LP ‐925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT 1 and SGLT 2

Sodium‐glucose cotransporter 2 ( SGLT 2) inhibitors are a new class of oral anti‐diabetic agents that improve glycemic control by inhibiting SGLT 2‐mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion ( UGE ) to <50% of maximal values because they do not inhibit SGLT 1, which reabsorbs >50% of filtered glucose when SGLT 2 is completely inhibited. This led us to test whether LP ‐925219, a small molecule dual SGLT 1/ SGLT 2 inhibitor, increases UGE to maximal values in wild‐type ( WT ) mice. We first tested LP ‐925219 inhibition of glucose transport by HEK 293 cells expressing SGLT 1 or SGLT 2, and then characterized LP ‐925219 pharmacokinetics. We found that LP ‐925219 was a potent inhibitor of mouse SGLT 1 ( IC 50 = 22.6 nmol/L) and SGLT 2 ( IC 50  = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half‐life (7 h). We next delivered LP ‐925219 by oral gavage to WT , SGLT 1 knockout ( KO ), SGLT 2 KO , and SGLT 1/ SGLT 2 double KO ( DKO ) mice and measured their 24‐h UGE . We found that, in vehicle‐treated mice, DKO UGE was maximal and SGLT 2 KO , SGLT 1 KO , and WT UGE s were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP ‐925219 dosed at 60 mg/kg twice daily increased UGE of SGLT 1 KO , SGLT 2 KO , and WT mice to DKO UGE levels. These findings show that orally available dual SGLT 1/ SGLT 2 inhibitors can maximize 24‐h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT 2 inhibitors.