Title: Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials
Authors: R.J. Stevens, R. Ali, C.R. Bankhead, M.A. Bethel, B.J. Cairns, R.P. Camisasca, F.L. Crowe, A.J. Farmer, S.Harrison, J.A. Hirst, P. Home, S.E. Kahn, J.H. McLellan, R. Perera, A. Plüddemann, A. Ramachandran, N.W. Roberts, P.W. Rose, A. Schweizer, G. Viberti, R.R. Holman
Reference: Diabetologia 55(10):2593-2603.
Aims/hypothesis Observational studies suggest that metformin may reduce cancer risk by approximately onethird. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs).
Methods RCTs comparing metformin with active glucoselowering 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 I2 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/interpretation 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
Keywords. Meta-analysis, Metformin, Neoplasms, Systematic review
Acknowledgement. We are grateful to the staff of the individual studies for their assistance in collating the data for analysis.
Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, U.K.