Efficacy and Safety of Enavogliflozin as Add-on in Adults with Type 2 Diabetes Mellitus Inadequately Controlled with Insulin or Insulin with Other Antidiabetic Drugs
Article information
Abstract
Background
The study evaluated the efficacy and safety of enavogliflozin, a novel, promising selective sodium-glucose cotransporter 2 inhibitor, as an add-on in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with insulin alone or combined with other antidiabetic drugs (OADs).
Methods
The double-blind, placebo-controlled, multicenter trial was conducted in South Korea and Thailand. Individuals with glycosylated hemoglobin (HbA1c) ≥7.5% after ≥8-week treatment with background insulin alone or combined with ≤2 OADs were randomized to receive enavogliflozin 0.3 mg or placebo (n=116 each) for 24 weeks. The primary outcome was a change in HbA1c at week 24. Secondary outcomes included, among others, changes in body weight, blood pressure, and other measures of glycemic control. Adverse events (AEs) were investigated throughout the study (Clinical trial registration number: NCT05466643).
Results
At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was –0.9% (P<0.001). Also, placebo-adjusted mean changes in fasting plasma glucose (–32.4 mg/dL, P<0.001), body weight (–1.3 kg, P<0.001), and total daily dose of insulin (–1.3 units, P=0.010) at week 24 were statistically significant. In addition, a significant decrease in blood pressure and fasting C-peptide was observed in the enavogliflozin group, along with a significant increase in homeostasis model assessment of β-cell function, yet without a concomitant change in homeostasis model assessment of insulin-resistance. No significant increase in treatment-related AEs was observed for enavogliflozin.
Conclusion
Enavogliflozin 0.3 mg/day is an efficacious and safe add-on treatment option in T2DM patients controlled inadequately with insulin alone or combined with OADs.
Highlights
• Enavogliflozin showed significant glycemic control when added to insulin therapy.
• Once-daily 0.3 mg of Enavogliflozin was well tolerated and effective.
• It is a viable option for patients with poor glycemic control on insulin.
INTRODUCTION
The prevalence of diabetes in adults was estimated at 589 million worldwide in 2024. The vast majority (>90%) of diabetes cases are type 2 diabetes mellitus (T2DM). Due to population aging, this number is projected to increase further, up to 853 million by 2050 [1]. Diabetes constitutes a serious epidemic problem in South Korea as well, affecting 5.3 million people in 2021 to 2022, and the prevalence is projected to increase further [2].
Adequate glycemic control is a cornerstone in managing T2DM. Published evidence suggests that early glycemic control reduces microvascular events and hence, confers macrovascular and mortality benefits [3,4]. Diabetes complications also impose a substantial burden on healthcare spending, 11.9% of which is related to diabetes in 2024, according to the global estimation [1].
Despite multiple antidiabetic drug classes, an individualized therapeutic choice remains challenging. For individuals with symptoms of hyperglycemia or glycosylated hemoglobin (HbA1c) >10%, insulin should be considered [3]. However, higher rates of complications and mortality or poor glycemic control are frequent issues encountered while treating patients using insulin, as shown in multiple studies [5-7]. Besides, the choice of oral antidiabetic agents that could be used alongside insulin and metformin becomes limited. For example, sulfonylurea can cause weight gain and increase the risk of hypoglycemia when introduced in conjunction with insulin [8], whereas concomitant administration of thiazolidinedione can lead to weight gain, edema, and increased risk of congestive heart failure [9]. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are one of the plausible options in this clinical scenario. Other choices, if expanded to injectables, include glucagon-like peptide-1 receptor agonist (GLP-1RA) or dual glucose-dependent insulinotropic polypeptide and GLP-1 RA [3]. SGLT-2 inhibitors selectively inhibit SGLT-2 transporters in the proximal convoluted tubule, preventing the renal reabsorption of glucose, with resultant increase in its urinary excretion [10]. This mechanism of action is independent of insulin function. Aside from its antihyperglycemic effect, SGLT-2 inhibitors have also been shown to reduce arterial blood pressure and to promote weight loss [11-13]. These properties make SGLT-2 inhibitors a credible choice for individuals on insulin therapy, particularly in those with risks of cardiorenal vascular diseases or in need of weight management [14].
Enavogliflozin, a recently developed and commercialized drug, is a novel selective SGLT-2 inhibitor [15], and its pharmacokinetic and pharmacodynamic properties were elucidated in several preclinical and clinical studies [16-19]. In an in vivo study using mice, the half-maximal inhibitory concentration to SGLT-2 was lowest with enavogliflozin (0.8±0.3 nM) compared to those with dapagliflozin (1.6±0.3 nM) or ipragliflozin (8.9±1.7 nM) [16,18]. In addition, a sustained SGLT-2 inhibition post-removal was demonstrated in vitro as well as in a human trial [16,17]. Moreover, the efficacy and safety of enavogliflozin were documented in multiple randomized clinical trials, testing the drug against placebo and active comparators in various cohorts of people with T2DM [20-23].
The aim of the present study was to evaluate the efficacy and safety of enavogliflozin as an add-on in adults with T2DM inadequately controlled with insulin or insulin with other antidiabetic drugs (OADs).
METHODS
Study design and participants
This phase 3 trial was designed as a double-blind, placebo-controlled, multicenter study and conducted in two countries, South Korea and Thailand, from March 2023 to September 2024. The study comprised a screening visit; a 2-week, single-blinded placebo run-in period; and a 24-week, double-blinded randomized treatment period. Among adults aged between 19 and 80 years, those diagnosed with T2DM with inadequate glycemic control (HbA1c ≥7.5%) on background insulin (basal or premixed insulin) alone or combined with up to two OADs were screened for the study. As an OAD, chlorpropamide, rosiglitazone, or SGLT-2 inhibitors were not permitted. To be eligible, participants had to be on background insulin treatment for at least 8 weeks, with the total daily dose (TDD) of insulin variability ≤20%. Additionally, HbA1c and fasting plasma glucose (FPG) were to be <10.5% and <220 mg/dL, respectively. Individuals with FPG <270 mg/dL at the initial screening were also eligible; however, a retest result had to be <220 mg/dL at the run-in visit. Major exclusion criteria included type 1 diabetes mellitus (T1DM); secondary diabetes mellitus (DM), such as Cushing’s syndrome induced diabetes, pancreatogenic diabetes, and drug-induced diabetes; diabetes due to genetic mutations, such as neonatal DM and Wolfram syndrome; use of pre-meal short-acting or rapid-acting insulin; estimated glomerular filtration rate <60 mL/min/1.73 m2; triglyceride >500 mg/dL; or uncontrolled hypertension, defined as systolic blood pressure (SBP) >180 mm Hg or diastolic blood pressure (DBP) >110 mm Hg. All participants provided a written informed consent before screening. The study protocol was approved by the Institutional Review Board or Ethics Committee of each study site and by the regulatory bodies (Institutional Review Board of Samsung Medical Center; SMC 2022-08-093), i.e., the Ministry of Food and Drug Safety, South Korea and the Food and Drug Administration, Thailand. The study was conducted according to the ethical principles of the Helsinki Declaration, Good Clinical Practice, and local regulatory guidelines of each country. The study was prospectively registered on ClinicalTrials.gov (identifier: NCT05466643).
Study procedures
Eligible participants were randomized in a 1:1 ratio to receive enavogliflozin 0.3 mg/day or a matching placebo for 24 weeks. A central, stratified block randomization method was employed using an interactive response technology, with stratification factors of country, HbA1c (<8.5%, ≥8.5%) at the run-in visit, and pre-study use of GLP-1RA. Post-randomization visits were made at a 6-week interval until week 24, and efficacy and safety variables were collected according to the schedule. Participants were instructed to swallow a single tablet daily with water, regardless of mealtime, but preferably before breakfast. A glucometer was dispensed at the run-in visit to self-monitor blood glucose (SMBG). Participants were instructed to contact the study site if the fasted SMBG reading was >230 mg/dL, the 2-hour post-prandial reading was >280 mg/dL, or any reading was <70 mg/dL. Depending on the SMBG readings, proper instructions to address any medical emergency were provided, and the necessity of rescue therapy using short-acting or rapid-acting insulins was assessed. Along with the diet plan and an exercise program, the regimen of background insulin and OADs was maintained throughout the study period. An increase in the TDD of background insulin was allowed within 10% after randomization, whereas its reduction could be made on clinical judgement without restrictions. Unless required as a rescue therapy, short-acting or rapid-acting insulins were prohibited. Additionally, the following drugs were also disallowed: glucose, glucagon, weight loss drugs, loop diuretics, iodinated contrast agents, systemic immunosuppressants, nifedipine immediate release, organic cation transporter 1 (OCT1) inhibitors or inducers (e.g., quinidine, verapamil, or clopidogrel), or OCT2 inhibitors (e.g., cimetidine, dolutegravir, or trimethoprim).
Study outcomes
The primary endpoint was the change in HbA1c from baseline to week 24. Secondary endpoints included changes in HbA1c (at timepoints before week 24), FPG, body weight, TDD of insulin, blood pressure, homeostasis model assessment of β-cell function (HOMA-β) and insulin-resistance (HOMA-IR), fasting C-peptide, urine albumin-creatinine ratio (UACR), urine glucose-creatinine ratio (UGCR), and lipid profile. Another secondary endpoints included therapeutic target achievement rates at week 24, which were assessed through four categories: (1) HbA1c goal 1 (<6.5%); (2) HbA1c goal 2 (<7.0%); (3) HbA1c goal 2 (<7.0%) without body weight gain and symptomatic hypoglycemia; and (4) HbA1c goal 2 (<7.0%) with body weight reduction ≥3.0% and without symptomatic hypoglycemia. Safety was evaluated through treatment-emergent adverse events (TEAEs), vital signs, physical examination, clinical laboratory tests, and 12-lead electrocardiography. Among TEAEs, hypoglycemia, urinary tract infection, genital infection, pollakiuria, and polyuria were classified as adverse events of special interest (AESI). Adverse drug reactions (ADRs) were defined as TEAEs with any degree of suspected causality in relation to the study drug, including those where causality was not assessable. Seriousness, severity (mild, moderate, and severe), outcome, and duration of TEAEs were also evaluated.
Statistical analysis
A minimum of 80 patients per group was required to secure a 90% power at a two-sided 5% significance level to test the superiority of enavogliflozin to placebo for the change of HbA1c from baseline to week 24. The effect size was assumed to be –0.71%, derived from a weighted mean difference between treatment and placebo groups based on the published results in similar populations [23-26]. For the sample size calculation, the largest standard deviation (SD, 1.37) among the referenced studies was adopted to ensure adequate statistical power. To account for a 25% dropout rate, 214 patients (107 per group) were targeted for enrollment.
All efficacy endpoints were interpreted in the estimand framework, consisting of the main and supplementary estimand, along with three intercurrent events (ICEs). The ICEs were predefined as (1) premature withdrawal from the study treatment due to any reason; (2) more than 10% increase in background insulin dose; and (3) ≥7 cumulative days of using rescue therapy or using rescue therapy after week 18. A mixed model for repeated measures (MMRM) was employed as a main estimator for all continuous endpoints. The model included fixed effects for treatment, visit, treatment-by-visit interaction, and stratification factors (pre-study treatment and country), with baseline HbA1c as a covariate. For the primary endpoint, in addition to the primary analysis with the MMRM, two sensitivity analyses using the analysis of covariance (ANCOVA) for the main estimand and three analyses for the supplementary estimand were conducted by modifying the strategy for addressing ICEs, handling methods for missing data unrelated to ICEs, and the analysis population (Supplementary Table 1). Changes within each group and between-group differences were presented as least-square mean (LSM) with standard error. A 95% confidence interval (CI) was provided for the latter with a P value. Subgroup analysis based on the stratification factors was also performed for the primary endpoint. As for the between-group comparison for the therapeutic target achievement rates, a logistic regression model was used, with stratification factors (pre-study treatment and country) and treatment group as fixed effects and baseline HbA1c as a covariate; the odds ratio and its corresponding two-sided 95% CI, and a P value were presented. TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 27.0. The chi-square or Fisher’s exact test was used to compare TEAE incidences between the groups. For safety endpoints with established normal ranges, the results were grouped as normal, abnormal without clinical significance, and abnormal with clinical significance, and proportions of each category were summarized for each visit. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC, USA), and statistical significance was declared at a P<0.05.
RESULTS
Out of 356 screened individuals, 240 were randomized and 232 completed the 24-week double-blinded study treatment (Fig. 1). Baseline characteristics were distributed evenly between the two groups (Table 1). Age ranged from 22 to 80 years, with a median of 61 years in the enavogliflozin group and 63 years in the placebo group. Median duration of T2DM was 15.1 years and 16.1 years, respectively, and 78.3% and 75.8% of the participants had a T2DM history longer than 10 years. More than 60% of the participants in both groups, 63.3% and 65.8%, respectively, had HbA1c ≥8.5% at the start of the run-in period. Insulin-only regimen was limited to 3.3% of the enavogliflozin group and 4.2% of the placebo group. The rest of the participants had been under combination therapy, and more than half of the participants, 56.7% and 61.7%, respectively, were using a triple therapy, i.e., background insulin plus two OADs (Table 1). Among the OADs used, metformin was the most common (72.5% and 74.2% at screening in the enavogliflozin and placebo groups, respectively) (Supplementary Table 2).
Disposition chart. OAD, other antidiabetic drug; FAS, full analysis set; PPS, per-protocol set. aFour participants were withdrawn from the study after randomization due to consent withdrawal (n=1), adverse event (n=1), physician’s decision (n=1), and lost to follow-up (n=1), bFour participants were withdrawn from the study after randomization due to consent withdrawal (n=1), adverse event (n=1), met withdrawal criteria (fasting plasma glucose >240 mg/dL twice) (n=1), and glycosylated hemoglobin >12% (n=1).
Demographics and baseline characteristics of the randomized participants
The majority of the participants, 96.7% in each group, received the study treatment for at least 20 weeks (mean number of tablets taken, 162.5 and 161.7 in the enavogliflozin and placebo groups, respectively) and followed the treatment schedule, with the compliance rate of 97.9% in both groups. Among the predefined ICEs, premature withdrawal from the study treatment occurred in three (2.5%) and two (1.7%) participants from the enavogliflozin and placebo groups, respectively. More than a 10% increase in background insulin dose was needed in five (4.2%) and eight (6.8%) participants, respectively, and the use of rescue therapy for ≥7 days was required in one participant from the placebo group (0.8%).
At baseline, mean±SD HbA1c was 8.6%±0.7% in both groups. A significant HbA1c reduction was observed with the enavogliflozin since week 6 (Fig. 2A). At week 24, the placebo-adjusted LSM change in HbA1c was –0.9% (95% CI, –1.2 to –0.7; P<0.001), demonstrating the superiority of enavogliflozin to placebo. The robustness of this conclusion was supported by sensitivity analyses of the main estimand, analyses of the supplementary estimand, and subgroup analyses of the primary efficacy endpoint (Supplementary Fig. 1). Enavogliflozin treatment also resulted in a significant FPG reduction from week 6 (Fig. 2B); at week 24, the placebo-adjusted LSM change was –32.4 mg/dL (95% CI, –41.8 to –23.0; P<0.001).
Changes in efficacy endpoints during 24 weeks of study period. Changes in (A) glycosylated hemoglobin (HbA1c), (B) fasting plasma glucose (FPG), (C) body weight, (D) total daily dose (TDD) of insulin. Least-square mean (LSM) change from baseline to each timepoint is plotted and the values are presented under each graph. CI, confidence interval. Statistical significance in between-group difference at aP<0.05 and bP<0.001, respectively.
Mean change in body weight showed a general trend of decrease in both groups; however, the level of reduction was significantly greater in the enavogliflozin group since week 12 (Fig. 2C). The placebo-adjusted LSM change at week 24 was –1.3 kg (95% CI, –1.9 to –0.8; P<0.001). TDD of insulin in the enavogliflozin group was significantly reduced compared with the placebo group since week 18 (Fig. 2D), and the placebo-adjusted LSM change at week 24 was –1.3 units (95% CI, –2.3 to –0.3; P=0.010). A greater proportion of participants in the enavogliflozin group had TDD of insulin reduced by 10% or more than those in the placebo group, but the difference was not statistically significant (16.0% vs. 8.5%; odds ratio, 1.99; P=0.101). SBP and DBP decreased significantly at week 24 from baseline in the enavogliflozin group, whereas blood pressure remained the same in the placebo group. The placebo-adjusted LSM change was –4.8 mm Hg (95% CI, –7.6 to –2.1; P<0.001) for SBP and –2.9 mm Hg (95% CI, –4.8 to –1.1; P=0.002) for DBP.
The therapeutic target achievement rates in the enavogliflozin group were modest (7.6% to 16.0%) but significantly higher than in the placebo group, with significantly greater odds ratios for reaching each target HbA1c and reaching HbA1c <7.0% without body weight gain and symptomatic hypoglycemia (Supplementary Table 3). However, no significant difference from the placebo group was found in the achievement rate of HbA1c <7.0% with body weight reduction >3.0% and without symptomatic hypoglycemia (Supplementary Table 3).
Whereas HOMA-β increased significantly since week 18, HOMA-IR did not show a significant change except for a significant decrease at week 6 (Table 2). Median (minimum to maximum) fasting C-peptide at baseline was 0.290 nmol/L (range, 0.020 to 1.280) in the enavogliflozin group and 0.350 (range, 0.020 to 0.960) in the placebo group. About one-third of the participants (33.6% in the enavogliflozin group and 32.2% in the placebo group) had baseline C-peptide below 0.230 nmol/L; those participants were enrolled in the study as T1DM could be ruled out. A slight, albeit significant, decrease in fasting C-peptide was observed in the enavogliflozin group compared with the placebo group, with the placebo-adjusted LSM change of –0.056 nmol/L (95% CI, –0.105 to –0.007; P=0.026) at week 24. Regarding UACR, substantial inter-individual variability was observed. At baseline, mean±SD UACR was 11.2±32.4 and 22.5±89.9 mg/mmol in the enavogliflozin and placebo groups, respectively. At week 24, no significant change was observed in the enavogliflozin group compared with the placebo group (Table 2). A significant increase in urinary glucose excretion, measured with UGCR, was observed in the enavogliflozin group, while no change in UGCR was documented in the placebo group (Supplementary Fig. 2). The placebo-adjusted LSM change in UGCR at week 24 was 11,251.3 mmol/mol (95% CI, –10,087.7 to 12,415.0; P<0.001). No significant changes were observed in the lipid profile.
Changes in efficacy endpoints at week 24
The incidence rate and profile of adverse events were similar between the groups (Table 3). The incidence rate of TEAEs was 50.0% (95% CI, 40.7, 59.3) in the enavogliflozin group and 56.7% (95% CI, 47.3 to 65.7) in the placebo group (P=0.301). Most of the TEAEs occurred in less than 5% of the study population and were not related to the study drug; the only TEAE with an incidence rate >5% was hypoglycemia (any documented hypoglycemia), observed in 29.2% (35/120) of the enavogliflozin group and 22.5% (27/120) of the placebo group. The incidence rate of symptomatic hypoglycemia was 17.5% (21/120) and 15.8% (19/120), respectively.
Summary of adverse events
The incidence rate of ADRs was 21.7% (95% CI, 14.7 to 30.1) and 16.7% (95% CI, 10.5 to 24.6) in the enavogliflozin and placebo groups, respectively (P=0.325). Most ADRs were attributed to hypoglycemia, including 62 out of 69 events in the enavogliflozin group and 28 out of 41 events in the placebo group (Supplementary Table 4). AESI were observed in 30.8% of the enavogliflozin group and 25.0% of the placebo group. The most frequent AESI was hypoglycemia as well, representing 109 out of 113 events in the enavogliflozin group and 77 out of 80 events in the placebo group. Infections in the genitourinary system were recorded in 3.3% of the enavogliflozin group and 2.5% of the placebo group. No AESI caused the discontinuation of the study treatment. Serious TEAEs occurred in 3.3% and 4.2% of participants from the enavogliflozin and placebo groups, respectively, but none of them were related to the study drug. One participant from each group was withdrawn due to a TEAE; both events, schizophrenia and cerebrovascular accident, respectively, were classified as serious and severe TEAEs but were not related to the study drug. No death was reported during the study period. No clinically relevant changes were observed with other safety endpoints.
DISCUSSION
The present placebo-controlled phase 3 trial demonstrated that a 24-week add-on treatment with enavogliflozin 0.3 mg/day significantly improved glycemic control in adults whose T2DM was inadequately controlled with insulin or insulin with OADs. Specifically, enavogliflozin therapy contributed to significant reductions in HbA1c and FPG and a significant decrease in the TDD of insulin. Additionally, enavogliflozin treatment was associated with an increase in HOMA-β (without a concomitant change in HOMA-IR), a slight albeit significant decrease in fasting C-peptide, reductions in body weight and blood pressure, and an increase in UGCR with no change in UACR. The safety profile of enavogliflozin appeared to be satisfactory.
At week 24, the placebo-adjusted LSM changes in HbA1c and FPG were –0.9% and –32.4 mg/dL, respectively. These values are within the ranges documented in previous clinical trials analyzing the efficacy of various SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin) as add-on therapies in patients with T2DM who did not respond adequately to insulin [24,27-38].
The population enrolled in the present study had a long duration of T2DM, with the median value exceeding 15 years in both groups. Approximately one-third of the study participants had a severely reduced β-cell function, as shown by the baseline C-peptide values below 0.230 nmol/L. However, a further significant decrease in C-peptide level throughout the study was unlikely related to a direct functional impairment of β-cells, rather resulted from the reduced demand for insulin in response to enavogliflozin treatment. This aligns with the statistically significant decrease in the TDD of insulin at weeks 18 and 24, although the actual reduction (1.0 to 1.3 units) was small and its clinical significance is uncertain. Nevertheless, an improvement in HOMA-β observed at weeks 18 and 24, in the absence of a significant change in HOMA-IR, is consistent with preserved β-cell secretory function, independent of insulin sensitivity [39,40].
Insulin therapy is commonly associated with weight gain as a side effect. A 1% decrease in HbA1c due to insulin administration is estimated to be associated with a 2 kg weight gain per year [8]. The addition of enavogliflozin in the study population mitigated this side effect and resulted in a body weight reduction. A negative energy balance created via glycosuria and mild osmotic diuresis, combined with an appropriate dietary and exercise regimen, leads to substantial weight loss. In the present study, the placebo-adjusted LSM change in body weight at week 24 was –1.3 kg, consistent with the results of previous studies using dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin as insulin add-ons [24,27-30,32-38]. However, these observations should be interpreted cautiously, as the increase in the TDD of insulin is tightly controlled in a clinical trial setting, in most cases at <10% to 20%, or a fixed insulin regimen is used [41]. Thus, participants are unlikely to gain a considerable weight. The maximum increase in the TDD of insulin allowed in the present study was 10% from the baseline. Such a modest increase in the TDD of insulin occurs rarely in a real-world setting. Thus, SGLT-2 inhibitors might be less effective in offsetting insulin-induced weight gain under such circumstances. Nevertheless, even a slight decrease in body weight should be considered a desirable outcome since it represents an established contributor to improved glycemic control [42].
The present study demonstrated that a 24-week add-on therapy with enavogliflozin 0.3 mg/day contributed to a significant blood pressure reduction, as shown by the placebo-adjusted LSM change of SBP and DBP by –4.8 and –2.9 mm Hg, respectively. A beneficial effect on blood pressure was also documented in previous studies of other SGLT-2 inhibitors added to insulin, namely dapagliflozin and canagliflozin [30,35]. However, in some studies, a significant change was observed only for one component of blood pressure or was not observed at all [28,29,33]. The reduction of blood pressure by SGLT-2 inhibitors results from osmotic diuresis, natriuresis, weight loss, and perhaps enhanced release of nitric oxide from the endothelium due to better glycemic control [43]. Further, producing natriuresis, SGLT-2 inhibitors might also counteract the sodium retention properties of insulin [44]. The fact that enavogliflozin therapy resulted in blood pressure reduction, in conjunction with the improvement of glycemic control and body weight reduction, implies that, similar to other SGLT-2 inhibitors, this drug might reduce cardiovascular risk in patients with T2DM.
Chronic hyperglycemia is a key driver of diabetic nephropathy, which manifests as an increase in UACR, especially in patients with a long-standing history of T2DM, like those included in our study population. SGLT-2 inhibitors produce a renoprotective effect via tubuloglomerular feedback; enhanced sodium passage through the nephron leads to constriction of afferent glomerular arterioles, eventually protecting glomeruli by reducing intraglomerular pressure [45]. While our study showed no significant improvement in UACR, this might be related to this parameter’s inherent variability, confirmed herein by substantial deviations in individual patient data. Further, the eligibility criteria for the present study did not define the level of UACR, and the sample was not powered enough to assess the effect of enavogliflozin on this parameter. Thus, this question needs to be addressed by future research.
The study did not demonstrate a significant difference in the occurrence of adverse events in the enavogliflozin 0.3 mg/day group and placebo group. The most common ADR in the enavogliflozin and placebo groups was hypoglycemia (18.3% and 12.5%, respectively). The incidence of hypoglycemia documented herein was similar to that in previous studies of SGLT-2 inhibitors as add-ons to insulin (20% to 30%) [24,36-38]. The lack of significant differences in the occurrence of hypoglycemia in the enavogliflozin and placebo groups implies that this ADR was related to insulin, especially since the therapeutic mechanism of enavogliflozin is independent of insulin. The incidence of genitourinary infections was low, 3.3% in the enavogliflozin group, which also agrees with the results of previous studies of SGLT-2 inhibitors [24,36]. The low genitourinary infection rate is worth emphasizing, given that their risk is generally increased in patients with T2DM [46,47], and administration of SGLT-2 inhibitors poses an additional risk, especially for genital infections [48-50]. Based on the present results, one may conclude that enavogliflozin 0.3 mg/day is a safe treatment option when used as an add-on to insulin therapy.
One potential weakness of the present study is its short duration, merely 24 weeks. However, the results of a few longer studies of other SGLT-2 inhibitors as add-ons to insulin, with follow-up durations of 52 to 104 weeks, imply that the efficacy and safety profiles of these drugs typically establish within the initial 24 weeks of treatment and remain unchanged thereafter [27-31,35,37,38].
In conclusion, enavogliflozin 0.3 mg/day is an efficacious and safe add-on treatment option in patients whose T2DM is controlled inadequately with insulin alone or combined with OADs.
SUPPLEMENTARY MATERIALS
Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2025.0477.
Handling strategies for intercurrent events and missing data
Use of insulin and other antidiabetic drugs
Therapeutic target achievement rate at week 24
Occurrence of adverse drug reactions
Placebo-adjusted least-square mean change from baseline in glycosylated hemoglobin (HbA1c) at week 24. The error bar denotes 95% confidence interval. To test the robustness of the primary estimate, sensitivity analyses and supplementary analyses were conducted (A) as well as subgroup analyses based on country and HbA1c at placebo run-in visit (B). PPS, per-protocol set; MMRM, mixed model for repeated measures; FAS, full analysis set; ANCOVA, analysis of covariance; S-analysis, sensitivity analysis.
Changes in the urinary glucose to creatinine ratio (UGCR). aSignificant between-group difference at P<0.0001.
Notes
CONFLICTS OF INTEREST
Younghee Kim, Jung A Heo, Jae Min Cho, Jae Jin Nah, and Mi Hee Park are full-time employees of Daewoong Pharmaceutical Co., Ltd., the sponsoring company. Jun Hwa Hong, Kyung Wan Min, Chang Beom Lee, Parinya Chamnan, Thanitha Sirirak, Kiran Sony, Sarinya Sattanon, Hae Jin Kim, Sang-Yong Kim, and Jae Hyeon Kim declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
Conception or design: J.H.H., J.H.K.
Acquisition, analysis, or interpretation of data: all authors.
Drafting the work or revising: all authors.
Final approval of the manuscript: all authors.
FUNDING
This study was supported by Daewoong Pharmaceutical Co., Ltd. The sponsor participated in the study design, data management and analysis, and preparation of this manuscript.
ACKNOWLEDGMENTS
None