Actos Bladder Cancer Risk Again Affirmed

Action Points

  • A meta-analysis found that pioglitazone increased the risk of bladder cancer in type 2 diabetics.
  • Note that any use of thiazolidinediones also increased this risk, the limited data available for rosiglitazone did not support an association for this drug.

The diabetes drug pioglitazone (Actos) appears to raise the risk of bladder cancer, but whether that is a class effect remains unclear, a meta-analysis affirmed.

Any use of a thiazolidinedione was associated with a nonsignificant 45% higher risk in the pooled randomized trials and a significant 15% elevated risk across the observational studies, Jeffrey A. Johnson, PhD, of the University of Alberta in Edmonton, and colleagues found.

Pioglitazone users had pooled risk ratios ranging from 1.22 to 4.30, the group reported online in CMAJ.

The little evidence available on rosiglitazone (Avandia) suggested no increased risk but wasn't conclusive.


Type 2 diabetes itself boosts bladder cancer risk by 40%, possibly because elevated insulin levels stimulate the insulin receptors on neoplastic cells that promote cancer growth and division.

The FDA warned last year of a further increase in bladder cancer risk with pioglitazone, now reflected in the drug's product label.

That move followed stronger action against sister drug rosiglitazone in 2010, severely restricting access in the U.S. over concerns about cardiovascular risk.

That risk didn't appear to be a class effect, but whether the bladder cancer risk applies to all thiazolidinediones hasn't been as clear.

Johnson's group pooled results from the available four randomized controlled trials, five observational cohort studies, and one case-control study that included data on incident bladder cancer in type 2 diabetes with ever versus never use of a thiazolidinedione.

Altogether the incidence rate was 53.1 bladder cancer cases per 100,000 person-years on a glitazone (3,643 in 2,657,365 patients across the studies).

For pioglitazone, the one randomized trial suggested a 2.36-fold elevated risk of bladder cancer compared with never having used the drug, but the 95% confidence interval was wide and nonsignificant at 0.91 to 6.13.

However, the one case-control study with pioglitazone pointed to a statistically significant 4.30-fold risk of developing bladder cancer on the drug (95% CI 2.82 to 6.52).

And the pooled results of the cohort studies -- which represented by far the largest number of patients studied at over 1.7 million -- indicated an increased risk with a risk ratio of 1.22 (95% CI 1.07 to 1.39).

The largest of those cohort studies, an analysis of bladder cancer incidence with pioglitazone in the French national healthcare databases that led regulators there to force the drug off the market, also included a rosiglitazone subgroup.

Rosiglitazone showed no significant impact on bladder cancer risk in that study (hazard ratio 1.08, 95% CI 0.92 to 1.26) or in the two randomized controlled trials (pooled RR 0.87, 95% CI 0.34 to 2.23), one of which was not blinded.

"Given the limited evidence among rosiglitazone users, it remains unclear if the association with bladder cancer is a class effect of all thiazolidinediones," Johnson's group wrote.

The researchers cautioned that the major limitation of their meta-analysis was the lack of primary studies to analyze and no individual patient data, which made it impossible to adjust for known bladder cancer risk factors, like smoking and occupational exposures.

The FDA warning suggested that longer duration of pioglitazone use was a greater hazard for bladder cancer, but the studies in the meta-analysis typically didn't provide duration of exposure data.

One study showed a significant increased risk after more than 1 year of exposure to the drug; both that looked for a link after more than 24 months found one.

Another limitation of the meta-analysis was classification by ever versus never use might have been affected by other agents like metformin in combination therapy.

The study was supported in part by grant funds from the Canadian Institutes of Health Research.

The researchers reported having no conflicts of interest to disclose.

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