Elsevier

The Lancet

Volume 374, Issue 9703, 21–27 November 2009, Pages 1754-1764
The Lancet

Articles
Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial

https://doi.org/10.1016/S0140-6736(09)61492-6Get rights and content

Summary

Background

Some studies suggest that patients with asthma who are homozygous for arginine at the 16th aminoacid position of the β2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting β2 agonist in combination with inhaled corticosteroid.

Methods

In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.

Findings

After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21·4 L/min (95% CI 11·8–31·1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0·0001). In Gly/Gly participants, morning PEF was 21·5 L/min (11·0–32·1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0·0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg–Gly/Gly] −0·1, −14·4 to 14·2; p=0·99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2·4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0·0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0·87). The 2·5 times higher genotype-specific difference in responsiveness to methacholine was significant (1·32 doubling dose difference between genotypes, 0·43–2·21, p=0·0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.

Interpretation

In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting β2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.

Funding

National Institutes of Health.

Introduction

Combination therapy with longacting β2 agonists and inhaled corticosteroids is one of the most widely prescribed treatments for the control of asthma in the world. Some studies suggest that, on average, this combination improves lung function and asthma control;1 others suggest that a subpopulation of patients with asthma could be at risk for severe exacerbations or death with use of longacting β2 agonists.2, 3

β2 agonists act primarily at the β2-adrenergic receptor (ADRB2). A common single nucleotide polymorphism in the coding region of ADRB2 codes for arginine instead of glycine at the 16th aminoacid of the receptor (allele frequency 0·4 in white people4). In retrospective and prospective studies in patients with asthma not taking inhaled corticosteroids, regular use of shortacting β2 agonists, such as salbutamol (albuterol), was associated with lower lung function in individuals homozygous for arginine at the 16th aminoacid position (B16 Arg/Arg) than in individuals homozygous for glycine at that position (B16 Gly/Gly).5, 6 Another study showed increased risk of exacerbations with regular use of salbutamol but not salmeterol in patients with the B16 Arg/Arg genotype.7

In view of these genotype-specific findings, we undertook a genotype-stratified retrospective analysis of patients with asthma who had participated in randomised trials of the longacting β2 agonist salmeterol.8 Patients with the B16 Arg/Arg genotype did not benefit from treatment with salmeterol, even when used with a concomitant inhaled corticosteroid. We have therefore examined prospectively whether there is a genotype-specific difference in the response to longacting β2 agonists, by undertaking a randomised controlled trial that compared the effects of salmeterol plus inhaled corticosteroid with inhaled corticosteroid alone in B16 Arg/Arg patients with asthma versus B16 Gly/Gly patients with asthma.

Section snippets

Participants

Seven centres recruited participants for the LARGE trial. Patients with asthma were recruited from the clinical practices of each study site and through community advertising by use of a variety of media. After patients had given written informed consent (approved by participating site institutional review boards), their medical history was reviewed (eg, medication use and history of asthma exacerbations) and they were screened for eligibility on the basis of the inclusion and exclusion

Results

Figure 2 shows the trial profile. Between 2004 and 2006, 474 patients were screened for the trial. The B16 alleles were in Hardy–Weinberg equilibrium (p=0·95) in this population. 244 patients had eligible genotypes. Several of these patients (Arg/Arg, n=9; Gly/Gly, n=42) withdrew consent after screening because no appropriate match was identified and they no longer wanted to participate in the pre-match protocol. 42 participants with the B16 Arg/Arg genotype and 45 with the B16 Gly/Gly genotype

Discussion

Over the past decade, several studies have investigated the effect of specific mutations of the β-adrenergic receptor gene on response to β2 agonists.6, 7 A previous retrospective analysis of ACRN trials suggested that individuals with the ADRB2 B16 Arg/Arg genotype might not benefit from treatment with longacting β2 agonists, with or without inhaled corticosteroids.8 However, in this prospective, randomised controlled trial, the addition of a longacting β2 agonist to inhaled corticosteroid for

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