Insulin Analogues and Cancer Risk: Cause for Concern or Cause Célèbre?

M. Pollak; D. Russell-Jones

Disclosures

Int J Clin Pract. 2010;65(5):628-636. 

In This Article

What is the Clinical Evidence Linking Insulins and Cancer?

First, it should be noted that, for patients with insulinopenic diabetes, insulin therapy is a clinical necessity to limit morbidity and mortality. With regard to cancer risk, it is therefore a matter of determining whether there are choices to be made based on any difference in risk between insulins. The available evidence is somewhat ambiguous and inconsistent. There are, however, some observations that we believe indicate the need for further study.

Hemkens and colleagues conducted a cohort study using insurance records of more than 127,000 patients treated in Germany with insulin glargine, insulin aspart, insulin lispro or human insulin.[1] They found a dose-dependent association between use of all these insulins and cancer. Compared with human insulin, the dose-dependent risk increase was steep for insulin glargine (HR 1.31 for 50 IU dose, p < 0.0001), but not for insulin aspart or insulin lispro. It should be noted that the finding of an excess cancer risk with insulin glargine only emerged after adjustment for dose; patients receiving human insulin had higher mean doses and the risk of malignancy before adjustment was lower with all three insulin analogues than with human insulin. This study is, nevertheless, important because of the large numbers of individuals involved. However, as with any retrospective cohort study, it is limited by the fact that patients were not randomised to treatment groups and despite corrections for all available confounders, several potentially relevant factors, such as body mass index and duration of diabetes were not available.

The serious questions raised by the analysis performed by Hemkens and colleagues and the equally serious reservations regarding its methodology and the apparent biological implausibility (to reviewers in the arena of diabetology) of cancer development in the short follow-up of 1.31 years, led to the commissioning of a number of confirmatory studies.[5] Jonasson and co-workers examined Swedish registry data for almost 115,000 patients who had received insulin during a 6-month period in 2005.[2] They found that during the subsequent 2-year period, the risk of developing breast cancer among women receiving insulin glargine monotherapy was significantly higher than among those using other insulins (RR 1.99, 95% CI, 1.31–3.03). Risk of development of other forms of cancer and of malignancy overall, however, was not significantly elevated with insulin glargine compared with other insulins. As with the German study, this analysis had limitations: principally that there was no dose information available, and thus no correction for dose was possible; that all other insulins including other analogues were combined in the control group (which raises the question of what is the most appropriate reference group in studies of cancer risk with insulin) and the fact that, again, this was not a randomised study and thus some degree of selection bias is inevitable.

Colhoun and colleagues examined the national registry data of almost 50,000 insulin-treated patients in Scotland.[3] Overall, exposure to insulin glargine (with or without bolus insulins) was associated with a reduced rate of total cancers (RR 0.66, 95% CI, 0.57–0.76). In common with the previous studies, however, patients receiving insulin glargine alone had a higher risk of cancer than those receiving another insulin without insulin glargine (RR 1.66, 95% CI, 1.06–2.60), with a significant increase in risk of breast cancer (RR 4.37, 95% CI, 1.64–11.7). The plausibility of a modifying effect of co-administration of another insulin on the relationship of glargine to cancer risk is open to question. A further UK analysis by Currie and co-workers examined people with type 2 diabetes treated in UK general practice and treated with insulin or oral antidiabetic agents.[4] Patients treated with metformin had significantly lower risk of development of solid tumours, compared with those treated with sulphonylurea (RR 1.36, 95% CI, 1.19–1.54) or insulin-based therapy (RR 1.42, 95% CI, 1.27–1.60). No significant differences in cancer risk were detectable among the four insulin categories, namely insulin glargine, human basal insulin, human biphasic insulin and analogue biphasic insulin. The apparent protective effect of metformin is consistent with other research, including an early study by Evans et al[49] and a more recent one by Libby and colleagues,[50] in which patients with type 2 diabetes treated with metformin had a lower risk of cancer than those without record of metformin use; it is plausible that the effects of metformin are mediated by the reduction of insulin levels observed when this agent is given to hyperinsulinaemic patients, and/or to direct antiproliferative actions on cancer cells involving activation of AMP kinase.[19,51–54]

A prospective trial assessing the effect of insulin glargine on proliferative retinopathy was also recently reported.[55] This 5-year study is of interest because IGF-1 is implicated in the pathophysiology of proliferative retinopathy.[56] The study reported by Rosenstock and colleagues showed no difference between insulin glargine and NPH insulin with regard to progression of retinopathy. When the database used for the retinopathy analysis was retrospectively analysed for cancer endpoints, no increase was seen with insulin glargine, although it is to be noted that the study was not designed nor powered to detect relatively infrequent cancer endpoints, the comparison of serious malignancies being based on up to 31 events per group. The findings regarding retinopathy are reassuring and robust; however, as the mechanism of IGF-1 involvement with retinopathy is likely to be paracrine, no extrapolation should be made from these results per se to systemic cancer risks.

Data from this study have, however, also been combined with those from a further 30 studies (mostly of 6 months' duration) from the manufacturer's database to enable a comparative assessment of glargine vs. pooled comparators (mostly NPH insulin) to be made in a total of 9235 patient-years of treatment exposure.[57] In this analysis, 52 treatment-emergent malignancies were documented in 45 of 5675 glargine-treated patients (0.8%), vs. 48 cases in 46 of 5223 patients from comparator groups. Most of these cases occurred in patients with type 2 diabetes and there were no significant differences in the overall or prespecified cancer rates between the insulin glargine and pooled comparator groups. Dose–response relationships or comparisons by regimen were not assessed in this analysis.

Further epidemiological data are available from a meta-analysis of the Novo Nordisk database of clinical trials involving insulin detemir.[58] Here, the data again suggest very low absolute event rates, with the relative risk for malignancy with insulin detemir being statistically significantly lower than for NPH insulin: 0.36 vs. 0.92 events per 100 patient-years of exposure, p < 0.05 (based, respectively, on 2252 and 1420 patient-years of exposure). A comparison of insulin detemir with insulin glargine (most data in type 2 diabetes) gave respective values of 0.87 and 1.27 events per 100 patient-years (NS), but this was based on only 917 and 628 patient-years of exposure.

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