Dapagliflozin Effect on FunctiOnal Mitral Regurgitation and Myocardial Remodeling

Study Overview
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Brief Summary
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Functional mitral regurgitation (FMR) leads to various adverse outcomes. Cardiac remodeling (CR) and myocardial fibrosis (MF) are closely related to FMR, forming a vicious circle of CR-FMR-MF and resulting in the end-stage heart failure (HF). The optimal therapeutic strategies of FMR require to effectively break the vicious circle of CR-FMR-MF and still remain full of controversy, especially in the appropriate selection of patients suitable for transcatheter treatment. Regardless, adequate guideline-directed medical therapy (GDMT) is always the most important therapy of FMR. Currently GDMT for FMR included β-blockers, renin-angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRA). Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, have been proven to be effectively in reducing cardiovascular death and worsening HF in HF patients. However, there is still no evidence support the use of SGLT2i in FMR therapy due to the lack of relevant clinical trial. The DEFORM trial aims to assess the efficacy of dapagliflozin in reducing the extent of mitral regurgitation and myocardial fibrosis in FMR patients. DEFORM trial is a multi-center, prospective, randomized, parallel controlled, investigator-initiated trial enrolling a planned 98 FMR patients. Patients will be randomly assigned in a 1:1 ratio to either dapagliflozin 10mg once daily for 3 months or placebo. The primary outcome is the change in effective regurgitant orifice area (EROA) of mitral regurgitation measured by echocardiography. Secondary end-points include change change in regurgitant volume (RV), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) (echocardiography), change in NT-proBNP levels and occurrence of major adverse cardiac events (MACEs).

Detailed Description
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Inclusion criteria: Patients aged >18 years and <90 years LVEF<60% and EROA of mitral regurgitation≥0.2cm2 on echocardiography The structure of mitral valve leaf and chordae tendineae is normal Patients have received GDMT for FMR including a stable, optimized dose of β-blocker and RAAS inhibitors for at least 2 weeks No intravenous anti-heart failure drugs used for the past 2 weeks Written informed consent Exclusion criteria: Allergic to dapagliflozin, or angioedema Already taking dapagliflozin or other SGLT2 inhibitors Presence of primary structural damage to the mitral valve, such as rheumatic heart disease, mitral valve prolapses Non-dialysis chronic kidney disease (CKD) patients with eGFR <30ml/min/1.73m2 or dialysis patients Acute myocardial infarction and acute myocarditis occurred within 3 months Revascularization procedure, CRT, TMVR, surgical valve repair or replacement were performed or planed 3 months before or after enrollment Combining significant aortic valve diseases (moderate or severe regurgitation or stenosis) Combining hyperthyroidism while thyroid function has not returned to normal Pregnant or lactation women

Official Title
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Dapagliflozin Effect on FunctiOnal Mitral Regurgitation and Myocardial Remodeling

Conditions
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Functional Mitral Regurgitation

Intervention / Treatment
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* Drug: Dapagliflozin
* Other: guideline-directed medical therapy (GDMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged >18 years and <90 years LVEF<60% and EROA of mitral regurgitation≥0.2cm2 on echocardiography The structure of mitral valve leaf and chordae tendineae is normal Patients have received GDMT for FMR including a stable, optimized dose of β-blocker and RAAS inhibitors for at least 2 weeks Exclusion Criteria: Allergic to dapagliflozin, or angioedema Already taking dapagliflozin or other SGLT2 inhibitors Presence of primary structural damage to the mitral valve, such as rheumatic heart disease, mitral valve prolapses Non-dialysis chronic kidney disease (CKD) patients with eGFR <30ml/min/1.73m2 or dialysis patients Acute myocardial infarction and acute myocarditis occurred within 3 months Revascularization procedure, CRT, TMVR, surgical valve repair or replacement were performed or planed 3 months before or after enrollment Combining significant aortic valve diseases (moderate or severe regurgitation or stenosis) Combining hyperthyroidism while thyroid function has not returned to normal Pregnant or lactation women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dapagliflozin group<br>GDMT and dapagliflozin 10mg once daily | Drug: Dapagliflozin<br>* dapagliflozin 10mg once daily for 3 months after randomization<br>Other: guideline-directed medical therapy (GDMT)<br>* guideline-directed medical therapy (GDMT)<br>|
| Active Comparator: control group<br>GDMT only | Other: guideline-directed medical therapy (GDMT)<br>* guideline-directed medical therapy (GDMT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EROA of FMR | Change in EROA of mitral regurgitation evaluated by echocardiography from baseline to 12 weeks follow-up | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cardiac structure | Change in RV measured by echocardiography from baseline to 12 weeks follow-up | 3 months | 
| MACE | Occurrence of MACE in 12 weeks follow-up | 3 months | 
| cardiac function | Change in serum NT-proBNP levels from baseline to 12 weeks follow-up | 3 months |