Endocrinol Metab.  2022 Dec;37(6):929-937. 10.3803/EnM.2022.1613.

Metformin and Cervical Cancer Risk in Patients with Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea

• Kim HM
• Kang MJ
• Song SO

• KMID: 2537293
• DOI: http://doi.org/10.3803/EnM.2022.1613

Abstract

Background
Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes.
Methods
This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication.
Results
In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; P<0.001; and HR, 0.141; 95% CI, 0.077 to 0.258; P<0.001). The incidence was also significantly lower in metformin users among those over 50 years old (HR, 0.791; 95% CI, 0.650 to 0.961; P<0.001).
Conclusion
Metformin use in patients with newly diagnosed diabetes was associated with a lower risk of cervical cancer in Korea. Furthermore, a significant association was found between the use of metformin and cervical cancer in a dose- and duration-dependent manner and among those over 50 years old.

Keyword

Metformin; Uterine cervical neoplasms; Diabetes mellitus; Population; Cohort studies

Figure

• 

  Fig. 1. Study flowchart.

• 

Reference

1. Johnson JA, Carstensen B, Witte D, Bowker SL, Lipscombe L, Renehan AG, et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia. 2012; 55:1607–18.

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71:209–49.

3. Hong S, Won YJ, Lee JJ, Jung KW, Kong HJ, Im JS, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2018. Cancer Res Treat. 2021; 53:301–15.

4. Quinn BJ, Kitagawa H, Memmott RM, Gills JJ, Dennis PA. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013; 24:469–80.

5. Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: a review of the current evidence. Life Sci. 2020; 254:117717.

6. Gao ZY, Liu Z, Bi MH, Zhang JJ, Han ZQ, Han X, et al. Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med. 2016; 11:1700–6.

7. Chu NJ, Armstrong TD, Jaffee EM. Nonviral oncogenic antigens and the inflammatory signals driving early cancer development as targets for cancer immunoprevention. Clin Cancer Res. 2015; 21:1549–57.

8. Li K, Zhang TT, Wang F, Cui B, Zhao CX, Yu JJ, et al. Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene. 2018; 37:2967–81.

9. Li L, Wang L, Li J, Fan Z, Yang L, Zhang Z, et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018; 78:1779–91.

10. Wang J, Li G, Wang Y, Tang S, Sun X, Feng X, et al. Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis. Oncotarget. 2015; 6:44579–92.

11. Kim HK, Song SO, Noh J, Jeong IK, Lee BW. Data configuration and publication trends for the Korean National Health Insurance and Health Insurance Review & Assessment database. Diabetes Metab J. 2020; 44:671–8.

12. Cho YY, Kang MJ, Kim SK, Jung JH, Hahm JR, Kim TH, et al. Protective effect of metformin against thyroid cancer development: a population-based study in Korea. Thyroid. 2018; 28:864–70.

13. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005; 330:1304–5.

14. Cheng K, Hao M. Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition via PKM2 relativemTOR/p70s6k signaling pathway in cervical carcinoma cells. Int J Mol Sci. 2016; 17:2000.

15. Chen YH, Yang SF, Yang CK, Tsai HD, Chen TH, Chou MC, et al. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep. 2021; 23:88.

16. Xiao X, He Q, Lu C, Werle KD, Zhao RX, Chen J, et al. Metformin impairs the growth of liver kinase B1-intact cervical cancer cells. Gynecol Oncol. 2012; 127:249–55.

17. Xia C, Liu C, He Z, Cai Y, Chen J. Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression. J Exp Clin Cancer Res. 2020; 39:127.

18. Tseng CH. Metformin use and cervical cancer risk in female patients with type 2 diabetes. Oncotarget. 2016; 7:59548–55.

19. Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G, et al. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia. 2010; 53:1838–45.

20. Wen Q, Zhao Z, Wen J, Zhou J, Wu J, Lei S, et al. The association between metformin therapy and risk of gynecological cancer in patients: two meta-analyses. Eur J Obstet Gynecol Reprod Biol. 2019; 237:33–41.

21. Yao K, Zheng H, Li T. Association between metformin use and the risk, prognosis of gynecologic cancer. Front Oncol. 2022; 12:942380.

22. Imai A, Ichigo S, Matsunami K, Takagi H, Yasuda K. Clinical benefits of metformin in gynecologic oncology. Oncol Lett. 2015; 10:577–82.

23. Kim J, Lee D, Son KB, Bae S. The burden of cervical cancer in Korea: a population-based study. Int J Environ Res Public Health. 2020; 17:6308.

24. Poorolajal J, Jenabi E. The association between BMI and cervical cancer risk: a meta-analysis. Eur J Cancer Prev. 2016; 25:232–8.

25. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009; 32:1620–5.

26. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010; 3:1451–61.

27. Han K, Pintilie M, Lipscombe LL, Lega IC, Milosevic MF, Fyles AW. Association between metformin use and mortality after cervical cancer in older women with diabetes. Cancer Epidemiol Biomarkers Prev. 2016; 25:507–12.

28. Hanprasertpong J, Jiamset I, Geater A, Peerawong T, Hemman W, Kornsilp S. The effect of metformin on oncological outcomes in patients with cervical cancer with type 2 diabetes mellitus. Int J Gynecol Cancer. 2017; 27:131–7.

29. Takiuchi T, Machida H, Hom MS, Mostofizadeh S, Frimer M, Brunette LL, et al. Association of metformin use and survival outcome in women with cervical cancer. Int J Gynecol Cancer. 2017; 27:1455–63.

30. Tang ZY, Sheng MJ, Qi YX, Wang LY, He DY. Metformin enhances inhibitive effects of carboplatin on HeLa cell proliferation and increases sensitivity to carboplatin by activating mitochondrial associated apoptosis signaling pathway. Eur Rev Med Pharmacol Sci. 2018; 22:8104–12.