Pioglitazone use associated with reduced risk of the first attack of ischemic stroke in patients with newly onset type 2 diabetes: a nationwide nested case–control study

Abstract

Background: Pioglitazone use is known to be associated with a reduced risk of recurrent stroke in patients with diabetes mellitus (DM) who have a history of stroke. However, it is unclear whether this benefit extends to patients without a history of stroke. We aimed to evaluate the association between pioglitazone use and development of first attack of ischemic stroke in patients with newly diagnosed type 2 DM. Methods: Using longitudinal nationwide data from the 2002–2017 Korean National Health Insurance Service DM cohort, we analyzed the association between pioglitazone use and incidence of primary ischemic stroke using a nested case–control study. Among 128,171 patients with newly onset type 2 DM who were stroke-free at the time of DM diagnosis, 4796 cases of ischemic stroke were identified and matched to 23,980 controls based on age, sex, and the onset and duration of DM. The mean (standard deviation) follow-up time was 6.08 (3.34) years for the cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ischemic stroke and pioglitazone use were analyzed by multivariable conditional logistic regression analyses adjusted for comorbidities, cardiometabolic risk profile, and other oral antidiabetic medications. Results: Pioglitazone use was associated with a reduced risk of first attack of ischemic stroke (adjusted OR [AOR] 0.69, 95% CI 0.60–0.80) when compared with non-use. Notably, pioglitazone use was found to have a dose-dependent association with reduced rate of ischemic stroke emergence (first cumulative defined daily dose [cDDD] quartile AOR 0.99, 95% CI 0.74–1.32; second quartile, AOR 0.77, 95% CI 0.56–1.06; third quartile, AOR 0.51, 95% Cl 0.36–0.71; highest quartile, AOR 0.48, 95% CI 0.33–0.69). More pronounced risk reduction was found in patients who used pioglitazone for more than 2 years. A further stratified analysis revealed that pioglitazone use had greater protective effects in patients with risk factors for stroke, such as high blood pressure, obesity, and current smoking. Conclusions: Pioglitazone use may have a preventive effect on primary ischemic stroke in patients with type 2 DM, particularly in those at high risk of stroke.