PROactive Study: (r)evolution in the therapy of diabetes?

, 22 , 1463–1464 1463 At the EASD meeting in Athens in September 2005, the final results of the PROactive study were officially presented. This study is a large trial (about 5000 patients) which aimed to determine the effects of pioglitazone treatment on total mortality and cardiovascular events in type 2 diabetic patients [1]. The primary endpoint was a composite endpoint, including the following events: all cause mortality, nonfatal MI (including silent MI), stroke, major leg amputation, acute coronary syndrome, cardiac intervention, including coronary artery bypass graft or percutaneous coronary intervention, and peripheral revascularization. The secondary endpoints, predefined in the statistical analysis plan, were the following: 1, all cause mortality, nonfatal MI (including silent MI), stroke; 2, cardiovascular mortality; 3, individual components of the primary composite endpoint. Defining the various endpoints is very important for the evaluation of the study. The primary endpoint has not been reached ( P < 0.096), while secondary endpoint 1 was statistically significant ( P < 0.027). These data suggest, even with much caution, that while pioglitazone treatment is successful in reducing major cardiovascular acute events, it does not reduce the probability of undergoing a cardiovascular procedure. Interestingly, patients on pioglitazone therapy had lower HbA 1c , and plasma triglycerides and higher HDL than those taking placebo. In addition, even though LDL was higher, the LDL/HDL ratio was lower, as was systolic blood pressure. These data may suggest that the beneficial effect of pioglitazone is simply related to an improved metabolic profile. However, a multivariate analysis did not show that these changes in metabolic status had a significant impact on the outcome. This is a very important issue, because many of the beneficial effects of TDZs on cardiovascular risk profile have been related to their ancillary properties [2]. Unfortunately, no plasma samples have been stored, so we cannot investigate further this aspect. An approximate answer may come from the subgroups analysis, when groups with the same levels of HbA 1c , triglycerides, etc. on pioglitazone therapy or on placebo will be compared. Another interesting metabolic endpoint was the 50% reduction in progression to permanent insulin use. An optimistic interpretation may suggest that this outcome is related to the well recognised sparing effect of pioglitazone on betacells [3]. Although this conclusion may be true, unfortunately data on insulin sensitivity are not available and will not be in the future. In all these exciting positive aspects of the study the major concerns are linked, not surprisingly, to an increased incidence of two adverse events: heart failure and oedema. The development of oedema during TDZs therapy is well recognised and therefore not new. However, to have a higher incidence of heart failure using a compound which is claimed to reduce cardiovascular disability and mortality is certainly not intuitively logical. We need to know much more detail on this issue, for at least two reasons. First, the appearance of heart failure was not diagnosed by an adjudication committee, but simply reported by the physician involved in the study, and we know just how difficult it is to make the correct diagnosis of the heart failure. Second, a logical issue: it is difficult to believe that an increased incidence of heart failure can be accompanied by a reduction in cardiovascular mortality! We need more details and explanations from the researchers of the PROactive on this key issue. The PROactive study has been conducted in a very high risk population, type 2 diabetic patients who already had established macrovascular disease, and pioglitazone was added on top of their existing therapy. Therefore, the chance of achieving positive results was extremely hard. While waiting for a detailed subgroups analysis, these characteristics of the study and the results obtained, in any case, suggest that high risk diabetic patients can benefit from pioglitazone treatment. It will be particularly interesting to know what happened in the subgroups on statin therapy and in those already taking optimal secondary prevention therapy for cardiovascular disease. In conclusion, while we await much needed more detailed explanations, it really seems that an important new step has come in the therapy of diabetes and particularly of its cardiovascular complications. Correspondence to: Professor Antonio Ceriello, Warwick Medical School, University of Warwick, Gibbett Hill, Coventry CV4 7AL, UK. E-mail: antonio.ceriello@uniud.it Blackwell Publishing, Ltd. Oxford, UK DME i betic Medic ne 0742-3071 2005 22 Misc llaneo s Spe ia rep rt PROactiv study: A. Ceriello PROactive Study: (r)evolution in the therapy of diabetes?