Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial

Abstract

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. Treatment-emergent 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/2017/07/009121.

Fig. 1

CONSORT diagram. eGFR estimated glomerular filtration rate, FPG fasting plasma glucose, HbA1c glycated hemoglobin, mITT modified intent-to-treat, PP per protocol

Fig. 2

Analysis of mean change in HbA1c concentration from baseline at week 12 and week 24 across the treatment groups. Data shown as least-squares mean (95% confidence interval); intergroup comparison p value; group 1, remogliflozin etabonate 100 mg; group 2, remogliflozin etabonate 250 mg; group 3, dapagliflozin 10 mg. Mean change in HbA1c concentration from baseline to week 24 of a PP population and b mITT population and from baseline to week 12 of c PP population and d mITT population. HbA1c glycated hemoglobin, mITT modified intent-to-treat, PP per protocol

Fig. 3

Forest plot of treatment difference of mean change in HbA1c (%) levels from baseline at 24 weeks (PP and mITT population). a PP: p values of noninferiority for remogliflozin etabonate 100 mg—dapagliflozin and remogliflozin etabonate 250 mg—dapagliflozin: < 0.001, < 0.001, respectively. b mITT: p values of noninferiority for remogliflozin etabonate 100 mg—dapagliflozin and remogliflozin etabonate 250 mg—dapagliflozin: 0.001, < 0.001, respectively. HbA1c glycated hemoglobin, mITT modified intent-to-treat, PP per protocol

Fig. 4

Mean change in difference in proportion of patients with < 7% HbA1c and patients using rescue medication at week 24. Data shown as least-squares mean (95% confidence interval); intergroup comparison p value; group 1, remogliflozin etabonate 100 mg; group 2, remogliflozin etabonate 250 mg; group 3, dapagliflozin 10 mg. a, b Difference in proportion of patients with < 7% HbA1c and patients using rescue medication at week 24. HbA1c glycated hemoglobin, mITT modified intent-to-treat, PP per protocol

Fig. 5

Mean change in FPG and PPG concentrations from baseline at week-12 and -24 across the treatment groups. Data shown as least-squares mean (95% confidence interval); intergroup comparison p value; group 1, remogliflozin etabonate 100 mg; group 2, remogliflozin etabonate 250 mg; group 3, dapagliflozin 10 mg. Mean change in FPG concentration from baseline to week 12 and 24 of a PP and b mITT populations. Mean change in PPG concentration from baseline to week 12 and 24 of c PP and d mITT populations. FPG fasting plasma glucose, HbA1c glycated hemoglobin, mITT modified intent-to-treat, PP per protocol, PPG postprandial plasma glucose

Fig. 6

Mean change in bodyweight from baseline at week 12 and 24 across the treatment groups. Mean change in bodyweight from baseline to week 12 and 24 of modified intent-to-treat population. Data shown as least-squares mean (95% confidence interval); intergroup comparison p value; group 1, remogliflozin etabonate 100 mg; group 2, remogliflozin etabonate 250 mg; group 3, dapagliflozin 10 mg

Fig. 7

Mean change in SBP and DBP at week 24 across the treatment groups. Data shown as mean change from baseline to week 24 in SBP and DBP in safety population. Group 1, remogliflozin etabonate 100 mg; group 2, remogliflozin etabonate 250 mg; group 3, dapagliflozin 10 mg. DBP diastolic blood pressure, SBP systolic blood pressure