ArticlesEffect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial
Introduction
Longacting inhaled β2-agonists (LABAs) are widely used as bronchodilators for maintenance treatment of chronic obstructive pulmonary disease (COPD).1 In general, LABAs are very effective, and most individuals seem to respond to these drugs. However, there is a small subset of patients who experience variation in response to a LABA that might be partly mediated by pharmacogenetic effects (due to genetic variation) in both asthma and COPD.2, 3 The β2-adrenergic receptor (ADRB2) is among the targets studied most extensively, and single nucleotide polymorphisms (SNPs) have been described that might be associated with variations in responses to β2-agonists.4 The most common of these polymorphisms result in aminoacid changes at the 16 aminoacid position (three genotypes: Arg16Arg, Arg16Gly, and Gly16Gly) and the 27 aminoacid position (three genotypes: Glu27Glu, Gln27Glu, and Gln27Gln). There is conflicting evidence in the scientific literature that the presence of the Arg16Arg genotype might negatively affect the clinical efficacy of regular use of LABAs in patients with asthma.5, 6, 7, 8, 9, 10 Larger studies with LABAs in asthma have not shown an Arg16Arg or Arg16Gly genotype effect,5, 10 although there might be a loss of bronchoprotection in response to methacholine challenge in Arg16 homozygotes receiving LABAs.10
In COPD, the role of ADRB2 polymorphisms in the treatment response to LABAs has been even less studied. In the most definitive study so far, Bleecker and colleagues11 did not identify an effect of Arg16Gly genotypes on the treatment response to LABA and small, short-term, and retrospective studies have shown conflicting effects of ADRB2 polymorphisms on the acute bronchodilator response to inhaled bronchodilators.12, 13, 14, 15, 16, 17 In particular, the possibility remains that there is a subgroup within patients with COPD who might benefit more from LABAs, alone or in combination with inhaled corticosteroids (ICS), than others.
The 1 year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial18 directly compared the efficacy of the longacting anticholinergic, tiotropium (Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany), with the LABA, salmeterol (GlaxoSmithKline, Uxbridge, UK), in preventing exacerbations in 7376 patients with moderate-to-very-severe COPD. This trial offered the unique opportunity to assess prospectively and in a sufficiently large sample whether Arg16 homozygous patients might have a differential treatment response to salmeterol than tiotropium.
The modulation of treatment response was expected in the salmeterol group but not in the tiotropium group. Our expectation was that the B27 polymorphism would not affect the response, thus serving as a negative control if indeed an effect of the B16 polymorphism was identified.
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Participants
POET-COPD was a 1 year, randomised, double-blind, double-dummy, parallel-group trial done at 725 centres in 25 countries to compare the efficacy of tiotropium with salmeterol regarding moderate and severe exacerbations of COPD. The study design has been described in detail elsewhere.18, 19 Briefly, patients were randomly assigned (1:1) to receive 18 μg tiotropium once daily (via HandiHaler; Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany) plus placebo twice daily (via
Results
Between Jan 12, 2010, and July 21, 2010, 5125 patients gave informed consent to genotyping (2564 in the tiotropium group and 2561 in the salmeterol group). The total number of patients who entered random assignment in the POET-COPD trial and were treated with at least one dose of study drug was 7376. The distributions of ADRB2 genotypes among patients in the tiotropium and salmeterol groups were well matched (table 1). Patient disposition for the Arg16Gly polymorphism is shown in figure 1 and
Discussion
We describe the effect of different ADRB2 polymorphisms (16 and 27 aminoacid positions) on COPD exacerbations in patients treated with salmeterol or tiotropium either alone or concomitantly with an ICS at baseline. The results of this subanalysis of the POET-COPD trial show that in patients receiving salmeterol, those with the homozygous Arg16Arg genotype had significantly better exacerbation outcomes than patients with the Arg16Gly or Gly16Gly genotypes. No association between ADRB2 genotype
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