2017, 64 (1), 1-10

Advance Publication

doi: 10.1507/endocrj.EJ17-0206

Original

Comparison of tofogliflozin 20 mg and ipragliflozin 50 mg
used together with insulin glargine 300 U/ml using continuous
glucose monitoring (CGM): A randomized crossover study
Soichi Takeishi, Hiroki Tsuboi and Shodo Takekoshi
Department of Diabetes, General Inuyama Chuo Hospital, Inuyama 484-8511, Japan

Abstract. To investigate whether sodium glucose co-transporter 2 inhibitors (SGLT2i), tofogliflozin or ipragliflozin,achieve optimal glycemic variability, when used together with insulin glargine 300 U/mL (Glargine 300). Thirty patientswith type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20 mg wasadministered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level with
Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using continuous glucose monitoring(CGM); Tofogliflozin was then washed out over 5 days; Subsequently, ipragliflozin 50 mg was administered; FPG levels
were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels
were continuously monitored for 2 days using CGM. For the second group, ipragliflozin was administered prior to
tofogliflozin, and the same regimen was maintained. Glargine 300 and SGLT2i were administered at 8:00 AM. Data
collected on the second day of measurement (mean amplitude of glycemic excursion [MAGE], average daily risk range[ADRR]; on all days of measurement) were analyzed. Area over the glucose curve (<70 mg/dL; 0:00 to 6:00, 24-h), M
value, standard deviation, MAGE, ADRR, and mean glucose levels (24-h, 8:00 to 24:00) were significantly lower inpatients on tofogliflozin than in those on ipragliflozin. Tofogliflozin, which reduces glycemic variability by preventing
nocturnal hypoglycemia and decreasing postprandial glucose levels, is an ideal SGLT2i when used together with Glargine
300 during basal insulin therapy.
Key words: Tofogliflozin, Insulin glargine 300 U/ml, Continuous glucose monitoring

BASAL INSULIN THERAPY, in which the patient’s
preferences and view-points are considered, is effective and safe, and has been commonly used as a partof insulin therapy. Basal insulin therapy can support basal and bolus insulin secretion by combining
once-daily dosage of basal insulin and oral hypoglycemic agents (OHA). In the ideal basal insulin therapy,
basal insulin is used to decrease fasting plasma glucose (FPG) levels, reducing the occurrence of hypoglycemia, while an oral hypoglycemic agent is used
to decrease postprandial glucose levels, reducing theoccurrence of hypoglycemia.
A relationship between nocturnal hypoglycemia
and sudden death has been suggested [1]. As per
Submitted May 12, 2017; Accepted Jul. 11, 2017 as EJ17-0206
Released online in J-STAGE as advance publication Aug. 18, 2017

Correspondence to: Soichi Takeishi, M.D., Department of
Diabetes, General Inuyama Chuo Hospital, 6, Futagozuka,
Goromaru, Inuyama-city, Aichi, 484-8511, Japan.
E-mail: souichi19811225@yahoo.co.jp
University Medical Information Network (no. UMIN000023972)©The Japan Endocrine Society

the Somogyi phenomenon, nocturnal hypoglycemia
causes an increase in the difference between pre- andpost-breakfast glucose levels [2], and this leads to anincrease in daytime glucose levels. Thus, hypoglycemia and increased glycemic variability occur at thesame time during the Somogyi phenomenon. Largeclinical studies have shown that hypoglycemia andglycemic variability are associated with mortality inpatients with diabetes mellitus [3-5]. We wanted to predict the Somogyi phenomenon, in which hypoglycemia
and increased glycemic variability occur concomitantly,
and we have previously reported that major increases
between pre- and post-breakfast glucose levels may
predict nocturnal hypoglycemia in type 2 diabetes [6].
When the Somogyi phenomenon is suspected,
reducing both nocturnal hypoglycemia and increases
in daytime glucose levels through increases between
pre- and post-breakfast glucose levels, establishing anappropriate control of pre-breakfast glucose levels, isnecessary [1, 4, 7]. We believe that long-acting insulin
to reduce nocturnal hypoglycemia, and OHA to reduce

2

Takeishi et al.

daytime (postprandial) glucose levels efficiently is useful in basal insulin therapy.
Sodium glucose co-transporter 2 inhibitors (SGLT2i)
are useful OHAs that decrease glucose levels in a glucose-level dependent manner with a single agent [8]and that leads to many second order effect, such as
decrease in body weight and blood pressure [9]. It
has been reported that tofogliflozin taken in the morning decreases postprandial glucose levels of about 70
mg/dL and FPG of about 35 mg/dL [10]. In contrast,
It has also been reported that ipragliflozin decreases
postprandial glucose levels of about 60 mg/dL andFPG of about 45 mg/dL [11]. From those reports, we
can estimate that the effect of tofogliflozin is stronger during the daytime and weaker during the nighttime than that of ipragliflozin even though there are nodifferences between the overall effects of tofogliflozin
or ipragliflozin. Thus, an optimal SGLT2i used inbasal insulin therapy, tofogliflozin taken in the morning may decrease postprandial glucose levels morethan ipragliflozin. In addition, SGLT2i when used
together with insulin, increases the risk of hypoglycemia. Therefore, when SGLT2i is used together withinsulin, if the effect of the SGLT2i remains at nighttime, the risk of hypoglycemia is thought to increase,because of the combined effect of SGLT2i and insulin.
It has been reported that tofogliflozin has the shortest
half-life among all other SGLT2i [12] and that a rate ofurinary tofogliflozin excretion is more than 80 % at thetime of 12 h after administration [12]. It has also beenreported that a rate of urinary tofogliflozin excretion ismore than 96 % at the time of 24 h after administrationand only about 3 % during 24 h ~ 48 h after administration [12]. Thus, morning administeration of tofogliflozin may reduce the risk of hypoglycemia because
the SGLT2i’s effects almost disappear by nighttime
and there are almost no overcarrying effect since 24 hafter administration.
Regarding reduction of nocturnal hypoglycemia, it
was observed that nocturnal and overall occurrenceof hypoglycemic events were significantly reduced inpatients on insulin glargine 300 U/ml (Glargine 300), as
opposed to insulin glargine 100 U/ml [13]. Therefore,
Glargine 300 is thought to be a useful long-acting insulin for reducing nocturnal hypoglycemia.
Thus, combination therapy using Glargine 300 (considered to help in decreasing pre-breakfast glucose levels, reducing the occurrence of nocturnal hypoglycemia) and tofogliflozin (considered to help in reducing

the occurrence of nocturnal hypoglycemia when used
together with insulin and in decreasing postprandial
glucose levels) administered in the morning, may be an
ideal basal insulin therapy using SGLT2i. To investigate whether tofogliflozin decreases the occurrence ofnocturnal hypoglycemia and postprandial glucose levels when used together with insulin, we compared theeffects of tofogliflozin 20 mg + Glargine 300, to thatof ipragliflozin 50 mg + Glargine 300, using continuous glucose monitoring (CGM) in a randomized crossover study.

Materials and Methods
Study design and patient selection
Nocturnal urinary frequency of the ipragliflozingroup is 1.7 ± 0.7 times, as reported by Yoshida in aclinical trial investigating urinary frequency of patientsadministered tofogliflozin [14]. Thirty individuals
were required in each control group and treatmentgroup, in order to be able to detect a 30% alteration in
the mean nocturnal urinary frequency, with an α valueof 0.05 and with a statistical power of 80%. We therefore determined that the total number of participantsrequired was 30.
Thirty patients with type 2 diabetes, treated with
Glargine 300 during basal insulin therapy for 3 months
or longer, were randomly allocated into 2 groups. For
the first group (T/I group): After admission, tofogliflozin 20 mg was administered once daily; FPG levels were titrated using an algorithm made refering to aclinical trial [FPG levels on the day of dosage adjustment, dosage adjustment of Glargine 300 (U/day): FPG
levels ≥ 180 mg/dL, +4; 140 mg/dL ≤ FPG levels <180 mg/dL, +3; 110 mg/dL ≤ FPG levels < 140 mg/
dL, +2; 90 mg/dL ≤ FPG levels < 110 mg/dL, +1; 80
mg/dl ≤ FPG levels < 90 mg/dl, no change; FPG levels < 80 mg/dL, -2; adjustment on every second day][13] and stabilized at 80 mg/dL level with Glargine
300 for 5 days; Next, glucose levels were continuously monitored for 2 days using the continuous glucose monitoring (CGM) device; Tofogliflozin was thenwashed out over the next 5 days; Subsequently, ipragliflozin 50 mg was administered once daily; FPG levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days;
Next, glucose levels were continuously monitored for
2 days using the CGM device. For the second group(I/T group), ipragliflozin was administered prior to

Endocrine Journal Advance Publication

3

Comparison of SGLT2i + Glargine 300 by CGM

tofogliflozin, and the same regimen was maintained(Fig. 1). Patients were allocated to groups using a random number table, and the study design was continuous and prospective. Glargine 300 and SGLT2i wereadministered at 8:00 AM. The Glargine 300 dose wasadjusted to be constant no later than start of continuous glucose monitoring. The Glargine 300 dose wasconstant during the CGM measurement period. FPG
levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 during washing out. Data collected on the second day of measurement (mean amplitude of glycemic excursion (MAGE)[15], mean of daily differences (MODD) [16], average daily risk range (ADRR) [17]: all days of measurement) were analyzed. Regarding other diabetic treatments, sulfonylurea agents, α- glucosidase inhibitors,
rapid-acting insulin secretagogues, and glucagon-like
peptide-1 receptor agonists were discontinued after
enrollment. All other treatments were continued during the research period. The total caloric intake forsubjects was defined by the attending physicians as
1,440 kcal, 1,600 kcal, or 1,840 kcal per day, to accommodate differences in physique among the subjects[18]. Test meals were given to each patient, based onrecommendations by the Japan Diabetes Society [component ratio of calories (carbohydrates 60%, proteins
18%, and lipids 22%), (breakfast 30% of total calories,

Tofogliflozin 20 mg(n=15)

Titration (FPG 80 level)

lunch 35% of total calories, and supper 35% of total
calories)], irrespective of differences in physique during the CGM measurement period. Physical activity
during the reserch period was 1.5 metabolic equivalents, based on the analysis of baseline data. Patients
whose estimated glomerular filtration rate was lessthan 45 ml/min/1.73m2 or were judged to be unsuitable for participation for other medical reasons, were
excluded from this study.
Patients who provided informed concent were
included in this study and we performed this study
based on Helsinki Declaration. The study protocol
was approved by the Ethical Committee of General
Inuyamachuo Hospital (authorization no. III, 2016),
and was registered in a clinical trial database with
the University Medical Information Network (no.
UMIN000023972).
Outcomes and statistical analysis
Nighttime was defined as 0:00-6:00 and hypoglycemia was defined as glucose level less than 70 mg/
dL [13].
The primary CGM endpoint included area over the
glucose curve (AOC) (<70 mg/dL) (0:00-6:00, 24 h),
M-value (0:00-6:00 (target glucose level = 90)) [19],MAGE, ADRR, mean glucose level (8:00-24:00), standard deviation (SD) (0:00-6:00, 8:00-24:00) [20].

Wash out
CGM

Subject

Ipragliflozin 50 mg
Titration (FPG 80 level)

CGM

Hospitalization(n=15)

Three month or longer

Ipragliflozin 50 mg

Wash out

Titration (FPG 80 level)

CGM

5 days2 daysTofogliflozin 20 mg
Titration (FPG 80 level)

CGM

5 days2 days

5 daysFig. 1 Study protocol
Thirty patients with type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20
mg was administered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level(80 level) with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using the continuous
glucose monitoring (CGM) device; Tofogliflozin was then washed out over the next 5 days; Subsequently, ipragliflozin 50 mg
was administered; FPG levels were titrated using the same algorithm and stabilized at 80 level with Glargine 300 for 5 days;
Next, glucose levels were continuously monitored for 2 days using the CGM device. For the second group, ipragliflozin was
administered prior to tofogliflozin, and the same regimen was maintained. The Glargine 300 dose was adjusted to be constant nolater than start of continuous glucose monitoring. The Glargine 300 dose was constant during the CGM measurement period.

Endocrine Journal Advance Publication

4

Takeishi et al.

The secondary CGM endpoint included AOC (<70mg/dL) (8:00-24:00), M-value (24 h (target glucose
level = 100), 8:00-24:00 (target glucose level = 120))[19], MODD, mean glucose level (24 h, 0:00-6:00),
SD (24 h) [20], area under the glucose curve (AUC)(≥140 mg/dL) within 3 hours of each meal [21], and
AUC (≥0 mg/dL) in 24 hours [21]. The secondary urinary endpoint included urinary glucose level (0:006:00, 6:00-24:00, 24 h), urinary frequency (0:00-6:00,
6:00-24:00, 24 h) and urinary volume (0:00-6:00,
6:00-24:00, 24 h).
Data are shown as median (interquartile range).
Statistical analysis was performed with Wilcoxon
signed-rank test. A p value of less than 0.05 was considered significant. The data were analyzed using the
BellCurve for Excel software program (Social Survey
Research Information Co., Ltd.).

Results
Clinical characteristics of the patient
Table 1 shows the patients’ clinical characteristics. The study included 20 men and 10 women. The
baseline characteristics were as follows: age, 73.0
(66.0-79.0) years; duration of diabetes, 10.0 (5.019.5) years; Body Mass Index (BMI), 23.1 (19.7-24.9)kg/m2; HbA1c, 8.3 (7.4-8.7) %; C-peptide immunoreactivity (CPR), 1.2 (0.6-1.7) ng/mL; FPG level, 123.0(94.5-147.0) mg/dL; C-peptide index, 0.8 (0.5-1.2);
urine-CPR, 25.6 (14.2-45.0) μg/day; and estimatedglomerular filtration rate (eGFR), 54.2 (46.6-72.6).
All the characteristics were not significantly different
between T/I group and I/T group (Table 1).
Outcomes
Fig. 2 shows the glycemic variability over 24 hoursof CGM in all patients.
The results of primary endpoint are shown as follows: AOC (<70 mg/dL) (0:00-6:00, 24 h) was significantly lower in patients on tofogliflozin than in thoseon ipragliflozin (p=0.001, p=0.0002, respectively); Mvalue (0:00-6:00) was significantly lower in patients on
tofogliflozin than in those on ipragliflozin (p<0.0001);
MAGE was significantly lower in patients on tofogliflozin than in those on ipragliflozin (p=0.0003);
ADRR was significantly lower in patients on tofogliflozin than in those on ipragliflozin (p=0.001); Mean
glucose levels (8:00-24:00) was significantly lower inpatients on tofogliflozin than in those on ipragliflozin(p=0.0001); SD (0:00-6:00, 8:00-24:00) was significantly lower in patients on tofogliflozin than in thoseon ipragliflozin (p=0.0007, p=0.0001, respectively).

Table 1 Baseline characteristics
Characteristic
Total
T/I group
I/T groupp (T/I versus I/T)
N (Male / Female)
30 (20 / 10)
15 (9 / 6)
15 (11 / 4)
p2=0.44
Age, years
73.0 (66.0-79.0)
74.0 (66.5-79.5)
71.0 (59.5-77.5)
p1=0.41
Duration of diabetes, years
10.0 (5.0-19.5)
10.0 (7.0-15.5)
7.0 (4.5-22.0)
p1=0.53
23.1 (19.7-24.9)
23.9 (20.8-25.5)
21.4 (19.3-24.7)
p1=0.47
BMI, kg/m2
HbA1c (NGSP), %8.3 (7.4-8.7)
8.4 (7.3-8.8)
7.8 (7.5-8.6)
p1=0.88GA, %22.7 (17.2-27.1)
22.2 (18.2-25.3)
24.1 (17.2-28.5)
p1=0.66
CPR, ng/mL
1.2 (0.6-1.7)
1.2 (0.7-1.7)
1.2 (0.6-1.7)
p1=0.88
FPG, mg/dL
123.0 (94.5-147.0)
122.0 (94.0-160.5)
124.0 (105.5-136.5)
p1=0.77CPI
0.8 (0.5-1.2)
0.8 (0.7-1.3)
0.9 (0.4-1.1)
p1=0.98
U-CPR, μg/day
25.6 (14.2-45.0)
21.8 (13.6-42.5)
26.2 (14.2-44.4)
p1=0.7154.2 (46.6-72.6)
55.6 (45.8-67.0)
54.2 (46.7-84.5)
p1=0.71
eGFR, ml/min/1.73m2
Biguanide agent, n (%)
18 (60.0)
8 (53.3)
10 (60.0)
p2=0.46
Thiazolidine, n (%)
3 (10.0)
3 (10.0)0 (0)p2=0.07
DPP4 inhibitor, n (%)
23 (76.7)
12 (80.0)
11 (73.3)
p2=0.67
ACE inhibitor, n (%)
1 (6.7)1 (6.7)0 (0)p2=0.31
ARB, n (%)
9 (30.0)
4 (26.7)
5 (33.3)
p2=0.69
Statin, n (%)
7 (23.3)
2 (13.3)
5 (33.3)
p2=0.2
Data are shown as median (interquartile range). p1: Mann-Whitney’s U test, p2 : Chi-square test. BMI, body mass index; HbA1c,
glycosylated hemoglobin; GA, glycoalbumin; CPR, C-peptide immunoreactivity; FPG, fasting plasma glucose; CPI, C-peptide index;
U-CPR, urine-CPR; eGFR, estimated glomerular filtration rate; DPP, dipeptidyl-peptidase; ACE inhibitor, angiotensin-converting
enzyme inhibitor; ARB, angiotensin II receptor blocker; T/I, Tofogliflozin (first) / Ipragliflozin (second); I/T, Ipragliflozin (first) /Tofogliflozin (second).

Endocrine Journal Advance Publication

5

Comparison of SGLT2i + Glargine 300 by CGM

300(N = 30)250

Glucose levels (mg/dL)

200

150

100

50
Thick lines: MedianFine lines: Interquartile ranges

Tofogliflozin 20 mg
Ipragliflozin 50 mg

0
0:00

2:00

4:00

6:00

8:00

10:00

12:00

14:00

16:00

18:00

20:00

22:00

24:00
Time

Fig. 2 The graph indicates glycemic variability over 24 h on CGM in patients during treatment with tofogliflozin 20 mg + Glargine
300 or ipragliflozin 50 mg + Glargine 300. Glucose levels were calculated from the value of CGM on the second measurementday. Data are shown as median (thick lines) and interquartile ranges (fine lines).

The results of secondary endpoint are shown as follows: M value (24 h, 8:00-24:00) was significantly
lower in patients on tofogliflozin than in those on ipragliflozin (p=0.008, p=0.0003, respectively); Mean glucose levels (24 h) was significantly lower in patients on
tofogliflozin than in those on ipragliflozin (p=0.009);
SD (24 h) was significantly lower in patients on tofogliflozin than in those on ipragliflozin (p=0.0002);
AUC (≥140 mg/dL) within 3 hours after every meal
was significantly lower in patients on tofogliflozin thanin those on ipragliflozin (p=0.02, p=0.003, p=0.0003,
respectively); AUC (≥0 mg/dL) in 24 hours was significantly lower in patients on tofogliflozin than inthose on ipragliflozin (p=0.007); Urinary glucose level(0:00-6:00, 24 h) was significantly lower in patients on
tofogliflozin than in those on ipragliflozin (p=0.0002,
p=0.03, respectively); Urinary glucose level (6:0024:00) was not significantly different between groups;
Urinary frequency (0:00-6:00, 6:00-24:00, 24 h) was
significantly lower in patients on tofogliflozin than inthose on ipragliflozin (p<0.0001, p=0.03, p<0.0001,
respectively); Urinary volume (0:00-6:00) was significantly lower in patients on tofogliflozin than in thoseon ipragliflozin (p=0.0007) (Table 2).

FPG levels and insulin doses on the last day of thefirst intervention were 85.0 (82.3-89.0) mg/dL, 21.5
(14.0-30.0) U/day, respectively. Those on the first dayof the second intervention were 91.0 (82.3-100.5) mg/
dL, 21.0 (12.5-29.5) U/day, respectively.
Table 3 shows parameters of Table 2 in T/I group
and I/T group.
In T/I group, FPG levels and insulin doses on thelast day of the first intervention were 87.0 (81.0-89.0)
mg/dL, 22.0 (12.0-30.0) U/day, respectively. Those on
the first day of the second intervention were 92.0 (84.098.0) mg/dL, 24.0 (10.0-29.0) U/day, respectively. In
I/T group, FPG levels and insulin doses on the last dayof the first intervention were 85.0 (83.0-89.0) mg/dL,
21.0 (16.0-28.0) U/day, respectively. Those on the firstday of the second intervention were 88.0 (82.5-100.0)
mg/dL, 20.0 (16.0-28.0) U/day, respectively.
In patients on ipragliflozin, 21 (70%) patients had
nocturnal hypoglycemia. We investigated the relationship between the risk of nocturnal hypoglycemia and
BMI in patients on ipragliflozin. Low BMI was significantly associated with increased nocturnal hypoglycemia (odds ratio 0.51, 95% confidence interval[CI] 0.29-0.88; p=0.02: logistic regression analysis).

Endocrine Journal Advance Publication

6

Takeishi et al.

Table 2 Parameters of glycemic variability and urinary (and basal insulin dose) in patients treated with
tofogliflozin 20 mg + insulin glargine 300 U/ml or ipragliflozin 50 mg + insulin glargine 300 U/ml
Tofogliflozin 20 mg
0:00 to 6:00 area over the glucose curve(AOC) (<70 mg/dL), mg·min/dL
24 h AOC (<70 mg/dL),mg·min/dL
8:00 to 24:00 AOC (<70 mg/dL),mg·min/dL
24 h M-value(target glucose level = 100 mg/dl)
0:00 to 6:00 M-value(target glucose level = 90 mg/dl)
8:00 to 24:00 M-value(target glucose level = 120 mg/dl)
Mean amplitude of glycemic
excursion (MAGE), mg/dL
Mean of daily difference (MODD),
mg/dL
Average daily risk range (ADRR)
24 h mean glucose level,
mg/dL
0:00 to 6:00 mean glucose level,
mg/dL
8:00 to 24:00 mean glucose level,
mg/dL
24 h standard deviation (SD),mg/dL
0:00 to 6:00 SD,
mg/dL
8:00 to 24:00 SD,
mg/dL

Ipragliflozin 50 mg

p

0 (0-0)162.2 (0-1,698.8)

0.001

0 (0-0)329.6 (0-2,596.9)

0.002

0 (0-0)0 (0-0)0.35

7.3 (4.0-14.6)

11.4 (5.1-20.6)

0.008

0.4 (0.1-1.0)

3.1 (1.3-5.4)<0.0001

3.8 (1.7-7.3)

6.6 (2.4-15.0)

0.000351.1 (36.7-74.6)

71.9 (48.0-87.2)

0.000321.5 (16.9-28.1)

22.9 (15.8-31.6)

0.57

10.3 (5.9-20.0)

22.0 (9.9-29.3)

0.001

132.8 (118.0-149.8)

141.7 (120.0-159.6)

0.009

92.2 (84.6-98.2)

96.4 (72.2-118.3)

0.86

147.3 (128.3-167.8)

157.9 (139.8-194.0)

0.000135.9 (23.6-54.1)

50.2 (31.7-62.5)

0.0002

6.3 (4.6-11.3)

12.3 (9.2-17.6)

0.000731.1 (20.0-40.9)

42.7 (24.8-52.8)

0.0001

6,648.8(2,796.9-10,985.3)
4,841.3(174.1-16,889.4)
5,520.8(1,643.3-12,327.9)
191,275.8(169,952.7-215,651.3)

8,983.1(3,859.4-19,010.9)
10,272.5(3,254.4-23,915.0)
12,574.4(4,997.8-23,417.1)
202,345.5(172,852.3-230,015.2)

20.5 (12.0-30.0)

21.5 (14.0-30.8)

0.16

2.9 (1.1-5.8)

6.8 (3.0-9.8)

0.000227.1 (16.3-41.0)

26.9 (15.9-40.1)

0.7

30.3 (20.7-45.0)

34.5 (20.7-49.8)

0.03

1.0 (1.0-2.0)

2.0 (1.25-3.0)<0.0001

6.0 (5.0-7.0)

7.0 (5.0-8.0)

0.03

7.0 (5.3-8.8)

9.0 (7.0-10.8)<0.0001

245.0 (102.5-400.0)

500.0 (350.0-500.0)

0.0007

1,175.0 (812.5-1,537.5)

1,110.0 (912.5-1,500.0)

0.73

1,400.0 (1,112.5-1,800.0)

1,635.0 (1,255.0-2,000.0)

0.08

Area under the glucose curve (AUC)(≥140 mg/dL) within 3 hours after
each meal, mg·min/dL
Breakfast
Lunch
Supper24 h AUC (≥0 mg/dL),mg·min/dL
Basal insulin dose,
U/day
0:00 to 6:00 urinary glucose level,g/day
6:00 to 24:00 urinary glucose level,g/day
24 h urinary glucose level,g/day
0:00 to 6:00 urinary frequency,
times/day
6:00 to 24:00 urinary frequency,
times/day
24 h urinary frequency,
times/day
0:00 to 6:00 urinary volume,
mL/day6:00 to 24:00 urinary volume,
mL/day24 h urinary volume,
mL/day0.02
0.003
0.00030.007

Data are shown as median (interquartile range). p: Wilcoxon signed-rank test. Primary endpoint parameters are
represented by bold font.

Endocrine Journal Advance Publication

7

Comparison of SGLT2i + Glargine 300 by CGM

Table 3 Parameters of Table 2 in T/I group and I/T group
T/I group
Tofogliflozin 20 mg
0:00 to 6:00 area over the glucose curve(AOC) (<70 mg/dL), mg·min/dL
24 h AOC (<70 mg/dL),mg·min/dL
8:00 to 24:00 AOC (<70 mg/dL),mg·min/dL
24 h M-value(target glucose level = 100 mg/dl)
0:00 to 6:00 M-value(target glucose level = 90 mg/dl)
8:00 to 24:00 M-value(target glucose level = 120 mg/dl)
Mean amplitude of glycemic
excursion (MAGE), mg/dL
Mean of daily difference (MODD),
mg/dL
Average daily risk range (ADRR)
24 h mean glucose level,
mg/dL
0:00 to 6:00 mean glucose level,
mg/dL
8:00 to 24:00 mean glucose level,
mg/dL
24 h standard deviation (SD),mg/dL
0:00 to 6:00 SD,
mg/dL
8:00 to 24:00 SD,
mg/dL

I/T group

Ipragliflozin 50 mg

p

0 (0-0)300.0 (0-1,931.3)

0.09

0 (0-30)

359.3 (0-2,145.0)

0 (0-0)Tofogliflozin 20 mg

Ipragliflozin 50 mg

p

0 (0-0)129.3 (3.8-1,545.0)

0.004

0.09

0 (0-0)300.0 (3.8-3,210.0)

0.004

0 (0-0)0.32

0 (0-0)0 (0-0)0.47

9.8 (5.8-17.2)

10.7 (4.2-21.9)

0.28

6.1 (2.5-11.1)

12.1 (5.5-18.8)

0.005

0.5 (0.1-1.3)

2.0 (1.0-4.4)

0.001

0.3 (0.1-0.7)

4.4 (2.8-5.4)

0.001

5.3 (2.4-11.3)

6.1 (2.8-14.9)

0.04

2.6 (1.0-5.9)

9.1 (2.2-14.8)

0.002

55.4 (38.3-82.7)

72.2 (48.6-91.2)

0.02

51.0 (33.1-64.9)

71.6 (44.7-86.8)

0.006

21.7 (19.3-26.2)

18.8 (17.2-29.2)

0.73

20.7 (15.8-29.6)

23.3 (15.3-31.4)

0.26

10.8 (6.9-16.2)

26.0 (11.2-28.7)

0.04

9.2 (5.5-21.3)

21.4 (9.2-29.4)

0.009

137.2 (129.0-159.2)

138.2 (130.6-153.2)

0.5

120.6 (108.4-140.8)

144.1 (119.3-165.9)

0.005

94.9 (84.8-101.9)

95.3 (73.2-115.0)

0.65

92.1 (85.5-95.5)

97.0 (75.8-119.4)

0.5

153.0 (144.4-174.9)

157.0 (144.3-191.6)

0.06

141.4 (125.5-159.5)

173.5 (140.3-192.3)

0.000735.0 (25.0-58.9)

50.3 (33.4-67.8)

0.009

36.8 (21.8-45.5)

50.0 (30.4-56.8)

0.006

5.7 (4.5-8.1)

13.1 (10.6-18.5)

0.003

8.9 (5.0-12.3)

9.4 (7.8-13.2)

0.13

37.6 (21.6-47.6)

45.0 (26.8-51.5)

0.009

25.0 (16.4-39.7)

42.5 (23.0-52.4)

0.005

9,436.3(4,365.6-17,183.8)
11,431.3(2,831.3-15,848.7)
10,412.5(3,698.8-15,230.6)
197,988.5(185,784.0-229,046.6)

10,125.0(4,791.3-19,475.0)
11,500.0(4,793.3-23,492.5)
13,298.8(5,028.1-24,641.9)
198,790.0(188,139.7-220,671.9)

5,385.0(408.8-8,377.5)
517.5(0-13,174.4)
5,061.7(6.4-8,938.8)
173,634.7(156,112.0-202,726.8)

6,598.8(1,685.0-17,868.1)
7,131.3(2,003.1-18,760.0)
11,850.0(5,919.8-19,151.4)
202,345.5(171,776.9-239,016.7)

22.0 (12.0-30.0)

24.0 (8.5-30.5)

0.53

18.0 (13.5-26.5)

21.0 (16.0-28.0)

0.17

3.1 (1.7-5.8)

6.2 (3.4-9.3)

0.03

2.5 (0.5-6.5)

7.4 (2.4-10.4)

0.001

25.8 (19.4-40.0)

26.6 (21.3-34.2)

0.61

30.1 (15.2-41.4)

30.8 (13.7-42.4)

0.75

30.2 (24.7-42.3)

34.3 (28.2-40.9)

0.51

33.4 (18.0-43.7)

40.2 (17.7-51.2)

0.02

1.0 (1.0-2.0)

2.0 (2.0-3.0)

0.003

1.0 (0.5-2.0)

2.0 (1.0-2.0)

0.008

6.0 (5.0-7.0)

6.0 (5.0-9.0)

0.07

5.0 (4.5-7.0)

7.0 (5.5-7.5)

0.15

7.0 (7.0-8.5)

9.0 (7.0-10.5)

0.003

7.0 (5.0-8.5)

8.0 (7.5-10.0)

0.007

200.0 (125.0-395.0)

500.0 (375.0-500.0)

0.008

300.0 (50.0-500.0)

500.0 (340.0-500.0)

0.02

1,100.0 (725.0-1,250.0)

1,100.0 (770.0-1,425.0)

0.88

Area under the glucose curve (AUC)(≥140 mg/dL) within 3 hours after
each meal, mg·min/dL
Breakfast
Lunch
Supper24 h AUC (≥0 mg/dL),mg·min/dL
Basal insulin dose,
U/day
0:00 to 6:00 urinary glucose level,g/day
6:00 to 24:00 urinary glucose level,g/day
24 h urinary glucose level,g/day
0:00 to 6:00 urinary frequency,
times/day
6:00 to 24:00 urinary frequency,
times/day
24 h urinary frequency,
times/day
0:00 to 6:00 urinary volume,
mL/day6:00 to 24:00 urinary volume,
mL/day24 h urinary volume,
mL/day1,200.0 (900.0-1,775.0)

0.11
0.05
0.02
0.53

1,200.0 (1,060.0-1,550.0) 0.65

1,400.0 (1,200.0-1,975.0) 1,700.0 (1,560.0-2,000.0) 0.2

0.046
0.02
0.005
0.003

1,400.0 (1,050.0-1,800.0) 1,500.0 (1,155.0-2,000.0) 0.17

Data are shown as median (interquartile range). p: Wilcoxon signed-rank test. Primary endpoint parameters are represented by bold font.

Endocrine Journal Advance Publication

8

Takeishi et al.

1

0.8

Sensitivity

We determined cut-off value of BMI, which has thehighest prediction ability for nocturnal hypoglycemia,
by using receiver operating characteristic analysis.
When the cutoff value was 24.4 kg/m2, which has thehighest prediction ability, the sensitivity was 81% andthe specificity was 89%. The area under the curve for
nocturnal hypoglycemia was 0.93 (95% CI, 0.83-1.00;
p<0.0001) (Fig. 3).

0.6

0.4

Discussion
The results of this study suggest that tofogliflozin,which reduces glycemic variability by avoiding nocturnal hypoglycemia and decreasing daytime (postprandial) glucose levels, is an ideal SGLT2i when used
together with Glargine 300, during basal insulin therapy.
In this study, FPG levels were titrated to 80 mg/dL
level by Glargine 300. In this case, if we think that
nocturnal glucose levels are affected only by Glargine
300, nocturnal glucose levels are thought to be theoretically titrated to almost 80 mg/dL level. Tofogliflozin
has a short half-life, and when administered in themorning, its effect almost disappears by nighttime[12]. Therefore, further decreases in nocturnal glucose levels are not thought to be caused due to intake
of tofogliflozin. In contrast, ipragliflozin is thought topose a risk of further decrease in nocturnal glucose levels, in combination with insulin because ipragliflozin
has a long half-life, and therefore acts firmly during thenighttime [22]. We think that occurrence of nocturnaland overall hypoglycemia was significantly lower inpatients on tofogliflozin, than in those on ipragliflozin
because of the above-mentioned difference between
tofogliflozin and ipragliflozin.
In this study, the mean glucose level (0:00-6:00)
was not significantly different between patients on
tofogliflozin and ipragliflozin (this was expected,
because FPG levels were titrated at 80 mg/dL level).
M value (0:00-6:00) was significantly lower in patientson tofogliflozin, than in those on ipragliflozin. This
was thought to occur because nocturnal glucose levels
came closer to the target glucose levels (90 mg/dL) inpatients on tofogliflozin, than in those on ipragliflozin,
since occurrence of nocturnal hypoglycemia was significantly lower in patients on tofogliflozin, than inthose on ipragliflozin.
In this study, mean glucose level (8:00-24:00) andSD (8:00-24:00) were significantly lower in patients on
tofogliflozin, than in those on ipragliflozin. These were0.2

0

AUC 0.93 (95% CI: 0.83 - 1.00, p < 0.0001)
Cutoff: 24.4 kg/m2,
Sensitivity: 81%, Specificity: 89%
0

0.2

0.4
0.6
1 - Specificity

0.8

1Fig. 3 A Receiver Operating Characteristic (ROC) curve for
nocturnal hypoglycemia in Body Mass Index (BMI)
When the cutoff value was 24.4 kg/m2, which has thehighest prediction ability, the sensitivity was 81% andthe specificity was 89%. The area under the curve for
nocturnal hypoglycemia was 0.93 (95% CI, 0.83-1.00;
p<0.0001).

thought to occur because the effect of tofogliflozin
is suggested to be stronger during the daytime (andweaker during the nighttime) than that of ipragliflozin
even though there are no differences between the overall effects of tofogliflozin or ipragliflozin [10, 11]. The
reason of the following is estimated that a half-life of
tofogliflozin is shorter than that of ipragliflozin [12,22]. In contrast, the nocturnal effect of ipragliflozin
became less because SGLT2i decreases glucose levels
in a glucose level-dependent manner. Therefore, thismay have led to mean glucose levels (24 hours) also
being significantly lower in patients on tofogliflozin,
than in those on ipragliflozin.
In this study, MAGE, ADRR, and SD (24 hours)
were significantly lower in patients on tofogliflozin,
than in those on ipragliflozin. The effect of tofogliflozin which has a short half-life is suggested to bestronger during the daytime and disappears quickly
during nighttime, as compared to that of ipragliflozin,even though there are no differences between the overall effects of tofogliflozin and ipragliflozin [10-12, 22].
Therefore, daytime glucose levels were lower, andoccurrence of nocturnal hypoglycemia was lower inpatients on tofogliflozin, than in those on ipragliflozin.
This leads to reduced glycemic variability overall, andmaybe responsible for the results observed in this study.

Endocrine Journal Advance Publication

Comparison of SGLT2i + Glargine 300 by CGM

Further, we believe that tofogliflozin’s short half-life
led to this study results of urinary endpoint. From theviewpoint of adverse effect, tofogliflozin is superior
in reducing urinary frequency. Regarding that urinary
glucose level during the daytime in patients on tofogliflozin were almost the same as in those on ipragliflozin
and urinary frequency during the daytime was lower inpatients on tofogliflozin than in those on ipragliflozin
but blood glucose level during the daytime was lower inpatients on tofogliflozin than in those on ipragliflozin,
SGLT2i decreases blood glucose levels by lowering
renal glucose threshold, therefore, there is less necessity for tofogliflozin to excrete urinary glucose during
the daytime than ipragliflozin because blood glucose
level during the daytime was lower in patients on tofogliflozin than in those on ipragliflozin.
In a report supporting the results of this study, it
has been stated that the clinical effect of Glargine 300
lasts for 24 hours (steady state) [23]. Glargine 300 isthought to be useful long-acting insulin to decrease
FPG levels, reducing the occurrence of nocturnal hypoglycemia. It has also been reported that time-to-maximum blood concentration (Tmax) of tofogliflozin is
1.1 hours, and the half-life of tofogliflozin is 5.4 hours[12]. Approximately 17 hours after tofogliflozin istaken, only 12.5% of the Tmax remains. Therefore,
this supports the hypothesis that the effect of tofogliflozin taken in the morning almost disappears during
the nighttime. In contrast, it has been reported that
Tmax of ipragliflozin is 1.4 hours and its half-life is 15
hours [22]. Therefore, ipragliflozin affects the individual for a constant duration (steady state). Considering
together with the previous reports [10, 11], this supports the hypothesis that the effect of ipragliflozin persists during the nighttime, and that it does not have astrong effect only during the daytime.
It has been reported that the risk factors for hypoglycemia are low BMI and concomitant insulin use in
the elderly subjects with type 2 diabetes treated withipragliflozin [24]. We might also investigate the relationship between nocturnal hypoglycemia and BMI
in patients on ipragliflozin, therefore, we didn’t set alimit of BMI in selection criteria of study subjects. The
present study results suggest that patients who aren’t
obecity should avoid taking ipragliflozin and shouldtake tofogliflozin especially.
Clarifying role-sharing of supporting basal andbolus insulin secretion is important in order to clarify an approach of basal insulin therapy, and to realize

9

ideal glycemic variability during basal insulin therapy.
We examine both these therapies in this study. In the
combination therapy consisting of Glargine 300 + tofogliflozin, Glargine 300 supplies basal insulin and tofogliflozin supports bolus insulin secretion. Thus, therole-sharing of “basal + bolus” in this combination isclearly defined. In contrast, in the combination therapy
consisting of Glargine 300 + ipragliflozin, Glargine
300 supplies basal insulin and ipragliflozin supports
basal and bolus insulin secretion. Thus, role-sharing
in this case “basal + (basal + bolus)” is not distinct. It
is thought to be ideal if supply of basal insulin is left
to Glargine 300, and effects of OHA as well as supplying of bolus insulin are integrated into one drug, suchas tofogliflozin. In basal insulin therapy, supporting
basal insulin secretion by OHA leads to loss of efficacyof the OHA which decreases glucose levels in a glucose level-dependent manner, and carries a very highrisk of nocturnal hypoglycemia in the case of OHA
which decreases glucose levels in a glucose level-independent manner. In the case of SGLT2i, the effect islost because SGLT2i decreases glucose levels in a glucose level-dependent manner, and risk of hypoglycemia increases in combination with insulin. This is inefficient and increases risk to the patient; therefore, thiscombination is undesirable. In contrast, tofogliflozin
administered in the morning is efficient because tofogliflozin almost affects to support bolus insulin secretion and reduces the risk of nocturnal hypoglycemia in
combination with insulin, because its effect is stronger during the daytime and disappears during the nighttime. Therefore, we believe that tofogliflozin which isefficient and reduces risk of nocturnal hypoglycemia is
an ideal SGLT2i.
The results of this study suggest that tofogliflozin, which reduces glycemic variability by preventing nocturnal hypoglycemia and decreasing daytime(postprandial) glucose levels, is superior when used
together with Glargine 300 for basal insulin therapy,
compared to ipragliflozin. The combination therapy of
Glargine 300 + tofogliflozin may be the ideal therapy,
since it improves glycemic variability by supporting
basal and bolus insulin secretion accurately, reducing
the risk of nocturnal hypoglycemia maximally, during basal insulin therapy in which the patient’s preferences and view-point are considered. Thus, the clinical significance of this study is high. However, thepresent study was limited by certain factors. First, it
is a single facility, open-label study; second, this study

Endocrine Journal Advance Publication

10

Takeishi et al.

is demonstrated in pretty much short time; third, the
PK/PD comparative data between the action of tofogliflozin and that of ipragliflozin is not exist. We shallendeavor to address these limitations by gathering
more cases and conducting further clinical studies in
the future.

Acknowledgments
This work was supported in part by the General
Inuyamachuo Hospital.
S.T. (corresponding author) designed the study,
collected and analyzed the data, wrote and reviewed

the manuscript, and revised it critically for important
intellectual content. H.T. and S.T. contributed to thereview of the manuscript. S.T. (corresponding author)
is the guarantor of this work and, as such, had fullaccess to all the data in the study, and takes responsibility for the integrity of the data and the accuracy ofthe data analysis.

Disclosure
None of the authors have any relevant conflicts ofinterest to disclose.

References
1.

2.
3.

4.

5.

6.

7.

8.

Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto
M, Noto H, et al. (2014) Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic
patients. Diabetes Care 37: 217-225.
Bolli GB, Perriello G, Fanelli CG, De Feo P (1993)
Nocturnal blood glucose control in type I diabetes mellitus. Diabetes Care 16: 71-89.
Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ,
et al. (2010) Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.
Lancet 375: 481-489.
Mendez CE, Mok KT, Ata A, Tanenberg RJ, CallesEscandon J, et al. (2013) Increased glycemic variability
is independently associated with length of stay and mortality in noncritically ill hospitalized patients. Diabetes
Care 36: 4091-4097.
Takeishi S, Mori A, Hachiya H, Yumura T, Ito S, etal. (2016) Hypoglycemia and glycemic variability areassociated with mortality in non-intensive care unit hospitalized infectious disease patients with diabetes mellitus. J Diabetes Investig 7: 429-435.
Takeishi S, Mori A, Kawai M, Yoshida Y, Hachiya H, et al.
(2016) Major Increases between Pre- and Post-breakfast
Glucose Levels May Predict Nocturnal Hypoglycemia in
Type 2 Diabetes. Intern Med 55: 2933-2938.
Tanaka Y, Atsumi Y, Asahina T, Hosokawa K, Matsuoka
K, et al. (1998) Usefulness of revised fasting plasma glucose criterion and characteristics of the insulin responseto an oral glucose load in newly diagnosed Japanese diabetic subjects. Diabetes Care 21: 1133-1137.
Nagata T, Suzuki M, Fukazawa M, Honda K, Yamane
M, et al. (2014) Competitive inhibition of SGLT2 by
tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys.
Am J Physiol Renal Physiol 306: F1520-1533.

9.

10.

11.

12.

13.

14.
15.

Utsunomiya K, Shimmoto N, Senda M, Kurihara Y,
Gunji R, et al. (2017) Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A post-marketing study (J-STEP/EL
Study). J Diabetes Investig (in press).
Kaku K, Watada H, Iwamoto Y, Utsunomiya K, Terauchi
Y, et al. (2014) Efficacy and safety of monotherapy with
the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebocontrolled, double-blind, parallel-group comparative
study. Cardiovasc Diabetol 13: 65.
Common Technical Document, A Phase I study of
ASP1941 in healthy male volunteers The effect offood on the bioavailability of ASP1941, Ipragliflozin,
Astellas Pharma Inc.. Available at: http://www.pmda.
go.jp/drugs/2013/P201300172/index.html. Accessed
May 10, 2017.
Common Technical Document, A Phase I study of
CSG452 in healthy male volunteers The effect offood on the bioavailability of CSG452, Tofogliflozin,
Sanofi K.K., Kowa Company, Ltd. Available at: http://
www.pmda.go.jp/drugs/2014/P201400036/index.html.
Accessed March 08, 2017.
Terauchi Y, Koyama M, Cheng X, Takahashi Y, Riddle
MC, et al. (2016) New insulin glargine 300 U/ml versus
glargine 100 U/ml in Japanese people with type 2 diabetes using basal insulin and oral antihyperglycaemic
drugs: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 2). Diabetes Obes
Metab 18: 366-374.
Yoshida T (2015) Tofogliflozin in patients with obese
type 2 diabetes: Efficacy and impact of urinary frequency. Pro Med 35: 1225 (In Japanese).
Service FJ, Molnar GD, Rosevear JW, Ackerman E,
Gatewood LC, et al. (1970) Mean amplitude of gly-

Endocrine Journal Advance Publication

Comparison of SGLT2i + Glargine 300 by CGM

16.
17.

18.

19.
20.

cemic excursion, a measure of diabetic instability.
Diabetes 19: 644-655.
Service FJ, Nelson RL (1980) Characteristics of glycemic stability. Diabetes Care 3: 58-62.
Kovatchev BP, Otto E, Cox D, Gonder-Frederick L,
Clarke W (2006) Evaluation of a new measure of blood
glucose variability in diabetes. Diabetes Care 29:
2433-2438.
Nishimura R, Tsujino D, Taki K, Morimoto A, Tajima N(2010) Continuous glucose monitoring with Humalog
Mix 25 versus Humalog Mix 50, twice daily: a comparative pilot study -results from the Jikei-EValuationof insulin Lispro mixture on pharmacodynamics andglycemic VariancE (J-EVOLVE) study. Cardiovasc
Diabetol 9: 16.
Schlichtkrull J, Munck O, Jersild M (1965) The M-Valve,
An Index Of Blood-Sugar Control In Diabetics. Acta
Med Scand 177: 95-102.
Juvenile Diabetes Research Foundation Continuous
Glucose Monitoring Study Group (2010) Effectivenessof Continuous Glucose Monitoring in a Clinical Care

21.

22.

23.

24.

11

Environment: Evidence from the Juvenile Diabetes
Research Foundation Continuous Glucose Monitoring(JDRF-CGM) trial. Diabetes Care 33: 17-22.
Sakamoto M, Nishimura R, Irako T, Tsujino D, Ando K,
et al. (2012) Comparison of vildagliptin twice daily vs.
sitagliptin once daily using continuous glucose monitoring (CGM): crossover pilot study (J-VICTORIA study).
Cardiovasc Diabetol 11: 92.
Kadokura T, Zhang W, Krauwinkel W, Leeflang S,
Keirns J, et al. (2014) Clinical pharmacokinetics andpharmacodynamics of the novel SGLT2 inhibitor ipragliflozin. Clin Pharmacokinet 53: 975-988.
Monnier L, Owens DR, Bolli GB (2016) The new longacting insulin glargine U300 achieves an early steadystate with low risk of accumulation. Diabetes Metab 42:
77-79.
Terauchi Y, Yokote K, Nakamura I, Sugamori H (2016)
Safety of ipragliflozin in elderly Japanese patients with
type 2 diabetes mellitus (STELLA-ELDER): Interim
results of a post-marketing surveillance study. Expert
Opin Pharmacother 17: 463-471.

Endocrine Journal Advance Publication