Use of antidiabetic medications and risk of chronic obstructive pulmonary disease exacerbation requiring hospitalization: a disease risk score-matched nested case–control study

Chronic obstructive pulmonary disease (COPD) is a globally prevalent disease with irreversible and persistent airway obstruction, currently affecting at least 380 million people worldwide [1]. According to recent statistics of World Health Organization, more than 3 million patients died of COPD globally in 2015, with a death rate of 5% [2]. Approximately 30% of COPD patients experienced one or more exacerbation events yearly [3], and COPD exacerbations often elicited severe clinical consequences, despite standard COPD treatments. Patients with COPD exacerbation had an inpatient death rate of 4–11% on index hospitalization, and 22–43% of them died within 1 year after discharge [4, 5]. Inhaled long-acting β₂ agonists, long-acting muscarinic antagonists, and inhaled corticosteroids are the mainstay therapies for managing COPD [6]; however, these medications could not entirely prevent COPD exacerbations [7]. Consequently, development of novel therapies for reducing COPD exacerbations is of great clinical importance.

Diabetes mellitus (DM) frequently coincides with COPD [8], and use of specific hypoglycemic agents (OHAs) may decrease COPD progression due to their anti-inflammatory effect based on preclinical data [9]. Exacerbation of COPD is primarily involved with systemic and pulmonary inflammation [10], which may be attenuated with using several antidiabetic agents [9]. According to in vitro and in vivo studies, metformin, thiazolidinedione (TZD), and dipeptidyl peptidase-4 (DPP-4) inhibitors produce anti-inflammatory effects by decreasing inflammatory biomarker levels [11, 12], activating peroxisome proliferator-activated receptor-γ [13], or improving insulin resistance [14, 15], but several OHAs, such as sulfonylureas, meglitinides, and α-glucosidase inhibitors, have not been fully assessed regarding their effects in inflammation and COPD. Therefore, further investigations are urgently required to assess whether or not each individual type of antidiabetic medications carries a beneficial effect on COPD outcomes.

Only one case–control study and a cohort-study have evaluated the association between risk of COPD exacerbation and use of antidiabetic drugs among COPD patients, which reported a 44% lower risk of COPD-related hospitalizations or emergency visits with metformin use [16] and a 19% reduced risk of COPD exacerbation requiring hospitalization with TZD use [17], respectively. Nevertheless, the two studies may be subject to selection bias, lack of control of important confounding factors, such as pneumonia and lung cancer, and confounding by DM and COPD severity. Additionally, the impact of other types of OHAs on COPD exacerbations has not been examined.

To the best of our knowledge, no study has extensively evaluated the association between risk of COPD exacerbations and each class of OHAs. Accordingly, this study was aimed to assess the association between use of various types of OHAs and the risk of severe COPD exacerbations in patients with COPD and DM.

The eligible study cohort comprised 23,875 COPD patients (mean age, 69.1 years; 59.4% men) co-diagnosed with diabetes and receiving OHAs (Fig. 1). The study cohort was followed for a mean of 5.2 years, contributing to 124,325 person-years. During the follow-up, 3266 patients with severe COPD exacerbation were identified, with an incidence rate of 2.62 per 100 person-years. After DRS matching, we included 2700 cases and 9272 randomly-selected matched controls.

Overall, the baseline characteristics were balanced between cases and controls, despite a few imbalanced covariates between the two groups (Table 1). During the follow-up, most factors remained balanced between cases and controls. However, cases had higher numbers of COPD exacerbations with ER visits, presence of stroke, heart failure, and pneumonia, as well as receipt with co-medications, such as short-acting insulin, diuretics, antiarrhythmic agents, and systemic corticosteroids. Controls had a higher proportion of hyperlipidemia and use of statins, nonsteroidal anti-inflammatory drugs, and vaccines than cases.

Table 2 presents the associations between current use of each type of OHA and risk of severe COPD exacerbation. Current use of metformin versus that of other OHAs yielded a 19% (adjusted odds ratio [aOR], 0.81; 95% CI 0.73–0.91) and a 15% (aOR, 0.85; 95% CI 0.75–0.95) decreased risk of severe COPD exacerbation when controlling for covariates with standardized differences greater than 0.1 (model 1) and further adjusting for diabetic medication regimens (model 2), respectively. In contrast, current use of other OHAs, like sulfonylureas or DPP-4 inhibitors, was not associated with the risk of severe COPD exacerbation.

The associations between current use of each type of OHA in varying durations of therapy and the risk of severe COPD exacerbation are presented in Table 3. Current use of metformin versus that of other OHAs during the first 30 days of therapy carried a 1.55-fold (aOR, 1.55; 95% CI 1.28–1.88) increased risk of COPD severe exacerbation, even when further adjusting for diabetic medication regimens (aOR, 1.61; 95% CI 1.32–1.69), whereas a 28% (aOR, 0.72; 95% CI 0.58–0.89), 37% (aOR, 0.63; 95% CI 0.51–0.77), and 32% (aOR, 0.68; 95% CI 0.57–0.79) lower risk of severe COPD exacerbation was observed for 91–180 days, 181–365 days, and more than 365 days of metformin therapy, respectively. Similarly, current use of sulfonylurea for more than 90 days led to an approximately 30% reduced risk of severe COPD exacerbation, although an increased risk of severe COPD exacerbation was observed within the first 30 days of sulfonylurea use. Furthermore, current use of TZD had a similar duration effect as the use of metformin and sulfonylurea.

Table 4 presents the dose effects of current use of OHAs on severe COPD exacerbation. Despite a 19%-22% (model 1: aOR, 0.78; 95% CI 0.69–0.88; model 2: aOR, 0.81; 95% CI 0.71–0.92) decreased risks of severe COPD exacerbation with use of metformin at a daily dose ≤ 0.50 DDD, the reduced risk was absent with 0.51–1 DDD and > 1 DDD of metformin therapy. A similar dose effect was also observed with other types of OHAs, such as sulfonylureas, TZDs, and meglitinides. However, there was no statistically significant linear trend in the risk of severe COPD exacerbation from the lowest to highest categories of daily dose of antidiabetic medications.

Table 5 indicates that patients currently receiving any type of oral hypoglycemic monotherapy did not present any change in the risk of severe COPD exacerbation compared with those presently using other classes of monotherapy. In contrast, dual therapy with metformin and sulfonylureas yielded a 22% (aOR, 0.78; 95% CI 0.64–0.95) reduction in the exacerbation risk as compared with other therapies comprising two or more components (Table 6).

Overall, the main findings were robust in most of the sensitivity analyses (Fig. 2). The findings regarding the decreased risks of severe COPD exacerbation with the current use of metformin were replicated when restricted to patients who had undergone spirometry testing, to those without severe COPD exacerbation at baseline, to patients without heart failure and use of insulin, and when adopting different statistical models. The observed protective effects of metformin were primarily confined to patients with outpatient-related or no COPD exacerbations during follow-up. When stratified by use of systemic corticosteroids, the reduced risk of severe COPD exacerbation with current metformin use was confined to those without prior systemic corticosteroid use. Figure 3 indicates that an unmeasured confounder needs to be 2 times less prevalent in metformin users then in non-metformin users and to increase the risk of severe COPD exacerbation by more than three to sixfold to completely explain the observed association between current use of metformin and risk of severe COPD exacerbation.

This DRS-matched nested case–control study of more than 23,000 patients with COPD diagnosed with DM revealed a significantly decreased risk (15–20%) of severe COPD exacerbation associated with current use of metformin versus that of other OHAs. This observed reduced risk with metformin therapy persisted in patients who had undergone spirometry testing, had no previous severe COPD exacerbation or heart failure, and when performing different statistical adjustment models. Additionally, current use of metformin, sulfonylureas, and TZDs lasting for > 90 days, respectively, was associated with an approximately 30–40% reduction in the risk of severe COPD exacerbation. Overall, we provided the first evidence that using certain types of OHAs, including metformin, sulfonylureas and TZD, is associated with a duration-dependent decreased risk of severe COPD exacerbation in patients with COPD and DM.

Partly, our findings agree with those of two previous reports [16, 17] that only examined the association between metformin or TZD use and COPD exacerbation, and our remaining findings provide new information. A cohort study of 11,260 US Medicare patients with low COPD complexity diagnosed with DM observed a 34% (aOR, 0.66; 95% CI 0.52–0.85) reduced risk of COPD-specific ER visits or hospitalizations with the use of metformin [16]. However, this study could have been threatened by immortal time bias, misclassification of drug exposure during follow-up, and selection bias. Moreover, the findings revealed a reduced COPD exacerbation risk when assessing the effects of metformin therapies lasting for > 90 days, similar to our findings. Assessment of a longer duration of treatment with metformin may be the main driver of the consistent findings of the two studies. Another cohort study of 50,243 US veterans reported a 19% (incidence rate ratio, 0.81; 95% CI 0.68–0.97) reduced risk of hospitalization for COPD exacerbations with TZD use [17], which is much lower than that observed with TZD therapy lasting for > 180 days in our study. The findings by Rinne et al., however, had several study limitations. First, the average duration of TZD therapy was undefined in Rinne’s study [17]. Second, TZD users could receive other antidiabetic medications [17], which were not addressed. On the other hand, our findings regarding the beneficial effect of sulfonylureas on COPD; the effects of α-glucosidase inhibitors, DPP-4 inhibitors, and meglitinides; and the reported duration-effects provide novel insights into the association between use of antidiabetic agents and risk of severe COPD exacerbation.

Despite not measuring COPD exacerbation, recent studies have revealed potentially beneficial effects with use of several types of antidiabetic agents in patients with COPD and DM [28]. Although DM is reported to have a negative impact on COPD, one study has found that COPD patients co-diagnosed with DM did not have an impaired pulmonary capillary function, such as the diffusing capacity of carbon monoxide, compared to patients with COPD only [29]. This phenomenon could probably be attributable to the systemic anti-inflammatory effects from use of antidiabetic medications in COPD patients [29]. Additionally, multiple studies have reported that use of insulin sensitizers, such as metformin and TZD in COPD may improve lung functions and reduce risks of all-cause mortality and lung cancer [30‐32]. Collectively, our data collide with the abovementioned studies indicating that patients with COPD and DM may benefit from use of antidiabetic medications in several important clinical outcomes.

Several potentially biological plausibilities may exist for the observed protective effect of metformin against severe COPD exacerbation. First, metformin exerts an anti-inflammatory effect by activating adenosine monophosphate-activated protein kinase [33], which could inhibit the pro-inflammatory and inflammatory responses in vascular endothelial and smooth muscle cells [34, 35] and generate anti-atherosclerotic effects by reducing inflammatory cell adhesion to the blood vessel endothelium [36]. Additionally, metformin used for 3 months significantly reduced the level of inflammatory markers ICAM-1, TNF-a, and IL-6 in patients with drug-naïve type II DM [37]. Second, metformin could improve respiratory muscle function, which may alleviate COPD symptom worsening. Specifically, Six-month metformin treatment significantly increased (11%) inspiratory muscle strength in patients with moderate-to-severe COPD diagnosed with DM [30], although its clinical significance is unclear owing to lack of clinical improvement in inspiratory muscle strength among patients with COPD. Third, mitigation of insulin resistance with metformin use could be another potential explanation. Chronic systemic inflammation in COPD is highly associated with insulin resistance [15, 38], which further impairs airway obstruction and increases COPD exacerbation occurrence [39, 40]. Therefore, as metformin effectively attenuates insulin resistance, it may benefit COPD exacerbation.

The observed beneficial effect of sulfonylureas on severe COPD exacerbation may result more from the drug’s potential influence on hypoxia-induced insulin resistance than from its anti-inflammatory effect, despite scant evidence. In vitro and in vivo studies have shown that K_ATP channel-specific sulfonylureas counteract the inflammatory effects of K_ATP channel stimulation via mitogen-activated protein kinase pathways in monocytes and macrophages [41]. Nevertheless, in humans, there are no documented decreased levels of systemic inflammatory biomarkers with the use of K_ATP channel-specific sulfonylureas glyburide [42], glimepiride [43], and gliclazide [44]. Conversely, the reduced hypoxia-induced insulin resistance from sulfonylureas could potentially act as an alternative mechanism. Chronic intermittent hypoxia could lead to insulin resistance, impair glucose tolerance, and consequently worsen COPD [45]. One animal study has reported that the sulfonylurea tolbutamide reversed the anoxic activation of K_ATP channels in the dorsal vagal neurons of mouse brainstem slices [46]. Sulfonylureas could indirectly improve pulmonary function by reducing hypoxia-induced insulin resistance.

There are several possible explanations for the observed increased risk of severe COPD exacerbation within the first 30 days after treatment with several OHA classes, especially sulfonylureas and meglitinide. A long time is probably required for the aforementioned mechanisms underlying the beneficial effect of OHAs on COPD exacerbation to kick in. For instance, at least 3-month treatment of metformin is needed to reduce inflammatory biomarker levels [37]. Therefore, patients with COPD receiving a short-term treatment with OHAs could not immediately attain the benefits against COPD progression. Alternatively, confounding by indication bias could contribute to our findings because uncontrolled hyperglycemia is associated with COPD exacerbation [40, 47] and a substantial proportion of patients initially receiving OHAs may have continuing, impaired fasting glucose and non-targeted hemoglobin A1c levels. Therefore, the observed increased risk during the first 30 days after using OHAs could simply result from an uncontrolled glucose level. If this bias truly exists, using all classes of OHAs should have led to similar positive results, which was not the case for α-glucosidase inhibitors and DPP-4 inhibitors in our study. Moreover, the adoption of the active-comparator design in our study may ease the concern about the presence of this bias. Another cause for the findings could be the initial OHA use for hyperglycemia induced by systemic corticosteroids [48, 49], which are most frequently prescribed for COPD worsening in outpatient settings that could progress to severe exacerbation requiring hospitalization [6]. Considering this, and given that sulfonylureas and meglitinide are the recommended therapies for corticosteroid-induced hyperglycemia [49], we could have observed a higher increased risk of COPD-related hospitalization within the first 30 days after the initial use of sulfonylureas and meglitinide.

Several attributes of our findings are pivotal from a clinical point of view. Our evidence on the reduction in the risk of severe COPD exacerbation following treatment with specific types of OHAs should be incorporated into the benefit-and-risk evaluation of pharmacological treatments for management of DM in patients with COPD. In the presence of COPD comorbidity, the use of OHAs needs to be considered according to their impact on COPD and antihyperglycemic effects. According to our findings, we suggest metformin as the first consideration for managing DM in patients with COPD if they have no contraindication for the drug. This recommendation is based on the evidence from the current treatment guidelines of DM management, suggesting metformin as the first-line therapy for patients with diabetes if tolerated and according to our real-world evidence on the reduced severe COPD exacerbation with metformin use. Under similar considerations, sulfonylureas may be considered as the preferred second-line therapy for patients in whom targeted glycemia levels have not been reached, for those intolerant to metformin, and for those not prone to sulfonylurea-induced adverse drug reactions, such as adverse hypoglycemia and cardiovascular events. According to our main findings and the fact that metformin has been reported as a safe medication in non-diabetic patients, such as polycystic ovary syndrome patients [50], well-designed randomized controlled trials are urgently required to confirm the observed beneficial effects of metformin in preventing COPD exacerbations.

This is the first large observational study that systemically assessed the effects of all classes of OHAs on severe COPD exacerbation in a nationwide population with COPD and DM. We also found that the timing and duration of oral antihyperglycemic therapy for management of DM play a pivotal role in protecting against severe COPD exacerbation. Furthermore, adopting a nested case–control design allowed the examination of numerous severe COPD exacerbation events. Moreover, employing a DRS-matching scheme could effectively minimize the impact of confounding and selection bias on our findings. As this study measured hard endpoints (severe COPD exacerbation requiring hospitalization), our findings could more closely reflect real-world conditions compared with those of previous studies that evaluated the impact of OHAs on changes in inflammatory biomarker levels or lung function data.

Our findings, however, should be interpreted with several limitations. First, as there are few imbalanced covariates between cases and controls, selection bias could not be entirely ruled out. To address this, we performed the DRS-matched process, adopted active-comparator analyses, and adjusted for all covariates with standard difference > 0.1. Second, the analyzed database lacked information on hemoglobin A1c, fasting glucose, forced expiratory volume in one second (FEV₁), COPD Assessment Test (CAT) data, and modified Medical Research Council (mMRC) parameters; therefore, a confounding effect resulting from these unmeasured parameters is possible. Nevertheless, we considered comprehensive proxy indicators for both DM and COPD severities, which were quite well-balanced at baseline. Additionally, an unmeasured confounder is unlikely to fully explain our observed reduced risk of severe exacerbation associated with current use of metformin based on the rule-out analysis. Third, our study was not equipped with sufficient statistical power to examine the effect of the individual agents within each class of the antidiabetic medications on the risk of severe COPD exacerbations. Fourth, novel antidiabetic medications like sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists could not be assessed because of limited sizes. Fifth, we considered only severe COPD exacerbations as this severity of exacerbation had the most impact on morbidity and mortality; our findings could not be applied to patients with mild or moderate COPD exacerbations. Finally, our findings may be subject to the healthy user bias because patients could have been carefully monitored by healthcare professionals or intensively received respiratory medications during follow-up. However, all patients included in the current study were required to use both COPD and antidiabetic medications. If healthy user bias did exist, it would have an impact not only in case groups but also in control groups. Additionally, our observed reduced risk of COPD exacerbations was confined to specific types of antidiabetic medications as opposed to all classes of OHAs, which may preclude the presence of health user bias in the present study. Moreover, we have performed a disease-risk score matching approach and multivariable analysis to control for severity of COPD and DM as well as use of COPD medications at baseline and during follow-up, respectively. The rule-out analysis, however, pointed out that it is unlikely for unmeasured confounder, such as training in disease management, to fully account for our main findings.

This large observational study of more than 23,000 COPD patients co-diagnosed with DM observed a duration-dependent beneficial effect of current use of metformin, sulfonylureas, and TZDs, respectively, on severe COPD exacerbation.