Combination therapy with indacaterol and glycopyrronium bromide in the management of COPD: an update on the evidence for efficacy and safety

Introduction

Inhaled bronchodilators are the currently recommended drugs for maintenance treatment for chronic obstructive pulmonary disease (COPD), according the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, because they the respiratory symptoms and the frequency of exacerbations, increase exercise tolerance and improve quality of life [Vestbo et al. 2013]. Currently available inhaled bronchodilators include anticholinergics and β2-agonist agents. According to the onset and duration of action they are classified as: short-acting bronchodilators (i.e. salbutamol and ipratropium bromide) that are the most effective drugs for rapidly improving respiratory symptoms as needed; long-acting β2-agonists (LABA) such as salmeterol, formoterol, indacaterol, vilanterol and olodaterol; and long-acting muscarinic antagonists such as tiotropium bromide, aclidinium bromide and glycopyrronium bromide that are used in the treatment of stable disease [Cazzola et al. 2013; Keating, 2012].

The ability of β2-agonists to relax airway smooth muscle is due to their binding to the active site of β2-adrenoceptors on such cells, which induces a signaling cascade resulting in muscle relaxation. Indacaterol was introduced in 2009 as the first once-daily, long-acting β2-agonist for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD with the denomination of ultra long-acting β2-agonist or very long-acting β2-agonist (VLABA) [Ridolo et al. 2013]. Glycopyrronium bromide is a long-acting muscarinic antagonist (LAMA) and acts as a competitive antagonist by selectively binding to the muscarinic receptors in the bronchial smooth musculature, thus inhibiting acetylcholine-mediated bronchoconstriction [Buhl and Banerji, 2012].

The efficacy and safety of both indacaterol and glycopyrronium bromide drugs in patients with moderate-to-severe COPD, given in monotherapies, has been demonstrated in several controlled trials [Donohue et al. 2010; Feldman et al. 2010; Vogelmeier et al. 2010a; Chapman et al. 2011; O’Donnell et al. 2011; Kornman et al. 2011; Korn et al. 2011; Laforce et al. 2011; Buhl et al. 2011; D’Urzo et al. 2011; Kerwin et al. 2012; Dahl et al. 2013b]. But despite the availability of effective bronchodilators, in some patients with moderate-to-severe COPD, symptoms can be poorly controlled by bronchodilator monotherapy; in these cases the addition of a second bronchodilator from a different pharmacological class could be beneficial [Vogelmeier et al. 2008; van Noord et al. 2010; Mahler et al. 2012].

Here we review the evidence from published randomized trials concerning the efficacy and safety of the once-daily fixed-dose dual bronchodilator combining indacaterol and glycopyrronium.

Efficacy data

The efficacy of the fixed-dose combination of indacaterol/glycopyrronium was shown by several trials in terms of improvement in lung function as well as clinical outcomes and quality of life in patients with moderate or severe COPD, defined as a postbronchodilator forced expiratory volume in 1 second (FEV1) of between 80% and 30% of the predicted value and a postbronchodilator FEV1/forced vital capacity <70%, compared with placebo, single components or other bronchodilators [van Noord et al. 2010a; van de Maele et al. 2010; Dahl et al. 2013b; Bateman et al. 2013; Vogelmeier et al. 2013b; Wedzicha et al. 2013; Beeh et al. 2014] (Table 1).

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Table 1.

Details of trials on fixed-dose indacaterol/glycopyrronium.

Study	Number of patients	Duration	Interventions	Main outcomes	Results
van Noord et al. [2010a]	154	7 days	- Indacaterol/glycopyrronium 300/50 µg - Indacaterol 300 µg, 600 µg - Placebo	Trough FEV1 on day 7	Mean difference for trough FEV1 on day 7 between inda/gly and placebo 226 ml (192–260 ml; p < 0.001); estimated treatment difference between inda/gly and indacaterol 300 and 600 μg was 123 ml (89–157 ml; p < 0.001) and 117 ml (83–150 ml; p < 0.001), respectively.
Bateman et al. [2013] (SHINE)	2144	26 weeks	- Indacaterol/glycopyrronium 110/50 µg - Indacaterol 150 µg - Glycopyrronium 50 µg - Tiotropium 18 µg - Placebo	Trough FEV1 at week 26	Trough FEV1 at week 26 significantly improved (p < 0.001) with inda/gly compared with indacaterol and glycopyrronium (mean differences 70 ml and 90 ml, respectively), tiotropium and placebo (differences 80 ml and 200ml, respectively).
Dahl et al. [2013b] (BEACON)	193	4 weeks	- Indacaterol/glycopyrronium 110/50 µg - Indacaterol 150 µg plus - Glycopyrronium 50 µg	Trough FEV1 at week 4	Trough FEV1 at week 4 similar between the two treatment groups (1.46 l ± 0.02 and 1.46 l ± 0.18)
Dahl et al. [2013a] (ENLIGHTEN)	339	52 weeks	- Indacaterol/- glycopyrronium 110/50 µg - Placebo	Safety and tolerability for treatment-emergent AEs	Incidence of AEs similar in the active (57.8%) and placebo (56.6%) groups
Mahler et al. [2012]	247	6 weeks	- Indacaterol/glycopyrronium 110/50 µg - Tiotropium 18 µg - Placebo	Dyspnea	After 6 weeks, SAC transition dyspnea index total score significantly higher with inda/gly versus placebo (p < 0.001) and tiotropium (p = 0.021).
Vogelmeier et al. [2013] (ILLUMINATE)	532	26 weeks	- Indacaterol/glycopyrronium 110/50 µg - Fluticasone/salmeterol 50/500 µg	Standardized area under the curve from 0 to 12 h post dose for FEV1 AUC0–12h)	At week 26, FEV1 AUC0–12h significantly higher with inda/gly than with fluticasone/salmeterol (p < 0.0001)
Wedzicha et al. [2013]	2224	64 weeks	- Indacaterol/glycopyrronium 110/50 µg - Glycopyrronium 50 µg - Tiotropium 18 µg	Exacerbations rate	Rate of moderate-to-severe exacerbations significantly reduced with inda/gly versus glycopyrronium by 12%; incidence of serious AEs similar between groups.
Van de Maele et al. [2010]	257	14 days	- Indacaterol/glycopyrronium 600/100 µg - Indacaterol/glycopyrronium 300/100 µg - Indacaterol/glycopyrronium 150/100 µg - Indacaterol 300 µg - Placebo	24 h heart rate	No clinically significant differences in the 24 h mean heart rate on day 14 between the three doses of inda/gly and placebo or indacaterol.
Beeh et al. [2014] (BRIGHT)	85	3 weeks	- Indacaterol/glycopyrronium 110/50 µg - Tiotropium 18 µg - Placebo	Exercise endurance time at day 21	Significantly improved exercise endurance time at day 21 with inda/gly compared with placebo No significant improvements in exercise endurance time at day 21 between inda/gly and tiotropium.

AE, adverse event; AUC, area under the curve; FEV1, forced expiratory volume in 1 second; inda/gly, indacaterol/glycopyrronium; SAC, self-administered computerized.

Coadministration of once-daily indacaterol and glycopyrronium was also evaluated [Vincken et al. 2014]. Investigated pulmonary function endpoints included trough FEV1 (measured 24 hours after the previous dose) and other time points post dose (from 5 minutes to 24 hours); an increase in FEV1 of 120 ml is generally considered to be the threshold for clinical relevance. Beyond lung function parameters, patient-oriented clinical endpoints were also considered such as patients’ symptoms, dyspnea, exacerbation rates, use of rescue medication, days with no symptoms and nights with no awakenings, and exercise tolerance. Evaluation of symptoms and health status was performed using questionnaires like the St George’s Respiratory Questionnaire (SGRQ) and Transition Dyspnea Index (TDI).

Safety

Due to their bioavailability, inhaled bronchodilators may have systemic effects, mediated by stimulation of β2-adrenergic and muscarinic receptors, which are particularly relevant in the cardiovascular system and include tachycardia, increased blood pressure, a prolonged QT interval, hyperglycemia, hypokalemia and muscle tremors. It must be considered that many patients with COPD are elderly and often have several comorbidities; thus it is particularly important to evaluate the safety of maintenance bronchodilator treatment, especially when multiple bronchodilators are administered simultaneously.

In controlled trials, overall incidence of adverse events (AEs) was similar in patients receiving indacaterol/glycopyrronium, indacaterol alone [Asai et al. 2013; Bateman et al. 2013; Vincken et al. 2014], glycopyrronium alone [Bateman et al. 2013; Wedzicha et al. 2013], tiotropium [Asai et al. 2013; Bateman et al. 2013; Mahler et al. 2014; Wedzicha et al. 2013; Beeh et al. 2014] or salmeterol/fluticasone [Vogelmeier et al. 2013].

In the study by Bateman and colleagues, 1.3% of patients in the indacaterol/glycopyrronium treatment group had AEs leading to discontinuation compared with 4.3% in the placebo group, 5.0% in the indacaterol group, 3.0% in the glycopyrronium group and 2.1% in the tiotropium group [Bateman et al. 2013].

Dahl and colleagues performed a 52-week double-blind, parallel-group, placebo-controlled study in order to compare safety and tolerability of indacaterol/glycopyrronium 110/50 µg versus placebo. The total incidence of AEs was similar for active and placebo group; moreover, no clinically relevant change in electrocardiographic parameters and vital signs was reported [Dahl et al. 2013b].

Cardiovascular safety was also confirmed by van de Maele and colleagues who compared indacaterol/glycopyrronium at different doses (600/100 µg, 300/100 µg and 110/50 µg), indacaterol 300 µg (that is the highest dose approved for clinical use in the European Union) and placebo; at the higher dose (not approved for clinical use), there were no clinically significant differences in the 24 h mean heart rate on day 14 between indacaterol/glycopyrronium and placebo or indacaterol monotherapy [van de Maele et al. 2010].

Comparison of fixed dose indacaterol/glycopyrronium 110/50 µg to concurrent administration of the single-components indacaterol 150 μg and glycopyrronium 50 μg failed to detect any difference in terms of AEs (25.6% versus 25.2%) [Dahl et al. 2013]. Moreover, coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone did not reveal any significant difference in the rate of AEs (37.6% versus 33.9%), though the percentage of patients with an increase in QTcF of 30–60 ms from baseline was slightly higher in the indacaterol/glycopyrronium group (6.5% versus 4.2%) [Vincken et al. 2014].

A pooled analysis of 14 trials on fixed-dose indacaterol/glycopyrronium, its monocomponents and tiotropium versus placebo, including 11,404 patients (of whom 1547 were receiving indacaterol/glycopyrronium) was recently performed [Wedzicha et al. 2014]. This analysis did not show an increased risk for the investigated safety endpoints for the fixed-dose indacaterol/glycopyrronium, which had a safety profile comparable with its monocomponents and tiotropium versus placebo; in particular, a similar risk for severe cardiovascular or cerebrovascular events, death and pneumonia with indacaterol/glycopyrronium versus placebo was reported.

The use of inhaled corticosteroids in COPD was reported to be associated with an increased risk of pneumonia. In the study by Vogelmeier and colleagues, pneumonia, confirmed with chest X-ray, was reported only in four patients (1.5%) in the salmeterol/fluticasone treatment group and in no patients in the indacaterol/glycopyrronium group, while bacterial upper respiratory tract infection were more common in the indacaterol/glycopyrronium group (2.7%) compared with salmeterol/fluticasone (0.8%) [Vogelmeier et al. 2013].

Conclusion

The currently recommended treatment for stable COPD is based on bronchodilators which include long-acting LABA, VLABA and LAMA. Drugs with a long duration are preferable to favor patients’ adherence to therapy. Clinical trials and observational studies have shown that associating a long-acting bronchodilator to another with a different mechanism of action allows the achievement of better symptomatic relief in moderate-to-severe COPD. In particular, the analysis of the published randomized, controlled trials shows a good efficacy and safety of the new association of the VLABA indacaterol and the LAMA glycopyrronium, as assessed by both symptom reduction and improvement of quality of life. However, thus far there is only evidence for improvement in FEV1, while the evidence needs to be expanded for improvement in patient reported outcomes. Moreover, when analyzing the effects on exacerbations the data should be measured (due to seasonality) over 1 year, as in the Wedzicha study [Wedzicha et al. 2013]. Still, the reduced risk of possible respiratory infections associated with prolonged use of inhaled corticosteroids, which is apparent with the indacaterol/glycopyrronium treatment, is important. These characteristics provide support for a role for indacaterol/glycopyrronium in the maintenance treatment of COPD.