diabetes research and clinical practice 176 (2021) 108848

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
journal homepage: www.elsevier.com/locat e/dia bre s

Comparison of insulin glargine 300 U/mL versus

glargine 100 U/mL on glycemic control and
hypoglycemic events in East Asian patients with
type 2 diabetes: A Patient-level meta-analysis of
phase 3 studies

Linong Ji a,*, Yan Bi b, Shandong Ye c, Yun Huang d, Xia Zhang d, Shuhua Shang d, Nan Cui d,
Huiqiu Yin d, Minlu Zhang d
a
Peking University People’s Hospital, China
b
Drum Tower Hospital Affiliated to Nanjing University Medical School, China
c
The First Affiliated Hospital of University of Science and Technology of China, China
d
Sanofi, Shanghai, China

A R T I C L E I N F O A B S T R A C T

Article history: Aims: To evaluate efficacy and safety of Gla-300 with Gla-100 in a patient-level meta-
Received 10 February 2021 analysis among large East Asian patients with type 2 diabetes mellitus (T2DM).
Received in revised form Methods: A patient level meta-analysis of three EDITION studies with similar design and
23 April 2021 endpoints were conducted over 6-months treatment period. The analysis included 547
Accepted 28 April 2021 patients treated with Gla-300 and 348 patients treated with Gla-100.
Available online 1 May 2021 Results: Over 6-month treatment period, mean change in HbA1c was similar for Gla-300
[Least square (LS) mean, (SE): 1.13 (0.05) % and Gla-100: 1.14 (0.05) %], showing non-
inferiority of Gla-300 to Gla-100 (LS mean difference: 0.02%, 95% CI: 0.08 to 0.11). Gla-
Keywords:
300 was associated with reduced risk of hypoglycemic event (confirmed  3.9 mmol/L or
Insulin glargine
severe) vs Gla-100 at any time of day or at night (00:00–05:59 h). The event rates of hypo-
EDITION
glycemia were consistently lower with Gla-300 than Gla-100. Severe hypoglycemia was rare
Asians
in both treatment groups. Weight gain was minimal in both treatment groups.
HbA1c
Conclusion: Gla-300 provides comparable glycemic control to Gla-100 in East Asian patients
Diabetes
with broad clinical spectrum of T2DM, with consistently less hypoglycemia at any time of
Pooled analysis
the day and night.
Ó 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).

* Corresponding author at: Department of Endocrinology and Metabolism, Peking University People’s Hospital, 11 Xizhimen South
Street, Xicheng District, Beijing 100044, China.
E-mail address: jiln@bjmu.edu.cn (L. Ji).
https://doi.org/10.1016/j.diabres.2021.108848
0168-8227/Ó 2021 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
2 diabetes research and clinical practice
1. Introduction
The prevalence of diabetes is increasing globally, and also
there is an alarming increase in Asia [1]. Based on the latest
International Diabetes Federation (IDF) report, the regional
prevalence was 9.6% in Western Pacific and 8.8% in South East
Asia [1]. China and Japan are among the top five global coun-
tries with an increasing number of people with diabetes (116.4
million and 7.4 million respectively) [1]. The management of
type 2 diabetes (T2DM) involves various approaches such as
changes in the lifestyle and use of pharmacological interven-
tions for maintaining glycemic control. However, as the dis-
ease progresses, exogenous insulin therapy is required in
many patients.
American Diabetes Association (ADA) guidelines recom-
mends basal insulin alone as the most convenient initial
insulin regimen and can be added to metformin and other
oral agents [2]. Early introduction of insulin should be consid-
ered if there is evidence of ongoing catabolism, symptoms of
hyperglycemia or when HbA1c levels (>10%) or blood glucose
levels (300 mg/dL) are very high [2]. Similarly, the Chinese
Diabetes Society (CDS) and Korean Diabetes Association
guidelines for T2DM recommends initiation of insulin therapy
within 3 months of failure to achieve blood glucose target
(<7% or < 6.5%) and on treatments with OAD(s) and lifestyle
interventions. Further, intensive insulin treatment may be
implemented in newly diagnosed patients with T2DM with
HbA1c > 9.0% or FPG  11.1 mmol/L and symptomatic hyper-
glycaemia with or without OADs [3,4].
Abundance of studies have demonstrated that timely
addition of insulin therapy in patients with T2DM could pro-
vide pronounced clinical improvements in glycemic control
and improve patient satisfaction and quality of life [5–9].
However, despite the proven efficacy of insulin therapy, evi-
dence suggests that insulin treatment is suboptimal in the
current clinical practice in Asia due to issues such as delay
in insulin initiation, inadequate insulin titration and rela-
tively poor glucose control [10,11]. The reasons are complex
and include both physician- and patient-related factors,
among which concerns of hypoglycemia remains one of the
main barriers [12–14].
Insulin glargine 300 U/mL (Gla-300), as a new generation of
basal insulin analogue, provides a constant and prolonged
pharmacokinetic and pharmacodynamic (PK/PD) profile com-
pared with insulin glargine 100 U/mL (Gla-100), with a longer
duration of action and more stable glucose-lowering activities
[15,16].
Various EDITION studies have reported comparable glyce-
mic control of Gla-300 versus Gla-100 in broad Caucasian/
non-Asian populations, with consistently lower risk of hypo-
glycemia at any time during the day and at night in patients
with type 2 diabetes [17–22]. Owing to physiological and
pathological differences, studies have reported some differ-
ences in treatment response including glycemic control and
hypoglycemia in Asians and non-Asians previously [23–26].
Thus, the efficacy of two insulin glargine Gla-300 and Gla-
100 in large East Asian population is worth exploration.
176 (2021) 108848
A comprehensive evaluation of the efficacy of insulin glargine
in East Asians is desirable to make better informed decisions
in the management of the disease. In this study, we present
the results of a patient-level meta-analysis based on the three
EDITION studies which compared the efficacy of Gla-300 over
Gla-100 during 6 months in East Asian population with T2DM.
2. Materials and Methods
2.1. Study design and participants
This patient level meta-analysis included participants from
three studies [27–29] (NCT01689142, NCT02855684 and
NCT01676220). All these three clinical trials were multicenter,
randomized, open-label, two-arm, parallel-group, phase III
study described previously [27–29]. The inclusion/exclusion
criteria have been described in the individual studies previ-
ously [27–29]. In brief, all patients were aged  18 years with
a diagnosis of T2DM (according to WHO criteria) [30] EDITION
JP2 was conducted in Japanese patients and on basal insulin
(BI) with OAD(s), while EDITION AP and EDITION 3 was con-
ducted in insulin-naı̈ve patients with T2DM not adequately
controlled with non-insulin antihyperglycemic drugs. Fur-
ther, EDITION AP included patients from Taiwan, Mainland
China, Korea, and only Japanese patients were included for
the analysis from EDITION 3 though the study was conducted
worldwide. The main exclusion criteria included glycated
haemoglobin levels (HbA1c) < 7.0% at screening for all three
studies, HbA1c > 11.0% for EDITION 3 and AP, and > 10.0%
for EDITION JP2. All the studies included a 2-week screening
phase, a 6-month treatment period and a 6-month safety
extension period; however, data from the first 6-month treat-
ment period are reported here.
The included patients were randomized (1:1) to receive
once-daily subcutaneous injections of Gla-300 or Gla-100 in
EDITION JP2 and 3, while in EDITION AP, patients were ran-
domized at a ratio of 2:1. Both the injections were self-
administered at the same time each evening throughout the
6-month treatment period. All participants were titrated to
a fasting self-monitored plasma glucose (SMPG) target of
4.4–5.6 mmol/l (80–100 mg/dl), with adjustments made at
least once per week, but no more often than every 3–4 days,
in the absence of hypoglycemia. A detailed titration algorithm
for individual studies is listed in the Table S1. All the studies
were approved by the institutional review boards and ethics
committees of the participating centers, and were conducted
in accordance with the Declaration of Helsinki and Good Clin-
ical Practice guidelines.
2.2. Endpoints and outcomes
The efficacy outcomes of this study were to assess change in
HbA1c from baseline to month 6; change in average pre-
breakfast SMPG (recognized as fasting SMPG) from baseline
to month 6; change in laboratory-measured fasting plasma
glucose (FPG) from baseline to month 6; percentage of partic-
ipants achieving HbA1c < 7.0%; percentage of participants
 diabetes research and clinical practice
achieving HbA1c < 7.0% without experiencing hypoglycaemia;
eight-point SMPG profile, change in mean 24-hour plasma
glucose (PG), variability of mean 24-hour PG, change in BI dose
from baseline to month 6 of treatment period.
The safety endpoints included percentages of participants
having at least one nocturnal (00:00–05:59 h) hypoglycaemic
event or hypoglycaemic event at any time of day (24 h) and
annualized rates (events per participant-year), by study per-
iod, and the cumulative mean number of hypoglycaemic
events per participant. All possible hypoglycaemic events
were recorded and categorized according to the definitions
recommended by the ADA 2005 Working Group on Hypogly-
caemia [31]. ‘Documented symptomatic hypoglycaemia’ was
defined as an event during which typical symptoms of hypo-
glycaemia are confirmed by a measured plasma glucose con-
centration of 3.9 mmol/l (70 mg/dl)], asymptomatic
hypoglycaemia confirmed by a measured plasma glucose con-
centration of 3.9 mmol/l (70 mg/dl) and ‘severe hypogly-
caemia’ as events requiring assistance by another person to
administer carbohydrate, glucagon or other therapy. For the
main analysis of hypoglycaemic outcomes, the confirmed
(with or without symptoms) and severe categories were com-
bined, and the hypoglycaemic events with a plasma glucose
measurement of <3.0 mmol/l (<54 mg/dl) were also analyzed.
Other safety endpoints included change in body weight and
adverse events.
2.3. Statistical analysis
Change from baseline in HbA1c and all other continuous vari-
ables were analyzed using analysis of covariance (ANCOVA)
model with treatment group (Gla-300 and Gla-100), screening
HbA1c (<8.0, 8.0%), use of sulfonylurea or glinides (Yes and
No) and studies (EDITION 3, EDITION JP2, EDITION AP) as fixed
effects and baseline measure as a covariate. In case, a partic-
ipant discontinued treatment prematurely or had no efficacy
measurement at month 6, the last post-baseline on-
treatment measurement was used as the efficacy value at
month 6 (last observation carried forward).
The percentage of participants reporting 1 hypogly-
caemic event and all other categorical variables were ana-
lyzed using the Cochran–Mantel–Haenszel method stratified
by randomization strata of screening HbA1c (<8.0 and
8.0%), use of sulfonylurea or glinides (Yes and No) and stud-
ies (EDITION 3; EDITION JP2; EDITION AP) and the relative risk
with 95% CI was estimated. The annualized rates of hypogly-
caemia (events per participant-year) were analyzed using an
over dispersed Poisson regression model stratified by ran-
domization strata of screening HbA1c (<8.0 and 8.0%), use
of sulfonylurea or glinides (yes; no) and studies (EDITION 3;
EDITION JP2; EDITION AP) and rate ratio with 95% CI was esti-
mated. Cumulative mean number of hypoglycaemic events by
participant was analysed using Nelson-Aelen estimates.
Adverse events were analysed descriptively. For each end-
point, homogeneity of treatment effect across all three stud-
ies was assessed by testing the study-by-treatment
interaction for each endpoint before pooling. Homogeneity
176 (2021) 108848 3
was found for endpoint of weight change; hence a random-
effect meta-analysis was conducted for weight change with
study-specific estimations using inverse-variance weights in
random-effect model.
Efficacy endpoints used the modified intention-to-treat
(mITT) population, which included all randomized patients
who received 1 dose of the open label study drugs and had
both a baseline assessment and 1 post baseline assessment
of any primary or secondary efficacy variables. The safety
population included all participants randomized and exposed
to 1 dose of study drug.
3. Results
3.1. Baseline characteristics
Of the 895 patients included in the pooled analysis of all three
EDITION studies [27–29], 547 were randomized to Gla-300 and
348 were randomized to Gla-100. The mITT and safety popu-
lation comprised 542 patients treated with Gla-300 and 346
patients treated with Gla-100 respectively. The baseline
demographic characteristics from the individual study popu-
lations and the pooled analysis population (all three studies)
are shown in Table 1.
3.2. Glycemic control
In the pooled dataset of the three studies, the mean change in
HbA1c from baseline to month-6 was similar in both treat-
ment groups [Least square (LS) mean, standard error (SE):
Gla-300 vs Gla-100: 1.13 (0.05) % vs. 1.14 (0.05) %] showing
non-inferiority of Gla-300 to Gla-100 [LS mean difference
(LSMD), 95% confidence interval (CI): 0.02% (-0.08 to 0.11)
(Fig. 1). The proportion of patients achieving an HbA1c target
of <7.0% at month 6 were 46.4% (248/535) for Gla-300 and
43.1% (147/341) for Gla-100, with 42.4% (227/535) and 37.0%
(126/341) achieved this target without hypoglycemia (con-
firmed <3.0 mmol/l or severe). Similar trend of results was
demonstrated in patients achieving HbA1c target of <6.5%
(Table S2).
The laboratory measured fasting plasma glucose (FPG)
decreased in both groups at month 6 from baseline [LS mean
(SE): Gla-300: 2.86 mmol/L (0.10) vs. Gla-100: 2.99 mmol/L
(0.11)] with LSMD (95% CI) between treatment groups of
0.13 mmol/L (-0.10 to 0.35) (Fig. 2A).
The mean change in pre-breakfast SMPG values also
showed comparable reduction in both treatment groups from
baseline to month 6 [LS mean (SE): Gla-300: 2.26 mmol/l
(0.08) vs. Gla-100: 2.40(0.08)], LSMD (95% CI) between treat-
ment groups: 0.14 (-0.03 to 0.30) (Fig. 2B). The eight-point
SMPG profiles in both groups showed a marked decrease from
baseline to month 6 (Fig. 2C), with the LS mean change in 24-
hour average SMPG values being similar between groups
(Table S2). There was also no between-treatment difference
in the variability of 24-hour SMPG at month 6 [LS mean (SE):
Gla-300: 4.86% (0.58) vs. Gla-100: 4.16% (0.62); LSMD (95% CI)
between two groups: 0.69% (-0.58 to 1.96) (Table S2).
 4
Table 1 – Baseline demographic characteristics for individual studies and pooled analysis of all three studies (randomized population).
Patient-level pooled analysis EDITION 3 EDITION AP EDITION JP2
Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100
N = 547 N = 348 N = 25 N = 25 N = 401 N = 203 N = 121 N = 120

diabetes research and clinical practice

Age, years 59.1 (9.9) 59.1 (10.8) 59.7 (9.6) 62.0 (7.6) 58.5 (9.6) 57.9 (10.2) 61.1 (10.8) 60.5 (12.0)
Gender: male, n (%) 325 (59.4) 195 (56.0) 14 (56.0) 17 (68.0) 234 (58.4) 108 (53.2) 77 (63.6) 70 (58.3)
Body weight, kg 68.0 (12.3) 67.8 (12.1) 67 (15) 68.6 (13.3) 68.3 (11.7) 68.8 (11.5) 67.4 (13.6) 65.9 (12.8)
BMI, kg/m2 25.3 (3.5) 25.2 (3.4) 25.6 (4.8) 26.0 (4.1) 25.2 (3.2) 25.3 (3.2) 25.7 (4.0) 24.8 (3.6)
eGFR, mL/min/1.73 m2 88.0 (20.3) 86.8 (19.6) 88 (15.6) 83.8 (18.1) 90.4 (20.5) 88.7 (20.7) 80.2 (18.8) 84.2 (17.7)
C-peptide, nmol/l 0.54 (0.28) 0.50 (0.27) 0.56 (0.34) 0.43 (0.17) 0.59 (0.23) 0.61 (0.26) 0.38 (0.28) 0.32 (0.20)
Region
Japan 146 (26.7) 145 (41.7) 25 (100.0) 25 (100.0) – – 121(100.0) 120 (100.0)
China 315 (57.6) 159 (45.7) – – 315 (78.6) 159 (78.3) – –
South Korea 77 (14.1) 34 (9.8) – – 77 (19.2) 34 (16.7) – –
Taiwan 9 (1.7) 10 (2.9) – – 9 (2.2) 10 (4.9) – –
Duration of diabetes, years 11.4 (7.0) 11.8 (7.2) 9.9 (7.6) 11.6 (7.5) 10.7 (6.4) 10.5 (5.8) 14.0 (8.0) 13.9 (8.7)
Duration of basal insulin treatment, years 2.39 (2.33)† 2.52 (2.44)† – – – – 2.39 (2.33) 2.52 (2.44)
Prior use of insulin glargine, n(%) 118 (98.3)*,† 110 (91.7)*,† – – – – 118 (98.3)* 110 (91.7)*
Prior non-insulin anti-hyperglycaemic treatment, n (%)

176 (2021) 108848

Biguanides 381 (69.7) 240 (66.7) 18 (72.0) 18 (72.0) 293 (73.1) 151 (74.4) 70 (57.9) 71 (59.2)
Sulphonylureas 314 (57.4) 216 (60.0) 18 (72.0) 20 (80.0) 232 (57.9) 130 (64.0) 64 (52.9) 66 (55.0)
Alpha-glucosidase inhibitors 195 (35.6) 94 (27.0) 6 (24.0) 9 (36.0) 146 (36.4) 59 (29.1) 43 (35.5) 26 (21.7)
DPP-4 inhibitors 133 (24.3) 116 (32.2) 17 (68.0) 20 (80.0) 65 (16.2) 43 (21.2) 51 (42.1) 53 (44.2)
Thiazolidinediones 51 (9.3) 39 (10.8) 1 (4.0) 7 (28.0) 38 (9.5) 23 (11.3) 12 (9.9) 9 (7.5)
SGLT-2 inhibitors 12 (2.2) 9 (2.5) 0 (0.0) 0 (0.0) 12 (3.0) 9 (4.4) 0 (0.0) 0 (0.0)
Glinides 50 (9.1) 22 (6.1) 1 (4.0) 0 (0.0) 38 (9.5) 10 (4.9) 11 (9.1) 12 (10.0)
Fixed-dose oral combination drugs 36 (6.6) 16 (4.4) 0 (0.0) 0 (0.0) 30 (7.5) 13 (6.4) 6 (5.0%) 3 (2.5%)
HbA1c, % 8.4 (0.9) 8.3 (0.9) 8.0 (0.7) 8.0 (0.7) 8.6 (0.9) 8.5 (1.0) 8.0 (0.7) 8.1 (0.8)
HbA1c, mmol/mol 68.6 (10.1) 67.5 (10.1) 64.2 (8.0) 63.7 (7.4) 70.5 (9.8) 69.4 (10.9) 63.8 (7.9) 64.6 (8.4)
*
N = 120.
†
Excludes participants from EDITION 3 and EDITION AP (insulin-naive).
 diabetes research and clinical practice 176 (2021) 108848 5

3.3. Hypoglycaemia

Over the 6-month treatment period, the number of partici-

Fig. 1 – HbA1c (mean ± SE) over the 6-month treatment
period (mITT population).
pants experiencing confirmed (3.9 mmol/L [70 mg/dL]) or
severe hypoglycaemia was lower on receiving Gla-300 than
Gla-100 at any time of the day (24 h) (66.6% vs. 74.0%; relative
risk: 0.90; 95% CI: 0.83 to 0.98). Similarly, the number of partic-
ipants with nocturnal confirmed [3.9 mmol/l (70 mg/dl)] or
severe hypoglycaemic events was lower with Gla-300 than
Gla-100 (34.5% vs. 44.5%; relative risk: 0.76; 95% CI: 0.64 to
0.90) (Fig. 3 and Table S3). When analyzed by study period,
the reduction in incidence with Gla-300 compared with Gla-
100 was even apparent during the first 12 weeks of treatment.
The annualized rate (events per participant-year) of con-
firmed [3.9 mmol/l (70 mg/dl)] or severe hypoglycaemia
at any time of day over the 6-month study period was 8.74
with Gla-300 and 11.83 with Gla-100 (rate ratio: 0.79, 95% CI:
0.65 to 0.96), showing a relative difference in rate of 21% in
favour of Gla-300 (Fig. 3). The annualized rates of nocturnal

Fig. 2 – (A) Laboratory-measured fasting plasma glucose (FPG) (B) Pre-breakfast Self-monitored plasma glucose (SMPG) (C)
Eight-point SMPG profile and (D) Insulin dose during the 6-month treatment period for pooled analysis of all three studies
(mITT population).
6 diabetes research and clinical practice 176 (2021) 108848

Fig. 3 – Percentage of participants with  1 hypoglycaemic event and annualized event rate (events per participant-year) over
the 6-month treatment period (Safety population). Abbreviations: RR, relative risk for percentage of participants with 1
event, rate ratio for annualized event rates; Gla-100, insulin glargine 100 U/ml, Gla-300, insulin glargine 300 U/ml.

events over the 6-month study period were lower with Gla-
300 than Gla-100 (2.26 vs. 3.27; rate ratio: 0.74; 95% CI: 0.53
to 1.04), with a relative difference of 26% in favour of Gla-
300 (Fig. 3). The cumulative number of confirmed
(3.9 mmol/l) or severe hypoglycaemic events per participant
was lower with Gla-300 compared with Gla-100 both at any
time and at night (Fig. 4).
Similar trends of reduction in hypoglycaemic events were
observed across other hypoglycaemia definitions, including
documented symptomatic hypoglycaemia (3.9 mmol/l),
and confirmed or severe hypoglycaemia at the lower thresh-
old of < 3.0 mmol/L (<54 mg/dL) (Table S3). The distribution
of annualized rates of confirmed (3.9 mmol/l) or severe
hypoglycaemic events over 24 h is reported in Fig. 5. A lower
rate of hypoglycaemia was shown during night and beyond
the predefined nocturnal period (00:00–05:59 h) with Gla-300
compared with Gla-100. Hypoglycemic events were most fre-
quently reported between 04:00 and 08:00 h.
Severe hypoglycemia was rare in both the treatment
groups. The number of participants experiencing severe
hypoglycaemia at any time of day was 4 (0.7%) with Gla-300
and 3 (0.9%) with Gla-100 (relative risk: 1.15 95% CI: 0.28 to
4.76) (Table S3).
3.4. Weight gain and insulin dose
There was a slight weight gain with Gla-300 and Gla-100 (LS
mean (SE): 0.40 (0.86) kg vs 0.65 (0.44) kg, respectively). LS
mean difference in weight change for Gla-300 versus Gla-
100 was 0.26 kg; (95% CI: 1.19 to 0.68). Mean daily basal
insulin dose was comparable at baseline between Gla-300
[mean (SD) 0.19 (0.08) U/kg [13.09 (6.05) U] and Gla-100 [0.20
(0.08) U/kg [13.56 (5.96) U]. The daily basal insulin dose
increased in both treatment groups at month 6 from baseline,
to a mean (SD) of 0.35 (0.18) U/kg [24.4 (13.7) U] with Gla-300
and to 0.30 (0.14) U/kg [20.7 (11.1) U] with Gla-100. The major-
ity of increase in insulin dose occurred during the first
12 weeks of treatment (Fig. 2D).
3.5. Adverse events
The percentages of participants experiencing treatment
emergent adverse events (TEAEs) were comparable for Gla-
300 and Gla-100 [52.2% (283/542) vs 54.3% (188/346)]. Serious
adverse events were infrequent, reported in 28 participants
(5.2%) in Gla-300 group and 18 participants (5.2%) in Gla-100
group.
Injection site reactions were rare and observed among 10
(1.8%) participants in Gla-300 group and 2 (0.6%) in the Gla-
100 group. Overall, 11 patients discontinued treatment due
to adverse events, 8 (1.5%) in Gla-300 and 3 (0.9%) in Gla-
100, respectively, while two patients (0.4%) in Gla-300 and 1
patient (0.3%) in Gla-100 had TEAEs leading to death
(Table S4).
4. Discussion
Studies in several Western populations with type 2 diabetes in
the EDITION programs have shown that treatment with Gla-
300 was associated with comparable glycemic control but
reduced incidence of hypoglycaemia than Gla-100 [17,18,29].
In this present pooled analysis, treatment with Gla-300 was
shown to be as effective as Gla-100 in improving glycaemic
control over 6 months, and was accompanied by a lower risk
of confirmed (3.9 mmol/l) or severe hypoglycemia at any
time during the day and at night. Weight gain was observed
low in both groups (<1kg). The present meta-analysis also
showed that the percentage of patients achieving HbA1c < 7%
without confirmed or severe hypoglycaemia was higher with
Gla-300 vs Gla-100. No new adverse events were identified
 diabetes research and clinical practice 176 (2021) 108848 7

Fig. 4 – Cumulative mean number of confirmed [3.9 mmol/l (70 mg/dl)] or severe hypoglycaemic events (A) at any time of
day (24 h) and (B) during the night (00.00–05.59 h) for pooled analysis of all three studies (safety population). Gla-100, insulin
glargine 100 U/ml; Gla-300, insulin glargine 300 U/ml.

during this 6-month analysis and were comparable between
the two treatment groups.
In the overall pooled analysis, the relative difference in
rate of confirmed [3.9 mmol/l (70 mg/dl)] or severe hypo-
glycaemia at any time of day was 21% in favour of Gla-300
over 6 months of treatment period. The corresponding differ-
ence in the individual studies were 36% for EDITION JP2, 12%
and 25% for EDITION AP and EDITION 3 respectively [27–29].
These findings suggest that the pooled analysis results were
mainly driven by the size of the reductions observed in EDI-
TION JP2 study [28]. One of the possible explanations is that
those insulin pre-treated patients who were included in EDI-
TION JP2 had rather higher hypoglycaemia risk than insulin
naı̈ve patients included in EDITION 3 and AP, allowing more
pronounced safety advantages of Gla-300 to be demonstrated.
A greater difference in the annualized rate and incidence of
nocturnal confirmed or severe hypoglycaemia in patients on
Gla-300 were observed (26% and 24% respectively during the
entire 6 months of treatment). Nocturnal hypoglycemia is
worrisome and need to be drawn attention, as it is often
undetected and may lead to unconsciousness and even death
in severe cases [32]. This important finding reveals the advan-
tage of using Gla-300 for better management of nocturnal
hypoglycemia. Our hypoglycemic findings are in accordance
with the real-world evidence studies which report lower
hypoglycemic events with Gla-300 over other insulin ana-
logues [33,34].
Over the course of 24-hours, it was noted that confirmed
[3.9 mmol/l (70 mg/dl)] or severe hypoglycemic events were
reported the most during 04:00 and 08:00 h, a lesser number
of events with Gla-300 than Gla-100. This lower frequency of
hypoglycemia extended from the early morning till the after-
noon (15:59 h) thus favouring treatment to Gla-300. This can
be attributed with the more stable and prolonged action of
8 diabetes research and clinical practice
Fig. 5 – Number of confirmed (3.9 mmol/L [70 mg/dL]) or
severe hypoglycaemic events per participant-year by time of
day; safety population.
Gla-300 previously described in various PK/PD studies [15,35]
and is similar to hypoglycaemia risk reduction beyond
06:00 h already reported in Western type 2 diabetes popula-
tions [17,29]. These results highlight that prescribing Gla-300
over Gla-100 may provide greater stability in patients suffer-
ing from hypoglycaemia during daytime in East Asian popula-
tion and thereby help to lessen the impact of diabetes on daily
activities.
Further, reduction in the incidences of hypoglycemia as
well as the annualized rates of hypoglycaemia even occurred
during first 12 weeks of treatment, where most of the basal
insulin dose titration takes place. Hypoglycaemia occurs fre-
quently during the titration period and hypoglycaemic events
during this period can lead to a higher risk in the longer term.
Therefore, it is important to minimize the risk of hypogly-
caemia within the initial weeks of starting basal insulin ther-
apy, which may facilitate to improve treatment adherence
and moreover the long-term clinical outcomes [36,37]. These
results are consistent with the BRIGHT treat-to-target trial
randomized controlled trial comparing efficacy of Gla-300
and IDeg-100 which showed a reduced risk of hypoglycaemia
with Gla-300 during 12-week active titration period, along
with majority of dose increase and HbA1c, FPG reductions
[38].
Increase in basal insulin dose from baseline to month 6
was observed in both treatment groups especially during
the first 12 weeks of treatment and quite slight change there-
after. There was higher dose with Gla-300 which was in line
with the observations from the individual EDITION studies.
This may be due to the subcutaneous administration of Gla-
300 which leads to increased residence time, thereby leading
to longer exposure to tissue peptidases and decreasing its
bioavailability [15,39]. Despite the higher dose of Gla-300,
comparable glycemic control with reduced incidence of hypo-
glycemia were observed.
The strength of this study lies in that three head-to-head
randomized trials with similar study designs were pooled
together, allowing to evaluate the efficacy and safety of Gla-
300 compared with Gla-100 in a large population of East
176 (2021) 108848
Asians. Our study results confirm the consistent glycemic
control effect and reduced hypoglycaemia risk of Gla-300 in
East Asian patients with T2DM, who usually have lower BMI
and demand lower insulin dose compared with Western pop-
ulation. However, this study is not without limitations. The
individual clinical trials were open-label in design that
reflects difficulties in blinding the two insulins, which has
the potential to introduce bias along with a shorter duration
of study period. Besides, the efficacy of Gla-300 in broader
East Asian population with other ethnic, or with various reg-
imens (e.g., basal bolus or switching from premix insulin)
could be further investigated. However, taking into considera-
tion the successful results found in the earlier EDITION stud-
ies on Asian populations and worldwide, initiating insulin
therapy with Gla-300 will be beneficial in the management
of diabetes control.
5. Conclusion
Patients receiving Gla-300 showed comparable glycemic con-
trol compared to patients on Gla-100 in East Asian patients
with a broad clinical spectrum of T2DM, with consistently
less hypoglycemia at any time of the day and at night. These
results show similar efficacy and safety profile of Gla-300 as
observed in the earlier global EDITION programs. In consider-
ation of these similarities, the present findings may have
meaningful clinical implications in successfully starting and
maintaining treatment with Gla-300.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
L.J. reports receiving consulting and lecture fees from Eli
Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck,
Bayer, Takeda, Sanofi, Roche and Boehringer Ingelheim and
research grants from Roche and Sanofi. Y.B. reports receiving
lecture fees from Eli Lilly, Bristol-Myers Squibb, Novartis,
Novo Nordisk, Merck, Bayer, Sanofi, Roche and Boehringer
Ingelheim. S.Y. has no conflicts of interests. Y.H., X.Z., S.S,
N.C., H.Y. and M.Z. are employees of Sanofi.
Acknowledgments
The authors thank the study participants, trial staff and
investigators for their participation. Editorial and writing
assistance was provided by Anwesha Mandal of Indegene
Pvt Ltd. Bangalore, India and was funded by Sanofi.
Funding
This study was funded by Sanofi China.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.diabres.2021.108848.
 diabetes research and clinical practice 176 (2021) 108848 9

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