Most of the glucose is reabsorbed in the kidney by the sodium-glucose cotransporters 2 (SGLT2): SGLT2i inhibitors significantly reduce the renal glucose threshold in the patient with and in the patient without diabetes. This effect explains the consistent drop in blood sugar in the patient with diabetes and a decrease (5-10 mg/dl) in the non-diabetic person. Notably, SGLT2i inhibit sodium reabsorption leading to a reduction in the expansion of plasma volume and blood pressure. At the cardiovascular level, SGLT2i reduce preload and post-load, improves cardiac metabolism and bioenergetics, inhibits the sodium hydrogen antiport, and reduce the adrenergic system’s activation. Glucagon-like peptide 1 receptor agonists (GLP-1RA) enhance endothelial function, stabilize atherosclerotic plaque and increase angiogenesis. Similar to SGLT2i, GLP-1RAs reduce arterial stiffness and low-grade inflammation. A peculiar action of GLP-1 is the inhibition of platelet aggregation, most likely linked to the ability of these drugs to stimulate nitric oxide synthesis in platelets. They also increase sodium excretion with a consequent drop in blood pressure and significantly reduce fatty liver disease, an important cardiovascular risk factor. The clinical characteristics of these two classes of drugs are described, and their benefits on the cardiovascular system in patients without diabetes are discussed.