Vol.3, No.4, 244-251 (2013) Journal of Diabetes Mellitus
http://dx.doi.org/10.4236/jdm.2013.34037
Compared with insulin glargine, insulin degludec
narrows the day-to-day variability in the
glucose-lowering effect rather than
lowering blood glucose levels*
Susumu Ogawa1,2#, Kazuhiro Nako1, Masashi Okamura1, Miho Senda1, Takuya Sakamoto1,
Sadayoshi Ito1
1Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Hospital, Sendai, Japan;
#Corresponding Author:
2Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan
Received 29 October 2013; revised 19 November 2013; accepted 25 November 2013
Copyright © 2013 Susumu Ogawa et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: Changes in the day-to-day vari-
ability in the glucose-lowering effect of insulin
[fluctuations of blood glucose levels (BG) seen
during the same time period] that occur when
insulin glargine (glargine) is replaced with insu-
lin degludec (degludec) have not been suffi-
ciently evaluated. Subjects: Five diabetics with
unstable BG undergoing basal-bolus treatment
using insulin glargine as basal insulin. Methods:
Basal insulin was changed from glargine to
same-dose degludec. The subjects’ HbA1c, gly-
coalbumin, and 1.5-anhydro-D-glucitol were meas-
ured before and after the switchover. Fasting
blood glucose concentration (FBG) and pre-
dinner blood glucose concentration (PDBG) were
measured continuously for 28 days immediately
before the switchover, and 28 days immediately
thereafter, to compare and evaluate 1) the chan-
ges in their mean values and standard devia-
tions (SDs) before and after the switchover, and
2) the frequency of appearance of BG of over
180 mg/dL (BG ≥ 180) and under 70 mg/dL (BG <
70), among other items. Bolus insulin remained
completely unchanged. Results: The levels of
HbA1c, glycoalbumin, FBG’s mean value, SDs,
BG ≥ 180 and BG < 70 all decreased. On the
other hand, although PDBG’s SD as well as BG ≥
180 and BG < 70 decreased, PDBG’s but not
FBG’s mean values remained unchanged. The
levels of 1.5-anhydro-D-glucitol rose. The mean
values of BG ≥ 180 decreased in all subjects.
Conclusion: The possibility was shown that de-
gludec, to a greater extent than glargine, sup-
pressed daily fluctuations of FBG and PDBG,
suppressed the occurrence frequency of hyper-
glycemia and hypoglycemia, and exerted more
steady hypoglycemic actions.
Keywords: Degludec; Glargine; Hyperglycemia;
Hypoglycemia; The Day-to-Day Variability in the
Glucose-Lowering Effect of Insulin
1. INTRODUCTION
Rigorous glycemic control that includes the suppres-
sion of glucose spikes is imperative to prevent diabetic
complications [1,2]. On the other hand, to prolong the
life prognosis of patients with diabetes, hypoglycemia
must be avoided [3]. In other words, blood glucose levels
should ideally be kept within a narrow set range that is
not too high or not too low. Insulin basal-bolus treatment
(intensive insulin therapy) is being used to attain these
conditions. However, there are numerous diabetic pa-
tients whose blood glucose levels cannot be sufficiently
controlled, even by using this basal-bolus treatment.
These patients include those whose blood glucose levels,
measured during the same time period, fluctuate dra-
matically from day to day (Ta ble 1 ). The fasting blood
glucose (FBG) of these patients, for example, may be
below 50 mg/dL in one day, but above 250 mg/dL on
another, making it difficult to set the dose of basal insulin,
which is the acting insulin (the insulin that influences
blood glucose at a particular time juncture the most
*Disclosure statement: no potential conflicts of interest.

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251 245
Table 1. One subject’s 4-week record of self-monitored blood
glucose (SMBG) for fasting blood glucose (FBG).
Day FBG (mg/dL) Day FBG (mg/dL)
1 217 15 245
2 289 16 322
3 205 17 178
4 197 18 205
5 65 19 57
6 248 20 285
7 350 21 46
8 217 22 214
9 269 23 309
10 304 24 178
11 216 25 283
12 185 26 37
13 62 27 85
14 203 28 217
strongly). As one reason for this, physicians suggest the
difference, with each injection, in the timing of the
manifestation of the effects of the basal insulin that is
currently being used [4]. In other words, because the way
insulin works differs day by day, blood glucose levels,
even when measured at the same point in the day, fluctu-
ate dramatically. The recently-developed drug insulin
degludec (degludec) is longer-acting than conventional
basal insulin, and gives smaller peaks [5]. Moreover, its
effects are reported to vary less with each injection [6].
Therefore, in patients it shows dramatic and sharp fluc-
tuations in FBG and pre-dinner blood glucose (PDBG)
concentration, despite already undergoing basal-bolus
treatment and those whose acting insulin is believed to
be basal insulin, their fluctuations in blood glucose are
expected to be improved (i.e., stabilized) by replacing
their basal insulin with degludec. However, this has not
yet been clinically confirmed. We therefore evaluated
blood glucose fluctuations in patients manifesting unsta-
ble FBG and PDBG despite undergoing basal-bolus
treatment using insulin glargine (glargine) as the basal
insulin, in case basal insulin had been changed from
glargine to same-dose degludec.
2. METHODS
The subjects of this study were five patients presenting
unstable FBG and PDBG despite undergoing basal-bolus
treatment that used glargine as basal insulin.
Table 1 shows one study-subject’s 4-week record of
self-monitored blood glucose (SMBG) for FBG. Even
his/her FBG, which is believed to be least influenced by
meals and is stable, varied drastically depending on the
day, from a minimum of 37 mg/dL to a maximum of 350
mg/dL. In this subject, 8 units of glargine were adminis-
tered in the morning, and 14 units were administered
before going to bed. Therefore, the insulin acting on
FBG appears to be glargine taken before going to bed.
We raised and lowered the dose in an attempt to make
adjustments, but failed. The dose of glargine could be
neither increased nor decreased, making blood glucose
control extremely difficult. We recruited such patients as
study subject.
The definition of unstable blood glucose was deter-
mined as follows: “Of the 28 measurements of FBG and
PDBG, respectively, hyperglycemia of over 180 mg/dl [7]
occurred more than 10 times, and hypoglycemia of under
70 mg/dl [8] occurred more than three times; the causes
of these blood glucose fluctuations could not be attrib-
uted to changes in meals or physical exercise.” 180
mg/dL is the blood glucose level at which urinary glu-
cose begins to appear. Basal insulin is believed to be the
acting insulin for FBG and PDBG; however, pre-lunch
blood glucose and pre-bed blood glucose were elimi-
nated from this study, since it would have been necessary
to consider the influence on their levels of bolus insulin.
We changed the subjects’ basal insulin (glargine) to
same-dose degludec, and then asked them to carry out
self-monitoring of blood glucose levels (FBG and PDBG)
every day for the 28 days immediately prior to the
change, and the 28 days immediately thereafter. We also
evaluated their body mass index (BMI), HbA1c (NGSP),
glycoalbumin (GA), and 1.5-anhydro-D-glucitol (1.5-AG)
levels immediately before the change and 28 days after
the change. The dose of bolus insulin remained un-
changed. Japanese regulations stipulate that degludec be
administered once daily, so we decided to inject degludec
once a day, regardless of the frequency of glargine injec-
tions.
The study fully conformed to the Helsinki Declaration
and it was approved by the ethics committee of the To-
hoku University Hospital. This study was only performed
after they had been fully explained to the subjects, and
obtaining their informed consent.
3. STATISTICAL ANALYSIS
Since all the measurement values evaluated in this
study showed a normal distribution (based on Shapiro-
Wilk test), they were shown in the form of mean ± SD.
Paired student’s t-test was performed to identify any sig-
nificant differences in the changes in numerical values
before and after switching the treatment regimen. P <
0.05 was regarded as significant.

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251
246
4. RESULTS
We provide basic information of studied subjects as
follows, e.g. type (the number of type 1 diabetes subjects
= 4, the number of type 2 diabetes subject = 1), duration
of diabetes (15.3 ± 7.3 years), reasons for basal-bolus
treatment (because of 4 type 1 diabetes and a brittle type
2 diabetes), blood pressure (125.3 ± 10.2/74.2 ± 5.7
mmHg), blood lipids (triglyceride: 69.7 ± 30.4 mg/dL,
total cholesterol: 186.5 ± 38.3 mg/dL, high density lipo-
protein: 58.9 ± 5.9 mg/dL) and diabetes complications
(retinopathy = 3, neuropathy = 4 and nephropathy = 2).
Table 2 shows the changes in the subjects’ blood glu-
cose control indicators before and after switching basal
insulin. Although BMI remained unchanged with the
change in treatment, HbA1c, GA, and 1.5-AG improved
significantly. The rate of change was –5.1% ± 1.3% for
HbA1c; –19.5% ± 4.6% for GA, and 39.2% ± 8.2% for
1.5-AG. The dose of basal insulin remained unchanged at
24.4 ± 5.3 U/day. Glargine was administered twice a day
in all subjects but degludec was administered once a day
in all subjects. After switching the basal insulin, the
mean value of FBG decreased from 212.4 ± 24.8 to
179.8 ± 23.8 mg/dL, and SD decreased from 92.9 ± 15.2
to 60.3 ± 11.8. In comparison, while the SD of PDBG
decreased from 80.7 ± 7.8 to 53.8 ± 4.9, the mean value
decreased from 183.6 ± 11.0 to 182.1 ± 13.5, which was
not a significant change. The maximum value of FBG
decreased from 345.4 ± 33.5 mg/dL to 292.8 ± 30.1
mg/dL, while the minimum value rose from 40.8 ± 8.5
mg/dL to 67.8 ± 18.5 mg/dL. The maximum value of
PDBG, moreover, decreased from 336.8 ± 27.3 mg/dL to
283.0 ± 16.6 mg/dL, and the minimum value rose from
49.8 ± 4.0 mg/dL to 61.6 ± 8.9 mg/dL.
Table 3 shows FBG’s mean and SD values for each
subject before and after changing the treatment regimen,
and Ta ble 4 shows the PDBG’s mean and SD values for
each subject before and after changing the treatment
regimen. FBG’s mean value decreased in three of the
five subjects, but did not show significant changes in two
subjects. None of the five subjects showed any signifi-
cant changes in PDBG’s mean value. However, all their
SD values had decreased.
Figure 1 shows the changes in mean values and SD
values of FBG and PDBG (measured 28 times) in each
subject. The mean value of FBG’s 28 measurements
dropped significantly in 3 of the 5 subjects, but remained
unchanged in 2 subjects (Table 3). It had dropped sig-
nificantly in 5 subjects as a whole (Figure 1(a)). FBG’s
SD decreased in all 5 subjects, and the mean value also
decreased significantly (Figure 1(b)). On the other hand,
the mean value of all 28 PDBG measurements remained
unchanged in all five subjects (Table 4), and the mean
value of the five subjects as a whole did not change
(Figure 1(c)). However, SD decreased in all the subjects,
and its mean value also decreased (Figure 1(d)). With
Table 2. The changes in the subjects’ glycemic control indicators between before and after switching basal insulin.
Basal insulin Glargine Degludec P
Age (Years) 51.2 ± 16.5 (28 - 72)
Gender (male/female) 2/3
Body mass index (kg/m2) 22.4 ± 1.5 22.4 ± 1.4 0.85
HbA1c (%) 8.7 ± 0.4 8.2 ± 0.4 <0.01
Glycoalbumin (%) 25.4 ± 1.2 20.4 ± 1.1 <0.01
1.5-anhydroglucitol (μg/mL) 6.7 ± 0.4 9.2 ± 0.7 <0.01
Mean of FBG (mg/dL) 212.4 ± 24.8 179.8 ± 23.8 <0.01
SD of FBG 92.9 ± 15.2 60.3 ± 11.8 <0.01
Mean of FBG max (mg/dL) 345.4 ± 33.5 292.8 ± 30.1 <0.01
Mean of FBG min (mg/dL) 40.8 ± 8.5 67.8 ± 18.5 <0.01
Mean of PDBG (mg/dL) 183.6 ± 11.0 182.1 ± 13.5 0.79
SD of PDBG 80.7 ± 7.8 53.8 ± 4.9 <0.01
Mean of PDBG max (mg/dL) 336.8 ± 27.3 283.0 ± 16.6 <0.01
Mean of PDBG min (mg/dL) 49.8 ± 4.0 61.6 ± 8.9 <0.01
Mean ± SD
H
bA1c: glycated hemoglobin A1c, FBG: fasting blood glucose concentration, PDBG: pre-dinner blood glucose concentration, SD: standard deviation.

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251 247
Table 3. FBG’s mean and SD values for each subject before
and after changing the treatment regimen.
Mean SD
Case
Glargine Degludec P Glargine Degludec
1 210.6 149.0 0.01 67.3 49.1
2 202.8 160.3 0.02 99.8 44.6
3 218.6 208.8 0.73 107.9 76.6
4 176.9 175.9 0.85. 84.3 66.0
5 253.4 205.3 0.04 105.1 65.3
Table 4. The PDBG’s mean and SD values for each subject
before and after changing the treatment regimen.
Mean SD
Case
G D P G D
1 176.4 174.4 0.69 79.4 45.9
2 187.2 180.5 0.66 77.5 53.2
3 191.7 200.4 0.81 96.0 61.3
4 166.1 162.2 0.90 75.7 55.2
5 196.8 193.0 0.87 75.1 53.4
G: glargine, D: degludec.
glargine degludec
100
120
140
160
180
200
220
240
260
280
Mean values of FBG (mg/dL)
179.8 ±23.8212.4 ±24.8
*
20
30
40
50
60
70
80
90
100
110
120
SD values of FBG (mg/dL)
glargine degludec
*
60.3 ±11.892.9 ±15.2
(a) (b)
150
160
170
180
190
200
210
glargine degludec
182.1 ±13.5
183.6 ±11.0
n.s.
Mean values of PDBG (mg/dL)
40
50
60
70
80
90
100
glargine degludec
53.8 ±4.9 80.7 ±7.8
*
SD values of PDBG (mg/dL)
(c) (d)
Figure 1. This figure illustrates the following when basal insulin was changed from glargine to same-
dose degludec: (1) the changes in each subject’s mean values and standard deviations (SD) of fasting
blood glucose (FBG) (the changes are shown as thin lines in (a) and (b)); (2) the changes in FBG’s mean
values and SD’s mean values in all five subjects (the changes are shown as bold lines in (a) and (b)); (3)
the changes in each subject’s mean values and SD of pre-dinner blood glucose (PDBG) (the changes are
shown as thin lines in (c) and (d)); and (4) the changes in PDBG’s mean values and SD’s mean values in
all five subjects (the changes are shown as bold lines in (c) and (d)).

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251
248
FBG, the mean blood glucose value decreased, and fluc-
tuations (variability in blood glucose levels) were sup-
pressed; while with PDBG, although its mean blood glu-
cose value did not drop, the fluctuations (variability in
blood glucose levels) were suppressed. This may be at-
tributable to the fact that, whereas glargine was adminis-
tered twice a day in all subjects (in the morning and at
night), degludec was administered once a day in the eve-
ning in all subjects.
Figure 2 shows the changes in frequency of blood glu-
cose levels exceeding 180 mg/dL or falling below 70
mg/dL in FBG ((a), (b)) and PDBG ((c), (d)). By switch-
ing from glargine to degludec, the frequency of blood
glucose levels exceeding 180 mg/dL in FBG decreased
from 19.2 ± 2.1 (times/28 days) to 13.0 ± 4.4 (times/28
days), while the frequency of blood glucose levels falling
below 70 mg/dL decreased from 5.0 ± 1.1 (times/28 days)
to 0.8 ± 1.0 (times/28 days) (Figures 2(a) and (b)). The
frequency of FBG exceeding 180 mg/dL decreased in
four subjects and increased in one subject because of the
switchover; FBG significantly decreased in five subjects
as a whole (Figure 2(a)). Moreover, the frequency of
FBG falling below 70 mg/dL decreased in all five sub-
jects; average FBG also decreased significantly in all
Glargine Degludec
19.2 ±2.1
13.0 ±4.4
0
5
10
15
20
25
Frequency of FBG ≥180 mg/dL(times/28 days）
5.0 ±1.1
0.8 ±1.0
Glargine Degludec
0
1
2
3
4
5
6
7
Frequency of FBG < 70 mg/dL(times/28 days）
(a) (b)
12.0 ±1.712.4 ±3.0
glargine degludec
0
2
4
6
8
10
12
14
16
18
Frequency of PDBG ≥180 mg/dL(times/28 days）
4.0 ±0.6 1.6 ±1.4
glargine degludec
0
1
2
3
4
5
6
Frequency of PDBG < 70 mg/dL(times/28 days）
(c) (d)
Figure 2. This figure focuses on each of the 28 measurements of fasting blood glucose (FBG) and pre-dinner
blood glucose (PDBG), and shows how the frequency of numerical values exceeding 180 mg/dL ((a), (c)), and the
frequency of the numerical values falling below 70 mg/dL ((b), (d)) changed if glargine was switched to degludec.

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251 249
five subjects as a whole (Figure 2(b)). On the other hand,
the frequency of PDBG exceeding 180 mg/dL decreased
in three subjects and increased in two subjects as a result
of the switchover. However, no changes in PDBG were
seen in five subjects as a whole (Figure 2(c)). In addi-
tion, the frequency of PDBG falling below 70 mg/dL
decreased in all five subjects, and PDBG also decreased
significantly in these individuals (Figur e 2(d)).
Figure 3 plots all the FBG (Figure 3(a)) values and
PDBG (Figure 3(b)) values before and after switchover
of insulin in each subject. The topmost line shows the
frequency of blood glucose levels exceeding 180 mg/dL,
and the bottommost line shows the frequency of the
blood glucose level falling below 70 mg/dL. The changes
in each subject’s mean values of FBG and PDBG ex-
ceeding 180 mg/dL are also shown. The frequency of
blood glucose levels exceeding 180 mg/dL in PDBG
remained unchanged from 12.7 ± 1.7 (times/28days) to
12.4 ± 3.0 (times/28days), but the frequency of blood
glucose levels falling below 70 mg/dL decreased from
(a)
12345Case
15
G
4
0
50
100
150
200
250
300
350
400
G
17
4
0
D
14
G
15
4
1
D
16
70
180
G
12
52
D
19
D
17
1
G
15
3
D
10
4
237.2
210.8
240.6
217.3
271.6
232.9
234.8
219.6
255.1
226.7
PDBG (mg / dl)
(b)
Figure 3. This figure plots all the fasting blood glucose (FBG) (a) values and pre-dinner
blood glucose (PDBG) (b) values before and after switchover of insulin in each subject.
The topmost line shows the frequency of blood glucose levels exceeding 180 mg/dL, and
the bottommost line shows the frequency of the blood glucose level falling below 70
mg/dL. The changes in each subject’s mean values of DBG and PDBG exceeding 180
mg/dL are also shown.

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251
250
4.0 ± 0.6 (times/28days) to 1.6 ± 1.4 (times/28days). The
mean value of blood glucose levels exceeding 180 mg/dL
had decreased in both FBG and PDBG. An examination
of the plotting of all the measurement values of FBG and
PDBG in these subjects revealed that the fluctuations in
blood glucose levels had decreased in all the subjects,
and that the blood glucose levels had converged.
Degludec and glargine treatments were well tolerated;
no serious adverse events were reported in either treat-
ment. No injection-site reactions or severe hypoglycemic
events were reported. In total, 21 confirmed hypoglyce-
mic episodes (self-declaration and/or BG < 70 mg/dL) in
5 subjects were observed with degludec compared with
65 episodes with glargine in 5 subjects. Fewer confirmed
hypoglycemic episodes were reported for degludec than
glargine.
5. DISCUSSION
Changing glargine to degludec reduced the mean FBG
value but not mean PDBG values. More important,
however, is that both the SD values and the fluctuations
in blood glucose became smaller (Figure 4). This is be-
cause, if blood glucose levels are stabilized, adjustment
of the insulin dose is made easier. (If the blood glucose
level is always high, you need only to increase the dose
of acting insulin; conversely, if it is always low, you need
only to decrease its dose.) By switching from glargine to
degludec, the mean value of FBG decreased, but that of
PDBG remained unchanged. This may have been be-
cause, whereas glargine was administered twice a day—
in the morning and evening—in all the subjects (with the
exception of one), degludec was administered once a day
in the evening. Glargine has a shorter duration of action
than degludec; however, if administered in the morning
as well, its effectiveness in reducing pre-dinner blood
glucose appears to be not inferior to that of degludec.
Since fluctuations were seen in the effects, however, hy-
perglycemic (≥180 mg/dL) days and hypoglycemic (<70
mg/dL) days were believed to have occurred frequently,
increasing the SD. Due to this switchover from glargine
to degludec, the SD values of both FBG and PDBG de-
creased, so degludec appears to have exerted more steady
hypoglycemic actions (the day-to-day variability in the
glucose-lowering effect is narrow) on a fasting and prior
to dinner. In other words, the appearance of insulin ac-
tion from about 8 hours after injection to about 15 hours
was believed to change less for each injection of de-
gludec than with glargine [4,6].
Because of the switchover to degludec, all the indica-
tors of blood glucose control, namely HbA1c, GA, and
1.5-AG, improved. The rate of improvement was the
greatest in 1.5-AG, followed by GA and HbA1c, in that
order. The major reason for this may have been that the
evaluation period was short, at only 28 days. The sup-
Mean
Blood glucose
Effect of insul in a t the sa m e ti me
2SD1 2SD1
2SD2 2SD2
70 mg / dL180 mg / dL
Insulin glargine
Insulin degludec
Figure 4. This figure schematically shows the changes in blood
glucose distribution that occurred as a result of switching from
insulin glargine to insulin degludec. Even though the mean
blood glucose value did not change very sharply, the SD nar-
rowed (from SD1 to SD2), so the frequency of hyperglycemia
exceeding 180 mg/dL and hypoglycemia falling below 70
mg/dL appears to have decreased. Especially problematic is the
reduction in the number of events of severe hypoglycemia of
below 50 mg/dL and severe hyperglycemia of over 200 mg/dL
(inside the circle in the diagram). This is because the blood
glucose levels at both of these extremes are the most strongly
related to the onset of such events in the patients. In other
words, this shows that manifestation of insulin effects at the
same time period is markedly more constant in degludec than in
glargine.
pression of a rise in blood glucose levels during brief
periods that are unlikely to be reflected in HbA1c (but
which are reflected in GA values), as well as a reduction
in the frequency and numerical value of blood glucose
levels exceeding the level at which urinary glucose gen-
erally begins appearing (≥180 mg/dL) (reflected in 1.5-
AG values), were largely reflected in GA and 1.5-AG
values, to a greater extent than HbA1c values. In other
words, minor fluctuations in blood glucose appear to
have decreased. This also shows that degludec demon-
strated more steady hypoglycemic actions (the day-to-
day variability in the glucose-lowering effect is narrow)
than glargine.
One option for patients with wide blood glucose fluc-
tuations that make setting the dose of long-acting insulin
difficult may be to switch long-acting insulin to degludec
with the aim of stabilizing their blood glucose level.
6. CONCLUSION AND LIMITATION
The biggest problem with this study is the very small
sample size and a single arm non-controlled study. Thus,
it will be necessary to carry out further studies on a lar-
ger scale randomized control trial or cross-over study.
The number of the study participants was too small to
draw any firm conclusion. Because this was a single arm

S. Ogawa et al. / Journal of Diabetes Mellitus 3 (2013) 244-251 251
non-controlled study, the improved glycemic fluctuation
could be explained by “regression to the mean” phe-
nomenon. The sample size was too small to do the analy-
sis and to compare the efficacy and safety of insulin de-
gludec and insulin glargine in diabetic patients. However,
this report is a previous work to lead a further research in
the future. We hope our report becomes provisions of a
further research in the future.
7. ACKNOWLEDGEMENTS
The authors acknowledge the editorial assistance and clinical support
of Miss Manami Simizu for her help with preparing the references and
for their expert assistance with the management of clinical data. We
would like to express our sincere gratitude to all the study subjects who
measured with many SMBG for this study.
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