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 2, February 2017, pages 154-162

Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: An Open-Label Study

Figure 1. Effect of ipragliflozin on efficacy parameters at week 24 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 24 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 24. 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 24. Error bars show SDs or IQRs.

Figure 2. Changes in systolic blood pressure (circles) and diastolic blood pressure (triangles) from baseline to week 24 after starting ipragliflozin administration, classified according to estimated glomerular filtration rate (eGFR): (a) eGFR ≥ 90 (n = 20), (b) eGFR ≥ 60 to < 90 (n = 22), and (c) eGFR < 60 (n = 8) at baseline. Data are means ± standard deviation (SD). *P < 0.05 versus baseline by the paired t-test. Error bars show SDs.

Figure 3. Effect of ipragliflozin on efficacy parameters at week 24 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 24 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 24. Data are means ± standard deviation (SD) or medians with the interquartile range (IQR). *P < 0.05 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 24. Error bars show SDs or IQRs.

Figure 4. Correlations among urinary albumin-to-creatinine ratio (UACR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). (a, b) All patients (n = 50). (c, d) Patients with diabetic nephropathy (n = 16). The relationship between change in UACR and blood pressure was assessed using Pearson’s correlation coefficients. Δ: the amount of change 24 weeks after baseline.

**Table 1.** Baseline Characteristics
	All patients	Diabetic nephropathy
Data are n (%), means ± standard deviation (SD), or medians with the interquartile range (IQR). HbA1c: glycated hemoglobin; eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; DPP-4: dipeptidyl peptidase-4; ARB: angiotensin 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 weight (kg)	78.4 ± 19.7	82.9 ± 15.7
Body mass index (kg/m²)	30.6 ± 6.2	32.1 ± 4.5
HbA1c (NGSP) (%)	8.7 ± 1.5	9.0 ± 1.8
Fasting plasma glucose (mg/dL)	165.5 ± 40.5	162.5 ± 32.1
Fasting C-peptide (ng/mL)	3.4 ± 1.8	3.5 ± 1.03
eGFR (mL/min/1.73 m²)	82.1 ± 19.8	77.9 ± 20.2
UACR (mg/gCr)	15.5 (8.0 - 85.7)	119.2 (98.9 - 201.8)
Systolic blood pressure (mm Hg)	131.8 ± 13.1	135.5 ± 17.2
Diastolic blood pressure (mm Hg)	80.7 ± 11.0	83.9 ± 12.4
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), or medians with the interquartile range (IQR). HbA1c: glycated hemoglobin; eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; DPP-4: dipeptidyl peptidase-4; ARB: angiotensin 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 weight (kg)

78.4 ± 19.7

82.9 ± 15.7

Body mass index (kg/m²)

30.6 ± 6.2

32.1 ± 4.5

HbA1c (NGSP) (%)

8.7 ± 1.5

9.0 ± 1.8

Fasting plasma glucose (mg/dL)

165.5 ± 40.5

162.5 ± 32.1

Fasting C-peptide (ng/mL)

3.4 ± 1.8

3.5 ± 1.03

eGFR (mL/min/1.73 m²)

82.1 ± 19.8

77.9 ± 20.2

UACR (mg/gCr)

15.5 (8.0 - 85.7)

119.2 (98.9 - 201.8)

Systolic blood pressure (mm Hg)

131.8 ± 13.1

135.5 ± 17.2

Diastolic blood pressure (mm Hg)

80.7 ± 11.0

83.9 ± 12.4

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 Characteristics of Patients Between Baseline and Week 24
	All patients (n = 50)	Diabetic nephropathy (n = 16)
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; eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment-β; 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	9.0 ± 1.8	8.0 ± 1.2	0.013
Fasting plasma glucose (mg/dL)	165.5 ± 40.5	137.6 ± 25.6	< 0.001	162.5 ± 32.1	135.9 ± 20.2	0.028
Body weight (kg)	78.4 ± 19.7	75.8 ± 20.1	< 0.001	82.9 ± 15.7	80.2 ± 15.9	< 0.001
Visceral fat area (cm²)	152.1 ± 72.2	124.5 ± 54.0	< 0.001	160.5 ± 58.4	130.1 ± 56.1	< 0.001
Subcutaneous fat area (cm²)	279.3 ± 154.2	252.0 ± 144.2	< 0.001	280.0 ± 135.0	249.0 ± 115.5	0.002
Waist circumference (cm)	100.6 ± 14.8	97.0 ± 15.2	< 0.001	103.5 ± 12.8	99.7 ± 12.7	< 0.001
UACR (mg/gCr)	15.5 (8.0 - 95.7)	12.9 (7.4 - 36.3)	0.011^†	119.2 (98.9 - 201.8)	52.9 (24.8 - 242.1)	0.049^†
eGFR (mL/min/1.73 m²)	82.1 ± 19.8	78.5 ± 17.4	0.007	77.9 ± 20.2	73.3 ± 16.9	0.080
SBP (mm Hg)	131.8 ± 13.1	130.1 ± 13.0	0.389	135.5 ± 17.2	134.3 ± 14.5	0.822
DBP (mm Hg)	80.7 ± 11.0	80.8 ± 10.5	0.888	83.9 ± 12.4	84.7 ± 11.4	0.769
Fasting serum insulin (μU/mL)	13.4 ± 6.3	13.2 ± 11.5	0.924	14.5 ± 6.0	18.3 ± 16.4	0.325
HOMA-IR	5.5 ± 3.4	4.7 ± 5.0	0.378	5.7 ± 2.5	6.5 ± 7.2	0.702
HOMA-β (%)	54.7 ± 35.3	67.0 ± 44.0	0.064	59.4 ± 41.3	88.5 ± 55.9	0.024
Total cholesterol (mg/dL)	180.8 ± 39.8	184.1 ± 39.8	0.274	184.6 ± 31.9	183.2 ± 19.7	0.848
LDL-cholesterol (mg/dL)	106.1 ± 32.2	109.3 ± 34.1	0.199	107.0 ± 32.2	104.6 ± 20.4	0.483
HDL-cholesterol (mg/dL)	48.3 ± 9.51	54.1 ± 10.4	< 0.001	48.9 ± 8.8	54.2 ± 10.5	0.036
Triglycerides (mg/dL)	157.1 ± 77.3	134.1 ± 71.7	0.028	168.1 ± 82.2	140.3 ± 84.3	0.160
Free fatty acids (mEq/L)	0.72 ± 0.31	0.76 ± 0.24	0.477	0.78 ± 0.41	0.77 ± 0.24	0.886
Adiponectin (μg/mL)	5.7 ± 1.4	6.7 ± 1.7	0.078	6.0 ± 0.6	6.4 ± 1.0	0.314
AST (IU/L)	39.4 ± 16.7	26.0 ± 8.6	< 0.001	39.0 ± 17.8	27.2 ± 11.5	< 0.001
ALT (IU/L)	56.2 ± 29.7	35.6 ± 19.5	< 0.001	55.9 ± 32.7	40.9 ± 27.9	< 0.001
γ-GT (IU/L)	62.3 ± 55.6	41.0 ± 34.5	< 0.001	54.2 ± 34.8	37.3 ± 22.6	< 0.001
Uric acid (mg/dL)	5.5 ± 1.3	4.7 ± 1.1	< 0.001	5.9 ± 1.4	5.2 ± 1.2	0.022

Table 2. Changes in the Characteristics of Patients Between Baseline and Week 24

All patients (n = 50)

Diabetic nephropathy (n = 16)

Baseline

Week 24

P value

Baseline

Week 24

P value

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; eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment-β; 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

9.0 ± 1.8

8.0 ± 1.2

0.013

Fasting plasma glucose (mg/dL)

165.5 ± 40.5

137.6 ± 25.6

< 0.001

162.5 ± 32.1

135.9 ± 20.2

0.028

Body weight (kg)

78.4 ± 19.7

75.8 ± 20.1

< 0.001

82.9 ± 15.7

80.2 ± 15.9

< 0.001

Visceral fat area (cm²)

152.1 ± 72.2

124.5 ± 54.0

< 0.001

160.5 ± 58.4

130.1 ± 56.1

< 0.001

Subcutaneous fat area (cm²)

279.3 ± 154.2

252.0 ± 144.2

< 0.001

280.0 ± 135.0

249.0 ± 115.5

0.002

Waist circumference (cm)

100.6 ± 14.8

97.0 ± 15.2

< 0.001

103.5 ± 12.8

99.7 ± 12.7

< 0.001

UACR (mg/gCr)

15.5 (8.0 - 95.7)

12.9 (7.4 - 36.3)

0.011^†

119.2 (98.9 - 201.8)

52.9 (24.8 - 242.1)

0.049^†

eGFR (mL/min/1.73 m²)

82.1 ± 19.8

78.5 ± 17.4

0.007

77.9 ± 20.2

73.3 ± 16.9

0.080

SBP (mm Hg)

131.8 ± 13.1

130.1 ± 13.0

0.389

135.5 ± 17.2

134.3 ± 14.5

0.822

DBP (mm Hg)

80.7 ± 11.0

80.8 ± 10.5

0.888

83.9 ± 12.4

84.7 ± 11.4

0.769

Fasting serum insulin (μU/mL)

13.4 ± 6.3

13.2 ± 11.5

0.924

14.5 ± 6.0

18.3 ± 16.4

0.325

HOMA-IR

5.5 ± 3.4

4.7 ± 5.0

0.378

5.7 ± 2.5

6.5 ± 7.2

0.702

HOMA-β (%)

54.7 ± 35.3

67.0 ± 44.0

0.064

59.4 ± 41.3

88.5 ± 55.9

0.024

Total cholesterol (mg/dL)

180.8 ± 39.8

184.1 ± 39.8

0.274

184.6 ± 31.9

183.2 ± 19.7

0.848

LDL-cholesterol (mg/dL)

106.1 ± 32.2

109.3 ± 34.1

0.199

107.0 ± 32.2

104.6 ± 20.4

0.483

HDL-cholesterol (mg/dL)

48.3 ± 9.51

54.1 ± 10.4

< 0.001

48.9 ± 8.8

54.2 ± 10.5

0.036

Triglycerides (mg/dL)

157.1 ± 77.3

134.1 ± 71.7

0.028

168.1 ± 82.2

140.3 ± 84.3

0.160

Free fatty acids (mEq/L)

0.72 ± 0.31

0.76 ± 0.24

0.477

0.78 ± 0.41

0.77 ± 0.24

0.886

Adiponectin (μg/mL)

5.7 ± 1.4

6.7 ± 1.7

0.078

6.0 ± 0.6

6.4 ± 1.0

0.314

AST (IU/L)

39.4 ± 16.7

26.0 ± 8.6

< 0.001

39.0 ± 17.8

27.2 ± 11.5

< 0.001

ALT (IU/L)

56.2 ± 29.7

35.6 ± 19.5

< 0.001

55.9 ± 32.7

40.9 ± 27.9

< 0.001

γ-GT (IU/L)

62.3 ± 55.6

41.0 ± 34.5

< 0.001

54.2 ± 34.8

37.3 ± 22.6

< 0.001

Uric acid (mg/dL)

5.5 ± 1.3

4.7 ± 1.1

< 0.001

5.9 ± 1.4

5.2 ± 1.2

0.022