Secondary Prevention of Macro Vascular Events in Patients With Type II Diabetes in the PROactive Study (PROspective Pioglitazone Clinical Trial and Macro Vascular Events): A Randomised Controlled Trial

Abstract

Conclusion: In patients with Type II diabetes felt to be at high risk for macro vascular events, Pioglitazone reduces the combination of all cause mortality, non fatal myocardial infarction, and stroke. Summary: This study sought to evaluate the effects of an antagonist of peroxisome proliferator-activated receptor gamma for its ability to reduce macro vascular complications in patients with Type II diabetes. This was a prospective, randomized control trial involving 5,238 patients with Type II diabetes and who had evidence of macro vascular disease. Patients were recruited from both hospitals and primary care practices. Patients were divided into two groups with one group treated with a titrated dose of pioglitazone from 15 mgs to 45 mgs (n = 2,605) with the second group being a placebo control (n = 2,603) study. Medications in both groups were taken in addition to glucose lowering drugs and other indicated medications. The primary end point in the study was a composite of all cause mortality, non fatal myocardial infarction, stroke, acute coronary syndrome, and endovascular or surgical intervention in the coronary or leg arteries, or amputation above the ankle. An intention to treat analysis was utilized. There were only two patients lost to followup in this study. Average observation time was 34.5 months. In the pioglitazone group, 514 patients had at least one event in the primary composite end point versus 572 patients in the placebo group (hazard ratio 0.9, 95% CI, 0.8-1.02, P = 0.095). With regard to the combination of all cause morality, non fatal myocardial infarction, and stroke, 301 patients in the Pioglitazone group and 358 patients in the placebo group achieved this end point (hazard ratio 0.84, 95% CI, 0.72-0.98, P = 0.027). There was no change in the safety profile of Pioglitazone noted. During the course of the study, 6% of the patients in the Pioglitazone group and 4% in the placebo group were admitted to the hospital with heart failure. There was no difference in mortality rates from heart failure between the two groups. Comment: Pioglitazone reduces levels of inflammatory markers such as C-reactive protein. These effects are independent of its affect on glycemic control. Detailed analysis of the data indicates the drug had no effect on leg revascularization or need for amputation. There is beginning to be accumulated evidence that systemic markers of inflammation are perhaps more important in predicting coronary events than events secondary to peripheral vascular disease. If this proves to be true, then the results of this study would make sense in that one of the primary effects of this drug is to lower markers of systemic inflammation.