DAPAgliflozin‐Related Cardiac REverse Remodeling by 2D and 3D Echocardiography in OptiMally Treated HFrEF Patients: The DAPA‐REM Study

Purpose Sodium‐glucose cotransporter‐2 inhibitors promote cardiac reverse remodeling in heart failure (HF), yet data integrating two‐dimensional and three‐dimensional echocardiography (2DE and 3DE, respectively) in optimally treated HFrEF populations are limited. This study aimed to evaluate heart chambers size and function by 2D/3DE after dapagliflozin initiation, and to explore whether baseline estimated glomerular filtration rate (eGFR) or myocardial fibrosis on cardiac magnetic resonance (CMR) influence reverse remodeling. Methods Seventy‐five patients with LVEF ≤40% on guideline‐directed therapy were prospectively enrolled. Echocardiographic and clinical data were collected at baseline and 6‐month follow‐up (6MFU) after introduction of dapagliflozin 10 mg daily. Sub‐analyses were performed according to eGFR (<45 vs. ≥45 mL/min/1.73 m 2 ) and extent of late gadolinium enhancement (LGE) on CMR. Results After 6MFU, left ventricular (LV) end‐diastolic and end‐systolic volumes reduced, and LVEF increased as assessed by both 2DE (respectively: 88[72–122] vs. 92[79–122]mL/m 2 , 58[42–80] vs. 57[48–88]mL/m 2 , 36.6±8.8 vs. 34.5±7.7%; p < 0.001) and 3DE (respectively: 100[79–140] vs. 108[90–136]mL/m 2 , 64[46–82] vs. 69[55–93]mL/m 2 , 37.4±8.7 vs. 34.4±7.9%; p < 0.001). No significant association between eGFR and the magnitude of LV reverse remodeling was detected, while CMR analyses suggested a possible inverse correlation between LGE burden and improvement in 2D LVEF. LV diastolic function improved (grade≥2 diastolic dysfunction: 4.7% vs. 18.7%; p = 0.015), along with systolic pulmonary artery pressure (25[23–29] vs. 27[24–29]mmHg; p = 0.037). Conclusion In optimally treated HFrEF patients, LV size and systolic and diastolic function significantly improved during the 6MFU following dapagliflozin initiation. No significant differences in the magnitude of LV reverse remodeling were detected according to eGFR or LGE burden. Trial registration number NCT05770167. Key Learning Points What is already know Sodium−glucose cotransporter‐2 inhibitors improve clinical outcomes in heart failure across a wide spectrum of left ventricular ejection fraction, with evidence of cardiac reverse remodeling. Dapagliflozin has been shown to reduce left ventricular and left atrial volumes, improve biventricular systolic function, and lower filling pressures, independent of diabetes status and baseline renal function. What this study adds In clinically stable HFrEF patients on fully optimized guideline‐directed medical therapy, significant left ventricular reverse remodeling and improvement in systolic and diastolic function within 6 months after introduction of dapagliflozin was observed, as consistently demonstrated by both 2D and 3D echocardiography. A proportion of patients with baseline LVEF ≤35% crossed the 35% threshold at 6‐month follow‐up. This observation is hypothesis‐generating and may warrant further investigation regarding the potential implications of reverse remodeling for subsequent device‐therapy assessment. Exploratory analyses did not detect a statistically significant association between baseline renal function and the magnitude of cardiac reverse remodeling. In the CMR subgroup, preliminary data suggest that the extent of LGE burden might inversely correlate with improvement in 2D LVEF.