Sulfonylurea Use in Patients with Type 2 Diabetes and COPD: A Nationwide Population-Based Cohort Study

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disorder with persistent airflow limitation, respiratory symptoms, and periodic exacerbation [1]. Inhaled particulate matter, physical inactivity, and aging are the main risk factors for COPD [2]. The prevalence of COPD has rapidly increased worldwide, probably due to industrialization, urbanization, and population aging [1,2]. The global prevalence of COPD among 30–79-year-olds was about 10.3% in 2019 [2], and the number of patients with COPD increased from 142 million in 1999 to 212 million in 2019 worldwide [3]. COPD is also a leading cause of death worldwide, accounting for the third leading cause of death in 2019 [1]. Patients with COPD are prone to type 2 diabetes (T2D) due to exposure to noxious particles, chronic inflammation, aging, and frequent corticosteroid use [4]. Diabetes mellitus shares common risk factors with COPD, and hyperglycemia can significantly decrease pulmonary function. Therefore, about 10% of patients with diabetes mellitus have COPD, and studies show that diabetes can worsen the progression and prognosis of COPD [4]. Both diabetes mellitus and COPD are linked to cardiovascular diseases [1,2,4]. However, few studies have attempted to identify which antidiabetic drug may interact with COPD and determine the most favorable therapeutic option in patients with COPD and T2D [4].

Sulfonylurea (SU) has been used as an antidiabetic since the 1950s [5]. One of the most used antidiabetic drugs worldwide [5], sulfonylurea shows a rapid onset of hypoglycemic activity and is inexpensive [5]. Although it may cause hypoglycemia, large clinical trials have proved the efficacy and safety of new-generation SUs and confirmed their place in diabetes management [5,6]. SU can trigger insulin secretion in a glucose-dependent manner, lower blood glucose levels, and partially improve insulin deficiency in T2D by binding to the sulfonylurea receptor (SUR) of the ATP-sensitive potassium (K_ATP) channel and inducing channel closure [5,6]. In addition to the pancreas, K_ATP channels are also present in cardiac, skeletal, and smooth muscles [6]. Preclinical studies have shown that the opening and closing of potassium channels in airway smooth muscle and nerves may affect the contraction of the tracheobronchial tree [7]. However, no study has examined the effects of sulfonylureas on respiratory outcomes in patients with COPD. Therefore, this study aimed to investigate the long-term outcomes of SU use in patients with COPD and T2D.

This nationwide population-based cohort study showed that SU use was associated with significantly lower risks of major adverse cardiovascular events, noninvasive positive pressure ventilation, invasive mechanical ventilation, bacterial pneumonia, and all-cause mortality than SU no-use in patients with COPD and T2D. A longer cumulative duration of SU use was associated with a lower risk of these outcomes.

Cardiovascular disease is the main comorbidity and cause of death in patients with COPD and T2D [1,2,14]. Previous studies have found that SUs increase the risk of cardiovascular diseases [15]. Reports show that glibenclamide may inhibit myocardial ischemic preconditioning and increase the risk of myocardial infarction [16]. However, subsequent large-scale clinical studies and randomized controlled trials showed no significantly higher risk of cardiovascular diseases with SUs [5]. Randomized controlled trials also showed no significant difference in the risk of cardiovascular diseases between SU and pioglitazone [17]. or linagliptin [18]. Our study revealed that SU use was associated with a significantly lower risk of composite major adverse cardiovascular events than SU no-use. A longer cumulative duration of SU use was associated with a lower risk of this outcome. The reduced risk of cardiovascular events among SU versus non-SU was prominent in patients with older age, higher disease burden, and more diabetes-related complications and severity. A 10-year follow-up analysis of the UK Prospective Diabetes Study demonstrated that intensive glucose control with SU or insulin was associated with a significantly lower risk of macrovascular complications [19]. Therefore, the reduction in cardiovascular events with SU use in this study may be due to the effective lowering of blood glucose levels.

COPD is an obstructive airway disease. Acute exacerbations often cause hypoxia and even respiratory failure [1,2]. Acute hypoxic respiratory failure may require endotracheal intubation for invasive mechanical ventilation. Studies have shown that noninvasive ventilation can decrease the risk of invasive ventilation and mortality in patients with hypoxia [1,20]. Invasive mechanical ventilation is required for patients with persistent hypercapnia and blood pH < 7.35 but >7.15 [21]. Our study showed that SU use was associated with a reduced risk of NIPPV and IMV in patients with COPD and T2D, and a longer cumulative duration of SU use was associated with a lower risk of these outcomes. SU may reduce the risk of hypoxia and respiratory failure in patients with COPD. Studies have shown that hyperglycemia can induce oxidative stress and pro-inflammatory cytokines, alter the structure of lung tissue and gas exchange, lead to respiratory muscle dysfunction, and decrease pulmonary function and physical endurance [4,22]. Therefore, the reduced risk of NIPPV and IMV may be attributed to the hypoglycemic effect of SU, to reduce oxidative stress, and improve lung function [4,22]. When sulfonylurea binds to SU receptor, it causes the closure of K_ATP channels, leads to the inhibited efflux of potassium ions, increased influx of sodium ions, cell membrane depolarization, the opening of voltage-gated calcium channels, and increased intracellular concentration of calcium ions; which can then cause the pancreatic β islet cells to release insulin, and the smooth muscle of the bronchus to contract [6]. Animal studies have shown that SUs may cause bronchoconstriction by the closure of K_ATP channels and worsen the clinical course of COPD [7]. However, the structure, size, physiology, and pathology of lungs between animals and humans have some differences [23,24]; the pharmacokinetics and pharmacodynamics of medications between animals and humans are also not identical [25,26]. Furthermore, our study showed no significantly higher risk of hospitalization for COPD with SU use. Wang et al. also showed that SU use was not associated with a higher risk of severe COPD exacerbation, and a longer cumulative duration of SU use was associated with a lower risk of this outcome [27]. Preclinical studies have shown that SU could mitigate the inflammatory reaction of K_ATP channel stimulation via mitogen-activated protein kinase (MAPK) pathways in macrophages and monocytes [28]. Studies show that tolbutamide can reverse the anoxic activation of K_ATP channels in the dorsal vagal neurons of the mouse brainstem [29]. Chronic intermittent hypoxia can result in insulin resistance and glucose intolerance [30]. SU may improve pulmonary function by decreasing hypoxia-induced glucose intolerance and insulin resistance. In brief, SU may ameliorate hyperglycemia and oxidative stress, reduce inflammation and insulin resistance, improve pulmonary function, and mitigate respiratory failure. More clinical studies are needed to realize the mechanisms of SU use and lung function change in patients with COPD.

More than 50% of patients with COPD have airway bacteria in the lower respiratory tract [31]. The frequent use of steroids and the airway retention of mucoid sputum may predispose patients with COPD to respiratory tract infections, exacerbation, and even bacterial pneumonia [2,4]. Diabetes mellitus may increase about two-fold the risk of bacterial pneumonia [8]. SUs were derived from sulfonamides, which were first used to treat typhoid fever in 1942 [5]. Furthermore, our study showed that SU could reduce the risk of bacterial pneumonia in patients with COPD and T2D. Clinical studies have shown that hyperglycemia may increase the glucose level in airway secretions and predispose patients to pulmonary infections [27,32]. This study showed a lower risk of bacterial pneumonia, which could be due to reduced airway glucose levels after SU use and decreased airway bacterial colonization.

COPD is a chronic lung disease with a high mortality rate. For several years it has been the third leading cause of death worldwide [1,2]. The main objective of COPD treatment is to mitigate disease progression and reduce exacerbations and even death [1,2]. Doctors should distinguish between dyspnea and exacerbation and prescribe adequate inhalers or medications according to the guidelines. Patients should also be encouraged to follow medical advice on medication use and discontinue smoking to reduce mortality risk [1,2]. Our study demonstrated that SUs were associated with a reduced risk of all-cause mortality in patients with COPD. A longer cumulative duration of SU use showed an association with a lower risk of death. Reduction in the risk of death with SU use was also significant in all subgroups of patients with COPD and T2D. The reduced risk of death from SU use in this study may be attributed to the decreased risk of cardiovascular events, ventilation use, and bacterial pneumonia.

The most worrying side effect of SU use is hypoglycemia. Clinical studies showed that about 1.8 % of patients receiving SUs had hypoglycemia per year, and the incidence of severe hypoglycemia was 0.86–5.6 per 1000 persons-years [5,6]. However, our study showed that SU was not associated with a significant difference in the risk of severe hypoglycemia. COPD and T2D are associated with a higher risk of lung cancer [22,33]. SU has been suspected to increase cancer risk because it promotes insulin secretion [34]. However, our study showed that SU use had no association with a significantly higher risk of lung cancer in patients with COPD and T2D.

Our study has several disadvantages. First, this administrative dataset lacks information on family history, dietary habits, physical activity, daily alcohol consumption, and smoking status, which may affect our comparison of the outcomes between SU users and nonusers. However, we used propensity score matching for 38 critical variables to align the health status of SU users and nonusers as much as possible. Second, this National Health Insurance database also lacks the results of biochemical and microbiological tests, hemoglobin A1C levels, and pulmonary function tests, precluding careful assessment of COPD and T2D severity. However, we used CCI, DCSI scores, the item and number of oral antidiabetic and antihypertensive drugs, insulin use, and the duration of T2D as a proxy for the severity of T2D. Third, this study mainly involved Taiwanese people with type 2 diabetes; therefore, these results may not apply to non-Taiwanese individuals or patients with non-T2D. Finally, there are always unknown, unmeasured confounding factors in a cohort study; randomized controlled trials are warranted to confirm our results. However, a well-designed real-world observational study can provide valuable information on clinical practice.

Our study showed that SU use was associated with lower risks of cardiovascular events, ventilation use, bacterial pneumonia, and all-cause mortality in patients with COPD and T2D. Perhaps, SU is a suitable option for diabetes management in patients with coexisting COPD and T2D.

We are grateful to Health Data Science Center, China Medical University Hospital for providing administrative, technical and funding support.

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijerph192215013/s1↗, Table S1: Diseases and related ICD-9-CM, ICD-10-CM codes, Table S2: Hazard ratios (HRs) and 95% confidence intervals (CIs) for death among the sampled patients, Table S3: Hazard ratios (HRs), and 95% confidence intervals (CIs) for cardiovascular events among the sampled patients; Table S4: Hazard ratios (HRs), and 95% confidence intervals (CIs) for non-invasive positive pressure ventilation among the sampled patients; Table S5: Hazard ratios (HRs), and 95% confidence intervals (CIs) for invasive mechanical ventilation among the sampled patients; Table S6: Hazard ratios (HRs), and 95% confidence intervals (CIs) for bacterial pneumonia among the sampled patients.

Conceptualization, F.-S.Y., C.-C.H., C.-M.H. and J.C.-C.W.; methodology, F.-S.Y., C.Y.H. and T.-S.Y.; software, C.-C.H., C.Y.H. and T.-S.Y.; validation, C.-C.H., C.-M.H. and T.-S.Y.; formal analysis, C.-C.H., C.Y.H. and T.-S.Y.; investigation, F.-S.Y., J.C.-C.W. and T.-S.Y.; resources, T.-S.Y., C.Y.H. and J.C.-C.W.; data curation, C.-C.H. and C.-M.H.; writing—original draft preparation, F.-S.Y. and C.-M.H.; writing—review and editing, F.-S.Y., C.-C.H., J.C.-C.W., C.Y.H. and T.-S.Y.; visualization, C.-C.H. and T.-S.Y.; supervision, C.-C.H. and C.-M.H.; project administration, C.-C.H., T.-S.Y. and C.-M.H.; funding acquisition, J.C.-C.W., C.Y.H. and C.-M.H. All authors have read and agreed to the published version of the manuscript.

This study was approved by the Research Ethics Committee of China Medical University and Hospital [CMUH110-REC1-038-(CR1)].

Informed consent was waived by the Research Ethics Committee.

Data of this study are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Administration. The data utilized in this study cannot be made available in the paper, the Supplemental Files, or in a public repository due to the ‘‘Personal Information Protection Act’’ executed by the Taiwan government starting in 2012. Requests for data can be sent as a formal proposal to the NHIRD Office (https://dep.mohw.gov.tw/DOS/cp-2516-3591-113.html↗, accessed on 15 August 2022) or by email to stsung@mohw.gov.tw.

The authors declare no conflict of interest.

This study was supported in part by the Ministry of Health and Welfare Clinical Trial Center, Taiwan (MOHW109-TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke (MOST 109-2321-B-039-002), China Medical University Hospital (DMR-110-222), 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 writing or preparation of this paper was not funded by any organization; the data analyses were not undertaken by individuals who are employees of funders, or any author who received funding from funders; and no writing support was provided by the funders. The corresponding authors had complete access to all data in the study and were responsible for the decision to submit this manuscript for publication.