Background
Stroke is the leading cause of death and disability worldwide. Type 2 diabetes mellitus (T2D) is characterized by insulin resistance and β-cell dysfunction, which is a strong independent risk factor for stroke and is a very prevalent comorbidity in patients with stroke [
1]. Stroke patients with T2D have worse prognoses and higher risks for recurrent cardiovascular events than those without diabetes [
2]. Guidelines for the secondary prevention of stroke recommend proper glycemic control with multifaceted lifestyle interventions and antidiabetic agents for stroke patients with diabetes who are at high-risk for recurrent cardiovascular complications [
3]. Experimental and epidemiologic data have suggested that some classes of antidiabetic medications have cardiovascular protective action beyond the glucose-lowering effect [
4,
5]. Pioglitazone has been proven to reduce cardiovascular complications in patients with ischemic stroke [
6‐
9]. It is a thiazolidinedione-type drug that acts as an insulin sensitizer through activation of the peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear hormone receptor that plays a key role in regulating energy homeostasis, anti-inflammation, lipid/glucose metabolism, and adipocyte function [
10].
Lobeglitazone (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea) is a newly developed thiazolidinedione [
11]. Compared to pioglitazone and other thiazolidinediones, lobeglitazone has a higher affinity to PPARγ [
12]. Considering the favorable safety and glucose-lowering effect of lobeglitazone in experimental and clinical trials, it has been approved as an oral antidiabetic agent and has been used in the treatment of T2D in Korea since July 2013 [
13‐
15]. Given the established secondary preventive effect of pioglitazone, lobeglitazone, another thiazolidinedione-based PPARγ agonist, likely plays a protective role in stroke patients with T2D. To evaluate the potential secondary preventive role of lobeglitazone, we performed a population-based nested case-control study on the development of recurrent cardiovascular events in patients with acute ischemic stroke and T2D. As a safety outcome, we also investigated whether the use of lobeglitazone increases the risk of heart failure (HF).
Discussion
In this population-based nested case-control study, we found that treatment with lobeglitazone was associated with a lower risk of secondary cardiovascular complications in T2D patients with acute ischemic stroke. The secondary preventive effect of lobeglitazone was similar to that of pioglitazone, a thiazolidinedione well-established to be effective in reducing recurrent stroke and major vascular events in ischemic stroke patients [
28]. The beneficial effect of lobeglitazone remained significant in the control of other antidiabetic medications and traditional cardiovascular medications, such as antithrombotics and statins. In a safety analysis, treatment with lobeglitazone did not increase the risk of HF.
Patients who survived ischemic stroke are at high risk of recurrent stroke or cardiovascular complications. One in four stroke survivors experience a second stroke within five years, and as many as 30% of all strokes are secondary strokes [
29]. The risk of recurrence is further increased in patients with cardiovascular risk factors, such as T2D or insulin resistance [
30]. Therefore, it is crucial to establish effective cardiovascular prevention strategies for the high-risk groups of ischemic stroke patients with T2D [
3]. Besides lowering the level of hemoglobin A1c, recent guidelines for T2D recommend that the selection and use of antidiabetic agents should address cardiovascular risk as well as glycemic control [
28,
31].
In the case of stroke patients, the cardiovascular protective role of pioglitazone has been well-established for more than a decade [
8,
28]. Pioglitazone is the most widely used thiazolidinedione and acts as an insulin sensitizer through the activation of PPARγ. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial showed that pioglitazone reduced the risk of fatal or nonfatal stroke (hazard ratio 0.53; 95% CI 0.34–0.85) in T2D patients with prior stroke [
8]. In the Insulin Resistance Intervention After Stroke Trial (IRIS), those taking pioglitazone with good adherence had reduced their risk for stroke by 33%, and acute coronary syndrome by 52% over a median follow-up of 4.8 years [
32]. In a meta-analysis of stroke patients with three randomized controlled trials, treatment with pioglitazone was significantly associated with a reduced risk of recurrent stroke (hazard ratio 0.68; 95% CI 0.50–0.92) and major vascular events (hazard ratio 0.75; 95% CI 0.64–0.87) [
33]. There are numerous examples of experimental and clinical evidence for the vascular protective role of pioglitazone in reducing atherosclerosis progression, atherosclerotic plaque inflammation, in-stent restenosis after coronary artery stent implantation, progression rate from persistent to permanent atrial fibrillation, and repeated ablation rate in patients with paroxysmal atrial fibrillation after catheter ablation [
34‐
36]. These data suggest that pioglitazone, a thiazolidinedione that is an insulin sensitizer by activating PPARγ, should be used more widely for cardiovascular prevention in high-risk patients, especially those with a history of stroke [
32,
37].
Currently, lobeglitazone and pioglitazone are two available thiazolidinediones for T2D in Korea [
11]. Like other thiazolidinediones, lobeglitazone promotes adipocyte differentiation, increases glucose uptake, and decreases pro-inflammatory responses, which leads to improved insulin sensitivity by PPARγ activation [
38,
39]. The activation of PPARγ promotes fatty acid uptake, triglyceride formation, and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism [
40]. PPARγ also exerts anti-inflammatory, anti-proliferative, and antiatherogenic effects on the vascular wall and immune cells, which can reduce cardiovascular risk. Considering the accumulating evidence, PPARγ has emerged as one of the promising therapeutic targets for cardiovascular disease [
41]. Lobeglitazone displays 12 times higher affinity to PPARγ than other thiazolidinediones [
12,
42]. Owing to its higher affinity to PPARγ, lobeglitazone (0.5 mg/day) has similar efficacy regarding glycemic control with a 30-times smaller dose compared to pioglitazone (15 mg/day) [
11,
43]. In a real-world observational study, treatment with 0.5 mg lobeglitazone had a good long-term safety profile with an apparent reduction in glycosylated hemoglobin; decreased levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol; and increased high-density lipoprotein cholesterol, suggesting both glucose-lowering and lipid-modifying effects [
44]. Lobeglitazone treatment for T2D patients with nonalcoholic fatty liver disease reduced intrahepatic fat content and improved glycemic, liver, and lipid profiles [
45]. Lobeglitazone is also effective in reducing albuminuria, a well-known marker of the increased risk of renal and cardiovascular disease [
46]. In experimental studies, lobeglitazone exerted anti-inflammatory and anti-atherosclerotic potentials like pioglitazone [
38,
47]. Our current data added clinical evidence that lobeglitazone, a novel thiazolidinedione, could be a good treatment option for T2D patients at high cardiovascular risk. There is a need for further studies on the pathophysiologic and practical role of lobeglitazone while controlling for residual cardiovascular risk [
48].
Even with the promising and proven cardiovascular preventive effects of pioglitazone, the use of pioglitazone for stroke treatment is not frequent in clinical practice [
48‐
50]. Indeed, the proportion of patients taking pioglitazone is low (< 4%) in our nationwide data. The main cause of the low use of pioglitazone in clinical practice is the concern for potential side effects, particularly the risk of HF [
36,
49,
50]. In the current study, we did not find any evidence of an increased risk of HF with lobeglitazone in patients without a prior diagnosis of HF. Additional research is needed, but our data suggest that lobeglitazone could be a good choice of thiazolidinediones not frequently used in practice due to the concern of HF despite the established cardiovascular benefits.
Advantages and limitations
The current study has several advantages and limitations. Using the nationwide health claims data, we could collect a large number of ischemic stroke patients with T2D in real-world practice. Evaluating a nationwide claims database, we were able to investigate the long-term incidence of cardiovascular complications of them. Because Korea has a public, single-payer health insurance system, and antidiabetic medications should be prescribed by a physician, all prescription data is available in the HIRA database. Based on the prescription data, we could get detailed information about the medications during a long-term follow-up period in individual patients. Ischemic stroke patients with T2D frequently take a combination of antithrombotics, statins, and multiple classes of antidiabetic medications. To reduce the potential bias with concomitant medications, we conducted a nested case-control study design that matched for individual antidiabetic medications and adjusted for the use of antithrombotics and statins. Our study findings showed a reduced risk for the primary outcome with the use of antithrombotics and statins and an increased risk of the primary outcome with concurrent risk factors. These findings were consistent with prior epidemiologic knowledge, which suggests the reliability of our data. As well as cardiovascular outcome, we evaluated the risk of HF, the most potential side effect and the reason for the reluctance to use the thiazolidinedione class.
We should also address the limitations of a retrospective study design based on a pre-existing health claims database. The information in the claims database is not made for clinical research purposes. There is lacked clinical information for important traditional risk factors such as smoking, physical activity, blood pressure, laboratory results such as lipid profiles or inflammatory markers, the severity of index stroke, duration of T2D, body weight, and the level of hemoglobin A1c, a marker of good glycemic control. This study was performed with only Korean patients with ischemic stroke and T2D. There might be racial and ethnic disparities in the characteristics of the stroke patients, health care delivery system, or the response to medications [
51]. We should also consider the possibility of hidden bias between patients who received lobeglitazone and those who did not. In addition, there might be a gap between prescription data and the actual intake of medications. Diagnosis of stroke/MI based on the Korean health claims data is known to be accurate, but since the events were defined as only hospitalized cases, those with cardiovascular complications who did not admit to the hospital may not have been captured. As the development of HF was determined based on the diagnostic code, we only evaluated the risk of HF in patients without a prior diagnosis of HF. We could not access clinical information such as echocardiography or patient symptoms related to HF. While our study did not find an association between lobeglitazone and the risk of HF, there was a possibility of selection bias that lobeglitazone was less frequently prescribed to individuals considered a high risk of HF. Thus, further research is needed to investigate the potential role of lobeglitazone in the development of HF.
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