Reassignment of insulin pre-treated participants with T2D from the EDITION 2 and EDITION 1 trials revealed subphenotypes MOD (70–78%), SIDD (9–13%), MARD (8–13%), and SIRD (0.1–0.6%), with similar distributions in the IGlar-300 and IGlar-100 treatment groups (Fig. S1). Distributions of age at diagnosis, BMI, HbA1c, and FCP at baseline for each subphenotype from the EDITION trials are illustrated in Fig. 1 and baseline characteristics and demographics for the SIDD, MARD, MOD, and SIRD subphenotypes are summarized in Table 1. More insulin pre-treated people were assigned to MOD and fewer to the SIDD and MARD subphenotypes compared to insulin-naïve participants in the T2D EDITION 3 trial. Median age at onset of diabetes was highest in MARD (58 years) and SIRD (58–67 years), with SIDD, MARD, and MOD subphenotypes pre-treated with insulin having a longer median diabetes duration of up to 16 years compared to insulin-naïve subphenotypes (8–10 years) (Table 1, Fig. S2). As expected, MOD subphenotypes across trials had the highest mean BMI (37–38 kg/m2) and insulin pre-treated SIDD subphenotypes had the highest proportion (73–75%) of individuals with FCP levels ≤ 0.4 nmol/L. Mean HbA1c levels at baseline were consistently lower in insulin pre-treated MARD (7.7–7.8%; 61–62 mmol/mol), MOD (8.1–8.4%; 65–68 mmol/mol), and SIDD subphenotypes (8.9–9.1%; 74–76 mmol/mol) than in corresponding insulin-naïve subphenotypes (Table 1, Fig. S2).

Fig. 1

Baseline cluster variables for pooled glargine treatment groups from EDITION T2D trials according to SIDD, MARD, MOD, and SIRD subphenotypes. ED 3 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), BI basal insulin, BB basal-bolus, FCP, fasting C-peptide; boxes represent median with 25th and 75th percentiles, whiskers indicate minimum and maximum ranges; n.a., not analyzed (only 1 patient)

Table 1 Demographics and characteristics of pooled glargine treatment groups from EDITION T2D trials according to SIDD, MARD, MOD, and SIRD subphenotypesGlycemic Responses to Glargine Regimens in SIDD, MARD, and MOD SubphenotypesHbA1c

Because of the very small number of participants (n = 32) assigned to the SIRD subphenotype across the trials, all treatment outcomes for these few participants are presented in the supplementary material only. The observed mean HbA1c for pooled glargine groups (IGlar-300 and IGlar-100) at baseline, 12 and 26 weeks and the change from baseline to 26 weeks as stratified by MARD, MOD, and SIDD subphenotypes are included in Fig. 2 (left panel) and summarized in Table S3. Despite the greatest mean HbA1c reduction from baseline to 26 weeks being observed in the pre-BI and pre-BB SIDD subphenotypes (− 1.2%, − 13 mmol/mol) compared to pre-BI and pre-BB MOD (− 0.7% to − 0.9%; − 8 to − 10 mmol/mol) and MARD (− 0.6% to − 0.7%; − 7 to − 8 mmol/mol), HbA1c levels remained unsatisfactory at 7.7–8.0% (61–63 mmol/mol) at the end of treatment in the pre-BI and pre-BB SIDD subphenotypes. Only 19–22% of individuals with SIDD achieved a target HbA1c < 7.0% (< 53 mmol/mol) at 26 weeks compared to 33–51% in the pre-BI and pre-BB MARD and MOD subphenotypes. In the pre-OAD MARD and MOD subphenotypes 56–62% reached the glycemic goal (Fig. 3). Compared to insulin-naïve (pre-OAD) T2D subphenotypes each insulin-pre-treated T2D subphenotype, when started at lower baseline levels, exhibited a smaller HbA1c reduction.

Fig. 2

Observed mean HbA1c (left panel) and FPG (right panel) over 26 weeks and change from baseline to week 26 in pooled glargine treatment groups from EDITION T2D trials according to SIDD, MARD, and MO subphenotypes. ED 3 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), OAD oral antihyperglycemic drug, BI basal insulin, BB basal-bolus

Fig. 3

Achievements of HbA1c and FPG targets at 26 weeks in pooled glargine treatment groups from EDITION T2D trials according to SIDD, MARD, and MOD subphenotypes. ED 3 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), OAD oral antihyperglycemic drug, BI basal insulin, BB basal-bolus

FPG and Eight-Point SMPG Profiles

Mean reductions in FPG from baseline to 26 weeks in the pre-BI and pre-BB subphenotypes ranged from − 24 to − 41 mg/dL (− 1.3 to − 2.3 mmol/L) in SIDD, from − 22 to − 28 mg/dL (− 1.2 to − 1.6 mmol/L) in MOD, and − 8 to − 13 mg/dL (– 0.4 to − 0.7 mmol/L) in MARD, respectively (Fig. 2 right panel, Table S4). The proportion of participants who achieved a FPG < 100 mg/dL (< 5.6 mmol/L) did not differ considerably between subphenotypes except for pre-BB MARD and MOD subphenotypes, in which the lowest proportions were observed (Fig. 3). With any of the glargine regimens (BI alone at ≥ 42 U/day with or without pre-prandial insulin) the MARD subphenotype attained the lowest FPG levels at 26 weeks (Table S4).

Eight-point SMPG profiles at baseline and 26 weeks according to differently pre-treated SIDD, MARD, and MOD subphenotypes showed that all pre-BB treated subphenotypes achieved flatter SMPG profiles with better post-prandial glycemic control at 26 weeks compared to pre-BI and pre-OAD treated subphenotypes (Fig. S3). Mean post-prandial reductions at breakfast, lunch, and dinner ranged similarly from − 20 to − 33 mg/dL (− 1.1 to − 1.8 mmol/L) in pre-BB SIDD, − 14 to − 32 mg/dL (− 0.8 to − 1.8 mmol/L) in pre-BB MARD, and − 20 to − 39 mg/dL (− 1.1 to − 2.2 mmol/L) in pre-BB MOD (Fig. 4, Table S5). The greatest post-prandial glucose reductions were observed in the pre-OAD treated SIDD (− 60 to − 92 mg/dL; − 3.3 to − 5.1 mmol/L) and pre-OAD treated MOD (− 40 to − 70 mg/dL; − 2.2 to − 3.9 mmol/L) subphenotypes. Lesser effects on SMPG reductions were observed across the differently pre-treated MARD subphenotypes. Notably, the SIDD subphenotypes remained at higher post-prandial glucose levels, not only in pre-OAD and pre-BI glargine regimens but also in the pre-BB glargine regimen when compared to MARD and MOD subphenotypes (Fig. 4).

Fig. 4

Change of post-prandial glucose from baseline to 26 weeks in pooled glargine treatment groups according to SIDD, MARD, and MOD subphenotypes from the EDITION T2D trials. Mean glucose values are derived from self-monitored glucose measurements; bars represent mean glucose change from baseline to week 26; ED 3 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), OAD oral antihyperglycemic drug, BI basal insulin, BB basal-bolus

Insulin Glargine 300 U/mL and 100 U/mL Dose in MARD, MOD, and SIDD Subphenotypes

The observed mean daily doses per body weight of IGlar-300 and IGlar-100 from study entry over 26 weeks are shown in Fig. 5 and summarized in Table S6. According to the study protocols the glargine starting doses differed considerably between pre-BI and pre-BB treated SIDD, MARD, and MOD subphenotypes (0.62–0.71 U/kg/day) and pre-OAD treated subphenotypes (0.19–0.20 U/kg/day). Subsequently, the mean insulin doses at 26 weeks reached 0.71–1.03 U/kg/day in insulin pre-treated and only 0.41–0.72 U/kg/day in insulin-naïve SIDD, MARD, and MOD subphenotypes. The lowest glargine dose increments of 0.24–0.34, 0.16–0.22, and 0.17–0.27 U/kg/day were recorded in pre-OAD, pre-BI, and pre-BB treated MARD subphenotypes at week 26, respectively. Except for the pre-BB treated SIDD subphenotypes, the final daily basal insulin dose was consistently higher for IGlar-300 than IGlar-100 at 26 weeks in all other subphenotypes, with the greatest differences in dose being observed in the leaner SIDD and MARD subphenotypes at 0.11 and 0.14 U/kg, respectively (Fig. 5, Table S6). In all pre-BB treated subphenotypes the average daily pre-prandial insulin dose was similar and remained stable at about 0.50 U/kg/day from baseline to week 26 (data not shown).

Fig. 5

Mean IGlar-300 and IGlar-100 dose over 26 weeks according to SIDD, MARD, and MOD subphenotypes from EDITION T2D trials. ED 3 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), OAD oral antihyperglycemic drug, BI basal insulin, BB basal-bolus

Hypoglycemia with Glargine Regimens in MARD, MOD, and SIDD Subphenotypes

The cumulative incidences and event rates of level 1 and level 2 hypoglycemia at any time (during 24-h) and of nocturnal hypoglycemia for pooled glargine treatment groups were consistently higher in pre-BI and pre-BB treated subphenotypes than in pre-OAD treated subphenotypes over 26 weeks (Fig. S4). The proportion of participants experiencing at least one episode of non-severe hypoglycemia ranged from 72% to 87% (level 1 at any time of day), 30–47% (level 2 at any time of day), 32–51% (level 1 and nocturnal), and 11–17% (level 2 and nocturnal) in pre-BI and pre-BB treated subphenotypes. The incidence of level 3 (severe) hypoglycemia was very low (0 to 3%) across most subphenotypes, except for pre-BB MARD and pre-BB MOD subphenotypes in which a slightly higher incidence (6%) was observed (Fig. S4).

Cumulative hypoglycemia incidences analyzed separately by IGlar-300 and IGlar-100 treatment regimens and subphenotypes are shown in Fig. 6. A general trend of a numerically lower risk was observed in the SIDD and MOD subphenotypes with IGlar-300 for most of the hypoglycemia categories, particularly level 1. Incidences were markedly lower for level 1 (any time) hypoglycemia in pre-BB SIDD by 46% (OR 0.54, 95% CI 0.34–0.85) and pre-BI MOD by 34% (OR 0.66, 95% CI 0.45–0.98). Similarly, for nocturnal hypoglycemia level 1 incidence was lower in pre-OAD SIDD by 51% (OR 0.49, 95% CI 0.24–0.99), pre-OAD MOD by 41% (OR 0.59, 95% CI 0.36–0.97), pre-BI MOD by 48% (OR 0.52, 95% CI 0.36–0.76), and pre-BB MOD by 36% (OR 0.64, 95% CI 0.46–0.89). Level 2 (any time) hypoglycemia was markedly lower in pre-OAD SIDD by 69% (OR 0.31, 95% CI 0.13–0.77) and pre-BI MOD by 36% (OR 0.54, 95% CI 0.34–0.85) with IGlar-300.

Fig. 6

Comparison of cumulative hypoglycemia incidences at 26 weeks between IGlar-300 and IGlar-100 treatment groups according to SIDD, MARD, and MOD subphenotypes from the EDITION T2D trials. ED 1 EDITION 3 (pre-OAD), ED 2 EDITION 2 (pre-BI ≥ 42 U/day), ED 1 EDITION 1 (pre-BB of BI ≥ 42 U/day plus thrice-daily pre-prandial insulin), OAD oral antihyperglycemic drug, BI basal insulin, BB basal-bolus, OR odds ratio, CI confidence interval, n.a. not applicable

Body Weight Change with Glargine Regimens in MARD, MOD, and SIDD Subphenotypes

Mean body weight at baseline and 26 weeks was consistently higher in pre-BI and pre-BB treated SIDD and MARD subphenotypes compared to corresponding pre-OAD subphenotypes (Table S7). Mean body weight increased in all T2D subphenotypes by 26 weeks and the effect of glargine regimens on body weight was greatest in the leaner SIDD subphenotypes (+ 1.2 to + 1.9 kg).