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 10, Number 9, September 2018, pages 679-687

Long-Term Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: 104-Week Follow-up of an Open-Label Study

Figure 2. Effects of ipragliflozin on efficacy parameters at week 104 in all patients (n = 50), classified according to estimated glomerular filtration rate (eGFR) at baseline into three groups; eGFR ≥ 90 (circles; n = 20), eGFR ≥ 60 to < 90 (triangles; n = 22), and eGFR < 60 (squares; n = 8). (a) Change from baseline in glycated hemoglobin (HbA1c) to week 104 after starting ipragliflozin administration. (b) Change from baseline in body weight. (c) Change from baseline in eGFR. (d) Change from baseline in urinary albumin-to-creatinine ratio (UACR) at week 104. Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). *P < 0.05, **P < 0.01 versus baseline by the paired t-test. For the UACR, the Wilcoxon signed-rank test was used to evaluate changes between the baseline and week 104. Error bars show SDs or IQRs.

Figure 3. Effects of ipragliflozin on efficacy parameters at week 104 in patients with diabetic nephropathy (n = 16), classified according to estimated glomerular filtration rate (eGFR) at baseline into two groups; eGFR ≥ 80 (circles; n = 7) and eGFR < 80 (triangles; n = 9). (a) Change from baseline in glycated hemoglobin (HbA1c) to week 104 after starting ipragliflozin administration. (b) Change from baseline in body weight. (c) Change from baseline in eGFR. (d) Change from baseline in urinary albumin-to-creatinine ratio (UACR) at week 104. Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). *P < 0.05, **P < 0.01 versus baseline by the paired t-test. For the UACR, the Wilcoxon signed-rank test was used to evaluate changes between the baseline and week 104. Error bars show SDs or IQRs.

**Table 1.** Baseline Characteristics
	All patients	Diabetic nephropathy
Data are n (%), means ± standard deviation (SD). DPP-4: dipeptidyl peptidase-4; ARB: angiotensin II receptor blocker; ACE: angiotensin-converting enzyme.
Number of patients	50	16
Male/female (n)	16/34	6/10
Age (years)	53.2 ± 12.5	53.8 ± 13.3
Duration of diabetes (years)	9.1 ± 6.0	9.9 ± 7.2
Body mass index (kg/m²)	30.6 ± 6.2	32.1 ± 4.5
Fasting C-peptide (ng/mL)	3.4 ± 1.8	3.5 ± 1.03
Medications
Metformin (%)	31 (62.0%)	10 (62.5%)
DPP-4 inhibitor (%)	31 (62.0%)	8 (50.0%)
Sulfonylurea (%)	10 (20.0%)	2 (12.5%)
Insulin (%)	12 (24.0%)	5 (31.3%)
ARB or ACE inhibitor (%)	32 (64.0%)	13 (81.3%)
Statin (%)	32 (64.0%)	10 (62.5%)

Table 1. Baseline Characteristics

All patients

Diabetic nephropathy

Data are n (%), means ± standard deviation (SD). DPP-4: dipeptidyl peptidase-4; ARB: angiotensin II receptor blocker; ACE: angiotensin-converting enzyme.

Number of patients

Male/female (n)

16/34

6/10

Age (years)

53.2 ± 12.5

53.8 ± 13.3

Duration of diabetes (years)

9.1 ± 6.0

9.9 ± 7.2

Body mass index (kg/m²)

30.6 ± 6.2

32.1 ± 4.5

Fasting C-peptide (ng/mL)

3.4 ± 1.8

3.5 ± 1.03

Medications

Metformin (%)

31 (62.0%)

10 (62.5%)

DPP-4 inhibitor (%)

31 (62.0%)

8 (50.0%)

Sulfonylurea (%)

10 (20.0%)

2 (12.5%)

Insulin (%)

12 (24.0%)

5 (31.3%)

ARB or ACE inhibitor (%)

32 (64.0%)

13 (81.3%)

Statin (%)

32 (64.0%)

10 (62.5%)

**Table 2.** Changes in the Parameters of All Patients Between Baseline and Week 104 (n = 50)
	Interventional trial period	P value (week 24 vs. baseline)	Post-trial monitoring period	P value (week 104 vs. baseline)
Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). P value versus baseline by the paired t-test. ^†P value versus baseline by the Wilcoxon signed-rank test. HbA1c: glycated hemoglobin; UACR: urinary albumin-to-creatinine ratio; eGFR: estimated glomerular filtration rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment of β-cell function; LDL-cholesterol: low-density lipoprotein cholesterol; HDL-cholesterol: high-density lipoprotein cholesterol; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: γ- glutamyltransferase.
HbA1c (%)	8.7 ± 1.5	7.7 ± 1.2	< 0.001	7.7 ± 1.3	7.6 ± 1.2	< 0.001
Fasting plasma glucose (mg/dL)	165.5 ± 40.5	137.6 ± 25.6	< 0.001	148.1 ± 39.4	146.9 ± 34.7	0.020
Body weight (kg)	78.4 ± 19.7	75.8 ± 20.1	< 0.001	76.0 ± 20.1	76.5 ± 20.6	< 0.001
UACR (mg/gCr)	15.5 (8.0 - 95.7)	12.9 (7.4 - 36.3)	0.011^†	15.2 (8.0 - 39.0)	14.0 (7.3 - 34.6)	0.053^†
eGFR (mL/min/1.73m²)	82.1 ± 19.8	78.5 ± 17.4	0.007	82.2 ± 20.7	81.0 ± 20.2	0.526
SBP (mm Hg)	131.8 ± 13.1	130.1 ± 13.0	0.389	130.1 ± 14.9	130.5 ± 12.0	0.755
DBP (mm Hg)	80.7 ± 11.0	80.8 ± 10.5	0.888	80.9 ± 12.9	79.4 ± 10.9	0.411
Fasting serum insulin (µU/mL)	13.4 ± 6.3	13.2 ± 11.5	0.924	13.4 ± 11.7	12.9 ± 11.2	0.745
HOMA-IR	5.5 ± 3.4	4.7 ± 5.0	0.378	5.0 ± 5.0	4.7 ± 4.8	0.369
HOMA-β (%)	54.7 ± 35.3	67.0 ± 44.0	0.064	62.4 ± 45.4	61.1 ± 42.9	0.336
Total cholesterol (mg/dL)	180.8 ± 39.8	184.1 ± 39.8	0.274	178.4 ± 34.9	182.3 ± 33.3	0.720
LDL-cholesterol (mg/dL)	106.1 ± 32.2	109.3 ± 34.1	0.199	105.2 ± 30.1	107.7 ± 25.9	0.655
HDL-cholesterol (mg/dL)	48.3 ± 9.51	54.1 ± 10.4	< 0.001	52.6 ± 9.5	53.5 ± 8.8	< 0.001
Triglycerides (mg/dL)	157.1 ± 77.3	134.1 ± 71.7	0.028	149.1 ± 80.7	159.8 ± 98.3	0.849
AST (IU/L)	39.4 ± 16.7	26.0 ± 8.6	< 0.001	28.2 ± 11.8	33.1 ± 19.7	0.044
ALT (IU/L)	56.2 ± 29.7	35.6 ± 19.5	< 0.001	38.8 ± 21.0	44.6 ± 33.4	0.003
γ-GT (IU/L)	62.3 ± 55.6	41.0 ± 34.5	< 0.001	45.1 ± 57.5	54.0 ± 84.0	0.396
Uric acid (mg/dL)	5.5 ± 1.3	4.7 ± 1.1	< 0.001	4.9 ± 1.2	4.9 ± 1.3	< 0.001
Serum creatinine (mg/dL)	0.68 ± 0.16	0.71 ± 0.16	0.011	0.68 ± 0.16	0.68 ± 0.17	0.721
Hematocrit (%)	42.6 ± 4.1	45.4 ± 4.5	< 0.001	44.8 ± 4.8	45.5 ± 4.3	< 0.001

Table 2. Changes in the Parameters of All Patients Between Baseline and Week 104 (n = 50)

Interventional trial period

P value (week 24 vs. baseline)

Post-trial monitoring period

P value (week 104 vs. baseline)

Baseline

Week 24

Week 52

Week 104

Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). P value versus baseline by the paired t-test. ^†P value versus baseline by the Wilcoxon signed-rank test. HbA1c: glycated hemoglobin; UACR: urinary albumin-to-creatinine ratio; eGFR: estimated glomerular filtration rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment of β-cell function; LDL-cholesterol: low-density lipoprotein cholesterol; HDL-cholesterol: high-density lipoprotein cholesterol; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: γ- glutamyltransferase.

HbA1c (%)

8.7 ± 1.5

7.7 ± 1.2

< 0.001

7.7 ± 1.3

7.6 ± 1.2

< 0.001

Fasting plasma glucose (mg/dL)

165.5 ± 40.5

137.6 ± 25.6

< 0.001

148.1 ± 39.4

146.9 ± 34.7

0.020

Body weight (kg)

78.4 ± 19.7

75.8 ± 20.1

< 0.001

76.0 ± 20.1

76.5 ± 20.6

< 0.001

UACR (mg/gCr)

15.5 (8.0 - 95.7)

12.9 (7.4 - 36.3)

0.011^†

15.2 (8.0 - 39.0)

14.0 (7.3 - 34.6)

0.053^†

eGFR (mL/min/1.73m²)

82.1 ± 19.8

78.5 ± 17.4

0.007

82.2 ± 20.7

81.0 ± 20.2

0.526

SBP (mm Hg)

131.8 ± 13.1

130.1 ± 13.0

0.389

130.1 ± 14.9

130.5 ± 12.0

0.755

DBP (mm Hg)

80.7 ± 11.0

80.8 ± 10.5

0.888

80.9 ± 12.9

79.4 ± 10.9

0.411

Fasting serum insulin (µU/mL)

13.4 ± 6.3

13.2 ± 11.5

0.924

13.4 ± 11.7

12.9 ± 11.2

0.745

HOMA-IR

5.5 ± 3.4

4.7 ± 5.0

0.378

5.0 ± 5.0

4.7 ± 4.8

0.369

HOMA-β (%)

54.7 ± 35.3

67.0 ± 44.0

0.064

62.4 ± 45.4

61.1 ± 42.9

0.336

Total cholesterol (mg/dL)

180.8 ± 39.8

184.1 ± 39.8

0.274

178.4 ± 34.9

182.3 ± 33.3

0.720

LDL-cholesterol (mg/dL)

106.1 ± 32.2

109.3 ± 34.1

0.199

105.2 ± 30.1

107.7 ± 25.9

0.655

HDL-cholesterol (mg/dL)

48.3 ± 9.51

54.1 ± 10.4

< 0.001

52.6 ± 9.5

53.5 ± 8.8

< 0.001

Triglycerides (mg/dL)

157.1 ± 77.3

134.1 ± 71.7

0.028

149.1 ± 80.7

159.8 ± 98.3

0.849

AST (IU/L)

39.4 ± 16.7

26.0 ± 8.6

< 0.001

28.2 ± 11.8

33.1 ± 19.7

0.044

ALT (IU/L)

56.2 ± 29.7

35.6 ± 19.5

< 0.001

38.8 ± 21.0

44.6 ± 33.4

0.003

γ-GT (IU/L)

62.3 ± 55.6

41.0 ± 34.5

< 0.001

45.1 ± 57.5

54.0 ± 84.0

0.396

Uric acid (mg/dL)

5.5 ± 1.3

4.7 ± 1.1

< 0.001

4.9 ± 1.2

4.9 ± 1.3

< 0.001

Serum creatinine (mg/dL)

0.68 ± 0.16

0.71 ± 0.16

0.011

0.68 ± 0.16

0.68 ± 0.17

0.721

Hematocrit (%)

42.6 ± 4.1

45.4 ± 4.5

< 0.001

44.8 ± 4.8

45.5 ± 4.3

< 0.001

**Table 3.** Changes in the Parameters of Patients With Diabetic Nephropathy Between Baseline and Week 104 (n = 16)
	Interventional trial period	P value (week 24 vs. baseline)	Post-trial monitoring period	P value (week 104 vs. baseline)
Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). P value versus baseline by the paired t-test. ^†P value versus baseline by the Wilcoxon signed-rank test. HbA1c: glycated hemoglobin; UACR: urinary albumin-to-creatinine ratio; eGFR: estimated glomerular filtration rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment of β-cell function; LDL-cholesterol: low-density lipoprotein cholesterol; HDL-cholesterol: high-density lipoprotein cholesterol; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: γ- glutamyltransferase.
HbA1c (%)	9.0 ± 1.8	8.0 ± 1.2	0.013	7.7 ± 1.4	7.7 ± 1.0	0.006
Fasting plasma glucose (mg/dL)	162.5 ± 32.1	135.9 ± 20.2	0.028	141.9 ± 32.5	138.5 ± 26.0	0.033
Body weight (kg)	82.9 ± 15.7	80.2 ± 15.9	< 0.001	80.5 ± 15.5	82.1 ± 18.2	< 0.001
UACR (mg/gCr)	119.2 (98.9 - 201.8)	52.9 (24.8 - 242.1)	0.049^†	81.8 (24.3 - 174.3)	36.9 (19.7 - 204.7)	0.011^†
eGFR (mL/min/1.73m²)	77.9 ± 20.2	73.3 ± 16.9	0.080	75.8 ± 17.3	77.9 ± 18.6	0.986
SBP (mm Hg)	135.5 ± 17.2	134.3 ± 14.5	0.822	134.1 ± 13.3	136.4 ± 11.6	0.596
DBP (mm Hg)	83.9 ± 12.4	84.7 ± 11.4	0.769	85.8 ± 11.0	82.7 ± 9.9	0.762
Fasting serum insulin (µU/mL)	14.5 ± 6.0	18.3 ± 16.4	0.325	17.5 ± 16.6	16.4 ± 16.2	0.632
HOMA-IR	5.7 ± 2.5	6.5 ± 7.2	0.702	6.6 ± 7.2	6.2 ± 7.2	0.838
HOMA-β (%)	59.4 ± 41.3	88.5 ± 55.9	0.024	76.6 ± 58.5	70.8 ± 52.8	0.236
Total cholesterol (mg/dL)	184.6 ± 31.9	183.2 ± 19.7	0.848	172.8 ± 28.0	181.0 ± 33.8	0.687
LDL-cholesterol (mg/dL)	107.0 ± 32.2	104.6 ± 20.4	0.483	99.4 ± 23.9	107.2 ± 22.9	0.976
HDL-cholesterol (mg/dL)	48.9 ± 8.8	54.2 ± 10.5	0.036	52.7 ± 7.2	54.2 ± 6.8	0.001
Triglycerides (mg/dL)	168.1 ± 82.2	140.3 ± 84.3	0.160	133.4 ± 44.3	158.4 ± 104.7	0.760
AST (IU/L)	39.0 ± 17.8	27.2 ± 11.5	< 0.001	25.5 ± 9.9	31.1 ± 16.9	0.075
ALT (IU/L)	55.9 ± 32.7	40.9 ± 27.9	< 0.001	37.1 ± 20.5	42.5 ± 29.2	0.003
γ-GT (IU/L)	54.2 ± 34.8	37.3 ± 22.6	< 0.001	33.8 ± 18.6	37.1 ± 29.2	0.003
Uric acid (mg/dL)	5.9 ± 1.4	5.2 ± 1.2	0.022	5.4 ± 1.4	5.3 ± 1.1	0.010
Serum creatinine (mg/dL)	0.73 ± 0.18	0.77 ± 0.19	0.113	0.73 ± 0.18	0.72 ± 0.18	0.261
Hematocrit (%)	42.8 ± 4.1	45.9 ± 4.9	< 0.001	46.2 ± 5.1	46.0 ± 4.9	< 0.001

Table 3. Changes in the Parameters of Patients With Diabetic Nephropathy Between Baseline and Week 104 (n = 16)

Interventional trial period

P value (week 24 vs. baseline)

Post-trial monitoring period

P value (week 104 vs. baseline)

Baseline

Week 24

Week 52

Week 104

HbA1c (%)

9.0 ± 1.8

8.0 ± 1.2

0.013

7.7 ± 1.4

7.7 ± 1.0

0.006

Fasting plasma glucose (mg/dL)

162.5 ± 32.1

135.9 ± 20.2

0.028

141.9 ± 32.5

138.5 ± 26.0

0.033

Body weight (kg)

82.9 ± 15.7

80.2 ± 15.9

< 0.001

80.5 ± 15.5

82.1 ± 18.2

< 0.001

UACR (mg/gCr)

119.2 (98.9 - 201.8)

52.9 (24.8 - 242.1)

0.049^†

81.8 (24.3 - 174.3)

36.9 (19.7 - 204.7)

0.011^†

eGFR (mL/min/1.73m²)

77.9 ± 20.2

73.3 ± 16.9

0.080

75.8 ± 17.3

77.9 ± 18.6

0.986

SBP (mm Hg)

135.5 ± 17.2

134.3 ± 14.5

0.822

134.1 ± 13.3

136.4 ± 11.6

0.596

DBP (mm Hg)

83.9 ± 12.4

84.7 ± 11.4

0.769

85.8 ± 11.0

82.7 ± 9.9

0.762

Fasting serum insulin (µU/mL)

14.5 ± 6.0

18.3 ± 16.4

0.325

17.5 ± 16.6

16.4 ± 16.2

0.632

HOMA-IR

5.7 ± 2.5

6.5 ± 7.2

0.702

6.6 ± 7.2

6.2 ± 7.2

0.838

HOMA-β (%)

59.4 ± 41.3

88.5 ± 55.9

0.024

76.6 ± 58.5

70.8 ± 52.8

0.236

Total cholesterol (mg/dL)

184.6 ± 31.9

183.2 ± 19.7

0.848

172.8 ± 28.0

181.0 ± 33.8

0.687

LDL-cholesterol (mg/dL)

107.0 ± 32.2

104.6 ± 20.4

0.483

99.4 ± 23.9

107.2 ± 22.9

0.976

HDL-cholesterol (mg/dL)

48.9 ± 8.8

54.2 ± 10.5

0.036

52.7 ± 7.2

54.2 ± 6.8

0.001

Triglycerides (mg/dL)

168.1 ± 82.2

140.3 ± 84.3

0.160

133.4 ± 44.3

158.4 ± 104.7

0.760

AST (IU/L)

39.0 ± 17.8

27.2 ± 11.5

< 0.001

25.5 ± 9.9

31.1 ± 16.9

0.075

ALT (IU/L)

55.9 ± 32.7

40.9 ± 27.9

< 0.001

37.1 ± 20.5

42.5 ± 29.2

0.003

γ-GT (IU/L)

54.2 ± 34.8

37.3 ± 22.6

< 0.001

33.8 ± 18.6

37.1 ± 29.2

0.003

Uric acid (mg/dL)

5.9 ± 1.4

5.2 ± 1.2

0.022

5.4 ± 1.4

5.3 ± 1.1

0.010

Serum creatinine (mg/dL)

0.73 ± 0.18

0.77 ± 0.19

0.113

0.73 ± 0.18

0.72 ± 0.18

0.261

Hematocrit (%)

42.8 ± 4.1

45.9 ± 4.9

< 0.001

46.2 ± 5.1

46.0 ± 4.9

< 0.001

**Table 4.** Correlations Among UACR and Blood Pressure, HbA1c, and Body Weight
	Interventional trial period (week 24)	Post-trial monitoring period (week 104)
The relationship between changes in UACR and blood pressure, HbA1c, and body weight were assessed using Pearson’s correlation coefficients. Δ: the amount of change week 24 or week 104 after baseline. UACR: urinary albumin-to-creatinine ratio; HbA1c: glycated hemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressure; BW: body weight.
ΔSBP (mm Hg)	0.342	0.015	0.504	0.047	0.074	0.619	0.140	0.606
ΔDBP (mm Hg)	0.110	0.445	0.148	0.585	0.057	0.698	0.044	0.870
ΔHbA1c (%)	0.041	0.780	0.048	0.860	-0.058	0.697	-0.135	0.617
ΔBW (kg)	0.218	0.128	0.476	0.062	-0.071	0.631	-0.017	0.949

Table 4. Correlations Among UACR and Blood Pressure, HbA1c, and Body Weight

Interventional trial period (week 24)

Post-trial monitoring period (week 104)

All patients (n = 50)

Diabetic nephropathy (n = 16)

All patients (n = 50)

Diabetic nephropathy (n = 16)

ΔUACR (mg/gCr)

The relationship between changes in UACR and blood pressure, HbA1c, and body weight were assessed using Pearson’s correlation coefficients. Δ: the amount of change week 24 or week 104 after baseline. UACR: urinary albumin-to-creatinine ratio; HbA1c: glycated hemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressure; BW: body weight.

ΔSBP (mm Hg)

0.342

0.015

0.504

0.047

0.074

0.619

0.140

0.606

ΔDBP (mm Hg)

0.110

0.445

0.148

0.585

0.057

0.698

0.044

0.870

ΔHbA1c (%)

0.041

0.780

0.048

0.860

-0.058

0.697

-0.135

0.617

ΔBW (kg)

0.218

0.128

0.476

0.062

-0.071

0.631

-0.017

0.949