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Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders
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Abstract
Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I2 = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I2 = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.
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“long-term use of metformin in type 2 diabetes patients has been linked to a decline in tumor incidence and a reduced rate of cancer-related deaths.192–196”
From Drug repurposing for cancer therapy (2024) · cites this paper as [192]
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“a more thorough analysis that included more data and accounted for heterogeneous comparators showed that overall cancer incidence was reduced by 31% and cancer mortality by 34% (Gandini et al., 2014).”
From Metformin as a tool to target aging (2016) · cites this paper as Gandini et al., 2014
In the citing paper
“Furthermore, retrospective clinical studies have found that metformin use is associated with improved cancer outcomes, reductions in cancer incidence, and decreased cancer mortality (Evans et al., 2005; Franciosi et al., 2013; Gandini et al., 2014; Lee et al., 2012; Noto et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gandini et al., 2014
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“Extensive support for a protective effect of metformin against cancer has been provided by numerous, but not all studies (237, 238).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [237]
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“In a meta-analysis(255), metformin-treated diabetic patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index(255).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [255]
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Metadata
- Authors
- Gandini, S., Puntoni, M., Heckman-Stoddard, B. M., Dunn, B. K., Ford, L., DeCensi, A., & Szabo, E.
- Affiliations
- European Institute of Oncology (IT)
- Ente Ospedaliero Ospedali Galliera (IT)
- 3Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
- National Institutes of Health (US)
- National Cancer Institute (US)
- Corresponding author
- Szabo, Eva
- Venue
- Cancer Prevention Research
- Published
- 2014-09-01
- Volume
- 7
- Issue
- 9
- Pages
- 867-885
- ISSN
- 1940-6207 (ISSN-L)
- 1940-6215
- PMC
- PMC4154969
- OpenAlex
- W1976655891
- Cited by
- 457
- References
- 115
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 34 · 2023: 37 · 2022: 47 · 2021: 43 · 2020: 40 · 2019: 43 · 2018: 43 · 2017: 41 · 2016: 43 · 2015: 28 · 2014: 10
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Prevention Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Keywords
- metformin, cancer incidence, cancer mortality, diabetes mellitus, body mass index, confounding, antidiabetic drugs, chemoprevention
- MeSH terms
- Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Metformin, Neoplasms, Risk
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