Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients

• Published in: Diabetes, obesity & metabolism Vol. 14; no. 1; pp. 15 - 22
• Main Authors: Dobbins, R. L., O'Connor-Semmes, R., Kapur, A., Kapitza, C., Golor, G., Mikoshiba, I., Tao, W., Hussey, E. K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Blood Glucose - drug effects; Blood pressure; Blood Pressure - drug effects; Body Mass Index; Body weight; Body Weight - drug effects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Double-Blind Method; Drug dosages; Female; Glucose; Glucose tolerance; Glucose Tolerance Test; Glucose transporter; Glucosides - pharmacokinetics; Glucosides - pharmacology; Glucosides - therapeutic use; Glycated Hemoglobin A - drug effects; Humans; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Male; Metformin; Middle Aged; Pharmacodynamics; Pharmacokinetics; Placebos; Plasma; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; remogliflozin etabonate; Renal function; Safety; SGLT2 inhibitor; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - blood; Treatment Outcome; urine glucose excretion
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01462.x

Aims: Remogliflozin etabonate (RE) is the pro‐drug of remogliflozin (R), a selective inhibitor of renal sodium‐dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). Methods: In a double‐blinded, randomized, placebo‐controlled trial, subjects who were drug‐naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24‐h glucose profiles and oral glucose tolerance tests. Results: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24‐h UGE increased in RE treatment groups. Compared with the placebo group, 24‐h mean (95% CI) changes in plasma glucose were −1.2 (−2.2 to −0.3) (100 mg BID), −0.8 (−1.7 to 0.2) (1000 mg QD) and −1.7 (−2.7 to −0.8) mmol/l (1000 mg BID). Conclusions: Administration of RE for 12 days is well‐tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.