Shinshu Med J, 66⑴：29～37, 2018

Long-term Effects of Ipragliflozin on Adipose Tissue in JapanesePatients with Obese Type 2 Diabetes
Shin-ichi Nishio1）2）＊†, Takashi Sekido1）†, Yohsuke Ohkubo1）2）
Ako Oiwa1） and Mitsuhisa Komatsu1）
1） Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine (4),Shinshu University School of Medicine
2） Research Center for Next Generation Medicine, Shinshu University School of Medicine

Objective and Methods : A long-term effect of ipragliflozin on adipose tissue mass reduction in Japanesepatients with obese type 2 diabetes (T2D) was investigated. Ipragliflozin was administered (50 mg/day) once
daily for 12 months. At 0, 3, 6 and 12 months, visceral and subcutaneous adipose tissue area was determined by
two different bioelectrical impedance methods, and blood samples for HbA1c, renal function, lipids and liverfunction obtained, and body weight and blood pressure recorded. The primary endpoint was decrease in bodyfat mass. Secondary endpoints included changes in body weight and the laboratory data.
Results : Seventeen of 20 participants (mean body mass index (BMI) 35.1±1.1 kg/m2) completed this prospective
observational study. Visceral fat area (cm2, mean±SD) at 0, 3, 6 and 12 months was 166.0±49.7, 149.7±46.1, 149.7±42.4 and 148.5±40.2, respectively : the value at 3 months was significantly lower than baseline (P＝0.027). Sub­cutaneous fat at the corresponding time points was 359.3±110.5, 316.6±87.1, 326.8±87.2 and 325.9±90.4, respec­tively : the values at each post treatment period was significantly less than the baseline (P＝0.003, 0.018 and0.036 for the three points, respectively). Body weight was significantly reduced by 12 months (P＝0.045). Serum
alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (γ-GTP) lev­els decreased significantly. There were no significant correlations between serum hepatobiliary enzyme levels
and Δbody weight or Δvisceral fat, but Δγ-GTP was correlated with Δsubcutaneous fat (Spearman’s P＝0.004).
Conclusion : During the 1 year interval, ipragliflozin significantly reduced subcutaneous adipose tissue andserum AST, ALT, and γ-GTP levels. Shinshu Med J 66 : 29―37, 2018
(Received for publication September 21, 2017 ; accepted in revised form September 26, 2017)
Key words : SGLT2 inhibitor, ipragliflozin, subcutaneous fat, γ-glutamyl transpeptidase
Ⅰ Introduction

are increasing1）, and obesity is becoming a major
public health problem. No drugs for treating obesity

Obesity rates are increasing worldwide, with ele­

were available until recently in Japan. The SGLT2

vated risk of T2D, high blood pressure, dyslipi­de­inhibitor, ipragliflozin (Astellas Pharma, Tokyo, Ja­

mia, and cardiovascular disease. In Japan, the mean

pan and Kotobuki Pharmaceutical, Nagano, Japan), abody mass indexes (BMI) of men and elderly women

drug approved for T2D treatment in Japan, was＊reported to induce weight loss2）3）. SGLT2 inhibitors

Corresponding author : Shin-ichi Nishio
Division of Diabetes, Endocrinology and Metabolism,

improve glycemia in T2D patients by enhancing

Department of Internal Medicine (4), Shinshu University

urinary glucose excretion via blocking its reabsorp­

School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano

tion in the renal proximal tubules and reduce body390-8621, Japan
E-mail : snishio@shinshu-u.ac.jp†

	Shin-ichi Nishio and Takashi Sekido contributed equally tothis work

No. 1, 2018weight due to urinary calorie loss4）5）. Therefore, they
may have an antiobesity effect. The observed bodyweight decrease may be attributed to visceral adi­
29

Nishio・Sekido et al.

pose tissue lipolysis and enhanced lipid metabolism6）.

C

7）Intervention/monitoring

Ipragliflozin reduced body fat in rats , and clinicalThis study was a prospective observational study.

reports indicated visceral fat reduction by ipragli­

The study population consisted of 20 patients withflozin in Asian people. Ipragliflozin significantly

obese T2D presenting to Shinshu University Hospi­

decreased visceral adipose tissue in 4-week observa­

tal outpatient clinic due to obesity between Augusttion in 25 Japanese T2D patients8）. Visceral fat area

2015 and January 2017. Oral ipragliflozin administra­

was significantly reduced in 6-month observation oftion (50 mg once daily) was continued for 12 months

9）64 diabetic patients . However, obesity is difficult toin 17 cases. Patients received diet and nutritional

treat as many subjects regain weight after tempo­

guidance before and at least once after initiation of

10）

rary weight loss , so it is important to observe re­ipragliflozin treatment. The primary endpoint was

search on obesity for a long term. Body fat reductionchange in adipose tissue. Secondary endpoints in­by sodium-glucose cotransporter 2 (SGLT2) inhibi­

cluded changes in body weight, HbA1c, blood pres­tors has been observed for up to 1 year in Caucasiansure, liver and renal function, and lipid profile.

patients11）. Nonetheless, there have been no long-term

D

Method of fat area measurement
The adipose tissue was estimated on a Dual Scan

(12-month) surveys of SGLT2 inhibitors in obeseⓇ (HDS 2000Ⓡ ; Omron, Kyoto, Japan) using the dual

T2D patients in Japan.
Therefore, we examined long-term effects of ip­

impedance method12） every 3 months at more than 2

ragliflozin in obese T2D patients and evaluated thehours after meals. The Dual Scan instrument consists

influence of ipragliflozin on adipose tissue and liverof a bioelectrical impedance component that measures

function by monitoring changes in serum AST, ALT,

truncal and surface impedance of the body. Thereand γ-GTP levels.

was a good agreement of measured values by DualⅡ
A

Scan and intra-abdominal fat area measured byMaterials and Methods

computed tomography (CT) with a correlation coef­
ficient of 0.888 (n＝98, P<.001)13）.

EthicsThis study conformed to the Declaration of Helsin­

E

Clinical parameter measurement

ki, received approval from our university ethics com­

The following variables were monitored before

mittee (Study no. 3049), and subjects provided writ­and at 3, 6, and 12 months after commencement of

ten informed consent before participation.

ipragliflozin treatment : HbA1c, body weight, BMI,

B

estimated visceral fat area, estimated subcutaneous

Inclusion/exclusion criteria
Inclusion criteria were age 20-65 years old, HbA1c2>6.2 %, BMI>25 kg/m , and estimated glomerular2

fat area, systolic blood pressure, diastolic blood pres­sure, serum ALT, AST, γ-GTP, blood urea nitrogen,filtration rate (eGFR)>60 ml/min/1.73 m . Subjects

creatinine, uric acid, glomerular filtration rate (eGFR),

with unstable diabetic retinopathy, serious hepaticand serum levels of low-density lipoprotein choles­

dysfunction, renal failure, heart complications, andterol (LDL-C), and high-density lipoprotein choles­

2

terol (HDL-C). The data were collected before or≥2and≥ 35 kg/m are defined as obesity and severe

hours after a meal. There were variations in timeobesity, respectively. Participants’ average BMI (±after meals, so we did not evaluate blood glucose

pregnancy were excluded. In Japan, BMI≥25 kg/m
22SD) was 35.1±1.1 kg/m , and 13 patients were se­level and TG value.

verely obese. Diet therapy, exercise therapy, and/orF

Statistical analysis

treatment with any antidiabetic drugs other than

Data were analyzed by paired t test. Microsoft Ex­

SGLT2 inhibitors were continued. No changes in an­

cel 2013 and SPSS ver. 22.0 for Windows (IBM Japan,

tidiabetic drug regimens were allowed during theTokyo, Japan) were used for statistical analyses.

observation period unless deemed necessary to pre­All P-values for comparison before and after admin­

vent hypo-/hyperglycemia.

istration were subjected to Bonferroni adjustment.

30

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Subcutaneous adipose tissue and γ-GTP

Relationships between changes in adipose tissue andTable 1

Participant characteristics

The values are expressed as means±SD.

ALT, AST, and γ-GTP were assessed using Spear­
man’s rank correlation coefficients. In all analyses,

Age (years)

47.1±2.5

P<0.05 was taken to indicate statistical significance.

Sex (male/female)

10/10

Diabetes duration (years)

9.8±1.6

Body weight (kg)97.6±15.2

Ⅲ

Results

Twenty T2D patients were enrolled in this study(Table 1). Three subjects dropped out : one failed tobe evaluated for urinary tract infections, and theother two discontinued ipragliflozin due to develop­

2

BMI (kg/m )35.1±1.1

Blood pressure (mmHg)

134±14/85±11

VAT (cm2)

166.0±49.72ment of eruptions within 1 week after administra­

SAT (cm )359.3±110.5

tion. Seventeen subjects completed the full protocol

HbA1c (%)

7.7±1.3

and were included in statistical analyses. Antidiabet­

BMI, body mass index ; VAT, visceral adipose tissue ;SAT, subcutaneous adipose tissue ; HbA1c, glycated he­moglobin

ic drugs other than SGLT2 inhibitors are shown in
Table 2. Table 3 shows changes in test items every 3months during ipragliflozin treatment.
Mean body weight decreased over the observation
period (Table 3, Fig. 1), with a significant decrease

Table 2 Antidiabetic drugs other than SGLT2 inhibitors
used in combination

at 12 months (97.8 kg to 93.8 kg ; P＝0.045). MeanDrugvisceral adipose tissue decreased at 3 months (166.0

Biganide

16 (80%)Sulfonylurea

8 (40%)

Pioglitazone

4 (20%)

DPP-4 inhibitors

10 (50%)Glinides1 (5%)

α-Glucosidase inhibitors

3 (15%)

Insulin

7 (35%)

decrease during the treatment period (not signifi­

GLP-1R agonists

3 (15%)

cant) (Table 3).

No concomitant drugs

2 (10%)

cm2 to 149.7 cm2 ; P＝0.027), but after 6 months there
was no significant difference (Fig. 2). Estimatedmean subcutaneous adipose tissue decreased signifi­
cantly from 359.3 cm2 to 316.6 cm2 at 3 months (P＝0.003), 326.8 cm2 at 6 months (P＝0.018), and 325.9
cm2 at 12 months (P＝0.036) (Fig. 3).
Systolic and diastolic blood pressures tended to

Changes in various clinical parameters with ad­
ministration of ipragliflozin are shown in Table 3.

Case (n) (%)

DPP-4, dipeptidyl peptidase-4 ; GLP-1R, glucagon-like
peptide-1 receptor

Mean HbA1c level improved, and decreased signifi­
cantly from 7.7 % at baseline to 7.2 % at 6 months

to baseline (Table 3, Fig. 4). Serum LDL-C tended to(P＝0.032) ; there was no significant difference at 12

decrease, while serum HDL-C tended to increase,months. Blood urea nitrogen and creatinine showed

but the differences were not significant (Table 3).

no significant changes. Mean uric acid level de­crea­

There were no correlations between changes in

sed significantly from 6.4 mg/dL at baseline to

ALT or AST levels and those in visceral adipose

5.1 mg/dL at 6 months (P＝0.030) ; however, there

tissue (Fig. 5A, B) or subcutaneous adipose tissue

was no significant difference at 12 months. eGFR re­(Fig. 5D, E). Change in γ-GTP levels was not related

mained unchanged during the 12 months of treat­to those in visceral adipose tissue (Fig. 5C), but

ment ; it tended to increase during the treatment

correlated with change in subcutaneous adipose tis­

period, but the differences were not statisticallysue volume (Spearman’s ρ＝0.664, P＝0.004) (Fig.

significant. AST, ALT, and γ-GTP levels at the end

5F).

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Nishio・Sekido et al.
Table 3 Changes in various values every 3 months with administration of ipragliflozin
The values are expressed as means±SD. BMI : body mass index ; HbA1c : glycated hemoglobin ; AST : aspartate
aminotransferase ; ALT : alanine aminotransferase ; γ-GTP : γ-glutamyl transferase ; BUN : blood urea nitrogen ; Cr :creatinine ; eGFR : estimated glomerular filtration rate ; UA : uric acid ; LDL-C : low-density lipoproteincholesterol ; HDL-C : high-density lipoprotein cholesterol.
P-values : 0 vs. 1 months, 0 vs. 3 months, 0 vs. 6 months, and 0 vs. 12 months (Bonferroni adgustment).
BeforenMonth 3(M0)nP-valueMonth 6

(M0 vs M3)nP-valueMonth 12

(M0 vs M6)nP-value(M0 vs M12)

BW (kg)1797.6±15.2

1794.1±14.1

0.006

17

93.4±14.1

0.003

17

93.8±13.4

0.045

VAT (cm2)

17

166.0±49.7

16149.7±46.1

0.027

14

149.7±42.4

0.121

17

148.5±40.2

0.159

17 359.3±110.5 16

2

SAT (cm )316.6±87.1

0.003

14

326.8±87.2

0.018

17

325.9±90.4

0.036

Systolic blood pressure (mmHg) 17

134±1416132±120.672

16131±17>0.99917132±16>0.999

Diastolic blood pressure (mmHg)

17

85±11

16

82±14

>0.999

16

80±14

0.867

17

81±9

0.498

HbA1c (%)

177.7±1.3177.1±1.1

0.099

17

7.2±1.2

0.03

177.2±1.3

0.387

AST (IU/l)

17

36±20

15

29±14

0.021

15

23±8

0.003

17

23±8

0.015

ALT (IU/l)

17

53±33

15

38±23

0.024

15

28±11

0.006

17

29±16

0.015

γGTP (IU/l)

17

61±46

15

46±30

0.047

15

40±25

0.021

17

39±26

0.043

BUN (mg/dl)

1715.1±3.51616±4.00.516

1617.4±4.1

0.054

17

17.3±5.6

0.231

Cr (mg/dl)

170.78±0.13160.79±0.14>0.999160.77±0.13>0.999170.80±0.14

0.834

eGFR (ml/min/1.73 m2)

17

77±18

16

76±18

>0.9991677±20>0.9991777±19>0.999UA (mg/dl)

176.4±.1.415

5.7±1.40.396

135.1±1.1

0.03

165.5±1.4

0.165

HDL-C (mg/dl)

1743±8.7

15

47±10

0.708

15

49±13

0.018

13

50±13

0.456

LDL-C (mg/dl)

17111±2315107±250.662

14105±24>0.99913107±26>0.999

BMI : body mass index ; HbA1c : glycated hemoglobin ; AST : aspartate aminotransferase ; ALT : alanine aminotransferase ; γ-GTP : γ-glutamyltransferase ; BUN : blood urea nitrogen ; Cr : creatinine ; eGFR : estimated glomerular filtration rate ; UA : uric acid ; LDL-C : low-density
lipoprotein cholesterol ; HDL-C : high-density lipoprotein cholesterol

Fig. 1 Changes in body weightThe data show the mean values of body weight at 0, 3, 6, and 12 months (thin gray lines indicate individual
data). P-values : 0 vs. 1 month, 0 vs. 3 months, 0 vs. 6 months, and 0 vs. 12 months (Bonferroni adgustment (n＝17).
32

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Subcutaneous adipose tissue and γ-GTP

Fig. 2 Changes in visceral adipose tissue
The data show the mean values of visceral adipose tissue at 0, 3, 6, and 12 months (thingray lines indicate individual data). P-values : 0 vs. 3 months, 0 vs. 6 months, and 0 vs. 12
months (Bonferroni adgustment) (n＝17). N.S : Not significant.

Fig. 3 Changes in subcutaneous adipose tissue
The data show the mean values of subcutaneous adipose tissue at 0, 3, 6, and 12 months(thin gray lines indicate individual data). P-values : 0 vs. 3 months, 0 vs. 6 months, and 0
vs. 12 months (Bonferroni adgustment) (n＝17).
No. 1, 201833

Nishio・Sekido et al.

Fig. 4 Change in ALT, AST, and γ-GTP
P-values : 0 vs. 3 months (n＝15), 0 vs. 6 months (n＝15), and 0 vs. 12 months (n＝17) (Bonferroni adgustment).

Fig. 5 Correlations between changes in serum hepatobiliary enzyme levels and visceral adipose tissue andsubcutaneous adipose tissue after 12 months of ipragliflozin treatment
The relationships between changes in adipose tissue and hepatobiliary enzymes were assessed using Spearman’s rankcorrelation coefficients. In all analyses, P<0.05 was taken to indicate statistical significance.
A : Correlation between changes in serum ALT levels and visceral adipose tissue (n＝17). B : Correlation betweenchanges in serum AST levels and visceral adipose tissue (n＝17). C : Correlation between changes in serum γ-GTP levels
and visceral adipose tissue (n＝17). D : Correlation between changes in serum ALT levels and subcutaneous adipose
tissue (n＝17). E : Correlation between changes in serum AST levels and subcutaneous adipose tissue (n＝17).
F : Correlation between changes in serum γ-GTP levels and subcutaneous adipose tissue (n＝17). The change insubcutaneous adipose tissue was significantly correlated with that in serum γ-GTP level.
34

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Subcutaneous adipose tissue and γ-GTP

term empagliflozin treatment significantly reduced

Ⅳ Discussion

weight of subcutaneous but not visceral fat in rats16）.

Long-term studies of the effects of SGLT 2 inhibi­

The authors concluded that the decrease in body

tor on body weight and body fat loss have been re­weight of rats treated with SGLT2 inhibitor was due

ported in Caucasians11）14）, but there have been no suchto a decrease in subcutaneous rather than visceralstudies in Japan. We clearly demonstrated long-term

fat. Our results were consistent with this previous

body fat reduction by SGLT2 inhibitor (ipragliflozin)

study. They also showed SGLT2 inhibitor signifi­

treatment in Japanese T2D patients. Ipragliflozin

cantly reduced the size of visceral adipocytes andreduced body weight in Japanese patients with obese

increased the number of smaller size adipocytes,

2

T2D (average BMI≥30 kg/m ), with no rebound aswhich was associated with the attenuation of oxida­

long as regular dietary guidance continued andtive stress. Detailed analyses of body fat content

lasted for >1 year. Ipragliflozin reduced both visceralcontributing to weight loss in humans are necessary.

and subcutaneous fat up to 3 months, but decreased

Canagliflozin improved liver dysfunction in pa­

subcutaneous fat mainly after 6 months. Ipragliflozin

tients with T2D, assessed by monitoring serum AST,

lowered ALT, AST, and γ-GTP levels after 12 months,

ALT, and γ-GTP levels16）. Ogawa and colleagues

which was not correlated with body weight loss orreported that ipragliflozin improved liver function

visceral fat reduction, while decreases in γ-GTP

in clinical and basic research17）. They showed thatwere correlated with subcutaneous fat reduction.

mouse liver weight and retroperitoneal fat mass

Oral SGLT2 inhibitor administration reduces body

were negatively correlated in mice. Our results indi­weight. Weight loss was reported with oral dapa­

cated that ALT, AST, and γ-GTP improvement15）

gliflozin administration , and with short-term (102）

was not correlated with decreases in visceral fat atdays) ipragliflozin treatment . Japanese subjects giv­

any time point. Ogawa et al. reported that liver fat

en oral ipragliflozin showed body weight re­duction

decreased and posterior peritoneal adipose tissue inof 3.3 % in 16 weeks8）. In our study, 12-month ipra­

visceral fat increased in mice treated with ipragliflozin.

gliflozin administration resulted in weight loss of

It is impossible to distinguish between liver fat and8）other visceral fat by dual scan, which represents a

3.6 %. The mean BMI in Yamamoto et al.’s cohort2

was 28.9 kg/m , while that in our study was 35.1 kg/
2

limitation of our study.

m . Moreover, 65 % of subjects in our study were se­

Mochizuki et al. showed the accumulation of vis­verely obese. Nevertheless, there was no difference

ceral fat is positively associated with γ-GTP inde­

in the weight reduction effect, suggesting that ip­

pendently of subcutaneous fat area in Japanese18）.

ragliflozin is also effective in severely obese patients.

Contrary to our expectations, changes in serum levels

SGLT2 inhibitors were reported to reduce visceralof γ-GTP associated with ipragliflozin treatment

fat and weight. Here, visceral fat was reduced by 7.8

were correlated with the rate of subcutaneous fat% in 3 months, which was similar to the previous

decrease after 12 months.

report of 8.2 % reduction by 16 weeks of 50 mg ip­
8）

ragliflozin . A visceral fat loss trend was recognized

Further analysis of the relationship between sub­cutaneous fat and γ-GTP levels is necessary.

after 6 months but was not significant. Visceral fat

This study had several limitations. First, the sam­

reduction by 8.1 % with 300 mg of canagliflozin forple size was small. We think that the mean HbA1c

11）52 weeks was reported . The lack of significant dif­level at 12 months did not differ from baseline be­ference in our study was probably due to the smallcause the sample size was small. Second, patients

sample size. Subcutaneous fat decreased at all timeusing drugs that affect lipid metabolism (insulin, pi­points. Body weight decrease may be attributed tooglitazone, and GLP1 analogs) were included. Third,

visceral fat tissue lipolysis due to SGLT2 inhibitor

this was a single-arm study. However, the number

induced enhancement in lipid metabolism6）. Long-of participants met the minimum requirement for a

No. 1, 201835

Nishio・Sekido et al.

prospective observational study, and concurrent use

wrote the manuscript. T.S performed the research,of antidiabetic drugs is inevitable in clinical practice.

and wrote the manuscript. Y.O. contributed to data
analysis. A.O. contributed to discussion. M.K. review­

Ⅴ Conclusion

ed and edited the manuscript. The authors thankWhere proper dietary and nutritional guidanceMiss Yoshie Takahashi (Shinshu University Hospital,are provided, administration of the SGLT 2 inhibitor,

Department of Nursing) for her continued support,

ipragliflozin, induced weight loss and subcutaneousand Dr. Toru Aizawa for invaluable comments.

fat reduction over 12 months. Furthermore, ipragli­

Disclosure Statement

flozin also improved liver function in obese patients,
which was correlated with decrease of subcutaneous

Mitsuhisa Komatsu has received honoraria for
lectures from Novo Nordisk, Sanofi, Eli Lilly, Kissei

fat.

Pharmaceutical Co., Ltd., MSD, Takeda Pharmaceuti­

Acknowledgments

cal Co., Ltd., Ono Pharmaceutical Co., Ltd., and Sumi­

S.N. designed and performed the research, andtomo Dainippon Pharma Co., Ltd.

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