Article Summary Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macrovascular events: a randomised controlled trial. Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefčbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Tatan J, on behalf of the PROactive Investigators. Lancet. 2005;366:1279-1289. Objective: To find out whether pioglitazone, an agonist of peroxisome proliferator–activated y used to treat patients with type 2 diabetes, helps to reduce cardiovascular risk in this patient population and to assess the safety and tolerability of pioglitazone. Methods: A prospective randomized controlled trial enrolled 5238 patients from 321 centers in 19 European countries; patients had been diagnosed with type 2 diabetes and exhibited signs of macrovascular disease. Median time since diagnosis was 8 years, and the overall mean age of those who participated was 61.8 years. Patients were randomly assigned to treatment groups and were given oral pioglitazone or placebo. Those allocated to the pioglitazone group were given 15 mg for the first month, 30 mg for the second month, and 45 mg thereafter, so that the maximum tolerated dose was achieved. Medication was to be taken in addition to all existing treatments. The primary study endpoint was the time from randomization to all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation. The main secondary endpoint was the composite of all-cause mortality, nonfatal myocardial infarction, and stroke. Intention-to-treat analysis was performed. Results: Among patients treated with pioglitazone, consistent benefit was derived for each of the individual components of the primary composite endpoint and for the total number of events reported. This finding was nonsignificant. The secondary endpoint, however, was significantly reduced in the pioglitazone group (P=0.027). At the end of the study, an improvement in glycemic control was noted in the group given pioglitazone; in addition, this group developed a more favorable metabolic profile regarding glucose, high-density lipoprotein cholesterol, and triglyceride concentrations, and demonstrated an improved blood pressure profile compared with baseline. Fewer serious adverse events were reported by those taking pioglitazone than by those taking placebo, and throughout the study, pioglitazone was well tolerated, with 89% of patients reaching the 45-mg dose at the 2-month visit (vs 91% of those taking placebo). Conclusions: Pioglitazone improves cardiovascular outcomes among patients with type 2 diabetes who are at high risk for cardiovascular events; it also improves glycemic control, thereby reducing the need for addition of insulin to glucose-lowering regimens compared with use of placebo. Overall safety and tolerability of pioglitazone were comparable with placebo.