All the HRs reported in the text below are adjusted for age (since age was the timescale of the model), calendar time, prior cancer and type of diabetes, as appropriate, and are stratified by sex, unless stated otherwise.
A total of 36,254 people were receiving any type of insulin therapy during the 4 month exposure evaluation period (July to October 2003). There were 3,959 people on insulin glargine; the majority (n = 3,512) were receiving insulin glargine with another insulin and the remaining 447 patients were receiving insulin glargine as their sole insulin. Table 1 shows the baseline characteristics of those included in the fixed cohort analysis according to insulin glargine exposure. There were significant and large differences in baseline characteristics across the three exposure groups especially, of course, with respect to the prevalence of type 1 diabetes. When these comparisons were restricted to the 19,899 insulin users with definite type 2 diabetes (Table 2), compared with users of non-glargine insulin alone, those on non-glargine plus glargine insulin were younger, and values adjusted for age and sex indicated that they had a lower BMI and less CVD, but worse glycaemic control. For diabetes duration, the non-glargine plus glargine insulin group had a lower prevalence of diabetes duration at least 5 years, but, adjusted for age, they had a higher prevalence (OR 1.38, 95% CI 1.25–1.52, p < 0.0001). They also had a lower prevalence of ever smoking and were less likely to be on any concomitant oral therapy at baseline. Compared with users of non-glargine insulin alone, insulin glargine only users were older, had similar BMI but higher diastolic BP, worse glycaemic control but shorter duration of diabetes, and were much more likely to be on concomitant oral therapy at baseline (Table 2).
A total of 715 incident cancers occurred in this cohort during follow-up in 36,254 subjects (1.97%, 0.95 events per 100 person-years at risk). Among those receiving any insulin glargine (regardless of whether they received any other type of insulin), 1.29% had a cancer compared with 2.06% of those on non-glargine insulin alone. There was no overall difference in all cancer rates in those receiving vs those not receiving insulin glargine (HR 1.02, 95% CI 0.77–1.36, p = 0.9). For breast cancer, there was no significant difference between insulin glargine users vs users of non-glargine insulin alone (HR 1.49, 95% CI 0.79–2.83, p = 0.22). None of the other site-specific cancer rates were associated with insulin glargine use.
Table 3 shows the number of cancers that occurred, together with their cumulative incidence (%), plus the age- and sex-adjusted HR for the fixed cohort for the three insulin exposure categories. Compared with those using non-glargine insulin alone, those who were using non-glargine plus glargine insulin had a slightly, but non-significantly, lower rate of cancer, but those using insulin glargine alone (all of whom would have type 2 diabetes) had a higher rate of cancer, which was of borderline statistical significance. Adjusting for further covariates in those on insulin glargine only made very little difference to the HR (change from 1.55 to 1.73, most of which was due to slight differences in the numbers available for the models; the HR for model 1 restricted to those with complete data for model 4 was 1.63, 95% CI 0.95–2.78, p = 0.074). Restricting the model to those without any prior cancer only slightly altered the HRs for those on non-glargine plus glargine insulin (0.78, 95% CI 0.53–1.16) and those on insulin glargine alone (1.64, 95% CI 1.05–2.54). In another model we examined the same associations conditional upon survival for the first year (to examine whether all the effects are early after treatment initiation or conversely affected by a lag time) but this made no difference (data not shown).
When the analyses were restricted to the 19,899 definite type 2 diabetic patients there was no difference in cancer rates between insulin glargine users (irrespective of whether they were using any other type of insulin) vs users of non-glargine insulin (HR 1.08, 95% CI 0.78–1.49, p = 0.64 ). When the three exposure categories were examined, a pattern similar to that in the cohort as a whole was seen, with higher rates in those using insulin glargine alone (HR 1.58, 95% CI 1.03–2.42, p = 0.037) compared with those using non-glargine insulin alone. There was no significant effect of baseline exposure to any of the oral diabetes drugs on cancer rate when evaluated separately, and adjusting for these variables made no difference to the effects of insulin glargine. When the analyses were restricted to type 1 diabetic patients, the HR for non-glargine plus glargine insulin users was closer to, and not statistically significantly different from, unity (HR 1.02, 95% CI 0.50–2.09, p = 0.9).
Table 4 shows the HRs for site-specific cancer associated with exposure to insulin glargine and the effect of adjusting for covariates in the fixed cohort. The number of cancers by site is so small that power is low. However, 92 cases of breast cancer occurred in the women, six of which were in insulin glargine only users. Overall, insulin glargine use was not associated with an increased risk of breast cancer (HR 1.49, 95% CI 0.79–2.83, p = 0.2), but as shown in Table 4, the pattern seen for all cancers combined was replicated: there was a significantly higher rate in insulin glargine only users compared with users of non-glargine insulin alone. Adjustment for covariates generally made little difference. When restricted to type 2 diabetes, the same pattern was observed. For lung and colon cancer, a similar pattern of HRs above 1 in insulin glargine only users and HRs below 1 in non-glargine plus glargine insulin users was observed, but none of the HRs was statistically significant.
Incident cohort analysis
There were 12,852 definite type 2 diabetic patients who received insulin for the first time between 1 January 2002 and 31 December 2005, 12,845 of which had follow-up data. Electronic supplementary material (ESM) Table 1 shows the baseline characteristics in the three exposure categories. The characteristics of these incident users differ from those of the fixed cohort, and the between-group differences in baseline characteristics are different to those seen in the fixed cohort. Compared with those on non-glargine insulin only, insulin glargine only users were, like those in the fixed cohort, older and had a higher BP but, unlike those in the fixed cohort, they had a slightly longer duration of diabetes, similar glycaemic control and less CVD.
A total of 378 cancers occurred in this incident cohort (Table 5). Overall, the incidence of cancer was not different between insulin glargine users (regardless of what other type of insulin was used by them) vs users of non-glargine insulin alone (HR 0.93, 95% CI 0.70–1.25, p = 0.64). Unlike in the fixed cohort analysis, the incidence rate in insulin glargine only users was not higher than in users of non-glargine insulin alone (HR 0.87, 95% CI 0.63–1.21, p = 0.41), and this was also the case when adjustment for covariates was made (Table 5). Restricting the analysis to only include patients with type 2 diabetes did not alter this pattern. For site-specific cancers, the numbers are very small, but show no significant difference in breast cancer rates, although the HR is 1.47 for insulin glargine only users vs non-glargine insulin only users. It should be noted that the number of insulin glargine only users in this analysis is higher than that in the fixed cohort, which is expected given that insulin glargine use has increased since its introduction.
Analysis summarising exposure across the entire follow-up
In the analysis in which we summarised exposure across the entire follow-up period overall (see ESM), we included 49,197 patients who received a prescription for insulin therapy at some point between 1 January 2002 and 31 December 2005, in whom 1,523 cancers occurred (see ESM Tables 2, 3, 4). Overall, among those receiving any insulin glargine (regardless of what other insulin was used by them), there was a significantly lower rate of total cancers (HR 0.69, 95% CI 0.60–0.79, p < 0.0001) when adjustments were made for sex, prior cancer, calendar period and type of diabetes. When we further examined whether the years of cumulative exposure to insulin glargine was associated with cancer rate, this lower HR was lowest in those with at least 2 years of exposure (HR 0.60, 95% CI 0.51–0.70). Those on non-glargine plus glargine insulin had a significantly lower incidence rate of cancers than those on non-glargine insulin only (HR 0.53, 95% CI 0.45–0.63), and those on insulin glargine alone had a significantly higher incidence rate of cancer than those on non-glargine insulin only (HR 1.28, 95% CI 1.04–1.59). The same pattern was seen when those with prior cancer were excluded and when the analysis was restricted to type 2 diabetes. For breast cancer, there was a slightly higher incidence among those on insulin glargine alone compared with those on non-glargine insulin (HR 1.33, 95% CI 0.69–2.56); this difference was non-significant.