tabs of dapagliflozin

Drug: dapagliflozin

Interventions

dapagliflozin DRUG

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.

Also known as: Forxiga

Active

Placebo OTHER

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• AstraZeneca: collaborator

Study Sites (1)

University of Washington

Seattle, Washington, 98104, United States

Location

Related Publications (3)

• Naumova AV, Cunha GM, Kim NJ, Lu J, Isquith D, Chu B, Maynard C, Mahdavi A, Firoozeh N, Ordovas K, Zhao XQ, Kim F. Dapagliflozin-Associated Reduction in Liver Fat Is Independent of Weight Loss in Patients With Type 2 Diabetes. Obesity (Silver Spring). 2026 Feb 2. doi: 10.1002/oby.70134. Online ahead of print.

  PMID: 41629250 DERIVED

• Wang DD, Naumova AV, Isquith D, Sapp J, Huynh KA, Tucker I, Balu N, Voronyuk A, Chu B, Ordovas K, Maynard C, Tian R, Zhao XQ, Kim F. Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure. Cardiovasc Diabetol. 2024 Jun 7;23(1):197. doi: 10.1186/s12933-024-02294-z.

  PMID: 38849829 DERIVED

• Wang D, Naumova A, Isquith D, Sapp J, Huynh KA, Tucker I, Balu N, Voronyuk A, Chu B, Ordovas K, Maynard C, Tian R, Zhao XQ, Kim F. Dapagliflozin Reduces Systemic Inflammation in Patients with Type 2 Diabetes Without Known Heart Failure. Res Sq [Preprint]. 2024 Mar 25:rs.3.rs-4132581. doi: 10.21203/rs.3.rs-4132581/v1.

  PMID: 38585865 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Myocarditis

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases

Limitations and Caveats

* Relatively small trial was not powered to detect small effect sizes. * Animal studies of SGLT2 inhibition used direct pathologic examination of inflammation and fibrosis; Cardiac MRI is known to be less sensitive. * 12-month treatment may not have been sufficient to detect meaningful changes in inflammation, fibrosis, and strain. * No matched, non-diabetic control group. * Higher ECV values (\>32) are associated with worse outcomes with known myocarditis.

Results Point of Contact

• Title: Francis Kim, MD
• Organization: University of Washington

fkim@uw.edu

206-744-8305

Study Officials

• Xue-Qiao Zhao, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor: School of Medicine

Model Details: Randomized, double-blind and placebo controlled cardiac MRI study

Study Record Dates

• First Submitted: October 24, 2018
• First Posted: December 20, 2018
• Study Start: February 26, 2019
• Primary Completion: November 16, 2022
• Study Completion: November 16, 2022
• Last Updated: December 29, 2023
• Results First Posted: December 29, 2023

Record last verified: 2023-12

Locations

US (1)