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.

Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke

“…The Charlson Comorbidity Index (CCI) score was calculated by using the diagnosis within 1 year before the DM diagnosis. As described in our previous study, 7 the following parameters were measured at a time point closest to the date of DM diagnosis; fasting blood glucose level, systolic blood pressure, diastolic blood pressure, total cholesterol level, creatinine level, body mass index, smoking status (none, past, and current), alcohol consumption (low: <1 time/wk, moderate: 1–4 times/wk, and heavy: 5–7 times/wk), and physical activity (yes: ≥1 time/wk, no: never).…”

“…19 In this study, a pioglitazone user was defined as a person with a total cumulative defined daily doses (cDDDs) of 90 or greater after initiation of DM treatment as previously described. 7 The same definition applies to other diabetes medications. To determine each patient's DDD, all pioglitazone prescriptions made within the landmark period after DM diagnosis were summed and converted to the corresponding number of cDDDs as defined by the World Health Organization.…”

“…4,5 Previous studies have found that pioglitazone has a role in primary and secondary stroke prevention. 6,7 These findings raise expectations concerning the protective role of pioglitazone against dementia because DM and stroke are considered among the most common conditions that predisposed to dementia in old age. 8,9…”

The Potential Roles of Post-Translational Modifications of PPARγ in Treating Diabetes

“…Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, the activation of which can heighten the sensitivity of peripheral tissues to insulin and therefore increase glucose uptake and utilization in muscle, promote adipocyte remodeling, fatty acid decomposition, and synthesis in adipose tissue while inhibiting gluconeogenesis in liver [ 6 , 7 ]. Thiazolidinediones (TZDs), PPARγ agonists, are crucial to modulating glucose and lipid metabolic homeostasis [ 8 , 9 ] and mainly act by increasing insulin sensitivity [ 10 ]. Moreover, it has been found in clinical studies that pioglitazone has potential therapeutic efficacy in reducing the risk of cerebrovascular disease in T2DM patients [ 9 ].…”

“…Thiazolidinediones (TZDs), PPARγ agonists, are crucial to modulating glucose and lipid metabolic homeostasis [ 8 , 9 ] and mainly act by increasing insulin sensitivity [ 10 ]. Moreover, it has been found in clinical studies that pioglitazone has potential therapeutic efficacy in reducing the risk of cerebrovascular disease in T2DM patients [ 9 ]. However, the use of TZDs has been prohibited in several countries due to their detriments, such as heart failure, weight gain, and edema [ 11 ].…”