A Clinical Study on the Association of Sodium-Glucose Cotransporter 2 Inhibitors and Acute Kidney Injury Among Diabetic Chinese Population

Figures & data

Table 1 Characteristics of the Drug Usage of the Type-2 Diabetes Patients

Drugs	SGLT 2 Inhibitors, n (%)				DPP4 Inhibitors, n (%)			NSAID, n (%)			First Line, n (%)		Antibiotics, n (%)
	Canagliflozin	Ipragliflozin	Jardiance	Dapagliflozin	Vildagliptin	Alogliptin	Linagliptin	Ibuprofen	Indomethacin	Celecoxib	Insulin	Metformin	Cephalexin	Amoxicillin
Pop (n)	418	314	409	474	337	318	266	404	334	408	406	412	245	221
Percent	8.42	6.32	8.24	9.54	6.79	6.4	5.36	8.14	6.73	8.21	8.17	8.3	4.93	4.45
Age (Years)	75.35	74.12	72.56	68.89	73.54	74.31	67.32	74.32	66.45	69.36	69.32	73.87	75.54	72.45
Hypertension	203 (48.56)	153 (48.88)	185 (45.45)	209 (44.09)	174 (51.63)	147 (46.23)	132 (49.62)	181 (44.8)	161 (48.2)	219 (53.68)	186 (45.81)	205 (49.76)	120 (49.98)	97 (43.89)
Diabetic Retinopathy	15 (3.59)	9 (2.88)	14 (3.44)	25 (5.27)	12 (3.56)	14 (4.4)	12 (4.51)	16 (3.96)	14 (4.19)	14 (3.43)	17 (4.19)	12 (2.91)	9 (3.67)	9 (4.07)
COPD	11 (2.63)	8 (2.56)	10 (2.46)	30 (6.33)	10 (2.97)	11 (3.46)	10 (3.76)	12 (2.97)	8 (2.4)	10 (2.45)	19 (4.68)	8 (1.94)	7 (2.86)	12 (5.43)
Diabetic neuropathy	12 (2.87)	7 (2.24)	13 (3.19)	8 (1.69)	15 (4.45)	16 (5.03)	5 (1.88)	11 (2.72)	12 (3.59)	12 (2.94)	9 (2.22)	15 (3.64)	8 (3.27)	7 (3.17)
Hypoglycemia	25 (5.98)	18 (5.75)	17 (4.18)	14 (2.95)	17 (5.04)	12 (3.77)	14 (5.26)	21 (5.2)	23 (6.89)	18 (4.41)	21 (5.17)	22 (5.34)	9 (3.67)	11 (4.98)
Congestive heart failure	21 (5.02)	14 (4.47)	22 (5.41)	11 (2.32)	11 (3.26)	19 (5.97)	12 (4.51)	18 (4.45)	14 (4.19)	14 (3.43)	18 (4.43)	13 (3.16)	12 (4.8)	8 (3.62)
Pulmonary vascular disease	29 (6.94)	18 (5.74)	23 (5.65)	19 (4.01)	14 (4.15)	10 (3.14)	15 (5.64)	21 (5.2)	19 (5.69)	13 (3.19)	11 (2.71)	17 (4.13)	10 (4.08)	13 (5.88)
Liver disease	6 (1.44)	8 (2.56)	18 (4.42)	21 (4.43)	9 (2.67)	15 (4.72)	6 (2.26)	14 (3.47)	12 (3.59)	17 (4.17)	12 (2.96)	14 (3.4)	8 (3.27)	9 (4.08)
Malignancy- To replace	8 (1.91)	10 (3.19)	7 (1.72)	12 (2.53)	12 (3.56)	7 (2.21)	7 (2.63)	9 (2.23)	8 (2.4)	12 (2.94)	8 (1.97)	23 (5.58)	14 (5.71)	6 (2.71)
Chronic Lung Disease	18 (4.31)	15 (4.79)	23 (5.65)	24 (5.06)	15 (4.45)	21 (6.6)	11 (4.14)	19 (4.7)	9 (2.69)	14 (3.43)	18 (4.43)	8 (1.94)	6 (2.45)	10 (4.52)
Cancer	27 (6.46)	19 (6.07)	19 (4.68)	29 (6.12)	10 (2.98)	16 (5.03)	14 (5.26)	23 (5.69)	8 (2.4)	21 (5.14)	27 (6.65)	27 (6.55)	7 (2.86)	12 (5.43)
Previous UTI	12 (2.87)	9 (2.88)	16 (3.93)	24 (5.06)	12 (3.56)	7 (2.2)	7 (2.63)	18 (4.46)	11 (3.29)	14 (3.43)	22 (5.42)	10 (2.43)	9 (3.61)	5 (2.26)
Pace Maker	10 (2.39)	11 (3.51)	11 (2.7)	12 (2.53)	9 (2.67)	9 (2.83)	8 (3.01)	13 (3.22)	14 (4.19)	13 (3.19)	13 (3.2)	16 (3.88)	5 (2.04)	9 (4.07)
Stroke	12 (2.87)	9 (2.88)	16 (3.93)	24 (5.1)	11 (3.27)	8 (2.52)	6 (2.26)	16 (3.96)	10 (2.99)	8 (1.96)	16 (3.94)	12 (2.91)	13 (5.31)	7 (3.18)
Atrial Fibrillation	9 (2.15)	5 (1.6)	13 (3.19)	12 (2.53)	6 (1.78)	6 (1.89)	7 (2.63)	12 (2.97)	11 (3.29)	9 (2.21)	9 (2.22)	10 (2.43)	8 (3.27)	6 (2.71)

Table 2 AKI Outcome During the Primary and Secondary Endpoints Caused by Different Types of the Investigated Drugs

Drug Class	SGLT 2 Inhibitors				DPP4 Inhibitors			NSAIDs			First-Line Drugs		Antibiotics
Drugs	Canagliflozin	Ipragliflozin	Jardiance	Dapagliflozin	Vildagliptin	Alogliptin	Linagliptin	Ibuprofen	Indomethacin	Celecoxib	Insulin	Metformin	Cephalexin	Amoxicillin
New Pop (n)	418	314	409	474	337	318	266	404	334	408	406	412	245	221
Events During the 90 days	66	58	57	73	79	91	56	124	106	112	58	69	50	48
Events at secondary end	201	211	220	225	237	273	228	433	391	421	290	261	283	245
Total endpoint	267	269	277	298	316	364	284	557	497	533	348	330	333	293
Total Percent	5.38	5.42	5.58	6	6.36	7.33	5.72	11.22	10.01	10.72	7.01	6.64	6.71	5.9

Table 3 Associations Between AKI and the Investigated Class of Drugs

Drug	Classification	Endpoint Diagnosis with 1047 Outcome		Secondary Diagnosis with 3919 Outcomes
		Unadjusted	Adjusted	Unadjusted	Adjusted
Metformin (Control)	First line	1	1	1.0 (Reference)	1.0 (Reference)
Indomethacin	NSAID	2.81 (2.32–2.94)	2.29 (2.05–2.65)	2.45(2.09–2.54)	2.63 (2.41–2.72)
Vildagliptin	DPP4 inhibitors	1.23 (0.97–1.32)	1.18 (0.92–1.35)	1.20 (0.72–1.38)	1.07 (0.95–1.45)
Canagliflozin	SGLT 2 inhibitors	0.85 (0.67–1.21)	1.06 (0.68–1.34)	0.89 (0.61–1.25)	1.06 (0.91–1.42)
Cephalexin	Anti-biotic	2.17 (1.78–2.37)	1.52 (1.31–2.16)	1.56 (1.27–1.92)	1.82 (1.31–2.25)
Ibuprofen	NSAID	3.14 (2.87–3.74)	2.41 (1.91–2.54)	2.68 (2.21–3.03)	2.36 (1.84–2.93)
Jardiance	SGLT 2 inhibitors	0.87 (0.69–1.12)	0.76 (0.58–1.18)	0.83 (0.68–1.14)	0.85 (0.67–1.18)
Linagliptin	DPP4 inhibitors	0.97 (0.68–1.32)	0.86 (0.72–1.46)	0.87 (0.72–1.21)	1.23 (0.73–1.65)
Ipragliflozin	SGLT 2 inhibitors	0.78 (0.61–1.08)	0.86 (0.69–1.31)	0.84 (0.69–1.16)	0.95 (0.62–1.45)
Amoxicillin	Anti-biotic	1.73 (1.16–1.85)	1.36 (1.06–1.54)	1.17 (0.88–1.43)	1.34 (1.07–1.82)
Insulin	First line	2.26 (1.95–2.64)	2.36 (1.81–2.87)	2.42 (1.25–2.61)	2.73 (2.28–2.90)
Alogliptin	DPP4 inhibitors	1.83 (1.75–2.16)	1.43 (1.31–2.04)	2.27 (1.08–3.12)	2.85 (2.26–3.07)
Celecoxib	NSAID	2.95 (2.68–3.25)	2.32 (2.12–2.68)	1.87 (1.64–2.43)	1.86 (1.53–2.77)
Dapagliflozin	SGLT 2 inhibitors	0.94 (0.71–1.25)	0.84 (0.72–1.32)	0.81 (0.63–1.33)	0.93 (0.58–1.24)

Table 4 Pharmacokinetics Analysis of the Investigated Drugs in Normal Mice and Their Time Course Changes in Plasma, Kidney and Liver

Drugs and Class		0h	3h	6h	9h	12h	15h	18h	21h	24h
Canagliflozin (SGLT2 inhibitor)	Plasma	0	500	300	50	0	0	0	0	0
	Kidney	0	5000	4300	900	300	0	0	0	0
	Liver	0	4700	3900	600	100	0	0	0	0
Ipragliflozin (SGLT2 inhibitor)	Plasma	0	300	250	30	0	0	0	0	0
	Kidney	0	16,700	14,500	8000	4500	3000	1500	1000	850
	Liver	0	7500	6000	1200	300	50	0	0	0
Jardiance (SGLT2 inhibitor)	Plasma	0	500	450	200	0	0	0	0	0
	Kidney	0	1800	1200	550	100	0	0	0	0
	Liver	0	1100	850	400	50	0	0	0	0
Dapagliflozin (SGLT2 inhibitor)	Plasma	0	1650	1430	400	100	0	0	0	0
	Kidney	0	6500	4200	2300	700	100	0	0	0
	Liver	0	5800	3600	1800	300	100	0	0	0
Vildagliptin (DPP4 inhibitor)	Plasma	0	7500	3000	1200	600	200	0	0	0
	Kidney	0	4500	3950	1650	100	25	0	0	0
	Liver	0	8300	4800	2900	300	50	0	0	0
Alogliptin (DPP4 inhibitor)	Plasma	0	400	250	50	0	0	0	0	0
	Kidney	0	6700	4300	2350	100	50	0	0	0
	Liver	0	6340	3500	1980	300	100	0	0	0
Linagliptin (DPP4 inhibitor)	Plasma	0	450	310	50	0	0	0	0	0
	Kidney	0	18,500	12,800	9500	5400	2500	500	0	0
	Liver	0	7500	6000	1200	300	50	0	0	0
Ibuprofen (NSAID)	Plasma	0	600	400	140	0	0	0	0	0
	Kidney	0	1950	16,500	9500	3500	1000	200	100	0
	Liver	0	9500	7600	1800	600	150	0	0	0
Indomethacin (NSAID)	Plasma	0	300	100	50	0	0	0	0	0
	Kidney	0	8240	5200	3880	700	250	0	0	0
	Liver	0	10,300	8700	5400	1200	150	0	0	0
Celecoxib (NSAID)	Plasma	0	250	50	30	0	0	0	0	0
	Kidney	0	10,340	8900	6480	2100	450	0	0	0
	Liver	0	13,200	9800	6250	2300	400	50	0	0
Insulin (First-Line drugs)	Plasma	0	640	450	310	50	0	0	0	0
	Kidney	0	14,200	10,400	6400	3700	500	0	0	0
	Liver	0	9400	5050	2380	370	0	0	0	0
Metformin (First-Line drugs- control)	Plasma	640	540	330	0	0	0	0	0	0
	Kidney	2700	1560	720	190	0	0	0	0	0
	Liver	1890	1450	650	150	0	0	0	0	0
Cephalexin (Antibiotics)	Plasma	0	360	70	30	0	0	0	0	0
	Kidney	0	8130	5630	2390	450	30	0	0	0
	Liver	0	1060	7460	4550	1650	340	80	0	0
Amoxicillin (Antibiotics)	Plasma	370	80	45	0	0	0	0	0	0
	Kidney	9860	7320	5670	2340	730	60	0	0	0
	Liver	12,110	8700	5470	1350	200	30	0	0	0

Table 5 Pharmacokinetics Analysis of the Investigated Drugs in Mouse Model Showing the Cmax, Tmax and Half Life

Drug	Classification	Tissue	Cmax (ng/mL)	Tmax (h)	t1/2 (h)	AUC (ng/mL)
Canagliflozin	SGLT2	Plasma	542	1	2.1	1432
		Kidney	3765	1	2.4	12,100
		Liver	3217	1	2.8	10,100
Ipragliflozin	SGLT2	Plasma	975	0.5	1.6	3020
		Kidney	4135	0.5	2.3	23,400
		Liver	3042	0.5	1.5	19,300
Jardiance	SGLT2	Plasma	412	1	1.8	626
		Kidney	1742	1	2.1	4200
		Liver	1154	1	2.2	2930
Dapagliflozin	SGLT2	Plasma	1434	1	2.8	2970
		Kidney	3448	1	3.1	12,610
		Liver	2043	1	1.7	6534
Vildagliptin	DPP4	Plasma	765	0.5	2.8	2967
		Kidney	5872	0.5	3.5	19,765
		Liver	5032	0.5	3.1	22,786
Alogliptin	DPP4	Plasma	943	1	2.4	3455
		Kidney	8562	1	4.4	3245
		Liver	6734	1	2.6	23,862
Linagliptin	DPP4	Plasma	578	1	2.6	2432
		Kidney	6438	1	3.7	25,331
		Liver	5051	1	2.8	19,653
Ibuprofen	NSAID	Plasma	1274	1	2.1	4896
		Kidney	8512	1	4.3	43,167
		Liver	8743	1	2.5	35,721
Indomethacin	NSAID	Plasma	1167	1	2.7	4327
		Kidney	10,257	1	3.8	37,432
		Liver	9654	1	3.1	35,776
Celecoxib	NSAID	Plasma	983	0.5	2.4	3422
		Kidney	12,091	0.5	4.5	46,325
		Liver	11,674	0.5	3.6	42,642
Insulin	First Line	Plasma	879	1	1.4	2985
		Kidney	6574	1	2.7	26,742
		Liver	6087	1	1.9	19,851
Metformin (Control)	First Line	Plasma	632	0.5	1.8	1985
		Kidney	5632	0.5	3.8	19,753
		Liver	4375	0.5	2.7	17,852
Cephalexin	Anti-biotics	Plasma	1356	1	1.7	4532
		Kidney	8703	1	2.3	25,842
		Liver	6753	1	2.9	23,452
Amoxicillin	Anti-biotics	Plasma	945	1	1.6	3423
		Kidney	4512	1	3.1	23,145
		Liver	3985	1	1.7	18,731