Dapagliflozin effect on functional mitral regurgitation and myocardial remodelling: The DEFORM trial

Abstract

Aims: Functional mitral regurgitation (FMR) is associated with adverse outcomes in patients with heart failure, and current guideline-directed medical therapy (GDMT) offers limited efficacy in managing FMR. This study aims to evaluate the therapeutic impact of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in patients with moderate or severe FMR.

Methods and results: In this randomized controlled trial, 104 patients with moderate or severe FMR were assigned in a 1:1 ratio to receive either dapagliflozin 10 mg once daily or no additional treatment alongside current GDMT for FMR, with a follow-up period of 3 months. The primary endpoint was the change in effective regurgitant orifice area (EROA) of mitral regurgitation (MR). Secondary endpoints included changes in regurgitant volume (RV), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular mass (LVM), left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), E/e' ratio, and left atrial volume index (LAVI). The incidence of hospitalization for heart failure or cardiovascular death was also compared between the groups. As a result, dapagliflozin significantly reduced the EROA of FMR (-0.074 ± 0.099 vs. -0.030 ± 0.058 cm² for dapagliflozin vs. control, P = 0.008). It also significantly decreased RV (-9.08 ± 15.27 vs. -2.98 ± 9.28 mL, P = 0.017), E/e' ratio (-5.88 ± 7.41 vs. -1.98 ± 7.63, P = 0.011), and LAVI (-2.50 ± 4.75 vs. -0.43 ± 3.14 mL/m², P = 0.011) while improving LVEF (6.57 ± 10.10 vs. 1.92 ± 9.57%, P = 0.017). No significant differences were observed in changes in LVEDV, LVESV, LVM, and LVMI between groups (P > 0.05). Hospitalization for heart failure occurred in 9.6% of the dapagliflozin group and 15.3% of the control group (hazard ratio, 0.60; 95% CI, 0.20-1.83; P = 0.368). Cardiovascular death occurred in 1.9% of the dapagliflozin group compared to 3.8% of the control group (hazard ratio, 0.49; 95% CI, 0.04-5.41; P = 0.561) during the 3-month follow-up.

Conclusions: Dapagliflozin demonstrates the potential to further reduce the degree of MR and enhance myocardial remodelling in patients with FMR when used in addition to current GDMT. These findings suggest the importance of SGLT2i in heart failure patients with FMR as an additive positive effect on echocardiographic parameter and possibly outcome.

Keywords: Dapagliflozin; Functional mitral regurgitation; Myocardial remodelling.

Figure 1

Study design of the DEFORM trial. EROA, effective regurgitant orifice area; FMR, functional mitral regurgitation; GDMT, guideline‐directed medical therapy; HF, heart failure; LAVI, left atrial volume index; LVEDD, left ventricular end‐diastolic dimension; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic dimension; LVESV, left ventricular end‐systolic volume; LVM, left ventricular mass; LVMI, left ventricular mass index; MR, mitral regurgitation; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; R, randomized; RV, regurgitant volume.

Figure 2

EROA of MR measured by PISA method. (A) Schematic example of the PISA method. (B) and (C) EROA measurement in echocardiography, calculated with PISA radius and peak velocity of the MR jet. EROA, effective regurgitant orifice area; MR, mitral regurgitation; PISA, proximal isovelocity surface area; RV, regurgitant volume; Va, aliasing velocity; VTI, velocity time integral.

Figure 3

Diagram of patient flow chart for the DEFORM trial. EROA, effective regurgitant orifice area; FMR, functional mitral regurgitation; GDMT, guideline‐directed medical therapy; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; TEER, transcatheter edge‐to‐edge repair.

Figure 4

Changes of FMR degree. (A) Number of patients with FMR degree changes from baseline to 3‐month follow‐up in both groups. (B) Proportion of FMR degree at baseline and 3‐month follow‐up of patients in both groups. (C) Proportion of patients with changes in FMR severity from baseline to 3‐month follow‐up. Ctrl, control group; Dapa, dapagliflozin group; FMR, functional mitral regurgitation.

Figure 5

Occurrence of hospitalization for heart failure and cardiovascular death. (A) Kaplan–Meier curve for occurrence of hospitalization for heart failure in both groups. (B) Kaplan–Meier curve for occurrence of cardiovascular death in both groups. (C) Cox proportional hazard regression analysis of dapagliflozin effect on the occurrences of hospitalization for heart failure and cardiovascular death. HR, hazard ratio.