BMJ publication of multi-country PASS study with contribution by PHARMO

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes

A Post Authorisation Safety Study (PASS), imposed by EMA after concerns had arisen of an increased risk of bladder cancer with pioglitazone use, was registered to the European Union electronic register of post-authorisation studies under register no EUPAS3626. Six cohorts were formed, consisting of a GP based cohort and a pharmacy-hospital based cohort from the Netherlands (PHARMO), one hospital-based cohort from Finland (EPID Research), one hospital-based cohort from Sweden (Karolinska Institutet) and a GP only and GP-hospital cohort from UK (CPRD).

Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients with type 2 diabetes who initiated pioglitazone in the period 2003-2011 (n=56 337) were matched with comparable patients in the same country initiating drug treatments other than pioglitazone (n=317 109). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation. Patients were followed from initiation of treatment until end of available health records or 30 June 2011, with a mean follow-up of 2.9 years.

Time dependent survival analyses of pooled data, adjusting for confounding, revealed no significant association: nearest match HR 0.99 (95% CI 0.75 – 1.30), multiple match HR 1.00 (0.83 – 1.21).

Differences did exist between countries and between cohorts within countries, with some cohorts showing a tendency towards protective effect of pioglitazone and others towards an increased risk of bladder cancer. Sensitivity analyses of broadening the definition of bladder cancer, demanding a minimum of 2 prescriptions of pioglitazone, or stratifying for setting (hospital or not), or cumulative pioglitazone exposure (dose or duration) did not change the conclusion. Inclusion of smoking, HbA1c, and body mass index into the adjusted model (excluding NL pharmacy-hospital and Finnish data) reduced the adjusted hazard ratio by 18.7%, from 1.02 (95% CI 0.70 – 1.49) to 0.83 (0.54 – 1.28).

In conclusion, this study shows no evidence of an association between ever use of pioglitazone and risk of bladder cancer compared with never use, which contradicts earlier studies with poor control of treatment allocation bias or short follow-up, but is consistent with results from other recent studies that included a long follow-up period.

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