Type 2 diabetes affects approximately 26 million Americans, with nearly 2 million newly diagnosed patients annually.1 In addition to contributing to cardiovascular morbidity and mortality, diabetes is the leading cause of kidney failure and dialysis, non-traumatic lower limb amputation, and new-onset blindness in the United States.1 Pioglitazone (Actos®), FDA approved for the treatment of type 2 diabetes, exhibits its action through activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR-γ activation increases insulin-dependent glucose disposal and decreases hepatic glucose output by decreasing insulin resistance in peripheral tissues and the liver.2 PPAR-γ is also involved in angiogenesis, which is essential for solid tumor growth. PPAR-γ up-regulates vascular endothelial growth factor (VEGF) in two human bladder cancer cell lines, promoting angiogenesis and tumor growth in vitro.3 In vitro data is supported by animal studies reporting higher incidence of bladder cancer in rats receiving pioglitazone doses equivalent to 45 mg daily in humans.2,4 In addition, pioglitazone has recently been associated with increased risk of bladder cancer in clinical trials, raising questions regarding the safety of long-term pioglitazone use.
The first clinical trial to suggest an association between pioglitazone and bladder cancer was the PROactive study.4-5 This randomized controlled trial compared pioglitazone with placebo in more than 5,200 patients with type 2 diabetes an average of 35 months. The primary outcome was a composite of all-cause mortality, cardiovascular events, and vascular events. Pioglitazone demonstrated significant benefit in one secondary composite outcome, but was unable to significantly reduce the rate of the primary outcome. The absolute risk of neoplasm in each group over the study period was low (4% in each), with no single type of cancer seeing rates above 2%. However, a non-significant trend toward increased risk of bladder cancer was observed. Fourteen patients (<1%) in the pioglitazone group developed bladder cancer, compared with six patients (<1%) in the placebo group (p=0.069). This study, in conjunction with in vivo and animal models served as the impetus for ongoing research to further investigate an association between pioglitazone and bladder cancer.
Piccinni and colleagues6 analyzed bladder cancer reports associated with antidiabetic medications (including pioglitazone) in the FDA’s voluntary Adverse Event Reporting System (AERS) over a nearly six year time period (January 2004 to December 2009). Pioglitazone was associated with a significant increase in reported odds ratio (ROR) for bladder cancer (ROR=4.30 [95% CI 2.82-6.52]; p<0.001). Based on the significantly elevated ROR, the authors concluded pioglitazone was associated with bladder cancer. This retrospective review of the voluntary AERS reporting system is subject to reporting bias, but the degree of increase in the reported odds ratio suggests association between pioglitazone and bladder cancer. The authors called for further epidemiologic surveillance until the results of the FDA’s 10-year investigation are known.
In response to data suggesting an association between pioglitazone and bladder cancer, the FDA commissioned Lewis and colleagues7 to conduct a longitudinal 10-year cohort study to further evaluate this risk. The 5-year interim report was published in 2011, and included over 193,000 patients (grouped by pioglitazone users and non-users) in the Kaiser Permanente Northern California diabetes registry between 1997 and 2002. Over 30,100 pioglitazone users were evaluated, with nearly 900 bladder cancer cases identified across all 193,000 patients. The bladder cancer incidence per 100,000 patient years for patients ever using pioglitazone was 81.5, compared to 68.8 for non-users (HR 1.2 [95% CI 0.9-1.5]). The risk of bladder cancer diagnosis increased with increasing dose and duration of pioglitazone use. There was a 50% higher risk of bladder cancer development in patients exposed to pioglitazone for greater than 24 months compared with patients ...