Pioglitazone: an agent which reduces stroke,myocardial infarction and death and is also a key component of the modern paradigm for the optimum management of type 2 diabetes

A randomised controlled trial (RCT), the PROactive study, was undertaken to see if pioglitazone improved cardiovascular outcomes in type 2 diabetes. Initially the results were controversial and pioglitazone was not widely recognised as a beneficial agent for cardiovascular disease. A meta-analysis of rosiglitazone studies raising the possibility that it was associated with cardiovascular harm received worldwide media attention and the negative concern spread to involve pioglitazone through presumed ‘class-effect’. A careful re-look at the detail of the PROactive’s primary composite endpoint, which led to the controversy over the outcome, suggests that medical statistics may have been inadequate to reveal the real clinical effect. A number of other studies support the interpretation that pioglitazone significantly improves cardiovascular outcomes. While the potential risk:benefit of pioglitazone needs to be acknowledged, it now also needs to be recognised that pioglitazone and metformin are the only glucose-lowering agents with RCT data demonstrating a reduction in stroke, myocardial infarction and death in type 2 diabetes. Furthermore there now exists a strong case that even in type 2 diabetes patients without known cardiovascular disease, the modern paradigm for management should involve the combination of metformin, pioglitazone and glucagon-like peptide 1 agonists used early and aggressively to achieve a target glycated haemoglobin A_1C <6%.