The safety of long-acting ß2-agonists in the treatment of stable chronic obstructive pulmonary disease

Marc L Decramer,¹ Nicola A Hanania,² Jan O Lötvall,³ Barbara P Yawn<sup>4

1</sup>Respiratory Division, University Hospital, KU Leuven, Belgium; ²Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; ³Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden; ⁴Department of Research, Olmsted Medical Center, Rochester, MN, USA

Background: Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting ß2-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.
Methods: We searched PubMed for placebo-controlled studies evaluating long-term (≥24 weeks) use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012. We summarized data relating to exacerbations and adverse events, particularly events related to COPD.
Results: From 20 studies examined (8774 LABA-treated patients), there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths. Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo. Incidences of COPD-related adverse events were similar for active and placebo treatments. The incidence of adverse events typically associated with the ß2-agonist drug class such as skeletal muscle tremors and palpitations was low (often <1% of patients), and there were no reports of increased incidence of cardiac arrhythmias. The systemic effects of ß2-adrenoceptor stimulation, such as high glucose and potassium levels, were considered minor.
Conclusion: Current evidence from clinical studies of the safety and tolerability profile of LABAs supports their long-term use in COPD.

Keywords: LABA, formoterol, salmeterol, indacaterol, bronchodilator, COPD