![]() ![]() ![]() Airway smooth muscle relaxation (leading to bronchodilation) can be achieved via two main routes: inhibition of acetylcholine signaling via muscarinic M 3 receptors on airway smooth muscle with a muscarinic antagonist, or stimulation of β 2-adrenoceptors with a β 2-agonist. The mechanistic rationale for combination of a muscarinic antagonist and a β 2-agonist has been reviewed in detail recently as such, we will only briefly discuss it here. Guidelines recommend combination therapy involving two long-acting bronchodilators with differing modes of action in patients whose COPD is not sufficiently controlled with monotherapy (Table 1). The once-daily LABA indacaterol, the once-daily LAMA glycopyrronium, and twice-daily LAMA aclidinium represent newer, recently licensed therapies, and there are also several once-daily LABAs and LAMAs in development, including olodaterol, vilanterol, and glycopyrrolate (Table 2). There are a variety of long-acting bronchodilators available (Table 2). Long-acting bronchodilators (e.g., tiotropium, salmeterol) also reduce lung hyperinflation and dyspnea, and increase exercise endurance, although a recent review suggested further data are required on the benefits of long-acting bronchodilators on exercise tolerance. Long-acting bronchodilators, such as tiotropium, formoterol, and salmeterol, are proven to provide long-term improvements in lung function, quality of life, and exacerbations in patients with COPD. Inhaled bronchodilators, as monotherapy or in combination, remain the mainstay for patients in all categories (Table 1). The twice-daily LABAs salmeterol and formoterol first became available for maintenance therapy of COPD more than 15 years ago, while the once-daily LAMA tiotropium has been available for 10 years and is the most widely prescribed maintenance monotherapy bronchodilator in COPD. Subsequently, long-acting bronchodilators were developed. Short-acting bronchodilators, such as ipratropium, albuterol, and metaproterenol, have formed the cornerstone of initial COPD therapy for the past two decades. Two key classes of bronchodilators have been developed in COPD: β 2-agonists and muscarinic antagonists. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β 2-agonists (LABAs), such as formoterol and salmeterol. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. ![]() ![]() Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. ![]()
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