Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis

• Sodium-glucose cotransporter 2 inhibitors suppress the coreabsorption of sodium and glucose in proximal tubules and enhance the glucose excretion into urine.
• Glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced.
• Because proximal tubular fluid constituting with low chloride concentration, because of sodium-glucose cotransporter 2 inhibition, is transferred to the loop of Henle, tubular reabsorption is inhibited as if loop diuretics. Therefore, blood pressure is lowered.
• Finally, the metabolic and hemodynamic combined systems may synergistically interact to suppress the risks leading to atherosclerosis and organs damage.

Primarily the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of proximal tubules to the blood and enhance the glucose excretion into urine. Therefore, glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced. On the other hand, the proximal tubular fluid, constituting with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. On the low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, as if loop diuretics are given. Finally, blood pressure is also lowered secondarily due to the loop diuretic action by SGLT2 inhibitions. Thus, the metabolic and hemodynamic combined systems synergistically interact further to suppress the risks leading to atherosclerosis and organs damage. Precise mechanisms for SGLT2 inhibitors to work in various aspects especially in preventing organ damage and cardiovascular events must be clarified further.