Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis

Background:

Patients with type 2 diabetes have a 40% increased risk of bladder cancer. Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review and meta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones.

Methods:

We searched key biomedical databases (including MEDLINE, Embase and Scopus) and sources of grey literature from inception through March 2012 for published and unpublished studies, without language restrictions. We included randomized controlled trials (RCTs), cohort studies and case–control studies that reported incident bladder cancer among people with type 2 diabetes who ever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione.

Results:

Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case–control study. The total number of patients was 2 657 365, of whom 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100 000 person-years. The one RCT that reported on pioglitazone use found no significant association with bladder cancer (risk ratio RR] 2.36, 95% confidence interval CI] 0.91–6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04–1.26; I² = 0%) and of pioglitazone specifically (pooled RR 1.22, 95% CI 1.07–1.39; I² = 0%) showed significant associations with bladder cancer. No significant association with bladder cancer was observed in the two RCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34–2.23; I² = 0%).

Interpretation:

The limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone, are associated with an increased risk of bladder cancer among adults with type 2 diabetes.People with type 2 diabetes are at increased risk of several types of cancer, including a 40% increased risk of bladder cancer, compared with those without diabetes.^1,2 The strong association with bladder cancer is hypothesized to be a result of hyperinsulinemia, whereby elevated insulin levels in type 2 diabetes stimulate insulin receptors on neoplastic cells, promoting cancer growth and division.^1,3–5 Additional risk factors for bladder cancer include increased age, male sex, smoking, occupational and environmental exposures and urinary tract disease.⁶ Exogenous insulin and other glucose-lowering medications such as sulfonylureas, metformin and thiazolidinediones, may further modify the risk of bladder cancer.¹Data from the placebo-controlled PROactive trial of pioglitazone (PROspective pioglitAzone Clinical Trial in macroVascular Events) suggested a higher incidence of bladder cancer among pioglitazone users than among controls.⁷ Subsequent randomized controlled trials (RCTs) and observational studies have reported conflicting results for pioglitazone, with various studies reporting a significant increase,^8,9 a nonsignificant increase¹⁰ and even a decreased risk¹¹ of bladder cancer.To test the hypothesis that pioglitazone use is associated with an increased risk of bladder cancer, we conducted a systematic review and meta-analysis of RCTs and observational studies reporting bladder cancer among adults with type 2 diabetes taking pioglitazone. To clarify the possibility of a drug-class effect, we also examined data for all thiazolidinediones and for rosiglitazone alone.