On June 9th, France suspended new prescriptions of pioglitazone due to concerns over an increased risk of bladder cancer. Within hours the Germans followed suit….
In early studies of pioglitazone (a PPAR alpha agonist), there were observations of transitional cell neoplasia in the bladders of male rats (but not in females nor in mouse models). Subsequently the clinical development of ragaglitazar, a dual PPAR agonist, was halted due to bladder tumours in rats and in one mouse.
This prompted the FDA to request a study to assess bladder cancer risk over a 10-year exposure and this is being undertaken using the Kaiser Permanente North Carolina (KPNC) registry. It also led to scrutiny of PROactive, a study of secondary cardiovascular prevention in type 2 diabetes, using pioglitazone.
In PROactive, there were 14 cases of bladder tumour in the pioglitazone group versus 6 with placebo. After independent assessment, the numbers fell to six and three, a non-significant difference. In a 5-year (interim) analysis of the KPNC, there was no increase in bladder cancer with pioglitazone use unless duration of exposure (>2years) was taken into account (when a statistically significant increase was shown). The full 10-year data are awaited, as are follow-on data from PROactive. The French dataset (CNAMTS study) has not been published.
These ‘imbalances’ seen with bladder cancer risk need to be taken into context of no overall increase in malignancy (indeed, ‘protection’ from some cancers such as breast and kidney) and significant benefits, such as a 50% reduction in secondary prevention of stroke.
The European Medicines Agency has taken the view that Pioglitazone should continue to be available for use, but be avoided in patients with bladder cancer or haematuria. Regular review is also recommended but since all patients will be having at least yearly checks of urine albumin creatine ratio (UACR), one could argue that this is already in place…
Professor Steve Bain
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