Pioglitazone and bladder cancer

Abstract

Pioglitazone, an agonist of the peroxisome-proliferator-activated receptor (PPAR), is a relatively new oral hypoglycaemic drug. Since its first approval in the USA in 1999, a potential link with bladder cancer has been a subject of debate. However, only in September, 2010, did the US Food and Drug Administration (FDA) issue an alert about a potential relation between the occurrence of bladder cancer and the prescription of pioglitazone at high doses for long periods.1Food and Drug AdministrationFDA drug safety communication: ongoing safety review of Actos (pioglitazone) and potential increased risk of bladder cancer after two years exposure.http://www.fda.gov/Drugs/DrugSafety/ucm226214.htmGoogle Scholar In April, 2011, Piccini and colleagues,2Piccinni C Motola D Marchesini G Poluzzi E Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting.Diabetes Care. 2011; 34: 1369-1371Crossref PubMed Scopus (196) Google Scholar using the FDA Adverse Event Reporting System database, revealed evidence to support a significant risk of bladder cancer associated with pioglitazone irrespective of treatment duration. In July, 2011, the European Medicines Agency issued a warning about the potential for bladder cancer with pioglitazone.3European Medicines AgencyEuropean Medicines Agency recommends new contra-indications and warnings for pioglitazone to reduce small increased risk of bladder cancer.http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/07/WC500109176.pdfGoogle Scholar In the PROactive study,4Dormandy JA Charbonnel B Eckland DJ et al.on behalf of the PROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Summary Full Text Full Text PDF PubMed Scopus (3668) Google Scholar published in 2005 by Dormandy and colleagues, 14 (0·5%) cases of bladder neoplasm were reported in the pioglitazone group and six (0·2%) in the placebo group. This difference did not reach significance (p=0·069). In the overview of PROactive data published in 2009,5Dormandy J Bhattacharya M van Troostenburg de Bruyn AR Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive.Drug Saf. 2009; 32: 187-202Crossref PubMed Scopus (192) Google Scholar Dormandy and colleagues anecdotally mentioned that, in the placebo group, one case in fact showed a benign histology. This information was presented in the text in brackets, but no new bladder cancer incidence was calculated. We reviewed the PROactive safety data presented in these two publications. We found that the recalculated overall incidence in the pioglitazone group was statistically greater than in the placebo group: 0·54% (14/2605) versus 0·19% (5/2633), respectively (Fisher's exact test p=0·040). The estimated crude relative risk of bladder cancer was 2·83 (95% CI 1·02–7·85). As in the original article, this incidence did not take into account concomitant potential risk factors or treatment duration. However, this result shows a significant relation between pioglitazone and bladder cancer, which has not been presented in the PROactive study reports. This finding, associated with the preclinical and clinical findings reported on the FDA website in 2004 (PPAR agonists were claimed to be multispecies, multistrain, multisex, and multisite carcinogens),6El-Hage J Preclinical and clinical safety assessments for PPAR agonists.http://www.docstoc.com/docs/75248557/Preclinical-and-Clinical-Safety-Assessments-for-PPAR-AgonistsGoogle Scholar could have led to an alert 5 years sooner. With this in mind, pioglitazone prescription could have been restricted, and monitoring of patients strengthened. Given the potential loss of opportunity for patients to have been treated otherwise or at least monitored carefully since 2005, vigilance and checking of all relevant safety data reported in clinical trials are crucial. We declare that we have no conflicts of interest. Pioglitazone and bladder cancer – Authors' replyIn their letter, Dominique Hillaire-Buys and colleagues draw attention to a potential increase in bladder cancer risk with pioglitazone in PROactive. Although preclinical studies with pioglitazone showed bladder tumours in male rats, none was seen in female rats, mice of either sex, or other organs.1,2 For pioglitazone, a sex-specific and species-specific mechanism involving formation of urinary solids probably underlies bladder tumour formation in male rats,3 with good evidence that pioglitazone is not genotoxic. Full-Text PDF