Overlap Syndrome (COPD and OSA): A Treatable Trait for Triple Treatment?

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are both highly prevalent respiratory diseases, with an estimated prevalence of approximately 10% each [1]. Their coexistence, otherwise known as overlap syndrome (OS), represents a distinct entity with complex pathophysiology and greater burden in clinical outcomes than either disease alone. Therefore, there is a need for timely diagnosis and appropriate management of both COPD and OSA [1].

Lately, OS has gained considerable attention due to its increased affinity with potential cardiovascular comorbidities [2], and also an increased risk of COPD exacerbations [3] and hospitalizations [4] compared to COPD alone, especially when OSA is left untreated [5]. It was recently reported [6, 7] that treatment of OSA with positive airway pressure (PAP) results in significant improvement in COPD-related exacerbations and hospitalizations, but not in all-cause hospitalizations [7]. Specifically, in the study of Marin et al., treatment with PAP reduced COPD exacerbations in patients with OS [5]. There is also evidence that PAP therapy leads to reduced mortality in patients with OS in comparison with those not receiving treatment [8], and this protective effect is correlated with the total hours of PAP usage [7].

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), treatment of patients with COPD should be based on disease severity (A, B, and E stages), which takes into consideration symptoms and number of exacerbations or hospitalizations [9]. Based on this classification, most patients will receive either dual bronchodilation therapy with a long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) or a triple therapy containing LABA-LAMA and inhaled corticosteroids (ICS) [9]. It is important to note that patients reporting more symptoms and/or frequent exacerbations or even who have been hospitalized for COPD exacerbation require augmented therapy with a triple combination [9]. This recommended approach should be individualized in specific populations or underlying conditions, (e.g., cardiovascular disease [CVD] and high blood eosinophils) accordingly [10, 11]. In addition, accumulating evidence supports the role of earlier initiation of ICS on top of dual bronchodilation (LABA and LAMA), especially in patients with COPD and coexistent CVD [12]. Specifically, triple therapy (ICS/LABA/LAMA) may be an appropriate initial medication for patients presenting with frequent exacerbations and/or CVD compared with dual bronchodilation, as it has been shown to reduce patients’ exacerbations and mortality [13, 14]. Nevertheless, there are also data indicating that initiation of triple therapy is related to more frequent CV events in patients with COPD compared to ICS/LABA therapy [10]. One reason could be the added LABA or LAMA to the initial therapeutic regimen, which has been shown to be associated with 1.5-fold increased cardiovascular risk in patients with COPD, irrespective of preexisting CVD [15]. Still, this issue is under debate, as recent randomized controlled trials have shown no evidence of excess cardiovascular risk by triple therapy in individuals with COPD [16, 17]. In summary, the existing evidence is controversial, but most studies have shown a safe profile of inhaled treatment regimens against the risk of CVD.

Regarding coexistent sleep disordered breathing (SDB) in patients with COPD, LABA and LAMA have each led to 2–3% increased average nocturnal oxygen saturation, compared to placebo, in patients with COPD and nocturnal hypoxemia [18, 19]. Concerning the effects of ICS, one study reported that ICS improved the apnea hypopnea index (AHI), nocturnal oxygenation, daytime partial pressure of carbon dioxide (pCO₂), and lung function via airway anti-inflammatory effects [20]. However, ICS monotherapy is not currently recommended for the treatment of COPD [9], as there is evidence that it may also lead to myopathy and predisposition to upper airway collapsibility, leading to thee development of OSA [1]. However, there are no direct studies evaluating the role of ICS monotherapy in outcomes of patients with OS, and further studies are needed.

Studies on the use of triple therapy comprising ICS, LABA, and LAMA regimens in patients with COPD are limited in patients with coexistent OSA, as they have been excluded in all of them. One study [21] comparing budesonide-formoterol-tiotropium versus placebo-tiotropium did not show any change in sleep architecture, nocturnal oxygenation, or daytime sleepiness, while another study [22] showed less nighttime awakening in the arm receiving fluticasone furoate (FF)-umeclidinium (UMEC)-vilanterol (VI) compared to FF/VI and UMEC/VI. Recently, the beclomethasone-formoterol-glycopyrronium combination was reported to improve sleep quality after 12 months of treatment compared to baseline in patients with COPD [23]. Nevertheless, this study examined only the benefit of this single-inhaler triple therapy (SITT) on the sleep quality of patients with COPD based on the COPD and Asthma Sleep Impact Scale (CASIS) [23]. CASIS is a questionnaire assessing sleep impairment in obstructive pulmonary diseases, like asthma and COPD [23]. In this study, potentially coexistent OSA was not diagnosed, and hence the effect of SITT on SDB was not evaluated.

But how does COPD medication affect the sleep characteristics and the outcomes of patients with OS? The question of whether specific COPD treatment regimens may have an advantage in this population remains open. Without doubt, patients with OS should receive the COPD treatment, according to existing guidelines. This means that most patients would receive one or two bronchodilators (LABA/LAMA) and, if indicated, ICS based on the current recommendations [9]. As previously mentioned, there are no studies addressing the effects of COPD medications with regard to the exacerbations and hospitalizations or even the mortality of patients with OS. Moreover, there is no evidence indicating that diagnosis of OSA in patients with COPD justifies the addition of ICS on top of dual bronchodilation. Lessons learned from the OSA studies [24] suggest that OSA treatment should not be based solely on metrics like the AHI, but rather on the presence or not of symptoms and comorbidities. Could this approach also be used in patients with OS while taking into consideration the COPD guidelines? For instance, should more symptomatic patients with OS or patients with additional comorbidities be treated more intensively, namely with triple therapy? Although OSA is not an indication for intensifying COPD treatment (e.g., LABA/LAMA) with an ICS regimen, it could be considered as an approach for some patients with COPD, especially in those patients who experience more exacerbations or have increased blood eosinophils [9]. Since patients with OS have an increased cardiovascular burden compared with COPD or OSA alone [25], should we reconsider our treatment approach and start with triple therapy [12]? These patients with OS who require ICS for their COPD may have better outcomes (exacerbations, hospitalizations, comorbidity burden, or even mortality) with ICS on top of bronchodilators than without ICS. Further studies are needed towards the identification of patients with OS who deserve triple therapy, in order to offer the proper COPD treatment along with the management of OSA. This approach will be beneficial for the management of these patients and could result in improved outcomes.

All in all, sleep and COPD specialists should come to a consensus about the optimal management of patients with OS in terms of the relevant COPD medication.