Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? (original) (raw)

• Tuffier, T. Diabete et neoplasmes. Archives generales de medecine 7, 129–140 (1888).
  Google Scholar
• Bapat, S. P. et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528, 137–141 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Langenberg, C. et al. Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study. PLoS Med. 9, e1001230 (2012).
  Article PubMed Google Scholar
• Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).
  Article PubMed PubMed Central Google Scholar
• Singh, G. M. et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PLoS ONE 8, e65174 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Berrington de Gonzalez, A. et al. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 363, 2211–2219 (2010).
  Article CAS PubMed Google Scholar
• [no authors listed]. Diabetes Fact Sheet. WHO http://www.who.int/mediacentre/factsheets/fs312/en/ (2015).
• Di Angelantonio, E. et al. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 52–60 (2015).
  Article CAS PubMed Google Scholar
• Murray, C. J. et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet http://dx.doi.org/10.1016/s0140-6736(15)61340-x (2015).
• Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).
  Article PubMed Google Scholar
• Guariguata, L. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract. 103, 137–149 (2014).
  Article CAS PubMed Google Scholar
• Ogden, C. L., Carroll, M. D., Fryar, C. D. & Flegal, K. M. Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS Data Brief 1–8 (2015).
• Youlden, D. R. et al. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 36, 237–248 (2012).
  Article PubMed Google Scholar
• Arnold, M. et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 36–46 (2015).
  Article PubMed Google Scholar
• Wells, J. C., Coward, W. A., Cole, T. J. & Davies, P. S. The contribution of fat and fat-free tissue to body mass index in contemporary children and the reference child. Int. J. Obes Relat. Metab. Disord. 26, 1323–1328 (2002).
  Article CAS PubMed Google Scholar
• Kaaks, R. & Kühn, T. Epidemiology: obesity and cancer — the evidence is fattening up. Nat. Rev. Endocrinol. 10, 644–645 (2014).
  Article PubMed Google Scholar
• Keum, N. et al. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. J. Natl Cancer Inst. 107, http://dx.doi.org/10.1093/jnci/djv088 (2015).
• 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 371, 569–578 (2008).
  Article PubMed Google Scholar
• World Cancer Research Fund and the American Institute for Cancer Research. Continuous update project report: diet, nutrition, physical activity and liver cancer. http://wcrf.org/sites/default/files/Liver-Cancer-2015-Report.pdf (2015).
• World Cancer Research Fund and the American Institute for Cancer Research. Continuous update project report. Food, nutrition, physical activity, and the prevention of breast cancer. http://wcrf.org/sites/default/files/Breast-Cancer-2010-Report.pdf (2015).
• World Cancer Research Fund and the American Institute for Cancer Research. Continuous update project report: diet, nutrition, physical activity, and prostate cancer. http://wcrf.org/sites/default/files/Prostate-Cancer-2014-Report.pdf (2015).
• Lerro, C. C., McGlynn, K. A. & Cook, M. B. A systematic review and meta-analysis of the relationship between body size and testicular cancer. Br. J. Cancer 103, 1467–1474 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Y. et al. Obesity and incidence of lung cancer: a meta-analysis. Int. J. Cancer 132, 1162–1169 (2013).
  Article CAS PubMed Google Scholar
• Song, M. et al. Trajectory of body shape across the lifespan and cancer risk. Int. J. Cancer http://dx.doi.org/10.1002/ijc.29981 (2015).
• Neuhouser, M. L. et al. Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the women's health initiative randomized clinical trials. JAMA Oncol. 1, 611–621 (2015).
  Article PubMed PubMed Central Google Scholar
• Reeves, G. K. et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335, 1134 (2007).
  Article PubMed PubMed Central Google Scholar
• Adams, T. D. et al. Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357, 753–761 (2007).
  Article CAS PubMed Google Scholar
• Sjostrom, L. et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 10, 653–662 (2009).
  Article PubMed Google Scholar
• Douglas, I. J., Bhaskaran, K., Batterham, R. L. & Smeeth, L. Bariatric surgery in the United Kingdom: a cohort study of weight loss and clinical outcomes in routine clinical care. PLoS Med. 12, e1001925 (2015).
  Article PubMed PubMed Central Google Scholar
• Eliassen, A. H., Colditz, G. A., Rosner, B., Willett, W. C. & Hankinson, S. E. Adult weight change and risk of postmenopausal breast cancer. JAMA 296, 193–201 (2006).
  Article CAS PubMed Google Scholar
• Parker, E. D. & Folsom, A. R. Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's Health Study. Int. J. Obes Relat. Metab. Disord. 27, 1447–1452 (2003).
  Article CAS PubMed Google Scholar
• Tsilidis, K. K., Kasimis, J. C., Lopez, D. S., Ntzani, E. E. & Ioannidis, J. P. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350, g7607 (2015).
  Article PubMed Google Scholar
• Carstensen, B., Witte, D. R. & Friis, S. Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia 55, 948–958 (2012).
  Article CAS PubMed Google Scholar
• Geier, A. S. et al. Cancer detection rates following enrolment in a disease management programme for type 2 diabetes. Diabetologia 56, 1944–1948 (2013).
  Article CAS PubMed Google Scholar
• Bansal, D., Bhansali, A., Kapil, G., Undela, K. & Tiwari, P. Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. Prostate Cancer Prostat. Dis. 16, 151–158 (2013).
  Article CAS Google Scholar
• Tseng, C. H. Diabetes and risk of prostate cancer: a study using the National Health Insurance. Diabetes Care 34, 616–621 (2011).
  Article PubMed PubMed Central Google Scholar
• Dhindsa, S. et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 5462–5468 (2004).
  Article CAS PubMed Google Scholar
• Freedland, S. J. & Aronson, W. J. Obesity and prostate cancer. Urology 65, 433–439 (2005).
  Article PubMed Google Scholar
• Ma, J. et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 9, 1039–1047 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Gandini, S. et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev. Res. (Phila.) 7, 867–885 (2014).
  Article CAS Google Scholar
• Wu, L., Zhu, J., Prokop, L. J. & Murad, M. H. Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies. Sci. Rep. 5, 10147 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005).
  Article PubMed PubMed Central Google Scholar
• Colhoun, H. M. & Group, S. E. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52, 1755–1765 (2009).
  Article PubMed PubMed Central Google Scholar
• Bronsveld, H. K. et al. Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence. Breast Cancer Res. 17, 100 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Kowall, B., Stang, A., Rathmann, W. & Kostev, K. No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol. Drug Saf. 24, 865–874 (2015).
  Article CAS PubMed Google Scholar
• Suissa, S. & Azoulay, L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35, 2665–2673 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Pocock, S. J. & Smeeth, L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 374, 511–513 (2009).
  Article PubMed Google Scholar
• Garber, A. J. et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr. Pract. 21, 438–447 (2015).
  Article PubMed Google Scholar
• Pollak, M. Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat. Med. 20, 591–593 (2014).
  Article CAS PubMed Google Scholar
• Pollak, M. N. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2, 778–790 (2012).
  Article CAS PubMed Google Scholar
• Decensi, A. et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.) 3, 1451–1461 (2010).
  Article CAS Google Scholar
• Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Noto, H., Goto, A., Tsujimoto, T. & Noda, M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE 7, e33411 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mamtani, R. et al. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Diabetes Care 37, 1910–1917 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Tsilidis, K. K. et al. Metformin does not affect cancer risk: a cohort study in the UK Clinical Practice Research Datalink analyzed like an intention-to-treat trial. Diabetes Care 37, 2522–2532 (2014).
  Article CAS PubMed Google Scholar
• Higurashi, T. et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. http://dx.doi.org/10.1016/s1470-2045(15)00565-3 (2016).
• Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).
  Article CAS PubMed Google Scholar
• Hemkens, L. G. et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52, 1732–1744 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jonasson, J. M. et al. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52, 1745–1754 (2009).
  Article CAS PubMed Google Scholar
• Mayer, D., Shukla, A. & Enzmann, H. Proliferative effects of insulin analogues on mammary epithelial cells. Arch. Physiol. Biochem. 114, 38–44 (2008).
  Article CAS PubMed Google Scholar
• Wu, J. W., Filion, K. B., Azoulay, L., Doll, M. K. & Suissa, S. The effect of long-acting insulin analogs on the risk of cancer: a systematic review of observational studies. Diabetes Care http://dx.doi.org/10.2337/dc15-1816 (2016).
• Proks, P., Reimann, F., Green, N., Gribble, F. & Ashcroft, F. Sulfonylurea stimulation of insulin secretion. Diabetes 51 (Suppl. 3), S368–S376 (2002).
  Article CAS PubMed Google Scholar
• Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).
  Article CAS PubMed Google Scholar
• Chang, C. H., Lin, J. W., Wu, L. C., Lai, M. S. & Chuang, L. M. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 97, E1170–1175 (2012).
  Article CAS PubMed Google Scholar
• Kowall, B., Rathmann, W. & Kostev, K. Are sulfonylurea and insulin therapies associated with a larger risk of cancer than metformin therapy? A retrospective database analysis. Diabetes Care 38, 59–65 (2015).
  Article CAS PubMed Google Scholar
• Tuccori, M., Wu, J. W., Yin, H., Majdan, A. & Azoulay, L. The use of glyburide compared with other sulfonylureas and the risk of cancer in patients with type 2 diabetes. Diabetes Care 38, 2083–2089 (2015).
  Article CAS PubMed Google Scholar
• Loke, Y. K. & Mattishent, K. Bladder cancer: pioglitazone—when is a prescription drug safe? Nat. Rev. Urol. 12, 655–656 (2015).
  Article CAS PubMed Google Scholar
• Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005).
  Article CAS PubMed Google Scholar
• Lewis, J. D. et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 34, 916–922 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Azoulay, L. et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 344, e3645 (2012).
  Article PubMed PubMed Central Google Scholar
• U.S. Food and Drug Administration. FDA Drug Safety Communication: update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm (2012).
• Levin, D. et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 58, 493–504 (2015).
  Article CAS PubMed Google Scholar
• Lewis, J. D. et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 314, 265–277 (2015).
  Article CAS PubMed Google Scholar
• Faillie, J. L. & Hillaire-Buys, D. Examples of how the pharmaceutical industries distort the evidence of drug safety: the case of pioglitazone and the bladder cancer issue. Pharmacoepidemiol. Drug Saf. http://dx.doi.org/10.1002/pds.3925 (2015).
• Tuccori, M. et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 352, i1541 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Elashoff, M., Matveyenko, A. V., Gier, B., Elashoff, R. & Butler, P. C. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 141, 150–156 (2011).
  Article CAS PubMed Google Scholar
• Raschi, E., Piccinni, C., Poluzzi, E., Marchesini, G. & De Ponti, F. The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database. Acta Diabetol. 50, 569–577 (2013).
  Article CAS PubMed Google Scholar
• Azoulay, L. Incretin-based drugs and adverse pancreatic events: almost a decade later and uncertainty remains. Diabetes Care 38, 951–953 (2015).
  Article PubMed Google Scholar
• Gokhale, M. et al. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes, Obes. Metabolism 16, 1247–1256 (2014).
  Article CAS Google Scholar
• Tseng, C. H. Sitagliptin and pancreatic cancer risk in patients with type 2 diabetes. Eur. J. Clin. Invest. 46, 70–79 (2016).
  Article CAS PubMed Google Scholar
• Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232–242 (2015).
  Article CAS PubMed Google Scholar
• Egan, A. G. et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N. Engl. J. Med. 370, 794–797 (2014).
  Article CAS PubMed Google Scholar
• Waser, B., Beetschen, K., Pellegata, N. S. & Reubi, J. C. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 94, 291–301 (2011).
  Article CAS PubMed Google Scholar
• Rosol, T. J. On-target effects of GLP-1 receptor agonists on thyroid C-cells in rats and mice. Toxicol. Pathol. 41, 303–309 (2013).
  Article CAS PubMed Google Scholar
• Drab, S. R. Glucagon-like peptide-1 receptor agonists for type 2 diabetes: a clinical update of safety and efficacy. Curr. Diabetes Rev. http://dx.doi.org/10.2174/1573399812666151223093841 (2015).
• Koehler, J. A. et al. GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell. Metab. 21, 379–391 (2015).
  Article CAS PubMed Google Scholar
• Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754–762 (2014).
  Article CAS PubMed Google Scholar
• Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N. Engl. J. Med. 348, 1625–1638 (2003).
  Article PubMed Google Scholar
• Calle, E. E. & Terrell, D. D. Utility of the National Death Index for ascertainment of mortality among cancer prevention study II participants. Am. J. Epidemiol. 137, 235–241 (1993).
  Article CAS PubMed Google Scholar
• Chan, D. S. et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann. Oncol. 25, 1901–1914 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Copson, E. R. et al. Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann. Oncol. 26, 101–112 (2015).
  Article CAS PubMed Google Scholar
• Playdon, M. C. et al. weight gain after breast cancer diagnosis and all-cause mortality: systematic review and meta-analysis. J. Natl Cancer Inst. 107, djv275 (2015).
  Article PubMed PubMed Central Google Scholar
• Pettersson, A. et al. Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG. J. Natl Cancer Inst. 105, 1881–1890 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Goodwin, P. J. et al. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial. J. Clin. Oncol. 32, 2231–2239 (2014).
  Article PubMed Google Scholar
• Rossi, E. L. et al. Obesity-associated alterations in inflammation, epigenetics, and mammary tumor growth persist in formerly obese mice. Cancer Prev. Res. (Phila.) 9, 339–348 (2016).
  Article CAS Google Scholar
• Widschwendter, P. et al. The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial. Breast Cancer Res. 17, 129 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Nagle, C. M. et al. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium. Br. J. Cancer 113, 817–826 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Hakimi, A. A. et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J. Natl Cancer Inst. 105, 1862–1870 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Lavie, C. J., McAuley, P. A., Church, T. S., Milani, R. V. & Blair, S. N. Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox. J. Am. College Cardiol. 63, 1345–1354 (2014).
  Article Google Scholar
• Tseng, C. H. Obesity paradox: differential effects on cancer and noncancer mortality in patients with type 2 diabetes mellitus. Atherosclerosis 226, 186–192 (2013).
  Article CAS PubMed Google Scholar
• Seshasai, S. R. et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).
  Article CAS Google Scholar
• Stein, K. B. et al. Colorectal cancer outcomes, recurrence, and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig. Dis. Sci. 55, 1839–1851 (2010).
  Article PubMed PubMed Central Google Scholar
• Snyder, C. F. et al. Does pre-existing diabetes affect prostate cancer prognosis? A systematic review. Prostate Cancer Prostat. Dis. 13, 58–64 (2010).
  Article CAS Google Scholar
• Bensimon, L., Yin, H., Suissa, S., Pollak, M. N. & Azoulay, L. Type 2 diabetes and the risk of mortality among patients with prostate cancer. Cancer Causes Control 25, 329–338 (2014).
  Article PubMed Google Scholar
• Haggstrom, C. et al. Prostate cancer, prostate cancer death, and death from other causes, among men with metabolic aberrations. Epidemiology 25, 823–828 (2014).
  Article PubMed PubMed Central Google Scholar
• Peairs, K. S. et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J. Clin. Oncol. 29, 40–46 (2011).
  Article PubMed Google Scholar
• Luo, J. et al. Pre-existing diabetes and breast cancer prognosis among elderly women. Br. J. Cancer 113, 827–832 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, A. H. et al. Diabetes and other comorbidities in breast cancer survival by race/ethnicity: the California Breast Cancer Survivorship Consortium (CBCSC). Cancer Epidemiol. Biomarkers Prev. 24, 361–368 (2015).
  Article CAS PubMed Google Scholar
• Fleming, S. T., Rastogi, A., Dmitrienko, A. & Johnson, K. D. A comprehensive prognostic index to predict survival based on multiple comorbidities: a focus on breast cancer. Med. Care 37, 601–614 (1999).
  Article CAS PubMed Google Scholar
• Srokowski, T. P., Fang, S., Hortobagyi, G. N. & Giordano, S. H. Impact of diabetes mellitus on complications and outcomes of adjuvant chemotherapy in older patients with breast cancer. J. Clin. Oncol. 27, 2170–2176 (2009).
  Article PubMed PubMed Central Google Scholar
• Margel, D. et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J. Clin. Oncol. 31, 3069–3075 (2013).
  Article CAS PubMed Google Scholar
• Bensimon, L., Yin, H., Suissa, S., Pollak, M. N. & Azoulay, L. The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol. Biomarkers Prev. 23, 2111–2118 (2014).
  Article CAS PubMed Google Scholar
• Stopsack, K. H., Ziehr, D. R., Rider, J. R. & Giovannucci, E. L. Metformin and prostate cancer mortality: a meta-analysis. Cancer Causes Control http://dx.doi.org/10.1007/s10552-015-0687-0 (2015).
• Zhang, Z. J. & Li, S. The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes. Metab. 16, 707–710 (2014).
  Article CAS PubMed Google Scholar
• He, X. et al. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann. Oncol. 23, 1771–1780 (2012).
  Article CAS PubMed Google Scholar
• Romero, I. L. et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstetr. Gynecol. 119, 61–67 (2012).
  Article Google Scholar
• Liu, Z. et al. High sensitivity of an Ha-RAS transgenic model of superficial bladder cancer to metformin is associated with approximately 240-fold higher drug concentration in urine than serum. Mol. Cancer Ther. 15, 430–438 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Peng, M. et al. High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model. Oncotarget http://dx.doi.org/10.18632/oncotarget.6933 (2016).
• Nayan, M. et al. The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder. Urol. Oncol. 33, 386.e387–e313 (2015).
  Article CAS Google Scholar
• US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?term=%22cancer%22+AND+%22metformin%22+AND+%22treating%22&Search=Search (2015).
• DeCensi, A. et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res. Treat. 148, 81–90 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lord, S. R. et al. Neoadjuvant window studies of metformin and biomarker development for drugs targeting cancer metabolism. J. Natl Cancer Inst. Monogr. 2015, 81–86 (2015).
  Article CAS PubMed Google Scholar
• Hadad, S. M. et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res. Treat. 150, 149–155 (2015).
  Article CAS PubMed Google Scholar
• Kordes, S. et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 839–847 (2015).
  Article CAS PubMed Google Scholar
• Reni, M. et al. (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase 2 trial. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.ccr-15-1722 (2015).
• Goodwin, P. J. et al. Effect of metformin versus placebo on and metabolic factors in NCIC CTG MA.32. J. Natl Cancer Inst. 107, http://dx.doi.org/10.1093/jnci/djv006 (2015).
• Goodwin, P. J. et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol. 20, 42–51 (2002).
  Article CAS PubMed Google Scholar
• Vissers, P. A. et al. The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res. Treatment 150, 427–437 (2015).
  Article CAS Google Scholar
• Gallagher, E. J. & LeRoith, D. Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol. Rev. 95, 727–748 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Pollak, M. Do cancer cells care if their host is hungry? Cell. Metabolism 9, 401–403 (2009).
  Article CAS PubMed Google Scholar
• Allott, E. H. & Hursting, S. D. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr. Relat. Cancer 22, R365–R386 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Iyengar, N. M., Hudis, C. A. & Dannenberg, A. J. Obesity and cancer: local and systemic mechanisms. Annu. Rev. Med. 66, 297–309 (2015).
  Article CAS PubMed Google Scholar
• Renehan, A. G., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat. Rev. Cancer 15, 484–498 (2015).
  Article CAS PubMed Google Scholar
• Tannenbaum, A. & Silverstone, H. The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res. 9, 724–727 (1949).
  CAS PubMed Google Scholar
• 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 17, 351–360 (2010).
  Article CAS PubMed Google Scholar
• Murphy, N. et al. A nested case–control study of metabolically defined body size phenotypes and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). PLoS. Med. 13, e1001988 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Wolpin, B. M. et al. Hyperglycaemia, insulin resistance, impaired pancreatic beta-cell function, and risk of pancreatic cancer. J. Natl Cancer Inst. 105, 1027–1035 (2013).
  Article PubMed PubMed Central Google Scholar
• Pal, A. et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N. Engl. J. Med. 367, 1002–1011 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ortega-Molina, A. et al. Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell. Metabolism 21, 558–570 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Belfiore, A., Frasca, F., Pandini, G., Sciacca, L. & Vigneri, R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr. Rev. 30, 586–623 (2009).
  Article CAS PubMed Google Scholar
• Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).
  Article CAS PubMed Google Scholar
• Travis, R. C. et al. A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk. Cancer Res. 76, 2288–2300 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Thissen, J. P., Underwood, L. E. & Ketelslegers, J. M. Regulation of insulin-like growth factor-I in starvation and injury. Nutr. Rev. 57, 167–176 (1999).
  Article CAS PubMed Google Scholar
• Baxter, R. C. IGF binding proteins in cancer: mechanistic and clinical insights. Nat. Rev. Cancer 14, 329–341 (2014).
  Article CAS PubMed Google Scholar
• Key, T. J. et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J. Natl Cancer Inst. 95, 1218–1226 (2003).
  Article CAS PubMed Google Scholar
• Hofmann, J. N. et al. A prospective study of circulating adipokine levels and risk of multiple myeloma. Blood 120, 4418–4420 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Inamura, K. et al. Prediagnosis plasma adiponectin in relation to colorectal cancer risk according to KRAS mutation status. J. Natl Cancer Inst. 108, http://dx.doi.org/10.1093/jnci/djv363 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Bao, Y. et al. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J. Natl Cancer Inst. 105, 95–103 (2013).
  Article CAS PubMed Google Scholar
• Hofmann, J. N. et al. Low levels of circulating adiponectin are associated with multiple myeloma risk in overweight and obese individuals. Cancer Res. 76, 1935–1941 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).
  Article CAS PubMed Google Scholar
• 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. (Phila.) 1, 369–375 (2008).
  Article CAS Google Scholar
• Vansaun, M. N. Molecular pathways: adiponectin and leptin signaling in cancer. Clin. Cancer Res. 19, 1926–1932 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Font-Burgada, J., Sun, B. & Karin, M. Obesity and cancer: the oil that feeds the flame. Cell. Metabolism 23, 48–62 (2016).
  Article CAS PubMed Google Scholar
• Iyengar, N. M. et al. Systemic correlates of white adipose tissue inflammation in early-stage breast cancer. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.ccr-15-2239 (2015).
• Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).
  Article CAS PubMed Google Scholar
• Ussar, S. et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell. Metabolism 22, 516–530 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12, 489–498 (2013).
  Article CAS PubMed Google Scholar
• Lee, S. Y. et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS ONE 10, e0135858 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Haywood, A. et al. Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst. Rev. 4, CD010756 (2015).
  Google Scholar
• Ferris, H. A. & Kahn, C. R. New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it. J. Clin. Invest. 122, 3854–3857 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mazziotti, G., Gazzaruso, C. & Giustina, A. Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metabolism 22, 499–506 (2011).
  Article CAS Google Scholar
• Fong, A. C. & Cheung, N. W. The high incidence of steroid-induced hyperglycaemia in hospital. Diabetes Res. Clin. Pract. 99, 277–280 (2013).
  Article CAS PubMed Google Scholar
• Ariaans, G. et al. Cancer-drug induced insulin resistance: innocent bystander or unusual suspect. Cancer Treat. Rev. 41, 376–384 (2015).
  Article CAS PubMed Google Scholar
• Sonabend, R. Y. et al. Hyperglycaemia during induction therapy is associated with poorer survival in children with acute lymphocytic leukemia. J. Pediatr. 155, 73–78 (2009).
  Article PubMed Google Scholar
• Chow, E. J. et al. Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer 60, 621–626 (2013).
  Article PubMed Google Scholar
• Dool, C. J. et al. IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer. Endocr. Relat. Cancer 18, 699–709 (2011).
  Article CAS PubMed Google Scholar
• Gosmanov, A. R., Goorha, S., Stelts, S., Peng, L. & Umpierrez, G. E. Management of hyperglycaemia in diabetic patients with hematologic malignancies during dexamethasone therapy. Endocr. Pract. 19, 231–235 (2013).
  Article PubMed Google Scholar
• Yu, I. C., Lin, H. Y., Sparks, J. D., Yeh, S. & Chang, C. Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome. Diabetes 63, 3180–3188 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Laaksonen, D. E. et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 27, 1036–1041 (2004).
  Article CAS PubMed Google Scholar
• Bosco, C., Crawley, D., Adolfsson, J., Rudman, S. & Van Hemelrijck, M. Quantifying the evidence for the risk of metabolic syndrome and its components following androgen deprivation therapy for prostate cancer: a meta-analysis. PLoS ONE 10, e0117344 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Keating, N. L., Liu, P. H., O'Malley, A. J., Freedland, S. J. & Smith, M. R. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur. Urol. 65, 816–824 (2014).
  Article CAS PubMed Google Scholar
• Keating, N. L., O'Malley, A. J., Freedland, S. J. & Smith, M. R. Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur. Urol. 64, 159–166 (2013).
  Article PubMed Google Scholar
• Lubik, A. A. et al. Insulin increases de novo steroidogenesis in prostate cancer cells. Cancer Res. 71, 5754–5764 (2011).
  Article CAS PubMed Google Scholar
• Gunter, J. H., Lubik, A. A., McKenzie, I., Pollak, M. & Nelson, C. C. The interactions between insulin and androgens in progression to castrate-resistant prostate cancer. Adv. Urol. 2012, 248607 (2012).
  Article PubMed PubMed Central Google Scholar
• Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer 6, 184–192 (2006).
  Article CAS PubMed Google Scholar
• Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol. 23, 98–107 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, C. X. et al. A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.ccr-15-2160 (2016).
• Busaidy, N. L. et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. 30, 2919–2928 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Geuna, E. et al. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on phase I clinical trials. Br. J. Cancer 113, 1541–1547 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Iams, W. T. & Lovly, C. M. Molecular pathways: clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clin. Cancer Res. 21, 4270–4277 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Haluska, P. et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother. Pharmacol. 65, 765–773 (2010).
  Article CAS PubMed Google Scholar
• Nellemann, B. et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol. (Oxford) 210, 392–402 (2014).
  Article CAS Google Scholar
• Yuen, K. C., Chong, L. E. & Riddle, M. C. Influence of glucocorticoids and growth hormone on insulin sensitivity in humans. Diabet. Med. 30, 651–663 (2013).
  Article CAS PubMed Google Scholar
• Puzanov, I. et al. A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors. Clin. Cancer Res. 21, 701–711 (2015).
  Article CAS PubMed Google Scholar
• Rini, B. I. et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J. Clin. Oncol. 32, 752–759 (2014).
  Article CAS PubMed Google Scholar
• Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, P. et al. Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo. Sci. Rep. 5, 14959 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Verges, B. & Cariou, B. mTOR inhibitors and diabetes. Diabetes Res. Clin. Pract. 110, 101–108 (2015).
  Article CAS PubMed Google Scholar
• Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).
  Article CAS PubMed Google Scholar
• Meacham, L. R. et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study. Arch. Intern. Med. 169, 1381–1388 (2009).
  Article PubMed PubMed Central Google Scholar
• Holmqvist, A. S. et al. Adult life after childhood cancer in Scandinavia: diabetes mellitus following treatment for cancer in childhood. Eur. J. Cancer 50, 1169–1175 (2014).
  Article PubMed Google Scholar
• van Nimwegen, F. A. et al. Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J. Clin. Oncol. 32, 3257–3263 (2014).
  Article PubMed Google Scholar
• Ray, W. A. Evaluating medication effects outside of clinical trials: new-user designs. Am. J. Epidemiol. 158, 915–920 (2003).
  Article PubMed Google Scholar
• van Staa, T. P., Patel, D., Gallagher, A. M. & de Bruin, M. L. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia 55, 654–665 (2012).
  Article CAS PubMed Google Scholar
• Jones, N. P., Curtis, P. S. & Home, P. D. Cancer and bone fractures in observational follow-up of the RECORD study. Acta Diabetol 52, 539–546 (2015).
  Article CAS PubMed Google Scholar
• Wang, H. et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.. Sci. Transl. Med. 8, 334ra351 (2016).
  Google Scholar
• Devaraj, S. & Maitra, A. Pancreatic safety of newer incretin-based therapies: are the “-tides” finally turning? Diabetes 63, 2219–2221 (2014).
  Article PubMed Google Scholar
• Bordeleau, L. et al. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 37, 1360–1366 (2014).
  Article CAS PubMed Google Scholar