Thiazolidinedione Use in Individuals With Type 2 Diabetes and Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) involves persistent inflammation of the airways and pulmonary microvasculature, leading to partially reversible airflow limitation (1). Inadequate treatment of acute COPD exacerbation can lead to hospital admission, respiratory failure, and even death (2). Approximately 10.1% of people in the world have COPD, and the prevalence of COPD continues to rise; this may be due to increased smoking and air pollution (3). COPD is the fourth leading cause of death in the world, causing approximately 3.2 million deaths in 2017 (2).

COPD often coexists with type 2 diabetes mellitus (T2DM) perhaps due to common pathogenic factors (4). Additionally, due to inflammatory processes or the use of high-dose steroids for its treatment, COPD may contribute to the development of T2DM (4). T2DM reduces lung function, aggravates bacterial infection, accelerates COPD progression, and increases mortality risk (4). The 2020 GOLD reports emphasizing that COPD often coexists with other diseases, through the related mechanisms such as chronic inflammation and smoking, which may have significant influences on disease course (5). Therefore, patients with both COPD and T2DM must be appropriately and carefully managed.

Few studies have evaluated the antidiabetic management in individuals with coexisted T2DM and COPD (6). Metformin use has been reported to be associated with a lower mortality risk in these patients (7, 8); but the long-term results of other anti-diabetic medications for these patients have not been carefully analyzed (6). Considerable efforts have been made to find new therapies that target inflammation in COPD but with little success.

TZDs are the ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) and are used as insulin sensitizers in T2DM treatment. Their use in individuals with diabetes also reduces systemic inflammation (6). Animal studies have discovered that TZD can attenuate airway inflammation and lung injury (6). Clinical studies have also revealed that TZD was associated with lower risks of COPD exacerbations (9) and lung cancer (6). However, one meta-analysis indicated that TZD increased the risk of pneumonia or lower respiratory tract infection (10). Thus, the effects of TZD use on patients with COPD remain uncertain. We therefore hypothesize that subjects with COPD and T2DM who are treated with TZD would demonstrate reduced risk of COPD exacerbation, major adverse cardiac events, and mortality.

Our study demonstrated that TZD use in patients with T2DM and COPD was associated with significantly higher risks of cardiovascular diseases, ventilation support, bacterial pneumonia, and lung cancer as compared with TZD non-users. Moreover, the results of stratified analysis revealed the association of TZD use with higher risks of IMV, bacterial pneumonia, and lung cancer in different subgroups of patients, with rosiglitazone use seeming to have higher risks than pioglitazone use.

Cardiovascular complications are the main cause of death in individuals with T2DM (11), and patients with COPD often develop cardiovascular diseases (12). One randomized trial demonstrated that in individuals with insulin resistance and stroke, pioglitazone use can reduce the risks of stroke or myocardial infarction compared with pioglitazone non-use (13). One cohort study using the Taiwan's National Health Insurance Database disclosed that TZD added on to metformin was associated with lower major cardiovascular risk when compared with sulfonylurea added to metformin (14). However, TZD use is generally associated with body weight increase and heart failure (15). In our study, compared with TZD non-use, TZD use was associated with significantly higher risks of stroke, CAD, and heart failure and a non-significantly higher risk of composite major adverse cardiovascular events (MACEs). The stratified analysis of our study disclosed that rosiglitazone, not pioglitazone, was associated with significantly higher risks of major cardiovascular events than TZD non-users. The different results between ours and the abovementioned two studies may be due to TZD use in different population (our study was for patients with T2DM and COPD, the randomized trial was for individuals with insulin resistance and stroke, the cohort study was for persons with T2DM and metformin failure). Taken together, the findings imply that individuals with T2DM and COPD taking rosiglitazone should be monitored for cardiovascular complications.

People with COPD have limited airway patency, mucus hypersecretion, and impaired pulmonary function, which increases their susceptibility to acute exacerbation or hospitalization (16). T2DM accelerates COPD progression and worsens its prognosis (4). One cohort study revealed that TZD use in patients with coexistent COPD and T2DM was associated with a small but significantly lower risk of COPD exacerbation (9). A disease risk score matched nested case–control study in Taiwan disclosed that current TZD use for more than 181 days yielded about 40% reduced risk of COPD exacerbation in patients with comorbid T2DM and COPD (17). By contrast, we found that TZD use in patients with T2DM and COPD was not significantly associated with the risk of COPD hospitalization, probably due to differences in the methods and demographics of these studies.

Acute exacerbations in patients with COPD are frequently accompanied by bacterial infections (2, 18), or necessitating systemic corticosteroids, both of which may increase the risk of pneumonia (19). T2DM impairs patients' immune responses and increases the risk of respiratory infections (4), which further enhances the propensity of patients with concomitant COPD and T2DM to develop bacterial pneumonia. A meta-analysis on TZD use in individuals with COPD demonstrated that TZD use may increase the risk of bacterial pneumonia and lower respiratory tract infection (10), which was consistent with our finding that TZD users had a higher risk of bacterial pneumonia than did non-users. The plausible mechanisms for this result may be that TZDs are PPAR-γ agonists, and TZD-mediated PPAR-γ activation has anti-inflammatory and immunomodulatory effects on the lungs (20). TZDs can also activate glucocorticoid receptors, increase glucocorticoid-like peptide secretion, and reduce host immune function (21, 22).

Oxygen therapy improves survival in patients with COPD with hypoxemia (19). Patients have hypoxemia with persistent hypercapnia benefit from non-invasive ventilation, but those who have hypercapnia with unstable condition require conventional mechanical ventilation (23). Our study revealed that TZD use might increase the risks of NIPPV and IMV. This may be because the higher risk of bacterial pneumonia and lung cancer associated with TZD use may increase the risks of hypoxia and respiratory failure.

Because most patients with COPD have a history of smoking, they are also more likely to develop lung cancer (24). Diabetes has been associated with a higher risk of lung cancer (6). TZDs bind to PPAR and have antitumor properties (6). Some studies have shown that TZDs may reduce the risk of lung cancer (6), whereas others have reported the opposite effect (25). Our study demonstrated that TZD use may increase the risk of lung cancers, and this result was persistent among different subgroups of patients with T2DM and COPD.

TZDs combined with DPP-4 inhibitors seemed to cause a higher risk [aHR 1.74 (1.28–2.36)] of IMV () than with the other antidiabetic agents. TZD use in patients with greater DSCI [DSCI≧2, aHR 2.46 (1.25–4.82)] and DPP-4 inhibitors [aHR 2.24 (1.18–4.25)] had a higher risk of lung cancer (). Patients who took TZD combined with DPP-4 inhibitor may indicate suboptimal control of blood glucose. Patients with higher DSCI may indicate higher severity of T2DM. These may suggest that TZD use in patients with more severe T2DM, their worsening effects of IMV and lung cancer are greater. Besides, in patients with severe exacerbation of COPD, TZDs seem to have higher aHRs of IMV [3.06 (0.87–10.7)] and pneumonia [1.75 (0.49–6.26)]; which may indicate that in patients with more severe COPD, TZD use may confer worse effects of IMV and pneumonia. Supplementary Table S1 Supplementary Table S3

In our cohort, rosiglitazone appeared to have higher risks of IMV, pneumonia, and lung cancer than pioglitazone. Rosiglitazone is a PPAR-γ agonist, but pioglitazone is both PPAR-α and -γ agonist (10); as a result, they have different anti-inflammatory, immunomodulatory, and antitumor effects. Compared with pioglitazone, rosiglitazone has more potent renal PPAR-γ agonistic effect (26) and a higher risk of cardiovascular diseases (27). Taken together, these findings may explain the higher risks of respiratory outcomes of rosiglitazone use in our study.

Diabetes can worsen the clinical course of COPD, including death risk (6). Clinical trials involving patients with T2DM have not revealed an effect of TZD use on mortality (28). Although our study revealed that TZD use may increase the risks of NIPPV, IMV, bacterial pneumonia, and lung cancer, it was not associated with an increased risk of COPD hospitalization or mortality.

This study has several limitations. First, the National Health Insurance Research Database (NHIRD) does not have complete information on family history, dietary patterns, and physical activity; accurate population data for alcohol drinking and smoking habits also are difficult to obtain from this database. The lack of these data may have influenced the results of TZD use and outcome analyses. However, we used propensity score matching to balance clinically relevant variables between the 2 groups to minimize the bias of the known confounding factors. Second, the NHIRD lacked biochemical and pulmonary function test results, precluding the calculation of COPD severity scores. Instead, we used clinical records to evaluate the number of moderate and severe exacerbations of COPD. Third, this study only included people with Chinese ethnicity; thus, the results may not be applied to other ethnicities. Finally, the retrospective study design precludes causal determination, matching, and investigation of underlying mechanism, and randomized controlled trials are warranted to verify our results.

In this nationwide cohort study, patients with T2DM and COPD using TZDs might be associated with higher risks of cardiovascular complications (mainly rosiglitazone), respiratory support, bacterial pneumonia, and lung cancer than did those not using TZDs. When prescribing TZDs, to these patients, cardiovascular (especially rosiglitazone) and respiratory complications should be closely monitored.

The original contributions presented in the study are included in the article/, further inquiries can be directed to the corresponding author/s. Supplementary Material

The studies involving human participants were reviewed and approved by Research Ethics Committee of China Medical University and Hospital (CMUH104-REC2-115-CR4). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

F-SY: study concept and design, drafting of the manuscript, revision of the manuscript for crucial intellectual content, and study supervision. JW: revision of the manuscript for crucial intellectual content, technical or material support, and study supervision. Y-CY: data acquisition, analysis and interpretation, and statistical analysis. C-CH: analysis and interpretation of data, drafting of the manuscript, and revision of the manuscript for crucial intellectual content. C-MH: study concept and design, data acquisition, analysis and interpretation, drafting of the manuscript, revision of the manuscript for crucial intellectual content, statistical analysis, obtained funding, technical or material support, and study supervision.

This study was supported in part by grants from the Taipei Veterans General Hospital (V105C-204 and V110C-175) and the Ministry of Science and Technology, R.O.C (MOST 110-2314-B-075-027-MY3), the Ministry of Health and Welfare Clinical Trial Center, Taiwan (MOHW109-TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke, Taiwan (MOST 108-2321-B-039-003-), and Tseng-Lien Lin Foundation, Taichung, Taiwan. These funding agencies did not influence the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

This manuscript was edited by Wallace Academic Editing.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.729518/full#supplementary-material↗