Impact of Sodium–Glucose Cotransporter-2 Inhibitors on Left Ventricular Reverse Remodeling and Myocardial Fibrosis Regression in Patients with Heart Failure with Reduced Ejection Fraction and Concomitant Type 2 Diabetes Mellitus: Insights from Multimodality Cardiac Imaging and Biomarkers

Abstract Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as disease-modifying therapies in heart failure with reduced ejection fraction (HFrEF), with robust evidence for improved clinical outcomes. However, their effects on left ventricular (LV) structural remodeling and myocardial fibrosis—especially in patients with concomitant type 2 diabetes mellitus (T2DM)—remain incompletely characterized. Multimodality cardiac imaging and biomarker analysis offer sensitive tools to quantify these tissue-level changes. Objectives: To evaluate the impact of SGLT2 inhibitor therapy on LV reverse remodeling and myocardial fibrosis regression in patients with HFrEF and T2DM, using advanced imaging modalities (echocardiography, cardiac magnetic resonance [CMR]) and circulating biomarkers of fibrosis and myocardial injury. Methods: In a prospective cohort of 180 patients with HFrEF (LVEF ≤40%) and T2DM, participants received guideline-directed medical therapy with initiation of an SGLT2 inhibitor (dapagliflozin or empagliflozin). Baseline and 12-month follow-up assessments included: Echocardiography, for LV volumes, ejection fraction, and global longitudinal strain (GLS); CMR, for LV mass index, extracellular volume fraction (ECV), and late gadolinium enhancement (LGE) quantification; Biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, soluble ST2 (sST2), and high-sensitivity cardiac troponin T (hs-cTnT). Results: After 12 months of SGLT2 inhibition, significant improvements in LV structure and function were observed: Echocardiography: mean LVEF increased from 30 ± 6% to 38 ± 7% (p < 0.001), and GLS improved (less negative strain) relative to baseline (p < 0.01). CMR: LV end-systolic volume index decreased by 18% (p < 0.001) and LV mass index reduced by 12% (p = 0.002). ECV decreased significantly, indicating regression of diffuse interstitial fibrosis (baseline 31.2 ± 4.9% vs 28.1 ± 4.5% at 12 months, p = 0.004). The extent of LGE remained stable. Biomarkers: NT-proBNP and sST2 levels declined significantly (p < 0.001 for both), while galectin-3 and hs-cTnT showed modest, but statistically significant, reductions (p < 0.05). Subgroup analysis suggested greater LV remodeling and fibrosis regression in patients with higher baseline ECV and elevated fibrosis biomarkers. Changes in imaging parameters correlated with decreases in NT-proBNP and sST2 (r = 0.47–0.56, p < 0.01), supporting linkage between structural changes and biomarker dynamics. Conclusions: In patients with HFrEF and T2DM, SGLT2 inhibitor therapy is associated with significant LV reverse remodeling and reductions in interstitial myocardial fibrosis over 12 months, as quantified by multimodality imaging and supported by reductions in fibrosis-related biomarkers. These findings suggest that beyond hemodynamic and metabolic effects, SGLT2 inhibitors may exert direct or indirect myocardial structural benefits, offering mechanistic insights into their favorable impact on clinical outcomes. Larger randomized studies are warranted to further elucidate these tissue-level effects and their relationship to long-term prognosis.