Background Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. Objective Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control. Methods A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remogliflozin etabonate 250 mg BID (group 2, n = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatmentemergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated. Results Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was − 0.72 ± 0.09, − 0.77 ± 0.09, and − 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (− 0.14%, 90% confidence interval [CI] − 0.38 to 0.10) and group 2 versus group 3 (− 0.19%; 90% CI − 0.42 to 0.05) was noninferior to that in group 3 (p < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported. Conclusion This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM. Trial Registration CTRI/2017/07...

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Introduction: Remogliflozin Etabonate (RE) and Vildagliptin are approved in India for management of type 2 diabetes mellitus (T2DM), which were evaluated as a fixed dose combination (FDC) in this pivotal phase III study. Methods: This 16 week, multi-centric, prospective, double blind, double dummy, parallel group, randomized controlled study compared efficacy and safety of FDC of RE 100mg + Vildagliptin 50mg (RV) given twice daily to active comparator of Empagliflozin 25mg + Linagliptin 5mg (EL) given once daily. Adult T2DM patients with HbA1c 8-11% on Metformin stable dose of ≥1500mg for ≥8 weeks before screening were randomized to either of treatment arms. The study endpoints were mean changes from baseline (CFB) in HbA1c (primary), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), body weight (BW) and blood pressure (BP) for efficacy and adverse events (AE) monitoring for safety assessments. Results: Of 182 eligible subjects (91 in each arm), 157 (86.3%) subjects completed the study. The baseline demographic characteristics were well balanced between 2 treatment arms. Adjusted mean (SE) change from baseline in HbA1c (%) at week 16 viz. EL arm -1.36 (0.15) vs. RV arm -1.41(0.16); (mITT population; p&lt;0.001 in each arm) was comparable between the two treatment arms (p=0.82). The mean difference of -0.05% (95%CI: -0.46, 0.36) in HbA1c demonstrated non-inferiority (NI) of RV compared to EL (p=0.016 for NI test). Similarly, significant reduction was observed in FPG, PPG, BW and BP which was found to be comparable between the two treatment arms. Drug related AEs were observed in 8.8% and 6.6% subjects of EL and RV arm respectively, with low incidence of hypoglycemia, genital and urinary tract infections (1-3%). Conclusion: Overall, FDC of Remogliflozin Etabonate + Vildagliptin was found to be efficacious, safe and well tolerated in the treatment of patients with T2DM, and demonstrated non-inferiority to Empagliflozin 25mg + Linagliptin 5mg treatment. Disclosure B. Mohan: None. M. S. Chawla: Speaker’s Bureau; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Colgate-Palmolive, Eli Lilly and Company, Glenmark Pharmaceuticals Limited, Novo Nordisk. R. R. Kodgule: Employee; Self; Glenmark Pharmaceuticals Limited. M. Tandon: Employee; Self; Glenmark Pharmaceuticals Limited. S. Katare: Employee; Self; Glenmark Pharmaceuticals Limited. S. Suryawanshi: Employee; Self; Glenmark Pharmaceuticals Limited. H. V. Barkate: None.

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