Of the 241
111 patients prescribed antidiabetic agents during the study period, 115
727 met the study inclusion criteria (figure). The mean age at cohort entry was 64.1 (SD 12.0) years, and the mean duration of follow-up was 4.6 (SD 3.6) years. At cohort entry, the median HbA1c
was 8.2%, and in descending order, most patients received metformin monotherapy (67%), followed by sulfonylurea monotherapy (30%), and thiazolidinedione monotherapy (0.5%), whereas the rest used other agents or combinations of agents (3%). No patients received insulin at cohort entry, as per the inclusion criteria. The mean duration of pioglitazone use among controls was 2.2 (SD 1.5) years (range 28 days to 6.7 years) and was similar for rosiglitazone, where the mean duration was 2.3 (SD 1.5) years (range 28 days to 7.6 years).
Fig 1Flow of participants through study
A total of 470 patients had a diagnosis of incident bladder cancer during 526
559 person years of follow-up, yielding an overall rate for bladder cancer of 89.4 per 100
000 person years (95% confidence interval 81.4 to 97.7); the incidence rate of bladder cancer in the general UK population was 73 per 100
000 person years in 2008, for a population aged at least 65 years.24
The higher incidence rate observed in our cohort is consistent with data suggesting an association between type 2 diabetes and an increased risk of bladder cancer.25
The primary analyses were restricted to 376 cases, matched to 6699 controls, with at least one year of follow-up between cohort entry and index date to account for latency. Table 1 presents the characteristics of these cases and matched controls. Cases were predominantly male. Known risk factors significantly associated with bladder cancer were smoking, previous diagnoses of cancer (other than non-melanoma skin cancer), and a higher comorbidity score. Table 2 presents the patterns of use of the different antidiabetic agents, measured between cohort entry and the year before the index date, among cases and matched controls.
Table 1 Baseline characteristics of bladder cancer cases and matched controls. Values are numbers (percentages) unless stated otherwise
Table 2 Patterns of antidiabetic agents received between cohort entry and year before index date among cases of bladder cancer and matched controls*
Exclusive ever use of pioglitazone was associated with an 83% increased rate of bladder cancer (adjusted rate ratio 1.83, 95% confidence interval 1.10 to 3.05, table 3). This corresponded to an absolute adjusted rate difference of 74 per 100
000 person years (95% confidence interval 9 to 140). This effect was not observed for exclusive ever use of rosiglitazone (adjusted rate ratio 1.14, 95% confidence interval 0.78 to 1.68), the other thiazolidinedione available in the United Kingdom during the study period.
Table 3 Thiazolidinediones and risk of bladder cancer among cases of bladder cancer and matched controls*
Participants prescribed thiazolidinediones were more likely to be obese, to have ever smoked, and to have uncontrolled diabetes than those who never used any thiazolidinedione. Exclusive ever users of pioglitazone and rosiglitazone, however, were generally similar on most variables, and both groups had lower comorbidity scores than participants who never used any thiazolidinedione (see supplementary table 1). In a sensitivity analysis to assess confounding by indication, we compared exclusive ever users of pioglitazone with exclusive ever users of rosiglitazone. The adjusted rate ratio was numerically increased but did not reach statistical significance (adjusted rate ratio 1.60, 95% confidence interval 0.88 to 2.90) owing to few users (19 v 36). None the less, the results of this sensitivity analysis are consistent with those of our primary analysis.
There was evidence of a dose-response relation between pioglitazone use and the rate of bladder cancer (table 4). In terms of cumulative duration of use, the rate of bladder cancer increased as a function of duration of use, with the highest rate observed in users of more than 24 months (adjusted rate ratio 1.99, 95% confidence interval 1.14 to 3.45), corresponding to an absolute adjusted rate difference of 88 per 100
000 person years (95% confidence interval 12 to 165). For cumulative dosage, a statistically significant association was observed in patients who received more than 28
000 mg (2.54, 1.05 to 6.14), corresponding to an absolute adjusted rate difference of 137 per 100
000 person years (95% confidence interval 4 to 271). There was no evidence of a dose-response relation with rosiglitazone, both for cumulative duration of use and cumulative dosage (see supplementary table 2).
Table 4 Pioglitazone cumulative duration of use and cumulative dosage and risk of bladder cancer among cases of bladder cancer and matched controls*
To incorporate a latency time window, the primary analysis was restricted to the 376 cases and their matched controls that had at least one year of follow-up before their index date. In a sensitivity analysis, we repeated the analyses without considering a latency time window. These analyses included all 490 cases and their matched controls. The exclusion of the latency window did not alter our results appreciably, as only one case was exposed to pioglitazone in the first year of follow-up (data not shown). In a second sensitivity analysis, we redefined exclusive ever use of pioglitazone and rosiglitazone as receiving at least three prescriptions within a 12 month period. Compared with the results of the primary analysis, this analysis yielded a slightly higher point estimate for pioglitazone (adjusted rate ratio 1.88, 95% confidence interval 1.10 to 3.22) but a slightly lower one for rosiglitazone (1.11, 0.74 to 1.66), indicating minimal misclassification of use. Finally, categorising cumulative duration and cumulative dosage of pioglitazone into three categories produced results consistent with those of our primary analyses on duration and dose (data not shown).