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Meta-Analysis
. 2024 Apr 5;116(4):518-529.
doi: 10.1093/jnci/djae021.

Association of metformin use and cancer incidence: a systematic review and meta-analysis

Lauren O'Connor  1 , Maeve Bailey-Whyte  2 , Manami Bhattacharya  3 , Gisela Butera  4 , Kaitlyn N Lewis Hardell  1   5 , Andrew B Seidenberg  6   7 , Philip E Castle  8 , Holli A Loomans-Kropp  9   10   11
Affiliations
Meta-Analysis

Association of metformin use and cancer incidence: a systematic review and meta-analysis

Lauren O'Connor et al. J Natl Cancer Inst. .

Abstract

Background: Metformin is among the most widely used antidiabetics medications because of its minimal toxicity, favorable safety profile, availability, and low cost. In addition to its role in diabetes management, metformin may reduce cancer risk.

Methods: We conducted a comprehensive systematic review and meta-analysis to investigate the association between metformin use and cancer risk, with evaluation by specific cancer type when possible. Applicable studies were identified in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from inception through March 7, 2023, with metformin use categorized as "ever" or "yes" and a cancer diagnosis as the outcome. Article quality was evaluated using National Heart, Lung, and Blood Institute guidelines, and publication bias was evaluated using the Egger test, Begg test, and funnel plots. Pooled relative risk (RR) estimates were calculated using random-effects models, and sensitivity analysis was completed through leave-one-out cross-validation.

Results: We included 166 studies with cancer incidence information in the meta-analysis. Reduced risk for overall cancer was observed in case-control studies (RR = 0.55, 95% confidence interval [CI] = 0.30 to 0.80) and prospective cohort studies (RR = 0.65, 95% CI = 0.37 to 0.93). Metformin use was associated with reduced gastrointestinal (RR = 0.79, 95% CI = 0.73 to 0.85), urologic (RR = 0.88, 95% CI = 0.78 to 0.99), and hematologic (RR = 0.87, 95% CI = 0.75 to 0.99) cancer risk. Statistically significant publication bias was observed within the studies (Egger P < .001).

Conclusions: Metformin may be associated with a decreased risk of many cancer types, but high heterogeneity and risk of publication bias limit confidence in these results. Additional studies in populations without diabetes are needed to better understand the utility of metformin in cancer prevention.

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Conflict of interest statement

P.C., who is a JNCI associate editor and co-author on this paper, was not involved in the editorial review or decision to publish the manuscript. The authors declare no conflicts of interest. The content presented here is the sole responsibility of the authors and does not reflect the official views of the NIH.

Figures

Figure 1.
Figure 1.
Preferred Reporting Items for Systematic Review and Meta-Analyses flow diagram for identification of relevant studies for inclusion.
Figure 2.
Figure 2.
Estimated summary relative risk for overall cancer risk with metformin use in a random-effects model. This summary includes article estimates for all malignancies, multiple cancers, or several cancers. CI = confidence interval; REML = residual maximum likelihood; RR = relative risk.
Figure 3.
Figure 3.
Estimated summary relative risk for breast cancer with metformin use in a random-effects model. CI = confidence interval; REML = residual maximum likelihood; RR = relative risk.
Figure 4.
Figure 4.
Estimated summary relative risk for colorectal cancer with metformin use in a random-effects model. CI = confidence interval; REML = residual maximum likelihood; RR = relative risk.
Figure 5.
Figure 5.
Estimated summary relative risk for liver cancer with metformin use in a random-effects model. CI = confidence interval; REML = residual maximum likelihood; RR = relative risk.
Figure 6.
Figure 6.
Estimated summary relative risk for prostate cancer with metformin use in a random effects model. CI = confidence interval; REML = residual maximum likelihood; RR = relative risk.
See this image and copyright information in PMC

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