[Evidences demonstrating the effects of anti-atherosclerotic actions of pioglitazone--special emphasis on PROactive...

Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of PPARgamma could reduce macrovascular complications. PROactive Study was conducted to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. Subjects were 5,238 patients with type 2 diabetes who had evidence of macrovascular disease. Subjects were assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2,605) or matching placebo (n=2,633), to be taken in addition to their glucose-lowering drugs and other medications. The primary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. The average time of observation was 34.5 months. 514 of 2,605 patients in the pioglitazone group and 572 of 2,633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, nonfatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Thus, pioglitazone reduced the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events. PERISCOPE Study, double-blind, randomized, multicenter trial in 543 patients with coronary disease and type 2 diabetes, was conducted to find out the reasons why pioglitazone demonstrated the anti-atherosclerotic action. A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination. As far as the change in percent atheroma volume (PAV) from baseline to study completion is concerned, mean PAV increased 0.73% (95% CI, 0.33-1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57-0.25%) with pioglitazone (p=0.002). Thus, in patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride.