J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website http://www.jofem.org

Original Article

Volume 10, Number 1, February 2020, pages 1-7

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Hepatic Fibrosis in Patients With Type 2 Diabetes: A Chart-Based Analysis

Figure 1. Changes in FIB4 index during SGLT2i treatment (*P = 0.003, **P = 0.005). FIB4: fibrosis-4; SGLT2i: sodium-glucose cotransporter 2 inhibitor.

**Table 1.** Baseline Characteristics of the Patients (n = 315)
BMI: body mass index; HbA1c: hemoglobin A1c; SGLT2i: sodium-glucose cotransporter 2 inhibitor.
Age	57.2 ± 14.6
Sex (M/F)	173/142
Body height (cm)	163 ± 9
Body weight (kg)	77.3 ± 18.9
BMI (kg/m²)	29.2 ± 6.4
Systolic blood pressure (mm Hg)	132 ± 18
Diastolic blood pressure (mm Hg)	77 ± 12
Plasma glucose (mg/dL)	197 ± 82
HbA1c (%)	8.4 ± 1.6
SGLT2i prescribed
Luseogliflozin	116 (33%)
Dapagliflozin	74 (23%)
Tofogliflozin	39 (12%)
Ipragliflozin	22 (7%)
Empagliflozin	30 (9%)
Canagliflozin	34 (10%)

Table 1. Baseline Characteristics of the Patients (n = 315)

BMI: body mass index; HbA1c: hemoglobin A1c; SGLT2i: sodium-glucose cotransporter 2 inhibitor.

Age

57.2 ± 14.6

Sex (M/F)

173/142

Body height (cm)

163 ± 9

Body weight (kg)

77.3 ± 18.9

BMI (kg/m²)

29.2 ± 6.4

Systolic blood pressure (mm Hg)

132 ± 18

Diastolic blood pressure (mm Hg)

77 ± 12

Plasma glucose (mg/dL)

197 ± 82

HbA1c (%)

8.4 ± 1.6

SGLT2i prescribed

Luseogliflozin

116 (33%)

Dapagliflozin

74 (23%)

Tofogliflozin

39 (12%)

Ipragliflozin

22 (7%)

Empagliflozin

30 (9%)

Canagliflozin

34 (10%)

**Table 2.** Change of the Clinical Parameters 6 and 12 Months After the Start of SGLT2is (n = 315)
	Baseline	6 months	P*	12 months	P*
*Compared to baseline. SGLT2i: sodium-glucose cotransporter 2 inhibitor; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate; FIB4: fibrosis-4.
Body weight (kg)	77.3 ± 18.9	75.4 ± 18.5	< 0.001	74.7 ± 18.5	< 0.001
BMI (kg/m²)	29.2 ± 6.4	28.5 ± 6.2	< 0.001	28.3 ± 6.3	< 0.001
Plasma glucose (mg/dL)	195 ± 82	159 ± 64	< 0.001	160 ± 61	< 0.001
HbA1c (%)	8.5 ± 1.6	7.5 ± 1.3	< 0.001	7.6 ± 1.4	< 0.001
AST (IU/L)	33 ± 25	28 ± 20	< 0.001	28 ± 17	< 0.001
ALT (IU/L)	40 ± 35	33 ± 30	< 0.001	32 ± 27	< 0.001
γGTP (IU/L)	58 ± 82	49 ± 63	< 0.001	49 ± 63	< 0.001
Total cholesterol (mg/dL)	192 ± 43	188 ± 37	0.019	186 ± 36	0.003
HDL cholesterol (mg/dL)	50 ± 14	52 ± 14	0.002	53 ±15	< 0.001
LDL cholesterol (mg/dL)	109 ± 35	106 ± 30	0.007	107 ± 30	0.018
Triglyceride (mg/dL)	197 ± 135	183 ± 126	0.025	172 ± 126	< 0.001
Creatinine (mg/dL)	0.79 ± 0.36	0.84 ± 0.45	< 0.001	0.85 ± 0.46	< 0.001
eGFR (mL/min/1.73 m²)	79 ± 30	76 ± 27	< 0.001	75 ± 29	< 0.001
Hemoglobin (g/dL)	13.9 ± 2.5	14.3 ±1.8	< 0.001	14.2 ± 1.9	0.001
Hematocrit (%)	41.6 ± 4.9	43.6 ± 4.9	< 0.001	43.3 ± 5.4	< 0.001
Platelet (× 10⁴/µL)	23.9 ± 6.9	23.4 ± 6.5	0.032	23.2 ± 6.3	0.002
FIB4 index	1.46 ± 1.15	1.45 ±1.21	0.560	1.46 ± 1.15	0.880

Table 2. Change of the Clinical Parameters 6 and 12 Months After the Start of SGLT2is (n = 315)

Baseline

6 months

12 months

*Compared to baseline. SGLT2i: sodium-glucose cotransporter 2 inhibitor; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate; FIB4: fibrosis-4.

Body weight (kg)

77.3 ± 18.9

75.4 ± 18.5

< 0.001

74.7 ± 18.5

< 0.001

BMI (kg/m²)

29.2 ± 6.4

28.5 ± 6.2

< 0.001

28.3 ± 6.3

< 0.001

Plasma glucose (mg/dL)

195 ± 82

159 ± 64

< 0.001

160 ± 61

< 0.001

HbA1c (%)

8.5 ± 1.6

7.5 ± 1.3

< 0.001

7.6 ± 1.4

< 0.001

AST (IU/L)

33 ± 25

28 ± 20

< 0.001

28 ± 17

< 0.001

ALT (IU/L)

40 ± 35

33 ± 30

< 0.001

32 ± 27

< 0.001

γGTP (IU/L)

58 ± 82

49 ± 63

< 0.001

49 ± 63

< 0.001

Total cholesterol (mg/dL)

192 ± 43

188 ± 37

0.019

186 ± 36

0.003

HDL cholesterol (mg/dL)

50 ± 14

52 ± 14

0.002

53 ±15

< 0.001

LDL cholesterol (mg/dL)

109 ± 35

106 ± 30

0.007

107 ± 30

0.018

Triglyceride (mg/dL)

197 ± 135

183 ± 126

0.025

172 ± 126

< 0.001

Creatinine (mg/dL)

0.79 ± 0.36

0.84 ± 0.45

< 0.001

0.85 ± 0.46

< 0.001

eGFR (mL/min/1.73 m²)

79 ± 30

76 ± 27

< 0.001

75 ± 29

< 0.001

Hemoglobin (g/dL)

13.9 ± 2.5

14.3 ±1.8

< 0.001

14.2 ± 1.9

0.001

Hematocrit (%)

41.6 ± 4.9

43.6 ± 4.9

< 0.001

43.3 ± 5.4

< 0.001

Platelet (× 10⁴/µL)

23.9 ± 6.9

23.4 ± 6.5

0.032

23.2 ± 6.3

0.002

FIB4 index

1.46 ± 1.15

1.45 ±1.21

0.560

1.46 ± 1.15

0.880

**Table 3.** Baseline Characteristics of Patients in Groups 1-3
Group	1	2	3	P
FIB4: fibrosis-4; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.
Baseline FIB4 index	≥ 2.67	< 2.67, ≥ 1.30	< 1.30
n (M/F)	32 (17/15)	104 (56/48)	179 (100/79)	-
Age	69.8 ± 12.1	64.7 ± 12.7	50.7 ± 12.4	< 0.001
Body weight (kg)	71.7 ± 18.2	74.0 ± 19.4	80.1 ± 18.2	0.010
BMI (kg/m²)	28.5 ± 6.6	27.9 ± 5.8	30.0 ± 6.6	0.038
Systolic blood pressure (mm Hg)	131 ± 16	133 ± 19	131 ± 17	0.702
Diastolic blood pressure (mm Hg)	76 ± 10	74 ± 13	78 ± 12	0.055
Plasma glucose (mg/dL)	226 ± 76	191 ± 89	192 ± 77	0.116
HbA1c (%)	8.1 ± 1.3	8.5 ± 1.8	8.5 ± 1.6	0.472
AST (IU/L)	54 ± 30	39 ± 30	25 ± 15	< 0.001
ALT (IU/L)	45 ± 30	45 ±43	37 ± 30	0.149
γGTP (IU/L)	114 ± 145	68 ± 98	45 ± 37	< 0.001
Total cholesterol (mg/dL)	173 ± 32	194 ± 41	195 ± 42	0.183
HDL cholesterol (mg/dL)	47 ± 13	53 ± 14	49 ± 12	0.027
LDL cholesterol (mg/dL)	93 ± 29	106 ± 27	112 ± 36	0.079
Triglyceride (mg/dL)	187 ± 112	188 ± 134	206 ± 141	0.507
Creatinine (mg/dL)	0.83 ± 0.22	0.80 ± 0.30	0.78 ± 0.41	0.589
eGFR (mL/min/1.73 m²)	65 ± 22	74 ± 25	85 ± 32	< 0.001
Hemoglobin (g/dL)	12.9 ± 1.9	13.8 ± 1.6	14.0 ± 2.9	0.055
Hematocrit (%)	39.3 ± 5.2	41.8 ± 4.5	41.9 ± 4.9	0.018
Platelet (× 10⁴/µL)	15.1 ± 4.9	21.5 ± 4.3	26.9 ± 6.5	< 0.001

Table 3. Baseline Characteristics of Patients in Groups 1-3

Group

FIB4: fibrosis-4; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.

Baseline FIB4 index

≥ 2.67

< 2.67, ≥ 1.30

< 1.30

n (M/F)

32 (17/15)

104 (56/48)

179 (100/79)

Age

69.8 ± 12.1

64.7 ± 12.7

50.7 ± 12.4

< 0.001

Body weight (kg)

71.7 ± 18.2

74.0 ± 19.4

80.1 ± 18.2

0.010

BMI (kg/m²)

28.5 ± 6.6

27.9 ± 5.8

30.0 ± 6.6

0.038

Systolic blood pressure (mm Hg)

131 ± 16

133 ± 19

131 ± 17

0.702

Diastolic blood pressure (mm Hg)

76 ± 10

74 ± 13

78 ± 12

0.055

Plasma glucose (mg/dL)

226 ± 76

191 ± 89

192 ± 77

0.116

HbA1c (%)

8.1 ± 1.3

8.5 ± 1.8

8.5 ± 1.6

0.472

AST (IU/L)

54 ± 30

39 ± 30

25 ± 15

< 0.001

ALT (IU/L)

45 ± 30

45 ±43

37 ± 30

0.149

γGTP (IU/L)

114 ± 145

68 ± 98

45 ± 37

< 0.001

Total cholesterol (mg/dL)

173 ± 32

194 ± 41

195 ± 42

0.183

HDL cholesterol (mg/dL)

47 ± 13

53 ± 14

49 ± 12

0.027

LDL cholesterol (mg/dL)

93 ± 29

106 ± 27

112 ± 36

0.079

Triglyceride (mg/dL)

187 ± 112

188 ± 134

206 ± 141

0.507

Creatinine (mg/dL)

0.83 ± 0.22

0.80 ± 0.30

0.78 ± 0.41

0.589

eGFR (mL/min/1.73 m²)

65 ± 22

74 ± 25

85 ± 32

< 0.001

Hemoglobin (g/dL)

12.9 ± 1.9

13.8 ± 1.6

14.0 ± 2.9

0.055

Hematocrit (%)

39.3 ± 5.2

41.8 ± 4.5

41.9 ± 4.9

0.018

Platelet (× 10⁴/µL)

15.1 ± 4.9

21.5 ± 4.3

26.9 ± 6.5

< 0.001

**Table 4.** Changes of the Clinical Parameters 6 and 12 Months After the Start of SGLT2is
	Baseline	6 months	P*	12 months	P*
*Compared to baseline. BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase.
Body weight (kg)
Group 1	71.7 ± 18.2	70.2 ± 18.2	< 0.004	69.9 ± 19.2	0.010
Group 2	74.0 ± 19.4	72.0 ± 18.4	< 0.001	70.6 ± 17.7	< 0.001
Group 3	80.1 ± 18.2	78.1 ± 17.5	< 0.001	77.8 ± 18.1	< 0.001
BMI (kg/m²)
Group 1	28.5 ± 6.6	27.9 ± 6.7	0.003	27.8 ± 7.0	0.009
Group 2	27.9 ± 5.8	27.3 ± 5.6	< 0.001	26.8 ± 5.4	< 0.001
Group 3	30.0 ± 6.6	29.3 ± 6.3	< 0.001	29.2 ± 6.4	< 0.001
Plasma glucose (mg/dL)
Group 1	226 ± 76	176 ± 69	0.004	168 ± 39	< 0.001
Group 2	191 ± 89	166 ± 67	0.010	160 ± 51	< 0.001
Group 3	192 ± 77	151 ± 60	< 0.001	158 ± 69	< 0.001
HbA1c (%)
Group 1	8.1 ± 1.3	7.5 ± 1.3	0.005	7.5 ± 1.4	0.029
Group 2	8.6 ± 1.7	7.5 ± 1.3	< 0.001	7.7 ± 1.5	< 0.001
Group 3	8.5 ± 1.6	7.5 ± 1.3	< 0.001	7.5 ± 1.4	< 0.001
AST (IU/L)
Group 1	54 ± 30	45 ± 29	0.038	38 ± 23	0.007
Group 2	39 ± 30	30 ± 22	< 0.001	30 ± 19	< 0.001
Group 3	25 ± 15	24 ± 15	0.098	24 ± 14	0.092
ALT (IU/L)
Group 1	45 ± 30	39 ± 29	0.087	35 ± 32	0.051
Group 2	45 ± 43	32 ± 37	< 0.001	30 ± 24	< 0.001
Group 3	37 ± 30	32 ± 26	0.002	32 ± 27	0.003
γGTP (IU/L)
Group 1	114 ± 145	85 ± 101	0.320	88 ± 107	0.183
Group 2	68 ± 98	52 ± 77	< 0.001	53 ± 73	0.075
Group 3	45 ± 37	39 ± 33	< 0.001	38 ± 34	0.001
Platelet (× 10⁴/µL)
Group 1	15.1 ± 4.9	15.2 ± 6.0	0.737	15.5 ± 5.3	0.355
Group 2	21.5 ± 4.3	21.3 ± 5.1	0.460	21.1 ± 5.1	0.174
Group 3	23.9 ± 6.9	23.3 ± 6.5	0.032	23.2 ± 6.3	0.002

Table 4. Changes of the Clinical Parameters 6 and 12 Months After the Start of SGLT2is

Baseline

6 months

12 months

*Compared to baseline. BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase.

Body weight (kg)

Group 1

71.7 ± 18.2

70.2 ± 18.2

< 0.004

69.9 ± 19.2

0.010

Group 2

74.0 ± 19.4

72.0 ± 18.4

< 0.001

70.6 ± 17.7

< 0.001

Group 3

80.1 ± 18.2

78.1 ± 17.5

< 0.001

77.8 ± 18.1

< 0.001

BMI (kg/m²)

Group 1

28.5 ± 6.6

27.9 ± 6.7

0.003

27.8 ± 7.0

0.009

Group 2

27.9 ± 5.8

27.3 ± 5.6

< 0.001

26.8 ± 5.4

< 0.001

Group 3

30.0 ± 6.6

29.3 ± 6.3

< 0.001

29.2 ± 6.4

< 0.001

Plasma glucose (mg/dL)

Group 1

226 ± 76

176 ± 69

0.004

168 ± 39

< 0.001

Group 2

191 ± 89

166 ± 67

0.010

160 ± 51

< 0.001

Group 3

192 ± 77

151 ± 60

< 0.001

158 ± 69

< 0.001

HbA1c (%)

Group 1

8.1 ± 1.3

7.5 ± 1.3

0.005

7.5 ± 1.4

0.029

Group 2

8.6 ± 1.7

7.5 ± 1.3

< 0.001

7.7 ± 1.5

< 0.001

Group 3

8.5 ± 1.6

7.5 ± 1.3

< 0.001

7.5 ± 1.4

< 0.001

AST (IU/L)

Group 1

54 ± 30

45 ± 29

0.038

38 ± 23

0.007

Group 2

39 ± 30

30 ± 22

< 0.001

30 ± 19

< 0.001

Group 3

25 ± 15

24 ± 15

0.098

24 ± 14

0.092

ALT (IU/L)

Group 1

45 ± 30

39 ± 29

0.087

35 ± 32

0.051

Group 2

45 ± 43

32 ± 37

< 0.001

30 ± 24

< 0.001

Group 3

37 ± 30

32 ± 26

0.002

32 ± 27

0.003

γGTP (IU/L)

Group 1

114 ± 145

85 ± 101

0.320

88 ± 107

0.183

Group 2

68 ± 98

52 ± 77

< 0.001

53 ± 73

0.075

Group 3

45 ± 37

39 ± 33

< 0.001

38 ± 34

0.001

Platelet (× 10⁴/µL)

Group 1

15.1 ± 4.9

15.2 ± 6.0

0.737

15.5 ± 5.3

0.355

Group 2

21.5 ± 4.3

21.3 ± 5.1

0.460

21.1 ± 5.1

0.174

Group 3

23.9 ± 6.9

23.3 ± 6.5

0.032

23.2 ± 6.3

0.002

**Table 5.** Correlations Between Changes of FIB4 Index During 12-Month SGLT2i Treatment and Clinical Parameters
	R	P
FIB4: fibrosis-4; SGLT2i: sodium-glucose cotransporter 2 inhibitor; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase.
Age	0.012	0.828
Baseline body weight	-0.097	0.290
Change of body weight	0.014	0.809
Baseline BMI	-0.064	0.269
Change of BMI	-0.005	0.927
Baseline HbA1c	0.028	0.626
Chang of HbA1c	-0.002	0.977
Baseline AST	-0.300	< 0.001
Change of AST	0.454	< 0.001
Baseline ALT	-0.128	0.023
Change of ALT	-0.154	0.006
Baseline γGTP	-0.187	0.003
Change of γGTP	0.348	< 0.001
Baseline platelet	0.139	0.014
Change of platelet	-0.175	0.002
Baseline FIB4 index	-0.375	< 0.001

Table 5. Correlations Between Changes of FIB4 Index During 12-Month SGLT2i Treatment and Clinical Parameters

FIB4: fibrosis-4; SGLT2i: sodium-glucose cotransporter 2 inhibitor; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase.

Age

0.012

0.828

Baseline body weight

-0.097

0.290

Change of body weight

0.014

0.809

Baseline BMI

-0.064

0.269

Change of BMI

-0.005

0.927

Baseline HbA1c

0.028

0.626

Chang of HbA1c

-0.002

0.977

Baseline AST

-0.300

< 0.001

Change of AST

0.454

< 0.001

Baseline ALT

-0.128

0.023

Change of ALT

-0.154

0.006

Baseline γGTP

-0.187

0.003

Change of γGTP

0.348

< 0.001

Baseline platelet

0.139

0.014

Change of platelet

-0.175

0.002

Baseline FIB4 index

-0.375

< 0.001

**Table 6.** Correlations Between Changes of FIB4 Index During 12-Month SGLT2i Treatment and Clinical Parameters in Patients of Group 1
	R	P
FIB4: fibrosis-4; SGLT2i: sodium-glucose cotransporter 2 inhibitor; BMI: body mass index; HbA1c: hemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transferase.
Age	0.105	0.567
Baseline body weight	0.034	0.860
Change of body weight	-0.325	0.085
Baseline BMI	0.081	0.676
Change of BMI	-0.312	0.099
Baseline HbA1c	0.145	0.452
Chang of HbA1c	-0.010	0.960
Baseline AST	-0.420	0.017
Change of AST	0.646	< 0.001
Baseline ALT	-0.133	0.467
Change of ALT	0.513	0.003
Baseline γGTP	-0.061	0.774
Change of γGTP	0.319	0.121
Baseline platelet	-0.028	0.880
Change of platelet	-0.533	0.002
Baseline FIB4 index	-0.510	0.003

Table 6. Correlations Between Changes of FIB4 Index During 12-Month SGLT2i Treatment and Clinical Parameters in Patients of Group 1

Age

0.105

0.567

Baseline body weight

0.034

0.860

Change of body weight

-0.325

0.085

Baseline BMI

0.081

0.676

Change of BMI

-0.312

0.099

Baseline HbA1c

0.145

0.452

Chang of HbA1c

-0.010

0.960

Baseline AST

-0.420

0.017

Change of AST

0.646

< 0.001

Baseline ALT

-0.133

0.467

Change of ALT

0.513

0.003

Baseline γGTP

-0.061

0.774

Change of γGTP

0.319

0.121

Baseline platelet

-0.028

0.880

Change of platelet

-0.533

0.002

Baseline FIB4 index

-0.510

0.003