Sodium-glucose co-transporter 2 inhibitors improve insulin resistance and β-cell function in type 2 diabetes: A meta-analysis

Table 1 Characteristics of the included studies[22-45]

Ref.	Country	Design	Patient number	Mean age (years)	Male (%)	Baseline HbA1c (%)	T2D duration (years)	Concurrent antidiabetic treatment	Intervention	Control	Treatment duration (weeks)	Outcomes reported
Inagaki et al[22]; 100 mg	Japan	R, DB, PC	111	57.7	71.2	8	NR	None	Canagliflozin, 100 mg/day	Placebo	12	HOMA-β
Inagaki et al[22]; 300 mg	Japan	R, DB, PC	113	57.3	72.6	8.1	NR	None	Canagliflozin, 300 mg/day	Placebo	12	HOMA-β
Jabbour et al[41]1	6 countries	R, DB, PC	447	54.9	54.8	8	5.7	Sitagliptin ± metformin	Dapagliflozin, 10 mg/day	Placebo	24	HOMA-IR
Kaku et al[23]	Japan	R, DB, PC	114	56.7	66.7	8.4	6.2	None	Tofogliflozin, 20 mg/day	Placebo	24	HOMA-IR and HOMA-β
Seino et al[42]; 2.5 mg	Japan	R, DB, PC	86	58.1	62.5	8.1	6.5	None	Luseogliflozin, 2.5 mg/day	Placebo	12	HOMA-IR and HOMA-β
Seino et al[42]; 5 mg	Japan	R, DB, PC	87	57	72.7	8.1	6.2	None	Luseogliflozin, 5 mg/day	Placebo	12	HOMA-IR and HOMA-β
Seino et al[24]; 2.5 mg	Japan	R, DB, PC	85	57.3	69.4	8	4.8	None	Luseogliflozin, 2.5 mg/day	Placebo	12	HOMA-IR and HOMA-β
Seino et al[24]; 5 mg	Japan	R, DB, PC	82	57.2	57.2	7.9	4.7	None	Luseogliflozin, 5 mg/day	Placebo	12	HOMA-IR and HOMA-β
Seino et al[25]	Japan	R, DB, PC	155	59.3	73.4	8.2	6.3	None	Luseogliflozin, 2.5 mg/day	Placebo	12	HOMA-IR and HOMA-β
Kashiwagi et al[26]	Japan	R, DB, PC	151	56.2	74.2	8.3	6.8	Pioglitazone	Ipragliflozin, 50 mg/day	Placebo	24	HOMA-β
Kashiwagi et al[27]	Japan	R, DB, PC	240	59.7	65.8	8.4	10.5	Sulfonylurea	Ipragliflozin, 50 mg/day	Placebo	24	HOMA-β
Kashiwagi et al[28]	Japan	R, DB, PC	129	59.4	69.8	8.3	6.7	None	Ipragliflozin, 50 mg/day	Placebo	16	HOMA-β
Kashiwagi et al[29]	Japan	R, DB, PC	168	56.7	58.9	8.3	7.7	Metformin	Ipragliflozin, 50 mg/day	Placebo	24	HOMA-IR and HOMA-β
Liao et al[30]	China	R, DB, PC	162	54	54.3	8	Newly diagnosed	None	Dapagliflozin, 10 mg/day	Placebo	12	HOMA-IR
Wang et al[43]	China	R, DB, PC	28	60.2	46.4	8.3	Newly diagnosed	With or without metformin	Dapagliflozin, 10 mg/day	Placebo	24	HOMA-β
Terra et al[31]2; 5 mg	7 countries	R, DB, PC	233	56.6	55.8	8.1	5	With or without metformin	Ertugliflozin, 5 mg/day	Placebo	26	HOMA-β
Terra et al[31]2; 15 mg	7 countries	R, DB, PC	228	56.2	57.5	8.3	5	With or without metformin	Ertugliflozin, 15 mg/day	Placebo	26	HOMA-β
Dagogo-Jack et al[32]3; 5 mg	12 countries	R, DB, PC	233	58.9	56.2	8.1	9.7	Metformin and sitagliptin	Ertugliflozin, 5 mg/day	Placebo	52	HOMA-β
Dagogo-Jack et al[32]3; 15 mg	12 countries	R, DB, PC	229	59.2	57.6	8	9.3	Metformin and sitagliptin	Ertugliflozin, 15 mg/day	Placebo	52	HOMA-β
Eriksson et al[33]	Sweden	R, DB, PC	40	65.3	78.6	7.4	6.6	Sulfonylurea or metformin	Dapagliflozin, 10 mg/day	Placebo	12	HOMA-IR
Han et al[34]	Korea	R, DB, PC	139	57.5	49.6	7.9	11.5	Metformin and sitagliptin	Ipragliflozin, 50 mg/day	Placebo	24	HOMA-IR and HOMA-β
Hattori[35]	Japan	R, OL, PC	109	NR	64.2	7.2	NR	Sulfonylureas, metformin, or an α-glucosidase inhibitor	Empagliflozin, 10 mg/day	Placebo	12	HOMA-IR
Brown et al[36]	United States	R, DB, PC	48	65.5	57.6	7.7	10	Metformin, sulfonylureas, DPP4 inhibitors, thiazolidinediones, or GLP-1 agonists	Dapagliflozin, 10 mg/day	Placebo	52	HOMA-IR
Chehrehgosha et al[44]	Iran	R, DB, PC	72	51.1	40.3	8	6.2	None	Empagliflozin, 10 mg/day	Placebo	24	HOMA-IR
Phrueksotsai et al[45]	Thailand	R, DB, PC	38	59.2	31.6	8	5	Metformin, sulfonylureas, DPP4 inhibitors, or thiazolidinediones,	Dapagliflozin, 10 mg/day	Placebo	12	HOMA-IR
Cheng et al[37]	China	R, DB, PC	124	71.5	53.4	7.7	NR	Insulin, sulfonylureas, DPP4 inhibitors, or metformin	Empagliflozin, 25 mg/day	Placebo	12	HOMA-IR
Gohari et al[38]	Iran	R, DB, PC	82	62.8	41.1	7.9	NR	Insulin, sulfonylureas, DPP4 inhibitors, or metformin	Empagliflozin, 10 mg/day	Placebo	26	HOMA-IR
Kwak et al[39]	Korea	R, DB, PC	152	59.8	50.3	7.8	6.4	None	Enavogliflozin, 0.3 mg/day	Placebo	24	HOMA-IR and HOMA-β
Yang et al[40]	Korea	R, DB, PC	96	58.3	54.2	8.1	5.9	None	Enavogliflozin, 0.3 mg/day	Placebo	12	HOMA-IR and HOMA-β

¹The study by Jabbour et al[41] was performed in Argentina, Germany, Mexico, Poland, the United Kingdom, and the United States.

²The study by Terra et al[31] was performed in the United States, Canada, Israel, Italy, Mexico, South Africa, and the United Kingdom.

³The study by Dagogo-Jack et al[32] was performed in the United States, Argentina, Colombia, Czech Republic, Hungary, Israel, Romania, Slovakia, Korea, Malaysia, Bulgaria, and Finland.

T2D: Type 2 diabetes; R: Randomized; DB: Double-blind; PC: Placebo-controlled; OL: Open-label; HbA1c: Hemoglobin A1c; NR: Not reported; DPP4: Dipeptidyl-peptidase 4; GLP-1: Glucagon-like peptide-1; HOMA-IR: Homeostasis model assessment of insulin resistance; HOMA-β: Homeostasis model assessment of β-cell function.

Table 2 Study quality evaluation via the Cochrane risk of bias tool[22-45]

Ref.	Random sequence generation	Allocation concealment	Blinding of participants	Blinding of outcome assessment	Incomplete outcome data addressed	Selective reporting	Other sources of bias
Inagaki et al[22]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Jabbour et al[41]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Kaku et al[23]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Seino et al[42]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Seino et al[24]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Seino et al[25]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Kashiwagi et al[26]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Kashiwagi et al[27]	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Kashiwagi et al[28]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Kashiwagi et al[29]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Liao et al[30]	Low risk	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Wang et al[43]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Terra et al[31]	Low risk	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Dagogo-Jack et al[32]	Low risk	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Eriksson et al[33]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Han et al[34]	Low risk	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Hattori[35]	Unclear	Unclear	Low risk	High risk	Low risk	Low risk	Low risk
Brown et al[36]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Chehrehgosha et al[44]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Phrueksotsai et al[45]	Low risk	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Cheng et al[37]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Gohari et al[38]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Kwak et al[39]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk
Yang et al[40]	Unclear	Unclear	Low risk	Low risk	Low risk	Low risk	Low risk

Table 3 Subgroup analyses for the influence of sodium-glucose co-transporter 2 inhibitors on homeostasis model assessment for insulin resistance in patients with type 2 diabetes

Characteristic	Datasets (n)	Patients (n)	MD (95%CI)	I2 (%)	P for subgroup difference
Countries
Asian	16	1737	-0.83 (-1.08 to -0.58)	63
Non-Asian	3	535	-0.93 (-2.13 to 0.28)	85	0.88
Sample size
< 100	10	712	-0.61 (-0.89 to -0.32)	36
≥ 100	9	1560	-0.93 (-1.41 to -0.45)	91	0.26
Mean age
< 58 years	9	1342	-0.65 (-1.02 to -0.28)	84
≥ 58 years	9	821	-1.03 (-1.54 to -0.51)	75	0.24
Men
< 55%	9	1312	-0.79 (-1.37 to -0.21)	88
≥ 55%	10	960	-0.78 (-1.03 to -0.52)	54	0.97
Baseline HbA1c
< 8%	8	773	-1.07 (-1.51 to -0.64)	72
≥ 8%	11	1499	-0.62 (-0.97 to -0.27)	81	0.12
T2D duration
< 6.3 years	9	1169	-0.58 (-0.96 to -0.19)	80
≥ 6.3 years	7	788	-1.14 (-1.61 to -0.66)	76	0.08
Concurrent antidiabetic treatments
No	10	1077	-0.86 (-1.22 to -0.50)	75
Yes	9	1195	-0.74 (-1.17 to -0.31)	70	0.67
SGLT2 inhibitor medications
Dapagliflozin	5	735	-0.86 (-1.67 to -0.05)	87
Luseogliflozin	5	491	-0.62 (-0.94 to -0.29)	64
Ipragliflozin	2	307	-0.95 (-1.32 to -0.58)	0
Empagliflozin	4	387	-0.56 (-0.88 to -0.24)	1
Enavogliflozin	2	248	-1.69 (-2.60 to -0.77)	46	0.13
SGLT2 inhibitor dose
Low dose	8	895	-0.75 (-1.01 to -0.50)	34
High dose	8	1025	-0.65 (-1.07 to -0.22)	83	0.67
Treatment duration
12 weeks	11	1060	-0.69 (-0.90 to -0.47)	43
24-52 weeks	8	1212	-1.04 (-1.75 to -0.34)	90	0.34

T2D: Type 2 diabetes; HbA1c: Hemoglobin A1c; SGLT2: Sodium glucose transporter 2; MD: Mean difference; CI: Confidence interval.

Table 4 Summarized certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation system

Outcome	Quality assessment							Absolute effect MD (95%CI)	Quality
	Number of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations
MD for HOMA-IR	17	RCTs	No serious risk of bias	Significant heterogeneity observed	No serious indirectness	No serious imprecision	None	-0.81 (-1.11 to -0.52)	Moderate
MD for HOMA-β	15	RCTs	No serious risk of bias	Significant heterogeneity observed	No serious indirectness	No serious imprecision	None	7.90 (5.44 to 10.37)	Moderate

Specific reasons for each Grading of Recommendations, Assessment, Development and Evaluation domain, including: Risk of bias: Downgraded if a significant proportion of studies had unclear or high risk of bias in key domains (e.g., random sequence generation, allocation concealment, or selective reporting); Inconsistency: Downgraded if substantial heterogeneity was observed (I² > 50%) and could not be explained by subgroup analyses or meta-regression; Indirectness: Evaluated but not downgraded, as all included studies directly assessed the population and outcomes of interest; Imprecision: Downgraded if confidence intervals were wide, overlapping no effect, or if the overall sample size was small; Publication bias: Assessed using funnel plots and Egger’s test, downgraded if significant asymmetry suggested potential bias. RCTs: Randomized controlled trials; MD: Mean difference; CI: Confidence interval; HOMA-IR: Homeostasis model assessment of insulin resistance; HOMA-β: Homeostasis model assessment of beta-cell function.

Table 5 Subgroup analyses for the influence of sodium-glucose co-transporter 2 inhibitors on homeostasis model assessment for β-cell function in patients with type 2 diabetes

Characteristic	Datasets (n)	Patients (n)	MD (95%CI)	I2 (%)	P for subgroup difference
Countries
Asian	15	1770	5.54 (3.99 to 7.10)	26
Non-Asian	2	461	20.86 (16.76 to 24.96)	0	< 0.001
Sample size
< 150	11	1056	6.64 (4.87 to 8.40)	0
≥ 150	9	1789	9.81 (5.02 to 14.60)	88	0.22
Mean age
< 58 years	11	1497	8.12 (4.57 to 11.67)	81
≥ 58 years	9	1348	7.61 (4.19 to 11.03)	61	0.84
Men
< 60%	10	1585	10.11 (5.14 to 15.08)	82
≥ 60%	10	1260	5.86 (3.93 to 7.78)	38	0.12
Baseline HbA1c
< 8.2%	12	1642	8.88 (6.08 to 11.69)	61
≥ 8.2%	8	1203	6.44 (2.15 to 10.73)	83	0.35
T2D duration
< 6.5 years	10	1246	8.50 (3.54 to 13.47)	84
≥ 6.5 years	8	1375	7.25 (4.59 to 9.91)	54	0.66
Concurrent antidiabetic treatments
No	11	1196	5.95 (4.19 to 7.70)	12
Yes	6	1160	7.11 (3.64 to 10.58)	64	0.56
SGLT2 inhibitor medications
Canagliflozin	2	224	6.49 (2.40 to 10.57)	29
Luseogliflozin	5	491	5.32 (2.59 to 8.05)	41
Ipragliflozin	5	827	5.72 (2.90 to 8.54)	46
Empagliflozin	4	923	17.13 (12.57 to 21.69)	53
Enavogliflozin	2	248	7.84 (0.48 to 15.19)	0	< 0.001
SGLT2 inhibitor dose
Low dose	11	1729	7.64 (4.52 to 10.77)	78
High dose	6	764	8.70 (3.21 to 14.19)	80	0.74
Treatment duration
12-16 weeks	9	940	6.13 (4.10 to 8.17)	29
24-52 weeks	11	1905	9.04 (4.70 to 13.37)	83	0.23

T2D: Type 2 diabetes; HbA1c: Hemoglobin A1c; SGLT2: Sodium glucose transporter 2; MD: Mean difference; CI: Confidence interval.