Low Doses of Long-Acting β-Agonists/Long-Acting Muscarinic Agents with Large Effects

摘要

In this issue of the Journal, the article by Mahler and colleagues (pp. 1068-1079) on the efficacy and safety of the fixed dose combination (FDC) of indacaterol (IND) and glycopyrrolate (GLY) (IND/GLY) in the FLIGHT studies is interesting from a number of viewpoints, but especially notable is the robust efficacy, given the seemingly lower doses used. Bronchodilators are first-line therapy to control symptoms in chronic obstructive pulmonary disease (COPD). Long-acting muscarinic agents (LAMAs) inhibit parasympathetic pathways, and long-acting β-agonists (LABAs) reduce airway smooth muscle tone via sympathomimetic pathways. LABAs and LAMAs are often combined clinically in free inhalers or as FDC in a variety of devices, and possibly soon in bifunctional muscarinic antagonist β-adrenergic formulations. The combinations are useful in symptomatic Global Initiative for Chronic Obstructive Lung Disease levels B and D. The approved dose in the United States for indacaterol is 75 μg once daily; 150 and 300 μg are used globally. Similarly, glycopyrronium is considered in the United States as a twice-daily drug but is used once daily globally. Therefore, IND/ GLY27.5/15.6 μg in the United States is developed for use twice a day versus the once-daily IND/GLY 110/50-μg dosage approved worldwide. The results on both lung function and patient-reported outcomes (PRO) in the FLIGHT studies compare well with the effects of once-daily higher doses of this FDC and that reported with other comparators. In addition, the information on the largest clinical trial using the COPD Assessment Test is novel and encourages further exploration. Practitioners are justifiably asking questions about all these combinations, as worldwide, there are multiple LABA/LAMA FDCs available, offering clinicians choices of once- versus twice-daily dosing, dry powder inhalers, metered dose inhalers, novel inhaled solutions, and mist formulations. In addition to a variety of novel LABAs, LAMA pharmaceutical agents in a potpourri of multiple devices, and now a range of doses, are also being introduced. Most studies are designed for regulatory approval, but head-to-head comparison studies of the FDCs are beginning, as are cost-effectiveness studies. The field is getting very crowded, but many research questions still need to be answered.