Remogliflozin Etabonate, a Selective Inhibitor of the Sodium-Glucose

Clinical Care/Education/Nutrition/Psychosocial Research BRIEF REPORT Remogliflozin Etabonate, a Selective Inhibitor of the Sodium-Glucose Transporter 2, Improves Serum Glucose Profiles in Type 1 Diabetes 1,2 3 SUNDER MUDALIAR, MD JUNE YE, PHD placebo (placebo), 2) mealtime insulin 1 3 DEBRA A. ARMSTRONG, BA, RN, CCRC ELIZABETH K. HUSSEY, PHARMD 2 3 injection + RE placebo (prandial insulin), ANNIE A. MAVIAN, MD DEREK J. NUNEZ, MD 3 3 1,2 ) placebo insulin injection + 50 mg RE (RE ROBIN O’CONNOR-SEMMES, PHD ROBERT R. HENRY, MD 3 3 50 mg), 4) placebo insulin injection + 150 PATRICIA K. MYDLOW, BS ROBERT L. DOBBINS, MD, PHD mg RE (RE 150 mg), and 5) placebo insulin injection + 500 mg RE (RE 500 mg). d fl Each individual received 75-g oral OBJECTIVES Remogli ozin etabonate (RE), an inhibitor of the sodium-glucose transporter glucose and identical meals during all 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes. treatment periods. Frequent samples were obtained for measurement of plasma RESEARCH DESIGN AND METHODSdTen subjects managed with continuous sub- glucose and insulin concentrations. Urine cutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five samples were collected for 24 h to assess randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500. creatinine clearance and glucose excre- d tion. Plasma samples were collected for RESULTS Adverse events and incidence of hypoglycemia with RE did not differ from placebo fl and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the the determination of RE, remogli ozin, rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted and GSK279782 (active metabolite) con- weighted mean glucose (0–4 h) values by 42–49 mg/dL and mean glucose (0–10 h) by 52–69 centrations. Baseline-adjusted weighted mg/dL. mean glucose (0–4h)and(0–10 h) concentrations were calculated for all treat- d CONCLUSIONS RE can be safely administered with insulin in type 1 diabetes and reduces ments, and comparisons were made by plasma glucose concentrations compared with placebo. ANCOVA. RESULTSdFrequency and severity of emogliflozin etabonate (RE) is of an SGLT2 inhibitor in this patient adverse events, including hypoglycemia, an oral prodrug of remogliflozin population. did not differ between treatments (Sup- R plementary Table 2). No hypoglycemic (1),aselectiveantagonistofthe sodium-dependent glucose transporter 2 RESEARCH DESIGN AND episodes were severe or resulted in study (SGLT2) located in renal proximal tu- METHODSdThis single-center, ran- discontinuation. Analyses of vital signs, bules (2–4). It lowers glucose concentra- domized, double-blinded, placebo- electrocardiograms, and laboratory re- tions in type 2 diabetes by inhibiting controlled trial enrolled 10 individuals sults did not indicate drug-related effects renal glucose reabsorption (5). Because with type 1 diabetes managed with con- after RE administration. this mechanism functions independently tinuous subcutaneous insulin infusion Figure 1 shows mean insulin and glu- of insulin, RE could be an effective oral (Supplementary Table 1). Each subject cose concentrations during each treatment adjunct to insulin for treatment of type 1 participated in five treatment periods period. Serum insulin concentrations were diabetes. This clinical trial evaluated the separated by 5–35 days. After an overnight elevated in the prandial insulin period safety, tolerability, pharmacokinetics, fast, they continued basal insulin infusion when subjects received individual prescribed insulin boluses ranging from 5 to and pharmacodynamics of RE adminis- (Novolin; Novo Nordisk, Princeton, NJ) 6 teredtosubjectswithtype1diabetes. and received randomized treatments as 12.5 units (0.098 0.023 units/kg). When This is the firstreportofadministration follows: 1) placebo insulin injection + RE mealtime boluses were withheld in the placebo period, mean (6SD) plasma glucose concentrations reached a maximum of ccccccccccccccccccccccccccccccccccccccccccccccccc 330 6 40 mg/dL. Glucose concentrations From the 1Medicine Service, Veterans Administration Medical Center, San Diego, California; 2Department of 3 were attenuated during other treatment pe- Medicine, University of California San Diego, San Diego, California; and GlaxoSmithKline Research & riods, reaching 247 6 86 mg/dL with pran- Development, Research Triangle Park, North Carolina. 6 Corresponding author: Robert L. Dobbins, [email protected]. dial insulin compared with 290 67, Received 15 March 2012 and accepted 23 May 2012. 274 6 56, and 270 6 58 mg/dL for RE DOI: 10.2337/dc12-0508. Clinical Trial reg. no. NCT00575159, clinicaltrials.gov. 50 mg, RE 150 mg, and RE 500 mg treat- This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 ments, respectively. .2337/dc12-0508/-/DC1. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly Baseline-adjusted weighted mean cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ glucose (0–4 and 0–10 h) concentrations licenses/by-nc-nd/3.0/ for details. for RE treatment periods differed from care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online September 25, 2012 Remogliflozin etabonate in type 1 diabetes and RE 500 mg periods, respectively. Im- proved mean glucose (0–4 h) concentrations resulting from SGLT2 inhibition represented 55 to 65% of the observed ef- fect of an insulin bolus. Glucose reductions were sustained through the lunch meal, confirming that effects applied to both oral glucose and mixed meals. Single doses of RE resulted in a trend toward more negative 24-h fluid balance than placebo or prandial insulin treatments (Supplementary Table 4). Increased frac- tional urine glucose excretion and total 24-h urine glucose excretion (Fig. 1) during RE treatment periods were associated with higher urine volumes. After administration of RE tablets to subjects with type 1 diabetes, the prodrug was absorbed and converted to the active entity, remogliflozin, followed by the for- mation of a second active metabolite, GSK279782. Pharmacokinetic parameters in this population were within the range of values reported for normal volunteers and subjects with type 2 diabetes (5). CONCLUSIONSdThis clinical trial was the first to explore the feasibility of administering an SGLT2 inhibitor with insulin to patients with type 1 diabetes. Single oral doses of up to 500 mg of RE were generally safe and well tolerated. All RE regimens significantly decreased glucose concentrations relative to placebo after a glucose load, and glucose improve- ments were sustained for 10 h, although no dose response was observed over the dose range studied. Drug administration augmented urine glucose excretion relative to placebo and prandial insulin treatment periods. These data build upon previous results from rodent models of insulin de- ficiency induced by streptozotocin (6). They address concerns that RE could worsen hypoglycemia when administered with insulin in type 1 diabetes. Two fac- tors favor a low hypoglycemia potential with SGLT2 inhibition as follows: 1)urine Figure 1dMean (6 SEM) 12-h serum insulin (A), 12-h plasma glucose (B), and urine glucose (C) profiles observed for each treatment period. After the overnight fast, basal insulin infusion was glucose excretion during SGLT2 inhibi- continued, and each subject received the following five treatments in random order: 1) placebo insulin tion decreases as plasma glucose concen- injection + RE placebo (▫;placebo),2) mealtime insulin injection + RE placebo (○; prandial insulin), trations fall into the hypoglycemic range; 3)placeboinsulininjection+RE50mg(C;RE50mg),4) placebo insulin injection + RE 150 mg (▲; and 2) blunting peak postprandial glu- RE 150 mg), and 5) placebo insulin injection + RE 500 mg (-; RE 500 mg). Relative to RE dosing, the cose excursions could simplify prandial morning glucose challenge, lunch, and supper were scheduled at 0.25, 4.25, and 10.25 h, respectively. insulin dose adjustments. Urine glucose All subjects received randomized insulin or placebo injections 15 min before the glucose challenge and excretion stimulated by RE could poten- lunch plus their regularly prescribed bolus of rapid-acting insulin 15 min before supper. tially limit weight gain in these patients. Type 2 diabetes trials with SGLT2 inhib- placebo and prandial insulin periods in the RE 50 mg, RE 150 mg, and RE 500 itors have demonstrated 2-kg weight (Supplementary Table 3). Compared mg periods, respectively. Mean glucose (0– loss linked to a change in fat mass (7,8). with placebo, mean glucose (0–4 h) values 10 h) values changed by 265, 269, and Weight loss is a perceived problem in changed by 249, 242, and 243 mg/dL 262 mg/dL in the RE 50 mg, RE 150 mg, type 1 diabetes, but intensive treatment 2 DIABETES CARE care.diabetesjournals.org Mudaliar and Associates strategies result in weight gain for many manuscript. R.O.-S. and P.K.M. participated in 2. Kanai Y, Lee WS, You G, Brown D, Hediger patients. Indeed, fears of hypoglycemia the design of the study, data analysis, and MA. The human kidney low affinity Na and weight gain are associated with wors- writing of the manuscript and approved the +/glucose cotransporter

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