Abstract
BackgroundRemogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.MethodsThis double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.ResultsRE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.ConclusionsThe results support progression of RE as a potential treatment for T2DM.Trial registrationClinicalTrials.gov NCT01571661
Highlights
Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans
By promoting urinary glucose excretion, SGLT2 inhibitors offer a novel mechanism of antidiabetic action that is complementary to currently available classes of drugs which reduce hepatic gluconeogenesis, increase glucose flux into muscle and fat or stimulate β-cell insulin secretion (e.g. glucagon-like peptide 1 (GLP-1)-based therapies)
In both healthy and Type 2 diabetes mellitus (T2DM) subject populations, the prodrug, remogliflozin etabonate was extensively converted to its active entity, remogliflozin, and to an active metabolite, GSK279782, which is as potent as remogliflozin in inhibiting SGLT-2 in vitro [23]
Summary
Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. Type 2 diabetes mellitus (T2DM) is characterized by abnormalities of glucose and lipid homeostasis, which drive secondary micro- and macrovascular complications. Clinical evidence indicates that maintaining glycemic control and reducing postprandial glucose excursions can lower the risk of diabetic complications, e.g. reduce the risk of myocardial infarction, renal disease and retinopathy [1,2]. Despite the availability of multiple classes and combinations of antidiabetic agents, the clinical management of T2DM remains challenging, with the majority of patients failing to achieve and maintain target glycemic levels in practice [3]. Glucose homeostasis is a complex process controlled by gastrointestinal absorption, tissue utilization, hepatic/ renal gluconeogenesis and renal filtration/reabsorption/ excretion. Under normal physiological conditions when the glomerular filtrate reaches the proximal tubule, glucose is primarily reabsorbed through the active sodiumdependent glucose transporter 2 (SGLT2) located on the apical or luminal membrane of the epithelial cell in the S1 segment [4,5,6]
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