Impact of SGLT2 inhibitors on myocardial fibrosis in diabetic HFpEF: a longitudinal study

Abstract

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors offer cardiovascular benefits in patients with heart failure, yet their direct effects on myocardial fibrosis-particularly in heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D)-remain underexplored. This study investigates the antifibrotic impact of dapagliflozin in diabetic HFpEF patients, with a focus on its potential as a disease-modifying therapy.

Methods: In a multicenter, double-blind, placebo-controlled trial, 100 patients with HFpEF and T2D were randomized (1:1) to receive dapagliflozin 10 mg daily or placebo for 12 months. Stratification was performed by baseline extracellular volume fraction (ECV). Myocardial fibrosis was assessed using cardiac MRI-derived ECV at baseline, 6 months, and 12 months. Secondary endpoints included changes in left ventricular mass index (LVMI), HbA1c, and 6-min walk test (6MWT) distance.

Results: Dapagliflozin significantly reduced myocardial fibrosis (mean ΔECV: - 3.5% [95% CI - 4.2 to - 2.8]) compared to placebo (- 0.8% [95% CI - 1.3 to - 0.4]; p < 0.001). Additional benefits included greater reductions in LVMI (- 8.2 g/m² vs. - 2.1 g/m²; p = 0.002), improved glycemic control (HbA1c: - 1.2% vs. - 0.4%; p = 0.01), and enhanced functional capacity (+ 45 m vs. + 10 m in 6MWT; p = 0.01).

Conclusions: Dapagliflozin demonstrated a significant reduction in myocardial fibrosis and improvements in cardiac structure, metabolic control, and exercise tolerance in HFpEF patients with T2D. These findings support the evolving role of SGLT2 inhibitors as validated components of guideline-directed therapy, with potential disease-modifying effects through targeted myocardial fibrosis regression.

Keywords: Cardiac MRI; Dapagliflozin; HFpEF; Myocardial fibrosis; SGLT2 inhibitors; Type 2 diabetes.

Fig. 1

CONSORT flow diagram of study enrollment and follow-up

Fig. 2

Longitudinal changes in myocardial extracellular volume (ECV) over 12 months in patients with HFpEF and T2D treated with dapagliflozin vs. placebo. Data are presented as mean ± 95% confidence interval. Dapagliflozin therapy led to a significant reduction in ECV at both 6 and 12 months, indicating regression of myocardial fibrosis. Placebo-treated patients showed minimal change. ECV was quantified using cardiac MRI with T1 mapping and hematocrit-adjusted calculations

Fig. 3

Change in Left Ventricular Mass Index (LVMI) over 12 months in HFpEF-T2D patients treated with dapagliflozin vs. placebo

Fig. 4

Pearson correlation matrix among key study variables

Fig. 5

Kaplan–Meier analysis of hospitalization-free survival over 12 months