beta-Adrenergic receptor polymorphisms and response to salmeterol

Abstract

Rationale: Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the beta2-adrenergic receptor may not benefit from short-acting beta-agonists.

Objectives: We investigated whether such genotype-specific effects occur when patients are treated with long-acting beta-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.

Methods: We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS.

Results: In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.

Conclusions: Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.

Figure 1.

The Salmeterol or Corticosteroid (SOCS) trial. After 6 wk of treatment with open-label inhaled corticosteroid (ICS; triamcinolone acetonide), subjects with asthma were randomized in a double-blind manner for 16 wk to the following: (1) to continue inhaled triamcinolone, (2) to substitute ICS with salmeterol xinafoate via metered-dose inhaler as monotherapy, or (3) to substitute ICS with placebo. The trial concluded with a 6-wk single-blind placebo run-out.

Figure 2.

The Salmeterol ± Corticosteroid (SLIC) trial. After a 6-wk run-in period with open-label ICS (triamcinolone acetonide), subjects whose asthma was not well controlled received add-on therapy with 42 μg of salmeterol xinafoate (two puffs) twice daily via metered-dose inhaler for 2 wk plus 400 μg of inhaled triamcinolone acetonide twice daily. Half the subjects were then randomly assigned to maintain triamcinolone dosage throughout the trial or to undergo a blinded, one-step 50% reduction in triamcinolone for 8 wk followed by an 8-wk triamcinolone elimination phase of salmeterol monotherapy. A small group of subjects received salmeterol with placebo ICS.

Figure 3.

Change from baseline in a.m. peak expiratory flow (PEF) in B16Arg/Arg and B16Gly/Gly subjects from the SOCS trial who were randomized to treatment with salmeterol compared with placebo; p values are for comparisons between genotype groups at the end of the treatment period (Week 16). Each line represents linear segmental depictions of mean data.

Figure 4.

Change from baseline in a.m. PEF in subjects from the SLIC trial who were treated with salmeterol and constant triamcinolone dose throughout entire trial period, in B16Arg/Arg and B16Gly/Gly subjects; p values are for comparisons between genotype groups at the end of the randomized treatment period (Week 18). Each line represents linear segmental depictions of mean data.