In order to investigate whether an association between anti-diabetic drugs and the risk of colorectal cancer exists in women with diabetes mellitus (DM) in Taiwan, we designed a population-based cohort study using data from Taiwan National Health Insurance Database. There were 19,863 women aged 20 or older with newly diagnosed DM (International Classification of Diseases (ICD) 9th Revision, ICD-9 codes 250 and A181) and currently using anti-diabetic drugs in 2000–2007 (mean age 54.5 years, standard deviation 12.9 years, and age range 20–93). The index date for each case was defined as the date of diagnosis of colorectal cancer. Subjects diagnosed with cancer before the index date were excluded from the study.
After adjusted for covariates, Cox proportional hazard analysis showed that the hazard ratios (HR) of colorectal cancer were 3.56 (95% CI=2.02–6.72) in women with ever-use of sulfonylureas and 0.42 (95% CI=0.28–0.64) in women with ever-use of metformin compared with the non-use group (Table 1).
Table 1.
Variable | Crude HR | 95% CI | Adjusted HR | 95% CI |
---|---|---|---|---|
Age group (years) | ||||
20–39 | 1.00 | – | 1.00 | – |
40–64 | 3.10 | 0.97–9.90 | 2.74 | 0.86–8.77 |
≥65 | 6.24 | 1.94–20.04 | 5.19 | 1.61–16.71 |
Medications | ||||
Sulfonylureas (ever-use vs non-use) | 2.47 | 1.45–4.20 | 3.56 | 2.02–6.72 |
Metformin (ever-use vs non-use) | 0.63 | 0.43–0.93 | 0.42 | 0.28–0.64 |
Insulins (ever-use vs non-use) | 0.75 | 0.38–1.48 | – | – |
Thiazolidinediones (ever-use vs non-use) | 0.88 | 0.54–1.48 | – | – |
Alpha-glucosidase inhibitors (ever-use vs non-use) | 0.92 | 0.56–1.51 | – | – |
Aspirin (ever-use vs non-use) | 1.05 | 0.70–1.57 | – | – |
Other non-steroidal anti-inflammatory drugs (ever-use vs non-use) | 1.25 | 0.46–3.40 | – | – |
Statins (ever-use vs non-use) | 1.21 | 0.83–1.76 | – | – |
Co-morbidities | ||||
Obesity (yes vs no) | 1.07 | 0.26–4.33 | – | – |
Colorectal adenomas (yes vs no) | 1.76 | 0.25–12.61 | – | – |
Inflammatory bowel diseases (yes vs no)* | – | – | – | – |
Alcoholism (yes vs no)* | – | – | – | – |
*No case was found
There is a growing body of evidence to show that metformin is associated with a substantially decreased risk of cancers (1–4). In Decensi et al.'s meta-analysis, a 31% reduction of overall cancer risk (95% CI=0.61–0.79) is found in patients using metformin compared with the other anti-diabetic drugs (2). The present study also showed women with ever-use of metformin could have a 58% reduced risk of colorectal cancer. Three studies in Japan recently have also revealed the effect of metformin on suppressing colonic epithelial proliferation in mice and in humans, and further inhibiting colorectal carcinogenesis (5–7). The authors suggest that metformin may play a promising role in the chemoprevention of colorectal cancer (5–7).
A retrospective cohort study by Currie et al. in UK (5–7) revealed that sulfonylurea monotherapy could increase 1.8-fold risk of colorectal cancer (95% CI=1.29–2.53). In the present study, women with ever-use of sulfonylureas increased 3.6-fold risk of colorectal cancer. Previous studies have supported the hypothesis that hyperinsulinemia may play a key role in colorectal carcinogenesis (8–10). Because sulfonylureas can stimulate secretion of insulin, it may partially explain why patients using sulfonylureas are at an elevated risk of colorectal cancer.
Because the mechanism of anti-diabetic drugs on the risk of colorectal cancer remains unproven, more prospective intervention trials are required to definitively address this issue.
Kuan-Fu Liao
Department of Internal Medicine, Taichung Tzu Chi
General Hospital, Taichung, Taiwan
School of Medicine, Tzu Chi University, Hualien, Taiwan
Department of health care administration
Central Taiwan University of Science and Technology
Taichung, Taiwan
Shih-Wei Lai
School of Medicine, China Medical University
Taichung, Taiwan
Department of Family Medicine, China Medical
University Hospital, Taichung, Taiwan
Email: wei@mail.cmuh.org.tw
Chia-Ing LiSchool of Medicine, China Medical University
Taichung, Taiwan
Department of Medical Research, China Medical
University Hospital
Taichung, Taiwan
References
- 1.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. doi: 10.2337/dc08-2175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.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. doi: 10.1158/1940-6207.CAPR-10-0157. [DOI] [PubMed] [Google Scholar]
- 3.Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a populationbased cohort study. Am J Gastroenterol. 2012;107:46–52. doi: 10.1038/ajg.2011.384. [DOI] [PubMed] [Google Scholar]
- 4.Lai SW, Liao KF, Chen PC, Tsai PY, Hsieh DP, Chen CC. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in taiwan. Clin Lung Cancer. 2012;13:143–8. doi: 10.1016/j.cllc.2011.10.002. [DOI] [PubMed] [Google Scholar]
- 5.Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci. 2008;99:2136–41. doi: 10.1111/j.1349-7006.2008.00933.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila) 2010;3:1077–83. doi: 10.1158/1940-6207.CAPR-10-0186. [DOI] [PubMed] [Google Scholar]
- 7.Hosono K, Endo H, Takahashi H, Sugiyama M, Uchiyama T, Suzuki K, et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog. 2010;49:662–71. doi: 10.1002/mc.20637. [DOI] [PubMed] [Google Scholar]
- 8.Currie CJ, Poole CD, Gale EA. The influence of glucoselowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766–77. doi: 10.1007/s00125-009-1440-6. [DOI] [PubMed] [Google Scholar]
- 9.Seow A, Yuan JM, Koh WP, Lee HP, Yu MC. Diabetes mellitus and risk of colorectal cancer in the Singapore Chinese Health Study. J Natl Cancer Inst. 2006;98:135–8. doi: 10.1093/jnci/djj015. [DOI] [PubMed] [Google Scholar]
- 10.Atchison EA, Gridley G, Carreon JD, Leitzmann MF, McGlynn KA. Risk of cancer in a large cohort of US veterans with diabetes. Int J Cancer. 2011;128:635–43. doi: 10.1002/ijc.25362. [DOI] [PMC free article] [PubMed] [Google Scholar]