J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 9, Number 5, May 2017, pages 403-409

The Effect of Tofogliflozin Treatment on Postprandial Glucose and Lipid Metabolism in Japanese Men With Type 2 Diabetes: A Pilot Study

Figure 1. The study protocol is shown. We conducted the cookies tolerance test on three points: 0 week (baseline), 8 weeks (after treatment) and 16 weeks (after washout). Tofogliflozin (20 mg per day) administration started from the next day of the first cookies tolerance test and continued for 8 weeks. After 8 weeks of tofogliflozin administration and a subsequent 8-week washout of the agent, the cookies tolerance test was again conducted exactly the same way it was done before starting tofogliflozin.

**Table 1.** Changes in Fasting and Postprandial Glycemic Control, Blood Pressure and Other Metabolic Parameter During the Study Period
	0 week	8 weeks	16 weeks	0→8	0→16
Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed. Homeostasis model assessment-insulin resistance was calculated as fasting insulin × fasting plasma glucose/405; CPR index was calculated by CPR × 100/plasma glucose. CPR: C-peptide immunoreactivity; IRG: immunoreactive glucagon; AUC: the area under the curve.
Age, years	60.9	2.8
Body weight , kg	75.4	4.1		73.0	4.2		74.0	4.7		-2.37	0.43		0.00	-1.39	0.95		0.18
Body mass index, kg/m²	26.7	1.1		25.8	1.2		26.1	1.3		-0.827	0.16		0.00	-0.51	0.33		0.16
Waist circumference, cm	91.7	3.0		89.3	3.0		90.3	3.8		-2.4	0.70		0.01	-1.37	1.14		0.26
Systolic blood pressure, mm Hg	139.9	4.5		133.5	3.8		136.3	5.9		-6.4	3.36		0.09	-3.60	3.28		0.30
Diastolic blood pressure, mm Hg	83.4	1.9		80.5	1.7		82.3	3.1		-2.9	1.65		0.11	-1.10	2.64		0.69
Plasma glucose_0 min, mg/dL	140.8	16.2		111.8	7.9		124.5	8.8		-29.0	14.66		0.08	-16.30	17.88		0.39
Plasma glucose_60 min, mg/dL	234.4	19.4		203.8	19.0		222.6	22.5		-30.6	12.67		0.04	-11.80	14.15		0.43
Plasma glucose_120 min, mg/dL	218.4	22.5		184.3	20.1		207.7	25.4		-34.1	15.34		0.05	-10.70	12.05		0.40
Insulin_0 min*, μU/mL	5.6	4.3	7.2	3.7	2.7	7.7	5.6	3.6	8.2	-1.655	-3.61	2.11	0.38	-0.38	-1.26	1.4	0.92
Insulin_60 min*, μU/mL	30.9	17	47.5	24.3	17.9	35.3	24.8	21.0	35.5	-6.235	-14.58	2.88	0.13	-4.15	-14.30	4.2	0.23
Insulin_120 min*, μU/mL	19.2	16.9	39.4	20.8	15.3	28.9	23.6	18.8	43.1	-3.7	-17.85	2.78	0.23	-0.15	-8.03	5.9	0.87
HOMA-IR*	1.7	1.5	2.2	1	0.7	2.1	1.6	1.2	2.8	-0.78	-1.14	0.01	0.13	-0.19	-0.49	0.6	1.00
CPR_0 min*, ng/mL	1.8	1.5	2.2	1.6	1.1	2.9	1.8	1.6	2.1	-0.23	-0.42	0.31	0.38	0.13	-0.34	0.3	0.92
CPR_60 min*, ng/mL	4.6	4.0	6.4	4.7	3.9	6.1	4.5	4.0	5.5	-0.25	-0.97	0.27	0.3	-0.23	-1.13	0.2	0.43
CPR_120 min*, ng/mL	6.1	5.0	7.3	6.1	4.7	7.0	5.8	4.8	7.0	-0.17	-2.10	0.94	0.38	-0.16	-0.94	0.2	0.49
CPR index*	1.4	1.0	1.6	1.6	0.9	2.5	1.3	1.1	2.0	0.105	-0.18	0.59	0.43	0.05	-0.09	0.4	0.33
IRG_0 min, pg/mL	160.1	5.9		172.4	7.1		149.0	7.3		12.3	6.47		0.09	-11.10	6.48		0.12
IRG_60 min, pg/mL	166.1	5.0		180.1	6.8		147.4	7.8		14.0	4.89		0.02	-18.70	6.03		0.01
IRG_120 min, pg/mL	159.6	4.8		169.7	7.1		147.8	6.3		10.1	5.81		0.12	-11.80	6.21		0.09
HbA1c (NGSP, %)	6.8	0.2		6.5	0.2		6.9	0.3		-0.3	0.10		0.01	0.05	0.19		0.79
AUC plasma glucose	24,840.0	2,213.9		21,111.0	1,911.3		23,322.0	2,305.1		-3,729.0	1,461.4		0.03	-1,518.00	1,583.42		0.36
AUC insulin	3,325.6	752.1		2,454.5	361.6		3,055.7	618.5		-871.05	462.18		0.09	-269.94	214.57		0.24
AUC CPR	597.3	81.2		546.3	52.0		562.8	73.4		-51.0	40.85		0.24	-34.44	20.66		0.13
AUC glucagon	19,557.0	521.0		21,069.0	747.2		17,748.0	831.7		1,512.0	509.83		0.02	-1,809.00	669.03		0.02

Table 1. Changes in Fasting and Postprandial Glycemic Control, Blood Pressure and Other Metabolic Parameter During the Study Period

0 week

8 weeks

16 weeks

0→8

0→16

Baseline

After treatment

After washout

Mean (median)

SEM

Mean (median)

SEM

Mean (median)

SEM

Changes

SEM

P-value

Changes

SEM

P-value

Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed. Homeostasis model assessment-insulin resistance was calculated as fasting insulin × fasting plasma glucose/405; CPR index was calculated by CPR × 100/plasma glucose. CPR: C-peptide immunoreactivity; IRG: immunoreactive glucagon; AUC: the area under the curve.

Age, years

60.9

2.8

Body weight , kg

75.4

4.1

73.0

4.2

74.0

4.7

-2.37

0.43

0.00

-1.39

0.95

0.18

Body mass index, kg/m²

26.7

1.1

25.8

1.2

26.1

1.3

-0.827

0.16

0.00

-0.51

0.33

0.16

Waist circumference, cm

91.7

3.0

89.3

3.0

90.3

3.8

-2.4

0.70

0.01

-1.37

1.14

0.26

Systolic blood pressure, mm Hg

139.9

4.5

133.5

3.8

136.3

5.9

-6.4

3.36

0.09

-3.60

3.28

0.30

Diastolic blood pressure, mm Hg

83.4

1.9

80.5

1.7

82.3

3.1

-2.9

1.65

0.11

-1.10

2.64

0.69

Plasma glucose_0 min, mg/dL

140.8

16.2

111.8

7.9

124.5

8.8

-29.0

14.66

0.08

-16.30

17.88

0.39

Plasma glucose_60 min, mg/dL

234.4

19.4

203.8

19.0

222.6

22.5

-30.6

12.67

0.04

-11.80

14.15

0.43

Plasma glucose_120 min, mg/dL

218.4

22.5

184.3

20.1

207.7

25.4

-34.1

15.34

0.05

-10.70

12.05

0.40

Insulin_0 min*, μU/mL

5.6

4.3

7.2

3.7

2.7

7.7

5.6

3.6

8.2

-1.655

-3.61

2.11

0.38

-0.38

-1.26

1.4

0.92

Insulin_60 min*, μU/mL

30.9

47.5

24.3

17.9

35.3

24.8

21.0

35.5

-6.235

-14.58

2.88

0.13

-4.15

-14.30

4.2

0.23

Insulin_120 min*, μU/mL

19.2

16.9

39.4

20.8

15.3

28.9

23.6

18.8

43.1

-3.7

-17.85

2.78

0.23

-0.15

-8.03

5.9

0.87

HOMA-IR*

1.7

1.5

2.2

0.7

2.1

1.6

1.2

2.8

-0.78

-1.14

0.01

0.13

-0.19

-0.49

0.6

1.00

CPR_0 min*, ng/mL

1.8

1.5

2.2

1.6

1.1

2.9

1.8

1.6

2.1

-0.23

-0.42

0.31

0.38

0.13

-0.34

0.3

0.92

CPR_60 min*, ng/mL

4.6

4.0

6.4

4.7

3.9

6.1

4.5

4.0

5.5

-0.25

-0.97

0.27

0.3

-0.23

-1.13

0.2

0.43

CPR_120 min*, ng/mL

6.1

5.0

7.3

6.1

4.7

7.0

5.8

4.8

7.0

-0.17

-2.10

0.94

0.38

-0.16

-0.94

0.2

0.49

CPR index*

1.4

1.0

1.6

0.9

2.5

1.3

1.1

2.0

0.105

-0.18

0.59

0.43

0.05

-0.09

0.4

0.33

IRG_0 min, pg/mL

160.1

5.9

172.4

7.1

149.0

7.3

12.3

6.47

0.09

-11.10

6.48

0.12

IRG_60 min, pg/mL

166.1

5.0

180.1

6.8

147.4

7.8

14.0

4.89

0.02

-18.70

6.03

0.01

IRG_120 min, pg/mL

159.6

4.8

169.7

7.1

147.8

6.3

10.1

5.81

0.12

-11.80

6.21

0.09

HbA1c (NGSP, %)

6.8

0.2

6.5

0.2

6.9

0.3

-0.3

0.10

0.01

0.05

0.19

0.79

AUC plasma glucose

24,840.0

2,213.9

21,111.0

1,911.3

23,322.0

2,305.1

-3,729.0

1,461.4

0.03

-1,518.00

1,583.42

0.36

AUC insulin

3,325.6

752.1

2,454.5

361.6

3,055.7

618.5

-871.05

462.18

0.09

-269.94

214.57

0.24

AUC CPR

597.3

81.2

546.3

52.0

562.8

73.4

-51.0

40.85

0.24

-34.44

20.66

0.13

AUC glucagon

19,557.0

521.0

21,069.0

747.2

17,748.0

831.7

1,512.0

509.83

0.02

-1,809.00

669.03

0.02

**Table 2.** Changes in Fasting and Postprandial Lipids During the Study Period
	0 week	8 weeks	16 weeks	0→8	0→16
Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed. RLP-C: remnant-like particles-cholesterol; AUC: the area under the curve.
Total cholesterol, mg/dL	179.1	7.8		178.3	6.38		178	8.7		-0.8	4.82		0.87	-1.1	5.0		0.83
HDL-cholesterol, mg/dL	51.8	3.8		53.8	4.64		57.8	5.0		2.0	2.18		0.38	6.0	2.0		0.02
LDL-cholesterol, mg/dL	101.3	8.0		105.1	4.29		101.3	6.1		3.8	5.67		0.52	0.0	4.2		1.00
Triglycerides_0 min*, mg/dL	94.5	68.8	171.00	85.5	68.00	138.00	92.5	69.0	115.50	-20.5	-56.00	18.5	0.27	-4.5	-84.5	9.75	0.38
Triglycerides_60 min*, mg/dL	134.5	115.0	188.75	129	92.50	182.25	122.0	101.8	198.00	-9.5	-54.00	16.25	0.34	-15.0	-56.3	31.00	0.41
Triglycerides_120 min*, mg/dL	178.5	131.0	230.75	156.5	110.50	197.25	155.0	114.5	239.75	-28.5	-66.75	12.25	0.06	-7.0	-64.5	28.75	0.59
RLP-C_0 min, mg/dL	8.25	4.30		3.94	0.49		3.87	0.8		-4.31	4.3		0.34	-4.38	3.6		0.26
RLP-C_120 min, mg/dL	10.59	3.9		6.21	0.67		6.73	1.1		-4.38	3.64		0.26	-3.86	3.8		0.34
Lipoprotein lipase mass_0 min, ng/mL	37.6	3.7		37.1	4.30		44.2	4.8		-0.5	2.12		0.82	6.6	2.8		0.04
Lipoprotein lipase mass_120 min, ng/mL	37.0	4.0		37.4	4.69		43.1	4.8		0.4	1.14		0.73	6.1	2.1		0.02
Apolipoprotein B48_0 min, ng/mL	4.41	1.6		3.89	0.66		4.08	0.9		-0.52	1.42		0.72	-0.33	0.8		0.69
Apolipoprotein B48_120 min, ng/mL	9.43	1.9		8.75	1.08		9.08	1.6		-0.68	1.25		0.6	-0.35	1.5		0.82
AUC triglycerides	24,546.0	8,149.1		16,416.0	2,016.5		17,010.0	2,295.8		-8,130.0	7,196.2		0.29	-7,536.0	6,725.6		0.29

Table 2. Changes in Fasting and Postprandial Lipids During the Study Period

0 week

8 weeks

16 weeks

0→8

0→16

Baseline

After treatment

After washout

Mean (median)

SEM

Mean (median)

SEM

Mean (median)

SEM

Changes

SEM

P-value

Changes

SEM

P-value

Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed. RLP-C: remnant-like particles-cholesterol; AUC: the area under the curve.

Total cholesterol, mg/dL

179.1

7.8

178.3

6.38

178

8.7

-0.8

4.82

0.87

-1.1

5.0

0.83

HDL-cholesterol, mg/dL

51.8

3.8

53.8

4.64

57.8

5.0

2.0

2.18

0.38

6.0

2.0

0.02

LDL-cholesterol, mg/dL

101.3

8.0

105.1

4.29

101.3

6.1

3.8

5.67

0.52

0.0

4.2

1.00

Triglycerides_0 min*, mg/dL

94.5

68.8

171.00

85.5

68.00

138.00

92.5

69.0

115.50

-20.5

-56.00

18.5

0.27

-4.5

-84.5

9.75

0.38

Triglycerides_60 min*, mg/dL

134.5

115.0

188.75

129

92.50

182.25

122.0

101.8

198.00

-9.5

-54.00

16.25

0.34

-15.0

-56.3

31.00

0.41

Triglycerides_120 min*, mg/dL

178.5

131.0

230.75

156.5

110.50

197.25

155.0

114.5

239.75

-28.5

-66.75

12.25

0.06

-7.0

-64.5

28.75

0.59

RLP-C_0 min, mg/dL

8.25

4.30

3.94

0.49

3.87

0.8

-4.31

4.3

0.34

-4.38

3.6

0.26

RLP-C_120 min, mg/dL

10.59

3.9

6.21

0.67

6.73

1.1

-4.38

3.64

0.26

-3.86

3.8

0.34

Lipoprotein lipase mass_0 min, ng/mL

37.6

3.7

37.1

4.30

44.2

4.8

-0.5

2.12

0.82

6.6

2.8

0.04

Lipoprotein lipase mass_120 min, ng/mL

37.0

4.0

37.4

4.69

43.1

4.8

0.4

1.14

0.73

6.1

2.1

0.02

Apolipoprotein B48_0 min, ng/mL

4.41

1.6

3.89

0.66

4.08

0.9

-0.52

1.42

0.72

-0.33

0.8

0.69

Apolipoprotein B48_120 min, ng/mL

9.43

1.9

8.75

1.08

9.08

1.6

-0.68

1.25

0.6

-0.35

1.5

0.82

AUC triglycerides

24,546.0

8,149.1

16,416.0

2,016.5

17,010.0

2,295.8

-8,130.0

7,196.2

0.29

-7,536.0

6,725.6

0.29

**Table 3.** Changes in Other Clinical Parameters During the Study Period
	0 week	8 weeks	16 weeks	0→8	0→16
Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed.
AST, IU/L	25.1	2.2		23.8	2.19		22.9	1.9		-1.3	1.68		0.46	-2.2	1.7		0.24
ALT, IU/L	30.2	3.4		27.1	1.86		27.1	1.5		-3.1	2.47		0.24	-3.1	2.7		0.28
Uric acid, mg/dL	5.38	0.4		4.61	0.41		5.25	0.5		-0.77	0.19		0.00	-0.13	0.2		0.60
Na, mEq/L	140.2	0.5		140.4	0.48		140.8	0.3		0.2	0.59		0.74	0.6	0.5		0.28
K, mEq/L	4.82	0.1		5.39	0.16		5.13	0.1		0.57	0.18		0.01	0.31	0.2		0.08
WBC, /μL	5,930	583.7		5,650	525.62		6,020	686.7		-280	438.38		0.54	90	277.9		0.75
RBC, /μL	480.4	13.8		510.3	10.28		492.2	11.3		29.9	7.05		0.00	11.8	4.0		0.02
Hb, g/dL	15.08	0.4		16.14	0.31		15.82	0.6		1.06	0.21		0.00	0.74	0.6		0.24
Ht, %	43.92	1.1		46.84	0.83		45.39	1.0		2.92	0.71		0.00	1.47	0.3		0.00
120 Ccr	176.577	14.3		154.449	12.65		165.028	17.7		-22.128	10.83		0.07	-11.549	14.7		0.45
uAlb/Cr, mg/gCRE	0.2144	0.1		0.550	0.242		0.575	0.324		0.336	0.165		0.073	0.361	0.3		0.25
HMW adiponectin*, μg/mL	1.98	1.35	3.30	2.535	1.56	4.08	2.66	1.27	4.25	0.475	0.15	0.91	0.00	0.205	-0.1	1.25	0.19
8-OHdG/Cre*, ng/mgCRE	0.097	0.08	0.13	0.118	0.09	0.14	0.084	0.08	0.11	0.019	0.00	0.04	0.16	-0.005	-0.027	0.00	0.13
8-OHdG, ng/mL	15.45	2.4		12.6	2.3		12.49	1.7		-2.85	2.8		0.34	-2.96	1.6		0.10

Table 3. Changes in Other Clinical Parameters During the Study Period

0 week

8 weeks

16 weeks

0→8

0→16

Baseline

After treatment

After washout

Mean (median)

SEM

Mean (median)

SEM

Mean (median)

SEM

Changes

SEM

P-value

Changes

SEM

P-value

Data are presented as mean ± SEM unless otherwise noted. *Date are presented as median (first and third quartile) when they are skewed.

AST, IU/L

25.1

2.2

23.8

2.19

22.9

1.9

-1.3

1.68

0.46

-2.2

1.7

0.24

ALT, IU/L

30.2

3.4

27.1

1.86

27.1

1.5

-3.1

2.47

0.24

-3.1

2.7

0.28

Uric acid, mg/dL

5.38

0.4

4.61

0.41

5.25

0.5

-0.77

0.19

0.00

-0.13

0.2

0.60

Na, mEq/L

140.2

0.5

140.4

0.48

140.8

0.3

0.2

0.59

0.74

0.6

0.5

0.28

K, mEq/L

4.82

0.1

5.39

0.16

5.13

0.1

0.57

0.18

0.01

0.31

0.2

0.08

WBC, /μL

5,930

583.7

5,650

525.62

6,020

686.7

-280

438.38

0.54

277.9

0.75

RBC, /μL

480.4

13.8

510.3

10.28

492.2

11.3

29.9

7.05

0.00

11.8

4.0

0.02

Hb, g/dL

15.08

0.4

16.14

0.31

15.82

0.6

1.06

0.21

0.00

0.74

0.6

0.24

Ht, %

43.92

1.1

46.84

0.83

45.39

1.0

2.92

0.71

0.00

1.47

0.3

0.00

120 Ccr

176.577

14.3

154.449

12.65

165.028

17.7

-22.128

10.83

0.07

-11.549

14.7

0.45

uAlb/Cr, mg/gCRE

0.2144

0.1

0.550

0.242

0.575

0.324

0.336

0.165

0.073

0.361

0.3

0.25

HMW adiponectin*, μg/mL

1.98

1.35

3.30

2.535

1.56

4.08

2.66

1.27

4.25

0.475

0.15

0.91

0.00

0.205

-0.1

1.25

0.19

8-OHdG/Cre*, ng/mgCRE

0.097

0.08

0.13

0.118

0.09

0.14

0.084

0.08

0.11

0.019

0.00

0.04

0.16

-0.005

-0.027

0.00

0.13

8-OHdG, ng/mL

15.45

2.4

12.6

2.3

12.49

1.7

-2.85

2.8

0.34

-2.96

1.6

0.10