Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes

Aims: To conduct a 10-year, observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time. Methods: Macrovascular endpoints and malignancies were compared based on original randomization to pioglitazone or placebo and 'any' versus 'no' pioglitazone use for bladder and prostate cancer. Results: Of 4873 patients completing the PROactive trial, 74% entered the follow-up. During follow-up (mean 7.8 years), there were no statistically significant differences in the primary [all-cause mortality, myocardial infarction (MI), cardiac intervention, stroke, major leg amputation, leg revascularization] or main secondary (death, MI, stroke) endpoints for subjects originally randomized to pioglitazone and placebo, except for leg amputations during follow-up [4.1% pioglitazone, 5.6% placebo; hazard ratio 0.74, 95% confidence interval (CI) 0.55-0.99; p = 0.046]. During follow-up, the incidence of total malignancies was similar between groups; bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group [relative risk (RR) 0.65, 95% CI 0.33-1.28], and prostate cancer was reported in 44 men (3.7%) in the pioglitazone versus 29 men (2.5%) in the placebo group (RR 1.47, 95% CI 0.93-2.34). Conclusions: The trends of macrovascular benefits of pioglitazone compared with placebo during PROactive did not persist in the absence of continued pioglitazone during this 10-year follow-up. Trends of decreased bladder cancer and increased prostate cancer were observed in the pioglitazone group during follow-up; however, these imbalances should be interpreted with caution because of the limitations of the observational study design.