SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

Table 1 Literature search strategy

S. No	Search terms
1	NAFLD
2	Nonalcoholic fatty liver disease
3	Non-alcoholic fatty liver disease
4	Non alcoholic fatty liver disease
5	NASH
6	Non-alcoholic steatohepatitis
7	Nonalcoholic steatohepatitis
8	Non alcoholic steatohepatitis
9	Fatty liver
10	1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9
11	Type 2 diabetes mellitus
12	Type 2 diabetes
13	Diabetes mellitus type 2
14	Diabetes type 2
15	11 OR 12 OR 13 OR 14
16	SGLT-2 inhibitors
17	Sodium glucose cotransporter-2 inhibitors
18	SGLT-2
19	SGLT2
20	SGLT 2
21	Canagliflozin
22	Dapagliflozin
23	Empagliflozin
24	Ipragliflozin
25	Luseogliflozin
26	Tofogliflozin
27	Sotagliflozin
28	Remogliflozin
29	Ertugliflozin
30	Sergliflozin
31	16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30
32	10 AND 15 AND 31

NAFLD: Non-alcoholic fatty liver disease; NASH: Non alcoholic steatohepatitis; SGLT-2: Sodium glucose cotransporter-2.

Table 2 Randomised controlled trials

S. No	Ref.	Inclusion criteria	Age (yr)	Male gender	Intervention arm	Control arm	Follow-up duration	Primary outcome
1	Kuchay et al[11], 2018	Age > 20 yr, hepatic steatosis (MRI-PDFF > 6%), HbA1c > 7.0% to < 10.0%	Intervention arm: 50.7 (12.8)	Intervention arm: 16 (64%)	Standard treatment + Empagliflozin 10 mg daily (n = 25)	Standard treatment (n = 25)	20 wk	Change in liver fat content by MRI-PDFF
			Control arm: 49.1 (10.3)	Control arm: 17 (68%)
2	Ito et al[12], 2017	Age 20-75 yr, HbA1c 7.0–11.0%, BMI < 45 kg/m2, On diet and exercise therapy alone or with oral hypoglycaemic agents other than SGLT-2 inhibitors and thiazolidinediones and/or insulin, NAFLD, findings suggesting hepatic steatosis and hepatic dysfunction on clinical laboratory tests or on imaging studies (e.g., computed tomography or ultrasound)	Pioglitazone arm: 59.1 (9.8)	Pioglitazone arm: 18 (53%)	Ipragliflozin 50 mg daily (n = 32)	Pioglitazone 15-30 mg daily (n = 34)	24 wk	Change in L/S attenuation ratio
			Ipragliflozin arm: 57.3 (12.1)	Ipragliflozin arm: 14 (44%)
3	Shibuya et al[13], 2018	Fatty liver diagnosed on the basis of computed tomography or abdominal sonography, HbA1c 6.0%–10.0%, age 20–70 yr	Luseogliflozin arm: 51 (47-62)	Luseogliflozin arm: 10 (62.5%)	Luseogliflozin 2.5 mg daily (n = 16)	Metformin 1.5 g daily (n = 16)	24 wk	Change in L/S attenuation ratio
			Metformin arm: 60 (53-66)	Metformin arm: 8 (50%)
4	Eriksson et al[14], 2018	Age 40–75 yr, treated with a stable dose of metformin or sulfonylurea alone or in combination for at least 3 mo, MRI-PDFF > 5.5%, BMI 25–40 kg/m2	Dapagliflozin arm: 65 (6.5)	Dapagliflozin arm: 16 (76.2%)	Dapagliflozin 10 mg daily (n = 21) or Omega 3-carboxylic acid 4 g daily (n = 20) or Combination (n = 22)	Placebo (n = 21)	12 wk	Change in liver fat content by MRI-PDFF
			Omega 3-carboxylic acid arm: 66.2 (5.9)	Omega 3-carboxylic acid arm: 11 (55%)
			O + D arm: 65(5.4)	O + D arm: 15 (68.2%)
			Placebo arm: 65.6 (6.1)	Placebo arm: 17 (81%)

MRI-PDFF: Magnetic resonance imaging-derived proton density fat fraction; L/S: Liver/spleen; O + D: Omega 3-carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2; NAFLD: Non-alcoholic fatty liver disease.

Table 3 Observational studies

S. No	Ref.	Design	Inclusion criteria	Age (yr)	Male gender	Sample size	SGLT-2 inhibitor	Follow-up duration
1	Ohki et al[15], 2016	Prospective study	Type 2 diabetes with NAFLD treated with GLP-1 analogues or DPP-4 inhibitors and failed to normalise serum ALT levels	54.2 (49.3-60.1)	19 (79.2%)	24	Ipragliflozin 25-50 mg daily	320 d (302-329)
2	Seko et al[16], 2016	Retrospective cohort study	Type 2 diabetes with NAFLD	SGLT-2 inhibitor arm: 60.3 (1.8)	SGLT-2 inhibitor arm: 9 (37.5%)	24 (SGLT-2 inhibitor); 21 (Sitagliptin )	Canagliflozin 100 mg (n = 18) or Ipragliflozin 50 mg daily (n = 6)	24 wk
				Sitagliptin arm: 59.4 (3.7)	Sitagliptin arm: 8 (38.1%)
3	Gautam et al[17], 2018	Prospective study	Type 2 diabetes with NAFLD	-	-	32	Canagliflozin 100 mg daily	24 wk
4	Sumida et al[18], 2018	Prospective study	Age > 20 yr, HbA1c > 6.5% to < 8.5%, NAFLD	55.4 (13.6)	28 (70%)	40	Luseogliflozin 2.5 mg daily	24 wk

NAFLD: Non-alcoholic fatty liver disease; SGLT-2: Sodium glucose cotransporter-2; GLP-1: Glucagon like peptide-1; DPP-4: Dipeptidyl peptidase-4.

Table 4 Assessment of study quality of randomised controlled trials

Study	Criteria	Risk of bias	Study quality
Kuchay et al[11]	Random sequence generation	Low risk	Good quality
	Allocation concealment	Low risk
	Selective reporting	Low risk
	Other bias	Low risk
	Blinding of participants and personnel	Low risk
	Blinding of outcome assessment	Low risk
	Incomplete outcome data	Low risk
Ito et al[12]	Random sequence generation	Low risk	Fair quality
	Allocation concealment	Unclear risk
	Selective reporting	Low risk
	Other bias	Low risk
	Blinding of participants and personnel	Low risk
	Blinding of outcome assessment	Low risk
	Incomplete outcome data	Low risk
Shibuya et al[13]	Random sequence generation	Unclear risk	Fair quality
	Allocation concealment	Unclear risk
	Selective reporting	Low risk
	Other bias	Low risk
	Blinding of participants and personnel	Low risk
	Blinding of outcome assessment	Low risk
	Incomplete outcome data	Low risk
Eriksson et al[14]	Random sequence generation	Low risk	Good quality
	Allocation concealment	Low risk
	Selective reporting	Low risk
	Other bias	Low risk
	Blinding of participants and personnel	Low risk
	Blinding of outcome assessment	Low risk
	Incomplete outcome data	Low risk

Table 5 Assessment of study quality of observational studies

S. No	Criteria	Ohki et al[15]	Seko et al[16]	Gautam et al[17]	Sumida et al[18]
1	A clearly stated aim	2	2	2	2
2	Inclusion of consecutive patients	0	2	2	1
3	Prospective collection of data	2	0	2	2
4	Endpoints appropriate to the aim of the study	2	2	2	2
5	Unbiased assessment of the study endpoint	0	0	0	0
6	Follow-up period appropriate to the aim of the study	2	2	2	2
7	Loss to follow up less than 5%	2	2	2	2
8	Prospective calculation of the study size	0	0	0	0
9	An adequate control group	NA	0	NA	NA
10	Contemporary groups	NA	2	NA	NA
11	Baseline equivalence of groups	NA	2	NA	NA
12	Adequate statistical analyses	NA	2	NA	NA
13	Total score	10/16	16/24	12/16	11/16

Table 6 Change in serum alanine aminotransferase levels in individual studies

Study	Serum ALT level (IU/L)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	64.3 (20.2)	49.7 (25.8)	0.001	0.005
	Control	65.3 (40.3)	61.6 (38.4)	0.422
Ito et al[12]	Ipragliflozin	57.4 (27.3)	38.2 (20.5)	< 0.05	0.642
	Pioglitazone	53.1 (26.6)	36.8 (15.1)	< 0.05
Shibuya et al[13]	Luseogliflozin	49.5 (31.0, 70.0)	31 (26.0, 55.0)	0.057	0.064
	Metformin	39 (23.0, 56.0)	39 (27.0, 51.0)	0.518
Eriksson et al[14]	Placebo	33.53 (12.4)	-0.2 (8.8)1	-	-
	Omega-3 CA	37.65 (14.7)	+5.9 (16.5)1	-	Non-significant2
	Dapagliflozin	39.41 (14.7)	-8.2 (8.2)1	-	< 0.052
	O + D	35.88 (17.1)	+0.1 (12.9)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	62 (43.0-75.0)	38.0 (31.0-65.0)	0.01	-
Seko et al[16]	SGLT-2 inhibitor	70.8 (8.1)	48.8 (5.5)	0.002	0.039
	Sitagliptin	92.4 (11.2)	71.1 (10.0)	0.012
Gautam et al[17]	Canagliflozin	96 (18.7)	60.0 (17.6)	< 0.00001	-
Sumida et al[18]	Luseogliflozin	54.7 (28.2)	42.4 (26.5)	< 0.001	-

¹Change from baseline.

²Compared to placebo.

ALT: Alanine aminotransferase; CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 7 Change in serum aspartate aminotransferase levels in individual studies

Study	Serum AST levels (IU/L)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	44.6 (23.5)	36.2 (9.0)	0.04	0.212
	Control	45.3 (24.3)	44.6 (23.8)	0.931
Ito et al[12]	Ipragliflozin	39.7 (16.7)	27.3 (8.9)	< 0.05	0.802
	Pioglitazone	43.3 (20.5)	32.4 (15.4)	< 0.05
Eriksson et al[14]	Placebo	29.4 (13.2)	-1.2 (7.2)1	-	-
	Omega-3 CA	30.6 (10.2)	+4.8 (9.0)1	-	Non-significant2
	Dapagliflozin	31.2 (11.4)	-4.2 (5.4)1	-	< 0.052
	O + D	30 (10.2)	+1.2 (5.4)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	37 (29.0-52.0)	28 (23.0-31.0)	0.03	-
Seko et al[16]	SGLT-2 inhibitor	54.4 (5.6)	38 (3.1)	0.001	-
	Sitagliptin	67 (7.7)	52.5 (7.7)	0.016
Gautam et al[17]	Canagliflozin	72 (16.7)	53 (10.3)	< 0.00001	-
Sumida et al[18]	Luseogliflozin	40.7 (22.2)	31.9 (18.2)	< 0.001	-

¹Change from baseline.

²Compared to placebo.

AST: Aspartate aminotransferase; CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 8 Change in serum gamma-glutamyl transferase levels in individual studies

Study	Serum GGT (IU/L )			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	65.8 (36.1)	50.9 (24.6)	0.002	0.057
	Control	63.9 (45.3)	60.0 (39.0)	0.421
Ito et al[12]	Ipragliflozin	62.8 (58.3)	44.0 (38.3)	< 0.05	0.642
	Pioglitazone	71.6 (54.1)	48.8 (61.2)	< 0.05
Eriksson et al[14]	Placebo	32.4 (17.4)	+2.4 (9.6)1	-	-
	Omega-3 CA	54.0 (57.6)	+2.4 (12.0)1	-	Non-significant2
	Dapagliflozin	58.2 (43.2)	-4.8 (13.8)1	-	< 0.052
	O + D	40.2 (14.4)	-0.6 (13.8)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	75.0 (47.0-105.0)	60.0 (40.0-101.0)	0.03	-
Seko et al[16]	SGLT-2 inhibitor	61.7 (9.1)	58.7 (11.5)	0.051	-
	Sitagliptin	89.2 (11.8)	82.4 (11.9)	0.36
Gautam et al[17]	Canagliflozin	75.1 (31.8)	69.2 (26.2)	0.003	-
Sumida et al[18]	Luseogliflozin	62.4 (77.1)	48.2 (56.3)	0.003	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; GGT: Gamma-glutamyl transferase; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 9 Change in hepatic fat in individual studies

Study	Parameter	Group	Baseline	Study completion	P value	P value between groups
Kuchay et al[11]	MRI-PDFF	Empagliflozin	16.2 (7)	11.3 (5.3)	< 0.0001	< 0.0001
		Control	16.4 (7.3)	15.5 (6.7)	0.054
Ito et al[12]	L/S ratio	Ipragliflozin	0.8 (0.2)	1.0 (0.2)	< 0.05	0.90
		Pioglitazone	0.8 (0.3)	1.0 (0.2)	< 0.05
Shibuya et al[13]	L/S ratio	Luseogliflozin	0.9 (0.6-1.0)	1.0 (0.8-1.2)	0.0008	0.00002
		Metformin	1.0 (0.8-1.1)	0.9 (0.7-1.0)	0.017
Eriksson et al[14]	MRI-PDFF	Placebo	15.1 (6.5)	-0.6 (1.9)1	-	-
		Omega-3 CA	22.2 (11.0)	-3.2 (2.9)1	-	Non-significant2
		Dapagliflozin	17.3 (9.1)	-2.2 (3.3)1	-	Non-significant2
		O + D	17.8 (9.2)	-3.2 (3.5)1	-	< 0.052
Sumida et al[18]	MRI-HFF	Luseogliflozin	21.5 (7.2)	15.7 (6.8)	< 0.001	-

¹Change from baseline.

² Compared to placebo.

MRI-PDFF: Magnetic resonance imaging-derived proton density fat fraction; L/S ratio: Liver/spleen attenuation ratio; MRI-HFF: Magnetic resonance imaging-hepatic fat fraction; CA: Carboxylic acid; O + D: Omega-3 CA + Dapagliflozin.

Table 10 Assessment of liver fibrosis in individual studies

Study	Parameter	Group	Baseline	Study completion	P value	P value between groups
Ito et al[12]	FIB-4 index	Ipragliflozin	1.44 (0.64)	1.22 (0.55)	< 0.05	0.596
		Pioglitazone	1.84 (1.13)	1.71 (1.19)	Non-significant
Ohki et al[15]	FIB-4 index	Ipragliflozin	1.75 (0.82-1.93)	1.39 (0.77-1.99)	0.04	-
Sumida et al[18]	FIB-4 index	Luseogliflozin	1.63 (1.19)	1.52 (0.92)	0.17	-
	NAFLD fibrosis score	Luseogliflozin	1.61 (0.71)	1.62 (0.88)	0.86	-

FIB: Fibrosis 4; NAFLD: Non-alcoholic fatty liver disease.

Table 11 Change in fasting plasma glucose in individual studies

Study	Fasting plasma glucose (mg/dL)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	173.0 (44.0)	124.0 (17.0)	< 0.001	0.85
	Control	176.0 (57.0)	120.0 (19.0)	< 0.0001
Ito et al[12]	Ipragliflozin	160.1 (38.7)	136.5 (26.7)	< 0.05	0.785
	Pioglitazone	169.4 (50.9)	139.0 (26.6)	< 0.05
Shibuya et al[13]	Luseogliflozin	127.0 (116.0, 136.0)	125.0 (113.0, 138.0)	0.87	0.583
	Metformin	147.0 (126.0, 161.0)	134.0 (122.0, 145.0)	0.32
Eriksson et al[14]	Placebo	169.2 (29.7)	+6.7 (14.8)1	-	-
	Omega-3 CA	162.4 (26.6)	+3.8 (19.3)1	-	Non-significant2
	Dapagliflozin	161.8 (33.3)	-17.6 (26.8)1	-	< 0.052
	O + D	168.8 (35.5)	-16.4 (36.0)1	-	< 0.052
Ohki et al[15]	Ipragliflozin	162.0 (135.0-189.0)	135.0 (120.0-166.0)	0.3	-
Seko et al[16]	SGLT-2 inhibitor	125.0 (6.0)	116.6 (4.2)	0.07	Non-significant
	Sitagliptin	114.6 (7.0)	134.0 (10.5)	0.067
Sumida et al[18]	Luseogliflozin	142.0 (30.3)	135.4 (25.6)	0.04	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 12 Change in glycosylated haemoglobin in individual studies

Study	Glycosylated haemoglobin (%)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	9.0 (1.0)	7.2 (0.6)	< 0.001	0.88
	Control	9.1 (1.4)	7.1 (0.9)	< 0.0001
Ito et al[12]	Ipragliflozin	8.5 (1.5)	7.6 (1.0)	< 0.05	0.522
	Pioglitazone	8.3 (1.4)	7.1 (0.9)	< 0.05
Shibuya et al[13]	Luseogliflozin	7.8 (7.2, 7.9)	6.5 (6.4, 7.0)	0.002	0.023
	Metformin	7.4 (6.9, 7.7)	7.3 (6.7, 7.6)	0.362
Eriksson et al[14]	Placebo	7.4 (0.8)	-0.1 (0.4)1	-	-
	Omega-3 CA	7.4 (0.7)	+0.1 (0.4)1	-	Non-significant2
	Dapagliflozin	7.4 (0.6)	-0.6 (0.7)1	-	< 0.052
	O + D	7.5 (0.8)	-0.5 (0.5)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	8.4 (7.8-8.9)	7.6 (6.9-8.2)	< 0.01	-
Seko et al[16]	SGLT-2 inhibitor	6.7 (0.1)	6.5 (0.1)	0.055	Non-significant
	Sitagliptin	7.0 (0.3)	6.9 (0.3)	0.331
Sumida et al[18]	Luseogliflozin	7.3 (0.7)	7.0 (0.7)	0.002	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 13 Change in homeostasis model assessment-estimated insulin resistance in individual studies

Study	HOMA-IR			P value	P value between groups
	Group	Baseline	Study completion
Ito et al[12]	Ipragliflozin	5.2 (2.5)	4.8 (5.5)	Non-significant	0.401
	Pioglitazone	5.7 (3.4)	4.5 (2.7)	< 0.05
Eriksson et al[14]	Placebo	4.2 (2.4)	-0.2 (1.4)1	-	-
	Omega 3-CA	5.4 (2.9)	+0.3 (2.4)1	-	Non-significant2
	Dapagliflozin	4.3 (1.9)	-1.1 (1.4)1	-	< 0.052
	O + D	4.4 (1.7)	-0.9 (1.6)1	-	< 0.052
Seko et al[16]	SGLT-2 inhibitor	4.5 (0.5)	7.9 (2.3)	0.955	-
	Sitagliptin	4.4 (0.5)	6.5 (0.8)	0.163

¹Change from baseline.

² Compared to placebo.

HOMA-IR: Homeostasis model assessment-estimated insulin resistance; CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 14 Change in serum triglycerides in individual studies

Study	Serum triglycerides (mg/dL)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	201.0 (124.0)	155.0 (52.0)	0.01	0.678
	Control	212.0 (115.0)	175.0 (43.0)	0.019
Ito et al[12]	Ipragliflozin	166.9 (76.4)	143.4 (81.4)	< 0.05	0.938
	Pioglitazone	188.4 (148.8)	169.3 (131.3)	Non-significant
Eriksson et al[14]	Placebo	169.2 (84.1)	-11.5 (45.6)1	-	-
	Omega-3 CA	186.9 (81.5)	-15.9 (47.4)1	-	Non-significant2
	Dapagliflozin	178.0 (103.6)	+14.2 (40.5)1	-	Non-significant2
	O + D	168.3 (72.6)	-25.7 (57.1)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	148.0 (107.0, 222.)	145.0 (114.0, 172.0)	0.75	-
Seko et al[16]	SGLT-2 inhibitor	153.8 (15.9)	137.8 (10.5)	0.236	-
	Sitagliptin	193.4 (25.2)	191.1 (23.8)	0.986
Sumida et al[18]	Luseogliflozin	158.1 (110.5)	129.4 (59.5)	0.062	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 15 Change in serum low-density lipoprotein cholesterol in individual studies

Study	Serum low-density lipoprotein cholesterol (mg/dL)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	112.0 (35.0)	95.0 (22.0)	0.018	0.512
	Control	114.0 (30.0)	96.0 (17.0)	0.001
Ito et al[12]	Ipragliflozin	108.3 (36.2)	110.7 (40.1)	Non-significant	0.057
	Pioglitazone	104.0 (27.9)	114.6 (29.5)	< 0.05
Eriksson et al[14]	Placebo	98.2 (34.4)	+1.6 (15.5)1	-	-
	Omega-3 CA	111.8 (34.4)	+2.3 (17.4)1	-	Non-significant2
	Dapagliflozin	109.4 (34.8)	+7.7 (20.5)1	-	Non-significant2
	O + D	88.9 (23.2)	+5.8 (21.7)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	113.0 (89.0-142.0)	103.0 (92.0-122.0)	0.08	-
Seko et al[16]	SGLT-2 inhibitor	119.2 (5.8)	119.8 (5.7)	0.943	-
	Sitagliptin	112.9 (4.9)	127.1 (8.8)	0.063
Sumida et al[18]	Luseogliflozin	101.0 (22.4)	105.0 (24.4)	0.11	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 16 Change in serum high-density lipoprotein cholesterol in individual studies

Study	Serum high-density lipoprotein cholesterol (mg/dL)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	42.0 (12.0)	45.0 (12.0)	0.087	0.752
	Control	45.0 (15.0)	47.0 (12.0)	0.097
Ito et al[12]	Ipragliflozin	48.9 (9.3)	54.7 (10.4)	< 0.05	0.82
	Pioglitazone	47.4 (11.6)	52.7 (13.5)	< 0.05
Eriksson et al[14]	Placebo	51.4 (14.9)	-0.4 (5.0)1	-	-
	Omega-3 CA	49.9 (14.1)	+0.4 (3.2)1	-	Non-significant2
	Dapagliflozin	49.9 (9.5)	+0.4 (4.8)1	-	Non-significant2
	O + D	51.4 (10.2)	+1.6 (5.0)1	-	Non-significant2
Ohki et al[15]	Ipragliflozin	42.0 (40.0-50.0)	44.0 (42.0-59.0)	0.01	-
Seko et al[16]	SGLT-2 inhibitor	53.9 (2.5)	55.4 (2.6)	0.043	-
	Sitagliptin	54.8 (3.3)	55.6 (2.3)	0.531
Sumida et al[18]	Luseogliflozin	55.6 (11.7)	57.5 (13.4)	0.062	-

¹Change from baseline.

²Compared to placebo.

CA: Carboxylic acid; O + D: Omega-3 carboxylic acid + Dapagliflozin; SGLT-2: Sodium glucose cotransporter-2.

Table 17 Change in body mass index in individual studies

Study	Body mass index (kg/m2)			P value	P value between groups
	Group	Baseline	Study completion
Kuchay et al[11]	Empagliflozin	30.0 (3.8)	28.7 (3.5)	0.001	0.124
	Control	29.4 (3.1)	28.8 (2.8)	0.019
Shibuya et al[13]	Luseogliflozin	27.9 (26.2, 28.7)	27.0 (25.6, 28.3)	0.002	0.031
	Metformin	27.2 (24.8, 32.1)	27.3 (24.3, 31.6)	0.646
Ohki et al[15]	Ipragliflozin	30.1 (26.1-31.4)	27.6 (25.3-30.2)	< 0.01	-
Seko et al[16]	SGLT-2 inhibitor	29.6 (0.7)	28.3 (0.7)	< 0.001	-
	Sitagliptin	29.2 (1.5)	28.9 (1.4)	0.295
Sumida et al[18]	Luseogliflozin	27.8 (3.6)	27.2 (1.0)	< 0.001	-

SGLT-2: Sodium glucose cotransporter-2.

Table 18 Adverse effects of sodium glucose cotransporter-2 inhibitors in individual studies

Study	No. of adverse events	No. of patients	Types of adverse events
Kuchay et al[11]	3	25	Nonspecific fatigue: 1
			Arthralgia: 1
			Balanoposthitis: 1
Ito et al[12]	9	32	UTI: 3
			Increased appetite: 2
			Nausea: 1
			Headache: 1
			Diarrhoea: 1
			Vaginal candidiasis: 1
Eriksson et al[14]	7	21	-
Seko et al[16]	2	26	UTI: 2
Gautam et al[17]	1	32	Recurrent UTI with genital candidiasis: 1
Sumida et al[18]	8	40	Low blood pressure: 3
			Vaginal itching: 2
			Constipation: 1
			Vertigo: 1
			Dehydration: 1
Total	30	176	Most common adverse event: Genitourinary tract infections-10

UTI: Urinary tract infection.