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Cited by 266Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 62 of the 65 references it cites were found in a registry or an index.

Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials

Open access
Boussageon, Rémy, Supper, Irène, Bejan-Angoulvant, Theodora, Kellou, Nadir, Cucherat, Michel, Boissel, Jean-Pierre, Kassai, Behrouz, Moreau, Alain, Gueyffier, François, Cornu, Catherine·2012·PLoS Medicine
DOI 10.1371/journal.pmed.1001204PMC PMC3323508
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Abstract

BACKGROUND: The 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 FINDINGS: This 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). CONCLUSIONS: Although 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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Figure 1 Flow chart.
Figure 1 Flow chart.CC BY · PubMed Central
Figure 2 Forest plot for primary end points. (A) All-cause mortality. (B) Cardiovascular mortality. df, degrees of freedom; M-H, Mantel–Haenszel odds ratio method.
Figure 2 Forest plot for primary end points. (A) All-cause mortality. (B) Cardiovascular mortality. df, degrees of freedom; M-H, Mantel–Haenszel odds ratio method.CC BY · PubMed Central
Figure 3 Forest plot for secondary end points. (A) All myocardial infarctions. (B) All strokes. (C) Heart failure. (D) Peripheral vascular events. (E) Amputation. (F) Microvascular complications. df, degrees of freedom; M-H, Mantel–Haenszel odds ratio method.
Figure 3 Forest plot for secondary end points. (A) All myocardial infarctions. (B) All strokes. (C) Heart failure. (D) Peripheral vascular events. (E) Amputation. (F) Microvascular complications. df, degrees of freedom; M-H, Mantel–Haenszel odds ratio method.CC BY · PubMed Central

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Metadata

Authors
Boussageon, R., Supper, I., Bejan-Angoulvant, T., Kellou, N., Cucherat, M., Boissel, J.-P., Kassai, B., Moreau, A., Gueyffier, F., & Cornu, C.
Affiliations
Lyon 1 Université (FR)
Corresponding author
Cornu, Catherine
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2012-04-10
Volume
9
Issue
4
Pages
e1001204
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.1001204
PMC
PMC3323508
OpenAlex
W2043807347
Cited by
266
References
65
Citations by year
2026: 8 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 12 · 2021: 19 · 2020: 30 · 2019: 19 · 2018: 28 · 2017: 18 · 2016: 24 · 2015: 23 · 2014: 23 · 2013: 27 · 2012: 9
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, type 2 diabetes, all-cause mortality, cardiovascular mortality, cardiovascular morbidity, myocardial infarction, stroke, congestive heart failure, peripheral vascular disease, leg amputation, microvascular complications, UK Prospective Diabetes Study, first-line therapy, drug efficacy
MeSH terms
Diabetes Mellitus, Type 2, Diabetic Angiopathies, Humans, Metformin, Sulfonylurea Compounds, Outcome Assessment, Health Care, Overweight

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