Abstract
Whether metformin therapy affects bladder cancer risk in patients with type 2 diabetes mellitus (T2DM) has not been extensively investigated. The reimbursement databases of all Taiwanese patients with a new diagnosis of T2DM between 1998 and 2002 (n = 940,708) were retrieved from the National Health Insurance for follow-up of bladder cancer up to the end of 2009. Metformin was treated as a time-dependent variable, and of these patients, 532,519 were never-users and 408,189 were ever-users of metformin. A time-dependent approach was applied in the calculation of bladder cancer incidence and in the estimation of hazard ratios by Cox regression for ever-users, never-users, and subgroups of metformin exposure (using tertile cutoffs of cumulative duration of therapy and cumulative dose). During the study period, 1,847 (0.45 %) metformin ever-users and 6,213 (1.17 %) metformin never-users developed bladder cancer, representing an incidence of 72.03 and 189.22 per 100,000 person-years, respectively. The age-sex-adjusted and multivariable-adjusted hazard ratios (95 % confidence intervals) for ever- versus never-users were 0.382 (0.360–0.405) and 0.600 (0.564–0.638), respectively. The multivariable-adjusted hazard ratios for the first, second, and third tertiles of cumulative duration of metformin therapy were 1.034 (0.954–1.120), 0.696 (0.632–0.766), and 0.258 (0.229–0.291), respectively (P trend <0.0001). Similarly, the multivariable-adjusted hazard ratios for the first, second, and third tertiles of cumulative dose of metformin were 0.997 (0.920–1.080), 0.615 (0.559–0.677), and 0.285 (0.253–0.321), respectively (P trend <0.0001). This study suggests that metformin use is associated with a decreased risk of bladder cancer in patients with T2DM.
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References
Perseghin G, Calori G, Lattuada G, Ragogna F, Dugnani E, Garancini MP, Crosignani P, Villa M, Bosi E, Ruotolo G, Piemonti L (2012) Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol 49:421–428
Yang X, So WY, Ma RC, Kong AP, Lee HM, Xu G, Ozaki R, Chan JC (2012) Synergistic effects of low LDL cholesterol with other factors for the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. Acta Diabetol 49(Suppl 1):S185–S193
Zhang F, Yang Y, Skrip L, Hu D, Wang Y, Wong C, Qiu J, Lei H (2012) Diabetes mellitus and risk of prostate cancer: an updated meta-analysis based on 12 case–control and 25 cohort studies. Acta Diabetol 49(Suppl 1):S235–S246
Onishi S, Takemoto M, Ishikawa T, Okabe E, Ishibashi R, He P, Kobayashi K, Fujimoto M, Kawamura H, Yokote K (2012) Japanese diabetic patients with Werner syndrome exhibit high incidence of cancer. Acta Diabetol 49(Suppl 1):S259–S260
Lauper JM, Monnat RJ Jr. (2013) Diabetes mellitus and cancer in Werner syndrome. Acta Diabetol. doi:10.1007/s00592-013-0456-z
Monami M, Dicembrini I, Mannucci E (2013) Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials. Acta Diabetol. doi:10.1007/s00592-013-0504-8
Tseng CH (2013) Diabetes, insulin use, smoking, and pancreatic cancer mortality in Taiwan. Acta Diabetol 50:879–886
Noto H, Tsujimoto T, Sasazuki T, Noda M (2011) Significantly increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Endocr Pract 17:616–628
Tseng CH (2011) Diabetes and risk of prostate cancer: a study using the National Health Insurance. Diabetes Care 34:616–621
Tseng CH (2011) Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia 54:2009–2015
Zhu Z, Zhang X, Shen Z, Zhong S, Wang X, Lu Y, Xu C (2013) Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. PLoS ONE 8:e56662
Zhu Z, Wang X, Shen Z, Lu Y, Zhong S, Xu C (2013) Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies. BMC Cancer 13:310
Jacobs BL, Lee CT, Montie JE (2010) Bladder cancer in 2010: how far have we come? CA Cancer J Clin 60:244–272
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Talaska G (2003) Aromatic amines and human urinary bladder cancer: exposure sources and epidemiology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 21:29–43
Tseng CH (2013) Benign prostatic hyperplasia is a significant risk factor for bladder cancer in diabetic patients: a population-based cohort study using the National Health Insurance in Taiwan. BMC Cancer 13:7
Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, Vaughn DJ, Nessel L, Selby J, Strom BL (2011) Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 34:916–922
Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H (2012) Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia 55:1953–1962
Tseng CH (2012) Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care 35:278–280
Tseng CH (2013) Insulin use and smoking jointly increase the risk of bladder cancer mortality in patients with type 2 diabetes. Clin Genitourin Cancer 11:508–514
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:854–865
Tseng CH (2012) Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol 167:409–416
Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, La Vecchia C, Mancia G, Corrao G (2012) Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 17:813–822
Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, Kip KE (2011) Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 34:2323–2328
Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT (2012) Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 135:639–646
Chlebowski RT, McTiernan A, Wactawski-Wende J, Manson JE, Aragaki AK, Rohan T, Ipp E, Kaklamani VG, Vitolins M, Wallace R, Gunter M, Phillips LS, Strickler H, Margolis K, Euhus DM (2012) Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol 30:2844–2852
Lehman DM, Lorenzo C, Hernandez J, Wang CP (2012) Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients. Diabetes Care 35:1002–1007
Hitron A, Adams V, Talbert J, Steinke D (2012) The influence of antidiabetic medications on the development and progression of prostate cancer. Cancer Epidemiol 36:e243–e250
Lin HC, Kachingwe BH, Lin HL, Cheng HW, Uang YS, Wang LH (2014) Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study. Pharmacotherapy 34:36–45
Hsieh MC, Lee TC, Cheng SM, Tu ST, Yen MH, Tseng CH (2012) The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res 2012:413782
Lai SW, Liao KF, Chen PC, Tsai PY, Hsieh DP, Chen CC (2012) Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin Lung Cancer 13:143–148
Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC (2011) 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 11:20
Chen HP, Shieh JJ, Chang CC, Chen TT, Lin JT, Wu MS, Lin JH, Wu CY (2013) Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 62:606–615
Noto H, Goto A, Tsujimoto T, Noda M (2012) Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE 7:e33411
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ, for the RECORD Study Team (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G, ADOPT Study Group, RECORD Steering Committee (2010) Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (a diabetes outcome progression trial) and RECORD (Rosiglitazone evaluated for cardiovascular outcomes and regulation of glycaemia in diabetes) clinical trials. Diabetologia 53:1838–1845
Johnson JA, Carstensen B, Witte D, Bowker SL, Lipscombe L, Renehan AG, Diabetes and Cancer Research Consortium (2012) Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia 55:1607–1618
Yang X, So WY, Ma RC, Yu LW, Ko GT, Kong AP, Ng VW, Luk AO, Ozaki R, Tong PC, Chow CC, Chan JC (2010) Use of sulphonylurea and cancer in type 2 diabetes—the Hong Kong Diabetes Registry. Diabetes Res Clin Pract 90:343–351
Kourelis TV, Siegel RD (2012) Metformin and cancer: new applications for an old drug. Med Oncol 29:1314–1327
Gallagher EJ, LeRoith D (2011) Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann NY Acad Sci 1243:54–68
Aljada A, Mousa SA (2012) Metformin and neoplasia: implications and indications. Pharmacol Ther 133:108–115
Zheng QY, Jin FS, Yao C, Zhang T, Zhang GH, Ai X (2012) Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells. Biochem Biophys Res Commun 419:741–747
Liu Z, Li X, Simoneau AR, Jafari M, Zi X (2012) Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog 51:257–267
Genua M, Xu SQ, Buraschi S, Peiper SC, Gomella LG, Belfiore A, Iozzo RV, Morrione A (2012) Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells. PLoS ONE 7:e40148
Szarvas T, vom Dorp F, Niedworok C, Melchior-Becker A, Fischer JW, Singer BB, Reis H, Bánkfalvi Á, Schmid KW, Romics I, Ergün S, Rübben H (2012) High insulin-like growth factor mRNA-binding protein 3 (IMP3) protein expression is associated with poor survival in muscle-invasive bladder cancer. BJU Int 110:E308–E317
Hursting SD, Perkins SN, Lavigne JA, Beltran L, Haines DC, Hill HL, Alvord WG, Barrett JC, DiGiovanni J (2009) Urothelial overexpression of insulin-like growth factor-1 increases susceptibility to p-cresidine-induced bladder carcinogenesis in transgenic mice. Mol Carcinog 48:671–677
Tseng CH, Tseng FH (2012) Peroxisome proliferator-activated receptor agonists and bladder cancer: lessons from animal studies. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30:368–402
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR (2012) Management of hyperglycemia in type 2 diabetes: a Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35:1364–1379
Tseng CH (2013) Rosiglitazone is not associated with an increased risk of bladder cancer. Cancer Epidemiol 37:385–389
Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158:915–920
Gerhard T (2008) Bias: considerations for research practice. Am J Health Syst Pharm 65:2159–2168
Yang XL, Ma RC, So WY, Kong AP, Xu G, Chan JC (2012) Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings-what, why and how? Diabetes Obes Metab 14:579–585
Tseng CH (2012) Pioglitazone and bladder cancer in human studies: is it diabetes itself, diabetes drugs, flawed analyses or different ethnicities? J Formos Med Assoc 111:123–131
Monen SH, Schmidt PH, Wondergem R (1998) Membrane potassium channels and human bladder tumor cells. I. Electrical properties. J Membr Biol 161:247–256
Oger S, Behr-Roussel D, Gorny D, Bernabé J, Comperat E, Chartier-Kastler E, Denys P, Giuliano F (2011) Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients. BJU Int 108:604–611
Wondergem R, Cregan M, Strickler L, Miller R, Suttles J (1998) Membrane potassium channels and human bladder tumor cells: II. Growth properties. J Membr Biol 161:257–262
Acknowledgments
The study was supported by the National Science Council (NSC102-2314-B-002-067) of Taiwan. It is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes (Registered number 99274). The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes. The excellent help in statistical analyses by Ting–Ting Chang was highly appreciated.
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The study was conducted according to local regulations.
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The identification information of the persons has been scrambled and handled by the National Health Research Institutes. No indentifying details are available in the databases provided for statistical analyses and personal information is not shown in the manuscript.
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Communicated by Massimo Porta.
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Tseng, CH. Metformin may reduce bladder cancer risk in Taiwanese patients with type 2 diabetes. Acta Diabetol 51, 295–303 (2014). https://doi.org/10.1007/s00592-014-0562-6
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DOI: https://doi.org/10.1007/s00592-014-0562-6