BACKGROUND: Sarcopenia is common in patients with heart failure (HF) and it is frequently associated with other comorbidities. Sarcopenia has been linked to an increased risk of major adverse cardiovascular events (MACE) in HF patients. AIMS: The aim of the present study was to evaluate, in a cohort of older adult's patients affected by HF with reduced ejection fraction (HFrEF) and sarcopenia, already being treated with sacubitril/valsartan, the effect of add-on therapy with SGLT2i on clinical, functional abilities, muscle performance and effects on quality of life. METHODS: We enrolled 147 outpatients. A simple linear regression analysis was performed to assess the correlation between the change in Cardiac Index (CI) and Short physical performance battery (SPPB) values, expressed as (Δ) between baseline and follow-up (ΔT0-12), and several covariates. RESULTS: After 12 months of treatment, we observed an improvement in the inflammatory profile, moreover there was a reduction of the oxidative stress (p <
0.0002) and platelets activation (p <
0.0002) parameters. In addition, there was a significant increase in CI and global longitudinal strain and a statistically significant improvement in cognitive function, as shown by Mini-Mental State examination (MMSE) (p <
0.0002) score and SPPB (p <
0.0002). Considering ΔCI as dependent variation, Δ8-isoprotane resulted the major predictor, justifying 13.3% of its variation. When ΔSPPB was considered as dependent variable, Δ8-Isoprostane was the main predictor of ΔSPPB, justifying 54.6% of its variation. DISCUSSION AND CONCLUSIONS: This study demonstrated that the addition of SGLT2i to therapy leads to improvements in echocardiographic and sarcopenia-related parameters and biomarkers of oxidative stress and platelet activation.