Based on our findings, the use of pioglitazone was associated with a decreased risk of ischemic stroke among Asian patients with type 2 diabetes but present risk factors for CV diseases. To the best of our knowledge, this is the first study to assess the efficacy of pioglitazone for primary stroke prevention alone in Asian patients with type 2 DM and no established CV diseases, but present risk factors for CV diseases.
Although pioglitazone is now generically available and more cost-effective than a sodium–glucose cotransporter 2 (SGLT2) inhibitor or a GLP–1 receptor agonist for CV protection, more clinical data may be needed to support the protective effects of pioglitazone against stroke in patients with type 2 DM and no established CV diseases. To date, RCTs assessing the effect of pioglitazone on primary stroke prevention in these patients are lacking. In 2006, the CHICAGO study (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) revealed that pioglitazone slowed the progression of CIMT over an 18-month treatment period in patients with type 2 DM and no prior CV disease compared to glimepiride . In 2017, the Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) included patients aged 50–75 years with inadequately controlled type 2 DM with metformin monotherapy from 57 diabetes clinics in Italy . Based on the findings, only 11% of patients had baseline CV disease and 1–2% of subjects had previous stroke. Nonetheless, the incidence of CV events, including non-fatal stroke, was similar to that with SUs and pioglitazone as add-on treatments to metformin . Considering the large heterogeneity of patients with type 2 DM and the need for a personalized approach, a recent post hoc analysis of TOSCA.IT found that men with a urine albumin/creatinine ratio greater than 9 mg/g and body mass index >28.8 kg/m2 presented benefits owing to pioglitazone at a hazard ratio of 0.48 (95% confidence interval, 0.25–0.76) compared to SUs . In Asian type 2 DM patients without prior CV diseases, the real-world data demonstrated controversial stroke protective effects of pioglitazone. Chan et al.  demonstrated that compared to sulfonylurea plus metformin, pioglitazone added to metformin therapy may have fewer major CV events, including ischemic stroke in type 2 DM patients. However, another real-world study conducted by Lu et al. did not reveal the protective effects of pioglitazone on ischemic stroke prevention . These conflicting results may be due to the different clinical characteristics of patients and an interaction with other glucose-lowering agents. In our study, we excluded patients who used insulin or GLP–1 agonist for more than three months and included patients with at least one or more CV risk factors. Moreover, “patients treated with pioglitazone” in our study included those who took pioglitazone during the follow-up period instead of baseline pioglitazone treatment. After PS matching was performed to match almost all baseline characteristics and adjusting for potential confounders, our study revealed that the use of pioglitazone was associated with a decreased risk of ischemic stroke. Thus, our data provided evidence that pioglitazone could be administered for the primary prevention of ischemic stroke in Asian type 2 DM patients without prior CV diseases, but present risk factors for CV diseases. Defining such group of patients with a different likelihood of benefitting from pioglitazone treatment represents an important clinical need. Further, this result was similar to the findings of a recent meta-analysis  that evaluated the effect of pioglitazone on the primary and secondary prevention of CV diseases in patients “with or at high risk” of type 2 DM. In this meta-analysis of 26 RCTs with 19,645 participants, although a greater reduction in non-fatal myocardial infarction, non-fatal stroke, or CV death was noted in patients with a history of established CV diseases than those without, the subgroup differences between the primary and secondary prevention were not statistically significant (p-value for subgroup heterogeneity >0.05) .
Previously, the relationship between pioglitazone dose and its protective effect on primary stroke prevention in patients with type 2 DM was unclear. A post hoc analysis of the IRIS study revealed that the hazard ratio of recurrent ischemic stroke could be lower for patients in the subgroup with a pioglitazone adherence ≥80% than for those in the intention-to-treat analysis . According to our study, there was a significant trend regarding the decreased risk of ischemic stroke and the increasing dose of pioglitazone (p-value for trend = 0.03). Further, as fluid retention is dose-related to pioglitazone, combination therapy with pioglitazone plus an SGLT2 inhibitor might reduce the frequency of edema  and beneficial effects of pioglitazone on stroke could additively improve CV outcome when combined with SGLT2 inhibitors .
Our study had several strengths. First, the use of an administrative database prevented the underreporting of medical visits. Second, its national population-based design enabled our study to be highly representative of the general population and prevented selection bias. Third, the risk of misclassification by excluding patients who might have had other types of diabetes (patients administered insulin for more than three months) was reduced. Fourth, PS matching was employed to match almost all baseline characteristics and adjust for potential confounders during the analysis of the risk of ischemic stroke between pioglitazone and non-pioglitazone users.
Nevertheless, this study had several limitations. First, because this was an observational study, it may be affected by bias and the poor control of confounding factors. Second, the identities of patients were encrypted for privacy and data security reasons. As a result, we could not contact patients to discuss their use of pioglitazone. Third, several potential confounding factors, such as blood pressure (BP), serum glucose level, and lipid panel were not included in the database. Nonetheless, the number of antihypertensive drugs and oral glucose-lowering agents, and the intensity of initial stain therapy were PS-matched to mitigate the bias associated with different levels of BP, blood sugar, and serum lipid between the two groups. Fourth, although experts from the NHI program regularly review randomly selected medical records to confirm the diagnosis from all hospitals, bias may still arise due to miscoding. However, the diagnoses in the NHIRD have previously been validated [27,28]. Finally, as our study included only Taiwanese patients who may have been at a greater risk of developing ischemic stroke due to their Asian descent, our results may not be applicable to other populations.