Our Newest Pharmacologic Class for Treatment of Diabetes: SGLT2 Inhibitors
The role of the kidney in glucose regulation has been underappreciated. Although perhaps counterintuitive, after persistent exposure to elevated glucose levels in the glomerular filtrate presented to the proximal renal tubule, the kidney adapts by reabsorbing increased amounts of glucose, thereby increasing blood sugar. The sodium glucose cotransporter (SGLT2) receptor is the primary pathway for renal tubular glucose reabsorption; blockade of this receptor results in enhanced urinary glucose excretion. Currently, the only FDA-approved agent for blockade of the SGLT2 receptor is canaglifozin.
In addition to potent SGLT2 receptor blockade, it has been suspected that canaglifozin might affect intestinal absorption of glucose by its modest inhibition of intestinal SGLT1. Polidori et al tested the impact of canagliflozin SGLT1 inhibition by examining the rate of gastrointestinal glucose absorption in healthy volunteers following a 600-kcal mixed-meal tolerance test.
Canagliflozin produced a very modest reduction in glucose absorption over a 6-hour interval (about 6%). The effects were accentuated in the early postprandial intervals, indicating a slowed absorption of glucose that was not attributable to delayed gastric emptying. Blunting of early postprandial glucose absorption should have a favorable effect on postprandial glucose excursions in diabetics.
Although enhanced urinary glucose excretion is the primary mechanism of plasma glucose lowering by SGLT2 inhibitors, modest gastrointestinal SGLT1 inhibition also appears to impact postprandial glucose excursion.
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