The study was conducted between March 2022 and July 2023. In total, 70 individuals were screened; 4 were excluded due to meeting exclusion or not meeting inclusion criteria, meaning 66 people with T2D were enrolled from 15 clinical sites (Supplementary Material: Table S1), all of whom were included in the safety analysis set (Fig. 1). Of these, five people were excluded, and 61 were included in the FAS.

Study participant disposition. aGastroenteritis. AE adverse event, HbA1c glycated hemoglobin

Over two-thirds of participants in the FAS were male (68.9%; Table 1). The mean ± SD age was 62.1 ± 13.3 years, with over half of the participants being aged 20 to < 65 years (55.7%). The mean ± SD body mass index (BMI) was 25.7 ± 3.9 kg/m2 and roughly equal proportions of participants had BMI < 25 and ≥ 25 to < 30 kg/m2 (45.9 and 49.2%, respectively). The mean ± SD duration of T2D was 11.8 ± 12.2 years, and 26.2% of participants had a T2D duration of ≥ 20 years. Nineteen participants (31.1%) had diabetic nephropathy, 17 (27.9%) had diabetic retinopathy and 15 (24.6%) had diabetic neuropathy. The most common comorbidities were dyslipidemia (elevated plasma cholesterol, triglycerides or both, or a decreased high-density lipoprotein cholesterol; n = 27, 44.3%), hypertension (n = 24, 39.3%), hepatic steatosis (n = 8, 13.1%) and hypercholesterolemia (elevated cholesterol only; n = 8, 13.1%). Before the study, 23 participants (37.7%) were not receiving any OADs. Of the remaining participants, 27 (44.3%) were taking one concomitant OAD, seven (11.5%) were taking two OADs and four (6.6%) were taking three or more OADs. The most common pre-study OAD classes were sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 17, 27.9%) and biguanides and dipeptidyl peptidase-4 (DPP-4) inhibitors (n = 16, 26.2% each). The mean ± SD HbA1c at baseline was 6.73 ± 0.66%, FPG was 126.1 ± 28.4 mg/dl and fasting serum C-peptide was 1.8 ± 1.0 ng/ml. Participants had a mean ± SD eGFR of 67.7 ± 18.1 ml/min/1.73 m2. Participants were receiving a mean ± SD total daily insulin dose of 20.9 ± 7.1 U at baseline, administered as a mean ± SD of 3.9 ± 0.4 injections daily. At baseline, the mean ± SD DTSQs total treatment satisfaction score was 22.4 ± 6.2, perceived hyperglycemia score was 1.9 ± 1.4 and the perceived hypoglycemia score was 1.5 ± 1.5. Individual items related to treatment satisfaction at baseline ranged from 3.4 to 4.0 (i.e.,  DTSQs scores for Q1, Q4–8; Supplementary Material: Fig. S1). The baseline characteristics of the safety analysis set (n = 66) were similar to those of the FAS. Baseline characteristics of participants stratified by β-cell function tertile (SUIT index) are shown in Supplementary Material: Table S2.

Among participants with HRQOL data in the FAS (n = 58), the mean ± SD total DTR-QOL score significantly increased from 63.2 ± 19.5 at baseline to 74.3 ± 16.6 at week 24, corresponding to a mean ± SD change of 10.8 ± 17.6 points (P < 0.001; Fig. 2). At week 12, the mean ± SD total DTR-QOL score had increased to 75.1 ± 14.9 (P < 0.001 vs. baseline). In addition, there were significant improvements in the individual DTR-QOL domain scores, including Domain 1 (burden on social activities and daily activities) at weeks 12 and 24 (P < 0.001 for both), Domain 2 (anxiety and treatment dissatisfaction) at weeks 12 and 24 (P = 0.007 for both), Domain 3 (hypoglycemia) at week 12 (P = 0.013) and Domain 4 (treatment satisfaction) at weeks 12 (P = 0.002) and 24 (P = 0.041; Fig. 2). The mean ± SD DTR-QOL scores for individual questions and domains are provided in Table 2.

Mean Diabetes Therapy-Related Quality of Life scores at baseline, week 12 and week 24. The total score and domain scores are converted to a scale of 0–100. *P < 0.05, **P < 0.01, ***P < 0.001 vs. baseline. DTR-QOL Diabetes Therapy-Related Quality of Life, SD standard deviation

The 24-week DTSQc scores showed positive changes in treatment satisfaction (11.6 ± 6.0), perceived hyperglycemia (− 0.5 ± 1.7) and perceived hypoglycemia (− 0.7 ± 1.5; Fig. 3a). The 24-week DTSQc scores for mean change (i.e.,  improvement) in individual treatment satisfaction questions ranged from 1.6 to 2.2 (Fig. 3b). DTSQc scores at 24 weeks showed that treatment satisfaction, perceived hyperglycemia and perceived hypoglycemia scores were similar in participants who received two or three bolus injections in the baseline period (data not shown).

Mean Diabetes Treatment Satisfaction Questionnaire, change version scores at week 24 for a treatment satisfaction, perceived hyperglycemia and perceived hypoglycemia, and b individual treatment satisfaction questions (n = 55). DTSQc Diabetes Treatment Satisfaction Questionnaire, change version, Q question, SD standard deviation

Mean ± SD HbA1c levels were 6.73 ± 0.66% at baseline, 7.00 ± 0.88% at week 12 and 7.02 ± 0.81% at week 24 (Fig. 4). The mean ± SD change in HbA1c from baseline was + 0.31 ± 0.52% at week 12 (P < 0.001) and + 0.31 ± 0.62% at week 24 (P < 0.001). HbA1c was < 7.0% in 38 participants (62.3%) at baseline, in 22 participants (36.1%) at week 12 and in 20 participants (32.8%) at week 24. At baseline, 48 participants (78.7%) were within their age-specific HbA1c targets. Age-specific HbA1c targets were achieved by 32 participants (52.5%) at both week 12 and week 24. Post hoc exploratory analyses by SUIT index tertile found that participants with highest levels of remaining β-cell function had the greatest proportion with an HbA1c < 7.0% at 24 weeks (P = 0.038; Supplementary Material: Table S2).

Mean glycated hemoglobin and bodyweight at baseline, week 12 and week 24. *P < 0.05 vs. baseline, **P < 0.01 vs. baseline. BL baseline, HbA1c glycated hemoglobin, SD standard deviation

Mean ± SD body weight was 70.2 ± 13.3 kg at baseline, 69.6 ± 13.9 kg at week 12 and 69.6 ± 13.7 kg at week 24 (Fig. 4). The mean ± SD change in body weight from baseline was − 0.7 ± 2.7 kg at week 12 (P = 0.046) and − 0.5 ± 4.0 kg at week 24 (P = 0.343).

The mean ± SD total daily insulin dose was 20.9 ± 7.1 U at baseline, 10.2 ± 4.5 U at week 12 and 10.7 ± 4.6 U at week 24 (Table 3). The mean ± SD change in total daily insulin dose from baseline was − 10.5 ± 5.6 U at week 12 and − 10.2 ± 5.7 U at week 24 (P < 0.001 for both). The mean ± SD BI daily dose was 9.4 ± 4.4 U at baseline, 10.2 ± 4.5 U at week 12 and 10.7 ± 4.6 U at week 24. Neither of these changes were statistically significant (P = 0.132 and P = 0.060, respectively). The mean number of total daily insulin injections decreased from 3.9 injections at baseline to 1.0 injection at weeks 12 and 24, as no participant used concomitant bolus insulin. The mean ± SD change from baseline in the total number of daily insulin injections was − 2.8 ± 0.4 at week 12 and − 2.9 ± 0.3 at week 24 (P < 0.001 for both).

Insulin treatment adherence data was available for 61 participants at week 12 and for 58 participants week 24. At week 12, self-reported insulin treatment adherence was classified as high in 51 participants (83.6%) and moderate in 10 (16.4%). At week 24, 45 participants (77.6%) reported high adherence and 13 (22.4%) had moderate adherence. No participants reported poor adherence at weeks 12 or 24. The most common reason for initiating iGlarLixi therapy was to reduce the number of types or number of insulin injections (82.0%; Supplementary Material: Table S3).

The mean ± SD daily dose of the insulin constituent of iGlarLixi was 6.9 ± 2.4 U at initiation, 10.2 ± 4.5 U at week 12 and 10.7 ± 4.6 U at week 24 (Table 3). The mean ± SD change from initiation of iGlarLixi in the daily insulin dose was + 3.4 ± 4.7 U at week 12 and + 3.9 ± 4.6 U at week 24 (P < 0.001 for both). During treatment, 15 participants (24.6%) had no increase in iGlarLixi dose (Supplementary Material: Table S3).

After switching to iGlarLixi therapy, the proportion of participants who were using SGLT2 inhibitors, biguanides and glinides increased, while the proportion of those who used DPP-4 inhibitors decreased (Fig. 5). The use of DPP-4 inhibitor fixed-dose combinations stopped altogether.

Proportion of participants receiving concomitant oral antidiabetic therapy before and after switching from multiple daily injections of insulin to iGlarLixi. DPP-4 dipeptidyl peptidase-4, FDC fixed-dose combination, GI glucosidase inhibitor, SGLT2 sodium-glucose cotransporter-2, SU sulphonylurea, TZD thiazolidinedione derivative

In the safety analysis set, five participants (7.6%) required interruption of iGlarLixi and six participants (9.1%) prematurely discontinued iGlarLixi therapy (Supplementary Material: Table S4). Two participants (3.0%) discontinued because of gastrointestinal AEs related to iGlarLixi use. There were no cases of iGlarLixi interruption for poor glycemic control.

During the baseline period, 27 hypoglycemic episodes were reported in 11/66 participants (16.7%) in the safety analysis set, corresponding to an incidence rate of 1.7 events per person-year. At weeks 12 and 24, ten participants (15.2%) had 21 hypoglycemic episodes and 12 participants (18.2%) had 30 hypoglycemic episodes, respectively (Table 4). The incidence rate of hypoglycemic episodes at weeks 12 and 24 was 1.1 and 1.0 events per person-year, respectively.

Overall, no severe hypoglycemic episodes were reported (Table 4). At week 24, six participants (9.1%) had seven documented symptomatic hypoglycemic episodes, five participants (7.6%) had 20 asymptomatic hypoglycemic episodes, and three participants (4.5%) had three episodes of probable symptomatic hypoglycemia. No hospitalizations or emergency room visits were required for hypoglycemia.

In total, 18 participants (27.3%) had 26 gastrointestinal AEs during iGlarLixi therapy (Table 5). At week 24, the incidence rate of gastrointestinal AEs was 0.8 events per person-year. The most common gastrointestinal AEs were decreased appetite, nausea and diarrhea. All gastrointestinal AEs were mild or moderate in severity.