DIABETES TECHNOLOGY & THERAPEUTICS

Volume 19, Number 11, 2017

ª Mary Ann Liebert, Inc.
DOI: 10.1089/dia.2017.0111

ORIGINAL ARTICLE

Observational Registry of Basal Insulin Treatment

in Patients with Type 2 Diabetes in China:
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Safety and Hypoglycemia Predictors

Tingting Zhang, MD,1 Linong Ji, MD,2,3 Yan Gao, MD,1 Puhong Zhang, PhD,3
Dongshan Zhu, MD,3 Xian Li, MD,3 Jiachao Ji, MD,3 Fang Zhao, MD,3
Heng Zhang, PhD,3 and Xiaohui Guo, MD1

Abstract
Background: The Observational Registry of Basal Insulin Treatment (ORBIT) study evaluated the safety of
basal insulin (BI) in real-world settings in China.
Methods: We analyzed 9002 patients with type 2 diabetes (T2D) inadequately controlled with oral hypogly-
cemic agents from 8 geographic regions and 2 hospital tiers in China who initiated and maintained BI treatment.
Body weight and hypoglycemic episodes were recorded at baseline and 3 and 6 months. Serious adverse events
(SAEs) were recorded at 3 and 6 months.
Results: Age, gender, inpatient/outpatient status, body mass index, glycated hemoglobin (HbA1c) at baseline
and at the end of study, T2D duration, microvascular complications, BI type, combination with insulin se-
cretagogues, self-monitoring of blood glucose frequency, and insulin dosage, all predicted hypoglycemia. BI
use generally did not induce significant weight gain (0.02 kg); weight gain with insulin detemir (-0.30 kg) was
less than that with neutral protamine Hagedorn (NPH) insulin (0.20 kg) or insulin glargine (0.05 kg). Overall,
general hypoglycemia incidence (5.6% vs. 7.7%) and annual event rate (1.6 vs. 1.8) were similar before and
after BI initiation, whereas a slight decrease was noted in severe hypoglycemia incidence (0.6%–0.3%) and
frequency (0.05–0.03 events/patient-year). The general hypoglycemia rate was lowest with insulin glargine,
whereas there was no significant difference in severe hypoglycemia among the three BI groups. Overall, 3.5%
of patients had at least one SAE during the study. Most SAEs were found to be unrelated to BI treatment.
Conclusions: Real-world BI use, particularly insulin detemir and glargine, was associated with only slight
weight gain and low hypoglycemia risk in patients with T2D in China.

Keywords: Basal insulin, Registry, Observational study, Type 2 diabetes, Hypoglycemia, Safety.

Introduction insulin secretion pattern as closely as possible. Various diabe-

s type 2 diabetes (T2D) progresses, pancreatic b-cell
A function decreases, and insulin treatment is eventually
needed to maintain glycemic control.1,2 Insulin secretion
physiologically involves the release of basal insulin (BI) dur-
ing fasting periods with an increase of prandial insulin release
following food ingestion. Because BI plays a crucial role in
maintaining blood glucose homeostasis, the aim of insulin
therapy in patients with T2D is to match this endogenous
tes management guidelines recommend adding BI as an option
of the initial insulin regimen for uncontrolled hyperglycemia,
with existing oral hypoglycemic agents (OHAs).3–5 The long-
acting BI analogs are promising in achieving glycemic targets,
with better safety than the intermediate-acting neutral prot-
amine Hagedorn (NPH) insulin in T2D patients.6–8 They are
being increasingly used as a result, particularly in patients with
increased risk of hypoglycemia in whom blood glucose re-
mains inadequately controlled despite treatment with OHAs.

1
Peking University First Hospital, Beijing, China.
2
Peking University People’s Hospital, Beijing, China.
3
The George Institute for Global Health at Peking University Health Science Center, Beijing, China.

1
 2 ZHANG ET AL.
In current clinical practice in China, NPH insulin and the
long-acting insulin analogs glargine and detemir are the most
commonly used BI formulations. Data from numerous ran-
domized controlled trials (RCTs) and observational studies
suggest that when added to OHAs and, or in combination
with prandial insulin, all these BI formulations provide ef-
fective glycemic control in patients with T2D.9,10 However,
besides efficacy, safety considerations are paramount when
considering treatment options. In general, hypoglycemia,
weight gain, tumor risk, allergies, and safety in pregnancy are
among the most important safety parameters relevant to insulin
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use in patients with T2D. The long-acting insulin analogs have
a lower risk of causing hypoglycemia than the intermediate-
acting insulin.11–16 Compared with NPH insulin and insulin
glargine, treatment with insulin detemir has been found to be
associated with less weight gain.7,10,17,18 Furthermore, no in-
creased risk of cancer was noted in T2D patients treated with
either insulin detemir19 or glargine20 in RCTs.
However, the safety of BI use in patients with T2D in real-
world settings may differ from that of RCTs. Previous ob-
servational studies conducted in China only offered a limited
understanding of the safety of BIs, because they did not
evaluate all the available BI formulations or include a suffi-
ciently large sample size covering all regions in China.21,22
The Observational Registry of Basal Insulin Treatment
(ORBIT) study was designed to evaluate the clinical effi-
cacy and safety of BI use in patients with T2D from differ-
ent geographic regions and hospital tiers across China.
In addition to body weight change and the incidence of
serious adverse events (SAEs), the present analysis focuses
on the predictors of hypoglycemia and the incidence of
hypoglycemia in patients with T2D. Our findings further
add to the evidence supporting BI treatment in China and
this study may better inform clinical decisions interna-
tionally.
Methods
Overall design and subjects
The details of the study design and patient inclusion/
exclusion criteria of the ORBIT study have been reported
previously.23 Briefly, ORBIT was a 6-month, multicenter,
observational, prospective, registry study in adult T2D pa-
tients (aged 18–80 years) inadequately controlled with OHAs
from eight geographic regions and two hospital tiers across
China. The decision regarding the type of BI to initiate was
at the physicians’ discretion, and insulin dosage titration was
based on the physicians’ clinical judgment and patients’
willingness. Interviews were conducted at baseline (month 0,
Visit 1 [V1]), mid-term (month 3, Visit 2 [V2]), and at the end
of the study (month 6, Visit 3 [V3]) to collect safety and
efficacy data. Further details regarding sample size estima-
tion, allocation of subjects, treatment, data collection, and
analysis have been published previously.23 All patients were
followed up every 2 weeks. The incidence of self-reported
general hypoglycemia in the past 1 month and severe hypo-
glycemia in the previous 3 months was recorded at each visit.
SAEs were recorded at V2 and V3.
Overall, 18,995 patients were recruited for the study.23
Patients who continued using the same BI from the start of the
study and never added any prandial insulin to the treatment
during their follow-up were analyzed (N = 9001 for body
weight gain; N = 9002 for hypoglycemia), thus allowing the
evaluation of the relative effect of a particular BI.24,25
All the patients in the study provided written informed
consent. The protocol was approved by the Institutional Re-
view Board (IRB) of Peking University and, when necessary,
by IRBs in other hospitals.
Study objectives
The primary objectives included the assessment of body
weight gain (the absolute change in weight from baseline and
the absolute change per 1% glycated hemoglobin [HbA1c]
reduction from baseline), hypoglycemia (counts and the
percentage of patients with hypoglycemia), and SAEs (cu-
mulative counts, incidence of SAEs, and proportion of related
SAEs among those reported).
The secondary objectives included the identification of the
predictors of hypoglycemia after BI initiation and a com-
parison of the hypoglycemia rates among people being given
insulin glargine, insulin detemir, and NPH insulin.
Hypoglycemia and SAEs
Hypoglycemia in diabetes was classified according to
the American Diabetes Association (ADA) criteria26 of five
separate groups. These are severe hypoglycemia (defined as
an event requiring assistance of another person to actively
administer carbohydrates, glucagon, or take other corrective
actions), general hypoglycemia, which included symptom-
atic hypoglycemia (defined as an event during which typical
symptoms of hypoglycemia are accompanied by a measured
plasma glucose concentration £3.9 mmol/L), asymptomatic
hypoglycemia (defined as an event not accompanied by
typical symptoms of hypoglycemia but with a measured
plasma glucose concentration £3.9 mmol/L), probable symp-
tomatic hypoglycemia (defined as an event during which
symptoms typical of hypoglycemia are not accompanied
by a plasma glucose determination but that was presumably
caused by a plasma glucose concentration £3.9 mmol/L), and
relative hypoglycemia (also known as pseudohypoglycemia,
an event during which the person with diabetes reports any
of the typical symptoms of hypoglycemia, with a measured
plasma glucose concentration >3.9 mmol/L).
The insulin dosage titrations following the episodes of
hypoglycemia were all administered under best clinical prac-
tice guidelines without intervention. Information regarding
adjustment of the insulin dosage was noted on an electronic
clinical research form designed by Medidata Rave (www
.mdsol.com/en). The frequency of insulin dosage adjustment
based on hypoglycemia, but not the number of insulin units
administered, was recorded on the form.
SAEs were defined as any adverse event that was not an-
ticipated (including death, life-threatening illness or injury,
inpatient hospitalization or prolongation of existing hos-
pitalization, permanent impairment of a body structure or
function, congenital abnormality or birth defect, or any other
important medical event).
Datasets for safety analysis
The baseline dataset consisted of all patients who fulfilled
the criteria for the study, had available information about the
OHAs used at baseline (to guarantee patients were taking
 SAFETY RESULTS OF THE ORBIT STUDY 3

OHAs before baseline but still uncontrolled, as determined
by a recent HbA1c ‡7%), and were prescribed a BI at V1.
The V2 dataset comprised patients who had a visit date
within the specific 3-month follow-up period with nonmiss-
ing answers for any two of the following variables: (1) insulin
use; (2) which OHAs were being taken; (3) body weight
measurements; and (4) hypoglycemic events.
The V3 dataset comprised patients from the baseline da-
taset who had a visit date within the specific 6-month follow-
up period and had data on body weight measurements or
hypoglycemic events.
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methods to ascertain factors relevant for hypoglycemia. The
large sample size allowed for a number of subgroup analyses
to be performed, including analyses based on age, gender,
patient resource (whether the patient was treated in an out-
patient clinic or inpatient ward), body mass index (BMI),
baseline HbA1c level, duration of diabetes, microvascular
complications, dosage of BI at the end of study, the type of BI
(glargine, detemir, or NPH), HbA1c level at the end of study,
self-monitoring of blood glucose (SMBG) frequency per
month before month 6, and OHA combinations.

The safety dataset comprised patients who used BI, com-

pleted at least one follow-up at either V2 or V3, or had partial
safety information by answering yes to whether they had
ever experienced SAEs in the past 3 months. This dataset
(N = 17,897) was only used for the analysis related to SAEs,
but not for the analyses related to hypoglycemic events or
body weight changes.
Statistics
Body weight is summarized as mean – standard deviation
(SD). Weight change per 1% HbA1c reduction was also
calculated. SAEs are summarized as counts and incidence
( = +counts of SAEs/number of patients · 100%). Hypogly-
cemia is presented as counts of hypoglycemic events (count
per person-year = +hypoglycemia counts/patient-year) and
the percentage of patients with hypoglycemia ( = +counts
of patients with hypoglycemia/number of patients · 100%).
Continuous variables with normal distribution are summa-
rized with descriptive statistics and presented as mean – SD.
Discrete variables are presented as n (%). The difference was
considered as significant with a P value <0.05.
The model analysis for the rate of general hypoglycemia
used univariate and multivariate logistic stepwise regression
Results
Demographic characteristics of subjects
Overall, 9002 patients who used the same BI from baseline
to month 6 without adding prandial insulin were included in
the body weight and hypoglycemia analyses. This population
had a mean age of 55.6 – 10.1 years, with the average diabetes
duration of 6.5 years, BMI 24.8 – 3.3 kg/m2, HbA1c 9.2%,
and fasting plasma glucose 11.1 – 3.5 mmol/L. Table 1 shows
the baseline demographics and clinical characteristics of pa-
tients in the three BI groups.
Predictors of hypoglycemia
To determine the predictors of hypoglycemia associated
with BI treatment, we performed a model analysis for the rate
of general hypoglycemia at the end of the study (Table 2).
Age, gender, outpatient/inpatient treatment status, BMI,
HbA1c level at baseline and at the end of the study, T2D
duration, microvascular complications, BI type, the combi-
nation with insulin secretagogues, SMBG frequency per
month before month 6, and insulin dosage at month 6 were all
predictors of hypoglycemia.

Table 1. Baseline Demographics and Clinical Characteristics of the Patients Who Used
the Same Basal Insulin Without Adding Prandial Insulin from Baseline to Month 6
Total Insulin glargine Insulin detemir NPH insulin
Characteristic N Mean (SD) Median N Mean (SD) Median N Mean (SD) Median N Mean (SD) Median
Age (years) 9002 55.6 (10.1) 56.0 6804 55.7 (10.1) 56.0 1122 55.1 (10.3) 55.0 1076 55.5 (9.6) 56.0
BMI (kg/m2) 9002 24.8 (3.3) 24.7 6804 24.7 (3.3) 24.6 1122 25.4 (3.4) 25.4 1076 24.6 (3.3) 24.5
Diabetes 9002 6.5 (5.1) 5.4 6804 6.5 (5.2) 5.4 1122 6.0 (4.9) 5.0 1076 7.0 (5.1) 6.3
duration
(years)
Regular OHA 9000 5.8 (4.9) 4.7 6802 5.7 (4.9) 4.6 1122 5.3 (4.7) 4.2 1076 6.4 (5.0) 5.5
treatment
duration
(years)
SBP (mmHg) 9002 129.8 (15.3) 130.0 6804 129.8 (15.1) 130.0 1122 130.2 (15.6) 130.0 1076 129.1 (16.0) 130.0
DBP (mmHg) 9002 79.5 (9.2) 80.0 6804 79.5 (9.2) 80.0 1122 79.9 (8.9) 80.0 1076 79.2 (9.1) 80.0
HbA1c (%) 9002 9.2 (1.8) 8.8 6804 9.2 (1.8) 8.8 1122 9.2 (1.7) 8.9 1076 9.6 (2.0) 9.0
Fasting blood 8720 11.1 (3.5) 10.4 6571 11.0 (3.5) 10.3 1092 11.0 (3.4) 10.3 1057 11.6 (3.8) 10.8
glucose
(mmol/L)
Weight (kg) 9002 67.7 (11.6) 67.5 6804 67.7 (11.6) 68.0 1122 69.1 (12.2) 69.0 1076 66.2 (11.3) 65.0
SMBG 9002 5.6 (10.1) 2.0 6804 5.8 (10.4) 2.0 1122 5.4 (9.3) 2.0 1076 4.5 (8.2) 2.0
frequency
per month
BMI, body mass index; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; N, number of patients; NPH, neutral protamine
Hagedorn; OHA, oral hypoglycemic agent; SBP, systolic blood pressure; SD, standard deviation; SMBG, self-monitoring of blood glucose.
 4 ZHANG ET AL.

Table 2. Model Analysis for the Rate of General Hypoglycemia at Month 6

Univariate logistic regression Multivariate logistic stepwise regression
General hypoglycemia
Overall Overall
Variable Odds ratio (95% CI) P P value Odds ratio (95% CI) P P value
Age (years) 0.0889 0.0187
<40 1 1
40–50 1.681 (1.114–2.536) 0.0133 1.471 (0.963–2.247) 0.0739
50–60 1.473 (0.984–2.203) 0.0596 1.189 (0.782–1.809) 0.4175
‡60 1.481 (0.991–2.214) 0.0552 1.051 (0.686–1.610) 0.8194
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Gender <0.0001 0.0097

Female 1 1
Male 0.733 (0.628–0.857) <0.0001 0.803 (0.680–0.948) 0.0097
Patient resource <0.0001 0.0126
Inpatient ward 1 1
Outpatient clinic 1.510 (1.286–1.773) <0.0001 1.252 (1.049–1.495) 0.0126
BMI (kg/m2) 0.0413 0.0105
<24 1 1
24–28 1.022 (0.866–1.206) 0.7973 1.005 (0.844–1.197) 0.9552
‡28 0.745 (0.579, 0.960) 0.0228 0.684 (0.524–0.893) 0.0052
HbA1c at baseline (%) 0.0157 0.0762
7–8 1 1 0.1476
8–9 1.200 (0.976–1.475) 0.0845 1.173 (0.945–1.456)
9–10 1.093 (0.866–1.380) 0.4536 1.109 (0.866–1.421) 0.4111
‡10 0.855 (0.689–1.061) 0.1543 0.882 (0.695–1.121) 0.3049
T2D duration (years) 1.025 (1.010–1.040) 0.0008 0.0008 1.025 (1.008–1.042) 0.0037 0.0037
Microvascular complications <0.0001 <0.0001
No 1 <0.000 1 <0.000
Yes 1.506 (1.278–1.776) 1 1.461 (1.223–1.744) 1
BI type <0.0001 <0.0001
NPH 1 1
Glargine 0.425 (0.347–0.519) <0.0001 0.454 (0.363–0.568) <0.0001
Detemir 0.833 (0.646–1.075) 0.1602 0.798 (0.602–1.056) 0.1141
HbA1c at month 6 (%) 0.0033 0.0014
<6.5 1 1
6.5–7.5 0.961 (0.792–1.166) 0.6865 0.890 (0.728–1.089) 0.2594
7.5–8.5 0.725 (0.569–0.923) 0.0092 0.656 (0.507–0.849) 0.0014
‡8.5 0.688 (0.525–0.901) 0.0066 0.626 (0.464–0.844) 0.0021
Secretagogue at month 6 <0.0001 <0.0001
No 1 <0.000 1 <0.00
Yes 1.552 (1.325–1.818) 1 1.574 (1.323–1.873) 01
SMBG frequency per month <0.0001 <0.0001
before month 6
0 1 1
1–5 2.867 (2.055–4.000) <0.0001 2.307 (1.639–3.248) <0.0001
6–10 2.572 (1.804–3.667) <0.0001 2.204 (1.531–3.172) <0.0001
‡11 3.168 (2.210–4.540) <0.0001 2.676 (1.844–3.885) <0.0001
Insulin dosage per kg per <0.0001 0.0009
day at month 6
0–0.15 1 1
0.15–0.20 0.770 (0.609–0.972) 0.0280 0.761 (0.598–0.968) 0.0262
0.20–0.25 0.858 (0.675–1.091) 0.2125 0.839 (0.653–1.078) 0.1690
‡0.25 1.419 (1.159–1.737) 0.0007 1.173 (0.938–1.466) 0.1623
BI, basal insulin; CI, confidence interval; T2D, type 2 diabetes.

Body weight changes
Body weight at baseline and month 6 in the three BI groups
are shown in Figure 1A. Overall, the mean weight gain from
baseline to month 6 was minimal (0.02 kg; Fig. 1B), and the
mean weight gain per 1% HbA1c reduction from baseline to
month 6 was -0.07 kg (Fig. 1C). Patients in the detemir group
had the lowest weight gain (-0.3 – 2.62 kg; P < 0.001) com-
pared with those in glargine (0.05 – 2.72 kg) and the NPH
(0.20 – 2.74 kg) groups (Fig. 1B). Similar results were noted
 SAFETY RESULTS OF THE ORBIT STUDY 5
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FIG. 1. Body weight (kg) at baseline and month 6 (A), body weight gained from baseline to month 6 (B), and body weight
gained per 1% HbA1c reduction from baseline to month 6 (C), by BI type (only includes patients who continued to use the
same BI formulation from baseline to month 6 without prandial insulin added and no missing body weight data). *P < 0.05;
***P < 0.001. BI, basal insulin; HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn.

for body weight gained per 1% HbA1c reduction from base-
line to month 6 (Fig. 1C).
Hypoglycemia
Table 3 summarizes the mean event rates (events/patient-
year) for the different types of hypoglycemia among patients
receiving insulin glargine, insulin detemir, or NPH insulin.
For all types of BI combined, there was a slight increase in
general hypoglycemic events from baseline (1.62) to month 6
(1.79), whereas there was a decrease in severe hypoglycemic
events (from 0.05 to 0.03). Table 4 shows the percentage
of patients with each type of hypoglycemia before baseline
and month 6 by BI type. At the end of the study, 0.3% of
patients had severe hypoglycemia and 7.7% of patients had
general hypoglycemia. Probable symptomatic hypoglyce-
mia accounted for the highest proportion of total hypogly-
cemic events.
There were no significant differences in severe hypogly-
cemia among three BI groups. However, for general hypo-
glycemia, the frequency was the lowest with insulin glargine
(1.33 events/patient-year) compared with insulin detemir
(3.25 events/patient-year) and NPH insulin (3.21 events/
patient-year; Table 3). Furthermore, the proportion of pa-
tients with severe hypoglycemia was similar in three BI
groups, whereas the proportion of patients with general hy-
poglycemia was highest in the NPH insulin group (13.4%)
and lowest in the glargine group (6.2%; Table 4).
Serious adverse events
Overall, 3.5% of patients had at least one SAE during the
6-month study period. Most SAEs (85.6%) resulted in hos-
pitalization and 7.5% led to death. Approximately two thirds
of patients (65.0%) improved after therapy, and 24.4% of
patients recovered. Most SAEs (86.8%) were deemed unre-
lated to BI treatment (Table 5). Five out of 56 patients died
during follow-up, but had no SAE record.
Discussion
The ORBIT study investigated the safety of three different
BI formulations in a real-world clinical setting in China. This
prospective, observational, registry-based study showed that
BI initiation in patients with T2D who were uncontrolled
with OHAs was associated with good safety outcomes.
Weight gain is a common concern of insulin therapy,
as was observed in the UK Prospective Diabetes Study
(UKPDS).27 However, in our study, BI was not associated
with significant weight gain, except for a slight increase in the
NPH insulin group. Moreover, weight gain with insulin de-
temir was less than that with NPH insulin or insulin glargine.
These results are similar to the findings of previous studies on
insulin detemir, compared with NPH insulin7,12 and insulin
glargine.10,17,18 This beneficial effect on body weight has also
been validated in cohort studies of insulin detemir.28–30 In-
sulin detemir has been shown to have a weight-sparing effect,
 6 ZHANG ET AL.

Table 3. Counts of Each Type of Hypoglycemia (Events/Patient-Year)

Before Baseline and Month 6 by Basal Insulin Type
Baseline Month 6
Type of BIa Type of hypoglycemia N Mean SD N Mean SD
Glargine Severe hypoglycemia 6804 0.04 0.84 6804 0.03 0.57
General hypoglycemia 6804 1.46 8.14 6804 1.33 6.42
Documented symptomatic hypoglycemia 6804 0.19 2.07 6804 0.22 2.17
Asymptomatic hypoglycemia 6804 0.13 1.87 6804 0.17 1.97
Probable symptomatic hypoglycemia 6804 0.95 6.68 6804 0.69 3.96
Relative hypoglycemia 6804 0.18 1.87 6804 0.24 2.51
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Detemir Severe hypoglycemia 1122 0.03 0.48 1122 0.02 0.41

General hypoglycemia 1122 0.89 5.30 1122 3.25 34.07
Documented symptomatic hypoglycemia 1122 0.20 2.75 1122 0.12 1.29
Asymptomatic hypoglycemia 1122 0.05 0.80 1122 0.10 1.07
Probable symptomatic hypoglycemia 1122 0.47 3.69 1122 2.68 33.79
Relative hypoglycemia 1122 0.16 1.99 1122 0.35 2.73
NPH Severe hypoglycemia 1076 0.13 1.78 1076 0.01 0.49
General hypoglycemia 1076 3.39 16.52 1076 3.21 10.41
Documented symptomatic hypoglycemia 1076 0.26 2.21 1076 0.33 2.29
Asymptomatic hypoglycemia 1076 0.19 1.58 1076 0.27 1.92
Probable symptomatic hypoglycemia 1076 2.75 15.87 1076 2.25 8.80
Relative hypoglycemia 1076 0.19 1.96 1076 0.36 2.67
Totala Severe hypoglycemia 9002 0.05 0.97 9002 0.03 0.54
General hypoglycemia 9002 1.62 9.31 9002 1.79 13.76
Documented symptomatic hypoglycemia 9002 0.20 2.18 9002 0.22 2.09
Asymptomatic hypoglycemia 9002 0.13 1.74 9002 0.17 1.87
Probable symptomatic hypoglycemia 9002 1.11 8.12 9002 1.13 12.80
Relative hypoglycemia 9002 0.18 1.89 9002 0.27 2.56
Hypoglycemia counts have been converted to 1 year before baseline and month 6. Frequency = +hypoglycemia counts/patient-year.
a
Only includes patients who continued to use the same BI formulation from baseline to month 6 without prandial insulin added. General
hypoglycemia here includes symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, and relative
hypoglycemia according to the ADA criteria.
ADA, American Diabetes Association; N, number of patients.

possibly related, in part, to the central nervous system-mediated
reduced energy intake,31 although the precise mechanisms
remain unclear.
Hypoglycemia is the most common adverse effect asso-
ciated with insulin treatment, and thus is a major barrier to
reach glycemic targets for both physicians and patients. In
our study, the incidence of general hypoglycemia increased
from 1.62 events/patient-year before BI initiation to 1.79
events/patient-year at the end of the study; however, severe
hypoglycemic events showed a decreasing trend from 0.05 to
0.03 events/patient-year. This was similar to the results of the
Study of Once-Daily Levemir (SOLVE).29 In our study, the
percentage of patients with severe hypoglycemia and general
hypoglycemia at month 6 was 0.3% and 7.7%, respectively.
In a subgroup analysis of an Indian population in A1chieve
study, major hypoglycemia was reported in 0.5% of patients
(0.08 events/patient-year) and reduced to 0% (0 events/
patient-year) over 6 months in those patients taking insulin
detemir.32 Also, in the A1chieve study, the proportion of
patients with at least one overall or major hypoglycemic
event over 6 months of therapy with insulin detemir in
insulin-naive T2D patients, aged 40–65 years, was 4.7% and
0%, respectively.33 In addition, the frequency of overall and
major hypoglycemia in this population was 1.35 and 0 events/
patient-year, respectively.33 As seen in the First Basal Insulin
Evaluation (FINE) study,22 which was also a prospective
observational study of insulin-naive T2D patients in Asia
with uncontrolled HbA1c at 9.8% at baseline, the frequency
of hypoglycemic events over 6 months of BI treatment was
even lower (the frequency of total hypoglycemic event was
0.287 events/patient-year; mild-to-moderate, 0.280 events/
patient-year; severe, 0.009 events/patient-year) than that of
the ORBIT study. Both of these two studies were conducted
in real-world settings. In the Treating to Target in Type 2
Diabetes (4-T) study, the mean number of hypoglycemic
episodes was 2.3 events/patient-year with a BI regimen alone.34
Therefore, the findings of hypoglycemia in our ORBIT study
were in line with those in the studies mentioned above.
However, the frequency of hypoglycemia in our study
was relatively lower than that reported in some other stud-
ies.16,17,35 In the EDITION 3 trial, which studied a population
of insulin-naive T2D patients on a BI regimen similar to that
of the ORBIT study, the annual rate of hypoglycemic epi-
sodes was 6.4 and 8.5 events/patient-year with glargine U300
and U100 formulation, respectively.35 This frequency was
three to four times greater than that reported in our study, and
the discrepancy may result from the differences in HbA1c
levels and insulin dosages at baseline and at the end of the
study. First, the mean HbA1c level at baseline in the ORBIT
study was much higher than that in the EDITION 3 study
(9.6% – 2.0% vs. 8.54% – 1.6%), whereas the dosage of BI at
initiation (0.18 – 0.07 IU/kg/d) was lower than that in the
EDITION 3 study (0.25 IU/kg/d). Second, to reach identi-
cal glucose control targets among comparative groups, the
 SAFETY RESULTS OF THE ORBIT STUDY 7

Table 4. Percentage of Patients with Each Type of Hypoglycemia

Before Baseline and Month 6 by Basal Insulin Type
Baseline Month 6
Type of BIa Type of hypoglycemia N % n %
Glargine (N = 6804) Severe hypoglycemia 41 0.6 25 0.4
General hypoglycemia 369 5.4 419 6.2
Documented symptomatic hypoglycemia 81 1.2 93 1.4
Asymptomatic hypoglycemia 48 0.7 48 0.7
Probable symptomatic hypoglycemia 245 3.6 259 3.8
Relative hypoglycemia 79 1.2 79 1.2
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Detemir (N = 1122) Severe hypoglycemia 5 0.4 4 0.4

General hypoglycemia 44 3.9 128 11.4
Documented symptomatic hypoglycemia 10 0.9 10 0.9
Asymptomatic hypoglycemia 5 0.4 5 0.4
Probable symptomatic hypoglycemia 25 2.2 109 9.7
Relative hypoglycemia 9 0.8 9 0.8
NPH (N = 1076) Severe hypoglycemia 10 0.9 1 0.1
General hypoglycemia 94 8.7 144 13.4
Documented symptomatic hypoglycemia 17 1.6 25 2.3
Asymptomatic hypoglycemia 16 1.5 16 1.5
Probable symptomatic hypoglycemia 65 6 109 10.1
Relative hypoglycemia 12 1.1 12 1.1
Totala (N = 9002) Severe hypoglycemia 56 0.6 30 0.3
General hypoglycemia 507 5.6 691 7.7
Documented symptomatic hypoglycemia 108 1.2 128 1.4
Asymptomatic hypoglycemia 69 0.8 69 0.8
Probable symptomatic hypoglycemia 335 3.7 477 5.3
Relative hypoglycemia 100 1.1 100 1.1
a
Only includes patients who continued to use the same BI formulation from baseline to month 6 without prandial insulin added. General
hypoglycemia here includes symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, and relative
hypoglycemia according to the ADA criteria.
N, total number of patients; n, number of patients in each category.

treat-to-target design in RCTs as in EDITION 3 may have
needed a higher dosage of insulin than that in real-world
clinical settings. The mean level of HbA1c at the end of the
study in ORBIT was 7.3%, which was higher than that in
EDITION 3 (7.05%–7.08%).35 The dosage of BI at the end of
the ORBIT study was 0.21–0.24 IU/kg/d,24 which was mark-
edly lower than that in EDITION 3 (0.5–0.6 IU/kg/d).35
Therefore, the observed lower hypoglycemic risk in the OR-
BIT study was associated with poor glycemic control at initi-
ation and suboptimal insulin dosage titration after initiation.
Moreover, the event rate depends on the method used to
detect hypoglycemia, and consequently, there exists broad
variation between studies. In the recently published VAR-
IATION (the Variability of Glucose in Patients with Type 2
Diabetes Treated with Four Different Insulin Combination
Regimens) study, the proportion of patients with at least
one reported hypoglycemic event within a 6-day study period
was 21%.36 This corresponds to *1 event per month, that
is, 12 events/year, which was also considerably higher than
that found in our study. However, it should be noted that
in the VARIATION study, the frequency of hypoglycemia
was recorded from a continuous glucose monitoring (CGM)
system, probably resulting in a more reliable estimation than
a subjective assessment. A recent observational prospective
study suggested that CGM showed a higher number of hy-
poglycemic events than SMBG in stable, well-controlled,
insulin-treated patients with T2D.37
In addition, hypoglycemic episodes could have been
underestimated due to low frequency of SMBG. The hy-
poglycemic events in the ORBIT study were recorded ac-
cording to self-report and the determination of the type of
hypoglycemia was based on these reports from patients
and the SMBG results. However, SMBG is not covered
by health insurance in China. The high out-of-pocket cost
related to SMBG also contributes to poor performance of
blood glucose monitoring that may lead to under-diagnosis
of hypoglycemia, as reflected in our data. The higher fre-
quency of SMBG could be indicative of a greater prob-
ability of detecting hypoglycemia in clinical practice in
China.
In our study, no significant differences in severe hypo-
glycemia were found among three BI groups, yet the rate
of general hypoglycemia was significantly lower in patients
treated with insulin glargine compared with those treated
with insulin detemir or NPH insulin. Insulin glargine has
shown a lower risk of hypoglycemia than NPH insulin in a
RCT,16 a real-world study,11 and reviews.10,15 In a recent
randomized crossover trial of hospitalized patients with T2D
in China, hypoglycemia rates increased when patients were
switched from insulin glargine to insulin detemir.38 Sys-
tematic reviews10,18 and a RCT17 have compared insulin
glargine with insulin detemir in T2D, and the results showed
no significant difference in the risk of hypoglycemia between
treatment with these two BIs.
 8 ZHANG ET AL.

Table 5. Percentage of Patients with Serious a real-world clinical setting in China, reflecting the actual
Adverse Events and Incidence use of therapies. The ORBIT study included a large sample
of Serious Adverse Events size drawn from all major regions in China, with a clinically
relevant heterogeneous population. The study was sufficiently
Patients with at least
one SAE SAE powered to investigate the use of BI for many subgroups and
enable ecologically valid assessment of the effects of BI
Cumulative Incidenceb regimens and diversity at both regional and hospital levels
Na n % counts (%) under real-world clinical practice in China.
Nevertheless, there are some limitations to the study. It is
Total 17,897 635 3.5 680 3.8 not a randomized study and the characteristics of patients in
Severity, prognosis, and relevance among SAEs different groups are not comparable. Also, there are consid-
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n Proportion erable regional differences in the timing of BI initiation and

(%) the use of OHAs.
c
Total counts of SAEs 680 100
In conclusion, initiating BI therapy was overall safe, and
Severity the long-acting insulin analogs were associated with minimal
Hospitalization 582 85.6 weight gain and low hypoglycemia rates in a large Chinese
Extended hospitalization 9 1.3
Disability/dysfunction 14 2.1 population of patients with T2D in real-world settings.
Life-threatening 5 0.7
Led to death 51 7.5 Acknowledgments
Other 19 2.8 The study was sponsored by Sanofi–Aventis (Shanghai,
Result China). The funder did not participate in the study design or
Cured 166 24.4 execution, drug choice, data analysis, and reporting. The
Improved 442 65.0 study was designed, executed, and analyzed at The George
Sustained worsening 21 3.1
Death 51 7.5 Institute for Global Health at Peking University Health Sci-
ence Center. The authors thank John Knight of The George
Relation to BI use Institute for Global Health (Newtown, Australia), for medical
Related 26 3.8
Not related 590 86.8 writing assistance, and Steven Tresker of Cactus Commu-
Not clear 64 9.4 nications, for medical editing assistance. The authors would
like to thank the many investigators and patients for their
a
The safety dataset was used; the denominator is patients with at participation, without which this study would not have been
least one follow-up visit or having part of the safety information possible. Members of the ORBIT study steering committee
record. are L.J., P.Z., Jianping Weng, Juming Lu, X.G., Weiping Jia,
b
Incidence = +counts of SAEs/number of patients · 100%; one
patient could have more than one SAE. Wenying Yang, Dajin Zou, Zhiguang Zhou, Changyu Pan,
c
Five out of 56 patients died during the follow-up, but had no Y.G., X.L., Yangfeng Wu, and Satish K. Garg. The study was
SAE record. funded by Sanofi–Aventis (Shanghai, China).
N, total number of patients; n, number of patients in each
category; SAE, serious adverse event.
Authors’ Contributions
T.Z. contributed to the data analysis, the interpretation of
Although BI has been studied for efficacy and safety in findings, and also drafting of the article and the tables. L.J.,
previous RCTs and observational studies, the safety of dif- P.Z., and X.G. contributed to the data analysis and the in-
ferent BIs in real-world clinical settings may differ from that terpretation of findings. L.J. and Y.G. contributed to study
in clinical trials. Despite the merits in determining the design, and the site selection. X.L. and J.J. contributed to the
safety of BIs, RCTs have been challenged for failing to data analysis. D.Z., F.Z., and H.Z. contributed to the data
predict outcomes in real world.39 The inherent poor external analysis and also the writing of article.
validity of RCTs limits the application of study results to
more complex patient populations in real-world clinical Author Disclosure Statement
practice.40 A few observational studies have prospectively
examined the real-world use of BI in patients uncontrolled on L.J. reports receiving consulting and lecture fees from Eli
OHAs. However, these studies had limitations of their own. Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck,
The SOLVE study had a large sample size, but analyzed only Bayer, Takeda, Sanofi, Roche, and Boehringer Ingelheim,
insulin detemir.21 The FINE study included three BIs and had and research grants from Roche and Sanofi. T.Z. reports re-
a similar design to the ORBIT study, but had a small sample ceiving consulting and lecture fees from Novo Nordisk, Sa-
size (with only 496 participants from China).22 Both studies nofi, Merck, and Bayer. All other authors have no competing
were performed in several countries, with limited data from financial interests exist.
China. Since China has the largest number of patients with
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