SynthesisPLoS medicine2012
Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials.
Synthesis in PLoS medicine, 2012. The graph read 8 numbers from its abstract, feeding 2 cells of the map: it finds no clear difference in 2. Cited by 73 papers, 10 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17).
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Where it lands on the map
Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.
What it adds to each cell
For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.
Metformin×cardiovascular events
InconclusiveOpen on the map →What to test next →5 readable studies in this cell: 4 favour the treatment, 1 find no difference, 0 favour the comparator.
This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.
Metformin×all-cause mortality
InconclusiveOpen on the map →What to test next →1 readable study in this cell: 0 favour the treatment, 1 find no difference, 0 favour the comparator.
This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
73 citing papers in PubMed, 10 syntheses or guidelines pooled it, 262 citations in OpenAlex.
- Glucagon-like peptide-1 receptor agonist-based regimens compared with metformin-based regimens for preventing cardiovascular disease in adults with type 2 diabetes mellitus.The Cochrane database of systematic reviews · 2026Pooled it
- American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists · 2022Guideline
- Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases.Drugs · 2022 · on this mapPooled it
- Sodium-glucose co-transporter-2 inhibitors with and without metformin: A meta-analysis of cardiovascular, kidney and mortality outcomes.Diabetes, obesity & metabolism · 2021 · on this mapPooled it
- Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus.Cardiovascular diabetology · 2021 · on this mapPooled it
- Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials.Scientific reports · 2020Pooled it
- Metformin monotherapy for adults with type 2 diabetes mellitus.The Cochrane database of systematic reviews · 2020 · on this mapPooled it
- GLUcose COntrol Safety & Efficacy in type 2 DIabetes, a systematic review and NETwork meta-analysis.PloS one · 2019Pooled it
- Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes.Diabetologia · 2017Pooled it
- Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials.BMC endocrine disorders · 2016Pooled it
- Trial
- Effect of Tofogliflozin on Urinary Albumin-to-Creatinine Ratio vs. Metformin in Diabetic Kidney Disease: Rationale and Study Protocol of the TRUTH-DKD Trial.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2026Article
- Comparative cardiovascular risk of sulfonylureas with low- and high-affinities for cardiac mitochondrial adenosine triphosphate-sensitive potassium channels versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A cohort study.Diabetes, obesity & metabolism · 2025Article
- Emerging uncertainty on the anti-aging potential of metformin.Ageing research reviews · 2025Review
- The impact of metformin on mortality in patients with type 2 diabetes mellitus: a prospective cohort study.Endocrine · 2025Article
- Metformin and the risks of cellulitis, foot infections, and amputation in patients with type 2 diabetes.Journal of the Chinese Medical Association : JCMA · 2024Article
- Effects of SGLT2 Inhibitors with and without Metformin in High-Risk, Treatment-Naïve Patients with Diabetes.Journal of clinical medicine · 2024Article
- The role of multimodality imaging in diabetic cardiomyopathy: a brief review.Frontiers in endocrinology · 2024Review
- Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice.Biomedicines · 2023Review
- Repurposing Metformin for Vascular Disease.Current medicinal chemistry · 2023Review
13 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The marked sentences are the ones the graph read a number from.
backgroundThe UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. METHODS AND
findingsThis meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2)=41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0.10 and 0.02, respectively).
conclusionsAlthough metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation.
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Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.