Human insulin and cancer

Insulin has long been known for its mitogenic effect, demonstrated both in vitro and in vivo. Exogenous insulin, whether given as monotherapy or in combination with oral agents, is frequently needed to treat hyperglycemia and to prevent vascular and other complications of type 2 diabetes. Endogenous insulin is partially cleared by the liver before exerting its metabolic effects upon peripheral tissues such as muscle and fat. Exogenous insulin, in contrast, is administered into the systemic circulation, increasing the exposure of peripheral tissues to its action. This is a possible explanation for the increased risk of cancer observed in insulin-using type 2 diabetics. This article offers an overview of recent observational studies on the risk of cancer associated with use of human insulin.

Background

Recent controversy concerning a possible association between insulin glargine and an increased risk of cancer has prompted increased interest in the relationship between treatment for diabetes and cancer risk. Several studies, discussed below, have suggested that people with type 2 diabetes who take insulin are more likely to develop cancer, and are also more likely to die from it. There are however many potential confounders (see Insulin and cancer), and the strongest argument against a causal relationship comes from studies showing that cancer is more likely to be diagnosed in people recently treated with insulin, as against those with longer term exposure. This is suggestive of reverse causation, most convincingly demonstrated in carcinoma of the pancreas - the tumour most unequivocally linked to the use of insulin. (see Pancreatic cancer)

Overview of recent observational studies

Early studies suggesting an overall increase in cancer risk in insulin-treated diabetes had important limitations, most commonly due to a failure to allow for possible confounders, and will not be discussed in more detail here.[1]

A recent systematic review and meta-analysis found a positive association between new use of human and glargine insulin and carcinoma of the pancreas, but no association between ever-use of either insulin and any form of cancer.[2] This emphasises the importance of the temporal relationship is assessing cancer risk.

Temporal Relationships

More recent studies have shown that there are indeed increased rates of cancer in insulin users, but that cancer incidence declined significantly during follow-up.[3] In the Danish population, the excess number of cancer diagnoses in those with diabetes was plotted against duration of insulin use, showing an increased rate ratio from 5 at the start of insulin therapy to about 1.25 after 5 years of insulin use.[4] One possible explanation for this is reverse causation whereby an undiagnosed malignancy causes a change in treatment. A second possibility is detection bias due to increased contact with the medical profession. Finally, it could be argued that insulin accelerates the progression of established but subclinical cancers, thus depleting susceptible individuals from the population and explaining the subsequent decline.

Similar patterns were seen in another study, covering 3.4 million patients. Here, the use of insulin was associated with an overall increased risk of cancer, but this increased risk was due to an association observed early in treatment only, suggesting that the association may not be causal.[5]

Breast cancer risk

Women using any type of insulin, as compared with metformin users, did not have an increased risk of breast cancer.[6] Others also described null-results for the risk of breast cancer for patients using insulin. [4][7]

Colorectal cancer risk

In 2004, Yang et al described an increased risk of colorectal cancer (CRC) for persons who used more than one year of insulin (insulin type unknown, HR 2.1 (95% CI: 1.2-3.4).[8] In 2008, this was also shown for prevalent users of insulin (insulin type unknown, OR 3.0 (95% CI: 1.1-8.9).[9] In 2009, the influence of glucose lowering therapies on cancer risk was evaluated in the THIN database. Compared with metformin, insulin therapy (any type) increased the risk of CRC (HR 1.7, 95% CI 1.2–2.3).[6] In addition, race specific estimates have also been described to differ.[10] However, others were not always able to confirm these increased risks.[4][11][12]

Lung cancer

Shortly after being introduced to the market, human insulin for inhalation was voluntarily withdrawn as a consequence of disappointing sales in 2008. However, there were also concerns about the suspicion that a high insulin concentration in the lung may increase the risk of lung cancer. Data from the pharmaceutical company showed an increased incidence of lung cancer of 0.13 per 100 patient years for those exposed, versus 0.02 for those unexposed. However, data were insufficient to establish a causal role for the product.[13]

For use of insulin via non-respiratory administration, others could not establish an increased risk of lung cancer.[14] However, more recently, it was described that incident users of non-respiratory administered insulin had increased rates of lung cancer in comparison to non-users.[4]

Pancreatic and liver cancer

Insulin has also been associated with an increased risk of pancreatic cancer and hepatocellular carcinoma. Patients with long-standing diabetes treated for more than five years with insulin, were described to have an increased risk of pancreatic cancer (insulin type unknown, RR 6.0 (1.5-24.4).[15] This was confirmed by others although different point estimates were described, depending on the used time windows.[4][6][16][17][18] In 2009, Li et. al. described that in diabetics, use of insulin was associated with a five times increased risk of pancreatic cancer compared to no use of insulin (OR 5.0, 95% CI 2.6-9.6).[17] Others described that use of oral glucose lowering drugs for five or more years was not associated with pancreatic cancer, but that insulin use for less than five years was associated with a nearly seven-fold increased risk (OR 6.8, 95% CI 3.7-12.0).[18] More recently, it was demonstrated that rate ratio curves by duration of insulin use show a high risk of pancreatic cancer at the beginning, decreasing during the first three year to moderately increased levels.[4] The authors suggested that this is most likely due to reverse causation where an undiagnosed malignancy causes a change in treatment (in this case start of insulin). Furthermore, an increased risk of hepatocellular carcinoma was described for use of insulin (insulin type unknown, OR 3.0, 95% CI 1.3 - 6.7).[19] Also, incident users of insulin, showed increased rate ratios compared to non-insulin users.[4] However, not all studies could confirm these associations.[12][20] In our opinion, especially with regard to pancreatic cancer and hepatocellular carcinoma, reverse causation is an issue of concern.

Prostate cancer risk

In 2008, in a case-control study in which users of glucose lowering drugs were compared with non-users, use of insulin was associated with a decreased risk of prostate cancer (OR 0.8, 95% CI 0.7-0.9).[21] However, also this finding could not be confirmed by others.[4][6]

Conclusion

Insulin has frequently been linked to an increased risk of pancreatic cancer, but this is mainly seen in recent users and might be due to detection bias or reverse causation. Here, hypothetically, a yet undiagnosed cancer causes changes in the glucose metabolism and may lead to the diagnosis of diabetes or changes in treatment. However, it could also be argued that there is depletion of susceptibles, leaving fewer people prone to develop cancer. More studies are needed to further unravel the association between diabetes and pancreatic cancer. It would be interesting to compare people with diabetes treated with glucose lowering drugs as against diet alone.

For breast cancer, no excess cancer risk could be established. For prostate cancer, which occurs less frequently in diabetic patients than in the healthy population, a decreased risk has been described. However, the number of studies is too small to allow firm conclusions.

Colorectal cancer has been more intensively studied, but with conflicting results. More studies on the risk of colorectal cancer in relation to insulin use are needed as well.

References

  1. ^ Hemkens LG, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52:1732-44.

  2. ^ Colmers IN et al. Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. Diabetes Metab 2012;38:485-506.

  3. ^ van Staa TP, et al. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia 2012;55:654-65.

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

  5. ^ Andersson C, et al. Risk of cancer in patients using glucose-lowering agents: a nationwide cohort study of 3.6 million people. BMJ Open 2012;2.

  6. ^ Currie CJ, et al. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-77.

  7. ^ Bodmer M, et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 2010;33:1304-8.

  8. ^ Yang YX, et al. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044-50.

  9. ^ Chung YW, et al. Insulin therapy and colorectal adenoma risk among patients with Type 2 diabetes mellitus: a case-control study in Korea. Dis Colon Rectum 2008;51:593-7.

  10. ^ Vinikoor LC, et al. The association between diabetes, insulin use, and colorectal cancer among Whites and African Americans. Cancer Epidemiol Biomarkers Prev 2009;18:1239-42.

  11. ^ Campbell PT, et al. Prospective study reveals associations between colorectal cancer and type 2 diabetes mellitus or insulin use in men. Gastroenterology 2010;139:1138-46.

  12. ^ Oliveria SA, et al. Cancer incidence among patients treated with antidiabetic therapy. Diabetes Metab Syndr 2008;2:45-57.

  13. ^ Mitri J, et al. Inhaled insulin--what went wrong. Nat Clin Pract Endocrinol Metab 2009;5:24-5.

  14. ^ Lai SW, et al. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin Lung Cancer 2012;13:143-8.

  15. ^ Bonelli L, et al. Exocrine pancreatic cancer, cigarette smoking, and diabetes mellitus: a case-control study in northern Italy. Pancreas 2003;27:143-9.

  16. ^ Bodmer M, et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012;107:620-6.

  17. ^ Li D, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009;137:482-8.

  18. ^ Wang F, et al. Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev 2006;15:1458-63.

  19. ^ Donadon V, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 2009;15:2506-11.

  20. ^ Hassan MM, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010;116:1938-46.

  21. ^ Murtola TJ, et al. Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am J Epidemiol 2008;168:925-31.

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