Observational follow-up of the PROactive study: a 6-year update

Abstract

Aims: The PROactive study investigated pioglitazone for secondary prevention of macrovascular events in type 2 diabetes mellitus. Pioglitazone showed a 10% (non-significant) relative risk (RR) reduction for the primary composite endpoint and a significant 16% reduction for the main secondary endpoint (death, myocardial infarction, stroke) after a mean 34.5 months. There was no difference in cumulative malignancy incidence, but an imbalance in bladder malignancies (pioglitazone 14, placebo 5). We present a pre-specified 6-year interim analysis of a 10-year observational follow-up.

Methods: Any patient completing PROactive was eligible. No study treatments were provided. A Cox proportional hazard model compared non-adjudicated macrovascular events (same endpoints as PROactive excluding acute coronary syndrome) based on original randomization. Malignancies were compared using conventional RR ratios.

Results: Of 5238 randomized patients, 3599 (74%) entered the follow-up. For the follow-up (mean 5.8 years) or combined double-blind and follow-up periods (≤9.5 years, mean 8.7), there were no statistically significant differences in primary or main secondary endpoints. For the combined period, a similar percentage of patients had any diagnosed malignancy (RR = 1.05, 95% CI [0.89, 1.24]) or bladder malignancy (RR = 1.06, 95% CI [0.59, 1.89]) in the pioglitazone and placebo groups. There were fewer cases of bladder malignancy with pioglitazone (15 [0.6%] vs. 19 [0.7%] for placebo) for the combined period when events diagnosed in the first 365 days were excluded, and fewer cases for the follow-up period alone (10 [0.5%] vs. 17 [1.0%] for placebo). Further analyses of pioglitazone use (including use during follow-up) found no significant difference in bladder malignancies between any and no pioglitazone use for the combined period.

Conclusions: These data suggest that improved macrovascular outcomes seen with pioglitazone subside without continued pioglitazone treatment. The double-blind period bladder cancer imbalance did not persist in follow-up.

Keywords: diabetes mellitus; pioglitazone; rosiglitazone; thiazolidinediones.