Pioglitazone may raise bladder cancer risk

By Laura Cowen

Study evidence supports a link between thiazolidinedione use, particularly pioglitazone, and bladder cancer in patients with Type 2 diabetes, Canadian researchers report.

In their systematic review and meta-analysis, Jeffrey Johnson and colleagues from the University of Alberta in Edmonton, found that patients who had ever used thiazolidinediones had a significant 15% increased risk for bladder cancer compared with those who had never used it. Patients who had ever used pioglitazone specifically had a 22% increased bladder cancer risk.

The analysis included data from four randomized, controlled trials, five cohort studies and one case-control study that collectively included over 2.6 million people with Type 2 diabetes. Of these, 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100 000 person-years.

Johnson and team explain that people with type 2 diabetes have a 40% increased risk for bladder cancer, which is thought to be a result of hyperinsulinemia, whereby elevated insulin levels stimulate insulin receptors on neoplastic cells, promoting cancer growth and division.

Exogenous insulin and other glucose-lowering medications such as sulfonylureas, metformin and thiazolidinediones, may further modify the risk, they add.

Previous studies suggested a higher incidence of bladder cancer among pioglitazone users than among controls, whereas others found the opposite. The researchers conducted the current analysis to investigate the relationship further.

While they found significant associations between thiazolidinedione use overall, and pioglitazone specifically, and bladder cancer, no such association was observed among patients who received rosiglitazone use.

"Although the absolute risk of bladder cancer associated with pioglitazone was small, other evidence-based treatments for type 2 diabetes may be equally effective and do not carry a risk of cancer," Johnson and co-authors remark in CMAJ.

"This study quantifies the association between pioglitazone use and bladder cancer and may help inform decisions around safer use of pioglitazone in individuals with type 2 diabetes."

However, they add that the evidence surrounding the association between pioglitazone and bladder cancer requires "cautious interpretation," because it is based on "only three, albeit large and well-conducted, observational studies."

The team concludes: "Future research is required to improve our understanding and should include large population-based cohort studies involving individuals with type 2 diabetes; include a reference group of individuals without diabetes; have a minimum dose and duration of exposure; and account for important risk factors for bladder cancer (eg, smoking status and history of bladder disease)."

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