Correspondence

Insulin glargine and cancer: another side to the story?

In their Comment (Aug 15, p 511),1 Stuart Pocock and Liam Smeeth review four papers25 and an editorial6 in Diabetologia, which raise concern about the possibility that insulin glargine might increase the risk of cancer, and declare that there is no conclusive evidence of this. They go on to remark that claims of harm not backed by adequate evidence can provoke unnecessary alarms and anxieties. Coming as it does from one of the iconic gures in medical statistics, this statement implies that the journal I edit has acted in an irresponsible and alarmist manner. I would like to suggest otherwise. The question at issue is whether insulin glargine promotes the growth of cancer cells in vivo, as it does in vitro. Insulin is mitogenic; it promotes DNA synthesis and cell division. Insulin glargine is 68-fold more mitogenic than human insulin, and breast cancer cells proliferate in response to near-therapeutic concentrations of this analogue.6 Since studies in man are clearly needed, it seems a pity that sanoaventis have denied a possible risk, rather than doing the studies needed to resolve it. Drug safety studies are rarely conclusive; their role is to draw attention to possible danger, and this is what we have done. In this instance two studies done in parallel found an increased risk of breast cancerthe prime suspectin women treated with insulin glargine alone. We consider this a warranted concern. We faced a dilemma when presented with a paper which reported a possible relation between insulin glargine and cancer development in human beings.2 Its strengths included large size (127 000 insulin-treated patients) and its attempt to consider cancer development in relation to insulin
www.thelancet.com Vol 374 August 15, 2009

dosean essential component of any future analysis. The study also had evident limitations.6 We therefore concluded that it was too important to ignore, yet too weak to be published in isolation. Replication is the constructive alternative to rejection, and national registries in Sweden3 and Scotland4 were invited to examine this question. Those concerned accepted that this was a matter of urgent public interest, and undertook the extensive analyses involved without external funding. The two national registry studies are dismissed by Pocock and Smeeth in three sentences, two of which contain important errors of fact. Pocock and Smeeth state that breast cancer was not predened as the tumour site of primary concern, but the analysis was indeed predened in terms of the tumours of greatest biological relevance, namely those of the breast, colon, and pancreas. The Swedish registry found a twofold increase in breast cancer in those treated with insulin glargine alone, compared with users of insulins other than glargine, and the Scottish study (incorrectly described as negative) made exactly the same ndingie, an increased rate of breast cancer in those using insulin glargine alone, compared with non-glargine insulin users (hazard ratio 339, 95% CI 146785; p=0004). Pocock and Smeeth are fully justied in pointing out the limitations of studies such as those we report, and they are right to highlight the heavy responsibility that rests on those who question the safety of a popular and widely used treatment such as insulin glargine. Readers must judge for themselves whether we discharged this responsibility adequately. They will, I hope, notice that no claims of harm were made in any of the four papers or the accompanying editorial. The initial study from Germany2 was published with clear acknowledgment of its limitations,

and the three commissioned studies, one of which was entirely negative,5 were carefully done and of high quality. Every eort was made to put this information into the public domain with the maximum of caution and the minimum of fuss. We acknowledge the anxiety and distress that these reports might have generated, but we also believe that people have every right to be informed of possible danger. Imperfect information is better than uninformed ignorance. Finally, we note that an expert panel convened by sano-aventis,7 although critical of the studies reported in Diabetologia, nonetheless acknowledged that important scientic and therapeutic questions have been raised which require investigation. This was our own conclusion.
I declare that I have no conicts of interest.

See Comment page 511

Edwin A M Gale
Edwin.Gale@bristol.ac.uk
Diabetes and Metabolism, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, UK 1 Pocock SJ, Smeeth L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 2009; 374: 51113. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; published online June 30. DOI:10.1007/s00125-009-1418-4. Jonasson JM, Ljung R, Talbck M, Haglund B, Gudbjrnsdttir S, Steineck G. Insulin glargine use and short-term incidence of malignanciesa population-based follow-up study in Sweden. Diabetologia 2009; published online July 9. DOI:10.1007/s00125009-1444-2. Scottish Diabetes Research Network. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; published online July 15. DOI:10.1007/s00125-009-1453-1. Currie CJ, Poole CD, Gale EAM. The inuence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; published online July 2. DOI:10.1007/s00125009-1440-6. Smith U, Gale EAM. Does diabetes therapy inuence the risk of cancer? Diabetologia 2009; published online July 14. DOI:10.1007/ s00125-009-1441-5. Sano-aventis expert statement, July 16th 2009. http://en.sano-aventis.com/ binaries/20090716_Expert_Statement_EN_ tcm28-25680.pdf (accessed July 21, 2009).

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