In individuals with diabetes, kidney size and glomerular filtration rate (GFR) tend to increase, and elevated GFR is a risk factor for diabetic kidney disease. Hyperfiltration occurs when high glucose levels in the glomerular filtrate causes increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. This hyperfiltration puts additional stress on the filtration barrier and increases the oxygen demand for reabsorption. Tubular growth is associated with a molecular signature that leads to inflammation and fibrosis. SGLT2 inhibitors play a significant role in mitigating hyperfiltration by reducing sodium and glucose reabsorption, normalizing feedback signals, and alleviating the physical stress on the filtration barrier. This tubule-centered model of diabetic kidney physiology explains the positive effects of SGLT2 inhibitors on renal outcomes, as demonstrated in large-scale clinical trials. Although these medications primarily target glucose reabsorption , patients with type 2 diabetes mellitus benefit from reduced blood glucose levels along with various other physiological advantages. Data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.