A total of 531 participants were screened at 27 university and general hospitals in South Korea; there were 36 screening failures, and one participant was excluded because of the loss of the informed consent form, resulting in 494 participants being enrolled (Supplementary Materials Fig. S1). Of the 494 enrolled participants, 406 completed the study and 369 were included in the FAS. In the FAS, 88 participants (23.8%) were included in the individualized target group and 281 participants (76.2%) were included in the general target group. In the individualized HbA1c target group, the HbA1c targets determined by the investigators were < 6% (2.3% of participants), < 6.5% (20.5%), < 7% (55.7%), < 7.5% (6.8%), < 8% (10.2%), < 8.5% (3.4%), and < 9% (1.1%). The safety analysis set included 488 participants who received at least one dose of Gla-300.

Baseline demographics and clinical characteristics of participants in the FAS and those who did or did not achieve their individualized or general HbA1c target are shown in Table 1 and Supplementary Materials Table S2. Overall, the mean age was 60.2 ± 11.4 years, mean duration of T2DM was 12.2 ± 7.8 years, and 207 participants (56.1%) were male. The mean HbA1c was 9.9 ± 1.6% and mean FPG was 224.3 ± 76.9 mg/dL. In total, 127 participants (34.4%) had one or more diabetes complication, the most common of which were diabetic neuropathy (20.3%, 75/369), diabetic retinopathy (11.4%, 42/369), and diabetic nephropathy (4.3%, 16/369). Most participants (93.5%, 345/369) had at least one comorbidity, which included dyslipidemia, hypertension, arteriosclerosis, chronic gastritis, and chronic kidney disease.

Most of the baseline demographics and clinical characteristics were generally similar between participants who did and did not achieve their HbA1c target in each study group. However, those participants achieving their glycemic target in each study group had a significantly shorter duration of T2DM than those who did not (individualized target group: 9.6 ± 8.0 versus 13.1 ± 8.4 years, P = 0.0454; general target group: 10.2 ± 8.6 versus 12.8 ± 7.4 years, P = 0.0378). Fewer participants in the individualized target group had diabetic complications compared with the general target group (18 versus 109, P = 0.0016).

Before study enrollment, all participants received diabetic medications, including sulfonylureas (25.9%), dipeptidyl peptidase 4 (DPP4) inhibitors (24.6%), metformin (22.2%), and a fixed-dose combination of metformin and a DPP4 inhibitor (10.5%). At the end of study, the most used diabetic medication was metformin (24.0%), followed by DPP4 inhibitors (13.5%), a fixed-dose combination of metformin and a DPP4 inhibitor (13.5%), and sulfonylureas (9.0%). There were no significant differences between the individualized and general target groups (Supplementary Materials Table S3). Most participants (91.1%, 336/369) were also taking concomitant medications before the trial including lipid-lowering agents (73.0%, 269/369) and antithrombotic agents (46.6%, 172/369).

A total of 72 participants (19.5%) achieved their HbA1c target at 24 week; 33 of 88 (37.5%) participants in the individualized target group and 39 of 281 participants (13.9%) in the general target group (HbA1c < 7%), (P < 0.0001; Table 2). Even if the HbA1c target < 7% was applied to both groups, significant differences in the proportions remained: 23 of 88 (26.1%) participants in the individualized target group versus 39 of 281 (13.9%) participants of the general target group (P < 0.0073). The rates of HbA1c target achievement in the individualized target group were as follows: < 6% (50.0%), < 6.5% (38.9%), < 7% (26.5%), < 7.5% (33.3%), < 8% (66.7%), < 8.5% (100%), and < 9% (100%). The mean HbA1c level in the overall study population at week 24 was 8.4% ± 1.6% and the mean change from baseline to week 24 was − 1.5% ± 1.9% (week 24 vs. baseline: P < 0.0001) (Table 2). The proportion of participants who achieved their glycemic target at any time during the study in the individualized target group, general target group, and the overall population was 43.2% (38/88 participants), 17.1% (48/281 participants; P < 0.0001), and 23.3% (86/369 participants), respectively (Fig. 1a). The proportion of participants who achieved their individualized HbA1c target at week 24 without documented symptomatic hypoglycemia during the study was 45.3% (34/75 participants).

a Proportion of participants achieving HbA1c target at any time during the study and b incidence of hypoglycemia at week 24 in the full analysis set (N = 369). Abbreviation: HbA1c glycated hemoglobin

At week 24, the mean FPG level in the overall study population was 157.6 ± 58.7 mg/dL and the mean change from baseline was − 68.7 ± 80.5 mg/dL (P < 0.0001) (Table 2). The mean body weight in the overall population at week 24 was 66.5 ± 10.9 kg and the mean change from baseline to week 24 was 0.9 ± 4.1 kg (P = 0.0016) (Table 2).

The mean Gla-300 dose was 17.5 ± 8.5 U at week 24, a mean increase of 4.1 ± 6.7 U (P < 0.0001), and there was no significant difference between the two groups (Table 2). During the 24-week study period, 84.3% of participants persisted with Gla-300 treatment. The mean duration of treatment with Gla-300 was 159.4 ± 68.2 days. The mean daily and total Gla-300 dose was 16.2 ± 7.1 U and 2613.1 ± 2044.5 U per participant, respectively.

TEAEs in the safety analysis set (N = 488) are shown in Table 3. In total, 132 participants (27.1%; 95% CI 23.1, 31.0) reported 210 TEAEs, the majority of which were mild (157 events) or moderate (46 events) and only seven events were severe. A causal relationship with Gla-300 was defined as certain for two events, probable/likely for one event, possible for 11 events, not likely/unlikely for 190 events, and not assessable/classifiable for six events. The most common TEAEs were hyperglycemia (2.0%, n = 10; 10 events), diarrhea (1.8%, n = 9; 10 events), dizziness (1.6%, n = 8; eight events), and nasopharyngitis (1.4%, n = 7; eight events). 38 participants (7.8%; 95% CI 5.41, 10.16; 39 events) reported serious TEAEs. The most common serious TEAE was uncontrolled hyperglycemia.

TEAEs leading to the temporary interruption of Gla-300 occurred in four participants (0.8%; 95% CI 0.22, 2.09; four events): hospitalization for hyperglycemia in two participants (0.4%; two events), and abdominal discomfort and renal cell carcinoma each in one participant (0.2%; one event). TEAEs leading to the permanent discontinuation of Gla-300 occurred in 15 participants (3.1%; 95% CI 1.54, 4.61; 16 events). The most common TEAEs leading to permanent discontinuation of Gla-300 were hospitalization for hyperglycemia in three participants (0.6%; three events), and edema in two participants (0.4%, two events). Three deaths occurred during the study, one due to hepatocellular carcinoma, one due to malignant neoplasm of the ampulla of Vater, and one with no recorded cause.

The incidence and event rate of documented symptomatic 24-h hypoglycemia was 9.0% (n = 44, 63 events) and 0.30 events per participant-year, respectively, in the overall population. The rate of severe documented hypoglycemia was 0.2% (n = 1, one event). The incidence and event rate of nocturnal hypoglycemia was 1.0% (n = 5, seven events) and 0.03 events per participant-year, respectively. There were no cases of severe nocturnal hypoglycemia. In the FAS, the incidence of hypoglycemia was 14.8% (13/88 participants), 8.9% (25/281 participants), and 10.3% (38/369 participants) in the individualized target group, general target group, and overall population, respectively (Fig. 1b).

In participants aged ≥ 65 years, the mean HbA1c at baseline was 9.7% ± 1.5%, the mean change at week 24 was − 1.4 ± 1.8% (P < 0.0001), and the proportion of participants achieving an individualized or general HbA1c target at week 24 was 18.8% (26/138) (Table 4). In participants aged < 65 years, the mean HbA1c at baseline was 10.0% ± 1.7%, the mean change at week 24 was − 1.6 ± 2.0% (P < 0.0001), and the proportion of participants achieving their HbA1c target at week 24 was 19.9% (46/231). The incidence of hypoglycemia was 6.5% (n = 9) in participants aged ≥ 65 years and 12.6% (n = 29) in those aged < 65 years (P = 0.0651).