Background: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the\r\nrenal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An\r\ninhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose\r\nconcentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as\r\nmonotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral\r\nantihyperglycemic agent widely used for the treatment of T2DM.\r\nMethods: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with\r\nT2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin\r\nalone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable\r\nduration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for\r\nthe duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma\r\nglucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid)\r\nassessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling\r\noccurred on Day 3 of each treatment period.\r\nResults: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin\r\ndid not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly\r\nlower for remogliflozin and its metabolite after co-administration with metformin compared with administration of\r\nRE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of\r\nmetformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in\r\nlactic acid.\r\nConclusions: Coadministration of metformin and RE was well tolerated in this study. The results support continued\r\ndevelopment of RE as a treatment for T2DM.
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