Abstract
Aims
To evaluate the glycaemic outcomes and safety of insulin glargine 300 U/mL (Gla‐300) in Chinese people with uncontrolled type 2 diabetes (T2D) by baseline age and disease duration.
Materials and Methods
INITIATION was a 24‐week, interventional, single‐arm study where adults with T2D (glycated haemoglobin [HbA1c] 7.5%–11.0%) received Gla‐300. This post‐hoc subgroup analysis assessed HbA1c change from baseline to week 24 (primary endpoint), other glycaemic endpoints, insulin dose, hypoglycaemia, body weight change, and treatment satisfaction (using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]) by baseline age (<60 or ≥ 60 years) and disease duration (<5, ≥5 to <10 or ≥10 years in insulin‐naïve participants, and <10, 10 to <15 or ≥15 years in those with prior basal insulin [BI]).
Results
Of 568 participants, 191 were insulin‐naïve and 377 had received prior BI. Over 24 weeks, Gla‐300 improved HbA1c in all age and disease duration subgroups. The least squares mean HbA1c change ranged from −1.02% (−11.1 mmol/mol) to −1.55% (−16.9 mmol/mol) in insulin‐naïve participants and from −0.55% (−6.0 mmol/mol) to −0.76% (−8.3 mmol/mol) in prior BI participants. HbA1c <7.0% (<53 mmol/mol) achievement (ranging from 19.5% to 40.7%), other glycaemic endpoints, insulin dose increases, body weight changes and DTSQ score improvements did not significantly differ across the majority of subgroups, and the hypoglycaemia risk remained low.
Conclusions
Gla‐300 improved glycaemic control with a low risk of hypoglycaemia in Chinese people with T2D across all ages and disease durations, including older individuals and those with long‐standing diabetes.
Keywords: basal insulin, insulin glargine, phase IV study, type 2 diabetes
1. INTRODUCTION
China has the largest population of adults (aged 20–79 years) with diabetes in the world, with an estimated 148 million cases in 2024 and over 168 million expected to have diabetes by 2050. 1 The most common disease type is type 2 diabetes (T2D), which accounts for >90% of all cases. 1
According to the Seventh National Population Census, an estimated 264 million people in China (18.7% of total population) were aged ≥60 years in 2020. 2 In China, the prevalence of diabetes increases with age, as shown by a national, cross‐sectional study conducted in mainland China, which reported the weighted prevalence of diabetes was 28.8% in adults aged 60–69 years and 31.8% in those aged ≥70 years in 2017 (i.e., ~30% of all individuals aged ≥60 years). 3 Therefore, an estimated 79 million people aged ≥60 years are affected by diabetes in China, with >90% of them (i.e., >71 million people) having T2D.
People with T2D often require insulin therapy to achieve glycated haemoglobin (HbA1c) goals due to the progressive nature of the disease, with basal insulin (BI) being the preferred first‐line treatment option. 4 Effective management of older people with T2D may be associated with challenges caused by age‐related factors and their psychological and clinical condition. 5 Second‐generation BI analogues may be particularly beneficial in this setting due to their long duration of action and lower risk of hypoglycaemia compared with first‐generation BIs. 5 The need to initiate injectable antidiabetic medications, such as BI analogues, to achieve optimal glycaemic control increases among individuals with long‐standing T2D. 6 Furthermore, individuals with a prolonged duration of T2D are known to have an increased risk for macrovascular and microvascular complications, as well as stroke, dementia, and mortality. 7 , 8 , 9
Insulin glargine 300 U/mL (Gla‐300) is a second‐generation, ultralong‐acting BI analogue. In the global EDITION randomised controlled trial (RCT) programme, Gla‐300 demonstrated comparable glycaemic efficacy and reduced hypoglycaemia risk versus insulin glargine 100 U/mL (Gla‐100). 10 , 11 , 12 , 13 , 14 , 15 The efficacy and safety of Gla‐300 have also been confirmed in Chinese people with suboptimally controlled T2D in close to real‐life conditions in the INITIATION study, including insulin‐naïve individuals and those switching from other BI therapy. 16 However, there is a lack of data on the efficacy and safety of Gla‐300 in older individuals and those with long‐standing T2D disease in China.
The aim of this post‐hoc analysis of the INITIATION study was to evaluate the effect of baseline age and T2D disease duration on the efficacy and safety of Gla‐300 in people with suboptimally controlled T2D in China.
2. METHODS
2.1. Study design and participants
The design of the phase IV INITIATION study (ClinicalTrials.gov identifier: NCT05002933) has been previously described. 16 Briefly, this prospective, interventional, single‐arm study was conducted at 30 clinical sites in mainland China. The study enrolled adults (aged ≥18 years) with suboptimally controlled T2D (HbA1c 7.5%–11.0% [58–97 mmol/mol]), including insulin‐naïve individuals receiving one or two oral antidiabetic drugs (OADs) and those previously receiving other BI treatment. All participants received once‐daily Gla‐300, self‐administered by subcutaneous injection in the evening, for 24 weeks.
The study was conducted according to the ethical principles of the Declaration of Helsinki and the International Conference on Harmonisation guidelines for good clinical practice. The study protocol was approved by the relevant independent ethics committees and/or institutional review boards for each study centre. All participants provided informed consent prior to study entry.
2.2. Subgroup analyses
In this analysis, patients were stratified by baseline treatment status (insulin‐naïve and prior BI use), and then outcomes were assessed in participant subgroups defined by baseline age (<60 or ≥60 years) and T2D disease duration (<5, ≥5 to <10 or ≥10 years in insulin‐naïve participants, and <10, ≥10 to <15 or ≥15 years in those with prior BI). Outcomes analysed in these subgroups were: the change in HbA1c from baseline to week 24 (primary); the proportion of participants who achieved an HbA1c <7.0% (<53 mmol/mol) at week 24; the change from baseline to week 24 in fasting plasma glucose (FPG), average 7‐point self‐monitored blood glucose (SMBG), daily insulin dose and body weight; the incidence and event rates of any hypoglycaemia, severe hypoglycaemia, confirmed hypoglycaemia with blood glucose (BG) ≤3.9 or <3.0 mmol/L (with or without symptoms), and documented symptomatic hypoglycaemia with BG ≤3.9 or <3.0 mmol/L; and the change from baseline to week 24 in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total score and item 2 (perception of hyperglycaemia) and item 3 (perception of hypoglycaemia) scores. 17
Severe hypoglycaemia was defined as any symptomatic hypoglycaemia event that required assistance from another person to administer carbohydrate, glucagon or other resuscitative measures.
2.3. Statistical analyses
Due to the exploratory nature of this post‐hoc analysis, no formal sample size calculations were conducted. Sample size calculations for the primary INITIATION study analysis have been described previously. 16
Data were summarised using descriptive statistics, with means and standard deviations (SD) presented for continuous variables and the numbers and proportions of participants for binary variables. Glycaemic efficacy endpoints and change in insulin dose were evaluated in the modified intention‐to‐treat population, defined as all enrolled participants who received at least one dose of Gla‐300 and had at least one post‐baseline efficacy assessment. Hypoglycaemia, body weight, and DTSQ endpoints were evaluated in the safety population, defined as all study participants who received at least one dose of Gla‐300.
The primary efficacy endpoint was evaluated using a last observation carried forward (LOCF) approach. For endpoints with continuous variables, a general linear model was used to estimate least squares mean (LSM) change from baseline for each subgroup, its accompanying standard error (SE), and the LSM difference between subgroups and corresponding 95% confidence intervals (CI) and p‐values. Endpoints with binary variables were presented using descriptive statistics, with odds ratios (OR) and corresponding 95% CIs and p‐values estimated by logistic regression. The hypoglycaemia event rate was defined as numbers of events per participant‐year (PY), and its rate ratio (RR) and corresponding 95% CI and p‐value were estimated by negative binomial regression. All estimates were adjusted for baseline disease duration (in the age subgroups) or age (in the disease duration subgroups), as well as baseline HbA1c, FPG, and body mass index (BMI). Sensitivity analyses were also conducted on the primary endpoint, with the age subgroups adjusted for all confounders listed above except for disease duration, and the disease duration subgroups adjusted for all confounders except for age. All p‐values were calculated without adjustment for multiplicity and were considered nominal.
Statistical analyses were conducted using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA).
3. RESULTS
3.1. Study population
In total, 568 participants were enrolled (insulin naïve, n = 191; prior BI, n = 377); the baseline characteristics of the overall study population have been published previously. 16
In the insulin‐naïve group, 63 participants (33.0%) were aged ≥60 years at baseline and 128 (67.0%) were aged <60 years, and in the prior BI group, 154 (40.8%) and 223 (59.2%) participants were in the respective age subgroups (Table 1). Participants aged ≥60 years had a longer disease duration and a higher prevalence of cardiovascular disease at baseline than those aged <60 years.
TABLE 1.
Participant baseline characteristics in the enrolled population by baseline age and prior insulin status.
| Insulin naïve (n = 191) | Prior BI (n = 377) | |||
|---|---|---|---|---|
| <60 years (n = 128) | ≥60 years (n = 63) | <60 years (n = 223) | ≥60 years (n = 154) | |
| Age, mean ± SD, years | 49.2 ± 7.9 | 65.6 ± 4.1 | 50.0 ± 7.8 | 67.1 ± 4.4 |
| Male sex, n (%) | 79 (61.7) | 36 (57.1) | 142 (63.7) | 71 (46.1) |
| T2D duration, mean ± SD, years | 6.9 ± 4.9 | 10.0 ± 5.9 | 9.4 ± 6.0 | 13.0 ± 7.3 |
| Category, n (%) | n = 125 | n = 59 | n = 220 | n = 149 |
| <10 years | 92 (73.6) | 31 (52.5) | 125 (56.8) | 52 (34.9) |
| ≥10 years | 33 (26.4) | 28 (47.5) | 95 (43.2) | 97 (65.1) |
| Microvascular complications, n (%) | ||||
| Retinopathy | 10 (7.8) | 4 (6.3) | 33 (14.8) | 17 (11.0) |
| Neuropathy | 20 (15.6) | 12 (19.0) | 104 (46.6) | 68 (44.2) |
| Nephropathy | 14 (10.9) | 6 (9.5) | 71 (31.8) | 34 (22.1) |
| CVD history, n (%) | 63 (49.2) | 40 (63.5) | 131 (58.7) | 122 (79.2) |
| BMI, mean ± SD, kg/m2 | 26.2 ± 3.6 | 25.3 ± 3.5 | 25.9 ± 3.2 | 24.9 ± 2.9 |
| HbA1c, mean ± SD, % [mmol/mol] |
8.89 ± 1.04 [74.0 ± 11.4] |
8.79 ± 0.99 [73.0 ± 10.8] |
8.30 ± 1.25 [67.0 ± 13.7] |
8.30 ± 1.17 [67.0 ± 12.8] |
| FPG, mean ± SD, mmol/L | 10.38 ± 2.68 | 10.16 ± 2.55 | 8.86 ± 2.76 | 8.32 ± 2.19 |
| Fasting SMBG, mean ± SD, mmol/L | 9.55 ± 2.70 | 9.52 ± 2.28 | 8.26 ± 2.55 | 7.54 ± 2.05 |
| Prior antidiabetic therapy, a n (%) | ||||
| OAD b | ||||
| α‐glucosidase inhibitor | 26 (20.3) | 23 (36.5) | 105 (47.1) | 85 (55.2) |
| Biguanide | 96 (75.0) | 46 (73.0) | 128 (57.4) | 81 (52.6) |
| Thiazolidinedione | 1 (0.8) | 1 (1.6) | 10 (4.5) | 7 (4.5) |
| DPP4 inhibitor | 11 (8.6) | 11 (17.5) | 43 (19.3) | 27 (17.5) |
| Glinide | 8 (6.3) | 3 (4.8) | 7 (3.1) | 21 (13.6) |
| SGLT2 inhibitor | 14 (10.9) | 8 (12.7) | 67 (30.0) | 36 (23.4) |
| Sulfonylureas | 40 (31.3) | 21 (33.3) | 20 (9.0) | 22 (14.3) |
| Combination of OADs | 2 (1.6) | 0 | 12 (5.4) | 6 (3.9) |
| TCM (herbal) c | 0 | 1 (1.6) | 0 | 2 (1.3) |
Abbreviations: BI, basal insulin; BMI, body mass index; CVD, cardiovascular disease; DPP4, dipeptidyl peptidase 4; FPG, fasting plasma glucose; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; HbA1c, glycated haemoglobin; OAD, oral antidiabetic drug; SD, standard deviation; SGLT2, sodium‐glucose cotransporter 2; SMBG, self‐monitoring blood glucose; T2D, type 2 diabetes; TCM, traditional Chinese medicine.
Individuals receiving prior GLP‐1 RA therapy were excluded from the study.
Participants may have received >1 OAD.
Tianqi hypoglycaemic capsules in 1 participant (insulin naïve group) and white mulberry root‐bark extract in 2 participants (prior BI group).
Among 553 participants with available disease duration data, in the insulin‐naïve group (n = 184), the T2D disease duration at baseline was <5 years in 60 participants (32.6%), ≥5 to <10 years in 63 (34.2%) and ≥10 years in 61 (33.2%; Table 2). In the prior BI group (n = 369), the baseline disease duration was <10 years in 177 participants (48.0%), ≥10 to <15 years in 92 (24.9%) and ≥15 years in 100 (27.1%). Participants in the longest disease duration subgroups (i.e., ≥10 years in the insulin‐naïve group or ≥15 years in the prior BI group) were older and had a higher prevalence of retinopathy and cardiovascular disease than those in the shorter disease duration subgroups.
TABLE 2.
Participant baseline characteristics in the enrolled population by baseline disease duration and prior insulin status.
| Insulin naïve (n = 184) | Prior BI (n = 369) | |||||
|---|---|---|---|---|---|---|
| <5 years (n = 60) | ≥5 to < 10 years (n = 63) | ≥10 years (n = 61) | <10 years (n = 177) | ≥10 to < 15 years (n = 92) | ≥15 years (n = 100) | |
| Age, mean ± SD, years | 52.1 ± 10.1 | 53.3 ± 11.1 | 58.2 ± 9.1 | 53.7 ± 11.4 | 57.4 ± 9.9 | 62.0 ± 8.1 |
| Male sex, n (%) | 34 (56.7) | 36 (57.1) | 40 (65.6) | 106 (59.9) | 52 (56.5) | 51 (51.0) |
| T2D duration, mean ± SD, years | 2.7 ± 1.4 | 6.9 ± 1.2 | 14.1 ± 4.4 | 5.2 ± 2.7 | 11.9 ± 1.5 | 19.9 ± 4.0 |
| Microvascular complications, n (%) | ||||||
| Retinopathy | 3 (5.0) | 1 (1.6) | 10 (16.4) | 18 (10.2) | 10 (10.9) | 18 (18.0) |
| Neuropathy | 8 (13.3) | 9 (14.3) | 13 (21.3) | 72 (40.7) | 50 (54.3) | 46 (46.0) |
| Nephropathy | 4 (6.7) | 7 (11.1) | 8 (13.1) | 47 (26.6) | 29 (31.5) | 24 (24.0) |
| CVD history, n (%) | 32 (53.3) | 31 (49.2) | 35 (57.4) | 102 (57.6) | 66 (71.7) | 78 (78.0) |
| BMI, mean ± SD, kg/m2 | 26.05 ± 3.76 | 25.93 ± 2.68 | 25.72 ± 4.22 | 25.77 ± 3.33 | 25.49 ± 2.71 | 25.06 ± 3.16 |
| HbA1c, mean ± SD, % [mmol/mol] |
8.76 ± 0.97 [72.0 ± 10.6] |
8.75 ± 1.08 [72.0 ± 11.8] |
9.00 ± 1.03 [75.0 ± 11.3] |
8.26 ± 1.27 [67.0 ± 13.9] |
8.21 ± 1.12 [66.0 ± 12.2] |
8.50 ± 1.18 [69.0 ± 12.9] |
| FPG, mean ± SD, mmol/L | 9.84 ± 2.25 | 10.07 ± 2.22 | 10.86 ± 3.15 | 8.76 ± 2.55 | 8.66 ± 2.35 | 8.51 ± 2.81 |
| Fasting SMBG, mean ± SD, mmol/L | 8.99 ± 2.02 | 9.68 ± 2.64 | 9.76 ± 2.73 | 8.11 ± 2.37 | 7.91 ± 2.15 | 7.81 ± 2.65 |
| Prior antidiabetic therapy, a n (%) | ||||||
| OAD b | ||||||
| α‐glucosidase inhibitor | 16 (26.7) | 16 (25.4) | 17 (27.9) | 88 (49.7) | 49 (53.3) | 52 (52.0) |
| Biguanide | 41 (68.3) | 48 (76.2) | 48 (78.7) | 95 (53.7) | 51 (55.4) | 62 (62.0) |
| Thiazolidinedione | 1 (1.7) | 1 (1.6) | 0 | 6 (3.4) | 4 (4.3) | 7 (7.0) |
| DPP4 inhibitor | 8 (13.3) | 7 (11.1) | 6 (9.8) | 39 (22.0) | 15 (16.3) | 16 (16.0) |
| Glinide | 2 (3.3) | 1 (1.6) | 7 (11.5) | 12 (6.8) | 7 (7.6) | 9 (9.0) |
| SGLT2 inhibitor | 5 (8.3) | 8 (12.7) | 8 (13.1) | 48 (27.1) | 25 (27.2) | 27 (27.0) |
| Sulfonylureas | 16 (26.7) | 17 (27.0) | 27 (44.3) | 21 (11.9) | 12 (13) | 9 (9.0) |
| Combination of OADs | 0 | 0 | 2 (3.3) | 5 (2.8) | 4 (4.3) | 7 (7.0) |
| TCM medicine (herbal) c | 1 (1.7) | 0 | 0 | 0 | 0 | 2 (2.0) |
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DPP4, dipeptidyl peptidase 4; FPG, fasting plasma glucose; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; HbA1c, glycated haemoglobin; OAD, oral antidiabetic drug; SD, standard deviation; SGLT2, sodium‐glucose cotransporter 2; SMBG, self‐monitoring blood glucose; T2D, type 2 diabetes; TCM, traditional Chinese medicine.
Individuals receiving prior GLP‐1 RA therapy were excluded from the study.
Participants may have received >1 OAD.
Tianqi hypoglycaemic capsules in 1 participant (insulin naïve group) and white mulberry root‐bark extract in 2 participants (prior BI group).
3.2. Glycaemic endpoints
At week 24 (LOCF), Gla‐300 was associated with marked reductions in HbA1c from baseline in the insulin‐naïve and prior BI groups, regardless of baseline age (Figure 1A) or disease duration (Figure 1B).
FIGURE 1.
Change in HbA1c from baseline to week 24 in the mITT population by prior insulin status and (A) baseline age or (B) baseline disease duration. †Estimated by a general linear model, adjusted for disease duration, baseline HbA1c, FPG and BMI. BI, basal insulin; BMI, body mass index; CI, confidence interval; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; LSM, least squares mean; mITT, modified intention‐to‐treat.
In subgroups defined by baseline age, significant HbA1c reductions were observed in participants aged <60 or ≥60 years in both the insulin‐naïve and prior BI groups (Figure 1A). The LSM change in HbA1c from baseline to week 24 was −1.32% (−14.4 mmol/mol) and −1.40% (−15.3 mmol/mol) in insulin‐naïve participants aged <60 and ≥60 years, respectively, and −0.69% (−7.5 mmol/mol) in both age subgroups in the prior BI group. The LSM difference between age subgroups for HbA1c change was −0.09% (−1.0 mmol/mol) in the insulin‐naïve group and −0.01% (−0.1 mmol/mol) in the prior BI group. Findings from the sensitivity analysis were in line with these results (data not shown).
HbA1c reductions from baseline to week 24 were also significant across subgroups defined by baseline disease duration (Figure 1B). The LSM change in HbA1c from baseline to week 24 ranged from −1.02% (−11.1 mmol/mol) in the ≥10 years subgroup to −1.55% (−16.9 mmol/mol) in the ≥5 to <10 years subgroup in the insulin‐naïve group and from −0.55% (−6.0 mmol/mol) in the ≥10 to <15 years subgroup to −0.76% (−8.3 mmol/mol) in the <10 years subgroup in the prior BI group. One exception was among insulin‐naïve participants, where HbA1c reductions were smaller in the ≥10 versus <5 years' disease duration subgroup (LSM difference 0.40% [4.4 mmol/mol]; p = 0.030). Sensitivity analysis HbA1c results were in line with the findings of the main analysis (data not shown), with the exception of the comparison between the ≥10 to <15 years and <10 years disease duration subgroups in the prior BI group, where the LSM difference reached statistical significance (0.22; 95% CI 0.01, 0.43; p = 0.038).
The proportion of participants who achieved HbA1c <7.0% (<53 mmol/mol) at week 24 ranged from 22.5% to 30.8% and from 19.5% to 40.7% across the subgroups defined by baseline age (Table 3) and disease duration (Table 4), respectively. Reductions from baseline in FPG and average 7‐point SMBG at week 24 were generally similar across all age and disease duration subgroups in insulin‐naïve participants and in most subgroups among participants in the prior BI group. However, exceptions to this were observed in the prior BI group, where FPG reductions were greater in participants aged ≥60 versus <60 years (LSM difference −0.55 mmol/L; p = 0.041), and the average 7‐point SMBG reductions were smaller in patients with ≥10 to <15 versus <10 years' disease duration (LSM difference 0.59 mmol/L; p = 0.020).
TABLE 3.
Other glycaemic outcomes with Gla‐300 in the modified intention‐to‐treat population by baseline age and prior insulin status.
| Insulin naïve (n = 185) | Prior BI (n = 369) | |||
|---|---|---|---|---|
| <60 years (n = 124) | ≥60 years (n = 61) | <60 years (n = 216) | ≥60 years (n = 153) | |
| HbA1c <7.0% [<53 mmol/mol] at week 24 | n = 107 | n = 56 | n = 186 | n = 129 |
| n (%) | 33 (30.8) | 17 (30.4) | 52 (28.0) | 29 (22.5) |
| OR (95% CI) a | Ref | 1.05 (0.48, 2.31) | Ref | 0.77 (0.39, 1.50) |
| p‐value a | – | 0.906 | – | 0.444 |
| FPG, mmol/L | ||||
| At week 24 (LOCF), mean ± SD | 7.39 ± 1.58 | 7.55 ± 1.94 | 8.03 ± 2.42 | 7.44 ± 1.88 |
| Change from baseline, LSM ± SE | −2.64 ± 0.17 | −2.56 ± 0.26 | −0.72 ± 0.16 | −1.27 ± 0.21 |
| LSM difference (95% CI) b | Ref | 0.08 (−0.54, 0.70) | Ref | −0.55 (−1.08, −0.02) |
| p‐value b | – | 0.800 | – | 0.041 |
| Average 7‐point SMBG, mmol/L | ||||
| At week 24 (LOCF), mean ± SD | 9.10 ± 1.96 | 9.25 ± 2.07 | 9.45 ± 2.24 | 9.32 ± 2.00 |
| Change from baseline, LSM ± SE | −2.30 ± 0.21 | −2.30 ± 0.31 | −1.05 ± 0.13 | −1.33 ± 0.16 |
| LSM difference (95% CI) b | Ref | 0 (−0.76, 0.75) | Ref | −0.28 (−0.70, 0.14) |
| p‐value b | – | 0.995 | – | 0.191 |
Abbreviations: BI, basal insulin; BMI, body mass index; CI, confidence interval; FPG, fasting plasma glucose; Gla‐300, insulin glargine 300 U/mL; HbA1c, glycated haemoglobin; LOCF, last observation carried forward; LSM, least squares mean; OR, odds ratio; Ref, reference; SD, standard deviation; SE, standard error; SMBG, self‐monitoring blood glucose.
Estimated by logistic regression, adjusted for disease duration, baseline HbA1c, FPG, and BMI.
A general linear model was used to estimate LSM ± SE change from baseline for each subgroup, and the LSM (95% CI) difference and P‐values between subgroups, adjusted for disease duration, baseline HbA1c, FPG, BMI and baseline value corresponding to the endpoint (if not included as a confounder).
TABLE 4.
Other glycaemic outcomes with Gla‐300 in the modified intention‐to‐treat population by baseline disease duration and prior insulin status.
| Insulin naïve (n = 180) | Prior BI (n = 362) | |||||
|---|---|---|---|---|---|---|
| <5 years (n = 60) | ≥5 to < 10 years (n = 62) | ≥10 years (n = 58) | <10 years (n = 172) | ≥10 to < 15 years (n = 90) | ≥15 years (n = 100) | |
| HbA1c <7.0% [<53 mmol/mol] at week 24 | n = 51 | n = 59 | n = 49 | n = 155 | n = 72 | n = 82 |
| n (%) | 15 (29.4) | 24 (40.7) | 11 (22.4) | 47 (30.3) | 17 (23.6) | 16 (19.5) |
| OR (95% CI) a | Ref | 1.63 (0.72, 3.70) | 0.75 (0.28, 2.02) | Ref | 0.54 (0.24, 1.18) | 0.63 (0.28, 1.43) |
| p‐value a | – | 0.245 | 0.573 | – | 0.121 | 0.267 |
| FPG, mmol/L | ||||||
| At week 24, mean ± SD | 7.20 ± 1.60 | 7.40 ± 1.92 | 7.60 ± 1.38 | 7.79 ± 2.50 | 7.79 ± 2.00 | 7.93 ± 1.95 |
| Change from baseline, LSM ± SE | −2.83 ± 0.24 | −2.64 ± 0.22 | −2.35 ± 0.26 | −1.02 ± 0.18 | −0.90 ± 0.27 | −0.76 ± 0.25 |
| LSM difference (95% CI) b | Ref | 0.20 (−0.44, 0.84) | 0.49 (−0.23, 1.20) | Ref | 0.12 (−0.52, 0.75) | 0.25 (−0.36, 0.87) |
| p‐value b | – | 0.542 | 0.181 | – | 0.720 | 0.421 |
| Average 7‐point SMBG, mmol/L | ||||||
| At week 24, mean ± SD | 8.97 ± 1.87 | 8.89 ± 1.90 | 9.65 ± 2.17 | 9.13 ± 2.26 | 9.62 ± 1.82 | 9.69 ± 2.16 |
| Change from baseline, LSM ± SE | −2.49 ± 0.29 | −2.55 ± 0.28 | −1.78 ± 0.32 | −1.41 ± 0.15 | −0.82 ± 0.21 | −1.02 ± 0.20 |
| LSM difference (95% CI) b | Ref | −0.06 (−0.85, 0.72) | 0.71 (−0.16, 1.59) | Ref | 0.59 (0.09, 1.09) | 0.39 (−0.10, 0.89) |
| p‐value b | – | 0.871 | 0.110 | – | 0.020 | 0.121 |
Abbreviations: BI, basal insulin; BMI, body mass index; CI, confidence interval; FPG, fasting plasma glucose; Gla‐300, insulin glargine 300 U/mL; HbA1c, glycated haemoglobin; LSM, least squares mean; OR, odds ratio; Ref, reference; SD, standard deviation; SE, standard error; SMBG, self‐monitoring blood glucose.
Estimated by logistic regression, adjusted for age, baseline HbA1c, FPG, and BMI.
A general linear model was used to estimate LSM ± SE change from baseline for each subgroup, and the LSM (95% CI) difference and p‐values between subgroups, adjusted for age, baseline HbA1c, FPG, BMI and baseline value corresponding to the endpoint (if not included as a confounder).
3.3. Daily insulin dose
The daily insulin dose increased from baseline to week 24 across all subgroups defined by baseline age (Table S1) and disease duration (Table S2). In insulin‐naïve participants aged <60 and ≥60 years, the LSM change in insulin dose at week 24 was 10.08 U (0.13 U/kg) and 9.21 U (0.13 U/kg), respectively. In the prior BI group, the LSM change in insulin dose at week 24 was 9.05 U (0.12 U/kg) and 8.12 U (0.11 U/kg) in the respective age subgroups. Across subgroups defined by baseline disease duration, the LSM change in insulin dose ranged from 8.84 to 11.45 U (0.11 to 0.15 U/kg) in the insulin‐naïve group and 7.71–9.10 U (0.11–0.13 U/kg) in the prior BI group.
3.4. Hypoglycaemia
The incidence and event rates of any hypoglycaemia (i.e., severe hypoglycaemia, confirmed hypoglycaemia with BG ≤3.9 or <3.0 mmol/L or documented symptomatic hypoglycaemia with BG ≤3.9 or <3.0 mmol/L) were generally similar across all subgroups defined by baseline age (36.7%–50.8% [2.87–4.13 per PY]; Table S3) and disease duration (38.3%–48.0% [2.82–4.53 per PY]; Table S4). However, exceptions to this were observed in the disease duration subgroups. The event rate of confirmed hypoglycaemia (BG <3.0 mmol/L) was lower in insulin‐naïve participants with ≥5 to <10 versus <5 years' duration (RR 0.27; p = 0.020). The event rate of documented symptomatic hypoglycaemia (BG ≤3.9 mmol/L) was higher in insulin‐naïve participants with ≥5 to <10 years' (RR 1.78; p = 0.041) or ≥10 years' (RR 2.95; p < 0.001) versus <5 years' duration, and lower in prior BI participants with ≥15 versus <10 years' duration (RR 0.62; p = 0.035). Over the 24‐week study period, severe hypoglycaemia was only reported in three participants aged ≥60 years and two participants with ≥15 years' duration; all cases of severe hypoglycaemia were from the prior BI group.
3.5. Body weight
Gla‐300 was associated with minimal changes in body weight from baseline to week 24 across all subgroups defined by baseline age (Table S5) and disease duration (Table S6). Among participants in the prior BI group with ≥15 years' disease duration, this change in body weight was significantly different from those with <10 years' disease duration (LSM difference −0.97 kg; p = 0.044). Similar changes in body weight were observed in all other subgroups.
3.6. Treatment satisfaction
Treatment satisfaction increased from baseline to week 24, as demonstrated by increases in DTSQ total score and decreases in DTSQ item 2 (perception of hyperglycaemia) and item 3 (perception of hypoglycaemia) scores. Similar increases in DTSQ total score were observed across all subgroups defined by age, with insulin‐naïve participants aged <60 and ≥60 years having LSM increases of 2.30 and 2.36, respectively, and participants in the prior BI group having LSM increases of 2.42 and 2.31 in the respective age subgroups (Table S7). In the prior BI group, the DTSQ item 3 score showed smaller reductions among participants aged ≥60 versus <60 years (LSM difference 0.27; p = 0.042); all other reductions in the DTSQ item 2 and item 3 scores were similar across the age subgroups. The increase in DTSQ score was also similar across all disease duration subgroups, with the LSM increases of 1.94–2.78 in the insulin‐naïve group and 2.25–2.45 in the prior BI group (Table S8). A greater reduction in the DTSQ item 3 score was observed among participants in the prior BI group with ≥15 versus <10 years' disease duration (LSM difference −0.35; p = 0.026); all other reductions in the DTSQ item 2 and item 3 scores were similar across the disease duration subgroups.
4. DISCUSSION
The findings of this post‐hoc analysis of the INITIATION study suggest that Gla‐300 provides improvements in glycaemic control and is well tolerated in people with suboptimally controlled T2D in China, regardless of baseline age and T2D disease duration. In this analysis, Gla‐300 provided clinically meaningful improvements in glycaemic control over 24 weeks' treatment in all study participants, including older individuals (aged ≥60 years) and those with long‐standing disease duration (≥10 or ≥15 years). These results are in line with the findings of previous RCTs and real‐world studies of Gla‐300 in older individuals with T2D, 18 , 19 , 20 , 21 , 22 although it should be noted that the age‐group cutoff for these prior analyses was 65 years, whereas the current analysis used an age‐group cutoff of 60 years as the large majority of individuals with T2D in China are aged ≥60 years, 3 and a 60‐year age threshold is more representative of China's older population. 23 Similar HbA1c reductions with Gla‐300 versus Gla‐100 over 26 weeks (or 6 months) were previously reported among participants with T2D aged ≥65 years in the SENIOR study 19 and in a patient‐level meta‐analyses of pooled data from the global EDITION studies. 20 A subanalysis of the BRIGHT study also reported similar glycaemic efficacy with Gla‐300 versus insulin degludec 100 U/mL over 24 weeks in participants aged <65 and ≥65 years, with Gla‐300 providing greater HbA1c reductions in those aged ≥75 years. 18 In the real‐world DELIVER 3 study, Gla‐300 was associated with similar or better glycaemic efficacy compared with first‐generation BIs (i.e., Gla‐100 or insulin detemir) in older people (aged ≥65 years) with T2D after switching from prior BI therapy. 21 Similarly, a multicentre observational study of individuals with T2D who switched from neutral protamine Hagedorn (NPH) insulin to Gla‐300 reported similar glycaemic efficacy in older (≥65 years) and younger (<65 years) individuals. 22
Among participants with prior BI therapy in this analysis, Gla‐300 provided glycaemic benefits regardless of T2D disease duration. Similarly, a patient‐level meta‐analysis of pooled EDITION data found that Gla‐300 had comparable glycaemic control to that of Gla‐100, regardless of the duration of prior BI therapy. 24 Furthermore, the REALI European study reported that Gla‐300 improved HbA1c reductions over 24 weeks in insulin‐naïve individuals with T2D, regardless of disease duration (<8 or ≥8 years). 25 In contrast, the previous observational study of individuals switching from NPH insulin to Gla‐300 reported greater HbA1c reductions in those with shorter (≤13 years) versus longer (>13 years) disease duration. 22 Taken together, these data suggests that individuals with long‐standing, suboptimally controlled T2D on other BI therapy may benefit from switching to Gla‐300.
In this analysis, insulin‐naïve participants with longer T2D disease duration (≥10 years) had smaller HbA1c reductions than those with shorter disease duration (<5 years), while reductions in FPG and average 7‐point SMBG were similar across disease duration subgroups. This emphasises the importance of early initiation of BI and avoiding clinical inertia in insulin‐naïve individuals with suboptimally controlled T2D. Indeed, evidence from the post‐trial monitoring of the 20‐year United Kingdom Prospective Diabetes Study (UKPDS) 26 and a retrospective cohort study from Japan 27 indicate that early initiation of insulin, in particular second‐generation BIs, may provide long‐term organ protection that helps to preserve β‐cell function and prevent diabetic complications. 28
The incidence and event rates of hypoglycaemia with Gla‐300 in this analysis were low and generally similar regardless of age or T2D disease duration. Of note, severe hypoglycaemia was observed only in the prior BI group among three participants aged ≥60 years and two with ≥15 years' T2D duration (both of whom were aged ≥60 years). In these individuals, the combined impact of advanced age and prolonged disease duration most likely led to impaired β‐cell function (i.e., reduced capacity to rapidly secrete insulin in response to blood glucose fluctuations), thereby causing greater blood glucose variability and an increased risk of severe hypoglycaemia. In contrast with our findings, a study in individuals who switched from NPH insulin to Gla‐300 reported a greater reduction in the incidence of hypoglycaemia among individuals aged ≥65 versus <65 years. 22 This previous observational study in individuals switching from prior NPH insulin also reported a lower hypoglycaemia event rate with Gla‐300 in those with >13 years' disease duration. 22 Consistent with the findings of the current analysis, the previous real‐world REALI study reported low incidence and event rates for symptomatic and severe hypoglycaemia with Gla‐300 in insulin‐naïve individuals, regardless of age (<50, 50–59, 60–69, 70–79 and ≥80 years) 29 or disease duration (<8 or ≥8 years). 25
The pharmacokinetic/pharmacodynamic profile of Gla‐300 is more stable than that of Gla‐100, 30 which may have contributed to the low incidence of hypoglycaemia with Gla‐300 in older individuals. The once‐daily dosing schedule of Gla‐300 may also help to reduce the risk of hypoglycaemia, particularly as simplified insulin regimens are recommended in older individuals with T2D to reduce the risk of hypoglycaemia. 31 Given that China has the largest population of older adults with T2D in the world, 1 and that many of these individuals will require insulin therapy as disease progresses, 4 Gla‐300 may offer clinically relevant benefits to this older population.
In addition to improvements in glycaemic control and low risk of hypoglycaemia, Gla‐300 was associated with improvements in treatment satisfaction, as reflected by DTSQ scores, across all baseline age and disease duration subgroups. Similarly, the previous real‐world TRANSITION2 study in France reported a 20% improvement in DTSQ scores among 136 individuals who switched from prior BI therapy to Gla‐300 (mean age 61.7 years; mean disease duration 14.6 years). 32 The global ATOS PRO study has also reported real‐world improvements in DTSQ scores over 12 months among 3801 insulin‐naïve individuals with T2D who initiated Gla‐300 treatment, with 76% of participants showing meaningful DTSQs improvement (DTSQs total score improvement of ≥4 points) at month 12. 33 Improvements in patient‐reported treatment satisfaction, as measured by the DTSQ, have been associated with enhanced treatment adherence and may lead to improved long‐term glycaemic control. 34 Therefore, improved treatment satisfaction with Gla‐300 may be expected to result in better treatment adherence and consequently glycaemic control in Chinese individuals with T2D.
The main strength of this post‐hoc analysis is that it is the first study to evaluate the glycaemic control and safety of Gla‐300 in older individuals and those with long‐standing T2D in China, including both insulin‐naïve individuals and those switching from prior BI therapy. The limitations of this analysis include those related to the lack of a control group in the primary study and the lack of prespecified subgroup analyses with sufficient statistical power due to small sample sizes, which can limit the generalisability of the results. However, the estimation of LSM differences between subgroups with corresponding 95% CIs allowed for exploratory comparison of treatment outcomes with Gla‐300 between subgroups.
In conclusion, Gla‐300 was associated with sustained glycaemic control across all ages and T2D disease durations in Chinese people with T2D, including older individuals and those with long‐standing disease, with a low hypoglycaemia risk. Thus, Gla‐300 may be a suitable treatment option for T2D management in older individuals and those with long‐standing disease in China.
AUTHOR CONTRIBUTIONS
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and had full access to all the data in this study, and take full responsibility for the integrity of the data and accuracy of the data analysis. All authors participated in the interpretation of the data, the writing, reviewing and editing of the manuscript, and had final responsibility for approving the published version.
FUNDING INFORMATION
This study was funded by Sanofi.
CONFLICT OF INTEREST STATEMENT
Weiwei Liu, Qin Du, Lei Kang, and Minlu Zhang are employees of Sanofi. Liming Chen, Qiu Zhang, Binhong Duan, Xiaohong Wu, Hailong Wan, Binhong Wen, Jie Han, Haixia Liu, and Caixian Yang have no conflicts of interest to declare.
Supporting information
Table S1: Gla‐300 insulin dose in the modified intention‐to‐treat population by baseline age and prior insulin status.
Table S2: Gla‐300 insulin dose in the modified intention‐to‐treat population by baseline disease duration and prior insulin status.
Table S3: Hypoglycaemic outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S4: Hypoglycaemic outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
Table S5: Body weight outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S6: Body weight outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
Table S7: Diabetes Treatment Satisfaction Questionnaire outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S8: Diabetes Treatment Satisfaction Questionnaire outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
ACKNOWLEDGEMENTS
We would like to thank Sarah Greig, PhD, CMPP, of Springer Health+, who assisted in the preparation of the outline and subsequent drafts of the manuscript. Post‐submission editorial assistance was provided by Simone Tait, CMPP, of Springer Health+. This medical writing assistance was funded by Sanofi, China.
Chen L, Zhang Q, Duan B, et al. Effects of age and disease duration on the glycaemic outcomes and safety of insulin glargine 300 U/mL in people with type 2 diabetes in China: A post‐hoc analysis of the INITIATION study. Diabetes Obes Metab. 2026;28(3):2255‐2264. doi: 10.1111/dom.70420
DATA AVAILABILITY STATEMENT
Qualified researchers may request access to participant‐level data and related documents (e.g., the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications). Participant‐level data will be anonymised, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies and process for requesting access can be found at https://vivli.org/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Gla‐300 insulin dose in the modified intention‐to‐treat population by baseline age and prior insulin status.
Table S2: Gla‐300 insulin dose in the modified intention‐to‐treat population by baseline disease duration and prior insulin status.
Table S3: Hypoglycaemic outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S4: Hypoglycaemic outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
Table S5: Body weight outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S6: Body weight outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
Table S7: Diabetes Treatment Satisfaction Questionnaire outcomes with Gla‐300 in the safety population by baseline age and prior insulin status.
Table S8: Diabetes Treatment Satisfaction Questionnaire outcomes with Gla‐300 in the safety population by baseline disease duration and prior insulin status.
Data Availability Statement
Qualified researchers may request access to participant‐level data and related documents (e.g., the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications). Participant‐level data will be anonymised, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies and process for requesting access can be found at https://vivli.org/.