Type 2 diabetes and cancer

Many epidemiological studies have shown an association between type 2 diabetes and a range of cancer types. The strongest associations have been seen with primary liver cancer and carcinoma of the pancreas, although there may be an element of reverse causality (i.e. the cancer promotes or aggravates diabetes). The risk of endometrial cancer is doubled in women, and risks of cancer of the breast, colorectum and bladder, together with non-Hodgkin’s lymphoma, are increased by 20-40%. In contrast, the risk of prostate cancer is reduced by around 15%. There is no consistent association with cancer of the lung and ovary, and no strong association with other types of cancer has emerged. People with diabetes have a higher mortality for some types of cancer, although this may partly be due to higher mortality from diabetes itself. Rather unexpectedly, the peak time for diagnosis of cancer is shortly following diagnosis of diabetes. This appears to be due to detection bias (increasing likelihood that cancer will be found in those attending doctors for other reasons), although reverse causality may also be a factor. Cancer risk is not associated with increasing exposure to hyperglycemia - suggesting that raised blood glucose is not an important risk factor for cancer.

Diabetes and cancer

Numerous epidemiologic studies have identified associations between diabetes and specific types of cancer in various populations (Figure 1), and numerous reviews have summarized the large amount of literature on this relationship [1][2][3]. Figure 1. Summary of Meta-Analyses of Cohort Studies linking Diabetes and Cancer
Figure 1. Summary of Meta-Analyses of Cohort Studies linking Diabetes and Cancer
While the literature indicates a strong association between type 2 diabetes and cancer, the magnitude and direction of the association varies according to the specific site of the cancer.[4]

The strongest relationships have been demonstrated for liver[5] and pancreatic[6] cancers, although these may also reflect some degree of ‘reverse causality’, with the cancer itself leading to onset of diabetes. The risk of endometrial cancer appears to be doubled in women with diabetes.[7]

Risks of breast, colorectal, bladder, and non-Hodgkin’s lymphoma are approximately 20-40% higher in people with type 2 diabetes[8][9][10]. Interestingly, there appears to be a protective effect of around 15% for prostate cancer, which is thought to be due, in part, to reduced levels of endogenous testosterone in men with type 2 diabetes.[11]

For other malignancies, the numbers of studies are generally small, and there appears to be no consistent association with lung[12] and ovarian[13]cancers.

Diabetes and Cancer Mortality

Diabetes is also associated with increased cancer mortality[8][9],[14][15][16][17]. As would be expected, the findings for cancer mortality in type 2 diabetes are fairly consistent with those observed for cancer incidence. There are positive associations between diabetes and mortality from colorectal, liver, pancreatic, and bladder cancers[17]. However, associations for diabetes and mortality from prostate, breast and endometrial cancers are inconsistent[17]. In fact, while men with type 2 diabetes are at reduced risk of developing prostate cancer, they appear to have a poorer prognosis once diagnosed with prostate cancer[18].

The reduced survival seen in people with diabetes who develop some types of cancer has several possible explanations. One is the increased morbidity and mortality of diabetes, exclusive of the diagnosis of cancer. Another is that certain types of cancer therapy may be contra-indicated or less well tolerated in diabetes, for example because of co-existing renal impairment or problems with glucose control in those requiring steroids.

How does type 2 diabetes promote cancer risk?

Type 2 diabetes, or rather the milieu associated with type 2 diabetes (obesity, hyperinsulinemia, altered metabolic pathways etc) does not appear to initiate cancer development. Instead, factors associated with type 2 diabetes may act to promote the growth and spread of pre-existing cancer foci.

Insulin resistance and hyperinsulinaemia are, for example, associated with higher cancer risk in non-diabetic individuals, and may predate the clinical diagnosis of type 2 diabetes by many years[19], as may obesity. The influence of such factors on cancer development might thus begin long before the diagnosis of diabetes.

Time-Varying Cancer Risk and Ascertainment bias

Observational studies of time-varying cancer incidence (i.e. the likelihood of cancer detection in relation to the onset and duration of diabetes) show that diabetes-related cancers are much more likely to be diagnosed in the period following diagnosis of diabetes, with a substantial decline in risk on longer term follow-up.

This pattern is seen with almost all cancers. In some cases the longer term risk falls but remains higher than in non-diabetics (e.g. for colorectal, liver and endometrial cancers), whereas the risk drops to the non-diabetic level for other types of cancer (e.g. lung, breast, cervical, bladder and ovarian cancers). In prostate cancer, men with diabetes have a reduced long term risk [20][22].

The observation of an increased cancer risk in those with recently-diagnosed diabetes has two possible explanations, ascertainment bias or reverse causality.

Ascertainment bias (i.e. increased likelihood of cancer detection in diabetic as against non-diabetic individuals) might explain increased detection of cancer soon after diabetes onset, since the newly diagnosed patient with diabetes is more likely to be examined and investigated, and a number of studies suggest a substantial degree of detection bias in the diabetic population [20][21][22].

Increased longer term surveillance might also be expected to influence ascertainment, however, since patients with diabetes are more likely to interact with the healthcare system (e.g. more frequent physician visits or hospitalisations).

Reverse causality (i.e. a pre-existing cancer promotes the onset of diabetes or progression to insulin therapy) is well-described with pancreatic cancer, in which the effect is largely due to humoral factors secreted by the tumor rather than to direct destruction of the pancreas. Primary liver cancers may do the same, and it is possible that some other types of tumor may secrete tumor products that promote insulin resistance.

References

  1. ^ Nicolucci A. Epidemiological aspects of neoplasms in diabetes. Acta Diabetol 2010 Jun;47(2):87-95.

  2. ^ Vigneri P et al. Diabetes and cancer. Endocr Relat Cancer 2009 Dec;16(4):1103-23.

  3. ^ Giovannucci E et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33(7):1674-85.

  4. ^ Johnson JA et al. On behalf of the Diabetes and Cancer Research Consortium. Diabetes and cancer (1): Evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia 2012;1607-18

  5. ^ El-Serag HB et al. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4:369-80.

  6. ^ Huxley R et al. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005;92:2076-83.

  7. ^ Friberg E et al. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007;50:1365-74.

  8. ^ Larsson SC et al. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007;121:856-62.

  9. ^ Larsson SC et al. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J NAtl Cancer Inst 2005;97:1679-86.

  10. ^ Larsson SC et al. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia 2006;49:2819-23.

  11. ^ Kasper JS et al. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006;15:2056-62.

  12. ^ Hall GC et al. Diabetes and the risk of lung cancer. Diabetes Care 2005;28:590–594

  13. ^ Weiderpass E et al. Diabetes mellitus and ovarian cancer (Sweden). Cancer Causes Control 2002;13:759–764

  14. ^ Saydah SH et al. Abnormal glucose tolerance and the risk of cancer death in the United States. Am J Epidemiol 2003;157:1092-1100.

  15. ^ Levine W et al. Post-load plasma glucose and cancer mortality in middle-aged men and women. 12-year follow-up findings of the Chicago Heart Association Detection Project in Industry. Am J Epidemiol 1990;131:254-62.

  16. ^ Coughlin SS et al. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004;159:1160-7.

  17. ^ Renehan AG et al. on behalf of the Diabetes and Cancer Research Consortium. Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer. Diabetologia 2012;55:1619-32.

  18. ^ 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 2008;9:1039-47.

  19. ^ Tabak AG et al. Trajectories of glycemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 2009;373:2215–2221.

  20. ^ Johnson JA et al. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia 2011;54:2263–2271.

  21. ^ Carstensen B et al. Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia 2012;55:948-58.

  22. ^ Colmers IN et al. Detection bias and overestimation of bladder cancer risk in type 2 diabetes: a matched cohort study. British Medical Journal (submitted)

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