International Journal of Colorectal Disease

, Volume 28, Issue 4, pp 469–476

Statin use is associated with a reduced incidence of colorectal adenomatous polyps

  • Thomas Broughton
  • Jamie Sington
  • Ian L. P. Beales
Original Article

Abstract

Background

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to have potentially useful anticancer effects against colorectal cancers in experimental studies, but clinical studies have shown inconsistent results on colorectal cancer incidence. Most colorectal cancers are believed to develop through the polyp-cancer sequence. We hypothesized that statins may protect against the development of adenomatous polyps, and this may contribute to the apparent cancer-protective effects.

Objective

This study aims to compare previous statin use in patients with newly diagnosed adenomatous polyps against a control group without polyps.

Method

A case–control study involving 264 patients attending for diagnostic colonoscopy at the Norfolk and Norwich University Hospital was used. Polyp cases were age and sex matched against controls with normal colonoscopies. Structured patient interviews and clinical notes were used to ascertain drug and risk factor. Logistic regression was used to compare statin exposure and correct for confounding factors.

Results

There was a significant negative association between prior statin use and a diagnosis of adenomatous polyps [odds ratio (OR) = 0.40 (0.24–0.76)]. The association was significantly stronger with higher statin doses [≥40 mg simvastatin or equivalent; OR 0.33 (0.10–0.53)] or longer duration of use [>5 years; OR 0.36 (0.10–0.67)]. Statin use was negatively associated with both high- and low-risk polyps.

Conclusions

Statins may have a protective effect against the development of adenomatous polyps. The negative association between statin use and polyp incidence showed a significant dose and duration relationship.

Keywords

Aspirin Chemoprevention Hydroxymethylglutaryl-CoA reductase inhibitors Colorectal adenocarcinoma Colorectal adenomas 

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355(9):873–874PubMedCrossRefGoogle Scholar
  3. 3.
    Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352(11):1071–1080PubMedCrossRefGoogle Scholar
  4. 4.
    Asano TK, McLeod RS (2004) Non steroidal anti-inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev (2):CD004079Google Scholar
  5. 5.
    Feleszko W, Jakobisiak M (2000) Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res 6(3):1198–1199PubMedGoogle Scholar
  6. 6.
    Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2010) Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 101(7):1701–1707PubMedCrossRefGoogle Scholar
  7. 7.
    Yasui Y, Suzuki R, Miyamoto S, Tsukamoto T, Sugie S, Kohno H, Tanaka T (2007) A lipophilic statin, pitavastatin, suppresses inflammation-associated mouse colon carcinogenesis. Int J Cancer 121(10):2331–2339PubMedCrossRefGoogle Scholar
  8. 8.
    Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G (2005) Statins and the risk of colorectal cancer. N Engl J Med 352(21):2184–2192PubMedCrossRefGoogle Scholar
  9. 9.
    Taylor ML, Wells BJ, Smolak MJ (2008) Statins and cancer: a meta-analysis of case–control studies. Eur J Cancer Prev 17(3):259–268PubMedCrossRefGoogle Scholar
  10. 10.
    Friedman GD, Flick ED, Udaltsova N, Chan J, Quesenberry CP Jr, Habel LA (2008) Screening statins for possible carcinogenic risk: up to 9 years of follow-up of 361,859 recipients. Pharmacoepidemiol Drug Saf 17(1):27–36PubMedCrossRefGoogle Scholar
  11. 11.
    Shadman M, Newcomb PA, Hampton JM, Wernli KJ, Trentham-Dietz A (2009) Non-steroidal anti-inflammatory drugs and statins in relation to colorectal cancer risk. World J Gastroenterol 15(19):2336–2339PubMedCrossRefGoogle Scholar
  12. 12.
    Lipkin SM, Chao EC, Moreno V, Rozek LS, Rennert H, Pinchev M, Dizon D, Rennert G, Kopelovich L, Gruber SB (2010) Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev Res (Phila) 3(5):597–603CrossRefGoogle Scholar
  13. 13.
    Hachem C, Morgan R, Johnson M, Kuebeler M, El-Serag H (2009) Statins and the risk of colorectal carcinoma: a nested case–control study in veterans with diabetes. Am J Gastroenterol 104(5):1241–1248PubMedCrossRefGoogle Scholar
  14. 14.
    Broughton T, Sington J, Beales IL (2012) Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case–control study. BMC Gastroenterol 12:36PubMedCrossRefGoogle Scholar
  15. 15.
    Singh H, Mahmud SM, Turner D, Xue L, Demers AA, Bernstein CN (2009) Long-term use of statins and risk of colorectal cancer: a population-based study. Am J Gastroenterol 20 104(12):3015-3023Google Scholar
  16. 16.
    Haukka J, Sankila R, Klaukka T, Lonnqvist J, Niskanen L, Tanskanen A, Wahlbeck K, Tiihonen J (2010) Incidence of cancer and statin usage—record linkage study. Int J Cancer 126(1):279–284PubMedCrossRefGoogle Scholar
  17. 17.
    Coogan PF, Smith J, Rosenberg L (2007) Statin use and risk of colorectal cancer. J Natl Cancer Inst 99(1):32–40PubMedCrossRefGoogle Scholar
  18. 18.
    Kaye JA, Jick H (2004) Statin use and cancer risk in the General Practice Research Database. Br J Cancer 90(3):635–637PubMedCrossRefGoogle Scholar
  19. 19.
    Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF (2007) Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case–control study. Gastroenterology 133(2):393–402PubMedCrossRefGoogle Scholar
  20. 20.
    Vinogradova Y, Coupland C, Hippisley-Cox J (2011) Exposure to statins and risk of common cancers: a series of nested case–control studies. BMC Cancer 11:409PubMedCrossRefGoogle Scholar
  21. 21.
    Jacobs EJ, Newton CC, Thun MJ, Gapstur SM (2011) Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. Cancer Res 71(5):1763–1771PubMedCrossRefGoogle Scholar
  22. 22.
    Bardou M, Barkun A, Martel M (2010) Effect of statin therapy on colorectal cancer. Gut 59(11):1572–1585PubMedCrossRefGoogle Scholar
  23. 23.
    Boudreau DM, Yu O, Johnson J (2010) Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf 9(4):603–621PubMedCrossRefGoogle Scholar
  24. 24.
    Ogunwobi OO, Beales IL (2008) Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells. Am J Gastroenterol 103(4):825–837PubMedCrossRefGoogle Scholar
  25. 25.
    Hill MJ, Morson BC, Bussey HJ (1978) Aetiology of adenoma—carcinoma sequence in large bowel. Lancet 1(8058):245–247PubMedCrossRefGoogle Scholar
  26. 26.
    Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, Parkin DM, Wardle J, Duffy SW, Cuzick J (2010) Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 375(9726):1624–1633PubMedCrossRefGoogle Scholar
  27. 27.
    Wu JS, Fazio VW (2000) Colon cancer. Dis Colon Rectum 43(11):1473–1486PubMedCrossRefGoogle Scholar
  28. 28.
    Teraoka N, Mutoh M, Takasu S, Ueno T, Yamamoto M, Sugimura T, Wakabayashi K (2011) Inhibition of intestinal polyp formation by pitavastatin, a HMG-CoA reductase inhibitor. Cancer Prev Res (Phila) 4(3):445–453CrossRefGoogle Scholar
  29. 29.
    Siddiqui AA, Nazario H, Mahgoub A, Pandove S, Cipher D, Spechler SJ (2009) The long-term use of statins is associated with a decreased incidence of adenomatous colon polyps. Digestion 79(1):17–22PubMedCrossRefGoogle Scholar
  30. 30.
    Parker-Ray N, Barakat J, Roy PK, White RE, Schrader RM, Hoffman RM (2010) Statin use does not prevent recurrent adenomatous polyp formation in a VA population. Indian J Gastroenterol 29(3):106–1PubMedCrossRefGoogle Scholar
  31. 31.
    Siddiqui A, Nazario HE, Patel M, Mahgoub A, Spechler SJ (2009) Reduction in low-density lipoprotein cholesterol levels during statin therapy is associated with a reduced incidence of advanced colon polyps. Am J Med Sci 338(5):378–381PubMedCrossRefGoogle Scholar
  32. 32.
    Wei JT, Mott LA, Baron JA, Sandler RS (2005) Reported use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors was not associated with reduced recurrence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 14(4):1026–1027PubMedCrossRefGoogle Scholar
  33. 33.
    Bertagnolli MM, Hsu M, Hawk ET, Eagle CJ, Zauber AG (2010) Statin use and colorectal adenoma risk: results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila) 3(5):588–596CrossRefGoogle Scholar
  34. 34.
    Morgan C, Lunt M, Bunn D, Scott DG, Symmons DP (2007) Five-year outcome of a primary-care-based inception cohort of patients with inflammatory polyarthritis plus psoriasis. Rheumatology (Oxford) 46(12):1819–1823CrossRefGoogle Scholar
  35. 35.
    Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP et al (2010) Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 59(5):666–689PubMedCrossRefGoogle Scholar
  36. 36.
    Swamy MV, Patlolla JM, Steele VE, Kopelovich L, Reddy BS, Rao CV (2006) Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCMin mice. Cancer Res 66(14):7370–7377PubMedCrossRefGoogle Scholar
  37. 37.
    Neale RE, Doecke JD, Pandeya N, Sadeghi S, Green AC, Webb PM, Whiteman DC (2009) Does type 2 diabetes influence the risk of oesophageal adenocarcinoma? Br J Cancer 100(5):795–798PubMedCrossRefGoogle Scholar
  38. 38.
    Cerda SR, Wilkinson J 4th, Broitman SA (1995) Regulation of cholesterol synthesis in four colonic adenocarcinoma cell lines. Lipids 30(12):1083–1092PubMedCrossRefGoogle Scholar
  39. 39.
    Minoo P, Zlobec I, Peterson M, Terracciano L, Lugli A (2010) Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol 37(3):707–718PubMedCrossRefGoogle Scholar
  40. 40.
    Lee JE, Baba Y, Ng K, Giovannucci E, Fuchs C, Ogino S, Chan AT (2011) Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies. Cancer Prev Res (Phila) 4(11):1808–1815CrossRefGoogle Scholar
  41. 41.
    Lee J, Lee I, Han B, Park JO, Jang J, Park C, Kang WK (2011) Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 103(8):674–688PubMedCrossRefGoogle Scholar
  42. 42.
    Jalving M, Koornstra JJ, De Jong S, De Vries EG, Kleibeuker JH (2005) Review article: the potential of combinational regimen with non-steroidal anti-inflammatory drugs in the chemoprevention of colorectal cancer. Aliment Pharmacol Ther 21(4):321–329PubMedCrossRefGoogle Scholar
  43. 43.
    Giouleme O, Diamantidis MD, Katsaros MG (2011) Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms. World J Gastroenterol 17(4):444–448PubMedCrossRefGoogle Scholar
  44. 44.
    Chan AO, Jim MH, Lam KF, Morris JS, Siu DC, Tong T, Ng FH, Wong SY, Hui WM, Chan CK et al (2007) Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA 298(12):1412–1419PubMedCrossRefGoogle Scholar
  45. 45.
    Siddiqui A, Pena Sahdala HN, Nazario HE, Mahgoub A, Patel M, Cipher D, Spechler S (2009) Obesity is associated with an increased prevalence of advanced adenomatous colon polyps in a male veteran population. Dig Dis Sci 54(7):1560–1564PubMedCrossRefGoogle Scholar
  46. 46.
    Kitahara CM, Berrington de Gonzales A, Freedman N, Huxley R, Mok Y, Jee SH, Samet JM (2011) Total cholesterol and cancer risk in a large prospective study in Korea. J Clin Oncol 29(12):1592–1598PubMedCrossRefGoogle Scholar
  47. 47.
    Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461CrossRefGoogle Scholar
  48. 48.
    Hippisley-Cox J, Coupland C (2010) Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 340:c2197PubMedCrossRefGoogle Scholar
  49. 49.
    Yang Z, Xiao H, Jin H, Koo PT, Tsang DJ, Yang CS (2010) Synergistic actions of atorvastatin with gamma-tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int J Cancer 126(4):852–863PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Thomas Broughton
    • 3
  • Jamie Sington
    • 2
  • Ian L. P. Beales
    • 1
    • 3
  1. 1.Gastroenterology DepartmentNorfolk and Norwich University HospitalNorwichUK
  2. 2.Histopathology DepartmentNorfolk and Norwich University HospitalNorwichUK
  3. 3.Norwich Medical SchoolUniversity of East AngliaNorwichUK

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