title: Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials.
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.
  
  
  RESULTS
  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.
authors.affiliation: Department of General Medicine, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Boussageon
authors.forename: Irène
authors.initials: I
authors.lastname: Supper
authors.forename: Theodora
authors.initials: T
authors.lastname: Bejan-Angoulvant
authors.forename: Nadir
authors.initials: N
authors.lastname: Kellou
authors.forename: Michel
authors.initials: M
authors.lastname: Cucherat
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Boissel
authors.forename: Behrouz
authors.initials: B
authors.lastname: Kassai
authors.forename: Alain
authors.initials: A
authors.lastname: Moreau
authors.forename: François
authors.initials: F
authors.lastname: Gueyffier
authors.forename: Catherine
authors.initials: C
authors.lastname: Cornu
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D003925:Diabetic Angiopathies / Q000401:mortality*; D006801:Humans; D008687:Metformin / Q000627:therapeutic use*; D017063:Outcome Assessment, Health Care; D050177:Overweight / Q000150:complications / Q000401:mortality; D013453:Sulfonylurea Compounds / Q000009:adverse effects
chemical_list: D013453:Sulfonylurea Compounds; D008687:Metformin