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 11, Number 4, April 2019, pages 267-274

Renoprotective Effects of Additional SGLT2 inhibitor Therapy in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3b-4: A Real World Report From A Japanese Specialized Diabetes Care Center

Figure 1. Urinary protein excretion (urinary protein-to-creatinine ratio) before and after 1-year treatment with sodium glucose cotransporter 2 inhibitors. In the box-and-whisker plots, lines within boxes represent median values; the top and bottom lines of the boxes represent the 25th and 75th percentiles, respectively; the top and bottom bars outside the boxes represent the 90th and 10th percentiles, respectively. N = 35, SGLT2i: sodium glucose cotransporter 2 inhibitor.

Figure 2. Serial changes in estimated glomerular filtration rate before and after treatment with sodium glucose cotransporter 2 inhibitors. SGLT2i: sodium glucose cotransporter 2 inhibitor; eGFR: estimated glomerular filtration rate; mean ± standard error.

Figure 3. Annual changes in estimated glomerular filtration rate before and after treatment with sodium glucose cotransporter 2 inhibitors. In the box-and-whisker plots, lines within boxes represent median values; the top and bottom lines of the boxes represent the 25th and 75th percentiles, respectively; the top and bottom bars outside the boxes represent the 90th and 10th percentiles, respectively. SGLT2i: sodium glucose cotransporter 2 inhibitor; eGFR: estimated glomerular filtration rate.

**Table 1.** Baseline Clinical Parameters
	Patients (n = 42)
SGLT2i: sodium glucose co-transporter 2 inhibitor; Dapa: dapagliflozin; Empa: empagliflozin; Cana: canagliflozin; Luse: Luseogliflozin; Tofo: tofogliflozin; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; eGFR: estimated glomerular filtration rate.
Age (years)	64.8 ± 9.8
Sex: male (%)	30 (71.4)
Body mass index (kg/m²)	28.2 ± 3.6
Hypertension (%)	40 (95.2)
Dyslipidemia (%)	40 (95.2)
Current smoking (%)	9 (21.4)
Retinopathy (%)	26 (61.9)
Cerebrovascular/cardiovascular diseases (%)	10 (23.8)
Duration of diabetes (years)	18.0 ± 7.4
Hemoglobin A1c (%)	7.6 (7.1 - 8.2)
Fasting plasma glucose (mg/dL) (n = 21)	158 (129 - 193)
Anti-diabetic drugs	-
Sulfonylureas (%)	9 (21.4)
Glinide (%)	1 (2.4)
Metformin (%)	21 (50.0)
Alpha-glucosidase inhibitor (%)	8 (19.0)
Thiazolidinedione (%)	5 (11.9)
Dipeptidyl peptidase-4 inhibitor (%)	10 (23.8)
Glucagon like peptide-1 receptor agonist (%)	9 (21.4)
Insulin (%)	30 (71.4)
Additional SGLT2i (Dapa/Empa/Cana/Luse/Tofo) (%)	33.0/19.0/4.8/31.0/11.9
Treatment duration of SGLT2i (months)	21.5 (15.0 - 31.0)
Treatment with ACEI or ARB (%)	30 (71.4)
Treatment with diuretics including aldosterone antagonist (%)	12 (28.6)
eGFR (mL/min/1.73m²)	40.4 (36.5 - 43.0)
Chronic kidney disease: stage-4 (eGFR< 30 mL/min/1.73m²) (%)	4 (9.5)
Qualitative assessment of urinary protein levels (%)	-
Negative (-) (< 15 mg/dL)	15 (35.7)
Borderline (±) (15 - 30 mg/dL)	8 (19.0)
Mild (+) (30 - 100 mg/dL)	6 (14.3)
Moderate (++) (100 - 300 mg/dL)	8 (19.0)
Severe (+++) (> 300 mg/dL)	5 (11.9)

Table 1. Baseline Clinical Parameters

Patients (n = 42)

SGLT2i: sodium glucose co-transporter 2 inhibitor; Dapa: dapagliflozin; Empa: empagliflozin; Cana: canagliflozin; Luse: Luseogliflozin; Tofo: tofogliflozin; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; eGFR: estimated glomerular filtration rate.

Age (years)

64.8 ± 9.8

Sex: male (%)

30 (71.4)

Body mass index (kg/m²)

28.2 ± 3.6

Hypertension (%)

40 (95.2)

Dyslipidemia (%)

40 (95.2)

Current smoking (%)

9 (21.4)

Retinopathy (%)

26 (61.9)

Cerebrovascular/cardiovascular diseases (%)

10 (23.8)

Duration of diabetes (years)

18.0 ± 7.4

Hemoglobin A1c (%)

7.6 (7.1 - 8.2)

Fasting plasma glucose (mg/dL) (n = 21)

158 (129 - 193)

Anti-diabetic drugs

Sulfonylureas (%)

9 (21.4)

Glinide (%)

1 (2.4)

Metformin (%)

21 (50.0)

Alpha-glucosidase inhibitor (%)

8 (19.0)

Thiazolidinedione (%)

5 (11.9)

Dipeptidyl peptidase-4 inhibitor (%)

10 (23.8)

Glucagon like peptide-1 receptor agonist (%)

9 (21.4)

Insulin (%)

30 (71.4)

Additional SGLT2i (Dapa/Empa/Cana/Luse/Tofo) (%)

33.0/19.0/4.8/31.0/11.9

Treatment duration of SGLT2i (months)

21.5 (15.0 - 31.0)

Treatment with ACEI or ARB (%)

30 (71.4)

Treatment with diuretics including aldosterone antagonist (%)

12 (28.6)

eGFR (mL/min/1.73m²)

40.4 (36.5 - 43.0)

Chronic kidney disease: stage-4 (eGFR< 30 mL/min/1.73m²) (%)

4 (9.5)

Qualitative assessment of urinary protein levels (%)

Negative (-) (< 15 mg/dL)

15 (35.7)

Borderline (±) (15 - 30 mg/dL)

8 (19.0)

Mild (+) (30 - 100 mg/dL)

6 (14.3)

Moderate (++) (100 - 300 mg/dL)

8 (19.0)

Severe (+++) (> 300 mg/dL)

5 (11.9)

**Table 2.** Changes in Glucose Metabolic Parameters and Clinical Variables Before and After SGLT2 Inhibitor Therapy
	SGLT2i therapy (n = 42)	P value
SGLT2i: sodium glucose cotransporter 2 inhibitor; HbA1c: hemoglobin A1c; eGFR: estimated glomerular filtration rate; UPCR: urine protein-creatinine ratio; Cre: creatinine. Data pertaining to normally distributed variables are presented as the mean (standard deviation) and variables with a skewed distribution are presented as median (interquartile range).
HbA1c (%)	7.6 (7.1 - 8.2)	7.5 (7.0 - 8.1)	0.17
Absolute change (%)	-0.1 (-0.9 - 0.3)
Fasting plasma glucose (mg/dL) (n = 11)	158 (129 - 236)	128 (118 - 149)	0.02
Absolute change (mg/dL)	-29 (-94 - -7)
Body mass index (kg/m²)	28.2 ± 3.6	27.6 ± 3.6	< 0.01
Absolute change (kg/m²)	-0.63 ± 1.07
Body weight (kg)	75.0 ± 11.8	73.3 ± 11.3	< 0.01
Absolute change (kg)	-1.7 ± 2.8
eGFR (mL/min/1.73m²)	40.4 (36.5 - 43.0)	41.0 (36.0 - 45.6)	0.18
Absolute change (mL/min/1.73m²)	0.3 (-0.9 - 2.7)
Serum creatinine (mg/dL)	1.38(1.25 - 1.50)	1.35 (1.16 - 1.54)	0.65
Absolute change (mg/dL)	0.00 (-0.08 - 0.05)
Serum blood urea nitrogen (mg/dL)	19.1 (16.2 - 23.1)	20.0 (16.2 - 25.1)	0.38
Absolute change (mg/dL)	0.5 (-2.8 - 4.3)
Uric acid (mg/dL)	5.8 ± 1.2	5.5 ± 1.3	0.20
Absolute change (mg/dL)	-0.45 (-1.03 - 0.40)
UPCR (g/g Cre) (n = 35)	0.36 (0.20 - 1.62)	0.23 (0.10 - 0.63)	< 0.01
Absolute change (g/g Cre)	-0.13 (-0.72 - -0.10)
Systolic blood pressure (mm Hg)	136.1 ± 13.2	128.3 ± 12.0	< 0.01
Absolute change (mm Hg)	-7.8 ± 12.0
Diastolic blood pressure (mm Hg)	75.3 ± 12.2	71.7 ± 9.7	0.01
Absolute change (mm Hg)	-3.5 ± 8.8
Pulse rate (beats/min)	77.7 ± 12.5	77.4 ± 11.7	0.85
Absolute change (beats/min)	-0.3 ± 9.0
Hemoglobin (g/dL)	13.6 ± 1.4	14.4 ± 1.4	< 0.01
Absolute change (g/dL)	0.8 ± 1.1
Hematocrit (%)	40.5 ± 3.7	43.0 ± 3.6	< 0.01
Absolute change (%)	2.5 ± 3.4

Table 2. Changes in Glucose Metabolic Parameters and Clinical Variables Before and After SGLT2 Inhibitor Therapy

SGLT2i therapy (n = 42)

P value

Baseline

1 year

SGLT2i: sodium glucose cotransporter 2 inhibitor; HbA1c: hemoglobin A1c; eGFR: estimated glomerular filtration rate; UPCR: urine protein-creatinine ratio; Cre: creatinine. Data pertaining to normally distributed variables are presented as the mean (standard deviation) and variables with a skewed distribution are presented as median (interquartile range).

HbA1c (%)

7.6 (7.1 - 8.2)

7.5 (7.0 - 8.1)

0.17

Absolute change (%)

-0.1 (-0.9 - 0.3)

Fasting plasma glucose (mg/dL) (n = 11)

158 (129 - 236)

128 (118 - 149)

0.02

Absolute change (mg/dL)

-29 (-94 - -7)

Body mass index (kg/m²)

28.2 ± 3.6

27.6 ± 3.6

< 0.01

Absolute change (kg/m²)

-0.63 ± 1.07

Body weight (kg)

75.0 ± 11.8

73.3 ± 11.3

< 0.01

Absolute change (kg)

-1.7 ± 2.8

eGFR (mL/min/1.73m²)

40.4 (36.5 - 43.0)

41.0 (36.0 - 45.6)

0.18

Absolute change (mL/min/1.73m²)

0.3 (-0.9 - 2.7)

Serum creatinine (mg/dL)

1.38(1.25 - 1.50)

1.35 (1.16 - 1.54)

0.65

Absolute change (mg/dL)

0.00 (-0.08 - 0.05)

Serum blood urea nitrogen (mg/dL)

19.1 (16.2 - 23.1)

20.0 (16.2 - 25.1)

0.38

Absolute change (mg/dL)

0.5 (-2.8 - 4.3)

Uric acid (mg/dL)

5.8 ± 1.2

5.5 ± 1.3

0.20

Absolute change (mg/dL)

-0.45 (-1.03 - 0.40)

UPCR (g/g Cre) (n = 35)

0.36 (0.20 - 1.62)

0.23 (0.10 - 0.63)

< 0.01

Absolute change (g/g Cre)

-0.13 (-0.72 - -0.10)

Systolic blood pressure (mm Hg)

136.1 ± 13.2

128.3 ± 12.0

< 0.01

Absolute change (mm Hg)

-7.8 ± 12.0

Diastolic blood pressure (mm Hg)

75.3 ± 12.2

71.7 ± 9.7

0.01

Absolute change (mm Hg)

-3.5 ± 8.8

Pulse rate (beats/min)

77.7 ± 12.5

77.4 ± 11.7

0.85

Absolute change (beats/min)

-0.3 ± 9.0

Hemoglobin (g/dL)

13.6 ± 1.4

14.4 ± 1.4

< 0.01

Absolute change (g/dL)

0.8 ± 1.1

Hematocrit (%)

40.5 ± 3.7

43.0 ± 3.6

< 0.01

Absolute change (%)

2.5 ± 3.4

**Table 3.** Annual Changes in Estimated Glomerular Filtration Rate Before and After Sodium Glucose Cotransporter 2 Inhibitor Therapy
	Before SGLT2i (n = 42)	P value	After SGLT2i (n = 42)
SGLT2i: sodium glucose cotransporter 2 inhibitor; eGFR: estimated glomerular filtration rate.
Annual changes in eGFR (mL/min/1.73m² per year)	-3.8 (-6.0 - -1.7)	< 0.01	0.1 (-0.8 - 1.5)

Table 3. Annual Changes in Estimated Glomerular Filtration Rate Before and After Sodium Glucose Cotransporter 2 Inhibitor Therapy

Before SGLT2i (n = 42)

P value

After SGLT2i (n = 42)

SGLT2i: sodium glucose cotransporter 2 inhibitor; eGFR: estimated glomerular filtration rate.

Annual changes in eGFR (mL/min/1.73m² per year)

-3.8 (-6.0 - -1.7)

< 0.01

0.1 (-0.8 - 1.5)