Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study

Abstract

Aim:Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes. Methods: Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke. Results: A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate 4.8% pioglitazone vs 10.5% control, hazard ratio 0.62, 95% confidence interval 0.13 -2.35, p 0.49]. However, differences were not statistically significant. Conclusions: While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes. J Atheroscler Thromb, 2015; 22: 1305-1316.

Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis

“…The studies included participants with or without prior cardiovascular diseases. Two studies (IRIS, J-SPIRIT)9 10 enrolled only participants with a stroke or transient ischaemic attack, while in the other studies the majority of participants had not experienced a stroke or transient ischaemic attack at the time of study entry. The number of participants ranged from 121 to 5238.…”

“…Since then, several randomised controlled trials have been published to evaluate the effect of pioglitazone on occurrence of cardiovascular events in various types of patients 8–14. These trials comprised patients with insulin resistance,9 pre-diabetes (eg, impaired fasting glucose and/or impaired glucose tolerance)8 10 or type 2 diabetes mellitus.…”

Pioglitazone for Secondary Stroke Prevention

“…Our final analysis included 3 randomized controlled trials that enrolled 4980 individuals, with 2488 participants (50%) randomly assigned to the pioglitazone group and 2492 participants (50%) to the control group (Figure 1). 16,19,20 The study design and patient baseline characteristics of these randomized controlled trials are shown in Table 1. Analyzed data were abstracted from whole trials that enrolled only stroke or TIA patients (2 trials) 16,19 and a separately reported subgroup of stroke patients (1 trial).…”

“…20,21 One trial included patients with insulin resistance and having their fasting glucose <126 mg/dL and hemoglobin A 1c <7%, 16 another trial included patients with impaired glucose tolerance or newly diagnosed diabetes mellitus, 19 and a third trial included patients with diabetes mellitus. 20 The number of participants ranged from 120 19 to 3876. 16 The median study duration was 4.4 years (ranged from 2.8 19 to 4.8 years 16 ).…”

“…Analyzed data were abstracted from whole trials that enrolled only stroke or TIA patients (2 trials) 16,19 and a separately reported subgroup of stroke patients (1 trial). 20,21 One trial included patients with insulin resistance and having their fasting glucose <126 mg/dL and hemoglobin A 1c <7%, 16 another trial included patients with impaired glucose tolerance or newly diagnosed diabetes mellitus, 19 and a third trial included patients with diabetes mellitus. 20 The number of participants ranged from 120 19 to 3876.…”