Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke - Results from PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events 04)

Background and Purpose - Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events ( PROactive) with a history of stroke or without stroke. Methods - The prospective, double-blind PROactive ( mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone ( titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with ( n = 984) and without ( n = 4254) prior stroke. Results - In patients with previous stroke ( n = 486 in the pioglitazone group and n = 498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention ( including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization ( hazard ratio[HR] = 0.78, event rate = 20.2% pioglitazone vs 25.3% placebo; 95% CI = 0.60 - 1.02; P = 0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke ( HR = 0.78, event rate = 15.6% pioglitazone vs 19.7% placebo; 95% CI = 0.58 - 1.06; P = 0.1095). Pioglitazone reduced fatal or nonfatal stroke ( HR = 0.53, event rate = 5.6% pioglitazone vs 10.2% placebo; 95% CI = 0.34 - 0.85; P = 0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke ( HR = 0.72, event rate = 13.0% pioglitazone vs 17.7% placebo; 95% CI = 0.52 - 1.00; P = 0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. Conclusions - In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.