Original Article

Metformin Use and the Risk of Esophageal Cancer in Barrett Esophagus

Authors: Sangeeta Agrawal, MD, Piyush Patel, MD, Ayush Agrawal , Neil Makhijani , Ronald Markert , William Deidrich, MD

Abstract

Objectives: Diabetes mellitus is a significant risk factor for total cancer incidence and mortality. Metformin, a commonly used antidiabetic drug, has been shown to be protective against different types of cancers; however, its role in esophageal cancer is unknown. The goal of this study was to determine whether the use of metformin modifies the risk of development of esophageal adenocarcinoma in patients with Barrett esophagus.

Methods: Patients with diagnoses of Barrett esophagus and esophageal cancer were identified during a 20-year period. Demographic and clinical data were collected. The outcome variable was esophageal adenocarcinoma. Univariate analysis was performed using two-sample t tests for continuous variables or the Fisher exact test for categorical variables. Multiple logistic regression analysis was then performed using the significant variables.

Results: A total of 583 patients were identified with the diagnosis of Barrett esophagus or esophageal adenocarcinoma from 1992 to 2012. Of these, 115 had esophageal adenocarcinoma and 468 had Barrett esophagus. Age, smoking, and diabetes mellitus were found to be significant risk factors for the development of esophageal cancer with the following results: age ( P < 0.001), smoking ( P = 0.003), diabetes mellitus ( P = 0.007). Statin use was protective against the development of cancer with P = 0.001. Metformin use was neither associated with an increased nor a decreased risk of esophageal cancer.

Conclusions: The three independent variables that predicted progression of Barrett esophagus to esophageal adenocarcinoma in our study were older age, smoking, and diabetes mellitus. Statin use showed protective effect against development of esophageal adenocarcinoma. Metformin use did not demonstrate any statistically significant protective effect.

This content is limited to qualifying members.

Existing members, please login first.

If you have an existing account please login now to access this article or view your purchase options.

Purchase only this article ($15)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. World Cancer Research Fund. Worldwide data. http://www.wcrf.org/int/cancer-facts-figures/worldwide-data. Accessed November 12, 2014.
 
2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
 
3. National Cancer Institute. SEER stat fact sheets: esophageal cancer. http://seer.cancer.gov/statfacts/html/esoph.html. Accessed November 12, 2014.
 
4. Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst 2008;100:1184-1187.
 
5. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-146.
 
6. Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut 2005;54(Suppl 1):i1-i5.
 
7. Blot WJ, Devesa SS, Kneller RW, et al. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-1289.
 
8. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104:510-513.
 
9. Chow WH, Finkle WD, McLaughlin JK, et al. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia. JAMA 1995;274:474-477.
 
10. Vaughan TL, Davis S, Kristal A, et al. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 1995;4:85-92.
 
11. Kabat GC, Ng SK, Wynder EL. Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia. Cancer Causes Control 1993;4:123-132.
 
12. Gammon MD, Schoenberg JB, Ahsan H, et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 1997;89:1277-1284.
 
13. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825-1831.
 
14. Wild CP, Hardie LJ. Reflux, Barrett’s oesophagus and adenocarcinoma: burning questions. Nat Rev Cancer 2003;3:676-684.
 
15. Gamliel Z. Incidence, epidemiology, and etiology of esophageal cancer. Chest Surg Clin N Am 2000;10:441-450.
 
16. Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008;103:788-797.
 
17. Roberts KJ, Harper E, Alderson D, et al. Long-term survival and cost analysis of an annual Barrett’s surveillance programme. Eur J Gastroenterol Hepatol 2010;22:399-403.
 
18. Eckardt VF, Kanzler G, Bernhard G. Life expectancy and cancer risk in patients with Barrett’s esophagus: a prospective controlled investigation. Am J Med 2001;111:33-37.
 
19. Witters LA. The blooming of the French lilac. J Clin Invest 2001;108:1105-1107.
 
20. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9:563Y575.
 
21. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269-10273.
 
22. Rattan R, Giri S, Hartmann LC, et al. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med 2011;15:166-178.
 
23. Hardie DG, Alessi DR. LKB1 and AMPK and the cancer-metabolism link--ten years after. BMC Biol 2013;11:36.
 
24. Isakovic A, Harhaji L, Stevanovic D, et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 2007;64:1290-1302.
 
25. Li D, Yeung SC, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009;137:482-488.
 
26. Yang YX. Do diabetes drugs modify the risk of pancreatic cancer? Gastroenterology 2009;137:412-415.
 
27. Bodmer M, Meier C, Krahenbuhl S, et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 2010;33:1304-1308.
 
28. Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010;116:1938Y-1946.
 
29. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control 2009;20:1617-1622.
 
30. Kobayashi M, Kato K, Iwama H, et al. Antitumor effect of metformin in esophageal cancer: in vitro study. Int J Oncol 2013;42:517-524.
 
31. Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011;11:20.
 
32. Becker C, Meier CR, Jick SS, et al. CaseYcontrol analysis on metformin and cancer of the esophagus. Cancer Causes Control 2013;24:1763-1770.
 
33. Hardikar S, Onstad L, Blount PL, et al. The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett’s esophagus. PLoS One 2013;8:e52192.
 
34. Lagergren J. Influence of obesity on the risk of esophageal disorders. Nat Rev Gastroenterol Hepatol 2011;8:340-347.
 
35. Ryan AM, Duong M, Healy L, et al. Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets. Cancer Epidemiol 2011;35:309Y319.
 
36. Neale RE, Doecke JD, Pandeya N, et al. Does type 2 diabetes influence the risk of oesophageal adenocarcinoma? Br J Cancer 2009;100:795Y798.
 
37. Rubenstein JH, Davis J, Marrero JA, et al. Relationship between diabetes mellitus and adenocarcinoma of the oesophagus and gastric cardia. Aliment Pharmacol Ther 2005;22:267-271.
 
38. Huang W, Ren H, Ben Q, et al. Risk of esophageal cancer in diabetes mellitus: a meta-analysis of observational studies. Cancer Causes Control 2012;23:263-272.
 
39. Skinner HD, McCurdy MR, Echeverria AE, et al. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol 2013;52:1002-1009.
 
40. Kantor ED, Onstad L, Blount PL, et al. Use of statin medications and risk of esophageal adenocarcinoma in persons with Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 2012;21:456-461.
 
41. Metformin hydrochloride in preventing esophageal cancer in patients with Barrett esophagus. http://clinicaltrials.gov/show/NCT01447927. Accessed November 13, 2014.