Abstract A1: Sglt2 Inhibition Via Empagliflozin Improves Endothelial Function And Reduces Mitochondrial Oxidative Stress: Insights From Hypertensive And Diabetic Frail Elders

Background: Frailty is a multidimensional condition very common in older adults that leads to physical impairment. Frail older adults have an increased risk of adverse outcomes such as disability, hospitalization, and mortality. Hypertension and diabetes are prevailing comorbidities in frail elders. Methods: We studied consecutive frail older patients presenting at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to January 2021. Exclusion criteria were: absence of frailty, hypertension, and diabetes; age <65 years; left ventricular ejection fraction <50%; previous myocardial infarction. In all patients we assessed blood samples for glycemia, HbA1c and creatinine; a physical frailty evaluation was performed following the Fried Criteria. Results: We evaluated 407 patients; 325 frail elders with diabetes and hypertension successfully completed the study. We propensity-score matched 75 patients treated with empagliflozin and 75 with no empagliflozin. We observed a strong correlation between glycemia and Montreal Cognitive Assessment (MoCA) Score (r 2 : 0.91; p<0.001) and between glycemia and 5 meters gait speed (5mGS) (r 2 : 0.79; p<0.001). We tested the differences in MoCA Score at baseline and at 3-month follow-up in empagliflozin treated and non-treated groups (20.32 vs. 22.41, p<0.01; 20.34 vs . 20.71). Moreover, we measured the differences in 5mGS (0.60 vs . 0.64, p<0.05; 0.58 vs . 0.59). We evaluated how many patients had frailty; the empagliflozin-treated group, at 3-month follow-up, only showed 25.3% of patients with frailty (n: 19), while the non-treated group had 73.3% of patients with frailty (n: 55) (p<0.001). Our results were confirmed by regression analyses with basal MoCA Score or 5mGS as the dependent variables, after adjusting for several covariates. Mechanistically, we found that Empagliflozin significantly reduced mitochondrial ROS production and leakage triggered by high glucose conditions in human endothelial cells. Conclusions: Taken together, our data indicate that empagliflozin treatment reduced frailty in diabetic and hypertensive patients, by reducing mitochondrial oxidative stress in endothelial cells.