The safety of long-acting β₂-agonists in the treatment of stable chronic obstructive pulmonary disease

Abstract

Background

Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting β₂-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 β₂-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 β₂-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

Acknowledgments

Writing and editorial assistance was provided by Claire Chinn and Sarah Filcek (CircleScience) and David Young (Novartis). This assistance was funded by Novartis Pharma (Basel, Switzerland).

Authors’ contributions

All authors contributed to the concept, design, and writing of this manuscript and approved the final contents. All authors are responsible for the decision to submit.

Disclosure

MD has been part of advisory boards for Boehringer-Pfizer, GlaxoSmithKline (GSK), Nycomed, and Altana. He has performed consulting work for Boehringer-Pfizer, GSK, AstraZeneca, and Dompé. He also received lecture fees from these companies. All of the above amounted to less than €10,000 per annum. He received a research grant of €45,000/year from AstraZeneca.

NAH has received honoraria for serving on the speakers’ bureau of GSK and Boehringer Ingelheim, as a member of advisory boards or as a consultant for GSK, Novartis, Forest Labs, Dey, and Pfizer. He has also received research grant support that went to his institution from GSK, Novartis, Pfizer, Boehringer Ingelheim, and Sunovion.

JL has received honoraria for consultations and lectures from AstraZeneca, GSK, Merck, Novartis, Oriel Pharmaceutics, and UCB. JL/University of Gothenburg has received fnancial support for clinical studies and research from Actelion, AstraZeneca, GSK, and Novartis, as well as different contract research organizations and related commercial entities.

BPY has served as a consultant and on advisory boards for Novartis, Boehringer Ingelheim, Pfizer, Merck, and GSK in the areas of asthma and COPD. She has research funding from Boehringer Ingelheim, Novartis, Merck, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute in the areas of asthma and COPD. She does not serve on any speakers’ bureaus.