title: Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials.
abstract: OBJECTIVE
  Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs).
  
  
  METHODS
  RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I                            (2)statistics for heterogeneity were calculated by fixed effects meta-analysis.
  
  
  RESULTS
  Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials.
  
  
  CONCLUSIONS
  Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK. richard.stevens@phc.ox.ac.uk.
authors.forename: R J
authors.initials: RJ
authors.lastname: Stevens
authors.affiliation: Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Ali
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Bankhead
authors.affiliation: Diabetes Trials Unit, Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Bethel
authors.affiliation: Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
authors.forename: B J
authors.initials: BJ
authors.lastname: Cairns
authors.affiliation: TGRD Europe, Takeda Pharmaceutical Company, London, UK.
authors.forename: R P
authors.initials: RP
authors.lastname: Camisasca
authors.affiliation: Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
authors.forename: F L
authors.initials: FL
authors.lastname: Crowe
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Farmer
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: S
authors.initials: S
authors.lastname: Harrison
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Hirst
authors.affiliation: ICM-Diabetes, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: P
authors.initials: P
authors.lastname: Home
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Kahn
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: McLellan
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Perera
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: A
authors.initials: A
authors.lastname: Plüddemann
authors.affiliation: India Diabetes Research Foundation, Dr A. Ramachandran's Diabetes Hospitals, Egmore, Chennai, India.
authors.forename: A
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: N W
authors.initials: NW
authors.lastname: Roberts
authors.affiliation: Department of Primary Care Health Sciences, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK.
authors.forename: P W
authors.initials: PW
authors.lastname: Rose
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Schweizer
authors.affiliation: Unit for Metabolic Medicine, School of Medicine, King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Viberti
authors.affiliation: Diabetes Trials Unit, Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: R R
authors.initials: RR
authors.lastname: Holman
mesh_terms: D000328:Adult; D000368:Aged; D048909:Diabetes Complications / Q000150:complications; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology / Q000401:mortality*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin