Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial

Abstract

Background: Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin. Methods: In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500). Results: Adjusted mean change of HbA1c at week 24 was -0.80% with enavogliflozin and -0.75% with dapagliflozin (difference, -0.04%; 95% confidence interval, -0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was -32.53 and -29.14 mg/dL. An increase in urine glucosecreatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (-1.85 vs. -1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (-3.77 kg vs. -3.58 kg) and blood pressure (systolic/diastolic, -5.93/-5.41 mm Hg vs. -6.57/-4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated. Conclusion: Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was noninferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.

A 52‐week efficacy and safety study of enavogliflozin versus dapagliflozin as an add‐on to metformin in patients with type 2 diabetes mellitus: ENHANCE‐M extension study

“…The level of UGCR increase was much greater with enavogliflozin 0.3 mg up to week 24 compared with dapagliflozin 10 mg, and the statistical significance of this difference was shown in the previous publication. 18 The UGCR increase from baseline remained at a similar level in the maintenance group during the OLE part, whereas in the switch group, a significant increase since week 24 was observed during the OLE part. Mean UGCR changes in the switch group at weeks 38 and 52 from week 24 were 20.02 and 22.90 g/g, respectively ( p < .0001 for both).…”

“…The design of the DB part has been described in the previous publication. 18 Briefly, the target patients were individuals aged 19-80 years with T2DM with inadequate glycaemic control [glycated haemoglobin (HbA1c) 7.0%-10.5%] after at least 8 weeks of stable-dose metformin monotherapy (≥1000 mg/day). Patients treated with metformin plus other antihyperglycaemic agent(s) whose HbA1c had been between 6.5% and 10.0% were also included after at least 8 weeks of washout from the other antihyperglycaemic agent(s) if HbA1c levels were between 7.0% and 10.5% after the washout period.…”

“…Patients' demographic and clinical characteristics of the OLE safety set at the time of screening were well distributed between the two groups with a mean age of ≈60 years (Table S1); they were similar to those results obtained with the randomized set (enavogliflozin = 101, dapagliflozin = 99), reported earlier. 18…”

“…11 Its pharmacokinetic and pharmacodynamic properties were verified in preclinical studies involving in vitro and animal models and healthy volunteers, [12][13][14][15][16] and its efficacy and safety in patients with T2DM were confirmed in several randomized trials analysing various clinical scenarios. [17][18][19][20] In one of those trials, a double-blind (DB) randomized phase 3 study, the efficacy and safety of enavogliflozin (0.3 mg/day) as an add-on to metformin were verified against dapagliflozin (10 mg/day). 18 The study, lasting for 24 weeks, showed that enavogliflozin added to metformin significantly improved glycaemic control in patients with T2DM and was noninferior to dapagliflozin, hence appearing as a viable treatment option for patients with inadequate glycaemic control on metformin alone.…”

“…[17][18][19][20] In one of those trials, a double-blind (DB) randomized phase 3 study, the efficacy and safety of enavogliflozin (0.3 mg/day) as an add-on to metformin were verified against dapagliflozin (10 mg/day). 18 The study, lasting for 24 weeks, showed that enavogliflozin added to metformin significantly improved glycaemic control in patients with T2DM and was noninferior to dapagliflozin, hence appearing as a viable treatment option for patients with inadequate glycaemic control on metformin alone. 18 The aim of the present study, an extension of the trial mentioned above, 18 was to evaluate the long-term safety and efficacy of enavo-gliflozin 0.3 mg/day as an add-on to metformin therapy in patients with T2DM during a 52-week observation.…”