Insulin glargine use and short-term incidence of breast cancer — a four-year population-based observation

To the Editor,

We have previously published cancer incidence data among insulin glargine users; during 2006 and 2007 we found an increased risk of breast cancer in Swedish women using insulin glargine alone [1]. In an updated analysis for 2008 we found no increased risk of breast cancer in 2008 among women using insulin glargine alone [2].

We have now updated our previously reported cohorts with breast cancer incidence data for 2009. The Prescribed Drug Register, the Cancer Register, and the Causes of Death Register were used to obtain information on targeted person-time and outcome. For details see Jonasson et al. and Ljung et al. [1,2].

Ethical considerations

This study was approved by the regional ethics committee in Gothenburg (DNR: 612-08).

We studied three separate cohorts based on when exposure was defined. In the first cohort we studied 47 765 women who were 35–84 years old at the end of 2005, had at least one prescription dispensed for insulin between 1 July and 31 December 2005, and were alive at the start of follow-up (1 January 2006). We studied the first diagnosis of a primary breast cancer as an outcome measure, excluding individuals who received this diagnosis at any time between 1 January 1958 and 31 December 2005. We followed the subjects from 1 January 2006 to 31 December 2009 for a diagnosis of breast cancer, loss to follow-up (censorship), death, or end of study. For the second, 49 227 women, and third, 50 909 women, cohort we defined exposure during the last six months in 2006 and 2007, respectively, with follow-up during 2007–2009 and 2008–2009, respectively.

Categories of insulin use

Individuals entered as having prescriptions dispensed for insulin glargine (Anatomical Therapeutic Chemical (ATC) code [3] A10AE04) but no prescriptions dispensed for other types of insulin (ATC code A10A) were classified as using insulin glargine alone. Having prescriptions dispensed for both insulin glargine and another type of insulin classified the individual as a user of insulin glargine in combination with other types of insulin. Having prescriptions dispensed for insulin but not insulin glargine classified the individual as a user of types of insulin other than insulin glargine. We also analysed insulin glargine use as a whole, regardless of whether it was used alone or in combination with other insulins.

Outcomes

We studied: ‘breast cancer’ (International Classification of Diseases, 10th revision (ICD-10) code C50) restricted to tumours that were histopathologically classified as adenocarcinoma. The number of subjects in the present analysis does not exactly match Jonasson et al. [1] or Ljung et al. [2] due to register updates correcting information and adding new late entries.

We used Poisson regression analyses to evaluate the association between the three groups of insulin users and breast cancer outcome. Table I shows the age-adjusted incidence rate ratios (IRR) for those who used insulin glargine alone, insulin glargine in combination with other insulin, and the joint group of any glargine users (the two previous groups combined), compared with those who only used types of insulin other than insulin glargine. For those on glargine alone during July–December 2005 with follow-up for 2006–2009, the IRR was 1.5 (1.1–2.1). For those where exposure was defined in 2006 and 2007, and with follow-up 2007 to 2009, and 2008 to 2009, respectively, the corresponding IRRs were 1.1 (0.7–1.8) and 0.5 (0.2–1.1), respectively.

Table I. Incidence rate ratio of breast cancer among users of insulin glargine compared with users of other types of insulins and not insulin glargine. Adjusted for age.

	2006–2007		2006–2008		2006–2009		2007–2009		2008–2009
	Cases	IRR (CI 95%)	Cases	IRR (CI 95%)	Cases	IRR (CI 95%)	Cases	IRR (CI 95%)	Cases	IRR (CI 95%)
Exp 2005*
Glargine alone	25	2.0 (1.3–3.0)	31	1.6 (1.1–2.3)	38	1.5 (1.1–2.1)
Glargine in combination	41	1.1 (0.8–1.5)	59	1.0 (0.7–1.3)	85	1.1 (0.8–1.4)
Any glargine use	66	1.3 (1.0–1.8)	90	1.1 (0.9–1.5)	123	1.2 (1.0–1.5)
Exp 2006*
Glargine alone							22	1.1 (0.7–1.8)
Glargine in combination							67	1.3 (1.0–1.7)
Any glargine use							89	1.2 (1.0–1.6)
Exp 2007*
Glargine alone									7	0.5 (0.2–1.1)
Glargine in combination									58	1.7 (1.2–2.3)
Any glargine use									65	1.3 (1.0–1.8)

*Filled prescriptions of glargine and other insulin during July to December the corresponding year.dfsd. CI, confidence interval; IRR, incidence rate ratio.

Discussion

With a follow-up in 2006 to 2009 the IRR of breast cancer is lower than when we observed 2006 and 2007 only and in the first update of 2006 to 2008. An analysis mirroring the approach in our previous publications, defining exposure during 2007 and follow-up in 2008 and 2009, did not yield an increased incidence of breast cancer for women who used insulin glargine alone compared with those who used types of insulin other than insulin glargine. This update adds to the impression that the increased incidence of breast cancer that we previously reported could be due to a random fluctuation in the studied Swedish population and did not reflect an actual effect of insulin glargine.

The main strengths of the present study include the large sample size, the complete nationwide coverage of all insulin prescriptions and of all primary breast cancer. The nationwide register-based design counteracts recall or selection bias. However, there are weaknesses that need a discussion. We did not use the possibility to adjust for confounding by relevant variables. However, previous analyses have shown no or little change in relative risk estimates before and after adjustment for confounding by relevant variables [1,2]. Also, we did not study whether there were signs of reverse causality as have been studied before [1].

It is not likely that a large-scale randomised trial to access the association of insulin glargine and other analogues with cancer incidence will be performed. Information on the safety of these drugs regarding cancer incidence will instead probably have to rely on observational studies. Two recent observational studies from other settings have analysed the association between insulin glargine and cancer incidence. In a study from the UK General Practice Research Database no association was found during the first five years of insulin glargine use and breast cancer, however, for long-term use there was an increased risk for breast cancer [4]. A case-control study from Italy found no association between insulin glargine use and all cause cancer. Though, among those on insulin glargine doses were higher among case subjects than among control subjects [5]. Thus, the scarce epidemiological data is inconclusive and we await with interest additional results from other settings.

We have previously reported on an increased incidence of breast cancer in 2006 and 2007 in Sweden among users of insulin glargine, in this update we do not see an increased risk during 2008 or 2009. We need data for additional years before we can state with reasonable certainty that the increase in breast-cancer incidence that we observed in Sweden in 2006 and 2007 happened by chance and not because insulin glargine increases breast-cancer risk.

Acknowledgements

Supported by Astrid and David Hagelén Foundation, Swedish Research Council, Swedish Diabetes Foundation, AGFOND, Konrad and Helfrid Johansson Foundation, VINNMER and VINNOVA. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Declaration of interest: RL and BH are also members of another international research collaboration that has received a grant from Sanofi-Aventis to study the association between insulin glargine and cancer.