Should we stop prescribing pioglitazone?

We read with interest the paper ‘Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis’ by Turner et al. [1]. The authors present the results of a meta-analysis including a large number of patients. They concluded that pioglitazone use is associated with a modest but significant increase in the risk of bladder cancer, which further increases with both higher cumulative dose (>28 g) and duration of exposure (>12–24 months). Interestingly, the effect of rosiglitazone on bladder cancer risk was not significant [1].

A few comments might be of interest, based on the results of a recent study (published in August 2013), not included in the meta-analysis [2]. This was an observational follow-up study of patients included in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, who had received pioglitazone for 2.6 years. PROactive had shown a modest but significant reduction in the composite of all cause mortality, non-fatal myocardial infarction (MI) and stroke in high cardiovascular disease (CVD) risk type 2 diabetes mellitus (T2DM) patients [3]. After a mean follow-up time of 8.7 years (including the PROactive period), the CVD benefit was lost, since only 13.5% continued on pioglitazone [2]. There was no evidence of increased risk of bladder cancer in these patients (89% of them were at the maximum dose of 45 mg day⁻¹) [2]. Interestingly, no significant between group differences were observed in the percentage of patients reporting any other malignancies, except for prostate malignancy, a finding that needs further confirmation [3].

The leading cause of death in patients with T2DM is CVD [3]. As PROactive has shown, 40 patients would need to be treated for 3 years in order to prevent one first CVD event. In other words, the number needed to treat is approximately 120 per year [3], while the number needed to treat for harm (that is to develop one case of bladder cancer) shown by the meta-analysis was 3408 for ever pioglitazone use, 1119 for >28 g cumulative dose and 1404 for >24 months cumulative duration [1]. On the contrary, rosiglitazone use has been associated with increased risk for MI (although not for CVD or all cause mortality) in an older meta-analysis, showing one additional MI per 52 patients treated for 5 years [4]. These results were confirmed by a comparative meta-analysis, showing a significant increase in the odds of MI, congestive heart failure and death (170 excess MIs, 649 excess cases of heart failure and 431 excess deaths for every 100 000 patients receiving rosiglitazone rather than pioglitazone) [5].

It seems therefore prudent to prescribe an agent that has been shown to protect the cardiovascular system, for at least 3 years, rather than avoid it for the fear of causing bladder cancer, the possibility of which for such a period seems very low (taking into account that the cumulative dose of 28 g stands for a 31 month period of 30 mg day⁻¹, which is the usual pioglitazone dose). This becomes more important in an era when clinicians, the Food and Drug Administration and the European Medicines Agency are very cautious about the effect of any anti-diabetic and anti-obesity drug on the cardiovascular system [6]. New studies are already being conducted to test the effect of other drug categories, such as glucagon-like peptide (GLP)-1 based therapies, on the cardiovascular system [6].

In conclusion, we believe that pioglitazone should continue to be considered a reliable therapeutic option in patients with T2DM for a period of up to 2 years (with a potential extension to 3 years), since its benefit and safety on the cardiovascular system overweigh the potential risk for bladder cancer. Patients at high risk for bladder cancer, such as those with a family history, microscopic haematuria and exposure to carcinogenic substances, should be excluded.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Contributors

PA wrote the letter and designed the study. SNK helped to search and retrieve studies and revised the paper. The final version has been approved by both authors.