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Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis

      Highlights

      • This meta-analysis studied the effect of metformin on colon neoplasia in diabetes.
      • Medical literature searches were performed using suitable keywords.
      • The risk of neoplasia was significantly lower among metformin users than controls.
      • The observation applied separately for colon cancer and polyps.

      Abstract

      Background

      A growing body of evidence has suggested that metformin potentially reduces the risk of cancer.

      Objective

      We performed a meta-analysis of available studies to better define the effect of metformin on colon neoplasia (cancer and polyps) in patients with type 2 diabetes.

      Methods

      Medical literature searches for human studies were performed through December 2015, using suitable keywords. Pooled estimates were obtained using fixed or random-effects models. Heterogeneity between studies was evaluated with the Cochran Q test whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the Begg and Mazumdar adjusted rank correlation test and by the Egger's regression test. In addition subgroup and sensitivity analyses were performed.

      Results

      A total number of 709,980 patients, with type 2 diabetes, were included in 17 studies eligible for meta-analysis [1 RCT and 16 observational studies (13 cohort and 3 case–controls)]. The risk of colon neoplasia was significantly lower among metformin users than controls (non-metformin users) [pooled RRs (95% CI) = 0.75 (0.65–0.87), test for overall effect Z = −3.95, p < 0.001]. This observation applied separately for colon cancer [0.79 (0.69–0.91), Z = −3.34, p < 0.001] and for colon polyps [0.58 (0.42–0.80), Z = −3.30, p < 0.001].

      Conclusion

      This meta-analysis shows that the use of metformin in patients with type 2 diabetes is associated with significantly lower risk of colon neoplasia.

      Abbreviations:

      OR (odds ratio), CI (confidence interval), RR (relative risk), CRC (colorectal cancer), NSAIDs (Non-steroidal anti-inflammatory drugs), AMPK (AMP activated protein kinase), LKB1 (liver kinase B1), RCT (randomized control trial)

      Keywords

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      References

        • Jemal A.
        • Bray F.
        • Center M.M.
        • et al.
        Global cancer statistics.
        CA Cancer J Clin. 2011; 61: 69-90
        • Anderson W.F.
        • Umar A.
        • Brawley O.W.
        Colorectal carcinoma in black and white race.
        Cancer Metastasis Rev. 2003; 22: 67-82
        • Das D.
        • Arber N.
        • Jankowski J.A.
        Chemoprevention of colorectal cancer.
        Digestion. 2007; 76: 51-67
        • Citarda F.
        • Tomaselli G.
        • Capocaccia R.
        • et al.
        Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence.
        Gut. 2001; 48: 812-815
        • Drazen J.M.
        COX-2 inhibitors–a lesson in unexpected problems.
        N Engl J Med. 2005; 352: 1131-1132
        • Meyskens Jr., F.L.
        • McLaren C.E.
        • Pelot D.
        • et al.
        Difluoromethylornithine plus sulindac for the prevention of sporadiccolorectal adenomas: a randomized placebo-controlled, double-blindtrial.
        Cancer Prev Res (Phila). 2008; 1: 32-38
        • Limburg P.J.
        • Vierkant R.A.
        • Fredericksen Z.S.
        • et al.
        Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study.
        Am J Gastroenterol. 2006; 101: 1872-1879
        • Larsson S.C.
        • Orsini N.
        • Wolk A.
        Diabetes mellitus and risk of colorectal cancer: a meta-analysis.
        J Natl Cancer Inst. 2005; 97: 1679-1687
        • Frezza E.E.
        • Wachtel M.S.
        • Chiriva-Internati M.
        Influence of obesity on the risk of developing colon cancer.
        Gut. 2006; 55: 285-291
        • Bhaskaran K.
        • Douglas I.
        • Forbes H.
        • et al.
        Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults.
        Lancet. 2014; 384: 755-765
        • Nathan D.M.
        • Buse J.B.
        • Davidson M.B.
        • et al.
        Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetologia. 2009; 52: 17-30
        • Cusi K.
        • DeFronzo R.A.
        Metformin: a review of its metabolic effects.
        Diabetes Rev. 1998; 6: 89-131
        • Papanas N.
        • Maltezos E.
        • Mikhailidis D.P.
        Metformin: diamonds are forever.
        Expert Opin Pharmacother. 2009; 10: 2395-2397
        • Nestler J.E.
        Metformin for the treatment of the polycystic ovary syndrome.
        N Engl J Med. 2008; 358: 47-54
        • Goodwin P.J.
        • Ligibel J.A.
        • Stambolic V.
        Metformin in breast cancer: time for action.
        J Clin Oncol. 2009; 27: 3271-3273
        • Li D.
        • Yeung S.C.
        • Hassan M.M.
        • Konopleva M.
        • Abbruzzese J.L.
        Antidiabetic therapies affect risk of pancreatic cancer.
        Gastroenterology. 2009; 137: 482-488
        • Bodmer M.
        • Meier C.
        • Krahenbuhl S.
        • Jick S.S.
        • Meier C.R.
        Long-term metformin use is associated with decreased risk of breast cancer.
        Diabetes Care. 2010; 33: 1304-1308
        • DeCensi A.
        • Puntoni M.
        • Goodwin P.
        • et al.
        Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis.
        Cancer Prev Res. 2010; 3: 1451-1461
        • Zhang Z.J.
        • Zheng Z.J.
        • Kan H.
        • Song Y.
        • Cui W.
        • Zhao G.
        • et al.
        Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes.
        Diabetes Care. 2011; 34: 2323-2328
        • Noto H.
        • Goto A.
        • Tsujimoto T.
        • Noda M.
        Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis.
        PLoS One. 2012; 7e33411
        • Luo J.
        • Beresford S.
        • Chen C.
        • Chlebowski R.
        • Garcia L.
        • Kuller L.
        • et al.
        Association between diabetes, diabetes treatment and risk of developing endometrial cancer.
        Br J Cancer. 2014; 111: 1432-1439
        • Wu G.F.
        • Zhang X.L.
        • Luo Z.G.
        • Yan J.J.
        • Pan S.H.
        • Ying X.R.
        • et al.
        Metformin therapy and prostate cancer risk: a meta-analysis of observational studies.
        Int J Clin Exp Med. 2015; 8: 13089-13098
        • Higgins J.P.T.
        • Green S.
        Cochrane handbook for systematic reviews of interventions, version 5.1.0 [updated March 2011]. The Cochrane collaboration.
        Date: 2011
        ([Available: http://www.cochrane-handbook.org])
        • Mantel N.
        • Haenszel W.
        Statistical aspects of the analysis of data from retrospective studies of disease.
        J Natl Cancer Inst. 1959; 22: 719-748
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Cochran W.G.
        The combination of estimates from different experiments.
        Biometrics. 1954; 8: 101-129
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Sutton A.J.
        • Abrams K.R.
        • Jones D.R.
        • et al.
        In: Methods for meta-analysis in medical research.
        John Wiley & Sons, Ltd, New York2000
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        Measuring inconsistency in meta-analysis.
        BMJ. 2003; 327: 557-560
      1. Borenstein M, Hedges LV, Higgins JPT, et al. Introduction to meta-analysis. New York: John Wiley & Sons Ltd; ….

        • Copas J.B.
        • Shi J.Q.
        A sensitivity analysis for publication bias in systematic reviews.
        Stat Methods Med Res. 2001; 10: 251-265
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • et al.
        Bias in meta-analysis detected by a simple graphical test.
        BMJ. 1997; 315: 29-34
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel plot- based method of testing and in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Yang Y.X.
        • Hennessy S.
        • Lewis J.D.
        Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients.
        Gastroenterology. 2004; 127: 1044-1050
        • Oliveria S.
        • Koro C.E.
        • Yood M.U.
        • Sowell M.
        Cancer incidence among patients treated with antidiabetic pharmacotherapy.
        Diabetes Metab Syndr Clin Res Rev. 2008; 2: 47-57
        • Currie C.J.
        • Poole C.D.
        • Gale E.A.
        The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.
        Diabetologia. 2009; 52: 1766-1777
        • Libby G.
        • Donnelly L.A.
        • Donnan P.T.
        • Alessi D.R.
        • Morris A.D.
        • Evans J.M.
        New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes.
        Diabetes Care. 2009; 32: 1620-1625
        • Home P.D.
        • Kahn S.E.
        • Jones N.P.
        • Noronha D.
        • Beck-Nielsen H.
        • Viberti G.
        Experience of malignancies with oral glucose-lowering drugs in the randomized 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: 1838-1845
        • Lee M.S.
        • Hsu C.C.
        • Wahlqvist M.L.
        • Tsai H.N.
        • Chang Y.H.
        • Huang Y.C.
        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
        • Morden N.E.
        • Liu S.K.
        • Smith J.
        • Mackenzie T.A.
        • Skinner J.
        • Korc M.
        Further exploration of the relationship between insulin glargine and incident cancer.
        Diabetes Care. 2011; 34: 1965-1971
        • Bodmer M.
        • Becker C.
        • Meier C.
        • Jick S.S.
        • Meier C.R.
        Use of metformin is not associated with a decreased risk of colorectal cancer: a case–control analysis.
        Cancer Epidemiol Biomarkers Prev. 2011; 21: 280-286
        • Hsieh M.C.
        • Lee T.C.
        • Cheng S.M.
        • Tu S.T.
        • Yen M.H.
        • Tseng C.H.
        The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese.
        Exp Diabetes Res. 2012; 2012: 413782
        • Ruiter R.
        • Visser L.E.
        • Van Herk-Sukel M.
        • Coebergh J.W.W.
        • Haak H.R.
        • Geelhoed-Duijvestijn P.H.
        • et al.
        Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives.
        Diabetes Care. 2012; 35: 119-124
        • Kanadiya M.K.
        • Gohel T.D.
        • Sanaka M.R.
        • Thota P.N.
        • Shubrook Jr., J.H.
        Relationship between type-2 diabetes and use of metformin with risk of colorectal adenoma in an American population receiving colonoscopy.
        J Diabetes Complications. 2013; 5: 463-466
        • Smiechowski B.
        • Azoulay L.
        • Yin H.
        • Pollak M.N.
        • Suissa S.
        The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus.
        Cancer Epidemiol Biomarkers Prev. 2013; 22: 1877-1883
        • Wang S.Y.
        • Chuang C.S.
        • Muo C.H.
        • Tu S.T.
        • Lin M.C.
        • Sung F.C.
        • et al.
        Metformin and the incidence of cancer in patients with diabetes: a nested case–control study.
        Diabetes Care. 2013; 36: e155-e156
        • Tsilidis K.K.
        • Capothanassi D.
        • Allen N.E.
        • Rizos E.C.
        • Lopez D.S.
        • van Veldhoven K.
        • et al.
        Metformin does not affect cancer risk: a cohort study in the U.K. clinical practice research datalink analyzed like an intention-to-treat trial.
        Diabetes Care. 2014; 37: 2522-2532
        • Cho Y.H.
        • Ko B.M.
        • Kim S.H.
        • Myung Y.S.
        • Cho J.H.
        • Han J.P.
        • et al.
        Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus?.
        Int Rescuer. 2014; 12: 139-145
        • Chen Y.C.
        • Kok V.C.
        • Chien C.H.
        • Horng J.T.
        • Tsai J.J.P.
        Cancer risk in patients aged 30 years and above with type 2 diabetes receiving antidiabetic monotherapy: a cohort study using metformin as the comparator.
        Ther Clin Risk Manag. 2015; 11: 1315-1323
        • Kim Y.H.
        • Noh R.
        • Cho S.Y.
        • Park S.J.
        • Jeon S.M.
        • Shin H.D.
        • et al.
        Inhibitory effect of metformin therapy on the incidence of colorectal advanced adenomas in patients with diabetes.
        Int Rescuer. 2015; 13: 145-152
        • Zhang Z.Z.
        • Zheng Z.J.
        • Kan H.
        • Song Y.
        • Cui W.
        • Zhao G.
        • et al.
        Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes.
        Diabetes Care. 2011; 34: 2323-2328
        • Franciosi M.
        • Lucisano G.
        • Lapice E.
        • Strippoli G.F.M.
        • Pellegrini F.
        • Nicolucci A.
        • et al.
        Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review.
        PLoS One. 2013; 8e71583
        • Singh S.
        • Singh H.
        • Singh P.P.
        • Murad H.
        • Limburg P.J.
        Antidiabetic medications and the risk of colorectal cancer in patients with diabetes mellitus: a systematic review and meta-analysis.
        Cancer Epidemiol Biomarkers Prev. 2013; 22: 2258-2268
        • Gandini S.
        • Puntoni M.
        • Heckman-Stoddard B.M.
        • Dunn B.K.
        • Ford L.
        • DeCensi A.
        • et al.
        Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.
        Cancer Prev Res. 2014; 7: 867-885
        • Lega I.C.
        • Shah P.S.
        • Margel D.
        • Beyene J.
        • Rochon P.A.
        • Lipscombe L.L.
        The effect of metformin on mortality following cancer among patients with diabetes.
        Cancer Epidemiol Biomarkers Prev. 2014; 23: 1974-1984
        • Zakikhani M.
        • Dowling R.J.
        • Sonenberg N.
        • Pollak M.N.
        The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase.
        Cancer Prev Res. 2008; 1: 369-375
        • Buzzai M.
        • Jones R.G.
        • Amaravadi R.K.
        • et al.
        Systemic treatment with the antidiabetic drug metformin selectively impairs p53- deficient tumor cell growth.
        Cancer Res. 2007; 67: 6745-6752
        • Algire C.
        • Amrein L.
        • Zakikhani M.
        • Panasci L.
        • Pollak M.
        Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase.
        Endocr Relat Cancer. 2010; 17: 351-360
        • Hosono K.
        • Endo H.
        • Takahashi H.
        • Sugiyama M.
        • Uchiyama T.
        • Suzuki K.
        • et al.
        Metformin suppresses azoxymethaneinduced colorectal aberrant crypt foci by activating AMP-activated protein kinase.
        Mol Carcinog. 2010; 49: 662-671
        • 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: 2136-2141
        • 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. 2010; 3: 1077-1083
        • Alessi D.R.
        • Sakamoto K.
        • Bayascas J.R.
        LKB1-dependent signaling pathways.
        Annu Rev Biochem. 2006; 75: 137-163
        • Zhou G.
        • Myers R.
        • Li Y.
        • Chen Y.
        • Shen X.
        • Fenyk-Melody J.
        • et al.
        Role of AMP activated protein kinase in mechanism of metformin action.
        J Clin Invest. 2001; 108: 1167-1174
        • Dong S.M.
        • Kim K.M.
        • Kim S.Y.
        • Shin M.S.
        • Na E.Y.
        • Lee S.H.
        • et al.
        Frequent somatic mutations in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer.
        Cancer Res. 1998; 58: 3787-3790
        • Park W.S.
        • Moon Y.W.
        • Yang Y.M.
        • Kim Y.S.
        • Kim Y.D.
        • Fuller B.G.
        • et al.
        Mutations of the STK11 gene in sporadic gastric carcinoma.
        Int J Oncol. 1998; 13: 601-604
        • Inoki K.
        • Guan K.-L.
        Complexity of the TOR signalling network.
        Trends Cell Biol. 2006; 16: 206-212
        • Yang Y.X.
        Do diabetes drugs modify the risk of pancreatic cancer?.
        Gastroenterology. 2009; 137: 412-415
        • Sandhu M.S.
        • Dunger D.B.
        • Giovannucci E.L.
        Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer.
        J Natl Cancer Inst. 2002; 94: 972-980
        • LeRoith D.
        • Baserga R.
        • Helman L.
        • Roberts Jr., C.T.
        Insulin-like growth factors and cancer.
        Ann Intern Med. 1995; 122: 54-59
        • Renehan A.G.
        • Tyson M.
        • Egger M.
        • Heller R.F.
        • Zwahlen M.
        Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.
        Lancet. 2008; 371: 569-578
        • Grenader T.
        • Goldberg A.
        • Shavit L.
        Metformin as an addition to conventional chemotherapy in breast cancer.
        J Clin Oncol. 2009; 35e259
        • Zhuang Y.
        • Miskimins W.K.
        Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1.
        J Mol Signal. 2008; 3: 18
        • Hirsch H.A.
        • Iliopoulos D.
        • Tsichlis P.N.
        • Struhl K.
        Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission.
        Cancer Res. 2009; 69: 7507-7511