Influence of metformin in colorectal cancer patients with type 2 diabetes mellitus: a systematic review_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIAO Jian ,  BAI Lian , XIE Jian , MENG Wenjun

Yongchuan Hospital of Chongqing Medical University, Yongchuan, Chongqing 402160, P. R. China;

Corresponding author：

BAI Lian, Email: 2040996478@qq.com

Keywords：

metformin; type 2 diabetes mellitus; colorectal cancer; prognosis; meta analysis

DOI：

10.7507/1007-9424.202005096

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To systematically evaluate effect of metformin on prognosis of colorectal cancer patients with type 2 diabetes mellitus (T2DM).Methods The PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, Wangfang, etc. databases for cohort studies over the past 10 years were systematically searched. The relationship between the metformin and the prognosis in the colorectal cancer patients with T2DM was assessed with RevMan 5.3 software.Results A total of 12 articles with 13 694 patients were included in this study, of which 9 069 patients treated by the metformin (metformin group) and 4 625 patients treated by the other antidiabetic agent (control group). The results of meta-analysis showed that the metformin group had higher over survival [HR=0.74, 95%CI (0.66, 0.82), P<0.000 01] and cancer-specific survival [HR=0.77, 95%CI (0.69, 0.86), P<0.000 01] as compared with the control group. The sensitivity analysis of the heterogeneity showed that the research results did not be changed when the study which might cause heterogeneity was excluded. Conclusion Metformin treatment could improve prognosis of colorectal cancer patients with T2DM and improve overall survival and cancer-specific survival.

Citation： LIAO Jian, BAI Lian, XIE Jian, MENG Wenjun. Influence of metformin in colorectal cancer patients with type 2 diabetes mellitus: a systematic review. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(3): 355-363. doi: 10.7507/1007-9424.202005096 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2.	孙可欣, 郑荣寿, 张思维, 等. 2015 年中国分地区恶性肿瘤发病和死亡分析. 中国肿瘤, 2019, 28(1): 1-11.
3.	Cheng I, Caberto CP, Lum-Jones A, et al. Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies. Gut, 2011, 60(12): 1703-1711.
4.	Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer, 2009, 16(4): 1103-1123.
5.	Richardson LC, Pollack LA. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol, 2005, 2(1): 48-53.
6.	Inoue M; JPHC Study Group. Impact of lifestyle on overall cancer risk among Japanese: the Japan Public Health Center-based Prospective Study (JPHC Study). J Epidemiol, 2010, 20(2): 90-96.
7.	Wotton CJ, Yeates DG, Goldacre MJ. Cancer in patients admitted to hospital with diabetes mellitus aged 30 years and over: record linkage studies. Diabetologia, 2011, 54(3): 527-534.
8.	Inoue M, Iwasaki M, Otani T, et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med, 2006, 166(17): 1871-1877.
9.	Griffiths RI, Lindquist KJ, O’Malley CD, et al. Undiagnosed diabetes in breast, colorectal, lung, and prostate cancer: incidence and risk factors. ISRN Oncol, 2014, 2014: 607850.
10.	De Bruijn KM, Arends LR, Hansen BE, et al. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg, 2013, 100(11): 1421-1429.
11.	Higurashi T, Takahashi H, Endo H, et al. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer, 2012, 12: 118.
12.	Garrett CR, Hassabo HM, Bhadkamkar NA, et al. Survival advantage observed with the use of metformin in patients with type Ⅱ diabetes and colorectal cancer. Br J Cancer, 2012, 106(8): 1374-1378.
13.	Tian S, Lei HB, Liu YL, et al. The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta-analysis. Chronic Dis Transl Med, 2017, 3(3): 169-175.
14.	Soo JS, Ng CH, Tan SH, et al. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis, 2015, 20(10): 1373-1387.
15.	Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, et al. Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study. Eur J Cancer Prev, 2020, 29(4): 289-293.
16.	Sui X, Xu Y, Yang J, et al. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One, 2014, 9(5): e97781.
17.	Bodmer M, Becker C, Meier C, et al. Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev, 2012, 21(2): 280-286.
18.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
19.	Xu H, Aldrich MC, Chen Q, et al. Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality. J Am Med Inform Assoc, 2015, 22(1): 179-191.
20.	Ramjeesingh R, Orr C, Bricks CS, et al. A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr Oncol, 2016, 23(2): e116-122.
21.	Cossor FI, Adams-Campbell LL, Chlebowski RT, et al. Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer Epidemiol, 2013, 37(5): 742-749.
22.	Mc Menamin ÚC, Murray LJ, Hughes CM, et al. Metformin use and survival after colorectal cancer: A population-based cohort study. Int J Cancer, 2016, 138(2): 369-379.
23.	Fransgaard T, Thygesen LC, Gögenur I. Metformin increases overall survival in patients with diabetes undergoing surgery for colorectal cancer. Ann Surg Oncol, 2016, 23(5): 1569-1575.
24.	Lee JH, Kim TI, Jeon SM, et al. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer, 2012, 131(3): 752-759.
25.	Spillane S, Bennett K, Sharp L, et al. A cohort study of metformin exposure and survival in patients with stage Ⅰ–Ⅲ colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2013, 22(8): 1364-1373.
26.	Ki YJ, Kim HJ, Kim MS, et al. Association between metformin use and survival in nonmetastatic rectal cancer treated with a curative resection: a nationwide population study. Cancer Res Treat, 2017, 49(1): 29-36.
27.	Zanders MM, van Herk-Sukel MP, Vissers PA, et al. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another? Br J Cancer, 2015, 113(3): 403-410.
28.	Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, et al. Metformin increases cancer specific survival in colorectal cancer patients–National cohort study. Cancer Epidemiol, 2019, 62: 101587.
29.	Al Omari A, Abdelkhaleq H, Al-Hussaini M, et al. Validation of the survival benefits of metformin in middle eastern patients with type Ⅱ diabetes mellitus and colorectal cancer. J Glob Oncol, 2018, 4: 1-10.
30.	Berster JM, Göke B. Type 2 diabetes mellitus as risk factor for colorectal cancer. Arch Physiol Biochem, 2008, 114(1): 84-98.
31.	Keku TO, Lund PK, Galanko J, et al. Insulin resistance, apoptosis, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev, 2005, 14(9): 2076-2081.
32.	Yang YX, Hennessy S, Lewis JD. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol, 2005, 3(6): 587-594.
33.	Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst, 2005, 97(22): 1679-1687.
34.	Okwan-Duodu D, Umpierrez GE, Brawley OW, et al. Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages. Am J Cancer Res, 2013, 3(1): 21-33.
35.	Yeh HC, Platz EA, Wang NY, et al. A prospective study of the associations between treated diabetes and cancer outcomes. Diabetes Care, 2012, 35(1): 113-118.
36.	Quinn BJ, Kitagawa H, Memmott RM, et al. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab, 2013, 24(9): 469-480.
37.	Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology, 2004, 127(4): 1044-1050.
38.	Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ, 2007, 335(7618): 497.
39.	Bowker SL, Majumdar SR, Veugelers P, et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care, 2006, 29(2): 254-258.
40.	Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ, 2005, 330(7503): 1304-1305.
41.	Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila), 2010, 3(9): 1077-1083.
42.	Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med, 2013, 2(1): 99-107.
43.	Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005, 310(5754): 1642-1646.
44.	Jeong YK, Kim MS, Lee JY, et al. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLoS One, 2015, 10(11): e0143596.
45.	Lin CC, Yeh HH, Huang WL, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol, 2013, 49(2): 241-250.
46.	Moon HS, Mantzoros CS. Adiponectin and metformin additively attenuate IL1β-induced malignant potential of colon cancer. Endocr Relat Cancer, 2013, 20(6): 849-859.
47.	Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem, 2008, 114(1): 63-70.
48.	Donnenberg VS, Donnenberg AD. Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol, 2005, 45(8): 872-877.
49.	Soritau O, Tomuleasa C, Aldea M, et al. Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade Ⅲ and Ⅳ malignant gliomas. J BUON, 2011, 16(2): 282-289.
50.	Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res, 2011, 71(9): 3196-3201.
51.	Choi S, Ku JL. Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochem Biophys Res Commun, 2011, 412(2): 207-213.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2. 孙可欣, 郑荣寿, 张思维, 等. 2015 年中国分地区恶性肿瘤发病和死亡分析. 中国肿瘤, 2019, 28(1): 1-11.
3. Cheng I, Caberto CP, Lum-Jones A, et al. Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies. Gut, 2011, 60(12): 1703-1711.
4. Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer, 2009, 16(4): 1103-1123.
5. Richardson LC, Pollack LA. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol, 2005, 2(1): 48-53.
6. Inoue M; JPHC Study Group. Impact of lifestyle on overall cancer risk among Japanese: the Japan Public Health Center-based Prospective Study (JPHC Study). J Epidemiol, 2010, 20(2): 90-96.
7. Wotton CJ, Yeates DG, Goldacre MJ. Cancer in patients admitted to hospital with diabetes mellitus aged 30 years and over: record linkage studies. Diabetologia, 2011, 54(3): 527-534.
8. Inoue M, Iwasaki M, Otani T, et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med, 2006, 166(17): 1871-1877.
9. Griffiths RI, Lindquist KJ, O’Malley CD, et al. Undiagnosed diabetes in breast, colorectal, lung, and prostate cancer: incidence and risk factors. ISRN Oncol, 2014, 2014: 607850.
10. De Bruijn KM, Arends LR, Hansen BE, et al. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg, 2013, 100(11): 1421-1429.
11. Higurashi T, Takahashi H, Endo H, et al. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer, 2012, 12: 118.
12. Garrett CR, Hassabo HM, Bhadkamkar NA, et al. Survival advantage observed with the use of metformin in patients with type Ⅱ diabetes and colorectal cancer. Br J Cancer, 2012, 106(8): 1374-1378.
13. Tian S, Lei HB, Liu YL, et al. The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta-analysis. Chronic Dis Transl Med, 2017, 3(3): 169-175.
14. Soo JS, Ng CH, Tan SH, et al. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis, 2015, 20(10): 1373-1387.
15. Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, et al. Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study. Eur J Cancer Prev, 2020, 29(4): 289-293.
16. Sui X, Xu Y, Yang J, et al. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One, 2014, 9(5): e97781.
17. Bodmer M, Becker C, Meier C, et al. Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev, 2012, 21(2): 280-286.
18. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
19. Xu H, Aldrich MC, Chen Q, et al. Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality. J Am Med Inform Assoc, 2015, 22(1): 179-191.
20. Ramjeesingh R, Orr C, Bricks CS, et al. A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr Oncol, 2016, 23(2): e116-122.
21. Cossor FI, Adams-Campbell LL, Chlebowski RT, et al. Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer Epidemiol, 2013, 37(5): 742-749.
22. Mc Menamin ÚC, Murray LJ, Hughes CM, et al. Metformin use and survival after colorectal cancer: A population-based cohort study. Int J Cancer, 2016, 138(2): 369-379.
23. Fransgaard T, Thygesen LC, Gögenur I. Metformin increases overall survival in patients with diabetes undergoing surgery for colorectal cancer. Ann Surg Oncol, 2016, 23(5): 1569-1575.
24. Lee JH, Kim TI, Jeon SM, et al. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer, 2012, 131(3): 752-759.
25. Spillane S, Bennett K, Sharp L, et al. A cohort study of metformin exposure and survival in patients with stage Ⅰ–Ⅲ colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2013, 22(8): 1364-1373.
26. Ki YJ, Kim HJ, Kim MS, et al. Association between metformin use and survival in nonmetastatic rectal cancer treated with a curative resection: a nationwide population study. Cancer Res Treat, 2017, 49(1): 29-36.
27. Zanders MM, van Herk-Sukel MP, Vissers PA, et al. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another? Br J Cancer, 2015, 113(3): 403-410.
28. Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, et al. Metformin increases cancer specific survival in colorectal cancer patients–National cohort study. Cancer Epidemiol, 2019, 62: 101587.
29. Al Omari A, Abdelkhaleq H, Al-Hussaini M, et al. Validation of the survival benefits of metformin in middle eastern patients with type Ⅱ diabetes mellitus and colorectal cancer. J Glob Oncol, 2018, 4: 1-10.
30. Berster JM, Göke B. Type 2 diabetes mellitus as risk factor for colorectal cancer. Arch Physiol Biochem, 2008, 114(1): 84-98.
31. Keku TO, Lund PK, Galanko J, et al. Insulin resistance, apoptosis, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev, 2005, 14(9): 2076-2081.
32. Yang YX, Hennessy S, Lewis JD. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol, 2005, 3(6): 587-594.
33. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst, 2005, 97(22): 1679-1687.
34. Okwan-Duodu D, Umpierrez GE, Brawley OW, et al. Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages. Am J Cancer Res, 2013, 3(1): 21-33.
35. Yeh HC, Platz EA, Wang NY, et al. A prospective study of the associations between treated diabetes and cancer outcomes. Diabetes Care, 2012, 35(1): 113-118.
36. Quinn BJ, Kitagawa H, Memmott RM, et al. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab, 2013, 24(9): 469-480.
37. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology, 2004, 127(4): 1044-1050.
38. Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ, 2007, 335(7618): 497.
39. Bowker SL, Majumdar SR, Veugelers P, et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care, 2006, 29(2): 254-258.
40. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ, 2005, 330(7503): 1304-1305.
41. Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila), 2010, 3(9): 1077-1083.
42. Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med, 2013, 2(1): 99-107.
43. Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005, 310(5754): 1642-1646.
44. Jeong YK, Kim MS, Lee JY, et al. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLoS One, 2015, 10(11): e0143596.
45. Lin CC, Yeh HH, Huang WL, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol, 2013, 49(2): 241-250.
46. Moon HS, Mantzoros CS. Adiponectin and metformin additively attenuate IL1β-induced malignant potential of colon cancer. Endocr Relat Cancer, 2013, 20(6): 849-859.
47. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem, 2008, 114(1): 63-70.
48. Donnenberg VS, Donnenberg AD. Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol, 2005, 45(8): 872-877.
49. Soritau O, Tomuleasa C, Aldea M, et al. Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade Ⅲ and Ⅳ malignant gliomas. J BUON, 2011, 16(2): 282-289.
50. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res, 2011, 71(9): 3196-3201.
51. Choi S, Ku JL. Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochem Biophys Res Commun, 2011, 412(2): 207-213.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Influence of metformin in colorectal cancer patients with type 2 diabetes mellitus: a systematic review

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content