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 8, Number 5, October 2018, pages 106-112

Effects of SGLT2 Inhibition on eGFR and Glomerular and Tubular Damage Markers in Japanese Patients With Type 2 Diabetes

Figure 1. Change in eGFR according to baseline eGFR group. Group 1: eGFR < 80.0 mL/min/1.73 m², Group 2: eGFR ≥ 80 mL/min/1.73 m². (a) Change in eGFR from baseline to 4 weeks. (b) Change in eGFR from baseline to 12 weeks.

**Table 1.** Mean Changes From Baseline in Glycemic Control, Lipid Profile, and Renal Function in Patients Receiving SGLT2 Inhibitors for 12 Weeks (N = 81)
	Baseline	4 weeks	12 weeks	P value
Mean ± standard deviation or medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. P values were determined by paired t-test or Wilcoxon signed-rank test. *P < 0.05.
Body weight (kg)	78.3 (68.0, 90.6)	77.4 (66.7, 90.0)	76.2 (67.0, 89.0)	< 0.0001*	< 0.0001*	< 0.0001*
Body mass index (kg/m²)	29.3 (26.6, 32.6)	28.4 (26.0, 32.3)	28.4 (25.7, 31.9)	< 0.0001*	< 0.0001*	< 0.0001*
HbA1c (mmol/mol)	65 (57, 75)	62 (55, 70)	58 (53, 67)	< 0.0001*	< 0.0001*	< 0.0001*
HbA1c (%)	8.1 (7.4, 9.0)	7.8 (7.2, 8.6)	7.5 (7.0, 8.3)	< 0.0001*	< 0.0001*	< 0.0001*
BUN (mg/dL)	14.5 (12.0, 16.8)	16.0 (13.0, 19.0)	16.0 (13.0, 19.0)	0.0031*	0.073	< 0.0001*
Cre (mg/dL)	0.74 (0.58, 0.84)	0.79 (0.63, 0.90)	0.76 (0.60, 0.95)	< 0.0001*	0.4	< 0.0001*
eGFR (mL/min/1.73 m²)	80.0 (69.4, 93.0)	74.7 (63.7, 91.6)	77.3 (65.4, 91.1)	< 0.0001*	0.37	< 0.0001*
CCr (mL/min)	131 (99.3, 178)	120 (87.0, 160)	120 (88.0, 160)	< 0.0001*	0.44	< 0.0001*
LDL-C (mg/dL)	101 (80.8, 130)	98.5 (80.9, 115)	104 (83.8, 127)	0.003*	0.0029*	0.49
HDL-C (mg/dL)	50.0 (41.8, 58.3)	48.5 (42.0, 57.5)	52.0 (43.0, 59.5)	0.28	0.0012*	0.096
TG (mg/dL)	152 (103, 223)	140 (97.5, 218)	145 (94.8, 215)	0.089	0.24	0.099
UA (mg/dL)	5.55 ± 1.29	4.93 ± 1.15	5.07 ± 1.18	< 0.0001*	0.028*	0.0002*

Table 1. Mean Changes From Baseline in Glycemic Control, Lipid Profile, and Renal Function in Patients Receiving SGLT2 Inhibitors for 12 Weeks (N = 81)

Baseline

4 weeks

12 weeks

P value

0 vs. 4 weeks

4 vs. 12 weeks

0 vs. 12 weeks

Mean ± standard deviation or medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. P values were determined by paired t-test or Wilcoxon signed-rank test. *P < 0.05.

Body weight (kg)

78.3 (68.0, 90.6)

77.4 (66.7, 90.0)

76.2 (67.0, 89.0)

< 0.0001*

Body mass index (kg/m²)

29.3 (26.6, 32.6)

28.4 (26.0, 32.3)

28.4 (25.7, 31.9)

< 0.0001*

HbA1c (mmol/mol)

65 (57, 75)

62 (55, 70)

58 (53, 67)

< 0.0001*

HbA1c (%)

8.1 (7.4, 9.0)

7.8 (7.2, 8.6)

7.5 (7.0, 8.3)

< 0.0001*

BUN (mg/dL)

14.5 (12.0, 16.8)

16.0 (13.0, 19.0)

0.0031*

0.073

< 0.0001*

Cre (mg/dL)

0.74 (0.58, 0.84)

0.79 (0.63, 0.90)

0.76 (0.60, 0.95)

< 0.0001*

0.4

< 0.0001*

eGFR (mL/min/1.73 m²)

80.0 (69.4, 93.0)

74.7 (63.7, 91.6)

77.3 (65.4, 91.1)

< 0.0001*

0.37

< 0.0001*

CCr (mL/min)

131 (99.3, 178)

120 (87.0, 160)

120 (88.0, 160)

< 0.0001*

0.44

< 0.0001*

LDL-C (mg/dL)

101 (80.8, 130)

98.5 (80.9, 115)

104 (83.8, 127)

0.003*

0.0029*

0.49

HDL-C (mg/dL)

50.0 (41.8, 58.3)

48.5 (42.0, 57.5)

52.0 (43.0, 59.5)

0.28

0.0012*

0.096

TG (mg/dL)

152 (103, 223)

140 (97.5, 218)

145 (94.8, 215)

0.089

0.24

0.099

UA (mg/dL)

5.55 ± 1.29

4.93 ± 1.15

5.07 ± 1.18

< 0.0001*

0.028*

0.0002*

**Table 2.** Linear Regression Analysis Between Δ eGFR and Variables (Between Before and 4 Weeks or 12 Weeks
	Between baseline and 4 weeks after SGLT-2 inhibitor treatment	Between baseline and 12 weeks after SGLT-2 inhibitor treatment
*P < 0.05.
Age (years)	0.091	0.068	0.18	-0.0079	0.082	0.92	0.14	0.080	0.083	-0.031	0.087	0.72
Sex	-0.15	0.85	0.86	-0.2	0.86	0.82	-0.97	1.00	0.33	-0.89	0.87	0.31
Body weight change (kg)	0.78	0.48	0.11	0.65	0.46	0.16	-0.21	0.34	0.55	-0.45	0.29	0.13
Basal eGFR (mL/min/1.73 m²)	-0.076	0.032	0.018*	-0.13	0.043	0.0046*	-0.16	0.034	< 0.0001*	-0.19	0.039	< 0.0001*
ACE inhibitor / ARB	-0.86	0.84	0.31	-0.4	0.86	0.64	-1.46	0.99	0.14	-0.22	0.88	0.80

Table 2. Linear Regression Analysis Between Δ eGFR and Variables (Between Before and 4 Weeks or 12 Weeks

Between baseline and 4 weeks after SGLT-2 inhibitor treatment

Between baseline and 12 weeks after SGLT-2 inhibitor treatment

Univariate regression model

Multivariate regression model

Univariate regression model

Multivariate regression model

P value

*P < 0.05.

Age (years)

0.091

0.068

0.18

-0.0079

0.082

0.92

0.14

0.080

0.083

-0.031

0.087

0.72

Sex

-0.15

0.85

0.86

-0.2

0.86

0.82

-0.97

1.00

0.33

-0.89

0.87

0.31

Body weight change (kg)

0.78

0.48

0.11

0.65

0.46

0.16

-0.21

0.34

0.55

-0.45

0.29

0.13

Basal eGFR (mL/min/1.73 m²)

-0.076

0.032

0.018*

-0.13

0.043

0.0046*

-0.16

0.034

< 0.0001*

-0.19

0.039

< 0.0001*

ACE inhibitor / ARB

-0.86

0.84

0.31

-0.4

0.86

0.64

-1.46

0.99

0.14

-0.22

0.88

0.80

**Table 3.** Mean Changes From Baseline in Glycemic Control, Lipid Profile, and Renal Function in Patients Receiving SGLT2 Inhibitors for 12 Weeks by Baseline eGFR Group (N = 81)
	Baseline - 4weeks	Baseline - 12weeks
Medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. P values were determined by Mann-Whitney U test. *P < 0.05.
Delta Body weight (kg)	-1.0 (-2.0, 0)	-1.0 (-2.3, 0)	0.50	-1.30 (-3.0, -0.45)	-1.90 (-4.0, -0.125)	0.36
Delta HbA1c (mmol/mol)	-2.0 (-5.0, 0)	-5.0 (-9.0, -1.0)	0.016*	-5.5 (-9.8, 1.0)	-7.0 (-14, -2.5)	0.12
Delta HbA1c (%)	-0.20 (-0.40, 0)	-0.40 (-0.80, -0.1)	0.016*	-0.50 (-0.88, 0.10)	-0.60 (-1.30, -0.25)	0.11
Delta BUN (mg/dL)	0 (-2.0, 2.0)	1.0 (-1.0, 4.0)	0.095	2.0 (0, 3.0)	1.0 (-1.0, 4.0)	0.83
Delta Cre (mg/dL)	0.03 (0, 0.088)	0.04 (0.01, 0.09)	0.54	0.015 (-0.03, 0.11)	0.05 (0.0005, 0.08)	0.37
Delta eGFR (mL/min/1.73 m²)	-3.05 (-5.9, 0)	-8.2 (-13.6, -1.5)	0.0075*	-2.05 (-6.9, 2.65)	-8.80 (-13.6, -1.40)	0.0009*
Delta CCr (mL/min)	-5.25 (-8.18, -0.14)	-14.8 (-25.6, -1.56)	0.0021*	-4.61 (-11.1, -3.28)	-14.6 (-30.3, -5.91)	0.0005*
Delta LDL (mg/dL)	-5.4 (-13.0, 7.05)	-7.6 (-15.6, 5.35)	0.38	5.8 (-10.2, 13.8)	-2.9 (-8.75, 12.8)	0.87
Delta HDL (mg/dL)	0 (-2.0, 2.5)	-1.0 (-4.0, 2.0)	0.12	2.0 (-3.0, 8.2)	0 (-3.0, 5.0)	0.43
Delta TG (mg/dL)	-6.0 (-31.0, 25.0)	-19.0 (-52.5, 24.0)	0.28	5.0 (-24.0, 26.0)	-17.0 (-67.0, 9.0)	0.052
Delta UA (mg/dL)	-0.65 (-1.25, 0)	-0.7 (-1.2, 0)	0.94	-0.6 (-1.1, 0.2)	-0.5 (-1.1, 0.05)	0.65

Table 3. Mean Changes From Baseline in Glycemic Control, Lipid Profile, and Renal Function in Patients Receiving SGLT2 Inhibitors for 12 Weeks by Baseline eGFR Group (N = 81)

Baseline - 4weeks

Baseline - 12weeks

Group 1

Group 2

P value

Group 1

Group 2

P value

Medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. P values were determined by Mann-Whitney U test. *P < 0.05.

Delta Body weight (kg)

-1.0 (-2.0, 0)

-1.0 (-2.3, 0)

0.50

-1.30 (-3.0, -0.45)

-1.90 (-4.0, -0.125)

0.36

Delta HbA1c (mmol/mol)

-2.0 (-5.0, 0)

-5.0 (-9.0, -1.0)

0.016*

-5.5 (-9.8, 1.0)

-7.0 (-14, -2.5)

0.12

Delta HbA1c (%)

-0.20 (-0.40, 0)

-0.40 (-0.80, -0.1)

0.016*

-0.50 (-0.88, 0.10)

-0.60 (-1.30, -0.25)

0.11

Delta BUN (mg/dL)

0 (-2.0, 2.0)

1.0 (-1.0, 4.0)

0.095

2.0 (0, 3.0)

1.0 (-1.0, 4.0)

0.83

Delta Cre (mg/dL)

0.03 (0, 0.088)

0.04 (0.01, 0.09)

0.54

0.015 (-0.03, 0.11)

0.05 (0.0005, 0.08)

0.37

Delta eGFR (mL/min/1.73 m²)

-3.05 (-5.9, 0)

-8.2 (-13.6, -1.5)

0.0075*

-2.05 (-6.9, 2.65)

-8.80 (-13.6, -1.40)

0.0009*

Delta CCr (mL/min)

-5.25 (-8.18, -0.14)

-14.8 (-25.6, -1.56)

0.0021*

-4.61 (-11.1, -3.28)

-14.6 (-30.3, -5.91)

0.0005*

Delta LDL (mg/dL)

-5.4 (-13.0, 7.05)

-7.6 (-15.6, 5.35)

0.38

5.8 (-10.2, 13.8)

-2.9 (-8.75, 12.8)

0.87

Delta HDL (mg/dL)

0 (-2.0, 2.5)

-1.0 (-4.0, 2.0)

0.12

2.0 (-3.0, 8.2)

0 (-3.0, 5.0)

0.43

Delta TG (mg/dL)

-6.0 (-31.0, 25.0)

-19.0 (-52.5, 24.0)

0.28

5.0 (-24.0, 26.0)

-17.0 (-67.0, 9.0)

0.052

Delta UA (mg/dL)

-0.65 (-1.25, 0)

-0.7 (-1.2, 0)

0.94

-0.6 (-1.1, 0.2)

-0.5 (-1.1, 0.05)

0.65

**Table 4.** Mean Changes From Baseline in Glycemic Control, Blood Pressure, Lipid Profile, and Renal Function in Patients Receiving SGLT-2 Inhibitors for 4 Weeks and 12 Weeks (N = 19)
	Standard value	Baseline	4 weeks	12 weeks	P value
Mean ± standard deviation or medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. †The reference value of β2 microglobulin was 11 - 253 µg/day in our hospital. We used the spot urine sample and the urinary excretion levels of β2 microglobulin were described as micrograms per gram of creatinine. P values were determined by paired t-test or Wilcoxon signed-rank test. NAG: N-acetyl-β-D-glucosaminidase; L-FABP: liver-type fatty acid binding protein; β2MG: β2 microglobulin. *P < 0.05.
Body weight (kg)		82.0 ± 15.3	81.6 ± 15.7	79.6 ± 16.1	0.53	0.0098*	0.0039*
Body mass index (kg/m²)		28.8 ± 3.51	28.6 ± 3.38	27.9 ± 3.67	0.44	0.0094*	0.0043*
HbA1c (mmol/mol)		68.6 ± 16.4	60.8 ± 9.28	54.6 ± 8.86	0.0022*	0.012*	0.0031*
HbA1c (%)		8.43 ± 1.50	7.71 ± 0.86	7.15 ± 0.82	0.0021*	0.012*	0.0031*
eGFR (mL/min/1.73 m²)		78.5 (67.1, 88.4)	75.0 (70.1, 79.0)	73.4 (66.8, 82.8)	0.027*	0.27	0.41
CCr (mL/min)		127 ± 26.7	122 ± 29.5	120 ± 29.7	0.12	0.37	0.048*
SBP (mm Hg)		135 ± 19.6	130 ± 16.0	128 ± 15.7	0.073	0.43	0.024*
DBP (mm Hg)		81.6 ± 14.3	80.7 ± 11.6	78.7 ± 10.9	0.51	0.61	0.27
LDL-C (mg/dL)		81.0 (72.2, 110)	74.8 (64.0, 83.2)	76.8 (64.2, 91.4)	0.074	0.28	0.52
HDL-C (mg/dL)		50.9 ± 15.0	51.9 ± 12.5	54.0 ± 14.6	0.46	0.15	0.079
TG (mg/dL)		177 (95, 289)	169 (94, 225)	139 (89, 247)	0.64	0.99	0.26
UA (mg/dL)		5.69 ± 1.39	5.00 ± 1.19	4.92 ± 1.28	0.0068*	0.56	0.0023*
Urinary albumin (mg/g Cre)	≤ 18.6	12.0 (6.6, 56.2)	12.1 (7.5, 28.7)	13.3 (6.3, 30.5)	0.52	0.059	0.078
Urinary NAG (U/g Cre)	≤ 5.6	5.97 (2.67, 7.79)	6.33 (5.31, 9.34)	5.83 (4.73, 7.88)	0.11	0.096	0.52
Urinary L-FABP (µg/g Cre)	≤ 8.4	2.70 (1.30, 5.80)	2.91 (1.90, 4.00)	2.30 (1.30, 4.16)	0.4	0.65	0.77
Urinary type IV collagen (µg/g Cre)	≤ 7.3	5.40 (2.00, 7.20)	5.30 (3.80, 6.70)	4.60 (3.70, 6.50)	0.19	0.52	0.71
Urinary β2MG (µg/g Cre)	†	78.6 (40.0, 181)	111 (65.9, 173)	133 (100, 243)	0.95	0.12	0.12

Table 4. Mean Changes From Baseline in Glycemic Control, Blood Pressure, Lipid Profile, and Renal Function in Patients Receiving SGLT-2 Inhibitors for 4 Weeks and 12 Weeks (N = 19)

Standard value

Baseline

4 weeks

12 weeks

P value

0 vs. 4 weeks

4 vs. 12 weeks

0 vs. 12 weeks

Mean ± standard deviation or medians (25th and 75th percentiles). CCr was calculated by Cockcroft and Gault equation. †The reference value of β2 microglobulin was 11 - 253 µg/day in our hospital. We used the spot urine sample and the urinary excretion levels of β2 microglobulin were described as micrograms per gram of creatinine. P values were determined by paired t-test or Wilcoxon signed-rank test. NAG: N-acetyl-β-D-glucosaminidase; L-FABP: liver-type fatty acid binding protein; β2MG: β2 microglobulin. *P < 0.05.

Body weight (kg)

82.0 ± 15.3

81.6 ± 15.7

79.6 ± 16.1

0.53

0.0098*

0.0039*

Body mass index (kg/m²)

28.8 ± 3.51

28.6 ± 3.38

27.9 ± 3.67

0.44

0.0094*

0.0043*

HbA1c (mmol/mol)

68.6 ± 16.4

60.8 ± 9.28

54.6 ± 8.86

0.0022*

0.012*

0.0031*

HbA1c (%)

8.43 ± 1.50

7.71 ± 0.86

7.15 ± 0.82

0.0021*

0.012*

0.0031*

eGFR (mL/min/1.73 m²)

78.5 (67.1, 88.4)

75.0 (70.1, 79.0)

73.4 (66.8, 82.8)

0.027*

0.27

0.41

CCr (mL/min)

127 ± 26.7

122 ± 29.5

120 ± 29.7

0.12

0.37

0.048*

SBP (mm Hg)

135 ± 19.6

130 ± 16.0

128 ± 15.7

0.073

0.43

0.024*

DBP (mm Hg)

81.6 ± 14.3

80.7 ± 11.6

78.7 ± 10.9

0.51

0.61

0.27

LDL-C (mg/dL)

81.0 (72.2, 110)

74.8 (64.0, 83.2)

76.8 (64.2, 91.4)

0.074

0.28

0.52

HDL-C (mg/dL)

50.9 ± 15.0

51.9 ± 12.5

54.0 ± 14.6

0.46

0.15

0.079

TG (mg/dL)

177 (95, 289)

169 (94, 225)

139 (89, 247)

0.64

0.99

0.26

UA (mg/dL)

5.69 ± 1.39

5.00 ± 1.19

4.92 ± 1.28

0.0068*

0.56

0.0023*

Urinary albumin (mg/g Cre)

≤ 18.6

12.0 (6.6, 56.2)

12.1 (7.5, 28.7)

13.3 (6.3, 30.5)

0.52

0.059

0.078

Urinary NAG (U/g Cre)

≤ 5.6

5.97 (2.67, 7.79)

6.33 (5.31, 9.34)

5.83 (4.73, 7.88)

0.11

0.096

0.52

Urinary L-FABP (µg/g Cre)

≤ 8.4

2.70 (1.30, 5.80)

2.91 (1.90, 4.00)

2.30 (1.30, 4.16)

0.4

0.65

0.77

Urinary type IV collagen (µg/g Cre)

≤ 7.3

5.40 (2.00, 7.20)

5.30 (3.80, 6.70)

4.60 (3.70, 6.50)

0.19

0.52

0.71

Urinary β2MG (µg/g Cre)

†

78.6 (40.0, 181)

111 (65.9, 173)

133 (100, 243)

0.95

0.12