follow-up (that is, the time since start of oral antidiabetic
therapy), which has been shown to be a good proxy for disease
and adjusting the models for HbA
, although this
information was missing for 19% of the cases and controls.
However, the lack of any association with rosiglitazone (a
thiazolidinedione sharing the same indication as pioglitazone)
both in crude and adjusted models and our direct comparison
of pioglitazone with rosiglitazone in a sensitivity analysis
strongly suggests that disease severity did not confound the
association between pioglitazone and bladder cancer. The
general practice research database does not collect information
on tumour grade and stage but has been shown to have
comparable case ascertainment rates as UK cancer registries.
Another limitation of the general practice research database is
the lack of information on certain risk factors for bladder cancer.
These include exposure to arsenic, occupational exposures,
race/ethnicity, and family history of bladder cancer. However,
it is unlikely that these variables were differentially distributed
between ever users of pioglitazone and ever users of other oral
hypoglycaemic agents. Thus we do not believe that the absence
of these variables affected the internal validity of the study,
although residual confounding may still be present. Finally, the
general practice research database contains information on
several important confounders, such as body mass index,
excessive alcohol use, and smoking. Therefore we were able to
adjust for a number of important variables often absent in
Conclusions and policy implications
In summary, the results of this study provide evidence that
pioglitazone is associated with an increased risk of bladder
cancer, whereas no increased risk was observed with the
thiazolidinedione rosiglitazone. The increased risk associated
with pioglitazone became apparent after use for at least 24
months and receiving cumulative dosages greater than 28 000
mg. Such associations may have been underestimated in the
previous observational studies that included prevalent users.
While the magnitudes of the rate ratios were relatively high, the
risks associated with pioglitazone are in absolute terms low.
Indeed, in this study the highest durations of use and cumulative
dosage increased the rate of bladder cancer by 88 and 137 cases
per 100 000 person years, respectively. Thus doctors, patients,
and regulatory agencies should be aware of this association
when assessing the overall risks and benefits of this therapy.
LA is the recipient of a Chercheur-Boursier award from the Fonds de
la recherche en santé du Québec and SS is the recipient of the James
Contributors: All authors participated in the study design. SS acquired
the data. LA and HY did the analyses. LA wrote the manuscript and all
authors participated in the interpretation of the results and critical revision
of the manuscript. LA is the guarantor.
Funding: This study was supported by grants from the Canadian
Institutes of Health Research and the Canadian Foundation for
Innovation. The funding sources had no role in the design, analysis,
and interpretation of the results, and thus the authors were independent
from the funding source.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author) and declare: MNP served as a
consultant for Novo Nordisk and Sanofi-Aventis and received research
funding from Novo Nordisk; no other financial relationships with any
organisations that might have an interest in the submitted work in the
previous three years; and no other relationships or activities that could
appear to have influenced the submitted work.
Ethical approval: This study was approved by the independent scientific
advisory committee of the general practice research database and the
research ethics committee of the Jewish General Hospital, Montreal,
Data sharing: No additional data available.
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BMJ 2012;344:e3645 doi: 10.1136/bmj.e3645 (Published 31 May 2012) Page 5 of 11