Diabetes Ther (2021) 12:2993–3009

[Link]

ORIGINAL RESEARCH

Effectiveness and Safety of Insulin Glargine 300 U/ml

in Comparison with Insulin Degludec 100 U/ml
Evaluated with Continuous Glucose Monitoring
in Adults with Type 1 Diabetes and Suboptimal
Glycemic Control in Routine Clinical Practice: The
OneCARE Study
Ignacio Conget . Miguel Ángel Mangas . Cristóbal Morales .
Juan Caro . Margarita Giménez . Mireia Borrell . Elı́as Delgado

Received: June 28, 2021 / Accepted: September 10, 2021 / Published online: October 2, 2021
Ó The Author(s) 2021

ABSTRACT terms of percentage of time in range (TIR);

70–180 mg/dl was obtained from CGM in sub-
Introduction: Data regarding efficacy of sec- optimally controlled patients with type 1 dia-
ond-generation basal insulins (BI) using con- betes (T1D) in routine clinical practice.
tinuous glucose monitoring (CGM) come from Methods: This observational, multicenter,
clinical trials. We evaluated the effectiveness of cross-sectional study included patients with
insulin glargine 300 U/ml (Gla-300) compared T1D ([ 3 years diabetes duration, HbA1c
to insulin degludec 100 U/ml (IDeg-100) in C 7.5%) who had switched from first-genera-
tion BI to Gla-300/IDeg-100 within the past
Supplementary Information The online version 24 months according to physician discretion.
contains supplementary material available at https:// Clinical and laboratory data were obtained from
[Link]/10.1007/s13300-021-01153-4.

I. Conget
M. Giménez M. Borrell

Hospital Clı́nic, C/de Villarroel, 170, 08036 C/de Josep Pla, 2, 08019 Barcelona, Spain
Barcelona, SpainM. Giménez e-mail: [Link]@[Link]
e-mail: gimenez@[Link]
E. Delgado
M. Á. Mangas Universidad de Oviedo, Oviedo, Spain
Hospital Universitario Virgen del Rocı́o, Avenida
Manuel Siurot s/n, 41013 Sevilla, Spain E. Delgado
e-mail: mangascruz@[Link] Hospital Universitario Central de Asturias, Avenida
Roma S/N, 33011 Oviedo, Spain
C. Morales
Hospital Universitario Virgen del Macarena, Calle E. Delgado
Dr. Fedriani, 3, 41009 Sevilla, Spain Instituto de Investigación Biomédica del Principado
de Asturias, Oviedo, Spain
C. Morales
Hospital Vithas Sevilla, Avda Plácido Fernández E. Delgado
Viagas s/n Castilleja de La Cuesta, 41950 Sevilla, CIBERER, Oviedo, Spain
Spain e-mail: eliasdelga@[Link]
e-mail: [Link]@[Link]

J. Caro
Clı́nica MediNorte, Av. del Marqués de Sotelo, 13, 18
2, 46002 Valencia, Spain
e-mail: juancaro84@[Link]
2994 Diabetes Ther (2021) 12:2993–3009

clinical records and during study visit, and OneCARE is a real-world study with time
CGM data were collected prior to the visit. in range as primary endpoint
Results: One hundred ninety-nine people with
T1D were included [42.6 ± 13.4 (mean ± SD) What was learned from the study?
years, 18.4 ± 10.4 years diabetes duration]; 104
The effectiveness and safety of Gla-300 are
received Gla-300, 95 IDeg-100. TIR 70–180
more similar to than different from IDeg-
throughout whole day was similar in both groups,
100, with a slightly better nocturnal
52.4 ± 14.0 vs. 49.3 ± 13.9% Gla-300/IDeg-100,
glucose profile, in persons with long-
respectively. At night, TIR 70–180 and TIR 70–140
standing sub-optimally controlled T1D
were significantly higher in the Gla-300 group
switching from first-generation BI in
compared to the IDeg-100 (52.4 vs. 46.2 and 31.8
routine clinical practice
vs. 26.9%, respectively, p = 0.0209 and
p = 0.0182), and time above range (180) was sig- Switch from first- to second-generation
nificantly lower in the Gla-300 group (40.1% vs. basal analogs led to a significant reduction
47.2%, p = 0.0199). Additional CGM glucometric in confirmed hypoglycemia and severe
data were comparable in both groups. Patient hypoglycemia episodes with no
treatment satisfaction score assessed through the significant differences between Gla-300
Diabetes Treatment Satisfaction Questionnaire and IDeg-100
(DTSQ) was high and similar for both insulins.
Conclusion: This real-world study shows the
effectiveness and safety of Gla-300 are more
similar to than different from IDeg-100, with a INTRODUCTION
slightly better nocturnal glucose profile, in sub-
optimally controlled T1D patients switching Diabetes mellitus (DM) is one of the leading
from a first-generation BI. causes of mortality and major morbidities,
including cardiovascular disease (CVD), kidney
Keywords: CGM; Gla-300; Glycemic control; disease (diabetic nephropathy), amputations
T1D and blindness. Such complications can be
avoided if blood glucose levels remain close to
normal glycemic levels [1]. Hypoglycemia is the
Key Summary Points complication most frequently associated with
the treatment of type 1 diabetes (T1D) and one
Why carry out this study? of the main challenges to achieving treatment
Effectiveness of Gla-300 compared to goals. Achieving glycemic objectives recom-
other basal insulins evaluated with mended by scientific societies is accomplished
continuous glucose monitoring (CGM) is in less than a third of patients with T1D [2]. Use
unknown in sub-optimally controlled of the second-generation basal insulin analogs
persons with type 1 diabetes (T1D) [3] with a longer duration of action (up to 24 h),
flatter action profiles and less day-to-day vari-
Most of the information available on the ability [4] and the incorporation of technology
efficacy of using new insulins and CGM for monitoring glucose profiles can be an
comes from clinical trials conducted advantage for improving glycemic targets
under optimal conditions or in highly without increasing the risk of hypoglycemia.
selected groups of patients There are currently two different second-
generation basal insulins: insulin glargine
I. Conget (&) 300 U/ml (Gla-300) and insulin degludec
Diabetes Unit, Endocrinology and Nutrition (IDeg). Gla-300 uses subcutaneous precipitation
Department, IDF Centre of Excellence in Diabetes
Care, [Link], Hospital Clı́nic i as a retarding principle providing consistent
Universitari, Barcelona, Spain activity and extended duration of action. All
e-mail: iconget@[Link] these properties provide a more constant and
Diabetes Ther (2021) 12:2993–3009 2995

prolonged pharmacokinetic and pharmacody- comparing Glar-300 and IDeg using a CGM
namic profile,[24 h blood glucose control with device [24]. However, most of the evidence on
less glycemic variability, a lower risk of hypo- the efficacy of using second-generation basal
glycemia and reduction in glycated hemoglobin insulins and CGM comes from clinical trials and
A1c (HbA1c), as observed in clinical trials [5–12] real-world studies conducted under optimal
and real-world studies [13–15], versus Gla-100. conditions or in highly selected groups of
IDeg has an ultralong duration of action and patients.
a long half-life with a flatter and stable glucose- The main objective of the ONECARE study
lowering effect. IDeg’s effect is based on the was to describe the effectiveness and safety of
formation of soluble multi-hexamers in subcu- Gla-300 versus Degludec 100U (IDeg-100),
taneous tissues. This creates a reservoir from defined as the percentage of time in range (TIR)
which monomers are released continuously and (glucose 70–180 mg/dl) during 14 consecutive
slowly to be finally absorbed into the blood days within a 4-week period measured using
flow. It has been demonstrated to have a CGM in patients with suboptimally controlled
stable pharmacodynamic profile, which leads to T1D in routine clinical practice in Spain.
lower fluctuations in glucose levels as also
observed in clinical trials [16] and real-world
studies [17, 18]. METHODS
Since the beginning of the century, it has
been possibile to measure glucose concentra- Study Design
tion using portable and minimally invasive
continuous glucose monitoring (CGM) systems This was an observational, retrospective, cross-
for 24 h. Within the different types of CGM, sectional, multicenter study conducted in
those called interactive or ‘‘real-time CGM’’ can endocrinology departments of 21 hospitals in
allow patients and healthcare professionals to Spain (Supplementary Material Table S1),
have access to glucose levels, fluctuations in including adults with T1D who had switched
glucose levels and real-time alerts about from a first-generation basal insulin (BI) analog
impending hypo- or hyperglycemia. There are (insulin glargine 100 U/ml or detemir) to a
two types of real-time CGM systems: those that second-generation basal insulin, either Gla-300
provide glucose information continuously and or IDeg-100, within 24 months of the study
those that provide the same information inter- visit. The study comprised two phases (Fig. 1):
mittently whenever the reading monitor (1) the period in which patients were treated
approaches the transmitter (intermittent-like, with basal bolus (BB) insulin (first generation
on demand or ‘‘flash’’-like). Use of these devices BI) for a minimum of 3 months [patients on
has shown benefits in terms of glycemic con- intermediate acting (NPH) and premixed insu-
trol, improving the quality of life and helping to lin were excluded]; (2) the period when the
reduce HbA1c and mean glucose in patients with patients, as per physician criteria, switched the
DM [19–22]. BI, within the last 24 months before the study
Limited evidence is available in the T1D visit, to either Gla-300 or IDeg-100. CGM was
population using CGM and about the compar- performed using the Freestyle LibreÒ CGM sys-
ison between first- and second-generation basal tem (Abbott Diabetes Care, Witney, UK), and
insulins and between the two second-genera- data from 14 consecutive days within the last
tion basal insulins. A current study conducted month were analyzed, the period recommended
by Miura et al. comparing the effects of IDeg by international consensus to assess the gly-
and Gla-300 on glycemic stability in T1D cemic profile and enable decision-making in
patients using CGM concluded that both insu- clinical practice [25].
lins were comparable in terms of glucose-stabi- The inclusion criteria were adults diagnosed
lizing effects [23]. These results were also with T1D at least 3 years prior to study enroll-
observed in terms of glycemic control in the ment; switched from C 3 months of treatment
type 2 diabetes (T2D) population when with BB insulin treatment (first-generation BI)
2996 Diabetes Ther (2021) 12:2993–3009

Fig. 1 Study design

to Gla-300 or IDeg-100 within the previous of Clarke’s questionnaire (a score \ 3 was con-
24 months; having HbA1c C 7.5% before the sidered normal perception) [28].
switch; maintaining current treat- The study protocol was approved by the
ment C 3 months; using a CGM device for at Spanish Agency of Medicines and Medical
least 1 month prior to enrollment in the study; Devices and by the Ethics Committee of the
having at least 70% of useable CGM data Hospital Clinic of Barcelona, Spain (reference
available. no. HCB/2018/0563). All procedures were per-
Exclusion criteria included: using an insulin formed in accordance with the Helsinki Decla-
pump; using NPH or premixed insulin (mixture ration of 1964 and its later amendments and
of NPH and rapid insulin) prior to or after the conformed with national regulations applicable
switch; treatment with non-insulin antidiabetic during the study (Order SAS/3470/2009 of 16
agents; having received or being treated with December 2009, which published the guidelines
oral or injectable corticosteroids; receiving [ 80 on observational studies on medicinal products
U/day of BI analogs and/or not receiving a for human use post-authorization). All patients
stable dose (± 20% of the total dose) within provided written informed consent for partici-
30 days prior to inclusion; having fewer than pation in this study.
two injections of fast-acting insulin analogs per
day within 30 days prior to inclusion. Endpoints
CGM data were obtained from the Freestyle
LibreÒ, while sociodemographic, clinical (treat- The primary endpoint was the percentage of
ment, laboratory) and safety data were collected time within the predefined CGM glucose range
retrospectively from the medical records and TIR of 70–180 mg/dl [complete day, night
directly from the patients during the study visit (24:000–05:59) or day (06:00–23-59) period]
in which two patient-reported outcomes (PRO) during 14 consecutive days within a 4-week
were also collected using the Diabetes Treat- period with CGM data obtained from the Free-
ment Satisfaction Questionnaire (DTSQ) [26] Style LibreÒ.
and Insulin Treatment Satisfaction Question- Secondary glucometric endpoints based on
naire (ITSQ) [27]. Hypoglycemia awareness was CGM data included other ranges in the full day,
evaluated using the Spanish-validated version daytime and nighttime periods: TIR 70–180 mg/
dl; TIR 70–140 mg/dl; time above range
Diabetes Ther (2021) 12:2993–3009 2997

(TAR) [ 180 mg/dl and [ 250 mg/dl; time International Diabetes Center (IDC), in Min-
below range (TBR): \ 70 mg/dl and \ 54 mg/dl, nesota. The comparison of results between the
mean glucose profile over 24-h period, per- two study groups, facilitated by the IDC, was
centage of estimated HbA1c, coefficient of vari- performed using IQVIA Information S.A.
ation (CV), interquartile range (IR), area under Percentage of time in TIR was compared
the curve (AUC), average daily risk range between groups with Student’s t-test. The sec-
(ADRR), high blood glucose index (HBGI) and ondary endpoints were tested for significance as
low blood glucose index (LBGI) [29], mean intergroup differences of normally or non-nor-
amplitude of glycemic excursions (MAGE) and mally distributed data with the unpaired Stu-
mean daily difference (MODD) in glucose. A dent’s t-test or Mann-Whitney U-test,
hypoglycemic episode was defined as a period respectively. A two-sided p value of \ 0.05 was
of [ 15 min duration below a specific thresh- considered statistically significant for all other
old. Likewise, a hyperglycemic episode was analyses. Percent of patients with hypo- and
defined as a period of [ 15 min duration above hyperglycemic episodes was compared between
a specific threshold. groups with the chi-square test, and McNemar’s
Other secondary endpoints collected Test was used for the comparison between seri-
through medical data were the percentage of ous events before and after the treatment.
patients with hypoglycemic events in the Continuous variables were described by the
12 months before the switch versus events after number of patients with valid observations,
the switch to study visit, mean HbA1c and fast- mean and standard deviation (SD). Categorical
ing plasma glucose (FPG), and number of variables were described by number and per-
adverse events. A confirmed hypoglycemia centages of patients per response category.
event was defined as an episode of symptomatic Statistical analyses were generated using SAS
or asymptomatic hypoglycemia with plasma software, version 7.15, Enterprise Guide or
glucose \ 54 mg/dl or \ 70 mg/dl, and a severe above.
hypoglycemia event was defined as an episode
of hypoglycemia at any time of the day (24 h)
and during the night that requires assistance RESULTS
from another person administering carbohy-
drates, glucagon, or any other corrective Patients and treatment characteristics
measure.
A total of 220 participants were included in the
Statistical Analyses study, and 21 were excluded for not having 70%
CGM data from the Freestyle LibreÒ device for
14-consecutive days within the last month prior
The sample size of 214 patients (107 patients
to inclusion in the study. Of the 199 valid
per group) allowed comparison of TIR
patients, 104 (52.3%) switched to Gla-300 and
70–180 mg/dl between patients with Gla-300
95 (47.7%) to IDeg-100.
and those with IDeg-100. A minimum differ-
Sociodemographic and clinical characteris-
ence of 3.3% was considered (difference
tics (BMI, height, blood pressure and heart rate)
between mean percentage of time within a glu-
were similar between the two groups, as shown
cose range of 70–180 mg in Gla-300 and other
in Table 1 and in the Supplementary Material
basal insulin of 57.8% and 54.5%, respectively,
Table S2. Hypercholesterolemia (23.6%),
in the Bergenstal et al. study [5]) with a signifi-
hypertension (12.1%) and diabetic retinopathy
cance level of 0.05 and a statistical power of
(20.6%) were the most frequent comorbidities
0.80.
observed in both groups, the proportion of
The analysis of the primary and some sec-
patients with retinopathy being statistically
ondary objectives (those related to data
higher in the IDeg-100 group than in the Gla-
obtained from the FreeStyle LibreÒ device) was
300 group (27.4% vs. 14.4%, p = 0.0241). Mean
performed by the HealthPartners Institute,
time since T1D diagnosis was 18.4 ± 10.4 years
2998 Diabetes Ther (2021) 12:2993–3009

Table 1 Participant characteristics

Total GLA-300 IDEG-100 p value
N = 199 N = 104 N = 95
Age years 42.6 ± 13.4 43.5 ± 14.3 41.7 ± 12.3 0.3500
Women, n (%) 100 ± 50.3 46 ± 44.2 54 ± 56.8 0.0755
BMI, kg/m2 26.0 ± 3.8 26.2 ± 4.0 25.7 ± 3.6 0.4425
Time since T1D diagnosis, years 18.4 ± 10.4 16.8 ± 10.1 20.2 ± 10.5 0.0218
Comorbidities Associated to T1D, n (%) 99.0 ± 49.7 45 ± 43.3 54 ± 56.8 0.0558
Dyslipidemia 47 ± 23.6 23 ± 22.1 24 ± 25.3 0.6015
Hypertension 24 ± 12.1 14 ± 13.5 10 ± 10.5 0.5254
Retinopathy 41 ± 20.6 15 ± 14.4 26 ± 27.4 0.0241
Nephropathy 12 ± 6.0 5 ± 4.8 7 ± 7.4 0.4485
Hypothyroidism 19 ± 9.5 9 ± 8.7 10 ± 10.5 0.6535
Total daily insulin dose, U/kg/day 0.6 ± 0.2 0.7 ± 0.2 0.6 ± 0.2 0.1456
Fast-acting insulin, n (%)
Lispro (HumalogÒ) 51 2 ± 5.6 23 ± 22.1 28 ± 29.5 0.5310
Ò
Aspart (Novorapid ) 106 ± 53.3 56 ± 53.8 50 ± 52.6
Glulisina (ApidraÒ) 36 ± 18.1 22 ± 21.2 14 ± 14.7
Ò Ò
Regular (Actrapid , Humulina regular ) 6 ± 3.0 3 ± 2.9 3 ± 3.2
Basal insulin, n (%)
Detemir (LevemirÒ) 18 ± 9.0 7 ± 6.7 11 ± 11.6 0.2758
Glargine 100 U/ml (LantusÒ) 180 ± 90.5 97 ± 93.3 83 ± 87.4
Ò
Glargine 100 U/ml (Abasaglar ) 1 ± 0.5 0 1 ± 1.1
Data are mean ± SD unless otherwise stated
BMI: body mass index; T1D, type 1 diabetes

overall, but it was significantly shorter in the groups (in 58% of participants before the
Gla-300 group than in the IDeg-100 group: switch vs. 60% after the switch). There were no
16.8 ± 10.2 vs. 20.2 ± 10.5 years (p = 0.0218), significant changes in the daily time schedule
respectively. of BI administration after changing BI in both
No significant differences were observed in groups. The most frequent reasons why physi-
the number of months that the patients were on cians decided to change the patient’s BI were a
the BI, either Gla-300 or IDeg-100, at the time suboptimal HbA1c in 52.3% of patients and
of the study, with time elapsed between recurrent hypoglycemia in 49.2%, and no dif-
the change in insulin and the study visit ferences were observed between the two
being 14.5 ± 6.6 months (14.3 ± 6.6 vs. groups.
14.7 ± 6.6 months for Gla-300 and IDeg-100, Before the switch, 90.5% of T1D patients
respectively; p = 0.6908). BI was most often were treated with Gla-100, 25.4 ± 12.5 UI/day,
administered in the evening in both study 9.0% with Detemir and 0.5% (1 patient) with
Diabetes Ther (2021) 12:2993–3009 2999

Table 2 Glucometric data of patients using either GLA-300 OR IDEG-100

Total Gla-300 IDeg-100 p value
n = 199 n = 104 n = 95
Mean glucose over 24-h period (mg/dl) 175.1 ± 31.6 171.6 ± 31.6 178.9 ± 31.3 0.1032
Estimated HbA1c (%) 7.7 ± 1.1 7.6 ± 1.1 7.9 ± 1.1 0.1032
TIR (%)
70–180 mg/dl 50.9 ± 14.0 52.4 ± 14.0 49.3 ± 13.9 0.1191
70–140 mg/dl 30.9 ± 10.7 31.9 ± 11.0 29.7 ± 10.2 [ 0.05
TAR (%)
[ 180 mg/dl 42.8 ± 15.9 41.0 ± 16.1 44.8 ± 15.6 0.0935
[ 250 mg/dl 16.8 ± 13.4 15.4 ± 13.0 18.2 ± 13.8 0.1453
TBR (%)
\ 54 mg/dl 2.3 ± 3.2 2.5 ± 3.7 2.2 ± 2.7 0.4433
\ 70 mg/dl 6.3 ± 5.4 6.6 ± 6.0 5.9 ± 4.7 0.3663
SD (mg/dl) 69.5 ± 15.0 67.8 ± 15.4 71.3 ± 14.4 0.0934
CV of glucose levels (%) 39.9 ± 6.8 39.8 ± 7.1 40.1 ± 6.5
\ 36% (stable) 29.1% 32.7% 25.3% 0.6903
C 36% (instable) 70.9% 67.3% 74.7% 0.2494
AUC (mg/dl) complete day 4098.3 ± 780.7 4008.4 ± 773.8 4196.7 ± 780.5 0.0893
LBGI 1.5 ± 1.4 1.6 ± 1.6 1.4 ± 1.2 0.3076
HBGI 4.6 ± 2.4 4.4 ± 2.4 4.9 ± 2.5 0.1215
ADRR 48.4 ± 11.8 47.4 ± 12.2 49.5 ± 11.3 0.1980
MAGE 24 h (mg/dl) 153.1 ± 33.2 149.4 ± 34.4 157.2 ± 31.6 0.1006
MODD in glucose (mg/dl) 68.4 ± 16.7 66.4 ± 18.0 70.5 ± 14.9 0.0822
Data are mean ± SD unless otherwise stated. Glucometric data analyzed in the full day period
TIR: time in range, TAR: time above range, TBR: time below range, SD: standard deviation, CV: coefficient of variation,
AUC: area under the curve, LBGI: low blood glucose Index, HBGI: high blood glucose index, ADRR: average daily risk
range, MAGE: mean amplitude of glycemic excursions, MODD: mean of daily difference

Gla-100 biosimilar (AbasaglarÒ). The total daily 100, 22.8 ± 10.7 (p = 0.0010). No difference in
insulin dose per kilogram body weight was prandial insulin dose was observed between
similar between study groups at the time of the Gla-300 and IDeg-100 (22.2 ± 13.8 vs.
study visit (0.7 U/kg/day for Gla-300 vs. 0.6 21.8 ± 11.6; p = 0.8199) respectively.
U/kg/day for IDeg-100; p = 0.1465). At the study The proportion of patients with normal
visit, mean Gla-300 dose was significantly hypoglycemia awareness measured using
higher, 28.5 ± 12.6 UI/day compared to IDeg- Clarke’s questionnaire was not different
3000 Diabetes Ther (2021) 12:2993–3009

between the study groups (65% of the Secondary Endpoints

participants).
Time at Glucose Target Levels Measured
Through CGM
ENDPOINTS OBTAINED There was no significant difference in TIR, TBR
FROM CGM and TAR for the full day period between the two
treatment groups, as shown in Fig. 2a, b and
Primary Endpoint Table 2.
When analyzing the day and night periods,
Effectiveness Measured as TIR 70–180 mg/dl significant differences between the two groups
The CGM device was active a mean time per- were observed in TIR 70–140 mg/dl, TIR
centage of 93.5% for both arms. The mean 70–180 mg/dl and TAR [ 180 mg/dl in the
percentage of time within TIR 70–180 mg/dl nocturnal period (24:00–06:00), as shown in
within the last 14-consecutive days for the full Fig. 2c, with no significant differences observed
day period was similar between the Gla-300 and in the day period. Those patients treated with
IDeg-100 groups: 52.4 ± 14.0% versus Gla-300 presented a higher percentage in the
49.3 ± 13.9% (Table 2 and Supplementary recommended range of 70–180 mg/dl (52.4%
Material Figure S1). The same was observed in Gla-300 vs. 46.2% IDeg-100, p = 0.0182) and
TIR 70–140 mg/dl. 70–140 mg/dl (31.8% Gla-300 vs. 26.9% IDeg-
100, p = 0.0209) and a lower percentage in
TAR [ 180 mg/dl (40.1% Gla-300 vs. 47.2%
IDeg-100, p = 0.0199).

Fig. 2 Percentage of time at glucose target levels for different periods during 24 h
Diabetes Ther (2021) 12:2993–3009 3001

Additional Glucometric Values from CGM the visit. The mean HbA1c value closest to the
No significant differences between groups in the study visit was similar in both groups:
full day period were observed in additional data 7.8% ± 1.0 in Gla-300 and 8.0% ± 0.9 in IDeg-
obtained from CGM including glycemic vari- 100 (p = 0.2529). The proportion of patients
ability metrics, as shown in Table 2. Mean 24-h achieving a HbA1c \ 7% was higher in Gla-300
glucose curves for the Gla-300 group were sig- compared with the IDeg-100 group (Table 3).
nificantly lower (lower glycemic excursions) at In the total population, it was observed that
night than for IDeg-100 patients (170.4 mg/dl patients with HbA1c \ 7 had a better nocturnal
vs. 181.9 mg/dl; p \ 0.05) (data not shown). TIR (TIR 70–180 mg/dl and TIR 70–140 mg/dl)
than patients with HbA1c [ = 7% (59.4% of the
Number of Episodes and Minutes time in TIR 70–180 mg/dl vs. 47.5% of the time
in Hypoglycemia in TIR 70–180 mg/dl, p = 0.0028 and 38.21% of
No significant differences in the average num- the time in TIR 70–140 mg/dl vs. 27.7% of the
ber of hypoglycemic episodes and in the average time in TIR 70–140 mg/dl, p = 0.0010).
minutes per day spent in hypoglycemia (\ 70 A relation was observed in the Gla-300 group
and \ 54 mg/dl) in the 14 consecutive days of between a better nocturnal TIR (70–140 mg/dl
CGM prior to study visit were observed between and 70–180 mg/dl) and lower HbA1c \ 7% level,
study groups in any of the periods analyzed indicating that Gla-300 has a better nocturnal
(complete day, night or day period) (Fig. 3a). profile in CGM and confers better glycemic
results in real-life clinical practice.
Number of Episodes and Minutes Patients with HbA1c \ 7% in the Gla-300
in Hyperglycemia group had a better nocturnal TIR (70–140 mg/dl
No significant differences in the number of and 70–180 mg/dl) than patients with
hyperglycemic episodes and in the average HbA1c [ = 7% (60.3% of the time in TIR
minutes per day spent in hyperglycemia 70–180 mg/dl vs. 50.2% of time in TIR
([ 180 mg/dl) in the 14-consecutive days prior 70–180 mg/dl, p = 0.0324, and 40.3% of the
to study visit were observed between study time in TIR 70–140 mg/dl vs. 29.8% of the time
groups in either the complete day or daytime in TIR 70–140 mg/dl, p = 0.0103). This relation
period. This remained the same when the was not observed in the IDeg-100 group.
number and minutes of hyperglycemia episodes Confirmed hypoglycemic events (\ 70 mg/
([ 250 mg) were analyzed for these same peri- dl, \ 54 mg/dl and severe hypoglycemia) were
ods of time. Nevertheless, during the nighttime obtained during the 12 months prior to switch
period, the number of episodes ([ 250 mg/dl) and in the period from switch to the study visit
per day was significantly lower in the Gla-300 [median time elapsed between switch and the
group (Fig. 3b). Likewise, in terms of average study visit of 14.5 (percentile 8.3–20.6 months)].
minutes per day spent [ 180 mg/dl, it was Data regarding confirmed hypoglycemic
observed that Gla-300-treated patients spent events \ 70 mg/dl and \ 54 mg/dl in medical
fewer minutes per day in hyperglycemia during records were available in 40.0% of patients; this
the nighttime period (Fig. 3b). figure increased to 82.0% in the case of severe
hypoglycemia. A decrease in the number of con-
firmed hypoglycemia and severe hypoglycemia
ENDPOINTS OBTAINED events after the switch from first-generation BI to
FROM CLINICAL RECORDS second-generation BI was observed, without sig-
nificant differences between the study groups.
AND AT THE STUDY VISIT Fewer patients had an episode of severe hypo-
glycemia when treated with a second-generation
HbA1c and FPG values obtained in the 4 months
BI (3.1% vs. 12.9%, second vs. first generation BI,
prior to the study visit were available in 88.0%
respectively; p = 0.0003).
of the study population: 74.9% in the last
Likewise, more patient-reported hypo-
2 months and 13.1% in the 2–4 months prior to
glycemic events were observed (\ 70 mg/
3002 Diabetes Ther (2021) 12:2993–3009

Fig. 3 Average number of episodes per day and average minutes per day of episodes in a hypoglycemia and b hyperglycemia

dl, \ 54 mg/dl and severe hypoglycemia) in the differences between groups were observed
12 months before the change of BI compared to (Table 3).
the period from the switch to the study visit. No
Table 3 HBA1C, FPG and hypoglycemic events according to the medical record
Before the switch At the study visit
Diabetes Ther (2021) 12:2993–3009

Total Gla-300 IDeg-100 p value Total Gla-300 IDeg-100 p value

HbA1c % (1) 8.4 ± 1.1 8.3 ± 0.9 8.6 ± 1.2 0.0680 7.8 ± 1.0 7.8 ± 1.0 8.0 ± 0.9 0.2529
HbA1c \ 6.5%, % 0 0 0 – 2.7 4.2 1.1 0.2112
HbA1c \ 7%, % 0 0 0 – 13.7 18.8 8.0 0.0352
Mean FPG, mg/dl (1) 172.9 ± 70.2 177 ± 70.7 168.5 ± 69.9 0.4530 151.3 ± 67 155.9 ± 65.4 146.1 ± 68.9 0.3519
Hypoglycemic events* \ 70 mg/dl, n (2) 10.5 ± 13.6 11.8 ± 16.1 8.4 ± 7.8 0.8042 7.9 ± 10.1 8.3 ± 11.8 7.3 ± 6.9 0.3488
Hypoglycemic events* \ 54 mg/dl, n (2) 4.9 ± 8.1 4.7 ± 8.1 5.2 ± 8.4 0.5761 3 ± 5.6 2.9 ± 5.3 3.2 ± 6.2 0.7544
Severe hypoglycemic events**, n (2) 0.3 ± 1.4 0.5 ± 1.9 0.2 ± 0.7 0.7002 0.1 ± 0.3 0.1 ± 0.3 0.1 ± 0.3 0.6327
Data are mean ± SD unless otherwise stated
HbA1c hemoglobin A1c, FPG fasting plasma glucose
*Confirmed hypoglycemia defined as an episode of symptomatic or asymptomatic hypoglycemia with plasma glucose \ 54 mg/dl (3.0 mmol/l) or \ 70 mg/dl
(3.9 mmol/l)
**Severe hypoglycemia is defined as an episode of hypoglycemia at any time of the day (24 h) and during the night that requires assistance from another person
administering carbohydrates, glucagon, or any other corrective measure
(1) HbA1c and FPG were collected in the 4 months prior to the switch to Gla-300 or IDeg-100 and in the 4 months prior to study visit
(2) Hypoglycemic events were collected in the 12 months before the switch and in the period from switch to study visit [time elapsed between switch and the study
visit of 14.5 months (6.6)]
3003
3004 Diabetes Ther (2021) 12:2993–3009

Results on Diabetes Treatment Satisfaction comparison of second-generation BI in T1D. As

Questionnaire and Insulin Treatment both types of studies are deemed complemen-
Satisfaction Questionnaire tary, this need applies not only to randomized
clinical trials but also to real-world pragmatic
The mean global score for DTSQs was 27.8, studies. In this context, a few months ago,
reflecting high treatment satisfaction with both Battelino et al. published the study design of the
insulins, without any difference between them InRange open-label, randomized, parallel trial
(Supplementary Material Figure S2). The same comparing Gla-300 and IDeg-100 in sub-opti-
result was obtained from the ITSQ question- mally controlled patients with T1D using CGM
naire, with a mean global score of 67.2 ± 21.5. and TIR consensus group recommendations for
the primary outcome [33]. The hypothesis being
tested is that Gla-300 is non-inferior to IDeg-
DISCUSSION 100 concerning the percentage TIR after
12-week follow-up. While we wait for the results
The OneCARE study provides, for the first time of the InRange trial, we think that the infor-
to our knowledge, information regarding the mation obtained in OneCare is worth of
comparison of effectiveness of second-genera- attention.
tion basal insulin analogs, Gla-300 and IDeg- In the real-world clinical practice scenario,
100, in terms of CGM-related metrics in Gla-300 is comparable to IDeg in terms of the
patients with T1D previously sub-optimally overall TIR and safety profile, similar to those
controlled with first-generation basal insulin found in published studies [34, 35]. However,
analogs. Our real-world study suggests that both Gla-300 showed more nocturnal time periods in
BIs are similar in achieving CGM targets the TIR range at night in suboptimally con-
according to international consensus, mainly trolled T1D patients switching from first-gen-
24-h TIR 70–180 mg/dl. The recent RESTORE eration BI compared with IDeg.
real-world retrospective study has also shown Our hypothesis is aligned with results
that switching from a first-generation BI to Gla- observed in the study by Carral et al. [36]. In
300 or IDeg-100 provided similar improvements this retrospective observational study, a higher
in glycemic control and a significant decrease in percentage of patients in the Gla-300 group
hypoglycemia [30]. reached the target of HbA1c B 7,% and more
To date, very scarce evidence comparing Gla- patients treated with IDeg-100 presented
300 and IDeg-100 in the T1D population is HbA1c [ 8%. In addition, in a subgroup of 71
available. Direct comparison of both insulins is patients (17%) who used CGM (FreeStyle Libre),
limited to two studies that did not use CGM a significant difference was observed in
information [31, 32]. The results regarding TIR [ 180 mg/dl not only in the nighttime
pharmacodynamics vary. Recently, Miura et al. period but also throughout the study period.
reported the effects of both insulins on glycemic The reason why Gla-300 has better results
stability in c-peptide-negative T1D patients could be explained by the different pharmaco-
using CGM [23]. In a multicenter randomized dynamic profiles of the two drugs. As stated by
crossover design including 46 patients, the Bailey et al., Gla-300 provides fewer fluctuating
authors suggested that Glarg-300 and IDeg-100 steady-state pharmacodynamic profiles (lower
have comparable stabilizing effects on the glu- within-day variability) and more evenly dis-
cose profile. They did not find any significant tributed pharmacokinetic profiles compared
difference in the percentage of CGM readings in with IDeg-100 [31].
the target glucose ranges with the exception of a These similar effects on the glucose profile
decrease in TBR \ 70 mg/dl in those patients are achieved using more units of Gla-300 than
switched from IDeg-100 to Gla-300. IDeg-100. As previously shown, this is not the
In this context, and as has been mentioned result of the lower potency of Gl-300 but of its
in a recent review [33], there is a need for lower bioavailability after subcutaneous injec-
studies utilizing CGM in a head-to-head tion [10, 37]. Related to its nature, there were
Diabetes Ther (2021) 12:2993–3009 3005

some differences in the clinical characteristics found with the IDeg switching as observed in
of the two groups of patients receiving the two the prospective real-world study of Fadine et al.,
second-generation insulin analogs. The dura- in which the switch to degludec from another
tion of T1D and presence of retinopathy were BI was associated with significantly lower rates
longer and higher, respectively, in patients of hypoglycemia and improved glycemic con-
using insulin IDeg-100. However, we think that trol [41].
in a population with, on average, nearly 2 dec- Our study has limitations; we are well aware
ades since the diagnosis of T1D, the impact of a of them, and some have already been men-
sparse difference of 3 years could be considered tioned. The lack of randomization, lack of a
almost negligible. The rest of the clinical, labo- centralized laboratory and lack of intensive
ratory and treatment characteristics, including control and monitoring of all aspects of usual
pre-switch HbA1c, and the reasons for the switch clinical practice are some of the weaknesses of
from a first-generation BI were comparable in real-world studies that undermines the internal
the two groups. validity of the results. Also, although the dia-
Regarding the results achieved by both insu- betes duration difference was only 3 years
lins in terms of CGM-based targets, it should be between groups, the IDeg-100 group presented a
underlined that in neither TIR nor TBR were the more severe course of the disease, (higher rates
recommendations of the ATTD consensus for of retinopathy). Nevertheless, a post-hoc anal-
CGM utilization achieved [38]. However, this is ysis has been performed aiming to assess the
not surprising considering the clinical character- effect of T1D duration and the presence or
istics of the participants in the real-world One- absence of retinopathy in both arms of the
Care study: T1D patients with longstanding study, and it was observed that the equivalent
disease, with poor metabolic control in which effectiveness of Gla-300 and IDeg-100 in sub-
may be less stringent A1C goals might be applied optimally controlled T1D patients switching
[39]. In addition, at the time of inclusion of par- from a first-generation basal insulin seems not
ticipants in our study, there was no reimburse- to be affected by either the duration of the dis-
ment for CGM by the national health care ease or the presence or absence of retinopathy
provider. Thus, the use of self-financing CGM by (data not shown). The results of this analysis are
participants could be related to their additional in line with the results observed in the main
difficulties in obtaining optimal metabolic con- results of the study. However, the strength of
trol despite using BB treatment including second- the study is, to the best of our knowledge, that
generation BI. Moreover, this use could also cre- this is one of the first studies comparing head-
ate a bias in the process of patient selection, to-head Gla-300 and IDeg-100 effectiveness in
including patients with more complications and clinical practice in a large sample size of sub-
more difficulties managing their glycemic control optimally controlled T1D patients using CGM
having more interest in participating in the study metrics demonstrating the similarities of both
and not all of the T1D population being included insulins after the assessment of outcomes based
[40]. on objectively collected data.
Regarding the result obtained from clinical
records, in fact, results of the real-world One-
CARE study show that both second-generation CONCLUSION
BIs, Gla-300 and IDeg, performed better than
first-generation BI in terms of glucose control In summary, in terms of the achievement of
and hypoglycemic events, supporting data CGM-based targets from the last consensus
obtained in the clinical program from both recommendations, this real-world study sug-
second-generation BIs. In the DELIVER-2 [13] gests that the effectiveness and safety of Gla-300
and DELIVER-3 [14] study, Gla-300 showed insulin is similar to those obtained with IDeg-
greater improvements in glycemic control and 100 in patients with long-standing sub-opti-
reduced the risk of hypoglycemia in T2D when mally controlled T1D switching from first-gen-
switching from Gla-100. Similar effects were eration BI.
3006 Diabetes Ther (2021) 12:2993–3009

ACKNOWLEDGEMENTS Disclosures. Ignacio Conget—Received a fee

from Sanofi Aventis for coordination of the
OneCARE study, and received lecturing and
Funding. This project was supported by consulting fees from Medtronic, Bayer,
Sanofi, which was involved in the study design; GlaxoSmithKline, Eli Lilly, Novo Nordisk,
in the collection, analysis and interpretation of Sanofi Aventis, Novartis, AstraZeneca and MSD.
the data; and in the decision to submit the Miguel Ángel Mangas—Received consulting fees
paper for publication. Medical writing support and/or honoraria for training activities, courses
was provided by Anna de Prado from IQVIA or advisory meetings Sanofi, Novo Nordisk, Eli
Information S.A. Spain, and the journal’s Rapid Lilly, AstraZeneca, Boehringer Ingelheim,
Service Fee was funded by Sanofi. Esteve Janssen, Abbot, and has received hono-
raria for participation as a researcher in clinical
Medical Writing and Editorial Assis- trials Sanofi, Novo Nordisk, AstraZeneca,
tance. We thank all participating physicians for GlaxoSmithKline, Millendo Therapeutics. Cris-
their dedication to participant care and Anna de tóbal Morales—Clinical Trials: Novo Nordisk,
Prado and Neus Canal from IQVIA Information Sanofi, AstraZeneca, Pfizer, Lilly, Merck, Lexi-
S.A Spain for conducting the study, medical con, FPS, Hanmi Janssen, Boehringer Ingel-
writing the statistical analysis. heim, Takeda, Roche, Theracos LeeGanz
Advisory board Novo Nordisk, Eli Lilly, MSD,
Prior Presentation. Data included in this Boehringer Ingelheim, AstraZeneca, Sanofi,
manuscript were presented, in part, at the 56th Abbott Speaker Sanofi, Novo Nordisk, AstraZe-
European Association for the Study of diabetes neca, Roche, Eli Lilly, Boehringer Ingelheim,
(EASD), Virtual Annual Meeting 2020 and in MSD, Ferrer Pharma, Janssen, Abbot. Juan Caro
Advanced Technologies & Treatments for Dia- -Reports no disclosures. Margarita Gimenez—
betes (ATTD), Virtual Meeting 2021. Received lecturing and consulting fees from
Medtronic, Eli Lilly, Novo Nordisk, Sanofi
Authorship. All named authors meet the Aventis, AstraZeneca and MSD. Mireia Borrell—
International Committee of Medical Journal Employed by and has ownership interest in
Editors (ICMJE) criteria for authorship for this Sanofi. Elı́as Delgado—Received unrestricted
article, take responsibility for the integrity of research support from AstraZeneca, Novo Nor-
the work, and have given their approval for this disk, Sanofi, Pfizer, and Roche, and has received
version to be published. consulting fees and/or honoraria for member-
ship on advisory boards and speaker’s bureau
Authorship Contributions. Ignacio Conget from AstraZeneca, Novo Nordisk, Eli Lilly,
contributed to the study design, conduct/data Sanofi, GlaxoSmithKline, Pfizer, Almirall
collection, analysis and writing of the manu- Novartis, Abbott Laboratories, Esteve and MSD.
script. Mireia Borrell contributed to the study
design, analysis and writing the manuscript. Compliance with Ethics Guidelines. The
The remaining authors contributed to the con- authors state that they have received approval
duct of the study/data collection and writing of from the Spanish Agency of Medicines and
the manuscript. All authors gave final approval Medical Devices and by the Ethics Committee of
of the version to be published, participated the Hospital Clinic of Barcelona (reference no.
sufficiently in the work to take public respon- HCB/2018/0563). All procedures were performed
sibility for appropriate portions of the content in accordance with the Helsinki Declaration of
and agreed to be accountable for all aspect of 1964, and its later amendments, and conformed
the work in ensuring that questions related to with national regulations applicable during the
the accuracy or integrity of any part of the work study (Order SAS/3470/2009, of 16 December
are appropriately investigated and resolved. 2009, which published the Guidelines On Stud-
ies Post-authorization Of Observational Type For
Medicinal Products For Human Use). The study
Diabetes Ther (2021) 12:2993–3009 3007

had a cross-sectional design, and all patients pharmacokinetic and pharmacodynamic properties
provided written informed consent for partici- and resulting clinical outcomes. Diabetes Obes
Metab. 2017;19(1):3–12.
pation in this study and publication of their
clinical data for research purpose. 5. Bergenstal RM, Bailey TS, Rodbard D, et al. Com-
parison of insulin glargine 300 units/ml and 100
Data Availability. All data generated or units/ml in adults with type 1 diabetes: continuous
glucose monitoring profiles and variability using
analyzed during this study are included in this
morning or evening injections. Diabetes Care.
published article as supplementary information 2017;40(4):554–60.
files.
6. Riddle M, Yki-Järvinen H, Bolli G, et al. One-year
Open Access. This article is licensed under a sustained glycaemic control and less hypogly-
caemia with new insulin glargine 300 U/ml com-
Creative Commons Attribution-NonCommer- pared with 100 U/ml in people with type 2 diabetes
cial 4.0 International License, which permits using basal plus meal-time insulin: the EDITION 1
any non-commercial use, sharing, adaptation, 12-month randomized trial, including 6-month
distribution and reproduction in any medium extension. Diabetes Obes Metab. 2015;17(9):
835–42.
or format, as long as you give appropriate credit
to the original author(s) and the source, provide 7. van Beers CA, DeVries JH, Kleijer SJ, et al. Contin-
a link to the Creative Commons licence, and uous glucose monitoring for patients with type 1
indicate if changes were made. The images or diabetes and impaired awareness of hypoglycaemia
(IN CONTROL): a randomised, open-label, cross-
other third party material in this article are over trial. Lancet Diabetes Endocrinol. 2016;4(11):
included in the article’s Creative Commons 893–902.
licence, unless indicated otherwise in a credit
line to the material. If material is not included 8. Bolli G, Riddle M, Bergenstal R, et al. New insulin
glargine 300 U/ml compared with glargine 100
in the article’s Creative Commons licence and U/ml in insulin-naive people with type 2 diabetes
your intended use is not permitted by statutory on oral glucose-lowering drugs: a randomized con-
regulation or exceeds the permitted use, you trolled trial (EDITION 3). Diabetes Obes Metab.
will need to obtain permission directly from the 2015;17(4):386–94.
copyright holder. To view a copy of this licence, 9. Yki-Järvinen H, Bergenstal R, Ziemen M, et al. New
visit [Link] insulin glargine 300 units/mL versus glargine 100
nc/4.0/. units/mL in people with type 2 diabetes using oral
agents and basal insulin: glucose control and
hypoglycemia in a 6-month randomized controlled
trial (EDITION 2). Diabetes Care. 2014;37(12):
3235–43.
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