Insulin analogs and cancer

One of the early insulin analogs, AspB10, was withdrawn from development because of an excess of mammary cancers in rats. This appeared to be related to increased mitogenicity relative to human insulin, and there have been concerns about insulin glargine which shares this property. Insulin glargine is however partially broken down into less mitogenic molecules following injection, so its in vivo properties cannot be inferred from laboratory studies. One epidemiologic analysis suggested an overall increase in cancer risk in patients taking insulin glargine, but subsequent epidemiologic and trial data have largely dispelled this concern. Furthermore, no overall increase in cancer risk was shown in ORIGIN, a large prospective trial which included patients on glargine. Several epidemiologic analyses have however suggested a small increase in risk of post-menopausal breast cancer in glargine users, whereas other studies have been negative. The possibility of a small excess risk of this cancer cannot therefore be excluded.

Epidemiologic Evidence

A number of epidemiologic studies have reported an increased risk of cancer outcomes associated with use of exogenous insulin [1][2]. There has been particular concern in relation to the long-acting analog, insulin glargine, which has been shown in vitro to have increased mitogenicity relative to human insulin[3]. Considerable controversy surrounded the publication of an initial observational study that suggested an increased overall cancer risk with insulin glargine therapy[4]. This finding has not been replicated in subsequent epidemiologic analyses nor in available available trial evidence. It is therefore generally accepted that insulin glargine is not associated with an overall increased risk of cancer.

It has further been shown that insulin glargine, while more mitogenic than human insulin in vitro, is partially broken down into less mitogenic moieties following injection, and that its in vivo effects cannot therefore be inferred from laboratory studies.

Of interest, recent findings from the ORIGIN trial found no difference in incident cancers with use of basal insulin (insulin glargine) for over 6 years, as compared with standard care (metformin and sulfonylurea therapy). Therefore, their data do not support previous epidemiologic analyses[5] While any conclusions are premature at this point, these results from the ORIGIN trial definitely raise questions as to strength of the hyperinsulinemia hypothesis in explaining this relationship.

Insulin Glargine and Breast cancer

Although no overall increase in cancer risk has emerged, a number of subsequent studies have reported an increased risk of post-menopausal breast cancer with longer-term insulin glargine use[6][7][8]. In contrast, a large French study found an increased risk of breast cancer in women taking human insulin as compared with insulin glargine[9]. A further study of older patients found no primary association with insulin glargine and breast cancer, but combination therapy (glargine plus non-glargine insulin) carried an increased risk, particularly at high dose[10]. A large-scale population-based epidemiologic study found no increase in the risk of breast cancer over 5 years of insulin glargine use, but there was a signal for an increased risk of breast cancer associated with longer-term use, particularly in women who were on other types of insulin prior to starting glargine[11].

In contrast to these findings, the ORIGIN Trial found no increased risk of breast cancer. However, the number of women exposed and breast cancer events was far fewer, and the duration of exposure shorter, as compared to the observational studies5.

In summary, no clear link has been established between use of insulin glargine and breast cancer, but a small increase in risk cannot be excluded.

References

  1. ^ 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.

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

  3. ^ Kurtzahls P et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005.

  4. ^ 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.

  5. ^ The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dyslgycemia. N Engl J Med 2012;367:319-28.

  6. ^ Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:1755-65.

  7. ^ Jonasson JM et al. Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden. Diabetologia 2009;52:1745-54.

  8. ^ Ruiter R et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia 2012;55:51-62.

  9. ^ Blin P et al. Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database. Diabetologia 2012;55:644-53

  10. ^ Morden NE et al. Further exploration of the relationship between insulin glargine and incident cancer. Diabetes Care 2011;34:1965-71.

  11. ^ Suissa S et al. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia 2011;54:2254-62.

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.