SGLT2 inhibitors (SGLT2i) not only have “on-target” mild glucose-lowering effects but also have profound “off-target” beneficial renal and cardiovascular effects in patients with CKD, CVD, and HF, through glucosuria, natriuresis, metabolic shifts, and reduction of oxidative stress, that are independent of hyperglycemia, sex, and insulin secretion/sensitivity. This evidence concerns the gene INS and Hyperglycemia.