Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?

Journal name:
Nature Reviews Clinical Oncology
Volume:
14,
Pages:
85–99
Year published:
DOI:
doi:10.1038/nrclinonc.2016.120
Published online

Abstract

The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer.

At a glance

Figures

  1. Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia.
    Figure 1: Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia.

    When caloric intake exceeds energy expenditure insulin levels rise and excess energy is stored in adipose tissue. Insulin signals adipocytes to take up glucose and convert it to lipids as a way of storing energy to be used at times of inadequate caloric intake. Chronic excess of caloric intake over energy consumption, however, can lead to insulin resistance in insulin-target tissues, one of the consequences of which is increased hepatic gluconeogenesis — an important cause of hyperglycaemia. If the degree of hyperglycaemia surpasses a defined threshold, type 2 diabetes mellitus (T2DM) will be diagnosed. Importantly, as glucose levels rise, insulin secretion increases, which can reduce glucose levels in some patients, leading to a normoglycaemic, but hyperinsulinaemic, state; however, T2DM characterized by both hyperglycaemia and hyperinsulinaemia develops eventually. Hyperinsulinaemia is hypothesized to stimulate the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway in at least a subset of cancers or cells at risk of malignant transformation, promoting tumour growth or resulting in increased rates of carcinogenesis, respectively. This hypothesis is supported by data from animal models, but remains to be investigated rigorously in the clinic. Other metabolic features of obesity that might influence neoplasia include increased levels of inflammatory cytokines, which stimulate various processes involved in cancer development, and reduced levels of adiponectin, an adipokine that normally inhibits cell proliferation via activation of AMP-activated protein kinase (AMPK). Metformin decreases hyperglycaemia, hyperinsulinaemia, and the consequences of these conditions predominantly by decreasing hepatic gluconeogenesis. This drug might also act directly on cancers or cells at risk of transformation by inducing energy stress, which slows cell proliferation via activation of AMPK and/or other mechanisms. On the other hand, the use of inhibitors of the PI3K pathway to target this signalling cascade in cancer cells could potentially have unintended metabolic consequences, such as hyperglycaemia, owing to off-tumour effects on tissues involved in the regulation of blood glucose, such as adipocytes. mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB.

  2. Clinical vignette and putative causal relationships between obesity, diabetes, antidiabetic medications, cancer, and cancer treatments.
    Figure 2: Clinical vignette and putative causal relationships between obesity, diabetes, antidiabetic medications, cancer, and cancer treatments.

    a | A hypothetical patient with obesity, type 2 diabetes mellitus (T2DM), and breast cancer is depicted. Treatment for early stage breast cancer is commenced on the background of dual antidiabetic therapy with metformin and a sulfonylurea (SU). Further dysglycaemia leads to metformin, thiazolidinedione (TZD), and a dipeptidyl peptidase-4 inhibitor (DPP4i) triple therapy for T2DM, with continuation of adjuvant hormonal therapy for breast cancer. When liver metastases are diagnosed and hyperglycaemia worsens, metformin and TZD are withdrawn; chemotherapy and irradiation are then administered as anticancer therapy, and long-acting (LA) insulin is prescribed to achieve better glycaemic control. Following the diagnosis of brain metastases, the patient is given steroids, necessitating the addition of short-acting (SA) insulin to antidiabetic therapy (with DPPi withdrawal). b | The directed acyclic schematic depicts the possible causal relationships between obesity, T2DM, antidiabetic medications, cancer, and cancer treatments. Obesity is associated with increased mortality in general, but can also lead to T2DM and, possibly, cancer, which further increase morbidity and mortality. Cancer and cancer treatment influence the progression and treatment of T2DM, and possibly vice versa. An example of a hypothesized interaction is the reduction of breast-cancer risk associated with metformin treatment of T2DM. An example of a known clinical interaction is that steroid treatments for brain metastases or chemotherapy-induced vomiting can lead to increased insulin requirements in patients with insulin-dependent diabetes and cancer. BMI, body mass index; HbA1c, haemoglobin A1c (glycated haemoglobin).

References

  1. Tuffier, T. Diabete et neoplasmes. Archives generales de medecine 7, 129140 (1888).
  2. Bapat, S. P. et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528, 137141 (2015).
  3. 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).
  4. 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, 766781 (2014).
  5. 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).
  6. Berrington de Gonzalez, A. et al. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 363, 22112219 (2010).
  7. [no authors listed]. Diabetes Fact Sheet. WHO http://www.who.int/mediacentre/factsheets/fs312/en/ (2015).
  8. Di Angelantonio, E. et al. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 5260 (2015).
  9. 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).
  10. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87108 (2015).
  11. Guariguata, L. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract. 103, 137149 (2014).
  12. 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 18 (2015).
  13. Youlden, D. R. et al. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 36, 237248 (2012).
  14. Arnold, M. et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 3646 (2015).
  15. 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, 13231328 (2002).
  16. Kaaks, R. & Kühn, T. Epidemiology: obesity and cancer — the evidence is fattening up. Nat. Rev. Endocrinol. 10, 644645 (2014).
  17. 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).
  18. 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, 569578 (2008).
  19. 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).
  20. 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).
  21. 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).
  22. 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, 14671474 (2010).
  23. Yang, Y. et al. Obesity and incidence of lung cancer: a meta-analysis. Int. J. Cancer 132, 11621169 (2013).
  24. 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).
  25. 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, 611621 (2015).
  26. 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).
  27. Adams, T. D. et al. Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357, 753761 (2007).
  28. 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, 653662 (2009).
  29. 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).
  30. 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, 193201 (2006).
  31. 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, 14471452 (2003).
  32. 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).
  33. Carstensen, B., Witte, D. R. & Friis, S. Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia 55, 948958 (2012).
  34. Geier, A. S. et al. Cancer detection rates following enrolment in a disease management programme for type 2 diabetes. Diabetologia 56, 19441948 (2013).
  35. 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, 151158 (2013).
  36. Tseng, C. H. Diabetes and risk of prostate cancer: a study using the National Health Insurance. Diabetes Care 34, 616621 (2011).
  37. Dhindsa, S. et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 54625468 (2004).
  38. Freedland, S. J. & Aronson, W. J. Obesity and prostate cancer. Urology 65, 433439 (2005).
  39. 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, 10391047 (2008).
  40. 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, 867885 (2014).
  41. 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).
  42. 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, 13041305 (2005).
  43. 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, 17551765 (2009).
  44. 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).
  45. 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, 865874 (2015).
  46. Suissa, S. & Azoulay, L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35, 26652673 (2012).
  47. Pocock, S. J. & Smeeth, L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 374, 511513 (2009).
  48. Garber, A. J. et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr. Pract. 21, 438447 (2015).
  49. Pollak, M. Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat. Med. 20, 591593 (2014).
  50. Pollak, M. N. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2, 778790 (2012).
  51. Decensi, A. et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.) 3, 14511461 (2010).
  52. 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, 16201625 (2009).
  53. 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).
  54. Mamtani, R. et al. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Diabetes Care 37, 19101917 (2014).
  55. 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, 25222532 (2014).
  56. 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).
  57. Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 17661777 (2009).
  58. Hemkens, L. G. et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52, 17321744 (2009).
  59. Jonasson, J. M. et al. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52, 17451754 (2009).
  60. Mayer, D., Shukla, A. & Enzmann, H. Proliferative effects of insulin analogues on mammary epithelial cells. Arch. Physiol. Biochem. 114, 3844 (2008).
  61. 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).
  62. Proks, P., Reimann, F., Green, N., Gribble, F. & Ashcroft, F. Sulfonylurea stimulation of insulin secretion. Diabetes 51 (Suppl. 3), S368S376 (2002).
  63. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159169 (2012).
  64. 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, E11701175 (2012).
  65. 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, 5965 (2015).
  66. 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, 20832089 (2015).
  67. Loke, Y. K. & Mattishent, K. Bladder cancer: pioglitazone—when is a prescription drug safe? Nat. Rev. Urol. 12, 655656 (2015).
  68. 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, 12791289 (2005).
  69. 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, 916922 (2011).
  70. 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).
  71. 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).
  72. Levin, D. et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 58, 493504 (2015).
  73. Lewis, J. D. et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 314, 265277 (2015).
  74. 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).
  75. Tuccori, M. et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 352, i1541 (2016).
  76. 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, 150156 (2011).
  77. 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, 569577 (2013).
  78. Azoulay, L. Incretin-based drugs and adverse pancreatic events: almost a decade later and uncertainty remains. Diabetes Care 38, 951953 (2015).
  79. Gokhale, M. et al. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes, Obes. Metabolism 16, 12471256 (2014).
  80. Tseng, C. H. Sitagliptin and pancreatic cancer risk in patients with type 2 diabetes. Eur. J. Clin. Invest. 46, 7079 (2016).
  81. Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232242 (2015).
  82. Egan, A. G. et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N. Engl. J. Med. 370, 794797 (2014).
  83. 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, 291301 (2011).
  84. Rosol, T. J. On-target effects of GLP-1 receptor agonists on thyroid C-cells in rats and mice. Toxicol. Pathol. 41, 303309 (2013).
  85. 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).
  86. Koehler, J. A. et al. GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell. Metab. 21, 379391 (2015).
  87. Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754762 (2014).
  88. 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, 16251638 (2003).
  89. 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, 235241 (1993).
  90. 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, 19011914 (2014).
  91. Copson, E. R. et al. Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann. Oncol. 26, 101112 (2015).
  92. 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).
  93. Pettersson, A. et al. Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG. J. Natl Cancer Inst. 105, 18811890 (2013).
  94. 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, 22312239 (2014).
  95. 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, 339348 (2016).
  96. 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).
  97. Nagle, C. M. et al. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium. Br. J. Cancer 113, 817826 (2015).
  98. Hakimi, A. A. et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J. Natl Cancer Inst. 105, 18621870 (2013).
  99. 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, 13451354 (2014).
  100. Tseng, C. H. Obesity paradox: differential effects on cancer and noncancer mortality in patients with type 2 diabetes mellitus. Atherosclerosis 226, 186192 (2013).
  101. Seshasai, S. R. et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829841 (2011).
  102. 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, 18391851 (2010).
  103. Snyder, C. F. et al. Does pre-existing diabetes affect prostate cancer prognosis? A systematic review. Prostate Cancer Prostat. Dis. 13, 5864 (2010).
  104. 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, 329338 (2014).
  105. Haggstrom, C. et al. Prostate cancer, prostate cancer death, and death from other causes, among men with metabolic aberrations. Epidemiology 25, 823828 (2014).
  106. Peairs, K. S. et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J. Clin. Oncol. 29, 4046 (2011).
  107. Luo, J. et al. Pre-existing diabetes and breast cancer prognosis among elderly women. Br. J. Cancer 113, 827832 (2015).
  108. 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, 361368 (2015).
  109. 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, 601614 (1999).
  110. 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, 21702176 (2009).
  111. Margel, D. et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J. Clin. Oncol. 31, 30693075 (2013).
  112. 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, 21112118 (2014).
  113. 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).
  114. 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, 707710 (2014).
  115. 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, 17711780 (2012).
  116. Romero, I. L. et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstetr. Gynecol. 119, 6167 (2012).
  117. 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, 430438 (2016).
  118. 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).
  119. 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.e387e313 (2015).
  120. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?term=%22cancer%22+AND+%22metformin%22+AND+%22treating%22&Search=Search (2015).
  121. 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, 8190 (2014).
  122. Lord, S. R. et al. Neoadjuvant window studies of metformin and biomarker development for drugs targeting cancer metabolism. J. Natl Cancer Inst. Monogr. 2015, 8186 (2015).
  123. 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, 149155 (2015).
  124. Kordes, S. et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 839847 (2015).
  125. 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).
  126. 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).
  127. Goodwin, P. J. et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol. 20, 4251 (2002).
  128. 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, 427437 (2015).
  129. Gallagher, E. J. & LeRoith, D. Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol. Rev. 95, 727748 (2015).
  130. Pollak, M. Do cancer cells care if their host is hungry? Cell. Metabolism 9, 401403 (2009).
  131. Allott, E. H. & Hursting, S. D. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr. Relat. Cancer 22, R365R386 (2015).
  132. Iyengar, N. M., Hudis, C. A. & Dannenberg, A. J. Obesity and cancer: local and systemic mechanisms. Annu. Rev. Med. 66, 297309 (2015).
  133. Renehan, A. G., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat. Rev. Cancer 15, 484498 (2015).
  134. 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, 724727 (1949).
  135. 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, 351360 (2010).
  136. 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).
  137. Wolpin, B. M. et al. Hyperglycaemia, insulin resistance, impaired pancreatic beta-cell function, and risk of pancreatic cancer. J. Natl Cancer Inst. 105, 10271035 (2013).
  138. Pal, A. et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N. Engl. J. Med. 367, 10021011 (2012).
  139. Ortega-Molina, A. et al. Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell. Metabolism 21, 558570 (2015).
  140. 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, 586623 (2009).
  141. Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563566 (1998).
  142. 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, 22882300 (2016).
  143. Thissen, J. P., Underwood, L. E. & Ketelslegers, J. M. Regulation of insulin-like growth factor-I in starvation and injury. Nutr. Rev. 57, 167176 (1999).
  144. Baxter, R. C. IGF binding proteins in cancer: mechanistic and clinical insights. Nat. Rev. Cancer 14, 329341 (2014).
  145. Key, T. J. et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J. Natl Cancer Inst. 95, 12181226 (2003).
  146. Hofmann, J. N. et al. A prospective study of circulating adipokine levels and risk of multiple myeloma. Blood 120, 44184420 (2012).
  147. 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).
  148. Bao, Y. et al. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J. Natl Cancer Inst. 105, 95103 (2013).
  149. Hofmann, J. N. et al. Low levels of circulating adiponectin are associated with multiple myeloma risk in overweight and obese individuals. Cancer Res. 76, 19351941 (2016).
  150. Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 7983 (1999).
  151. 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, 369375 (2008).
  152. Vansaun, M. N. Molecular pathways: adiponectin and leptin signaling in cancer. Clin. Cancer Res. 19, 19261932 (2013).
  153. Font-Burgada, J., Sun, B. & Karin, M. Obesity and cancer: the oil that feeds the flame. Cell. Metabolism 23, 4862 (2016).
  154. 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).
  155. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528532 (2015).
  156. Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).
  157. Ussar, S. et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell. Metabolism 22, 516530 (2015).
  158. Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12, 489498 (2013).
  159. 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).
  160. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262266 (2015).
  161. Haywood, A. et al. Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst. Rev. 4, CD010756 (2015).
  162. Ferris, H. A. & Kahn, C. R. New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it. J. Clin. Invest. 122, 38543857 (2012).
  163. Mazziotti, G., Gazzaruso, C. & Giustina, A. Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metabolism 22, 499506 (2011).
  164. Fong, A. C. & Cheung, N. W. The high incidence of steroid-induced hyperglycaemia in hospital. Diabetes Res. Clin. Pract. 99, 277280 (2013).
  165. Ariaans, G. et al. Cancer-drug induced insulin resistance: innocent bystander or unusual suspect. Cancer Treat. Rev. 41, 376384 (2015).
  166. Sonabend, R. Y. et al. Hyperglycaemia during induction therapy is associated with poorer survival in children with acute lymphocytic leukemia. J. Pediatr. 155, 7378 (2009).
  167. Chow, E. J. et al. Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer 60, 621626 (2013).
  168. 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, 699709 (2011).
  169. 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, 231235 (2013).
  170. 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, 31803188 (2014).
  171. Laaksonen, D. E. et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 27, 10361041 (2004).
  172. 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).
  173. 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, 816824 (2014).
  174. 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, 159166 (2013).
  175. Lubik, A. A. et al. Insulin increases de novo steroidogenesis in prostate cancer cells. Cancer Res. 71, 57545764 (2011).
  176. 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).
  177. 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, 184192 (2006).
  178. Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol. 23, 98107 (2015).
  179. 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).
  180. Busaidy, N. L. et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. 30, 29192928 (2012).
  181. 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, 15411547 (2015).
  182. Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 10081018 (2014).
  183. 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, 42704277 (2015).
  184. 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, 765773 (2010).
  185. Nellemann, B. et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol. (Oxford) 210, 392402 (2014).
  186. Yuen, K. C., Chong, L. E. & Riddle, M. C. Influence of glucocorticoids and growth hormone on insulin sensitivity in humans. Diabet. Med. 30, 651663 (2013).
  187. 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, 701711 (2015).
  188. 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, 752759 (2014).
  189. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 18031813 (2015).
  190. Yang, P. et al. Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo. Sci. Rep. 5, 14959 (2015).
  191. Verges, B. & Cariou, B. mTOR inhibitors and diabetes. Diabetes Res. Clin. Pract. 110, 101108 (2015).
  192. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520529 (2012).
  193. 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, 13811388 (2009).
  194. Holmqvist, A. S. et al. Adult life after childhood cancer in Scandinavia: diabetes mellitus following treatment for cancer in childhood. Eur. J. Cancer 50, 11691175 (2014).
  195. van Nimwegen, F. A. et al. Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J. Clin. Oncol. 32, 32573263 (2014).
  196. Ray, W. A. Evaluating medication effects outside of clinical trials: new-user designs. Am. J. Epidemiol. 158, 915920 (2003).
  197. 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, 654665 (2012).
  198. Jones, N. P., Curtis, P. S. & Home, P. D. Cancer and bone fractures in observational follow-up of the RECORD study. Acta Diabetol 52, 539546 (2015).
  199. Wang, H. et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.. Sci. Transl. Med. 8, 334ra351 (2016).
  200. Devaraj, S. & Maitra, A. Pancreatic safety of newer incretin-based therapies: are the “-tides” finally turning? Diabetes 63, 22192221 (2014).
  201. 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, 13601366 (2014).

Download references

Author information

Affiliations

  1. Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada.

    • Adi J. Klil-Drori &
    • Laurent Azoulay
  2. Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Purvis Hall, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada.

    • Adi J. Klil-Drori &
    • Laurent Azoulay
  3. Departments of Oncology and Medicine, McGill University, McIntyre Medical Building, 3655 Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.

    • Laurent Azoulay &
    • Michael N. Pollak
  4. Segal Cancer Centre, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1E2, Canada.

    • Michael N. Pollak

Contributions

A.J.K.-D. and M.N.P. researched data for the article and wrote the manuscript. All authors contributed to discussions of content, and reviewed and/or edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Adi J. Klil-Drori

    Adi J. Klil-Drori received his MD in 2007 from the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. In 2013, he completed residency and fellowship training in internal medicine and haematology at the Rambam Health Care Campus in Haifa, Israel. In 2016, Dr Klil-Drori completed a 2-year research fellowship in pharmacoepidemiology at the Centre for Clinical Epidemiology of the Jewish General Hospital, Montreal, Quebec, Canada. Currently, Dr Klil-Drori is a clinical fellow with the Clinical Research Unit at the Jewish General Hospital. He continues research in pharmacoepidemiology with a special interest in haematological malignancies and venous thrombosis. Dr Klil-Drori is a recipient of a 2016 Young Investigator Award from the Conquer Cancer Foundation of ASCO.

  • Laurent Azoulay

    Laurent Azoulay is an Associate Professor in the Department of Epidemiology, Biostatistics, and Occupational Health and in the Gerald Bronfman Department of Oncology at McGill University, Montreal, Quebec, Canada. Dr Azoulay has expertise in the design and analysis of pharmacoepidemiological studies using large patient databases. He has published extensively on the safety of antidiabetic drugs, including their effects on cancer incidence and cancer-related outcomes. To date, he has been published close to 100 papers, several of which were published in top-tier journals. His research programme is supported by provincial and national funding agencies.

  • Michael N. Pollak

    Michael N. Pollak is a professor in the Departments of Oncology and Medicine at McGill University, and holds the Alexander-Goldfarb Research Chair. His research training was conducted in the laboratory of Ron Buick at the Ontario Cancer Institute, Toronto, Ontario, Canada. He practices medical oncology at the Jewish General Hospital, and also actively involved in laboratory and clinical research. His lab includes a section that acts as a resource for the measurement of peptide hormone levels in tissue specimens from collaborative population-based research projects and clinical trials. He heads the Division of Cancer Prevention at the Department of Oncology at McGill and the Stroll Cancer Prevention Centre at the Jewish General Hospital. His interests include cancer metabolism and the roles of peptide growth factors and hormones in cancer biology. He has published more than 420 papers with a total of over 16,000 citations. He was awarded the Harold Warwick Prize by the Canadian Cancer Society Research Institute in 2012.

Additional data