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Pioglitazone use is associated with reduced risk of Parkinson’s disease in patients with diabetes: A systematic review and meta-analysis

  • Author Footnotes
    1 These authors contributed equally to this study.
    Liudan Chen
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Yangu Tao
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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  • Jianjun Li
    Correspondence
    Corresponding author at: Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yan Jiang Xi Road, Guangzhou 510120, China.
    Affiliations
    Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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  • Mengru Kang
    Correspondence
    Corresponding author at: Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yan Jiang Xi Road, Guangzhou 510120, China.
    Affiliations
    Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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  • Author Footnotes
    1 These authors contributed equally to this study.

      Highlights

      • There was a significant reduction in the risk of parkinson’s disease in pioglitazone users.
      • Pioglitazone could reduce the risk of parkinson’s disease in diabetes patients.
      • 438 dose-duration-days of pioglitazone could be beneficial for parkinson’s disease in diabetes patients.

      Abstract

      Objective

      This meta-analysis aimed to evaluate the effect of pioglitazone on Parkinson’s disease (PD) in diabetes patients.

      Methods

      A study search was carried out in PubMed, Embase, and Web of Science databases from inception to July 22, 2021. The Newcastle-Ottawa scale was used to evaluate the quality of the eligible studies. The risk ratio (RR) and 95% confidence intervals (CI) were used as effect size indicators in this meta-analysis to evaluate the risk association between pioglitazone and PD. The Cochran’s Q and I2 tests were used to assess statistical heterogeneity. A dose–response meta-analysis was conducted using the least squares trend estimation method.

      Results

      Three studies were eligible for this meta-analysis. Compared with diabetes patients who did not use pioglitazone, there was a significant reduction in the risk of PD (RR of 0.87 [95 % CI 0.62–0.99, P = 0.039]) in pioglitazone users. No significant difference in PD risk was noted in diabetes patients taking 438 dose-duration-days (DDDs) of pioglitazone or lower compared with those who did not. When the DDD of pioglitazone was 438, the RR was 0.85 (95 % CI [0.72–1.00], P = 0.05). When the DDD of pioglitazone was > 438, the risk of PD in patients with diabetes was significantly decreased (P < 0.05) and showed an approximate linear correlation trend.

      Conclusion

      Pioglitazone administration in PD in diabetes patients is significantly associated with a decrease in the risk of PD.

      Keywords

      1. Introduction

      Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in middle-aged and elderly people, mainly due to the depletion of dopamine and the increase of neurotransmitters in the brain [
      • Reich S.G.
      • Savitt J.M.
      Parkinson's Disease.
      ]. In recent years, the incidence of PD is continue rising, and PD has become one of the major diseases threatening the physical and mental health of middle-aged and elderly people [
      • Kovács M.
      • et al.
      Screening for Problematic Internet Use May Help Identify Impulse Control Disorders in Parkinson's Disease.
      ]. At present, the specific pathogenesis and etiology of PD are not fully clarified, which may be closely related to various factors, such as genetics, immunity, environment, and apoptosis [
      • Noyce A.J.
      • et al.
      Meta-analysis of early nonmotor features and risk factors for Parkinson disease.
      ]. In addition, it has been reported that diabetes may be a risk factor for PD. PD and diabetes may have similar pathophysiology [
      • Cereda E.
      • et al.
      Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis.
      ,
      • Schernhammer E.
      • et al.
      Diabetes and the risk of developing Parkinson's disease in Denmark.
      ,
      • Lima M.M.
      • et al.
      Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments?.
      ]. Numerous studies have also found an association between diabetes and PD [
      • De Pablo-Fernandez E.
      • et al.
      Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study.
      ,
      • Chohan H.
      • et al.
      Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression.
      ,
      • Driver J.A.
      • et al.
      Prospective cohort study of type 2 diabetes and the risk of Parkinson's disease.
      ]. Thus, anti-hyperglycemic agents may have beneficial effects on PD.
      The main PD treatment strategy is to administer levodopa (l-dopa) [
      • LeWitt P.A.
      Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics.
      ], and Deep brain stimulation (DBS) [
      • Malek N.
      Deep Brain Stimulation in Parkinson's Disease.
      ], apomorphine [
      • Carbone F.
      • et al.
      Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations.
      ], Duodopa [
      • Nyholm D.
      Duodopa® treatment for advanced Parkinson's disease: a review of efficacy and safety.
      ] were the therapeutic strategies for late phase of PD. Pioglitazone is a peroxisome proliferator activated receptor (PPAR) agonist that can improve hyperglycemia and insulin resistance [
      • Al-Majed A.
      • et al.
      Pioglitazone.
      ,
      • DeFronzo R.A.
      • et al.
      Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.
      ]. In addition, pioglitazone has also been reported to be a promising drug for the treatment of PD [
      • Pinto M.
      • et al.
      Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation.
      ,
      • Welling L.C.
      • et al.
      Parkinson Disease and Pioglitazone: Could Traumatic Brain Injury Catch a Lift?.
      ], and the treatment effect of pioglitazone as a neuroprotective agent for PD has been confirmed in non-human primate and rodent models [
      • Breidert T.
      • et al.
      Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease.
      ]. However, whether pioglitazone can minimize the risk of PD in patients with diabetes remains controversial. For instance, Chang et al. indicated that pioglitazone could reduce the risk of PD in diabetes patients [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ], while Wu et al. did not find a relationship between pioglitazone and PD incidence in diabetes patients [
      • Wu H.F.
      • et al.
      Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
      ]. Thus, meta-analysis is needed to analyze the relationship between the use of pioglitazone and the risk of PD in diabetes patients.
      In this meta-analysis, the effect of pioglitazone on PD in diabetes patients was evaluated. A recent study also showed that the relationship between pioglitazone and the risk of PD was dose-dependent [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ]. Therefore, there might be an association between the dose and duration–day (DDD) of pioglitazone and the risk of PD. This study provides a theoretical reference for the effect of pioglitazone on PD in diabetes patients.

      2. Materials

      2.1 Data sources

      From inception to until July 22, 2021, a literature search was carried out in PubMed, Embase, and Web of Science databases with the keywords “Parkinson disease,” “pioglitazone,” “thiazolidinediones,” and “glitazone.” The search was performed based on a combination of subject and free words (specific search steps in each database are shown in Supplementary Tables 1–3), without language restrictions. In addition, this study manually searched the literature and screened relevant reviews and references included in the literature.

      2.2 Inclusion and exclusion criteria

      The inclusion criteria for the literature in this meta-analysis were as follows: 1) the subjects were diabetes patients; 2) observational studies, such as cohort studies and case-control studies; 3) the literature reported a difference in the risk of PD (risk ratio [RR]/hazard ratio [HR] and 95 % confidence intervals [CI]) between pioglitazone users and non-users, or different dose groups of pioglitazone. Meanwhile, studies meeting the following criteria were excluded: 1) reviews, conference abstracts, and comments; 2) diabetes patients taking glitazone, with no independent data on the use of pioglitazone; 3) for repeated literature or the same data reported in multiple studies, only one literature with the most complete study information was extracted, and others were excluded.

      2.3 Data extracting and quality evaluation

      Two independent researchers participated in data extraction. The available data included first author name, year of publication, study type, study area, study time, basic characteristics of study objects (sample size, age, sex, etc.), study groups (whether patients were administered pioglitazone and pioglitazone dose grouping), confounding factors, and study outcomes. The extraction tables were exchanged after the data extraction was completed by both researchers. Any inconsistencies in the extracted results were resolved by discussion. Furthermore, the Newcastle-Ottawa scale (NOS) was used to evaluate the quality of the study object selection, comparability, and exposure in the included studies [

      Wells G. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomised Studies in Meta-Analyses. In Symposium on Systematic Reviews: Beyond the Basics; 2014.

      ] (8 scoring items with a full score of 9). A score of 7–9 indicates a high-quality study, 4–6 indicates a medium-quality study, and < 4 indicates a low-quality study.

      2.4 Statistical analysis

      Stata software (version 12.0) was used for the statistical analysis. The RR and 95 % CI were used as effect size indicators in this analysis to evaluate the risk association between pioglitazone (pioglitazone users vs non-pioglitazone users) and PD. Statistical heterogeneity was assessed using the Cochran’s Q test and the I2 test [
      • Higgins J.
      • et al.
      Measuring inconsistency in meta-analyses.
      ]. Values of P < 0.05, I2 > 50 % showed significant heterogeneity, and a random-effects model was applied, whereas P ≥ 0.05 or I2 ≤ 50 % indicated a lack of heterogeneity, and the fixed-effects model was used.
      According to the DDD of pioglitazone, the studies were divided into at least three dose groups. The studies could be included in the dose–response meta-analysis if the study met the following criteria: 1) the study showed the HR/RR and 95 % CI of each dose group; 2) the study reported the number of person-years and PD cases in each dose group. A dose–response meta-analysis was conducted using the least squares trend estimation method reported by Greenland et al. [
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
      ] and Orsini et al. [
      • Orsini N.
      • et al.
      Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software.
      ].

      3. Results

      3.1 Eligible studies

      The detailed screening process of this study is illustrated in Fig. 1. A total of 101, 462, and 131 studies were searched in the PubMed, Embase, and Web of Science databases, respectively. After eliminating duplicate studies, a total of 540 studies were obtained, with 529 studies further excluded as they failed to meet the inclusion criteria after assessing the abstract and title. Among the remaining 11 studies, three relevant studies [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ,
      • Wu H.F.
      • et al.
      Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
      ,
      • Brauer R.
      • et al.
      Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
      ] were identified after reading the full text. Manual retrieval did not detect any studies that could be included in the current analysis.
      Figure thumbnail gr1
      Fig. 1Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) diagram showing the study screening process.

      3.2 Study characteristics and quality assessments of the eligible studies

      The characteristics of eligible studies are illustrated in Table 1. This study included three retrospective cohort studies conducted in Taiwan and the UK with 131,410 participants; the publication years ranged from 2015 to 2020. The mean age and follow-up duration of the participants were 57.91–63.60 and 5–6.13 years, respectively. Detailed information on the eligible studies has been illustrated in Table 1. In addition, the NOS score of the eligible studies was 7–8, suggesting that the included studies had relatively high quality (Table 2).
      Table 1Characteristics of the included studies.
      Study (Area)DurationFollow-up, yearsAge, yearsn, M/FGroupnPerson-yearCase of PDHR/RR (95 %CI)Adjusted factors
      Chang, YH 2021 (Taiwan)1996–2013mean 6.1357.91 ± 10.2748828, 27508/

      21,320
      Non-pioglitazone user24,414147006.424171age, gender, DM duration, insurance range, comorbidities, CCI score, insulin
      Pioglitazone user24,414152541.382750.66 (0.57, 0.78)
      DDDs category
      024,414147006.424171
      <453815147102.591321.03 (0.84, 1.26)
      453–820812549598.14790.58 (0.45, 0.75)
      >820813555840.65640.43 (0.33, 0.56)
      Wu, HF 2018 (Taiwan)2002–2008mean 561.15 ± 10.7515812, 7392/

      8420
      Non-pioglitazone user790639,5301381sex, age, the index year, region, urbanisation level, income, hyperlipidaemia, hypertension, depression, insomnia, head injury, stroke, aspirin, statins and ARB use
      Pioglitazone user790639,5301190.90 (0.68, 1.18)
      DDDs category
      0790639,5301381
      <365394919,745640.82 (0.59, 1.15)
      ≥365395719,785550.94 (0.66, 1.34)
      Brauer, R 2015 (UK)1999–20135.23 ± 3.7563.6 (54.4–71.1)66770, NR/

      NR
      Non-pioglitazone user51,403250,9961801age, gender, practice, and treatment stage
      Pioglitazone user15,36794,218570.89 (0.65, 1.24)
      ARB, angiotensin receptor blockers; CCI: Deyo-Charlson Comorbidity Index; CI, confidence interval; DDD, dose-duration-day; DM, diabetes mellitus; F, female; M, male; HR, hazard ratio; PD, Parkinson disease; RR, risk ratio; UK, United Kingdom.
      Table 2Quality assessment (the Newcastle-Ottawa Scale) of the included studies.
      StudyRepresentati-veness of the exposed cohortSelection of the unexposed cohortAscertainment of exposureOutcome of interest not present at start of studyControl for important factor or additional factorOutcome assessmentFollow-up long enough for outcomes to occurAdequacy of follow-up of cohortsTotal quality scores
      Chang, YH 20217
      Wu, HF 2018☆☆8
      Brauer, R 20157

      3.3 Results of meta-analysis

      All studies [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ,
      • Wu H.F.
      • et al.
      Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
      ,
      • Brauer R.
      • et al.
      Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
      ] reported a significant risk association between pioglitazone and PD (Fig. 2). The heterogeneity was statistically significant (I2 = 61.8 %, P = 0.073), the combined result of RR was 0.78.0 (95 % CI [0.62–0.99]), and the difference between the pioglitazone users and non-users was significant (P = 0.039), suggesting that the risk of PD in pioglitazone users in diabetes patients was significantly lower than that in the controls.
      Figure thumbnail gr2
      Fig. 2Forest plot showing the risk association between pioglitazone and Parkinson’s disease (PD).

      3.4 Results of dose–response meta-analysis

      Two studies [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ,
      • Wu H.F.
      • et al.
      Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
      ] reported a risk association between DDD of pioglitazone and PD. First, the risk association between pioglitazone and PD was evaluated using linear correlation hypothesis testing, and the result (P = 0.010) was consistent with the nonlinear correlation. The risk association between pioglitazone and PD was evaluated using nonlinear fitting to conduct a dose–response meta-analysis. As shown in Fig. 3, with the increase in pioglitazone intake days, the risk of PD first increased and then decreased. However, the difference between the risk of PD in diabetes patients taking 438 DDDs of pioglitazone or lower and in those not taking pioglitazone was not significant. When the DDD of pioglitazone was 438, the RR was 0.85 (95 % CI [0.72–1.00], P = 0.05). When the DDD of pioglitazone was>438, the risk of PD in patients with diabetes was significantly decreased (P < 0.05) and showed an approximate linear correlation trend.
      Figure thumbnail gr3
      Fig. 3Forest plot showing the risk association between dose-duration-day (DDD) of pioglitazone and Parkinson’s disease (PD).

      4. Discussion

      Herein, the results showed that pioglitazone administration in PD in diabetes patients is significantly associated with a decrease in the risk of PD, but this beneficial effect was also dose-dependent. As this meta-analysis was conducted on a large sample size, the results were accurate and reliable. Additionally, the methodology of the included studies was of high quality, and the control of selection bias and hybrid bias was reasonable. Moreover, to the best of our knowledge, this is the first meta-analysis to analyze the effect of pioglitazone on PD in diabetes patients.
      Numerous studies have investigated the relationship between pioglitazone and PD due to pioglitazone’s neuroprotective effects and its ability to restrain inflammatory responses. Liu et al. found that pioglitazone can reduce neuroinflammation in the nigrostriatal system and improve the survival of dopaminergic neurons after diffuse brain injury in rats [
      • Liu M.
      • et al.
      Pioglitazone Attenuates Neuroinflammation and Promotes Dopaminergic Neuronal Survival in the Nigrostriatal System of Rats after Diffuse Brain Injury.
      ]. In mouse models of PD, pioglitazone has been shown to be an effective neuroprotectant [
      • Breidert T.
      • et al.
      Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease.
      ]. However, it has been reported that diabetes patients are at risk for PD, and diabetes can facilitate the incidence of PD [
      • Cereda E.
      • et al.
      Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis.
      ,
      • Schernhammer E.
      • et al.
      Diabetes and the risk of developing Parkinson's disease in Denmark.
      ]. Moreover, the relationship between pioglitazone and the risk of PD in diabetes patients remains controversial. This meta-analysis found that pioglitazone administration in PD in diabetes patients is significantly associated with a decrease in the risk of PD. The results of the meta-analysis were in accordance with those of other studies. Chang et al. revealed that pioglitazone is a potential drug for minimizing the incidence of PD in diabetes patients [
      • Chang Y.H.
      • et al.
      Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
      ]. Brauer et al. have illustrated that pioglitazone is responsible for reduction in the incidence of PD, and PPAR gamma pathways may be a fruitful drug target in PD [
      • Brauer R.
      • et al.
      Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
      ]. In addition, a previous study found that PPAR pathways play important roles in the pathogenesis of PD [
      • Li T.
      • Tang W.
      • Zhang L.
      Monte Carlo cross-validation analysis screens pathway cross-talk associated with Parkinson's disease.
      ]. However, the mechanisms underlying the effect of pioglitazone on PD in diabetes patients should be further investigated.
      Moreover, some reports indicated that pioglitazone could not minimize the risk of PD, which needs to be further discussed. For instance, Connolly et al. found that pioglitazone was not related to a longer duration of PD diagnosis [
      • Connolly J.G.
      • Bykov K.
      • Gagne J.J.
      Thiazolidinediones and Parkinson Disease: A Cohort Study.
      ]. Wu et al. showed that pioglitazone may not minimize the risk of PD with diabetes [
      • Wu H.F.
      • et al.
      Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
      ]. However, these results may be due to several inherent limitations, such as follow-up duration and ethnicity variance, because PD is a multifactorial disease, which may be affected by ethnic, genetic, and environmental factors. In addition, PD is a progressive disease, and these results may be affected by insufficient exposure to pioglitazone [

      Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 2015;14(8):795-803.

      ]. This meta-analysis indicated that only > 438 DDDs of pioglitazone would be beneficial. In combination with other studies showing the risk of pioglitazone for PD [
      • Lin H.L.
      • et al.
      Association of thiazolidinedione with a lower risk of Parkinson's disease in a population with newly-diagnosed diabetes mellitus.
      ,
      • Brakedal B.
      • et al.
      Glitazone use associated with reduced risk of Parkinson's disease.
      ], this study may provide a clearer view of the impact of pioglitazone on the risk of PD in diabetes patients.
      There are some limitations in this study. First, most of the indicators have been included in a few studies; therefore, we were unable to analyze the source of heterogeneity through subgroup analysis, meta-regression, and other quantitative methods. Second, all the included studies were retrospective cohort studies, although multivariate analyses were conducted to correct the effects of confounding factors on the results, the inconsistency of the corrected factors would also bring heterogeneity to the results. Third, only three studies were eligible for this meta-analysis, and the efficacy of either the Egger’s test or the qualitative method was relatively low; therefore, publication bias tests were not performed in this meta-analysis. Finally, the studies included in this study did not report the reaction of PD drug treatment, whether the PD exists in the family history, gene mutation and other information, and it was uncertain whether these features have been included in the correction factors, which should be further explored.

      5. Conclusion

      In summary, our meta-analysis results indicated that pioglitazone administration in PD in diabetes patients is significantly associated with a decrease in the risk of PD. More high-quality studies may be worthwhile to confirm the treatment effect of pioglitazone on PD prevention. This study provides new insights into the effects of pioglitazone on the risk of PD in diabetes patients.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      Not applicable.

      Funding

      This study was supported by the Guangdong province bureau of traditional Chinese medicine (No. 20201059 ).

      Availability of data and materials

      The data and materials used in this study are available from the corresponding authors upon request.

      Authors’ Contributions

      Liudan Chen drafted the manuscript. Yangu Tao carried out the literature search, data acquisition, data analysis and manuscript preparation. Jianjun Li and Mengru Kang performed concepts design and confirmed the authenticity of the raw data. All authors read and approved the final manuscript.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Reich S.G.
        • Savitt J.M.
        Parkinson's Disease.
        Med Clin North Am. 2019; 103: 337-350
        • Kovács M.
        • et al.
        Screening for Problematic Internet Use May Help Identify Impulse Control Disorders in Parkinson's Disease.
        Behav Neurol. 2019; 2019: 4925015
        • Noyce A.J.
        • et al.
        Meta-analysis of early nonmotor features and risk factors for Parkinson disease.
        Ann Neurol. 2012; 72: 893-901
        • Cereda E.
        • et al.
        Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis.
        Diabetes Care. 2011; 34: 2614-2623
        • Schernhammer E.
        • et al.
        Diabetes and the risk of developing Parkinson's disease in Denmark.
        Diabetes Care. 2011; 34: 1102-1108
        • Lima M.M.
        • et al.
        Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments?.
        CNS Neurol Disord Drug Targets. 2014; 13: 418-428
        • De Pablo-Fernandez E.
        • et al.
        Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study.
        Neurology. 2018; 91: e139-e142
        • Chohan H.
        • et al.
        Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression.
        Mov Disord. 2021; 36: 1420-1429
        • Driver J.A.
        • et al.
        Prospective cohort study of type 2 diabetes and the risk of Parkinson's disease.
        Diabetes Care. 2008; 31: 2003-2005
        • LeWitt P.A.
        Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics.
        Mov Disord. 2015; 30: 64-72
        • Malek N.
        Deep Brain Stimulation in Parkinson's Disease.
        Neurol India. 2019; 67: 968-978
        • Carbone F.
        • et al.
        Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations.
        CNS Drugs. 2019; 33: 905-918
        • Nyholm D.
        Duodopa® treatment for advanced Parkinson's disease: a review of efficacy and safety.
        Parkinsonism Relat Disord. 2012; 18: 916-929
        • Al-Majed A.
        • et al.
        Pioglitazone.
        Profiles Drug Subst Excip Relat Methodol. 2016; 41: 379-438
        • DeFronzo R.A.
        • et al.
        Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.
        Diab Vasc Dis Res. 2019; 16: 133-143
        • Pinto M.
        • et al.
        Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation.
        Mol Neurodegener. 2016; 11: 25
        • Welling L.C.
        • et al.
        Parkinson Disease and Pioglitazone: Could Traumatic Brain Injury Catch a Lift?.
        World Neurosurg. 2016; 95: 580-581
        • Breidert T.
        • et al.
        Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease.
        J Neurochem. 2002; 82: 615-624
        • Chang Y.H.
        • et al.
        Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.
        Eur J Neurol. 2021; 28: 430-437
        • Wu H.F.
        • et al.
        Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan.
        BMJ Open. 2018; 8: e023302
      1. Wells G. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomised Studies in Meta-Analyses. In Symposium on Systematic Reviews: Beyond the Basics; 2014.

        • Higgins J.
        • et al.
        Measuring inconsistency in meta-analyses.
        Br Med J. 2003; 327: 557-560
        • Greenland S.
        • Longnecker M.P.
        Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
        Am J Epidemiol. 1992; 135: 1301-1309
        • Orsini N.
        • et al.
        Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software.
        Am J Epidemiol. 2012; 175: 66-73
        • Brauer R.
        • et al.
        Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
        PLoS Med. 2015; 12: e1001854
        • Liu M.
        • et al.
        Pioglitazone Attenuates Neuroinflammation and Promotes Dopaminergic Neuronal Survival in the Nigrostriatal System of Rats after Diffuse Brain Injury.
        J Neurotrauma. 2017; 34: 414-422
        • Li T.
        • Tang W.
        • Zhang L.
        Monte Carlo cross-validation analysis screens pathway cross-talk associated with Parkinson's disease.
        Neurol Sci. 2016; 37: 1327-1333
        • Connolly J.G.
        • Bykov K.
        • Gagne J.J.
        Thiazolidinediones and Parkinson Disease: A Cohort Study.
        Am J Epidemiol. 2015; 182: 936-944
      2. Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 2015;14(8):795-803.

        • Lin H.L.
        • et al.
        Association of thiazolidinedione with a lower risk of Parkinson's disease in a population with newly-diagnosed diabetes mellitus.
        Ann Med. 2018; 50: 430-436
        • Brakedal B.
        • et al.
        Glitazone use associated with reduced risk of Parkinson's disease.
        Mov Disord. 2017; 32: 1594-1599