TY - JOUR
T1 - Effect of ADRB2 polymorphisms on response to longacting β2-agonist therapy
T2 - a pharmacogenetic analysis of two randomised studies
AU - Bleecker, Eugene R.
AU - Postma, Dirkje S.
AU - Lawrance, Rachael M.
AU - Meyers, Deborah A.
AU - Ambrose, Helen J.
AU - Goldman, Mitch
N1 - Funding Information:
ERB has received grant support to perform clinical trials from AstraZeneca and GlaxoSmithKline, has served as a consultant with AstraZeneca and GlaxoSmithKline, and has presented CME and other lectures sponsored by AstraZeneca and GlaxoSmithKline. DAM has received grant funding from AstraZeneca for directing a 2-day postgraduate course on human genetics and pharmacogenetics in 2006 and 2007. DSP has received research funding from AstraZeneca. RL, HA, and MG are employees of AstraZeneca and hold stock in the company. All the pharmaceutical industry grant support was administered through their respective University/Medical Centers for the above authors and no financial support was received by any of the authors for the studies presented in this report.
PY - 2007/12/22
Y1 - 2007/12/22
N2 - Background: New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the β2-adrenergic receptor (ADRB2) might not benefit from longacting β2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting β2-agonists in combination with inhaled corticosteroids. Methods: Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting β2-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. Findings: In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Interpretation: Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting β2-agonists.
AB - Background: New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the β2-adrenergic receptor (ADRB2) might not benefit from longacting β2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting β2-agonists in combination with inhaled corticosteroids. Methods: Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting β2-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. Findings: In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Interpretation: Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting β2-agonists.
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U2 - 10.1016/S0140-6736(07)61906-0
DO - 10.1016/S0140-6736(07)61906-0
M3 - Article
C2 - 18156033
AN - SCOPUS:37349091262
SN - 0140-6736
VL - 370
SP - 2118
EP - 2125
JO - Lancet
JF - Lancet
IS - 9605
ER -