The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol

Abstract

Aims: The relationship between beta2-adrenoceptor polymorphisms and bronchoprotective response with long-acting beta2-adrenoceptor agonists is unknown.

Methods: We retrospectively analysed data from six placebo-controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1-2-week period, with prior 1-2 week washout, assessing the primary end point of methacholine PD20 and adenosine monophosphate PC20, following first and last dose, expressed as doubling dose difference from placebo.

Results: There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine-16 genotype (Gly16-Gly16), amounting to a mean doubling dose difference of 1.49 (95% CI 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine-16 polymorphism, amounting to a doubling dose difference of 3.00 (95% CI 1.01, 4.99) between formoterol and salmeterol.

Conclusions: Our retrospective analysis showed that the arginine-16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations.

Figure 1

Doubling dose shift for the single endpoint of MCh PD₂₀ alone, for the effect of genotype on bronchoprotection with long-acting β₂-adrenoceptor agonists, as change from placebo, with SEM. A positive value indicates an increase whereas a negative value indicates a decrease in protection for a given genotype, relative to placebo. There was a greater degree of protection loss between first and last doses, for the Arg16-Arg16 or Arg16-Gly16 genotype (), compared with the Gly16-Gly16 genotype ().

Figure 2

Doubling dose/dilution shift for the composite end point of MCh PD₂₀ and AMP PC₂₀ together, in patients who possess either homozygous (Arg16-Arg16) or heterozygous (Arg16-Gly16) genotypes containing the Arg-16 allele, comparing formoterol () and salmeterol (), with SEM. A positive value indicates an increase whereas a negative value indicates a decrease in protection for either formoterol or salmeterol, relative to placebo. There was no significant difference between the formoterol and salmeterol for the degree of protection loss between first and last doses.

Figure 3

Scatter plot of individual data for doubling dose/dilution shift, as change from placebo, with mean values as horizontal lines, for composite end point of MCh PD₂₀ and AMP PC₂₀ together, in patients who possess either homozygous (Arg16-Arg16) or heterozygous (Arg16-Gly16) genotypes containing the Arg-16 allele. The corresponding mean (± SEM) values for each drug are given in Table 5.