Abstract
Introduction
The phase 3 QWINT-2 study demonstrated that once-weekly insulin efsitora alfa (efsitora) was noninferior to once-daily insulin degludec (degludec) in reducing glycated hemoglobin (HbA1c) at week 52 when added to existing noninsulin glucose-lowering agents in adults with type 2 diabetes who were insulin-naïve. A Japan subgroup analysis of QWINT-2 using two dosing algorithms is presented here.
Methods
Participants from Japan were randomized 1:1 to efsitora or degludec and followed one of two dosing algorithms: a general dosing algorithm or an optional alternative dosing algorithm available for participants anticipated to require less insulin, characterized by a body weight ≤ 60 kg or HbA1c level ≤ 7.5% at baseline. Assessments included changes in HbA1c and fasting blood glucose from weeks 0–52, time spent in target glucose range (TIR) from weeks 48–52, and hypoglycemia from weeks 0–52.
Results
In total, 144 participants from Japan were included (efsitora, n = 71; degludec, n = 73). Demographic and baseline characteristics were generally balanced between treatment groups. From weeks 0–52, mean HbA1c decreased from 8.04% to 6.63% with efsitora and from 8.00% to 6.64% with degludec (estimated treatment difference, −0.01%). TIR was similar between efsitora and degludec from weeks 48–52. Rates of combined level 2 or 3 hypoglycemia were low overall (weeks 0–52) and during the initial dosing period (weeks 0–12). Level 3 hypoglycemia was not reported in any participants with efsitora and two participants with degludec. The incidence of adverse events was similar between efsitora and degludec. The efficacy and safety of efsitora were comparable with degludec using the general and alternative dosing algorithms in Japanese participants.
Conclusions
Once-weekly efsitora was comparable to once-daily degludec in reducing HbA1c in Japanese participants who were insulin-naïve. The efficacy and safety of efsitora in Japanese participants were consistent with the overall QWINT-2 study population.
ClinicalTrials.gov Identifier
Supplementary Information
The online version contains supplementary material available at 10.1007/s13300-026-01860-w.
Keywords: Basal insulin, Insulin efsitora alfa, Japanese subgroup analysis, QWINT-2, Type 2 diabetes, Phase 3
Plain Language Summary
Japanese people with type 2 diabetes tend to have a lower body mass index and less impairment of the effects of insulin than Western people. Thus, they require less insulin to achieve comparable reductions in blood sugar. This study looked at Japanese participants who had not used insulin before in a clinical trial called QWINT-2. This trial compared two types of insulin: (1) efsitora, a new insulin taken once a week, and (2) degludec, a widely used insulin taken once a day. Some participants received a lower dose of insulin efsitora or degludec if they weighed 60 kg or less or had relatively good blood sugar control (blood sugar less than or equal to 7.5%). Once-weekly insulin (efsitora) worked just as well and was just as safe as once-daily insulin (degludec) in Japanese people with type 2 diabetes. This was true regardless of which of the two different methods was used to optimize the insulin dose. These results were also similar to those seen in the overall QWINT-2 trial. This study shows that once-weekly insulin efsitora could help people, including Japanese people, with type 2 diabetes initiate and continue insulin treatment. The study also shows that adjusting insulin doses on the basis of individual factors—such as body mass index or blood sugar levels—has benefit for some Japanese people.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13300-026-01860-w.
Key Summary Points
| Why carry out this study? |
| This subgroup analysis of the phase 3 QWINT-2 study was conducted to evaluate the efficacy and safety of efsitora alfa (efsitora) versus insulin degludec (degludec) in Japanese participants who are insulin-naïve using two different dosing algorithms, as Japanese people with type 2 diabetes (T2D) require less insulin than Western people and may achieve comparable reductions in glycated hemoglobin (HbA1c) with lower insulin doses. |
| What was learned from the study? |
| Once-weekly efsitora was comparable to once-daily degludec in reducing HbA1c and maintaining time in glucose range from weeks 48–52 in Japanese participants. |
| The one-time starting dose of efsitora, which was three-times the weekly dose, did not increase the risk of hypoglycemia. |
| The efficacy and safety of efsitora were comparable to degludec using both the general dosing algorithm and the alternative dosing regimen that was available for participants anticipated to require less insulin, characterized by a body weight ≤ 60 kg or HbA1c level ≤ 7.5% at baseline. |
| Despite differences in general characteristics between people with T2D in Japan versus Western countries, the efficacy and safety in the Japan subgroup were consistent with the overall QWINT-2 study population. |
Introduction
Consistent with global trends [1], type 2 diabetes (T2D) is a major health concern in Japan due to its increasing prevalence, severity, and associated complications [2]. The development of T2D is primarily driven by insulin resistance and β-cell dysfunction leading to hyperglycemia [3]. However, differences have been reported between Japanese and Western people with T2D. For instance, Japanese people with T2D have lower insulin resistance, reduced insulin secretion, a relatively younger age of onset, and a lower body mass index (BMI) compared with Western people [4–7]. It is important to consider these differences to effectively treat Japanese people with T2D [8].
Effective management of T2D relies on achieving glycemic targets, often using insulin therapy. However, most people with T2D treated with insulin do not achieve good glycemic control [9] due to challenges such as the complexity of treatment regimens, fear of hypoglycemia, delays in insulin initiation and intensification, and suboptimal insulin dosing [10–13].
A basal insulin with a low peak-to-trough ratio, administered weekly, has the potential to reduce barriers to initiating insulin therapy, improve treatment adherence, and reliably achieve glucose targets with a low risk of hypoglycemia [14]. Insulin efsitora alfa (efsitora) is a long-acting insulin receptor agonist for the treatment of hyperglycemia in people with T2D requiring basal insulin therapy. Its once-weekly formulation is less disruptive than daily dosing and results in more stable insulin levels [15]. The phase 3 QWINT-2 study evaluated the efficacy and safety of once-weekly efsitora compared with once-daily insulin degludec (degludec) in adults with T2D who were insulin-naïve [16]. QWINT-2 met its primary endpoint, demonstrating that once-weekly efsitora was noninferior to once-daily degludec in reducing mean glycated hemoglobin (HbA1c) levels at week 52 when added to existing noninsulin glucose-lowering agents [16].
To better understand the use of efsitora in the treatment of T2D in Japanese adults, the aim of this subgroup analysis was to compare the efficacy and safety of efsitora versus degludec in Japanese QWINT-2 participants using two different dosing algorithms. This preplanned subgroup analysis was limited by sample size and therefore descriptive only and not intended to demonstrate noninferiority in the Japan subgroup.
Methods
Study Design and Participants
The study design and participants for QWINT-2 have been published previously (ClinicalTrials.gov identifier: NCT05362058) [16]. QWINT-2 was a phase 3, parallel-design, open-label, treat-to-target, randomized controlled trial that comprised a 3-week screening and lead-in period, a 52-week treatment period, and a 5-week follow-up period. Participants were adults (≥ 18 years of age) with T2D who were insulin-naïve, had an HbA1c level of 7.0–10.5%, had a BMI of ≤ 45.0 kg/mg2, and had received stable treatment with one to three noninsulin glucose-lowering agents for at least 3 months before screening. For the Japanese subgroup, in addition to the QWINT-2 exclusion criteria, participants undergoing major surgery and those with retinopathy or maculopathy were also excluded.
The study was conducted at 18 locations in Japan. The protocol was approved by the independent ethics committee or institutional review board at each participating center, and the trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Details of the ethics committees have been published previously [16]. All participants provided written informed consent. The analyses presented are based on a database lock date of 3 May 2024.
Procedures
Details of the randomization and interventions for QWINT-2 have been published previously [16]. It was planned that 50% of participants would use glucagon-like peptide-1 (GLP-1) receptor agonists, with use balanced between treatment groups. Eligible participants from Japan were randomized 1:1 to efsitora or degludec and followed one of two dosing algorithms: a general algorithm or an optional alternative algorithm available for East Asian participants anticipated to require less insulin, characterized by a body weight ≤ 60 kg or HbA1c level ≤ 7.5% at baseline. The choice of dosing algorithm for both efsitora and degludec was made by the study physician at each study site according to the criteria described above.
The general dosing algorithm for efsitora had a one-time starting dose of 300 U, followed by an initial weekly dose of 100 U. This one-time starting dose of 300 U enabled efsitora concentrations to reach efficacious levels more quickly. For degludec, the initial dose was 10 U. The subsequent weekly doses of efsitora and daily doses of degludec were calculated according to median fasting blood glucose (FBG) values and hypoglycemic events, as described previously [16]. The alternative dosing algorithm for efsitora had a one-time starting dose of 150 U, followed by an initial weekly dose of 50 U. For degludec, the initial dose was 5 U.
Assessments and Statistical Analysis
Detailed assessments and statistical methods for QWINT-2 have been published previously [16]. Participants were given blood glucose meters to monitor their own blood glucose levels and monitor for hypoglycemia. Participants also wore blinded continuous glucose monitoring (CGM) devices intermittently throughout the study. This preplanned subgroup analysis investigated change in the HbA1c level from weeks 0–52. This analysis also investigated changes in FBG (as measured by participant monitoring) and average weekly insulin dose from weeks 0–52; changes in HbA1c by GLP-1 receptor agonist use; incidence and rate of hypoglycemic events, as measured by participant monitoring, assessed by combined level 2 (glucose < 54 mg/dL) or level 3 (severe) hypoglycemic events from weeks 0–52; and the percentage of time glucose level that was within target range (time in target glucose range [TIR] 70–180 mg/dL) or above target range (181–250 mg/dL or > 250 mg/dL) from weeks 0–52. CGM was also conducted from weeks 0–4 and 8–12 for all participants, and for weeks 4–8 for Japanese participants only, to evaluate the safety of the one-time starting dose by assessing the percentage of time glucose level was below target range (time below range [TBR] 54–69 mg/dL or < 54 mg/dL). Treatment-emergent adverse events (TEAEs) were recorded throughout the study.
This subgroup analysis included all participants randomized and treated from Japan. Efficacy and safety analyses were performed in all randomly assigned participants who received at least one dose of efsitora or degludec. Continuous endpoints were analyzed using a mixed model for repeated measures. The model included treatment, randomization strata (GLP-1 receptor agonist use and sulfonylurea use), visit, and treatment-by-visit interaction as fixed effects, and the baseline of the dependent variable as a covariate. For analyses other than HbA1c, the model also included baseline HbA1c stratum (< 8.0% versus ≥ 8.0%). Data were summarized descriptively using least-squares means (LSMs), estimated treatment differences, and 95% confidence intervals.
Results
Participants
A total of 144 participants from Japan were randomized to receive efsitora (n = 71) or degludec (n = 73) (Table 1). Of these, 99 participants (68.8%) received the general dosing algorithm (efsitora, n = 50; degludec, n = 49) and 45 participants (31.3%) received the alternative dosing algorithm (efsitora, n = 21; degludec, n = 24).
Table 1.
Demographic and baseline clinical characteristics of Japanese QWINT-2 participants
| Parameter | All Japanese participants N = 144 |
General dosing algorithm N = 99 |
Alternative dosing algorithm N = 45 |
|||
|---|---|---|---|---|---|---|
| Efsitora n = 71 |
Degludec n = 73 |
Efsitora n = 50 |
Degludec n = 49 |
Efsitora n = 21 |
Degludec n = 24 |
|
| Age, years | 58.6 (10.8) | 58.1 (11.6) | 56.4 (11.0) | 57.2 (11.7) | 63.9 (8.4) | 60.0 (11.6) |
| Male, n (%) | 51 (71.8) | 49 (67.1) | 39 (78.0) | 37 (75.5) | 12 (57.1) | 12 (50.0) |
| Female, n (%) | 20 (28.2) | 24 (32.9) | 11 (22.0) | 12 (24.5) | 9 (42.9) | 12 (50.0) |
| Body weight, kg | 73.5 (12.2) | 74.7 (16.2) | 76.7 (10.4) | 78.6 (12.6) | 65.9 (12.9) | 66.8 (19.8) |
| BMI, kg/m2 | 26.5 (3.8) | 27.3 (4.9) | 27.0 (3.3) | 28.2 (4.1) | 25.3 (4.7) | 25.4 (5.8) |
| Duration of diabetes, years | 13.4 (7.2) | 12.3 (6.7) | 12.4 (6.9) | 12.3 (6.3) | 15.7 (7.6) | 12.3 (7.5) |
| Baseline HbA1c, % | 8.04 (0.8) | 8.00 (0.7) | 8.28 (0.7) | 8.28 (0.6) | 7.46 (0.6) | 7.42 (0.6) |
| Fasting serum glucose, mg/dL | 150.8 (39.2) | 151.8 (36.2) | 161.3 (40.8) | 157.0 (37.7) | 125.6 (18.6) | 141.6 (31.4) |
| Estimated GFR, mL/min/1.73 m2, n (%) | ||||||
| ≥ 30–< 60 | 13 (18.3) | 10 (13.7) | 9 (18.0) | 8 (16.3) | 4 (19.0) | 2 (8.3) |
| ≥ 60–< 90 | 42 (59.2) | 43 (58.9) | 26 (52.0) | 28 (57.1) | 16 (76.2) | 15 (62.5) |
| ≥ 90 | 16 (22.5) | 20 (27.4) | 15 (30.0) | 13 (26.5) | 1 (4.8) | 7 (29.2) |
| Noninsulin glucose-lowering agents, n (%) | ||||||
| Metformin | 48 (67.6) | 55 (75.3) | 35 (70.0) | 39 (79.6) | 13 (61.9) | 16 (66.7) |
| GLP-1 receptor agonist | 35 (49.3) | 37 (50.7) | 24 (48.0) | 28 (57.1) | 11 (52.4) | 9 (37.5) |
| SGLT2 inhibitor | 50 (70.4) | 34 (46.6) | 38 (76.0) | 22 (44.9) | 12 (57.1) | 12 (50.0) |
| Sulfonylurea | 13 (18.3) | 14 (19.2) | 8 (16.0) | 9 (18.4) | 5 (23.8) | 5 (20.8) |
| DPP-4 inhibitor | 29 (40.8) | 28 (38.4) | 21 (42.0) | 15 (30.6) | 8 (38.1) | 13 (54.2) |
| Thiazolidinedione | 2 (2.8) | 7 (9.6) | 2 (4.0) | 5 (10.2) | 0 | 2 (8.3) |
| α-Glucosidase inhibitor | 4 (5.6) | 7 (9.6) | 3 (6.0) | 6 (12.2) | 1 (4.8) | 1 (4.2) |
Data are presented as mean (standard deviation), unless otherwise specified. To convert values for glucose to millimoles per liter (mmol/L), multiply by 0.05551. BMI body mass index, DPP-4 dipeptidyl peptidase-4, GFR glomerular filtration rate, GLP-1 glucagon-like peptide-1, HbA1c glycated hemoglobin, SGLT2 sodium–glucose cotransporter 2
Demographic and baseline characteristics were generally balanced between the efsitora and degludec groups. As expected, on the basis of differences in the criteria for the dosing algorithms, participants who received the alternative dosing algorithm had lower mean body weight, HbA1c levels, BMI, and fasting serum glucose levels at baseline. Compared with the general dosing algorithm group, the average age of participants in the alternative dosing algorithm group was higher, with a lower percentage of male participants. Participants had received a range of different noninsulin glucose-lowering agents, with no apparent differences in patterns of agent between treatment groups or dosing algorithms.
Change in HbA1c from Baseline to Week 52
Efsitora showed comparable efficacy to degludec, irrespective of the dosing algorithm, as evidenced by the LSM change in HbA1c level from baseline to week 52 (Figs. 1A, B). Over this period, mean HbA1c decreased from 8.04% to 6.63% with efsitora (LSM change, −1.37%) and from 8.00% to 6.64% with degludec (LSM change, −1.36%; estimated treatment difference, −0.01%) (Fig. 1A). Participants who received efsitora according to the alternative dosing algorithm had a smaller decrease in mean HbA1c compared with those following the general dosing algorithm (LSM change −0.92% versus −1.56%), likely due to the lower baseline HbA1c in participants who received the alternative dosing algorithm (Fig. 1B). A mean HbA1c level of less than 7% was reached with efsitora at week 12 with both dosing algorithms and was maintained through the end of the treatment period (Fig. 1B).
Fig. 1.
Change in HbA1c (%) over time in Japanese QWINT-2 participants. Data are presented as least-squares mean (LSM) ± standard error. Error bars represent standard error. The delta symbol (Δ) indicates the LSM change from baseline to week 52. A Overall Japanese population. B General dosing algorithm and alternative dosing algorithm. C Change in HbA1c in participants who received the general and alternative dosing algorithms from weeks 0–52 by GLP-1 RA use. CI confidence interval, ETD estimated treatment difference, GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglobin
Similar trends in efficacy were observed when participants were analyzed by GLP-1 receptor agonist use (Fig. 1C). Among participants who used GLP-1 receptor agonists, the estimated treatment difference (95% CI) between efsitora and degludec was −0.12 (−0.52, 0.27) with the general dosing algorithm and −0.27 (−0.67, 0.13) with the alternative dosing algorithm. Among participants who did not use GLP-1 receptor agonists, the estimated treatment difference was +0.28 (−0.14, 0.70) with the general dosing algorithm and −0.06 (−0.45, 0.34) with the alternative dosing algorithm.
TIR from Baseline to Weeks 48–52
From weeks 48–52, TIR was comparable between participants in the efsitora and degludec groups. TIR increased from baseline to the final 4 weeks of treatment (weeks 48–52) (Fig. 2A). TBR was also comparable between the efsitora and degludec groups (Figs. 2A, B).
Fig. 2.
Percentage of time in different ranges measured by continuous glucose monitoring over 24 h in Japanese QWINT-2 participants. The percentage of time spent at various glucose levels, as measured by continuous glucose monitoring, are presented as least-squares means (LSMs). A Overall Japanese population at baseline and weeks 48–52. B Overall Japanese population at weeks 0–4, weeks 4–8, and weeks 8–12. Percentages may not total 100% because of rounding
Change in FBG from Baseline to Week 52
From baseline to week 52, mean FBG level decreased from 177.6 to 118.1 mg/dL with efsitora (LSM change, −60.6 mg/dL) and from 182.2 to 119.3 mg/dL with degludec (LSM change, −59.4 mg/dL; estimated treatment difference, −1.18) (Fig. 3A). Participants who received efsitora according to the alternative dosing algorithm had the lowest FBG levels among all treatment groups throughout the treatment period (Fig. 3B). Furthermore, with the alternative dosing algorithm, the LSM mean change in mean FBG at week 52 was larger in the efsitora group than in the degludec group (Fig. 3B).
Fig. 3.
Change in fasting blood glucose measured by participant-monitored glucose testing over time in Japanese QWINT-2 participants. Data are presented as least-squares mean (LSM) ± standard error. Error bars represent standard error. The adjusted fasting blood glucose values were based on participant-assigned fasting time point and the first reading between 5:00 AM and 10:00 AM. The delta symbol (Δ) indicates the LSM change from baseline to week 52. A Overall Japanese population. B General dosing algorithm and alternative dosing algorithm. CI confidence interval, ETD estimated treatment difference, SMBG self-monitored blood glucose
Change in Insulin Dose from Baseline to Week 52
At week 52, the total weekly insulin dose was 194.3 U/week (27.8 U/day) for efsitora and 226.5 U/week (32.4 U/day) for degludec, with an estimated treatment difference of –32.3 U/week (Fig. 4A). At week 52, weekly efsitora doses were also lower than weekly degludec doses for both dosing algorithms (Fig. 4B). The difference in insulin dose between the efsitora and degludec groups was greater with the alternative dosing algorithm than with the general dosing algorithm (Fig. 4B).
Fig. 4.
Change in insulin dose over time in Japanese QWINT-2 participants. Data are presented as the least-squares mean (LSM) weekly insulin dose over time. Error bars represent standard error. A Overall Japanese population. B General dosing algorithm and alternative dosing algorithm. CI confidence interval, ETD estimated treatment difference, U units
Rate and Incidence of Hypoglycemia from Baseline to Week 52
The rate of combined level 2 or 3 hypoglycemic events was generally low and similar between the efsitora and degludec groups throughout the treatment period (Table 2). No participants treated with efsitora reported a level 3 hypoglycemic event with either dosing algorithm. Level 3 hypoglycemia was reported in one participant treated with degludec with each dosing algorithm.
Table 2.
Event rate per year of hypoglycemia in Japanese QWINT-2 participants
| Hypoglycemic event | All Japanese participants N = 144 |
General dosing algorithm N = 99 |
Alternative dosing algorithm N = 45 |
|||
|---|---|---|---|---|---|---|
| Efsitora n = 71 |
Degludec n = 73 |
Efsitora n = 50 |
Degludec n = 49 |
Efsitora n = 21 |
Degludec n = 24 |
|
| Level 1 | ||||||
| 0–52 weeks | 3.02 | 2.28 | 4.00 | 1.97 | 1.20 | 2.82 |
| Relative rate (95% CI) | 1.33 (0.73, 2.39) | 2.03 (1.09, 3.78) | 0.43 (0.13, 1.36) | |||
| Level 2/3 | ||||||
| 0–52 weeks | 0.37 | 0.36 | 0.46 | 0.27 | 0.18 | 0.55 |
| Relative rate (95% CI) | 1.02 (0.42, 2.49) | 1.72 (0.67, 4.43) | 0.34 (0.05, 2.34) | |||
| Nocturnal level 2/3 | ||||||
| 0–52 weeks | 0.12 | 0.07 | 0.12 | 0.10 | 0.05 | 0 |
| Relative rate (95% CI) | 1.74 (0.38, 8.08) | 1.19 (0.20, 7.14) | NC | |||
CI confidence interval, NC not calculable
Safety of the One-Time Starting Dose of Efsitora
TIR increased from weeks 0–12 during the initial dosing period and was comparable between the efsitora and degludec groups. TBR was also comparable between efsitora and degludec during the initial dosing period, with values for efsitora versus degludec of 0.5% versus 0.3% at weeks 0–4, 0.5% versus 0.5% at weeks 4–8, and 0.7% versus 0.6% at weeks 8–12. CGM data collection during weeks 0–12 showed no evidence of increased TBR due to the one-time starting dose of efsitora.
The rates of combined level 2 or 3 hypoglycemia during the initial dosing period (weeks 0–12) were low and comparable between the efsitora and degludec groups. During this period, seven episodes of combined level 2 or 3 hypoglycemic events were reported with efsitora in 71 participants and six events were reported with degludec in 73 participants (Supplementary Table 1).
Adverse Events
The overall incidence of TEAEs was similar between the efsitora and degludec groups. TEAEs were reported in 50 participants (70.4%) who received efsitora and 57 participants (78.1%) who received degludec. A similar number of TEAEs were reported between the efsitora and degludec groups for each dosing algorithm. Serious adverse events were reported by three participants with efsitora (angina unstable, glaucoma, and cellulitis) and six participants with degludec (chronic tonsillitis, cholecystitis acute, meniscus injury, tibia fracture, osteoarthritis, benign spleen tumor, and hypoglycemia [n = 2]). No participants using either dosing algorithm discontinued the study or study treatment due to an adverse event, and no deaths were reported during the study (Supplementary Table 2).
Serious adverse events (SAEs) were comparable between the efsitora and degludec groups. Seven participants (7.1%) who received the general dosing algorithm experienced at least one SAE during the study, with similar SAE incidence rates between the efsitora and degludec groups. Among participants who received the alternative dosing algorithm, no SAEs were reported in the efsitora group, and two participants (8.3%) experienced at least one SAE in the degludec group.
Discussion
This subgroup analysis of the phase 3 QWINT-2 study demonstrates that once-weekly efsitora is comparable to once-daily degludec in reducing HbA1c in Japanese adults with T2D who are insulin-naïve, with similar safety outcomes between the efsitora and degludec groups. These findings are consistent with the efficacy and safety results observed in the overall QWINT-2 study population [16], despite general differences in clinical characteristics between Japanese and Western people with T2D. Glycemic control was also similar between weekly efsitora and daily degludec, regardless of the dosing algorithm used.
Glycemic control in Japanese participants was similar for efsitora and degludec, as evidenced by similar TIR from weeks 48–52. These results are consistent with the overall QWINT-2 study population [16]. Furthermore, overall rates of hypoglycemia were low, in particular level 2 or 3 hypoglycemia. There was also no severe hypoglycemia reported during efsitora treatment. Overall, clinically meaningful hypoglycemia and other safety measures were similar between the two treatment groups in Japanese participants, without severe hypoglycemia during efsitora treatment.
To help efsitora reach effective concentrations more rapidly, participants in that group received a three-fold-higher one-time starting dose at the first injection. Glycemic control was achieved with efsitora in Japanese participants, with no evidence of increased TBR from weeks 0–12 as a result of this higher starting dose. Furthermore, the one-time starting dose of efsitora was not associated with an increased risk of hypoglycemia in Japanese participants, as demonstrated by the low rates of combined level 2 or 3 hypoglycemia during the initial dosing period (weeks 0–12).
Japanese people have lower insulin resistance, reduced insulin secretion, and a lower BMI compared with people from Western countries [4–6]. Decreased insulin secretory capacity due to pancreatic β-cell dysfunction has also been shown to play a greater role in the onset of T2D in Japanese people than in Western people [17]. Optimizing insulin dosing regimens on the basis of individual characteristics is therefore essential for the effective management of T2D in Japan. Consequently, at East Asian QWINT-2 study sites only, an optional and alternative dosing algorithm was available for participants who weighed ≤ 60 kg or had a HbA1c level ≤ 7.5% at baseline, as they were anticipated to require less insulin. In the current subgroup analysis, comparable glycemic control was achieved in Japanese participants with weekly efsitora or daily degludec, regardless of the dosing algorithm used. While the scale of change in HbA1c from baseline to week 52 in the alternative dosing algorithm group was less than in the general dosing algorithm group (efsitora, –0.92% versus –1.56%; degludec, –0.75% versus –1.63%, respectively), this can be attributed to differences in baseline HbA1c levels.
Similar trends in FBG levels were observed in Japanese participants with both the general and alternative dosing algorithms, reflecting similar dose adjustments over time. Throughout the treatment period, changes in mean FBG were comparable between the efsitora and degludec groups and consistent across the general and alternative dosing algorithms. Although HbA1c and FBG at week 52 were similar between the efsitora and degludec groups with both dosing algorithms, the levels were slightly lower with the alternative dosing algorithm for efsitora. This may be explained by the more gradual insulin titration with this algorithm: while doses were decreased by the same amount with both algorithms in response to low FBG or hypoglycemia, dose increases were made in smaller increments based on FBG, potentially allowing tighter control of FBG levels. Overall, these results suggest that both dosing algorithms were effective in achieving glycemic control.
Event rates and incidences of combined level 2 or 3 hypoglycemia were low overall and comparable with both the general and alternative dosing algorithms in Japanese participants. Three participants in the efsitora group who received the general dosing algorithm experienced SAEs, whereas no SAEs were reported with efsitora in those who received the alternative dosing algorithm. The low incidence and event rates of hypoglycemia and low SAE rate indicate that efsitora was well tolerated with a low risk of hypoglycemia in Japanese participants, regardless of the dosing algorithm used.
In this subgroup analysis, daily and weekly insulin doses were lower with efsitora than with degludec for most of the treatment period. However, potential confounding factors, such as BMI and renal function, impact interpretation of this finding. Furthermore, the small cohort size and complexities in converting insulin units make interpretation of this finding a challenge. Consequently, the clinical relevance of the differences in insulin doses are unknown.
There is an increasing recognition of the distinct clinical features and treatment responses of Japanese people with T2D compared with Western people [18]. This study is the first to evaluate an insulin treatment regimen adapted to East Asian people with T2D who may require lower insulin doses. It also provides useful data on the benefits of efsitora treatment while using GLP-1 receptor agonists, which is common in clinical practice. Nonetheless, there were limitations to this subgroup analysis. First, it included a relatively small number of participants. Second, the QWINT-2 trial was not designed or powered to demonstrate significance in subgroups. Thus, the results of this subgroup analysis are descriptive in nature and should be interpreted with caution. Finally, because only Japanese participants were included, it is unclear whether these findings can be extrapolated to other ethnicities. Future studies specifically powered for Japanese subpopulations or conducted under real-world conditions would further validate the clinical utility and flexibility of efsitora in Japanese adults with T2D.
Conclusions
This subgroup analysis of QWINT-2 shows that once-weekly efsitora is comparable to once-daily degludec in reducing HbA1c in Japanese adults with T2D who are insulin-naïve. The one-time starting dose with efsitora reduced FBG levels in parallel with degludec without increasing the risk of hypoglycemia. The efficacy and safety of efsitora were comparable to degludec with both the general and alternative dosing algorithms. These findings are consistent with the overall QWINT-2 study population, demonstrating that once-weekly efsitora is effective and well tolerated in Japanese adults with T2D.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors wish to thank the participants of the QWINT-2 study whose contributions made this research possible.
Medical Writing and/or Editorial Assistance
Medical writing support was provided by Nicola Welch, Ph.D., CMPP and Andrew Sakko, Ph.D., CMPP, and editorial support was provided by Abbas Kassem of Syneos Health and funded by Eli Lilly and Company in accordance with Good Publication Practice (2022) guidelines (www.ismpp.org/gpp-2022).
Author Contributions
Arihiro Kiyosue and Hirotaka Watada collected data. Mariko Inoue, Yasushi Takita, and Risa Nasu analyzed data. All authors interpreted the data, contributed to the writing of the manuscript, and approved the final version for submission.
Funding
This study was funded by Eli Lilly and Company. The study sponsor funded the journal’s Rapid service fees.
Data Availability
Eli Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Declarations
Conflict of Interest
Mariko Inoue, Yasushi Takita, and Risa Nasu are full-time employees of Eli Lilly Japan K.K. and own stock in Eli Lilly and Company. Arihiro Kiyosue has received honoraria from AstraZeneca, Eli Lilly and Company, and Sumitomo Pharma. Hirotaka Watada has received research funding from Abbott, Boehringer Ingelheim, Kowa, Lifescan Japan, Sanwa Kagaku Kenkyusyo, SBI Pharma, Sumitomo Pharma, Taisho Pharmaceutical, Takeda, and Teijin and lecture fees from Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly and Company, Embecta, GlaxoSmithKline, Kowa, Kyowa Kirin, Mitsubishi Tanabe, MSD, Novo Nordisk, Roche, Sanofi, Sanwa Kagaku Kenkyusyo, Sumitomo Pharma, Taisho Pharmaceutical, and Teijin. Hirotaka Watada is also an Editorial Board member of Diabetes Therapy. Hirotaka Watada was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.
Ethical Approval
The protocol was approved by the independent ethics committee or institutional review board of each participating center, and the trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. All participants provided written informed consent.
Footnotes
Prior Presentation: Yoshino M, Takita Y, Nasu R, Goncalves LF, Bue-Valleskey JM, Kiyosue A. 810-P: Insulin efsitora alfa vs. insulin degludec in adults with insulin-naïve T2D (QWINT-2)—a Japan subgroup analysis. Diabetes. 2025;74(Suppl 1):810–P. 10.2337/db25-810-P.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Eli Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.