Beier and Beeh including airflow (forced expiratory volume in 1 second [FEV1]), hyperinflation, symptom control, dyspnea, quality of life, physical activity, and exacerbations.2,3 Recent data from large-scale clinical trials may also indicate a beneficial effect of long-acting bronchodilators on disease progression4 and even mortality in subsets of patients.5 Finally, a reduc- tion of dosing frequency for inhaled therapies will simplify the management of COPD, ultimately leading to improved patient adherence and compliance,6 contributing to better clinical outcomes.7 The aim of this review is to summarize relevant data and landmark studies comparing the efficacy of short- versus longer-acting bronchodilators in COPD, including new data for once-daily indacaterol. Clinical benefits of twice-daily long-acting β-2-agonists in COPD The long-acting β(2)-agonists (LABA) formoterol and salmeterol were licensed for the treatment of COPD over a decade ago. Both drugs have a duration of action of approxi- mately 12 hours, requiring a twice-daily dosage.8,9 Formoterol and salmeterol are more effective than short-acting broncho- dilators in improving lung function (FEV1),10–13 with improve- ments in symptoms for formoterol versus ipratropium,10 but no consistent effect on exacerbations versus regular ipratro- pium for both.10,12,13 In a study by Rennard et al13 salmeterol 50 microgram (mcg) twice daily was also not superior to regular ipratropium in regard to improving symptoms, dyspnea, and exercise. To date, there are no conclusive data from comparative studies investigating the effects of sal- meterol and formoterol head to head on relevant long-term outcomes in COPD.14 As was already known from asthma trials, formoterol has a faster onset of bronchodilator action in COPD versus salmeterol.15,16 Due to the lack of any fur- ther supporting data, current guidelines do not recommend any of theses two twice-daily LABAs over the other for the maintenance treatment of COPD. Both formoterol and salmeterol have been extensively studied as monotherapy for COPD as control arms in the pivotal studies investigating the efficacy of inhaled cor- ticosteroids/LABA fixed-dose combination.17–20 In these studies, LABA monotherapy was associated with numerous clinical improvements; however, as no regular short-acting bronchodilator comparator was investigated in any of these trials, the data do not allow any definite conclusion about the comparative efficacy of twice-daily versus short-acting β-agonists in COPD. Direct comparisons between twice- daily LABAs and the once-daily anticholinergic tiotropium in patients with COPD have generally been short term, with 238 submit your manuscript | www.dovepress.com Dovepress Dovepress one report of two combined studies of 6 months’ duration.21 In comparison with salmeterol, tiotropium provided greater improvements in lung function and symptoms,21,22 whereas there was only a numerical reduction in exacerbations com- pared with salmeterol. A subsequent 12-week randomized, double-blind study versus salmeterol documented superior bronchodilation during 12-hour testing.23 Formoterol pro- vided similar bronchodilation to tiotropium 12 hours after inhalation, but the magnitude of effect was higher during the first 2 hours post-dose, consistent with a faster onset of bronchodilator action for formoterol.24 A 6-month study comparing the combination of tiotropium and formoterol with single components and placebo reported no differences in outcomes of formoterol monotherapy versus tiotropium.25 In general, the evidence level has not shown clear distinctions between twice-daily LABAs and tiotropium on more clini- cally oriented outcomes. Currently, an ongoing large-scale study will directly compare the effect of tiotropium with salmeterol on COPD exacerbations.26 Indacaterol: once-daily β-2-agonist with 24-hour duration of action In December 2009, the once-daily LABA indacaterol was approved for the maintenance treatment of COPD in the European Union at a recommended dose of 150 mcg once daily and a maximum dose of 300 mcg once daily. Indacaterol is a partial β(2)-agonist with high intrinsic efficacy at the receptor level. Unlike other partial agonists, it does not exhibit antagonistic behaviour in the presence of isoprenaline (“near full agonist”).27 Potency and intrinsic efficacy have been demonstrated in various models, including recombinant recep- tors, guinea pig trachea, isolated human bronchus, and human lung slices, with a selectivity ratio for indacaterol of 28 and 22 against β1 and β3 receptors.27–29 In these studies, a fast onset of action and longer duration of action versus formoterol and salmeterol were also demonstrated. Although the prolonged duration of action of indacaterol versus other lipophilic β(2)- agonists like salmeterol can potentially be explained by the higher affinity of indacaterol to lipid raft domains within the membrane,30 its fast onset of action is related to the high intrinsic efficacy at the receptor level.31 Pharmacokinetic data taken during multiple-dose studies of indacaterol 400 mcg or 800 mcg once daily for 14 days demonstrated rapid absorption and a mean elimination half life of .30 hours, whereas, in a single-dose study, doses between 600 mcg and 2000 mcg were rapidly absorbed with maximum serum concentrations reached within 15 minutes.32,33 Steady state after inhalation was reached within 12 days of once-daily dosing.34 International Journal of COPD 2011:6