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

Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
The Lancet (Impact Factor: 45.22). 11/2009; 374(9703):1754-64. DOI: 10.1016/S0140-6736(09)61492-6
Source: PubMed


Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 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 beta2 agonist in combination with inhaled corticosteroid.
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 beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg 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, number NCT00200967.
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.
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 beta2 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.
National Institutes of Health.

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Available from: Michael E Wechsler, Oct 03, 2015
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    • "There was no difference in lung function improvement between the groups when ICS was added. Remarkably, airway responsiveness in the patients with B16 Gly/Gly did improve significantly when ICS was added to the treatment, while it did not in the B16 Arg/Arg group.98 Airway responsiveness was measured as methacholine PC20 doubling dose: the dose of methacholine that provokes a 20% drop in the volume of exhaled air during the first second of a forced expiratory maneuver. "
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    • "Two studies have implicated variations in ARDB2 as modulators of response to inhaled bronchodilators. 118,119 However, a randomized double-blind study was performed in which subjects were genotyped before being enrolled so that they could be stratified by genotype before receiving prescriptions.120 This study showed no association of genotype with the response to beta-agonists. "
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    International Journal of General Medicine 04/2013; 6:253-65. DOI:10.2147/IJGM.S28156
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    • "In some studies, a difference in clinical response to short-acting β2-adrenergic agonist (SABA) and long-acting β2-adrenergic agonist (LABA) therapies has been observed in asthma patients with specific ADRB2 genotypes [8-11]. Recent pharmacogenetic analyses have shown no effect of ADRB2 variation on clinical response to inhaled corticosteroid (ICS)/LABA combination therapy [12-15]. However, these studies did not explore the effect of diversity in the poly-C repeat on the 3′ untranslated region (3′UTR) of ADRB2. "
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