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 https://www.jocmr.org

Original Article

Volume 12, Number 11, November 2020, pages 724-733

Initial Acute Decline in Estimated Glomerular Filtration Rate After Sodium-Glucose Cotransporter-2 Inhibitor in Patients With Chronic Kidney Disease

Figure 1. IAD-eGFR after starting SGLT2i therapy in T2DM patients with CKD stage 3b. The line graph indicates serial changes in eGFR before and early after treatment with SGLT2is. The serial changes in eGFR were analyzed by Student’s paired t-test (n = 87, P < 0.01). SGLT2i: sodium-glucose cotransporter-2 inhibitor; eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SEM: standard error of mean; SD: standard deviation.

Figure 2. Distribution of percent changes in IAD-eGFR after starting SGLT2i therapy in T2DM patients with CKD stage 3b. Bar histogram indicates patient number in each percent change in eGFR. eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; CKD: chronic kidney disease.

Figure 3. Proportion of IAD-eGFR after starting SGLT2i therapy in T2DM patients with CKD stage 3b. (a) Proportion of any eGFR decline in and (b) proportion of large eGFR decline more than 10%. eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; CKD: chronic kidney disease.

Figure 4. Time course effects of IAD-eGFR after starting SGLT2i therapy on levels of 6 months eGFR in T2DM patients with CKD stage 3b. The line graph indicates serial changes in eGFR before and after treatment with SGLT2is according to the degree of IAD-eGFR. eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; CKD: chronic kidney disease.

Figure 5. Time course effects of large IAD-eGFR (≥ 10%) after starting SGLT2i therapy on levels of 6 months eGFR in T2DM patients with CKD stage 3b. The line graph indicated serial changes in eGFR before and after treatment with SGLT2is according to the presence or absence of large IAD-eGFR (≥ 10%). eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; CKD: chronic kidney disease; SEM: standard error of mean.

Figure 6. Effects of large IAD-eGFR (≥ 10%) after starting SGLT2i therapy on the changes in 6 months eGFR in T2DM patients with CKD stage 3b. eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; CKD: chronic kidney disease.

**Table 1.** Clinical Characteristics of Patients
	Total patients (n = 87)	Large IAD-eGFR (≥ 10%) (n = 36)	No or mild IAD-eGFR (< 10%) (n = 51)	P value
SGLT2i: sodium-glucose cotransporter-2 inhibitor; DPP-4: dipeptidyl peptidase; GLP-1: glucagon like peptide-1; eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; BMI: body mass index; Hb: hemoglobin; ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; Dapa: dapagliflozin; Empa: empagliflozin; Cana: canagliflozin; Ipra: ipragliflozin; Luse: luseogliflozin; Tofo: tofogliflozin.
Age (years)	69.8 ± 9.5	68.6 ± 11.5	70.7 ± 7.8	0.34
Sex (male %)	74.7	66.7	80.4	0.21
BMI (kg/m²)	26.9 ± 3.5	26.9 ± 4.1	27.0 ± 3.6	0.92
Hypertension (%)	90.8	91.7	90.2	1.00
Dyslipidemia (%)	92.0	94.4	90.2	0.70
Current smoking (%)	17.2	19.4	15.7	0.78
Retinopathy (%)	60.9	63.9	56.6	0.66
Cerebral or cardiovascular diseases (%)	40.2	38.9	41.2	1.00
Duration of diabetes (years)	21.7 ± 9.4	23.2 ± 9.2	20.7 ± 9.4	0.23
HbA1c (%)	7.3 (6.6 - 8.0)	7.0 (6.4 - 8.2)	7.4 (6.8 - 7.9)	0.44
Casual plasma glucose (mg/dL)	185 (143 - 232)	181 (126 - 201)	194 (150 - 238)	0.10
Anti-diabetic medicine (%)
Sulfonylureas (%)	19.5	13.9	23.5	0.29
Glinide (%)	11.5	16.7	7.8	0.31
Metformin (%)	32.2	27.8	35.3	0.49
Alpha-glucosidase inhibitor (%)	21.8	22.2	21.6	1.00
Thiazolidinedione (%)	5.7	0.0	9.8	0.07
DPP-4 inhibitor (%)	43.7	41.7	45.1	0.83
GLP-1 receptor agonist (%)	13.8	19.4	9.8	0.22
Insulin (%)	60.9	69.8	54.9	0.19
Additional SGLT2i (Dapa/Empa/Cana/Ipra/Luse/Tofo) (%)	35/16/1/6/38/4	33/14/0/6/44/3	35/18/2/6/33/6
Treatment duration of SGLT2i (months)	37.8 ± 4.6	37.2 ± 4.6	38.2 ± 4.5	0.32
Proteinuria (> 30 mg/dL) (%)	44.8	58.3	35.3	0.049
Hematuria (> 10 red blood cells/µL) (%)	32.2	38.9	27.5	0.35
Treatment with ACEi or ARB (%)	70.1	75.0	66.7	0.48
Treatment with diuretics (%)	28.7	36.1	23.5	0.23
Treatment with β-blockers (%)	46.0	41.7	49.0	0.52
Treatment with statin (%)	79.3	83.3	76.5	0.59
Start of SGLT2i therapy (from spring or summer) (%)	36.8	44.4	31.4	0.26

Table 1. Clinical Characteristics of Patients

Total patients (n = 87)

Large IAD-eGFR (≥ 10%) (n = 36)

No or mild IAD-eGFR (< 10%) (n = 51)

P value

SGLT2i: sodium-glucose cotransporter-2 inhibitor; DPP-4: dipeptidyl peptidase; GLP-1: glucagon like peptide-1; eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; BMI: body mass index; Hb: hemoglobin; ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; Dapa: dapagliflozin; Empa: empagliflozin; Cana: canagliflozin; Ipra: ipragliflozin; Luse: luseogliflozin; Tofo: tofogliflozin.

Age (years)

69.8 ± 9.5

68.6 ± 11.5

70.7 ± 7.8

0.34

Sex (male %)

74.7

66.7

80.4

0.21

BMI (kg/m²)

26.9 ± 3.5

26.9 ± 4.1

27.0 ± 3.6

0.92

Hypertension (%)

90.8

91.7

90.2

1.00

Dyslipidemia (%)

92.0

94.4

90.2

0.70

Current smoking (%)

17.2

19.4

15.7

0.78

Retinopathy (%)

60.9

63.9

56.6

0.66

Cerebral or cardiovascular diseases (%)

40.2

38.9

41.2

1.00

Duration of diabetes (years)

21.7 ± 9.4

23.2 ± 9.2

20.7 ± 9.4

0.23

HbA1c (%)

7.3 (6.6 - 8.0)

7.0 (6.4 - 8.2)

7.4 (6.8 - 7.9)

0.44

Casual plasma glucose (mg/dL)

185 (143 - 232)

181 (126 - 201)

194 (150 - 238)

0.10

Anti-diabetic medicine (%)

Sulfonylureas (%)

19.5

13.9

23.5

0.29

Glinide (%)

11.5

16.7

7.8

0.31

Metformin (%)

32.2

27.8

35.3

0.49

Alpha-glucosidase inhibitor (%)

21.8

22.2

21.6

1.00

Thiazolidinedione (%)

5.7

0.0

9.8

0.07

DPP-4 inhibitor (%)

43.7

41.7

45.1

0.83

GLP-1 receptor agonist (%)

13.8

19.4

9.8

0.22

Insulin (%)

60.9

69.8

54.9

0.19

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

35/16/1/6/38/4

33/14/0/6/44/3

35/18/2/6/33/6

Treatment duration of SGLT2i (months)

37.8 ± 4.6

37.2 ± 4.6

38.2 ± 4.5

0.32

Proteinuria (> 30 mg/dL) (%)

44.8

58.3

35.3

0.049

Hematuria (> 10 red blood cells/µL) (%)

32.2

38.9

27.5

0.35

Treatment with ACEi or ARB (%)

70.1

75.0

66.7

0.48

Treatment with diuretics (%)

28.7

36.1

23.5

0.23

Treatment with β-blockers (%)

46.0

41.7

49.0

0.52

Treatment with statin (%)

79.3

83.3

76.5

0.59

Start of SGLT2i therapy (from spring or summer) (%)

36.8

44.4

31.4

0.26

**Table 2.** Clinical and Body Composition Parameters Before Treatment With SGLT2i
	Total patients (n = 87)	Large IAD-eGFR (≥ 10%) (n = 36)	No or mild IAD-eGFR (< 10%) (n = 51)	P value
eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; Hb: hemoglobin; ToBW: total body water; ECW: extracellular water; ICW: intracellular water; SMM: skeletal muscle mass; SGLT2i: sodium-glucose cotransporter-2 inhibitor.
Body weight (kg)	70.8 (62.4 - 78.0)	70.0 (60.8 - 76.8)	70.8 (62.4 - 78.5)	0.45
Waist circumference (cm)	95.0 ± 11.5	93.4 ± 13.0	96.2 ± 10.2	0.31
Hb (g/dL)	13.2 ± 1.5	12.7 ± 1.3	13.5 ± 1.5	0.01
Serum creatinine (mg/dL)	1.40 ± 0.21	1.40 ± 0.23	1.40 ± 0.19	0.99
Blood urea nitrogen (mg/dL)	21.5 ± 5.7	21.6 ± 6.1	21.4 ± 5.4	0.86
Serum albumin (mg/dL)	4.1 (3.8 - 4.3)	3.9 (3.8 - 4.1)	4.1 (3.9 - 4.3)	0.019
Systolic blood pressure (mm Hg)	132 ± 14	132 ± 14	133 ± 15	0.70
Diastolic blood pressure (mm Hg)	71 ± 13	70 ± 14	72 ± 12	0.55
Pulse pressure (mm Hg)	61 ± 12	62 ± 12	61 ± 13	0.83
Pulse rate (beats/min)	73 (68 - 80)	73 (68 - 77)	73 (68 - 82)	0.44
Estimated daily salt intake (g/day)	8.8 (7.8 - 10.6)	10.3 (8.1 - 11.1)	8.4 (7.8 - 9.5)	0.016
Body composition by InBody
ToBW (kg)	35.5 ± 5.9	35.2 ± 4.9	35.7 ± 6.6	0.74
Body-ToBW percentage (%)	50.1 ± 6.1	50.6 ± 6.9	49.8 ± 5.6	0.57
ECW (kg)	13.9 ±2.3	13.9 ± 2.0	13.9 ± 2.6	0.99
Body weight-ECW percentage (%)	19.7 ± 2.4	20.0 ± 2.7	19.5 ± 2.1	0.31
ICW (kg)	21.5 ± 2.6	21.3 ± 2.9	21.6 ± 4.0	0.64
Body weight-ICW percentage (%)	30.4 ± 3.7	30.6 ± 4.2	30.2 ± 3.3	0.68
Percentage of ECW to ToBW (%)	39.3 ± 0.9	39.6 ± 1.0	39.1 ± 0.8	0.03
Total body fat (kg)	23.3 ± 7.5	22.7 ± 8.6	23.7 ± 6.7	0.57
Body weight-fat percentage (%)	32.3 ± 8.1	31.6 ± 9.2	32.8 ± 7.2	0.55
Total body muscle mass (kg)	45.3 ± 7.5	45.0 ± 6.2	45.5 ± 8.4	0.75
Body-muscle percentage (%)	64.0 ± 7.7	64.7 ± 8.8	63.5 ± 6.9	0.55
SMM (kg)	26.0 ± 4.6	25.7 ± 3.8	26.2 ± 5.2	0.67
Body-SMM percentage (%)	36.7 ± 4.7	37.0 ± 5.4	36.5 ± 4.3	0.69
Urinary specific gravity	1.015 (1.010 - 1.020)	1.015 (1.010 - 1.020)	1.015 (1.010 - 1.019)	0.11
Annual eGFR decline before SGLT2i (mL/min/1.73 m²)	-3.71 ± 4.04	-2.88 ± 3.93	-4.28 ± 4.05	0.11
Annual eGFR decline before SGLT2i (%)	-8.32 ± 9.50	-6.51 ± 10.11	-9.56 ± 8.94	0.16

Table 2. Clinical and Body Composition Parameters Before Treatment With SGLT2i

Total patients (n = 87)

Large IAD-eGFR (≥ 10%) (n = 36)

No or mild IAD-eGFR (< 10%) (n = 51)

P value

eGFR: estimated glomerular filtration rate; IAD-eGFR: initial acute decline in eGFR; Hb: hemoglobin; ToBW: total body water; ECW: extracellular water; ICW: intracellular water; SMM: skeletal muscle mass; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Body weight (kg)

70.8 (62.4 - 78.0)

70.0 (60.8 - 76.8)

70.8 (62.4 - 78.5)

0.45

Waist circumference (cm)

95.0 ± 11.5

93.4 ± 13.0

96.2 ± 10.2

0.31

Hb (g/dL)

13.2 ± 1.5

12.7 ± 1.3

13.5 ± 1.5

0.01

Serum creatinine (mg/dL)

1.40 ± 0.21

1.40 ± 0.23

1.40 ± 0.19

0.99

Blood urea nitrogen (mg/dL)

21.5 ± 5.7

21.6 ± 6.1

21.4 ± 5.4

0.86

Serum albumin (mg/dL)

4.1 (3.8 - 4.3)

3.9 (3.8 - 4.1)

4.1 (3.9 - 4.3)

0.019

Systolic blood pressure (mm Hg)

132 ± 14

133 ± 15

0.70

Diastolic blood pressure (mm Hg)

71 ± 13

70 ± 14

72 ± 12

0.55

Pulse pressure (mm Hg)

61 ± 12

62 ± 12

61 ± 13

0.83

Pulse rate (beats/min)

73 (68 - 80)

73 (68 - 77)

73 (68 - 82)

0.44

Estimated daily salt intake (g/day)

8.8 (7.8 - 10.6)

10.3 (8.1 - 11.1)

8.4 (7.8 - 9.5)

0.016

Body composition by InBody

ToBW (kg)

35.5 ± 5.9

35.2 ± 4.9

35.7 ± 6.6

0.74

Body-ToBW percentage (%)

50.1 ± 6.1

50.6 ± 6.9

49.8 ± 5.6

0.57

ECW (kg)

13.9 ±2.3

13.9 ± 2.0

13.9 ± 2.6

0.99

Body weight-ECW percentage (%)

19.7 ± 2.4

20.0 ± 2.7

19.5 ± 2.1

0.31

ICW (kg)

21.5 ± 2.6

21.3 ± 2.9

21.6 ± 4.0

0.64

Body weight-ICW percentage (%)

30.4 ± 3.7

30.6 ± 4.2

30.2 ± 3.3

0.68

Percentage of ECW to ToBW (%)

39.3 ± 0.9

39.6 ± 1.0

39.1 ± 0.8

0.03

Total body fat (kg)

23.3 ± 7.5

22.7 ± 8.6

23.7 ± 6.7

0.57

Body weight-fat percentage (%)

32.3 ± 8.1

31.6 ± 9.2

32.8 ± 7.2

0.55

Total body muscle mass (kg)

45.3 ± 7.5

45.0 ± 6.2

45.5 ± 8.4

0.75

Body-muscle percentage (%)

64.0 ± 7.7

64.7 ± 8.8

63.5 ± 6.9

0.55

SMM (kg)

26.0 ± 4.6

25.7 ± 3.8

26.2 ± 5.2

0.67

Body-SMM percentage (%)

36.7 ± 4.7

37.0 ± 5.4

36.5 ± 4.3

0.69

Urinary specific gravity

1.015 (1.010 - 1.020)

1.015 (1.010 - 1.019)

0.11

Annual eGFR decline before SGLT2i (mL/min/1.73 m²)

-3.71 ± 4.04

-2.88 ± 3.93

-4.28 ± 4.05

0.11

Annual eGFR decline before SGLT2i (%)

-8.32 ± 9.50

-6.51 ± 10.11

-9.56 ± 8.94

0.16

**Table 3.** Logistic Regression Analysis for a Large IAD-eGFR More Than 10% of Among Pretreatment Factors
Baseline variable	Univariate logistic regression	Multivariate logistic regression using forced inclusion model
OR: odds ratio; CI: confidence interval; CVD: cerebro-cardio vascular disease; DM: diabetes mellitus; Hb: hemoglobin; eGFR: estimated glomerular filtration rate; ACEi, angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; BP: blood pressure; ToBW: total body water; ECW: extracellular water; Hosmer-Lemeshow test showed P = 0.87 in multivariate analysis.
Age (per 1.0; year)	0.977	0.933 - 1.022	0.308
Gender (male)	0.488	0.183 - 1.300	0.151
Body mass index (per 1.0)	0.994	0.887 - 1.114	0.920
Body weight (per 1.0; kg)	0.980	0.944 - 1.018	0.980
Hypertension (yes)	1.196	0.267 - 5.356	0.815
Dyslipidemia (yes)	1.848	0.338 - 10.102	0.479
Current smoker (yes)	1.297	0.424 - 3.970	0.648
CVD history (yes)	0.909	0.380 - 2.174	0.830
DM retinopathy (yes)	1.237	0.514 - 2.984	0.634
HbA1c (per 1.0; %)	1.001	0.967 - 1.037	0.945
Duration of DM (per 1.0; years)	1.029	0.984 - 1.078	0.229
Insulin therapy (yes)	1.867	0.760 - 4.584	0.173
eGFR (per 1.0; mL/min/1.73 m²)	0.953	0.867 - 1.048	0.320
Presence of proteinuria (yes)	2.567	1.068 - 6.168	0.035	1.789	0.539 - 5.945	0.342
Presence of hematuria (yes)	1.682	0.677 - 4.176	0.263
Annual eGFR decline (per 1.0; %)	0.920	0.844 - 1.002	0.054
ACEi or ARB treatment (yes)	1.500	0.578 - 3.890	0.404
Diuretics treatment (yes)	1.837	0.719 - 4.696	0.204
Systolic BP (per 1.0; mmHg)	0.994	0.964 - 1.025	0.699
Estimated daily salt intake (per 1.0; g/day)	1.324	1.062 - 1.649	0.013	1.334	1.023 - 1.738	0.033
Body-fat percentage (per 1.0; %)	0.982	0.926 - 1.040	0.530
Percent of ToBW to weight (per 1.0; %)	1.023	0.948 - 1.105	0.554
Percent of ECW to ToBW (per 1.0; %)	1.879	1.059 - 3.333	0.031	1.152	0.587 - 2.262	0.680
Serum albumin (per 0.1; mg/dL)	0.878	0.775 - 0.995	0.042	0.874	0.724 - 1.056	0.162
Hb (per 1.0; g/dL)	0.655	0.469 - 0.916	0.013	0.656	0.409 - 1.050	0.079
Urinary specific gravity (per 0.001)	0.948	0.888 - 1.012	0.108

Table 3. Logistic Regression Analysis for a Large IAD-eGFR More Than 10% of Among Pretreatment Factors

Baseline variable

Univariate logistic regression

Multivariate logistic regression using forced inclusion model

95% CI

OR: odds ratio; CI: confidence interval; CVD: cerebro-cardio vascular disease; DM: diabetes mellitus; Hb: hemoglobin; eGFR: estimated glomerular filtration rate; ACEi, angiotensin converting enzyme inhibitor; ARB: angiotensin-II receptor blocker; BP: blood pressure; ToBW: total body water; ECW: extracellular water; Hosmer-Lemeshow test showed P = 0.87 in multivariate analysis.

Age (per 1.0; year)

0.977

0.933 - 1.022

0.308

Gender (male)

0.488

0.183 - 1.300

0.151

Body mass index (per 1.0)

0.994

0.887 - 1.114

0.920

Body weight (per 1.0; kg)

0.980

0.944 - 1.018

0.980

Hypertension (yes)

1.196

0.267 - 5.356

0.815

Dyslipidemia (yes)

1.848

0.338 - 10.102

0.479

Current smoker (yes)

1.297

0.424 - 3.970

0.648

CVD history (yes)

0.909

0.380 - 2.174

0.830

DM retinopathy (yes)

1.237

0.514 - 2.984

0.634

HbA1c (per 1.0; %)

1.001

0.967 - 1.037

0.945

Duration of DM (per 1.0; years)

1.029

0.984 - 1.078

0.229

Insulin therapy (yes)

1.867

0.760 - 4.584

0.173

eGFR (per 1.0; mL/min/1.73 m²)

0.953

0.867 - 1.048

0.320

Presence of proteinuria (yes)

2.567

1.068 - 6.168

0.035

1.789

0.539 - 5.945

0.342

Presence of hematuria (yes)

1.682

0.677 - 4.176

0.263

Annual eGFR decline (per 1.0; %)

0.920

0.844 - 1.002

0.054

ACEi or ARB treatment (yes)

1.500

0.578 - 3.890

0.404

Diuretics treatment (yes)

1.837

0.719 - 4.696

0.204

Systolic BP (per 1.0; mmHg)

0.994

0.964 - 1.025

0.699

Estimated daily salt intake (per 1.0; g/day)

1.324

1.062 - 1.649

0.013

1.334

1.023 - 1.738

0.033

Body-fat percentage (per 1.0; %)

0.982

0.926 - 1.040

0.530

Percent of ToBW to weight (per 1.0; %)

1.023

0.948 - 1.105

0.554

Percent of ECW to ToBW (per 1.0; %)

1.879

1.059 - 3.333

0.031

1.152

0.587 - 2.262

0.680

Serum albumin (per 0.1; mg/dL)

0.878

0.775 - 0.995

0.042

0.874

0.724 - 1.056

0.162

Hb (per 1.0; g/dL)

0.655

0.469 - 0.916

0.013

0.656

0.409 - 1.050

0.079

Urinary specific gravity (per 0.001)

0.948

0.888 - 1.012

0.108