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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03782259

Enrollment

Registered

2018-12-20

Start date

2019-02-26

Completion date

2022-11-16

Last updated

2023-12-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Myocardial Fibrosis, Myocardial Inflammation, Type 2 Diabetes Mellitus

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.

Interventions

DRUGdapagliflozin

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.

OTHERPlacebo

Placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SCREENING

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention model description

Randomized, double-blind and placebo controlled cardiac MRI study

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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

Measure	Time frame	Description
HbA1C	Approximately 12 Months	Hemoglobin A1c (HbA1c) assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported
Fasting Glucose	Approximately 12 Months	Fasting glucose assessed at Baseline and every 3 months for approximately 12 months, Baseline and 12 months reported
hsCRP	Approximately 12 Months	Inflammatory marker hsCRP assessed at Baseline and every 6 months for approximately 12 months, Baseline and 12 months reported

Countries

United States

Participant flow

Participants by arm

Arm	Count
Placebo 10mg tabs placebo matching dapagliflozin. Placebo: Placebo	31
Dapagliflozin 10mg tabs of dapagliflozin 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.	31
Total	62

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	1
Overall Study	Moved out of state	0	2
Overall Study	MRI incompatibility: Pacemaker implanted prior to subject final MRI scan	0	1
Overall Study	Subject discontinued intervention	1	0

Baseline characteristics

Characteristic	Placebo	Dapagliflozin	Total
Age, Continuous	62 years STANDARD_DEVIATION 11	62 years STANDARD_DEVIATION 9	62 years STANDARD_DEVIATION 10
Angina	2 Participants	1 Participants	3 Participants
Coronary artery bypass surgery	2 Participants	0 Participants	2 Participants
Current smoker	3 Participants	2 Participants	5 Participants
Diabetes mellitus	31 Participants	31 Participants	62 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	1 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	27 Participants	30 Participants	57 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Family history myocardial infarction	11 Participants	12 Participants	23 Participants
Family history stroke	11 Participants	14 Participants	25 Participants
History myocardial infarction	2 Participants	1 Participants	3 Participants
Hyperlipidemia	18 Participants	21 Participants	39 Participants
Hypertension	19 Participants	19 Participants	38 Participants
Percutaneous coronary intervention	1 Participants	3 Participants	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	2 Participants	3 Participants
Race (NIH/OMB) Asian	6 Participants	3 Participants	9 Participants
Race (NIH/OMB) Black or African American	3 Participants	3 Participants	6 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) White	20 Participants	23 Participants	43 Participants
Region of Enrollment United States	31 participants	31 participants	62 participants
Sex: Female, Male Female	5 Participants	6 Participants	11 Participants
Sex: Female, Male Male	26 Participants	25 Participants	51 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 31	0 / 31
other Total, other adverse events	0 / 31	0 / 31
serious Total, serious adverse events	1 / 31	0 / 31

Outcome results

Primary

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).