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SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (also known as gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty.