ADRB2 polymorphisms and budesonide/formoterol responses in COPD

Abstract

Background: Effects of β(2)-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD.

Methods: Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 μg or 160/9 μg, budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg (trial II), budesonide pMDI 320 μg (trial II), formoterol dry powder inhaler 9 μg, or placebo. The effect of Gly16Arg on predose FEV(1) and 1-h postdose FEV(1), exacerbations, diary variables, and adverse events were analyzed.

Results: No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV(1) (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment.

Conclusion: Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD.

Figure 1.

Patient disposition by β₂-adrenergic receptor gene (ADRB2) Gly16Arg genotype. A, Study I. B, Study II. ^aOf the 1,490 patients with DNA samples in study I, genotype data were missing for seven patients; n = 1,483 for genotyped patients. ^bOf the 1,393 patients in study II, genotype data were missing for 10 patients; n = 1,383 for genotyped patients.

Figure 2.

Adjusted mean change from baseline (95% CI) in predose FEV₁ by treatment and ADRB2 Gly16Arg genotype. A, Study I. B, Study II. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; LS = least squares; PBO = placebo; pMDI = pressurized metered-dose inhaler. See Figure 1 legend for expansion of other abbreviation.

Figure 3.

Adjusted mean change from baseline (95% CI) in postdose FEV₁ by treatment and ADRB2 Gly16Arg genotype. A, Study I. B, Study II. See Figure 1 and 2 legends for expansion of abbreviations.

Figure 4.

Number of exacerbations per patient-treatment year by treatment and ADRB2 Gly16Arg genotype. A, Study I. B, Study II. See Figure 1 and 2 legends for expansion of abbreviations.