Metformin fails to prevent diabetes in non-diabetic cardiovascular patients: Systematic review and meta-analysis

Table 1 Characteristics of eligible studies

Ref.	Country	Study duration (month)	Follow-up duration (month)	Drop-out rate, n (%)
Preiss et al[22], 2014	Scotland, United Kingdom	18	0	13 (7.5)
Lexis et al[23], 2015	Netherlands	4	0	0 (0.0)
Hartman et al[24], 2017	Netherlands	28	24	0 (0.0)
Mohan et al[25], 2019	Scotland, United Kingdom	12	0	5 (7.4)

Table 2 Characteristics of participants

Ref.	Sample size	Gender %, male/female	Mean age in years	Ethnicities (%)	Mean baseline BMI (I/ C)	Risk factors for T2DM
						Overall	Potential coexistence
Preiss et al[22], 2014	173	54.5/45.5	63.5	Caucasian (100)	30.2/30.5	CHD, central adiposity, obesity	N/A
Lexis et al[23], 2015	346	13.0/87.0	58.1	Caucasian (97), Asian (2.0), African (1.0)	32.2/31.9	CAD (STEMI), obesity	N/A
Hartman et al[24], 2017	379	75.0/25.0	58.1	Caucasian (97.0), Asian (2.0), African (1.0)	26.5/26.9	CAD (STEMI), overweight	N/A
Mohan et al[25], 2019	68	47.0/53.0	64.5	Caucasians (100)	26.5/26.9	CAD, overweight	Prediabetes, HY

BMI: Body mass index; I: Intervention; C: Control; T2DM: Type 2 diabetes mellitus; CHD: Coronary heart disease; CAD: Coronary artery disease; STEMI: ST elevation myocardial infraction; HY: Hypertension.

Table 3 Characteristics of interventions and comparators

Ref.	Characteristics of compared arms
	Component of compared arms	Dosage, description	Duration (month)	Assessment of adherence
Preiss et al[22], 2014	Metformin	850 mg twice daily; initial dose 850 mg once daily for one week	18.0	Tablet counts of numbered bottles
	Placebo	Matching placebo
Lexis et al[23], 2015	Metformin plus standard care	Metformin 500 mg twice daily	4.0	NR
		Standard care
	Standard care	Standard care		N/A
Hartman et al[24], 2017	Metformin plus standard care	Metformin 500 mg twice daily	4.0	NR
		Standard care
	Standard care	Standard care		N/A
Mohan et al[25], 2019	Metformin	Metformin 1000 mg twice daily; initial dosage 500 mg twice daily for two weeks	12.0	NR
	Placebo	Matching placebo

NR: Non-reported; N/A: Not applicable.

Table 4 Efficacy and safety of metformin’s included interventions in preventing type-2 diabetes

Overall effectiveness and safety of metformin
Ref.	Outcome of T2DM assessed as primary or secondary	Participants at risk for T2DM (I/C)	Events of T2DM n (%) (I/C)	Diagnostic modalities	Total adverse events, side effects, n (%) (I/C)
Preiss et al[22], 2014	Secondary	86/87	2 (2)/6 (7)	HbA1c	Gastrointestinal symptoms 28 (32.6)/5 (5.7), CVD events 7 (8.1)/16 (18.4), newly diagnosed neoplasm 1 (1.0)/4 (5.0), deaths 1 (1.0)/0 (0.0)
Lexis et al[23], 2015	Secondary	162/156	20 (12.3)/18 (11.5)	FPG, 2 hours 75 g OGTT, HbA1c	NR
Hartman et al[24], 2017	Secondary	191/188	34 (17.8)/32 (17.0)	HbA1c	NR
Mohan et al[25], 2019	Secondary	31/32	0 (0)/1 (3.1)	FPG, HbA1c	Mild-to-serious gastrointestinal symptoms 24 (70.6)/19 (55.9), stroke 1 (2.9)/0 (0.0)

T2DM: Type-2 diabetes mellitus; I: Intervention; C: Comparator; HbA1c: Hemoglobin A1c; CVD: Cardiovascular disease; FPG: Fasting plasma glucose; OGTT: Oral glucose tolerance test.

Table 5 Quality of reporting for eligible studies

Ref.	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (attrition bias)	Selective reporting (reporting bias)	Other bias
Preiss et al[22], 2014	L	L	L	L	L	L	L
Lexis et al[23], 2015	L	L	L	L	L	L	L
Hartman et al[24], 2017	L	L	L	L	L	L	L
Mohan et al[25], 2019	L	L	L	L	L	L	L

L: Low risk.

Table 6 Grading of Recommendations, Assessment, Development, and Evaluation evaluation of overall evidence of studies according to analyses

Metformin compared to placebo for T2DM prevention
Patient or population: Patients with CAD without T2DM; settings: Randomized controlled trials; intervention: Metformin; comparison: Placebo
Outcomes	Illustrative comparative risks1 (95%CI)		Relative effect (95%CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Metformin
T2DM	Study population		OR: 0.97 (0.65-1.45)	933 (4 studies)	Very low
	123 per 1000	120 per 1000 (84-169)

¹The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% confidence interval). Grading of Recommendations, Assessment, Development, and Evaluation Working Group grades of evidence high quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. T2DM: Type-2 diabetes mellitus; CAD: Coronary artery disease; CI: Confidence interval; OR: Odds ratio; GRADE: Grading of Recommendations, Assessment, Development, and Evaluation.