Reconsidering the overuse of short-acting β₂-agonists: clinical relevance beyond symptom relief

Extract

In recent years, increasing attention has been direct toward the overuse of short-acting β₂-agonist (SABA) in asthma management. Previously considered a simple and safe way to relieve asthma symptoms, frequent reliance on these rescue medications is now recognised as a marker of poor disease control and a predictor of adverse outcomes, including hospitalisation and emergency department visit [1]. A recent meta-analysis of 27 studies reported that SABA overuse, defined as ≥3 canisters per year, was associated with increased mortality (risk ratio 2.04; 95% CI 1.37–3.04) and a higher rate of acute exacerbations (risk ratio 1.93; 95% CI 1.24–3.03) [2].

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Overuse of short-acting β₂-agonists in asthma may reflect a pattern of persistent eosinophilic inflammation, highlighting the need for individualised assessment and treatment strategies based on inflammatory markers and patient-reported inhaler use https://bit.ly/3H8rB0z

In recent years, increasing attention has been direct toward the overuse of short-acting β₂-agonist (SABA) in asthma management. Previously considered a simple and safe way to relieve asthma symptoms, frequent reliance on these rescue medications is now recognised as a marker of poor disease control and a predictor of adverse outcomes, including hospitalisation and emergency department visit [1]. A recent meta-analysis of 27 studies reported that SABA overuse, defined as ≥3 canisters per year, was associated with increased mortality (risk ratio 2.04; 95% CI 1.37–3.04) and a higher rate of acute exacerbations (risk ratio 1.93; 95% CI 1.24–3.03) [2].

The SABINA study is one of the most referenced investigations into SABA overuse. When SABA overuse was defined as ≥3 canisters per year, 30% of patients fell into this category, and 2% used ≥11 annually [3]. Recent database studies across the globe have reported a wide range in prevalence, from 6.4% to 59.1% using ≥3 canisters per year, and from 2.0% to 30.3% for ≥11 canisters per year [3–9]. Moreover, the economic burden associated with SABA overuse has been highlighted in several studies [10, 11]. Reflecting these findings, the Global Initiative for Asthma (GINA) no longer recommends SABA monotherapy [12]. Despite the robust data from prescription databases, limited real-world evidence has been available regarding factors that drive SABA overuse on the patient interview.

In the current issue of ERJ Open Research, Louis et al. [13] report a study analysing 2167 asthma patients collected between 2011 and 2023 at the asthma clinic, which offers valuable insight into this neglected area. Louis et al. [13] analyse the associations between patient-reported use of SABA and multiple clinical, demographic and inflammatory parameters. Importantly, this study diverges from previous database-based studies by collecting direct patient reports of daily puff counts through an asthma control questionnaire, offering a more patient-centred view of SABA use. Patients were categorised into three groups: non-users, moderate users (1–4 puffs per day), and overusers (≥5 puffs per day). The definition of overuser was derived from the previous reports that the dose of salbutamol yielding optimal bronchodilation [14]. This study found that 13% of patients were overusers, a concerning proportion, particularly given that most were already receiving maintenance therapy such as inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations.

One of the most important findings of this study is the strong and independent association between SABA overuse and markers of airway eosinophilic inflammation. Specifically, sputum eosinophil counts were significantly higher in overusers, and more than half of the overusers had sputum eosinophils ≥3%. These associations persisted even after adjusting for other variables. This supports a key hypothesis: patients with uncontrolled eosinophilic inflammation may experience more frequent or severe symptoms such as chest tightness or dyspnoea, leading them to seek rapid relief through frequent SABA use. This raises an important question: is SABA overuse a behavioural marker of an underlying eosinophilic phenotype, or does SABA overuse itself exacerbate eosinophilic inflammation? Previous study by Gauvreau et al. [15] has shown that regular albuterol use may amplify eosinophilic airway inflammation, suggesting that SABA overuse may both reflect and reinforce this inflammatory process. Recent study has also reported that SABA overuse may itself exacerbate airway inflammation by inducing pro-inflammatory mediators both in vitro and in vivo [16]. Accordingly, tailoring asthma treatment based on sputum eosinophil counts may reduce the frequency of exacerbations, as demonstrated in a Cochrane Database systemic review [17]. However, fractional exhaled nitric oxide (F_ENO), often used as a surrogate for eosinophilic inflammation, was not associated with SABA overuse [13]. This discrepancy may be partially explained by the suppressive effect of smoking on F_ENO levels.

The role of systemic inflammation was also explored. Overusers exhibited elevated blood eosinophils, neutrophils and total serum immunoglobulin E levels. However, these biomarkers lost significance in the multivariable model, suggesting that localised airway inflammation measured via sputum analysis remains the most relevant determinant of SABA overuse. These findings provide the argument for integrating sputum eosinophil analysis into routine assessment in patients with frequent SABA use and inconclusive F_ENO results.

In addition to biological markers, several demographic and clinical correlates of SABA overuse were reaffirmed. Current smoking, higher body mass index, and younger age were all independently associated with increased SABA use. These factors likely contribute to symptom perception and self-management behaviours. For instance, younger adults may interpret symptoms more intensely and may be more inclined to self-medicate rather than escalate controller therapy or seek medical advice. Similarly, obesity can exacerbate dyspnoea and wheezing, leading to more frequent SABA use regardless of airway inflammation. Figure 1 provides a visual synthesis of the clinical implications of SABA overuse based on this and prior studies [7–9, 18–21].

FIGURE 1.

Patterns and associated factors of short-acting β₂-agonist (SABA) overuse in asthma. SABA overuse is commonly defined as the use of ≥3 canisters per year; however, Louis et al. [13] proposed an alternative definition of ≥5 puffs per day based on an asthma control questionnaire. Multiple factors are associated with SABA overuse, and these may vary depending on the definition used. Louis et al. [13] demonstrated an association between SABA overuse and elevated sputum eosinophil levels, although SABA overuse itself may exacerbate eosinophilic inflammation [15, 16]. Ultimately, SABA overuse is linked to increased risks of asthma exacerbation and mortality. AE: asthma exacerbation; AR: allergic rhinitis; BMI: body mass index; CRS: chronic sinusitis; FEV₁: forced expiratory volume in 1 s; GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; LABA: long-acting β₂-agonist.

Importantly, SABA overuse was prevalent even among patients receiving maintenance therapy, including ICS/LABA with or without other medications. Surprisingly, patients on such regimens had higher rates of overuse than those using SABA alone. This paradox highlights a critical issue in asthma management: being on maintenance therapy does not guarantee optimal disease control. The causes may include poor adherence, inappropriate treatment selection or persistent eosinophilic inflammation despite maintenance therapy. Previous studies have shown that good adherence to ICS/LABA significantly reduces the risk of SABA overuse, highlighting the need to monitor and support treatment adherence in clinical practice [22, 23].

From a therapeutic perspective, the findings by Louis et al. [13] support the implementation of the Maintenance and Reliever Therapy (MART) approach, which uses a combination of controller and reliever, as endorsed by GINA [12]. MART is often recommended before considering biologic therapies in patients with SABA overuse. Large trials such as PRACTICAL and SYGMA have demonstrated that MART not only reduces SABA use but also lowers exacerbation rates [24, 25]. In the Louis et al. study [13], the high prevalence of eosinophilic inflammation among overusers suggests that many of these patients may benefit from MART, which aligns both anti-inflammatory and bronchodilatory actions in one inhaler. Furthermore, the recent report PRIME study demonstrated that more patients are now receiving as-needed ICS/formoterol than SABA alone, suggesting a shift in clinical practice in line with updated guidelines [26].

The findings by Louis et al. [13] also highlight the need to consider biologics in patients who remain symptomatic and dependent on rescue medication despite appropriate controller use, and underscore the clinical value of sputum analysis over peripheral blood markers or symptom-based tools for identifying eosinophilic phenotypes. Agents targeting interleukin (IL)-5, IL-4/13, or thymic stromal lymphopoietin may be particularly useful in patients with persistently high eosinophilic inflammation.

Looking forward, several key research directions emerge. First, longitudinal studies are needed to track SABA use over time and link it with outcomes such as exacerbation frequency, lung function decline and healthcare utilisation. The study by Louis et al. [13] assessed SABA use on a one-week snapshot. Calculating one SABA inhaler contains 200 puffs, using ≥5 puffs per day is equivalent to ≥9 canisters per year. Then, the 13% overuse rate observed is substantial. However, the actual usage pattern throughout the year remains unclear. Asthma is a variable disease, and its symptom patterns fluctuate with seasons and environmental exposures. This may explain discrepancies with previous database studies, such as the inverse association with age seen in some reports. Although season did not correlate with the overuse, repeated longitudinal assessments would enhance the identification of high-risk patients and enable timely interventions. Second, the study by Louis et al. [13] did not include objective measures of adherence, such as electronic monitoring, and it remains possible that many patients were not taking their maintenance therapy as prescribed. The use of digital health technologies such as smart inhalers that record usage could refine data accuracy and further personalised care. Lastly, future trials should assess whether treatment decisions based on SABA use patterns (e.g., stepping up therapy in persistent overusers) result in better outcomes.

Clinically, Louis et al. [13] deliver an important message: excessive SABA use is not simply a behavioural issue, but may reflect a pattern of persistent eosinophilic inflammation potentially exacerbated by the pharmacologic effects of SABA itself [15, 16]. These patients often remain inadequately controlled and have unmet treatment needs. This has two main implications. First, clinicians must actively ask about actual SABA use rather than relying on prescription frequency. Second, we must be ready to act on that information, by evaluating eosinophilic inflammation, reviewing adherence, optimising controller therapy, or initiating biologics where indicated. When using the Asthma Control Test, it is worth noting that even if overuse of SABA only reduces the score slightly, the total score may still reach ≥20, thereby meeting the threshold for “clinical remission” in most countries. A more stringent Asthma Control Test cutoff (e.g., ≥23, as used in Japan) may better detect the phenotype associated with SABA overuse [27–29], a topic that warrants further discussion. As asthma management evolves toward precision medicine, studies like this remind us that simple, patient-reported metrics such as daily puff counts can hold profound clinical meaning.