Introduction
Diabetes mellitus is one of the most common chronic diseases worldwide and its global prevalence continues to increase due to urbanization, ageing population, obesity and changes associated with lifestyle such as physical inactivity. The WHO estimated that, in 2014, there were ∼422 million adults (8.5% of the population) with diabetes compared with 108 million (4.7%) in 1980.1 According to Diabetes UK reports, there are ∼4 million people living with diabetes in the UK.2
Among men, prostate cancer is the most common cancer, with an overall reported incidence of 307/100 000 men aged 40 years and older3 and is the second most common cause of cancer-related death, after lung cancer. One in eight men will be diagnosed with prostate cancer during their lifetime. Prostate cancer incidence rates have more than doubled since the late 1970s, though this is thought to be associated with intensified diagnostic efforts and, with greater screening, over 90% of men aged 50–69 years diagnosed with prostate cancer survive for 5 years or more.4 Evidence indicates that the incidence of prostate cancer among patients with type 2 diabetes mellitus (T2DM) is 320/100 000 person-years.5
Pioglitazone is an agonist of peroxisome proliferator-activated receptor-γ (PPARγ) and an antidiabetic drug in the thiazolidinedione (TZD) class used to treat T2DM. First authorized for use in the European Union (EU) in October 2000, pioglitazone has been used in the UK as a third-line treatment to improve glycemic levels in patients with T2DM, following patient education and treatment with metformin.6 ,7
In the preclinical studies of pioglitazone, tumors were observed in the urinary bladder of male rats, but not in female rats or mice of either gender.8 Drug-induced tumors were not observed in any other organ. Specifically, there were no treatment-related prostate tumors in the 2-year carcinogenicity studies in rats and mice. In a mechanistic study, expression of PPARγ and the inhibitory effects of TZDs on tissue samples from patients with prostate cancer, benign prostatic hyperplasia (BPH) and normal prostate tissue were investigated.9 Significant expression of PPARγ was observed in prostate cancer cells, whereas normal prostate cells and BPH cells had minimal expression of PPARγ. Exposure of prostate cancer cell lines to TZDs resulted in marked inhibition of tumor cell growth. This finding suggests that pioglitazone may play a role in the prevention and/or treatment of prostate cancers.
Following continued concern suggesting a potential association between exposure to pioglitazone and the risk of bladder cancer, a US-based long-term study using the Kaiser Permanente Northern California (KPNC) database was carried out, which investigated both bladder cancer and also other common cancers in patients with diabetes. In this analysis, there was no association with 8 of the 10 additional cancers; however, ever use of pioglitazone was associated with a small increase in the HR for prostate cancer (HR 1.13, 95% CI 1.02 to 1.26).10
To investigate whether cardiovascular and macrovascular effects observed with pioglitazone during the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial would be maintained over time, a 10-year, observational, follow-up study was conducted after the double-blind treatment phase had been completed. During both study periods combined (original clinical trial and 10-year observational period), prostate cancer was reported in 58 men in the pioglitazone group (3.3%) and 35 men in the placebo group (2.0%; risk ratio 1.59, 95% CI 1.04 to 2.41).11
In the Insulin Resistance Intervention after Stroke (IRIS) trial, which was an international, double-blind, placebo-controlled clinical trial and was designed to test the hypothesis that pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or transient ischemic attack in patients without diabetes who have insulin resistance, the primary outcome of stroke or myocardial infarction occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (HR in the pioglitazone group 0.76; 95% CI 0.62 to 0.93). In this study, the total incidence of cancer did not differ significantly between the two groups and the number of patients with adjudicated prostate cancer was reported as 28 (1.4%) and 25 (1.3%) for pioglitazone and placebo, respectively (p=0.68).12
In addition, a retrospective population-based cohort study of 204 741 Taiwanese men aged 40 years and older showed no association between pioglitazone use and the risk of prostate cancer (OR 0.77, 95% CI 0.10 to 5.75).13
Considering the mixed results from these randomized trials and observational studies and the fact these studies were not specifically designed to evaluate prostate cancer risk, this current study using data from the Clinical Practice Research Datalink (CPRD) GOLD database was designed to further investigate a potential association between pioglitazone use and prostate cancer. Specifically, a matched case–control study nested in a cohort of men aged 40 years and older diagnosed with T2DM between January 1, 2001 and January 5, 2015 was conducted to evaluate the potential association of exposure to pioglitazone and risk of prostate cancer in a cohort of male patients with T2DM.