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Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial

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Summary

Background

The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol.

Methods

We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381.

Findings

5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events.

Interpretation

Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD.

Funding

Boehringer Ingelheim and Pfizer.

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.

Section snippets

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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