Effects of sodium-glucose cotransporter-2 inhibitors on left ventricular-arterial coupling and myocardial extracellular volume in patients with type 2 diabetes mellitus and HFpEF

Abstract Introduction In Heart failure with preserved ejection fraction (HFpEF) vascular-ventricular uncoupling, contributing to poor outcomes. Left ventricular-arterial coupling (LVAC) interact with HFpEF pathophysiology. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as promising therapeutic agents in HFpEF, demonstrating cardiovascular benefits independent of their glucose-lowering effects. However, the impact of SGLT2i on LVAC and its associated mechanisms remains incompletely understood. Aims We investigate the effects of SGLT2i on LVAC in patients with type 2 diabetes mellitus (T2DM) and HFpEF and the mechanisms underlying these effects by assessing changes in left atrial (LA) strain, myocardial fibrosis (extracellular volume (ECV), and systemic inflammation (high-sensitivity C-reactive protein (hsCRP). Methods We recruited 32 patients with T2DM and HFpEF from the outpatient HF office, and randomly assigned them to initiate an SGLT2i or placebo. Demographic and clinical characteristics were recorded. Moreover, baseline (T0) and follow-up measurements at 6 months post-treatment initiation (T1) were performed for echocardiographic left ventricular global longitudinal strain (LV-GLS) and LA strain. At the same time points, arterial stiffness was estimated through carotid-femoral pulse wave velocity (PWV) and changes in myocardial fibrosis with the cardiac magnetic resonance-derived ECV. LVAC was estimated with the PWV/LV-GLS ratio. HsCRP was measured as a marker of systemic inflammation. Over-time changes in the above-mentioned parameters were assessed, as well as the correlation of changes in LVAC with changes in those parameters. Results Patients treated with SGLT2i were more frequently hypertensive (SGLT2i: 94.1% vs. Control: 66.7%, p=0.047) and had greater DM duration (SGLT2i: 8.4 (3.9) years vs. Control: 5.3 (3.3) years, p=0.03). The were no major differences in the other demographic and clinical variables of the two groups (Figure 1). There were no significant differences in the measured parameters at baseline between SGLT2i users and the control group. At the 6-month follow-up, we noted a significant improvement in PWV, LV-GLS, and LVAC only in patients treated with SGLT2i. Changes in LVAC were correlated with changes in PWV (R=-0.94, p0.001), LV-GLS (R=-0.91, p0.001), LA strain (R=0.49, p=0.005), ECV (R=-0.64, p0.001), and hsCRP (R=-0.76, p0.001) (Figure 2). Conclusion SGLT2i treatment in patients with T2DM and HFpEF significantly improved myocardial fibrosis, ECV, and parameters of left ventricular systolic LV-GLS and diastolic function LAstrain which are linked to improvement in arterial stiffness – PWV, ventriculoarterial coupling LVAC and systemic inflammation hsCRP. Our findings reinforce the cardioprotective role of SGLT2i beyond glucose control, supporting their use as a therapeutic strategy to optimize vascular-ventricular interaction and improve cardiovascular performance.