Drugs (2020) 80:587–600 https://doi.org/10.1007/s40265-020-01285-0 ORIGINAL RESEARCH ARTICLE Efcacy and Safety of Remoglifozin 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 Mala Dharmalingam1 · S. R. Aravind2 · Hemant Thacker3 · S. Paramesh4 · Brij Mohan5 · Manoj Chawla6 · Arthur Asirvatham7 · Ramesh Goyal8 · Jayashri Shembalkar9 · R. Balamurugan10 · Pradnya Kadam11 · Hansraj Alva12 · Rahul Kodgule13 · Monika Tandon13 · Sivakumar Vaidyanathan13 · Amol Pendse13 · Rajesh Gaikwad13 · Sagar Katare13 · Sachin Suryawanshi13 · Hanmant Barkate13 Published online: 11 March 2020 © The Author(s) 2020 Abstract Background Metformin is the frst-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. Remoglifozin etabonate, a novel agent, is an orally bioavailable prodrug of remoglifozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. Objective Our objective was to evaluate the efcacy and safety of remoglifozin etabonate compared with dapaglifozin 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, multi- center, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving met- formin ≥ 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 remoglifozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remoglifozin etabonate 250 mg BID (group 2, n = 241) or dapaglifozin 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 diference in mean HbA1c of group 1 versus group 3 (− 0.14%, 90% confdence interval [CI] − 0.38 to 0.10) and group 2 versus group 3 (− 0.19%; 90% CI − 0.42 to 0.05) was non- inferior to that in group 3 (p < 0.001). No signifcant diference 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 remoglifozin etabonate 100 and 250 mg compared with dapa- glifozin, from the frst analysis of an initial 612 patients. Remoglifozin etabonate therefore may be considered an efective and well-tolerated alternative treatment option for glycemic control in T2DM. Trial Registration CTRI/2017/07/009121. Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4026 5-020-01285 -0) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article Vol.:(0123456789) 588 M. Dharmalingam et al. with T2DM, including reductions in both bodyweight and Key Points blood pressure (BP). As this mechanism of action is inde- pendent of insulin sensitivity and metformin’s mechanism of Remoglifozin etabonate 100 and 250 mg achieved action, SGLT2 inhibitors are considered important glucose- greater reductions in glycated hemoglobin (HbA1c) and lowering agents as monotherapy or in combination with demonstrated noninferiority in reducing HbA1c levels other antidiabetic agents [8–10]. compared with dapaglifozin 10 mg over 24 weeks. Remoglifozin etabonate, a novel agent, is an orally bio- The use of rescue medication was lower, and the propor- available prodrug of remoglifozin, which is a potent and tion of patients achieving therapeutic glycemic response selective inhibitor of SGLT2. Signifcant urinary glucose was higher, in patients receiving remoglifozin etabonate. excretion has been observed with single doses of remoglifo- zin etabonate. Compared with other approved SGLT2 inhibi- Reductions in blood glucose levels and bodyweight were tors such as dapagliflozin, canagliflozin, empagliflozin, also similar among the three study groups. No severe which have longer half-lives, remoglifozin etabonate has adverse events were observed. a short elimination half-life and requires twice daily (BID) Remoglifozin etabonate could be an efective and administration to obtain 24-h glucose-lowering effects well-tolerated alternative treatment option for glycemic [11–15]. Dapaglifozin is an approved SGLT2 inhibitor control in patients with type 2 diabetes mellitus. widely used in India [16]. The present phase III study aimed to evaluate the ef- cacy and safety of remoglifozin etabonate 100 and 250 mg compared with dapaglifozin 10 mg over 24 weeks of treat- ment in patients with T2DM for whom glycemic control with metformin monotherapy was inadequate. This paper discusses the frst analysis of this study performed to evalu- 1 Introduction ate the noninferiority of the two doses of remoglifozin eta- bonate compared with dapaglifozin. According to the International Diabetes Federation [1], 425 million people worldwide have diabetes mellitus (DM), accounting for two-thirds of adults aged 20–64 years, and the 2 Methods proportion of deaths due to DM before the age of 60 years ranges from 36 to 73% [1]. The ten countries with the high- 2.1 Trial Design and Oversight est prevalence of DM account for almost 60% of the global disease burden, with China (114 million people), India (73 The study was conducted in accordance with the Declaration million people), and the USA (30 million people) contribut- of Helsinki and International Conference on Harmonization ing to most of this [1]. Therefore, the management of DM guidelines for good clinical practice. The study protocol was through efective treatment interventions is of the utmost reviewed and approved by the institutional ethics committee importance in the feld of clinical research. at each study site. Written informed consent was obtained To achieve glycemic targets, multiple agents with com- from all patients prior to their enrolment into the study. plementary mechanisms are frequently required, and treat- This was a randomized, double-blind, double-dummy, ment for type 2 DM (T2DM) is evolving. Metformin is the multicenter, active-controlled phase III clinical trial con- frst-line treatment for T2DM [2–5], but many patients either ducted at 55 sites in India between 1 December 2017 and cannot tolerate metformin or cannot achieve glycemic con- 26 December 2018. trol with metformin monotherapy. Consequently, treatment with other glucose-lowering agents as monotherapy or in 2.2 Subjects combination with metformin is required [3–7]. Sodium glucose co-transporter-2 (SGLT2) inhibitors To be eligible for the study, patients were aged ≥ 18 are a new class of antidiabetic drugs. SGLT2 is primarily and ≤ 65 years, had been diagnosed with T2DM, were expressed on the luminal side of the renal proximal tubule receiving a stable dose of metformin ≥ 1500 mg/day as and absorbs almost all glucose fltered in the glomerular monotherapy for at least 8 weeks prior to screening, and fltrate. Glucose absorption by the SGLT2 receptor is con- had inadequate glycemic control (glycated hemoglobin sidered a primary pathway for renal glucose reabsorption. [HbA1c] ≥ 7 to ≤ 10%) at screening. We excluded patients Inhibition of this pathway thus enhances urinary glucose with a diagnosis of type 1 DM or secondary DM, a history excretion and consequently reduces blood glucose levels. In of metabolic acidosis or diabetic ketoacidosis, a body mass addition, SGLT2 inhibitors have other advantages in patients Remoglifozin in T2DM 589 index (BMI) ≥ 45 kg/m2 at screening, or estimated glomeru- These examinations were repeated at each study visit up lar fltration rate (eGFR) < 60 mL/min/1.73 m2. to 24 weeks. FPG and lipids were assessed on samples Eligible patients entered at least 2 weeks of an open- collected before breakfast, whereas PPG was assessed label lead-in period. During this time, all patients received on samples collected 2 h after breakfast as per standard a standard consultation for dietary and exercise modifca- clinical practice. These assessments were performed tion in accordance with the applicable national/international at a central laboratory. Additionally, patients received guidelines, along with continuation of metformin at doses glucose meters to monitor their blood glucose levels at recorded during