CHICAGO, PERISCOPE and PROactive: CV risk modification in diabetes with pioglitazone

Recent trials of intensive glycaemic control in patients with type 2 diabetes and its impact on cardiovascular disease have led to confusion and speculation amongst physicians. The Action to Control Cardiovascular Risk in Diabetes Study was terminated early because of a significant excess all-cause mortality in the intensively-treated group. Furthermore the ADVANCE and VADT trials did not demonstrate cardiovascular benefit with more intensive glycaemic control. Against this background, it is pertinent to re-visit and critically appraise the results of the PROactive study which examined the effects of the thiazolidinedione, pioglitazone, on cardiovascular end-points in a large, randomized, placebo-controlled clinical trial in type 2 diabetic patients with symptomatic disease. PROactive has been rightly criticized in the choice of its composite primary end-point which included a physician-driven as opposed to a disease-driven outcome, namely peripheral vascular re-vascularization. This was primarily responsible for the primary composite end-point not being achieved; whereas there was a significant beneficial impact on the major secondary end-point of death, non-fatal myocardial infarction and stroke. The results of PROactive have been supported by two subsequent studies examining the impact of pioglitazone on important surrogates of atherosclerosis, namely carotid intima/medial thickness (IMT) and coronary atheroma volume as delineated with intravascular ultrasound. The CHICAGO study demonstrated that IMT in type 2 diabetic patients treated with pioglitazone did not progress whereas those treated with glimepiride showed progression. In PERISCOPE atheroma volume progressed with glimepiride but did not with pioglitazone. This is exciting data pointing to the cardiovascular benefits of pioglitazone. In PROactive, CHICAGO and PERISCOPE there was a sustained effect of pioglitazone on glycaemic control and, in addition, beneficial effects in reducing triglycerides and increasing HDL-cholesterol beyond that seen with concomitant statin therapy. These findings strongly suggest that pioglitazone has an important place in the management of type 2 diabetes.