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-Adrenoceptor Polymorphisms

Focus Moves to Long-Acting -Agonists

Nottingham University and Nottingham City Hospital, Nottingham, United Kingdom

Timothy W. Harrison, D.M.

Nottingham City Hospital, Nottingham, United Kingdom

-Agonists are among the most widely used drugs worldwide and much is known about their pharmacology. For subjects with asthma, the short-acting -agonists provide rapid relief and protect against bronchoconstrictor stimuli, whereas the long-acting -agonists, salmeterol and formoterol, are effective when taken regularly, as shown in a large number of well-designed clinical trials (1). Important questions remain unanswered, however. When short-acting -agonists are taken regularly, the outcome has usually differed little from that seen with placebo (2, 3), and in some studies it has been worse (4, 5). Long-acting -agonists have not shown benefit in terms of reduced mortality in postmarketing trials (1, 6), and they may even be associated with a small increase in serious asthma-related adverse effects, including death (1).

One possible explanation for these puzzling and counterintuitive findings is that the response of patients to -agonists depends on genetic factors. -Adrenoceptor polymorphisms have been under particular scrutiny in recent years. Four single nucleotide polymorphisms in the coding region of the -adrenoceptor gene cause amino acid changes in the -adrenoceptor. Two of these are common: namely, those causing substitution of glycine for arginine at codon 16 and substitution of glutamic acid for glutamine at codon 27 (7). Both polymorphisms affect -adrenoceptor down-regulation in vitro. Cells transfected with the Gly 16 polymorphism show increased down-regulation and those with the Glu 27 polymorphism are relatively resistant (8). A recent study by Israel and colleagues provided evidence to suggest that a -adrenoceptor polymorphism at the 16 locus has important clinical consequences. They found that patients who were homozygous for arginine at codon 16 (B16 Arg/Arg) had a reduced response to the short-acting -agonist albuterol compared with patients who were homozygous for glycine (B16 Gly/Gly) (9). Although the data showed some inconsistencies, the findings were in keeping with a reanalysis according to genotype of three of the larger clinical studies that had compared the use of albuterol taken regularly or as needed. The gly 16 polymorphism was associated with a more favorable response to regular albuterol treatment in all three studies (10–12).

The study by Wechsler and colleagues (13) in this issue (pp. 519–526) moves the spotlight to long-acting -agonists, and salmeterol in particular. The authors have looked retrospectively at data from two published studies of salmeterol: one involved patients taking an inhaled corticosteroid, whereas in the other, triamcinolone was stopped when salmeterol was started. The main endpoint was the morning peak flow (PEF) response to salmeterol in subjects homozygous for arginine (B16 Arg/Arg) compared with those who were homozygous for glycine (B16 Gly/Gly). In the first study (Salmeterol or Corticosteroid [SOCS] trial) (14), triamcinolone was taken for a 6-week run-in period after which subjects continued triamcinolone or changed to salmeterol or placebo alone for 16 weeks; the difference in response to placebo and salmeterol has now been compared between genotype groups. In the second study (Salmeterol ± Inhaled Corticosteroid [SLIC] trial) (15), salmeterol was added to triamcinolone in one arm of the study and the subsequent response over 18 weeks in these subjects was compared between genotype groups. Albuterol was taken as required during both studies.

The B16 Gly/Gly subjects showed an increase in morning PEF with salmeterol in both studies and this was maintained throughout the treatment period. The B16 Arg/Arg subjects showed an initial increase in morning PEF with salmeterol, but after a few weeks this started to fall, and after 16 and 18 weeks of treatment, values were lower than they were at the start. By the end of the salmeterol treatment period, the genotype-specific differences for change in morning PEF were 51 and 37 L/min, respectively. Among a number of secondary analyses, the authors found that change in other endpoints followed a broadly similar pattern, although none apart from the PEF data were statistically significant in the SOCS study. Subjects who were heterozygous at the B16 locus (i.e., B16 Arg/Gly) showed responses that were closer to the B16 Gly/Gly genotype. Finally, none of the other polymorphisms or haplotypes studied showed a consistent relationship with the salmeterol response.

The question the authors address here is extremely important and the implications for genotyping of patients with asthma are enormous. The authors have adopted a practical approach to answering the question, making best use of information that is already available to inform debate and justify further studies. The data they provide are persuasive but not definitive. The numbers in some groups are small, with only five subjects in one group in the SOCS study, and small chance disparities in exacerbation rates between genotype groups could have a large effect on the findings. There were also marked differences in baseline morning PEF between genotype groups in the SOCS study and no suggestion of a genotype effect on FEV₁. The use of the short-acting -agonist albuterol as relief medication during the studies introduces a potential confounding factor because low doses of albuterol were associated with fairly large genotype-specific effects in the authors' previous study (9). The SOCS study is also complicated by the fact that triamcinolone was stopped at the start of the study and the study design does not exclude a corticosteroid–-adrenoceptor polymorphism interaction. Finally, the two studies have been analyzed differently in that a placebo response was subtracted from the salmeterol response for the SOCS study but not for the SLIC study. These factors may explain why the initial response in the B16 Arg/Arg group was less positive in the SOCS study compared with the SLIC study. Interpretation of the findings therefore has to be cautious in view of these caveats and also because clinical evidence of tolerance has been less apparent with the long-acting than with the short-acting -agonists (1).

Predictable adverse effects from -agonists include tremor, hypokalemia, and palpitations. Whether such effects also relate to -adrenoceptor polymorphisms is unknown, and there are limited data on whether or to what extent patients with a particular polymorphism are overrepresented among patients presenting with acute exacerbations or among patients dying of asthma (16). These are all important questions, and studies designed specifically to address them are now required with some urgency.

FOOTNOTES

Conflict of Interest Statement: A.E.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.W.H. has received lecture fees and advisory board payments from AstraZeneca in 2004/2005 totaling approximately £5,000.

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