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://jocmr.elmerjournals.com

Original Article

Volume 17, Number 2, February 2025, pages 76-88

Impact of Prior Metformin Use on Stroke Outcomes: A Systematic Review and Updated Meta-Analysis

↓ Figure 1. PRISMA flow diagram. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

↓ Figure 2. Forest plot of modified Rankin Scale (mRS 0 - 2) outcome. RR: risk ratio; CI: confidence interval; mRS: modified Rankin Scale.

↓ Figure 3. Forest plot of modified Rankin Scale (mRS 3 - 6) outcome. RR: risk ratio; CI: confidence interval; mRS: modified Rankin Scale.

↓ Figure 4. Forest plot of NIHSS at discharge outcome. SD: standard deviation; MD: mean difference; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale.

↓ Figure 5. Forest plot of NIHSS at admission outcome. SD: standard deviation; MD: mean difference; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale.

↓ Figure 7. Forest plot of length of stay outcome. SD: standard deviation; MD: mean difference; CI: confidence interval.

↓ Figure 8. Leave-one-out meta-analysis for mRS 0 - 2. RR: risk ratio; CI: confidence interval; mRS: modified Rankin Scale.

↓ Figure 9. Leave-one-out meta-analysis for mRS 3 - 6. RR: risk ratio; CI: confidence interval; mRS: modified Rankin Scale.

↓ Figure 10. Leave-one-out of the meta-analysis for NIHSS at admission. MD: mean difference; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale.

↓ **Table 1.** Summary Characteristics of the Included Studies
Study	Study design	Country	Total participants	Time frame	Duration of follow-up	Inclusion criteria	Exclusion criteria	Results
AIS: acute ischemic stroke; mRS: modified Rankin Scale; CT: computed tomography; MRI: magnetic resonance imaging; ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; ICD: International Classification of Diseases; IVT: intravenous thrombolysis; EVT: endovascular treatment; END: early neurological deterioration; END-prog: END as stroke progression; END-SHT: END as symptomatic hemorrhagic transformation; RT: reperfusion therapy; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; HbA1c: hemoglobin A1c; T2DM: type 2 diabetes mellitus; LAA: large-artery atherosclerosis; CES: cardioaortic embolic stroke; SVO: small-vessel occlusion; WHO: World Health Organization; NIHSS: National Institutes of Health Stroke Scale; N/A: not available.
Akhtar et al, 2022 [14]	Prospective cohort	Qatar	1,132	1,025	2013 - 2020	N/A	All patients with acute stroke admitted to the Hamad General Hospital (HGH) and prospectively entered the Qatar Stroke database	Patients with stroke mimics, transient ischemic attacks, ICH, cerebral venous thrombosis, and new-onset diabetes	Patients with diabetes on chronic pre-stroke treatment with metformin had improved recovery following the ischemic event.
Jian et al, 2023 [15]	Retrospective cohort	China	124	130	2017 - March 2021	N/A	Patients: 1) were diagnosed with AIS by cranial CT or MRI; 2) the time from onset to admission was < 7 days; 3) were diagnosed with T2DM, including self-reported diabetes and newly diagnosed diabetes at admission.	Patients with: 1) unclear hypoglycemic therapy before stroke onset or after admission; 2) a mRS > 1 before stroke onset; 3) an estimated glomerular filtration rate < 45 mL/min; 4) metformin withdrawal within 90 days; or 5) lost to follow-up.	Patients with diabetes who were treated with metformin continuously before stroke onset and after admission had a better 90-day functional outcome.
Tu et al, 2022 [22]	Prospective cohort	China	3,593	3,994	August - September 2019	12 months	All patients with the first-ever stroke (ischemic stroke (ICD63), ICH (ICD61), and SAH (ICD60)) and T2DM were included. Patients were eligible for inclusion if admitted to the hospitals with a stroke defined according to the WHO criteria and with symptom onset within 14 days.	Hospitals with a sample size of less than 50 and a follow-up rate of less than 80% will be excluded. Also, patients with 1) lack of informed consent; 2) lost to follow-up; and 3) lack of crucial clinical information (such as MT information (yes or no) and functional scores during follow-up) would be excluded.	Metformin use in stroke patients with T2DM resulted in a less severe stroke and lower fatality and disability rates.
Kersten et al, 2022 [17]	Retrospective cohort	Netherlands	592	345	2017 - June 2021	N/A	All consecutive patients with AIS and known T2DM aged 18 years or older were included between 2017 and June 2021	N/A	Pre-stroke metformin use was associated with favorable outcomes in a large group of patients with T2DM after AIS.
Mima et al, 2016 [7]	N/A	Japan	77	163	April 2010 - September 2014	N/A	Only patients with brain infarction complicated by DM who were admitted to National Hospital Organization Kyushu Medical Center between April 2010 and September 2014 were included.	Mild stroke severity	Metformin use in stroke patients with T2DM resulted in a less severe stroke and lower fatality and disability rates.
Westphal et al, 2020 [19]	Multicenter retrospective analysis	Switzerland	757	757	N/A	N/A	Data from patients diagnosed with type 2 diabetes before stroke or at the time of stroke based on admission HbA1c values ≥ 6.5% were included.	Either diagnosed with type-1 diabetes or diabetes type was not specified	Stroke patients with diabetes on treatment with metformin receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests that metformin has a protective effect, resulting in less severe strokes and beneficial thrombolysis outcomes.
Kim et al, 2024 [12]	Cohort	Korea	137	94	March 2015 - September 2023	N/A	Patients with AIS with large artery occlusion of the anterior circulation who received EVT. Among these EVT-patients diagnosed as T2DM before stroke or who had an admission of HbA1c ≥ 6.5% at the time of stroke.	Patients with a mRS score ≥ 2 before stroke, patients without initial brain CT or MRI scan within 24 h of stroke onset, patients with an ASPECTS > 6, and patients without a 3-month mRS score	Subjects with prior metformin use, before EVT, the initial NIHSS and infarct volume were lower than those without prior metformin use. Prior metformin use could reduce the risk of END-prog and END-SHT after EVT and prior. Metformin use was associated with a 3-month mRS of 0 to 2 after EVT in patients with T2DM.
Akiyama et al, 2024 [13]	Retrospective cohort	Japan	55	105	2010 - 2021	N/A	Only patients with ischemic stroke subtypes defined as LAA, CES, or SVO were consecutively selected, and T2DM	Patients’ wide variety of etiologies of stroke, patients without antidiabetic agents before stroke, with only insulin, and with missing data on medication, and patients with a mRS score ≥ 3 before stroke onset were excluded.	Metformin treatment before stroke was associated with lower stroke severity and favorable functional outcome.
Allahverdiyev et al, 2020 [20]	Cohort	Turkey	42	28	January 2017 - April 2019	N/A	Patients with AIS and T2DM	Patients had a hemorrhagic stroke, T1DM, severe renal failure and severe deterioration in daily life activities before stroke (mRS score ≥ 3)	There was not any significant difference between the groups of severity and prognosis of AIS.
Abbasi et al, 2018 [21]	RCT	Iran	N/A	N/A	N/A	3 months	Ischemic stroke patients and focal neurological symptoms	Patients with ICH, SAH, subdural hematoma (SDH), hypoglycemia, contraindications for metformin use, venous sinus thrombosis, and drug side effects and diabetic patients.	There was a significant difference in metformin taking in the reduction of NIHSS score in non-diabetic stroke patients. There was a significant association between metformin taking and a decrease in NIHSS scores in patients with cortical ischemic stroke.
Curro et al, 2022 [18]	Retrospective cohort	N/A	Overall = 170	February 2014 - December 2019	N/A	Patients underwent IVT within 4.5 h after ischemic stroke onset. Patients underwent MT within a time frame from symptom onset to treatment ≤ 6 h for anterior circulation and ≤ 24 h for posterior circulation.	Patients with large territorial infarction are defined as ASPECTS < 5, hospital arrival beyond the time window, and elevated bleeding risk for IVT.	A lower mRs was associated with lower glycemia and admission NIHSS (aNIHSS) in all RT and MT; lower aNIHSS and younger age in IVT.

↓ Table 1. Summary Characteristics of the Included Studies

Study

Study design

Country

Total participants

Time frame

Duration of follow-up

Inclusion criteria

Exclusion criteria

Results

Metformin

Non-metformin

AIS: acute ischemic stroke; mRS: modified Rankin Scale; CT: computed tomography; MRI: magnetic resonance imaging; ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; ICD: International Classification of Diseases; IVT: intravenous thrombolysis; EVT: endovascular treatment; END: early neurological deterioration; END-prog: END as stroke progression; END-SHT: END as symptomatic hemorrhagic transformation; RT: reperfusion therapy; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; HbA1c: hemoglobin A1c; T2DM: type 2 diabetes mellitus; LAA: large-artery atherosclerosis; CES: cardioaortic embolic stroke; SVO: small-vessel occlusion; WHO: World Health Organization; NIHSS: National Institutes of Health Stroke Scale; N/A: not available.

Akhtar et al, 2022 [14]

Prospective cohort

Qatar

1,132

1,025

2013 - 2020

N/A

All patients with acute stroke admitted to the Hamad General Hospital (HGH) and prospectively entered the Qatar Stroke database

Patients with stroke mimics, transient ischemic attacks, ICH, cerebral venous thrombosis, and new-onset diabetes

Patients with diabetes on chronic pre-stroke treatment with metformin had improved recovery following the ischemic event.

Jian et al, 2023 [15]

Retrospective cohort

China

124

130

2017 - March 2021

N/A

Patients: 1) were diagnosed with AIS by cranial CT or MRI; 2) the time from onset to admission was < 7 days; 3) were diagnosed with T2DM, including self-reported diabetes and newly diagnosed diabetes at admission.

Patients with: 1) unclear hypoglycemic therapy before stroke onset or after admission; 2) a mRS > 1 before stroke onset; 3) an estimated glomerular filtration rate < 45 mL/min; 4) metformin withdrawal within 90 days; or 5) lost to follow-up.

Patients with diabetes who were treated with metformin continuously before stroke onset and after admission had a better 90-day functional outcome.

Tu et al, 2022 [22]

Prospective cohort

China

3,593

3,994

August - September 2019

12 months

All patients with the first-ever stroke (ischemic stroke (ICD63), ICH (ICD61), and SAH (ICD60)) and T2DM were included. Patients were eligible for inclusion if admitted to the hospitals with a stroke defined according to the WHO criteria and with symptom onset within 14 days.

Hospitals with a sample size of less than 50 and a follow-up rate of less than 80% will be excluded. Also, patients with 1) lack of informed consent; 2) lost to follow-up; and 3) lack of crucial clinical information (such as MT information (yes or no) and functional scores during follow-up) would be excluded.

Metformin use in stroke patients with T2DM resulted in a less severe stroke and lower fatality and disability rates.

Kersten et al, 2022 [17]

Retrospective cohort

Netherlands

592

345

2017 - June 2021

N/A

All consecutive patients with AIS and known T2DM aged 18 years or older were included between 2017 and June 2021

N/A

Pre-stroke metformin use was associated with favorable outcomes in a large group of patients with T2DM after AIS.

Mima et al, 2016 [7]

N/A

Japan

163

April 2010 - September 2014

N/A

Only patients with brain infarction complicated by DM who were admitted to National Hospital Organization Kyushu Medical Center between April 2010 and September 2014 were included.

Mild stroke severity

Metformin use in stroke patients with T2DM resulted in a less severe stroke and lower fatality and disability rates.

Westphal et al, 2020 [19]

Multicenter retrospective analysis

Switzerland

757

N/A

Data from patients diagnosed with type 2 diabetes before stroke or at the time of stroke based on admission HbA1c values ≥ 6.5% were included.

Either diagnosed with type-1 diabetes or diabetes type was not specified

Stroke patients with diabetes on treatment with metformin receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests that metformin has a protective effect, resulting in less severe strokes and beneficial thrombolysis outcomes.

Kim et al, 2024 [12]

Cohort

Korea

137

March 2015 - September 2023

N/A

Patients with AIS with large artery occlusion of the anterior circulation who received EVT. Among these EVT-patients diagnosed as T2DM before stroke or who had an admission of HbA1c ≥ 6.5% at the time of stroke.

Patients with a mRS score ≥ 2 before stroke, patients without initial brain CT or MRI scan within 24 h of stroke onset, patients with an ASPECTS > 6, and patients without a 3-month mRS score

Subjects with prior metformin use, before EVT, the initial NIHSS and infarct volume were lower than those without prior metformin use. Prior metformin use could reduce the risk of END-prog and END-SHT after EVT and prior. Metformin use was associated with a 3-month mRS of 0 to 2 after EVT in patients with T2DM.

Akiyama et al, 2024 [13]

Retrospective cohort

Japan

105

2010 - 2021

N/A

Only patients with ischemic stroke subtypes defined as LAA, CES, or SVO were consecutively selected, and T2DM

Patients’ wide variety of etiologies of stroke, patients without antidiabetic agents before stroke, with only insulin, and with missing data on medication, and patients with a mRS score ≥ 3 before stroke onset were excluded.

Metformin treatment before stroke was associated with lower stroke severity and favorable functional outcome.

Allahverdiyev et al, 2020 [20]

Cohort

Turkey

January 2017 - April 2019

N/A

Patients with AIS and T2DM

Patients had a hemorrhagic stroke, T1DM, severe renal failure and severe deterioration in daily life activities before stroke (mRS score ≥ 3)

There was not any significant difference between the groups of severity and prognosis of AIS.

Abbasi et al, 2018 [21]

RCT

Iran

N/A

3 months

Ischemic stroke patients and focal neurological symptoms

Patients with ICH, SAH, subdural hematoma (SDH), hypoglycemia, contraindications for metformin use, venous sinus thrombosis, and drug side effects and diabetic patients.

There was a significant difference in metformin taking in the reduction of NIHSS score in non-diabetic stroke patients. There was a significant association between metformin taking and a decrease in NIHSS scores in patients with cortical ischemic stroke.

Curro et al, 2022 [18]

Retrospective cohort

N/A

Overall = 170

February 2014 - December 2019

N/A

Patients underwent IVT within 4.5 h after ischemic stroke onset. Patients underwent MT within a time frame from symptom onset to treatment ≤ 6 h for anterior circulation and ≤ 24 h for posterior circulation.

Patients with large territorial infarction are defined as ASPECTS < 5, hospital arrival beyond the time window, and elevated bleeding risk for IVT.

A lower mRs was associated with lower glycemia and admission NIHSS (aNIHSS) in all RT and MT; lower aNIHSS and younger age in IVT.

↓ **Table 2.** Baseline Characteristics of the Included Population
Country	Author, year	Study design	Group	Number of participants	Basic patient characteristics	Risk factors	On admission parameters
BMI: body mass index; SD: standard deviation; CHD: coronary heart disease; INR: international normalized ratio; DBP: diastolic blood pressure; SBP: systolic blood pressure; MET: metformin; HbA1c: hemoglobin A1c.
Qatar	Akhtar et al, 2022 [14]	Prospective cohort	Met +	1,132	54.4 (13.2)	910	-	7.5 (2.5)	-	-	623	848	48	350	59.9 (35.4)	131	-	95.8 (64.4)	-	-	134
			Met -	1,025	54.6 (13.1)	842	-	7.6 (4.3)	-	-	537	766	42	276	59.8 (39.8)	112	-	97.0 (66.6)	-	-	137
China	Jian et al, 2023 [15]	Retrospective cohort	Met +	124	63.16 (12.33)	87	-	8.1 (2)	85.88 (13.93)	152.39 (23.26)	11	99	7	36	-	19	224.6 (40.5)	57.43 (16.45)	206.35 (70.06)	0.93 (0.08)	39
			Met -	130	65 (13.49)	78	-	8.5 (2.2)	82.8 (12.9)	148.5 (22.4)	18	95	12	40	-	29	234.52 (74.16)	59.73 (19.34)	199.67 (74.22)	0.93 (0.07)	39
China	Tu et al, 2022 [22]	Prospective cohort	Met +	3,593	64.67 (11.12)	2,015	-	-	-	-	867	2,789	167	-	-	-	-	-	-	-	-
			Met -	3,994	65.67 (12.61)	2,336	-	-	-	-	967	3,158	254	-	-	-	-	-	-	-	-
Netherlands	Kersten et al, 2022 [17]	Retrospective cohort	Met +	592	75 (10)	332	28 (4.46)	-	-	-	164	67	-	182	-	-	174.6 (48.2)	-	-	-	Excluded from the study
			Met -	345	76 (11)	167	28 (4.47)	-	-	-	108	41	-	87	-	-	166.86 (63)	-	-	-	Excluded from the study
Japan	Mima et al, 2016 [7]		Met +	77	67.7 (10.3)	56	25.7 (5.5)	7.5 (1.2)	83 (17)	154 (25)	52	64	-	20	-	9	175 (71)	-	-	-	-
			Met -	163	73.2 (9.2)	119	23.6 (3.2)	7.3 (1.3)	85 (17)	160 (27)	93	133	-	45	-	21	179 (70)	-	-	-	-
Switzerland	Westphal et al, 2020 [19]	Multicenter retrospective analysis	Met +	757	71.4 (9.5)	478	84.1 (16.8)	-	83.2 (16.2)	159.6 (24.8)	481	673	176	135	161.4 (96.8)	183	169.2 (63)	87.0 (47.7)	232.5 (71.3)	1.0 (0.2)	145
			Met -	757	71.8 (10.9)	458	-	-	-	158.8 (25.9)	450	656	187	139	158.4 (120.2)	182	169.2 (70.2)	92.0 (51.7)	238.3 (79.8)	1.0 (0.1)	271
Korea	Kim et al, 2024 [12]	Cohort	Met +	137	71.2 (11.5)	76	-	7.5 (1.4)	-	151.7 (26.5)	32	94	73	18	123 (48.9)	-	180.8 (70.1)	97.26 (53.05)	-	1.06 (0.29)	34
			Met -	94	72.5 (13.1)	49	-	7.2 (1.6)	-	151.9 (28.3)	26	68	50	13	121 (56.3)	-	175.6 (86.7)	106.1 (106.1)	-	1.03 (0.18)	32
Japan	Akiyama et al, 2024 [13]	Retrospective cohort	Met +	55	73.3 (11.4)	44	22.9 (2.7)	7.37 (0.99)	84.7 (17.5)	161.7 (31.2)	35	44	-	33	-	8	175.3 (73)	75.16 (17.68)	-	-	15
			Met -	105	73.3 (8.3)	78	23 (3.4)	7 (0.98)	84.7 (16.5)	160 (26.3)	70	89	-	59	-	20	158.3 (57.1)	85.77 (43.33)	-	-	28
Turkey	Allahverdiyev et al, 2020 [20]	Cohort	Met +	42	70.02 (10.92)	18	-	8.11 (1.78)	80.71 (14.69)	145.33 (27.86)	10	34	4	10	-	17	144.94 (60.74)	-	-	-	7
			Met -	28	68.43 (11.09)	16	-	8.84 (3.16)	81.32 (17.83)	155.8 (33.24)	8	26	2	13	-	11	159.23 (87.31)	-	-	-	4
Iran	Abbasi et al, 2018 [21]	RCT	Met +	Overall 100	68.9 (10.6)	Overall 50	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
			Met -		67 (11.63)		-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Italy	Curro et al, 2022 [18]	Retrospective cohort	Met +	Overall 170	76.72 (8.72)	84	-	-	81.88 (15.52)	154.81 (25.53)	56	140	-	26	251.88 (107.26)	47	185.33 (69.52)	96.38 (49.52)	237.73 (91.96)	-	31
			Met -

↓ Table 2. Baseline Characteristics of the Included Population

Country

Author, year

Study design

Group

Number of participants

Basic patient characteristics

Risk factors

On admission parameters

Age (years), mean (SD)

Sex (males), n

BMI, mean (SD)

HbA1c %, mean (SD)

DBP, mean (SD)

SBP, mean (SD)

Hypercholesterolemia, n

Hypertension, n

Atrial fibrillation, n

Current smoking, n

Stroke-to-needle-time (min), mean (SD)

CHD, n

Glucose (mg/dL), mean (SD)

Creatinine (mmol/L), mean (SD)

Platelets, mean (SD)

INR, mean (SD)

History of previous stroke, n

BMI: body mass index; SD: standard deviation; CHD: coronary heart disease; INR: international normalized ratio; DBP: diastolic blood pressure; SBP: systolic blood pressure; MET: metformin; HbA1c: hemoglobin A1c.

Qatar

Akhtar et al, 2022 [14]

Prospective cohort

Met +

1,132

54.4 (13.2)

910

7.5 (2.5)

623

848

350

59.9 (35.4)

131

95.8 (64.4)

134

Met -

1,025

54.6 (13.1)

842

7.6 (4.3)

537

766

276

59.8 (39.8)

112

97.0 (66.6)

137

China

Jian et al, 2023 [15]

Retrospective cohort

Met +

124

63.16 (12.33)

8.1 (2)

85.88 (13.93)

152.39 (23.26)

224.6 (40.5)

57.43 (16.45)

206.35 (70.06)

0.93 (0.08)

Met -

130

65 (13.49)

8.5 (2.2)

82.8 (12.9)

148.5 (22.4)

234.52 (74.16)

59.73 (19.34)

199.67 (74.22)

0.93 (0.07)

China

Tu et al, 2022 [22]

Prospective cohort

Met +

3,593

64.67 (11.12)

2,015

867

2,789

167

Met -

3,994

65.67 (12.61)

2,336

967

3,158

254

Netherlands

Kersten et al, 2022 [17]

Retrospective cohort

Met +

592

75 (10)

332

28 (4.46)

164

182

174.6 (48.2)

Excluded from the study

Met -

345

76 (11)

167

28 (4.47)

108

166.86 (63)

Excluded from the study

Japan

Mima et al, 2016 [7]

Met +

67.7 (10.3)

25.7 (5.5)

7.5 (1.2)

83 (17)

154 (25)

175 (71)

Met -

163

73.2 (9.2)

119

23.6 (3.2)

7.3 (1.3)

85 (17)

160 (27)

133

179 (70)

Switzerland

Westphal et al, 2020 [19]

Multicenter retrospective analysis

Met +

757

71.4 (9.5)

478

84.1 (16.8)

83.2 (16.2)

159.6 (24.8)

481

673

176

135

161.4 (96.8)

183

169.2 (63)

87.0 (47.7)

232.5 (71.3)

1.0 (0.2)

145

Met -

757

71.8 (10.9)

458

158.8 (25.9)

450

656

187

139

158.4 (120.2)

182

169.2 (70.2)

92.0 (51.7)

238.3 (79.8)

1.0 (0.1)

271

Korea

Kim et al, 2024 [12]

Cohort

Met +

137

71.2 (11.5)

7.5 (1.4)

151.7 (26.5)

123 (48.9)

180.8 (70.1)

97.26 (53.05)

1.06 (0.29)

Met -

72.5 (13.1)

7.2 (1.6)

151.9 (28.3)

121 (56.3)

175.6 (86.7)

106.1 (106.1)

1.03 (0.18)

Japan

Akiyama et al, 2024 [13]

Retrospective cohort

Met +

73.3 (11.4)

22.9 (2.7)

7.37 (0.99)

84.7 (17.5)

161.7 (31.2)

175.3 (73)

75.16 (17.68)

Met -

105

73.3 (8.3)

23 (3.4)

7 (0.98)

84.7 (16.5)

160 (26.3)

158.3 (57.1)

85.77 (43.33)

Turkey

Allahverdiyev et al, 2020 [20]

Cohort

Met +

70.02 (10.92)

8.11 (1.78)

80.71 (14.69)

145.33 (27.86)

144.94 (60.74)

Met -

68.43 (11.09)

8.84 (3.16)

81.32 (17.83)

155.8 (33.24)

159.23 (87.31)

Iran

Abbasi et al, 2018 [21]

RCT

Met +

Overall 100

68.9 (10.6)

Overall 50

Met -

67 (11.63)

Italy

Curro et al, 2022 [18]

Retrospective cohort

Met +

Overall 170

76.72 (8.72)

81.88 (15.52)

154.81 (25.53)

140

251.88 (107.26)

185.33 (69.52)

96.38 (49.52)

237.73 (91.96)

Met -