Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Epidemiology

Improved prognosis in gastric adenocarcinoma among metformin users in a population-based study

British Journal of Cancer volume 125, pages 277–283 (2021)Cite this article

Subjects

Abstract

Background

Metformin may improve the prognosis in gastric adenocarcinoma, but the existing literature is limited and contradictory.

Methods

This was a Swedish population-based cohort study of diabetes patients who were diagnosed with gastric adenocarcinoma in 2005–2018 and followed up until December 2019. The data were retrieved from four national health data registries: Prescribed Drug Registry, Cancer Registry, Patient Registry and Cause of Death Registry. Associations between metformin use before the gastric adenocarcinoma diagnosis and the risk of disease-specific and all-cause mortality were assessed using multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for sex, age, calendar year, comorbidity, use of non-steroidal anti-inflammatory drugs or aspirin, and use of statins.

Results

Compared with non-users, metformin users had a decreased risk of disease-specific mortality (HR 0.79, 95% CI 0.67–0.93) and all-cause mortality (HR 0.78, 95% CI 0.68–0.90). The associations were seemingly stronger among patients of female sex (HR 0.66, 95% CI 0.49–0.89), patients with tumour stage III or IV (HR 0.71, 95% CI 0.58–0.88), and those with the least comorbidity (HR 0.71, 95% CI 0.57–0.89).

Conclusions

Metformin use may improve survival in gastric adenocarcinoma among diabetes patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Kaplan–Meier survival curves for patients with gastric adenocarcinoma and diabetes by metformin use.
Fig. 2: Cumulative mortality curves comparing metformin-users with non-users by competting-risks model.

Similar content being viewed by others

References

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  Google Scholar 

  2. Fitzmaurice, C., Akinyemiju, T. F., Al Lami, F. H., Alam, T., Alizadeh-Navaei, R., Allen, C. et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 4, 1553–1568 (2018).

    Article  Google Scholar 

  3. Asplund, J., Kauppila, J. H., Mattsson, F. & Lagergren, J. Survival trends in gastric adenocarcinoma: a population-based study in sweden. Ann. Surg. Oncol. 25, 2693–2702 (2018).

    Article  Google Scholar 

  4. Joo, M. K., Park, J. J. & Chun, H. J. Additional benefits of routine drugs on gastrointestinal cancer: statins, metformin, and proton pump inhibitors. Dig. Dis. 36, 1–14 (2018).

    Article  Google Scholar 

  5. Coyle, C., Cafferty, F. H., Vale, C. & Langley, R. E. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann. Oncol. 27, 2184–2195 (2016).

    Article  CAS  Google Scholar 

  6. Valaee, S., Yaghoobi, M. M. & Shamsara, M. Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial-mesenchymal transition in a glucose-independent manner. PLoS ONE 12, e0174486 (2017).

    Article  Google Scholar 

  7. Lu, C.-C., Chiang, J.-H., Tsai, F.-J., Hsu, Y.-M., Juan, Y.-N., Yang, J.-S. et al. Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J. Oncol. 54, 1271–1281 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lee, C. K., Jung, M., Jung, I., Heo, S. J., Jeong, Y. H., An, J. Y. et al. Cumulative metformin use and its impact on survival in gastric cancer patients after gastrectomy. Ann. Surg. 263, 96–102 (2016).

    Article  Google Scholar 

  9. Lacroix, O., Couttenier, A., Vaes, E., Cardwell, C. R., De Schutter, H. & Robert, A. Impact of metformin on gastric adenocarcinoma survival: A Belgian population based study. Cancer Epidemiol. 53, 149–155 (2018).

    Article  Google Scholar 

  10. Dulskas, A., Patasius, A., Linkeviciute-Ulinskiene, D., Zabuliene, L. & Smailyte, G. A cohort study of antihyperglycemic medication exposure and survival in patients with gastric cancer. Aging 11, 7197–7205 (2019).

    Article  CAS  Google Scholar 

  11. Baglia, M. L., Cui, Y., Zheng, T., Yang, G., Li, H., You, M. et al. Diabetes medication use in association with survival among patients of breast, colorectal, lung, or gastric cancer. Cancer Res. Treat. 51, 538–546 (2019).

    Article  CAS  Google Scholar 

  12. Xie, S.-H., Santoni, G., Mattsson, F., Ness-Jensen, E. & Lagergren, J. Cohort profile: the Swedish Prescribed Drugs and Health Cohort (SPREDH). BMJ Open 9, e023155 (2019).

    Article  Google Scholar 

  13. Wallerstedt, S. M., Wettermark, B. & Hoffmann, M. The First Decade with the Swedish Prescribed Drug Register - A Systematic Review of the Output in the Scientific Literature. Basic Clin. Pharmacol. Toxicol. 119, 464–469 (2016).

    Article  CAS  Google Scholar 

  14. Wettermark, B., Hammar, N., Fored, C. M., Leimanis, A., Otterblad Olausson, P., Bergman, U. et al. The new Swedish Prescribed Drug Register-opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol. Drug Saf. 16, 726–735 (2007).

    Article  Google Scholar 

  15. Ekstrom, A. M., Signorello, L. B., Hansson, L. E., Bergstrom, R., Lindgren, A. & Nyren, O. Evaluating gastric cancer misclassification: a potential explanation for the rise in cardia cancer incidence. J. Natl. Cancer Inst. 91, 786–790 (1999).

    Article  CAS  Google Scholar 

  16. Brooke, H. L., Talback, M., Hornblad, J., Johansson, L. A., Ludvigsson, J. F., Druid, H. et al. The Swedish cause of death register. Eur. J. Epidemiol. 32, 765–773 (2017).

    Article  CAS  Google Scholar 

  17. Jakobsson, G. L., Sternegard, E., Olen, O., Myrelid, P., Ljung, R., Strid, H. et al. Validating inflammatory bowel disease (IBD) in the Swedish National Patient Register and the Swedish Quality Register for IBD (SWIBREG). Scand. J. Gastroenterol. 52, 216–221 (2017).

    Article  CAS  Google Scholar 

  18. Ludvigsson, J. F., Andersson, E., Ekbom, A., Feychting, M., Kim, J. L., Reuterwall, C. et al. External review and validation of the Swedish national inpatient register. BMC Public Health 11, 450 (2011).

    Article  Google Scholar 

  19. Charlson, M. E., Pompei, P., Ales, K. L. & MacKenzie, C. R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis. 40, 373–383 (1987).

    Article  CAS  Google Scholar 

  20. Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 367, 1792–1802 (2012).

    Article  CAS  Google Scholar 

  21. Frouws, M. A., Bastiaannet, E., Langley, R. E., Chia, W. K., van Herk-Sukel, M. P., Lemmens, V. E. et al. Effect of low-dose aspirin use on survival of patients with gastrointestinal malignancies; an observational study. Br. J. Cancer 116, 405–413 (2017).

    Article  CAS  Google Scholar 

  22. Hua, X., Phipps, A. I., Burnett-Hartman, A. N., Adams, S. V., Hardikar, S., Cohen, S. A. et al. Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival. J. Clin. Oncol. 35, 2806–2813 (2017).

    Article  CAS  Google Scholar 

  23. Fine, J. P. & Gray, R. J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509 (1999).

    Article  Google Scholar 

  24. Ekström, N., Schiöler, L., Svensson, A. M., Eeg-Olofsson, K., Miao Jonasson, J., Zethelius, B. et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ open 2, e001076 (2012).

    Article  Google Scholar 

  25. Craney, T. A. & Surles, J. G. Model-Dependent Variance Inflation Factor Cutoff Values. Qual. Eng. 14, 391–403 (2002).

    Article  Google Scholar 

  26. Zheng, J., Xie, S. H., Santoni, G. & Lagergren, J. Population-based cohort study of diabetes mellitus and mortality in gastric adenocarcinoma. Br. J. Surg. 105, 1799–1806 (2018).

    Article  CAS  Google Scholar 

  27. Chung, W. S., Le, P. H., Kuo, C. J., Chen, T. H., Kuo, C. F., Chiou, M. J. et al. Impact of metformin use on survival in patients with gastric cancer and diabetes mellitus following gastrectomy. Cancers https://doi.org/10.3390/cancers12082013 LID - 2013.

  28. Seo, H. S., Jung, Y. J., Kim, J. H., Lee, H. H. & Park, C. H. The effect of metformin on prognosis in patients with locally advanced gastric cancer associated with type 2 diabetes mellitus. Am. J. Clin. Oncol. 42, 909–917 (2019).

  29. Cho, M. H., Yoo, T. G., Jeong, S. M. & Shin, D. W. Association of aspirin, metformin, and statin use with gastric cancer incidence and mortality: a nationwide cohort study. Cancer Prev. Res. (Phila). https://doi.org/10.1158/1940-6207.CAPR-20-0123 (2020).

  30. Courtois, S., Lehours, P. & Bessede, E. The therapeutic potential of metformin in gastric cancer. Gastric Cancer. 22, 653–662 (2019).

    Article  CAS  Google Scholar 

  31. Daugan, M., Dufay Wojcicki, A., d’Hayer, B. & Boudy, V. Metformin: an anti-diabetic drug to fight cancer. Pharmacol. Res. 113, 675–685 (2016).

    Article  CAS  Google Scholar 

  32. Yu, G., Fang, W., Xia, T., Chen, Y., Gao, Y., Jiao, X. et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget 6, 12748–12762 (2015).

    Article  Google Scholar 

  33. Wu, X. Effect of metformin combined with chemotherapeutic agents on gastric cancer cell line AGS. Pak. J. Pharm. Sci. 30, 1833–1836 (2017).

    CAS  PubMed  Google Scholar 

  34. Park, J. W., Lee, J. H., Park, Y. H., Park, S. J., Cheon, J. H., Kim, W. H. et al. Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. World J. Gastroenterol. 23, 5196–5205 (2017).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Author information

Authors and Affiliations

  1. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Jiaojiao Zheng, Giola Santoni, Shao-Hua Xie & Jesper Lagergren

  2. School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK

    Jesper Lagergren

Authors
  1. Jiaojiao Zheng
    View author publications

    Search author on:PubMed Google Scholar

  2. Giola Santoni
    View author publications

    Search author on:PubMed Google Scholar

  3. Shao-Hua Xie
    View author publications

    Search author on:PubMed Google Scholar

  4. Jesper Lagergren
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All listed authors designed the study. J.L. and S.X. collected the data for the study. J.Z and G.S. analysed the data. J.Z. interpreted the results and drafted the manuscript. All listed authors revised the manuscript and approved the final version of the article, including the authorship list. J.L. is the guarantor of this work. Both J.L. and the corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Shao-Hua Xie.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the “Declaration of Helsinki”, and was approved by the Regional Ethical Review Board in Stockholm (2018/271-32). No individual informed consent was needed according to the Swedish regulation.

Consent to publish

Not applicable.

Data availability

All the data were retrieved from the Swedish Prescribed Drugs and Health Cohort. The original data are available from the registries listed above, but restrictions apply to the availability of these data, which were used under license for the current study and therefore are not publicly available. Data may however be available through applications to these registries or reasonable request to the corresponding author (S.X.). The codes for the data analysis are archived by the first author (J.Z.).

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the Swedish Cancer Society (grant number 180684 to J.L. and 190043 to S.X.); and the Swedish Research Council (grant number 2019-00209 to J.L.). J.Z. receives a scholarship from China Scholarship Council (student number 201700260292). The founding resources were not involved in the study design, data collection, data analysis and interpretation of the results; nor in the writing of the report; and in the decision to submit the article for publication.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, J., Santoni, G., Xie, SH. et al. Improved prognosis in gastric adenocarcinoma among metformin users in a population-based study. Br J Cancer 125, 277–283 (2021). https://doi.org/10.1038/s41416-021-01408-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41416-021-01408-8

This article is cited by

Search

Advanced search

Quick links