SGLT2 Inhibitors Reduce Myocardial Fibrosis in Patients with HFpEF and T2D

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, significantly reduces myocardial fibrosis and improves cardiac structure, exercise tolerance, and metabolic control in patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D), according to a recent study.¹

Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF is notably lacking in evidence-based, disease-modifying therapies. This has been attributed to difficulty in differentiating HFpEF from other causes of dyspnea, which requires advanced and invasive diagnostic measures.²

“Despite promising mechanistic insights, human studies directly quantifying the impact of SGLT2 inhibitors on myocardial fibrosis in HFpEF remain limited,” wrote Arif Albulushi, MD, department of adult cardiology, National Heart Center, Royal Hospital, Oman, and colleagues. “This study aims to address this knowledge gap by investigating the effects of dapagliflozin on myocardial fibrosis regression, left ventricular remodeling, and functional capacity in HFpEF patients with T2D.”¹

This multicenter, double-blind, placebo-controlled, randomized trial was conducted at three tertiary care centers and included 100 patients aged 40 to 80 years. For inclusion, participants had to have a clinical diagnosis of HFpEF, defined as LVEF ≥50% and evidence of elevated left ventricular filling pressures based on echocardiographic and hemodynamic criteria, and T2D, with an HbA1c level between 7% and 10% at baseline.¹

Additionally, patients considered for the study had to have myocardial fibrosis, defined as extracellular volume fraction (ECV) ≥27% on cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE). Patients were excluded if they had experienced active malignancy in the past 5 years, exhibited severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), or had contraindications to MRI.¹

The 100 included patients were randomized in a 1:1 ratio to either dapagliflozin 10 mg daily or placebo. Investigators noted that, while empagliflozin has been investigated in several trials cited in this study, both treatments belong to the same SGLT2 inhibitor class and exhibit overlapping cardiometabolic and antifibrotic effects. Any findings from this study can therefore be reliably extrapolated to the class.¹

Investigators measured change in myocardial fibrosis, measured by ECV (%) from baseline to 12 months. Secondary endpoints included change in left ventricular mass index (LVMI) from baseline to 12 months, change in glycemic control measured by HbA1c reduction (%), and change in functional capacity as measured by a 6-minute walk test (6MWT, meters).¹

Over the 12-month study period, dapagliflozin treatment caused a substantial reduction in myocardial fibrosis. Mean ECV decreased by 3.5% (95% CI, -4.2 to -2.8) in the dapagliflozin group versus .8% (95% CI, -1.3 to -.4) in placebo (P <.001). LVMI also decreased by 8.2 g/m² (95% CI, -9.5 to -7) versus 2.1 g/m² (95% CI, -3 to -1.2) in placebo (P = .002). Glycemic control also improved in the dapagliflozin group, reducing HbA1c by 1.2% (95% CI, -1.5 to -1) versus .4% (95% CI, -.6 to -.2) in placebo (P = .01). Functional capacity also saw a significant improvement, with dapagliflozin exhibiting a 45-m increase in 6MWT distance (95% CI, 35 to 55) versus a 10-m increase (95% CI, 5 to 15) in placebo (P = .01).¹

NT-proBNP levels also decreased in the dapagliflozin group, with a median reduction of 212 pg/mL (interquartile range [IQR]: -320 to -105), compared to an insignificant change of 58 pg/mL (IQR: -90 to 50) in placebo (P = .02).¹

Investigators ultimately cited the study as supporting a growing body of evidence highlighting the modulatory effects of SGLT2 inhibitors on adverse cardiac remodeling in addition to their traditional metabolic benefits.¹

“These results reinforce the antifibrotic and cardiometabolic benefits of SGLT2 inhibitors and support their inclusion in phenotype-guided treatment strategies for HFpEF,” wrote Albulushi and colleagues. “Further validation in larger, multiethnic cohorts is needed to confirm generalizability and evaluate long-term outcomes.”¹

References

1. Albulushi A, Askari KM, Al-Abedi AM, et al. Impact of SGLT2 inhibitors on myocardial fibrosis in Diabetic HFPEF: A longitudinal study. European Journal of Medical Research. 2025;30(1). doi:10.1186/s40001-025-02834-7

2. Gevaert AB, Van De Bruaene A, Van Mieghem NM, et al. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms, and management. Heart. 2022;108(17):1342–50.