title: Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice.
abstract: An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting β-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that β-agonist monotherapy facilitates airway inflammation, although when co-administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of β-agonist safety. The FDA's meta-analysis of over 60,000 patients ultimately concluded that long-acting β-agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA co-administration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and near-fatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA's de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different β-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events.
authors.affiliation: Respiratory Medical Sciences, Mundipharma Research Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0G, UK, sanjeeva.dissanayake@mundipharma-rd.eu.
authors.forename: Sanjeeva B
authors.initials: SB
authors.lastname: Dissanayake
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000401:mortality; D005541:Forced Expiratory Volume; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D015201:Meta-Analysis as Topic; D012107:Research Design; D000068299:Salmeterol Xinafoate; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D000068299:Salmeterol Xinafoate; D000420:Albuterol