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Long-acting β2-adrenoceptor agonists: a smart choice for asthma?
Opinion
TRENDS in Pharmacological Sciences
Vol.28 No.6
Long-acting b2-adrenoceptor agonists: a smart choice for asthma? Brian J. Lipworth Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
An endogenous defect in b2-adrenoceptors that results in impaired relaxation of airway smooth muscle was originally proposed as a putative underlying cause of the asthmatic condition. Short-acting b2-adrenoceptor agonists such as salbutamol are still recommended for relieving acute episodes of bronchial smooth muscle spasm. Twice-daily long-acting b2-adrenoceptor agonists (LABAs) such as salmeterol are advocated for use as add-on bronchodilator therapies to inhaled corticosteroids such as beclomethasone, which are used as firstline anti-inflammatory therapy. There is recent evidence of increased asthma exacerbations and associated deaths in subjects taking salmeterol compared with those taking placebo. My opinion is that, in certain situations, the use of LABAs could have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. In this article, I examine the possible pharmacological mechanisms and use of LABAs in certain situations, which are relevant to the benefits and risks of these drugs in asthma. Pharmacology of b2-adrenoceptors An intrinsic defect in b2-adrenoceptors that results in impaired function of airway smooth muscle was originally hypothesized as one of the possible mechanisms underlying the asthmatic condition, resulting in bronchial smooth muscle constriction from an imbalance between sympathetic (bronchorelaxation) and acetylcholine-mediated (bronchoconstriction) airway tone [1]. Inhaled b2-adrenoceptor agonists have been the mainstay of bronchodilator therapy for asthma for >40 years, initially with the short-acting nonselective (i.e. b1- and b2-adrencoceptor stimulant) isoprenaline, followed by the short-acting b2-adrenoceptor-selective salbutamol, fenoterol and terbutaline, and subsequently the long-acting b2-adrenoceptor-selective salmeterol and formoterol. Salmeterol and formoterol both have a duration of action of 12 h, which makes them suitable for a regular twice-daily dosing regimen. However, formoterol has a faster onset of action than does salmeterol, which means that the former, like salbutamol, can also be used to relieve acute bronchoconstriction (Table 1). In terms of relative intrinsic agonist activity, formoterol – like isoprenaline – is almost a full agonist compared with salmeterol, which is a partial agonist. Corresponding author: Lipworth, B.J. ([email protected]). Available online 26 April 2007. www.sciencedirect.com
Effects on exacerbations Current national asthma management guidelines recommend the preventative use of inhaled corticosteroids (ICSs) such as beclomethasone, budesonide, fluticasone, mometasone and ciclesonide as first-line anti-inflammatory therapy, with short-acting b2-adrenoceptor agonists being used on demand for the rapid relief of episodes of breakthrough bronchoconstriction [2]. The frequency of salbutamol reliever use is sometimes considered to be a surrogate marker of disease control when adjusting the dose of ICS to suppress the underlying inflammatory process. This might not be appropriate, however, because the demand for salbutamol is reduced when patients are using a regular treatment of a twice-daily long-acting b2adrenoceptor agonist (LABA). Measures of airway calibre such as the peak expiratory flow rate are also sometimes used as surrogate markers of disease control. However, these are smooth muscle responsive outcomes that are improved because of the sustained bronchodilator effects of regular LABA therapy. LABAs are currently advocated in guidelines as an add-on bronchodilator therapy to low–medium-dose ICS – instead of using a higher dose of ICS, which might be associated with local and systemic adverse effects [2]. The use of LABAs as the second-line controller of choice has been driven by evidence from large multicentre randomized controlled trials, including a meta-analysis of 12 randomized controlled trials (comprising 4576 patients) showing that the addition of a LABA to low–medium-dose ICS is more effective at controlling moderate–severe asthma exacerbations (as defined by a need for oral corticosteroid, emergency hospital treatment or additional asthma medication not permitted in a study) than is increasing the dose of ICS [3]. The odds ratio for an asthma
Glossary Forced expiratory volume in 1 s (FEV1): a measure (in litres) of airway calibre. Genotype: a combination of two polymorphisms (e.g. homozygous Arg–Arg at position 16 of the b2-adrenoceptor. Haplotype: a combination of genotypes at different positions. Methacholine challenge: bronchial challenge with repeated doses of acetylcholine receptor agonist to induce a 20% decrease in FEV1 – a measure of airway hyperresponsiveness. Peak flow: peak expiratory flow rate (l/min) – a measure of airway calibre. Polymorphism: an allelic variant of a gene (e.g. Gly or Arg amino acids at position 16 of the b2-adrenoceptor). Tachyphylaxis: a progressive reduction in response following repeated exposure to agonist (i.e. when comparing responses to single and chronic dosing).
0165-6147/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.04.003
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Table 1. Pharmacological properties of b2-adrenoceptor agonists used to treat asthma Agonist Salbutamol Salmeterol Formoterol
Peak onset 5–15 min 30–60 min 5–15 min
Duration 4h 12 h 12 h
Indication a Reliever Controller Reliever or controller
Combination NA Fluticasone Budesonide
a Reliever, used on demand for acute relief of episodes of bronchoconstriction; controller, a long-acting bronchodilator agent used on a regular basis as an add-on to ICS, either as separate components or as a combination inhaler (with fluticasone or budesonide). Formoterol has a fast onset and a long duration, so can be used as either a reliever or a controller, whereas salmeterol has a slower onset and can be used only as a controller.
exacerbation was greater in association with a higher dose of ICS compared with adding a LABA: 1.35 [95% confidence interval (CI) 1.10–1.66]. Treatment of 58 patients with LABA plus ICS prevented one additional person from experiencing a moderate–severe exacerbation, compared with a higher dose of ICS alone. A meta-analysis of 54 randomized controlled trials (comprising 10 231 patients) evaluated the relative efficacy of LABAs plus ICSs versus three different maintenance ICS strategies in asthmatics (i.e. a similar ICS dose, a higher ICS dose or a similar ICS dose in corticosteroid-naive individuals). The addition of a LABA significantly reduced the risk of severe exacerbations (defined by requirement for oral corticosteroids), but only when compared with a similar ICS dose (data from 20 randomized trials in 4312 patients) [4]. Treatment of 18 people with LABA plus ICS prevented one additional person from experiencing a severe exacerbation, compared with a similar dose of ICS alone. The uptake of LABAs has greatly increased because of the availability of combination inhalers that contain both ICS and LABA in a twice-daily fixed-dose formulation comprising either fluticasone–salmeterol or budesonide– formoterol. Indeed, the number of available combination inhalers is likely to increase, including those comprising mometasone–formoterol, ciclesonide–formoterol and several other generic formulations. This will be compounded by the advent of newer, ultra-long-acting b2-adrenoceptor agonists for once-daily use, such as indacaterol, carmoterol and arformoterol – once these are approved [5]. Asthmatic exacerbations are thought to be due mainly to active airway inflammation, which is suppressed by ICSs, although it is likely that instability of airway smooth muscle also contributes to exacerbations, which are suppressed by LABAs (Box 1). A potential concern for clinicians is that conventional markers of disease control (i.e. peak expiratory flow and salbutamol requirement) are smooth-muscle-responsive outcomes and, because of Box 1. Markers of treatment response to LABAs Asthmatic exacerbations are due mainly to active airway inflammation, which is suppressed by ICSs, although instability of airway smooth muscle, which is suppressed by LABAs, also contributes. Conventional markers of disease control such as airway calibre (e.g. peak expiratory flow) and salbutamol rescue requirement are smooth-muscle-responsive outcomes and, therefore, might be relatively disconnected from the underlying inflammatory process in patients who take LABAs regularly. It might be difficult to determine whether anti-inflammatory therapy with ICSs has been optimized by using a fixed-dose ICS–LABA combination inhaler. Untreated asthmatic inflammation might result in exacerbations and bronchial scar tissue, which – in turn – cause permanent airway damage (i.e. airway remodelling). www.sciencedirect.com
24-h b2-adrenoceptor occupancy, might be relatively disconnected from the underlying inflammatory process in patients taking LABAs regularly. Therefore, it might be difficult to know whether anti-inflammatory therapy has been optimized with a particular dose of ICS in someone using a fixed-dose ICS–LABA combination inhaler. Untreated asthmatic inflammation might result in exacerbations, in addition to bronchial scar tissue being laid down in the longer term, which could lead to permanent airway damage – the so-called airway-remodelling process. This theoretical concern must be weighed against the potential benefits for improved patient compliance of having the convenience of both drugs in a single inhaler. Moreover, patients can often perceive the feeling of having their airway dilated and stabilized by taking LABAs regularly, which reinforces them to continue using their combination inhaler. The SMART study The potential safety problems with LABAs were recently highlighted in the Salmeterol Multicenter Asthma Research Trial (SMART) study, which evaluated the use of salmeterol or placebo in 26 355 asthmatic patients for seven months and was prematurely terminated because of findings obtained from African American patients and because of enrolment difficulties [6]. The early termination made it less likely that there would be statistically significant results for all outcomes. The results for the primary outcome of combined respiratory-related deaths or lifethreatening experiences showed no significant difference between salmeterol and placebo: N = 50 and 36, respectively, relative risk (RR) = 1.40 (95% CI 0.91–2.14). Corresponding values for secondary outcomes showed a ‘small but significant increase’ in asthma-related deaths – 13 versus three, RR = 4.37 (95% CI 1.25–15.34) – combined asthma deaths or life-threatening experiences – 37 versus 22, RR = 1.71 (95% CI 1.01–2.89) – and respiratory-related deaths – 24 versus 11, RR = 2.16 (95% CI 1.06–4.41) – for patients receiving salmeterol compared with those receiving placebo. The study was not sufficiently powered a priori to evaluate properly post hoc subgroup analysis for the effects of ICS use or ethnic origin, but indicated that the risks were greater in African Americans who were using ICS less frequently. Thus, it is not possible to deduce meaningful conclusions from the SMART study with regard to the effects of LABAs when used as a monotherapy or in combination with ICSs, although my opinion is that ICSs might be expected to protect against exacerbations owing to their anti-inflammatory activity. The asthma death rate associated with salmeterol was originally quoted in the SMART study as 1.22 per 1000 person-years but, following a rebuttal from Sears, the authors admitted that they had inadvertently reported
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an erroneous value and that the true estimate was 1.98, which is approximately fourfold what would be expected in the US asthmatic population of that age (i.e. 0.48 per 1000 person-years) [7,8]. This is similar to the death rate from the previous UK salmeterol surveillance study (2.32 per 1000 person-years) [9]. It is interesting to speculate whether similar findings to those from the SMART study would have been obtained had compliance with ICS been enforced by giving the fluticasone–salmeterol combination. In a subsequent meta-analysis of 12 trials, it was found that 53/3083 patients receiving LABA versus 12/2008 patients receiving placebo were hospitalized for asthma exacerbations, with a calculated odds ratio of 2.6 (95% CI 1.6–4.3) [10]. Then, seven trials were pooled to assess lifethreatening asthma exacerbations, showing 50/15 443 versus 25/14 538 events with LABA compared with placebo, respectively, with an odds ratio of 1.8 (95% CI 1.1–2.9). On the basis of a review of the SMART study and other data, the US Food and Drug Administration (FDA: http:// www.fda.gov/) imposed a safety warning on the prescribing information and package labelling of all LABAs, including combination inhalers [11,12]. In the UK, the Commission of Human Medicines has set up an expert working group (under the auspices of the Medicines and Healthcare Products Regulatory Agency) to review the safety of LABAs [13]. My opinion is that, in certain susceptible individuals, the use of LABAs might have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. Therefore, it seems timely and appropriate to address the potential pharmacological mechanisms of the adverse effects of LABAs on asthma control. Tachyphylaxis with LABAs Given that tachyphylaxis (see Glossary) occurs readily with regular exposure to short-acting b2-adrenoceptor agonists, the advent of LABAs soon led to concerns about the potential for more-profound tachyphylaxis. This is because of prolonged, 24-h receptor occupancy and the associated propensity for agonist-promoted reduction in the number and coupling efficiency of b2-adrenoceptors on airway smooth muscle and inflammatory cells, where such receptors are expressed (Box 2). The first clinical study to address this issue evaluated salmeterol (or placebo) as an add-on therapy to ICS for one month in moderate persistent asthmatics; it showed that, even 36 h after stopping the administration of salmeterol, there was a persistent reduction in the number of ex vivo peripheral blood mononuclear cells, which was also associated with blunting of the acute bronchodilator response to repeated doses of inhaled salbutamol [14]. In the same study, the peak flow response (a measure of airway calibre) to salmeterol was maintained over the four weeks. Similar findings were subsequently reported with formoterol as an add-on therapy to ICS [15]. To mimic more closely the clinical scenario in acute asthma, it is more informative to examine what happens in the setting of acetylcholine-induced airway constriction by measuring the degree of bronchoprotection (i.e. www.sciencedirect.com
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Box 2. Tachyphylaxis of the b2-adrenoceptor-mediated response An intrinsic defect of b2-adrenoceptors that results in impaired function of airway smooth muscle was originally hypothesized as being one of the possible mechanisms underlying the asthmatic condition. This defect, in turn, results in bronchial smooth muscle constriction because of an imbalance between sympathetic (bronchorelaxation) and acetylcholine-mediated (bronchoconstriction) airway tone. Continuous, twice-daily exposure to an exogenous LABA such as salmeterol results in reduced receptor numbers (i.e. downregulation) on bronchial smooth muscle and inflammatory cells, together with uncoupling of the b2-adrenoceptor from the G protein adenylyl cyclase. This, in turn, produces progressive diminution of the agoniststimulated response (i.e. tachyphylaxis or subsensitivity of response). In addition, 24-h occupancy of receptors by regular exposure to twice-daily LABAs results in the relative antagonism of salbutamol when the latter is used for rescue treatment of acute episodes of bronchoconstriction.
functional antagonism) conferred against a standardized bronchial challenge test. Subjects inhale cumulative doses of the acetylcholine receptor agonist methacholine to produce a 20% reduction in the forced expiratory volume in 1 s (FEV1). Studies with salmeterol twice daily as an add-on to ICS have demonstrated loss of protection against methacholine challenge after three repeated doses, compared with placebo [16]. Similar results were reported after regular exposure to salmeterol following four weeks of treatment, showing loss of protection against exerciseinduced bronchoconstriction [17]. For formoterol given as an add-on to ICS, loss of protection against methacholine occurred with doses of 6 mg or 24 mg twice daily or 12 mg once daily, when comparing first with last doses, such that the residual protection was not significantly better than that obtained with placebo [18]. Moreover, with both salmeterol and formoterol, this loss of protection against methacholine cannot be overcome by administering eight times the usual recommended dose of salbutamol (i.e. 1200 mg) [19]. Cross-tachyphylaxis between LABAs and salbutamol in the presence of increased airway tone has been demonstrated in other studies [16,20,21]. These findings all indicate that concomitant administration of ICS does not protect against tachyphylaxis of response to LABAs or against cross-tachyphylaxis to salbutamol, although a bolus high dose of systemic corticosteroid might increase the number of b2-adrenoceptors and resensitize them ex vivo and in vivo in asthmatics [22]. Another possible mechanism is prolonged receptor occupancy by LABAs resulting in relative antagonism of salbutamol [23]. There is evidence to support this from a study in which a single dose of salmeterol or formoterol (compared with placebo) attenuated salbutamol-induced bronchorelaxation in methacholine-constricted airways of asthmatics in vivo [24]. The obvious question is whether this interaction between LABAs and salbutamol as reliever therapy might, in part, explain the findings of the SMART study, in terms of delaying recovery from episodes of acute bronchoconstriction, and whether susceptible individuals might be
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genetically predisposed to such adverse effects of LABAs. Unfortunately, no information on salbutamol use or genotype was collected in the SMART study. Genetic variation of b2-adrenoceptors Several polymorphisms of the b2-adrenoceptor have potential functional consequences for ligand–receptor interactions. Of these polymorphisms, most attention has been focused on allelic variants at position 16 of the b2-adrenoceptor, where a single nucleotide polymorphism results in an amino acid substitution of glycine (Gly) for arginine (Arg) [25]. The allelic frequencies are 36% and 64% for Arg and Gly polymorphisms, respectively, with genotypic frequencies of 14%, 42% and 44% for homozygous Arg16, homozygous Gly16 and heterozygote, respectively [26]. In vitro experiments using b2-adrenoceptors expressed in airway smooth muscle cells cultured from humans showed that agonist-promoted reductions in receptor number occur to a greater degree with Gly16 than with Arg16 receptors [27]. However, this does not take into account the potential influence of exogenous circulating catecholamines that occurs in vivo. The putative effect of catecholamines in vivo is to reduce the number of b2-adrenoceptors so that there are fewer Gly-form receptors than there are Arg-form receptors before exposure to an exogenous agonist. The result is that further reduction in receptor numbers by an exogenous agonist would be expected to be relatively greater in individuals expressing the Arg polymorphism than in those expressing the Gly polymorphism [28]. However, there is contradictory evidence from a study in which ex vivo peripheral blood mononuclear cells, taken from asthmatic patients, that were washed-out of exogenous b2-adrenoceptor agonists showed no difference in the numbers of b2-adrenoceptors or adenylyl cyclase activity when different b2-adrenoceptor polymorphisms or extended haplotypes were compared [29]. There are important racial differences in the prevalence of extended haplotypes, which might explain the ethnic differences in adverse events seen in the SMART study in African Americans [25], who have an increased frequency of the homozygous Arg16 genotype [30]. One study indicated that the Arg–Cys19 polymorphism in the b-upstream peptide of the b2-adrenoceptor, but not the Arg–Gly16 polymorphism, might have a role in salbutamol bronchodilator responsiveness in African American subjects [31]. This, in turn, raises the issue of whether a possible increased rate of severe deterioration in asthma symptoms and/or death in African Americans receiving salmeterol, as documented in the SMART study, is related to an ethnicspecific pharmacogenetic difference. In this regard, b2adrenoceptor agonists produce dose-related prolongation of cardiac repolarization, and genetic polymorphisms in African Americans might have been a contributory cause of death in the SMART study [32–34]. A retrospective genotyped analysis of data from steroid-treated asthmatics exposed to regular LABAs or placebo showed loss of bronchoprotection between first and last doses in Gly16 and Arg16 genotypes, with the degree of protection being significantly less in Arg16 than in Gly16 genotypes [35]. Moreover, the level of protection from www.sciencedirect.com
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LABAs in Arg16 patients was lower than that from placebo for both first and last doses. In susceptible Arg16 patients, the protection afforded by formoterol was significantly less than that obtained with salmeterol after first and last doses. These findings were supported by other retrospective genotyped data in which the peak flow response to salmeterol (compared with placebo) over four months was worse in homozygous Arg than in homozygous Gly genotypes, irrespective of concomitant ICS use [36]. A post hoc genotype analysis of a study in which a fluticasone–salmeterol combination was given for three months showed no difference in peak flow response between Arg and Gly genotypes, although it was not possible to distinguish the effects that were attributable to the ICS and LABA moieties because there was no LABA placebo arm for comparison [37]. Moreover, the study was biased towards b2-adrenoceptor responders because, at initial screening, the degree of bronchodilator response to salbutamol was large for all genotypes at position 16. Because salbutamol and salmeterol both act on the same b2-adrenoceptor, it is perhaps not surprising that the results also showed such an excellent response to salmeterol for all genotypes at position 16. In 164 asthmatic children taking ICS plus salmeterol, there was a 3.4-fold (95% CI 1.19–9.4) increased risk of asthma exacerbation over six months when comparing Arg16 and Gly16 patients [38]. However, data regarding 108 adult asthmatics showed no difference in exacerbations over one year when comparing genotypes at position 16 [39]. Another relevant issue is whether the interaction between LABAs and salbutamol is genotype dependent. In a prospective randomized controlled crossover trial, patients selected with either the Arg or the Gly genotype received a fluticasone–salmeterol or a budesonide–formoterol combination [40]. The acute salbutamol recovery after a standardized methacholine challenge, when comparing first and last doses, was significantly delayed to a similar degree by both combinations in both genotypes. Furthermore, after the last dose of each combination, there were no differences between genotypes in pre-challenge FEV1 or in the degree of protection conferred by LABAs against methacholine challenge (as the 20% threshold value). These findings raise the issue of whether the adverse effects of LABAs on exacerbations and lung function can be explained by enhanced cross-tachyphylaxis of b2-adrenoceptors. The way forward There is clearly a potential problem with LABAs whereby worsening asthma control might result in life-threatening exacerbations. The subgroup analysis from the SMART study was inadequate for drawing valid conclusions, but it has been used in some circles to make the point that physicians should not be concerned about using LABAs, as long as they are prescribed for Caucasians and for use in combination inhalers in conjunction with ICSs, which have beneficial anti-inflammatory activity and putative protective effects against tachyphylaxis. This assumption about ICSs is misguided because other data clearly indicate that concomitant administration of ICS does not prevent LABAinduced tachyphylaxis or prevent cross-tachyphylaxis
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between LABAs and salbutamol. Pointedly, the FDA imposed the product label warning on all LABAs, including combination inhalers, on the basis that the data from the SMART study did not conclusively show that adverse effects were confined to patients taking unopposed LABAs without ICSs. The dilemma for clinicians is to know which patients are most at risk when taking LABAs. On the one hand, LABAs are effective second-line bronchodilator controller agents that improve airway calibre and quality of life, and reduce salbutamol reliever use but, on the other hand, they might also increase the risk of hospitalization and asthmarelated death in certain situations. It is tempting to attribute all harmful effects of LABAs to the 15% of patients who have the Arg16 homozygous genotype. Although some data indicate that such patients might fare worse with regular exposure to LABAs, the situation is far from clear-cut. The Long-acting bAgonist Response by Genotype (LARGE) study, run by the Asthma Clinical Research Network (http://www. acrn.org/), is underway in the USA to evaluate prospectively the effects of ICSs plus LABAs or placebo in Arg versus Gly homozygous genotypes, looking at effects on peak flow over 18 weeks. However, until there are longerterm (i.e. longer than one year) prospective studies that look at exacerbations (rather than airway calibre, as measured by peak flow) in genotyped patients, we will be no closer to resolving this issue. With the current evidence, it would be unethical to withhold LABAs on the basis of genetic screening. However, it might be equally unethical to prescribe LABAs on the basis of genetic screening because there are no real assurances that any subgroup of patients is immune to the adverse effects. It would be hard to imagine a twofoldincreased risk of asthma hospitalization in pooled data solely related to increased events in the 15% of patients with the homozygous Arg genotype. Therefore, the proposal to provide genotyping of individuals to help with decision making might not result in fewer serious adverse events. In my opinion, a more pragmatic approach would be to consider stopping the use of pre-existing LABAs in patients who experience a severe exacerbation, particularly with lifethreatening features, and in those who have increasing salbutamol use or for whom salbutamol is no longer effective as a reliever. Such susceptible patients would, therefore, be effectively risk stratified, and a cogent case could then be made for genotyping with informed consent to aid decision making. It should also be pointed out that, in these circumstances, there are effective alternatives for secondline controllers that, unlike LABAs, are not bronchodilators but, instead, exhibit non-steroidal anti-inflammatory activity, such as anti-leukotrienes, theophylline or antiIgE. The possible role of long-acting acetylcholine receptor antagonist drugs such as tiotropium, instead of LABAs, as a second-line bronchodilator therapy for more-severe asthma that is not controlled by ICSs is worthy of further investigation [41]. It is also worth emphasizing that ICSs should always be used as a first-line anti-inflammatory therapy for all asthmatics and that LABAs should never be used as a monotherapy, in keeping with present guidelines [2]. www.sciencedirect.com
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Concluding remarks The dilemma for clinicians will increase because LABAs are likely to become more prevalent in a market driven by an ever-increasing number of proprietary and generic combination inhalers. Moreover, the imminent availability of ultra-long-acting once-daily drugs means that b2-adrenoceptors might be exposed to continuous 24-h occupancy by a high-efficacy, high-affinity agonist that would be expected to induce an even more profound tachyphylaxis. In this regard, opinion leaders need to take a step sideways to appraise the situation more critically and to refine the position of LABAs in asthma management guidelines so that the blanket use of combination inhalers for all severities of asthma can be avoided. This problem will persist and it is now down to clinicians to work in a responsible fashion with the pharmaceutical industry and the regulatory authorities to ensure that LABAs are prescribed in a safe and responsible fashion. Disclosure statement B.J.L. and the Asthma and Allergy Research Group have received funding support for performing clinical trials, consulting activity, advisory work, giving postgraduate educational talks and departmental meetings from companies that make LABA and ICS, including AstraZeneca, GlaxoSmithKline, Altana, Sanofi-Aventis, Ivax, Schering Plough, Noelab, Cipla, Novartis, Innovata and Verus. References 1 Szentivanyi, A. (1968) The b-adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 42, 203–232 2 Global Initiative for Asthma (2006) Global strategy for asthma management and prevention (http://www.ginasthma.org) 3 Masoli, M. et al. (2005) Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 60, 730–734 4 Gibson, P.G. et al. (2007) Differential effects of maintenance long-acting b-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J. Allergy Clin. Immunol. 119, 344–350 5 Cazzola, M. et al. (2005) Ultra long-acting b2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs 14, 775–783 6 Nelson, H.S. et al. (2006) The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129, 15–26 7 Sears, M.R. (2006) The Salmeterol Multicenter Asthma Research Trial. Chest 130, 928–929 8 Nelson, H.S. and Dorinsky, P.M. (2006) The Salmeterol Multicenter Asthma Research Trial. Chest 130, 928–929 9 Castle, W. et al. (1993) Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 306, 1034–1037 10 Salpeter, S.R. et al. (2006) Meta-analysis: effect of long acting bagonists on severe asthma exacerbations and asthma related deaths. Ann. Intern. Med. 144, 904–912 11 US Food and Drug Administration (2003) Labelling changes for drug products that contain salmeterol. FDA Talk Paper (www.fda.gov/bbs/ topics/ANSWERS/2003/ANS01248.html) 12 US Food and Drug Administration (2005) FDA Public Health Advisory. Serevent, Advair, Foradil (http://www.fda.gov/cder/drug/advisory/ LABA.htm) 13 Medicines and Healthcare Products Regulatory Agency (2007) MHRA review of formoterol and salmeterol in asthma and chronic obstructive pulmonary disease (http://www.mhra.gov.uk/home/idcplg?IdcService= SS_GET_PAGE&nodeId=1016) 14 Grove, A. and Lipworth, B.J. (1995) Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 346, 201–206
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15 Newnham, D.M. et al. (1994) Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am. J. Med. 97, 29–37 16 Kalra, S. et al. (1996) Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 109, 953–956 17 Ramage, L. et al. (1994) Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir. Med. 88, 363–368 18 Lipworth, B. et al. (1998) Effects of treatment with formoterol on bronchoprotection against methacholine. Am. J. Med. 104, 431–438 19 Lipworth, B.J. and Aziz, I. (1999) A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol. J. Allergy Clin. Immunol. 103, 88–92 20 van der Woude, H.J. et al. (2001) Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting b2 agonists. Thorax 56, 529–535 21 Lee, D.K. et al. (2003) Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Br. J. Clin. Pharmacol. 56, 494–500 22 Tan, K.S. et al. (1997) Systemic corticosteriod rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am. J. Respir. Crit. Care Med. 156, 28–35 23 Grove, A. and Lipworth, B.J. (1996) Evaluation of the b2 adrenoceptor agonist/antagonist activity of formoterol and salmeterol. Thorax 51, 54–58 24 Aziz, I. and Lipworth, B.J. (1999) In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J. Allergy Clin. Immunol. 103, 816–822 25 Liggett, S.B. (2006) Genetic variability of the b2 adrenergic receptor and asthma exacerbations. Thorax 61, 925–927 26 Fowler, S.J. et al. (2000) Screening for bronchial hyperresponsiveness using methacholine and adenosine monophosphate: relationship to asthma severity and b2-receptor genotype. Am. J. Respir. Crit. Care Med. 162, 1318–1322 27 Green, S.A. et al. (1995) Influence of b2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 13, 25–33 28 Liggett, S.B. (2000) The pharmacogenetics of b2-adrenergic receptors: Relevance to asthma. J. Allergy Clin. Immunol. 105, s487–s492
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29 Lipworth, B. et al. (2002) b2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells. Thorax 57, 61–66 30 Ellsworth, D.L. et al. (2002) Influence of the b2-adrenergic receptor Arg16Gly polymorphism on longitudinal changes in obesity from childhood through young adulthood in a biracial cohort: the Bogalusa Heart Study. Int. J. Obes. Relat. Metab. Disord. 26, 928– 937 31 Tsai, H.J. et al. (2006) b2-Adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum. Genet. 119, 547–557 32 Ackerman, M.J. et al. (2003) Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin. Proc. 78, 1479–1489 33 Lipworth, B.J. et al. (1989) Prior treatment with diuretic augments the hypokalaemic and electrocardiographic effects of inhaled albuterol. Am. J. Med. 86, 653–657 34 Williams, C. (2006) Cause of death in the SMART trial. Chest 130, 929– 930 35 Lee, D.K. et al. (2004) The arginine-16 b2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br. J. Clin. Pharmacol. 57, 68–75 36 Wechsler, M.E. et al. (2006) b-Adrenergic receptor polymorphisms and response to salmeterol. Am. J. Respir. Crit. Care Med. 173, 519–526 37 Bleecker, E.R. et al. (2006) Salmeterol response is not affected by b2adrenergic receptor genotype in subjects with persistent asthma. J. Allergy Clin. Immunol. 118, 809–816 38 Palmer, C.N. et al. (2006) Arginine-16 b2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 61, 940–944 39 Taylor, D.R. et al. (2000) Asthma exacerbations during long term b agonist use: influence of b2 adrenoceptor polymorphism. Thorax 55, 762–767 40 Lee, D.K. et al. (2004) Cross tolerance to salbutamol occurs independently of b2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol. Thorax 59, 662–667 41 Fardon, T. et al. (2007) A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Resp. Med. 101, 1218–1228
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Long-acting b2-adrenoceptor agonists: a smart choice for asthma? Brian J. Lipworth Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
An endogenous defect in b2-adrenoceptors that results in impaired relaxation of airway smooth muscle was originally proposed as a putative underlying cause of the asthmatic condition. Short-acting b2-adrenoceptor agonists such as salbutamol are still recommended for relieving acute episodes of bronchial smooth muscle spasm. Twice-daily long-acting b2-adrenoceptor agonists (LABAs) such as salmeterol are advocated for use as add-on bronchodilator therapies to inhaled corticosteroids such as beclomethasone, which are used as firstline anti-inflammatory therapy. There is recent evidence of increased asthma exacerbations and associated deaths in subjects taking salmeterol compared with those taking placebo. My opinion is that, in certain situations, the use of LABAs could have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. In this article, I examine the possible pharmacological mechanisms and use of LABAs in certain situations, which are relevant to the benefits and risks of these drugs in asthma. Pharmacology of b2-adrenoceptors An intrinsic defect in b2-adrenoceptors that results in impaired function of airway smooth muscle was originally hypothesized as one of the possible mechanisms underlying the asthmatic condition, resulting in bronchial smooth muscle constriction from an imbalance between sympathetic (bronchorelaxation) and acetylcholine-mediated (bronchoconstriction) airway tone [1]. Inhaled b2-adrenoceptor agonists have been the mainstay of bronchodilator therapy for asthma for >40 years, initially with the short-acting nonselective (i.e. b1- and b2-adrencoceptor stimulant) isoprenaline, followed by the short-acting b2-adrenoceptor-selective salbutamol, fenoterol and terbutaline, and subsequently the long-acting b2-adrenoceptor-selective salmeterol and formoterol. Salmeterol and formoterol both have a duration of action of 12 h, which makes them suitable for a regular twice-daily dosing regimen. However, formoterol has a faster onset of action than does salmeterol, which means that the former, like salbutamol, can also be used to relieve acute bronchoconstriction (Table 1). In terms of relative intrinsic agonist activity, formoterol – like isoprenaline – is almost a full agonist compared with salmeterol, which is a partial agonist. Corresponding author: Lipworth, B.J. ([email protected]). Available online 26 April 2007. www.sciencedirect.com
Effects on exacerbations Current national asthma management guidelines recommend the preventative use of inhaled corticosteroids (ICSs) such as beclomethasone, budesonide, fluticasone, mometasone and ciclesonide as first-line anti-inflammatory therapy, with short-acting b2-adrenoceptor agonists being used on demand for the rapid relief of episodes of breakthrough bronchoconstriction [2]. The frequency of salbutamol reliever use is sometimes considered to be a surrogate marker of disease control when adjusting the dose of ICS to suppress the underlying inflammatory process. This might not be appropriate, however, because the demand for salbutamol is reduced when patients are using a regular treatment of a twice-daily long-acting b2adrenoceptor agonist (LABA). Measures of airway calibre such as the peak expiratory flow rate are also sometimes used as surrogate markers of disease control. However, these are smooth muscle responsive outcomes that are improved because of the sustained bronchodilator effects of regular LABA therapy. LABAs are currently advocated in guidelines as an add-on bronchodilator therapy to low–medium-dose ICS – instead of using a higher dose of ICS, which might be associated with local and systemic adverse effects [2]. The use of LABAs as the second-line controller of choice has been driven by evidence from large multicentre randomized controlled trials, including a meta-analysis of 12 randomized controlled trials (comprising 4576 patients) showing that the addition of a LABA to low–medium-dose ICS is more effective at controlling moderate–severe asthma exacerbations (as defined by a need for oral corticosteroid, emergency hospital treatment or additional asthma medication not permitted in a study) than is increasing the dose of ICS [3]. The odds ratio for an asthma
Glossary Forced expiratory volume in 1 s (FEV1): a measure (in litres) of airway calibre. Genotype: a combination of two polymorphisms (e.g. homozygous Arg–Arg at position 16 of the b2-adrenoceptor. Haplotype: a combination of genotypes at different positions. Methacholine challenge: bronchial challenge with repeated doses of acetylcholine receptor agonist to induce a 20% decrease in FEV1 – a measure of airway hyperresponsiveness. Peak flow: peak expiratory flow rate (l/min) – a measure of airway calibre. Polymorphism: an allelic variant of a gene (e.g. Gly or Arg amino acids at position 16 of the b2-adrenoceptor). Tachyphylaxis: a progressive reduction in response following repeated exposure to agonist (i.e. when comparing responses to single and chronic dosing).
0165-6147/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.04.003
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Table 1. Pharmacological properties of b2-adrenoceptor agonists used to treat asthma Agonist Salbutamol Salmeterol Formoterol
Peak onset 5–15 min 30–60 min 5–15 min
Duration 4h 12 h 12 h
Indication a Reliever Controller Reliever or controller
Combination NA Fluticasone Budesonide
a Reliever, used on demand for acute relief of episodes of bronchoconstriction; controller, a long-acting bronchodilator agent used on a regular basis as an add-on to ICS, either as separate components or as a combination inhaler (with fluticasone or budesonide). Formoterol has a fast onset and a long duration, so can be used as either a reliever or a controller, whereas salmeterol has a slower onset and can be used only as a controller.
exacerbation was greater in association with a higher dose of ICS compared with adding a LABA: 1.35 [95% confidence interval (CI) 1.10–1.66]. Treatment of 58 patients with LABA plus ICS prevented one additional person from experiencing a moderate–severe exacerbation, compared with a higher dose of ICS alone. A meta-analysis of 54 randomized controlled trials (comprising 10 231 patients) evaluated the relative efficacy of LABAs plus ICSs versus three different maintenance ICS strategies in asthmatics (i.e. a similar ICS dose, a higher ICS dose or a similar ICS dose in corticosteroid-naive individuals). The addition of a LABA significantly reduced the risk of severe exacerbations (defined by requirement for oral corticosteroids), but only when compared with a similar ICS dose (data from 20 randomized trials in 4312 patients) [4]. Treatment of 18 people with LABA plus ICS prevented one additional person from experiencing a severe exacerbation, compared with a similar dose of ICS alone. The uptake of LABAs has greatly increased because of the availability of combination inhalers that contain both ICS and LABA in a twice-daily fixed-dose formulation comprising either fluticasone–salmeterol or budesonide– formoterol. Indeed, the number of available combination inhalers is likely to increase, including those comprising mometasone–formoterol, ciclesonide–formoterol and several other generic formulations. This will be compounded by the advent of newer, ultra-long-acting b2-adrenoceptor agonists for once-daily use, such as indacaterol, carmoterol and arformoterol – once these are approved [5]. Asthmatic exacerbations are thought to be due mainly to active airway inflammation, which is suppressed by ICSs, although it is likely that instability of airway smooth muscle also contributes to exacerbations, which are suppressed by LABAs (Box 1). A potential concern for clinicians is that conventional markers of disease control (i.e. peak expiratory flow and salbutamol requirement) are smooth-muscle-responsive outcomes and, because of Box 1. Markers of treatment response to LABAs Asthmatic exacerbations are due mainly to active airway inflammation, which is suppressed by ICSs, although instability of airway smooth muscle, which is suppressed by LABAs, also contributes. Conventional markers of disease control such as airway calibre (e.g. peak expiratory flow) and salbutamol rescue requirement are smooth-muscle-responsive outcomes and, therefore, might be relatively disconnected from the underlying inflammatory process in patients who take LABAs regularly. It might be difficult to determine whether anti-inflammatory therapy with ICSs has been optimized by using a fixed-dose ICS–LABA combination inhaler. Untreated asthmatic inflammation might result in exacerbations and bronchial scar tissue, which – in turn – cause permanent airway damage (i.e. airway remodelling). www.sciencedirect.com
24-h b2-adrenoceptor occupancy, might be relatively disconnected from the underlying inflammatory process in patients taking LABAs regularly. Therefore, it might be difficult to know whether anti-inflammatory therapy has been optimized with a particular dose of ICS in someone using a fixed-dose ICS–LABA combination inhaler. Untreated asthmatic inflammation might result in exacerbations, in addition to bronchial scar tissue being laid down in the longer term, which could lead to permanent airway damage – the so-called airway-remodelling process. This theoretical concern must be weighed against the potential benefits for improved patient compliance of having the convenience of both drugs in a single inhaler. Moreover, patients can often perceive the feeling of having their airway dilated and stabilized by taking LABAs regularly, which reinforces them to continue using their combination inhaler. The SMART study The potential safety problems with LABAs were recently highlighted in the Salmeterol Multicenter Asthma Research Trial (SMART) study, which evaluated the use of salmeterol or placebo in 26 355 asthmatic patients for seven months and was prematurely terminated because of findings obtained from African American patients and because of enrolment difficulties [6]. The early termination made it less likely that there would be statistically significant results for all outcomes. The results for the primary outcome of combined respiratory-related deaths or lifethreatening experiences showed no significant difference between salmeterol and placebo: N = 50 and 36, respectively, relative risk (RR) = 1.40 (95% CI 0.91–2.14). Corresponding values for secondary outcomes showed a ‘small but significant increase’ in asthma-related deaths – 13 versus three, RR = 4.37 (95% CI 1.25–15.34) – combined asthma deaths or life-threatening experiences – 37 versus 22, RR = 1.71 (95% CI 1.01–2.89) – and respiratory-related deaths – 24 versus 11, RR = 2.16 (95% CI 1.06–4.41) – for patients receiving salmeterol compared with those receiving placebo. The study was not sufficiently powered a priori to evaluate properly post hoc subgroup analysis for the effects of ICS use or ethnic origin, but indicated that the risks were greater in African Americans who were using ICS less frequently. Thus, it is not possible to deduce meaningful conclusions from the SMART study with regard to the effects of LABAs when used as a monotherapy or in combination with ICSs, although my opinion is that ICSs might be expected to protect against exacerbations owing to their anti-inflammatory activity. The asthma death rate associated with salmeterol was originally quoted in the SMART study as 1.22 per 1000 person-years but, following a rebuttal from Sears, the authors admitted that they had inadvertently reported
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an erroneous value and that the true estimate was 1.98, which is approximately fourfold what would be expected in the US asthmatic population of that age (i.e. 0.48 per 1000 person-years) [7,8]. This is similar to the death rate from the previous UK salmeterol surveillance study (2.32 per 1000 person-years) [9]. It is interesting to speculate whether similar findings to those from the SMART study would have been obtained had compliance with ICS been enforced by giving the fluticasone–salmeterol combination. In a subsequent meta-analysis of 12 trials, it was found that 53/3083 patients receiving LABA versus 12/2008 patients receiving placebo were hospitalized for asthma exacerbations, with a calculated odds ratio of 2.6 (95% CI 1.6–4.3) [10]. Then, seven trials were pooled to assess lifethreatening asthma exacerbations, showing 50/15 443 versus 25/14 538 events with LABA compared with placebo, respectively, with an odds ratio of 1.8 (95% CI 1.1–2.9). On the basis of a review of the SMART study and other data, the US Food and Drug Administration (FDA: http:// www.fda.gov/) imposed a safety warning on the prescribing information and package labelling of all LABAs, including combination inhalers [11,12]. In the UK, the Commission of Human Medicines has set up an expert working group (under the auspices of the Medicines and Healthcare Products Regulatory Agency) to review the safety of LABAs [13]. My opinion is that, in certain susceptible individuals, the use of LABAs might have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. Therefore, it seems timely and appropriate to address the potential pharmacological mechanisms of the adverse effects of LABAs on asthma control. Tachyphylaxis with LABAs Given that tachyphylaxis (see Glossary) occurs readily with regular exposure to short-acting b2-adrenoceptor agonists, the advent of LABAs soon led to concerns about the potential for more-profound tachyphylaxis. This is because of prolonged, 24-h receptor occupancy and the associated propensity for agonist-promoted reduction in the number and coupling efficiency of b2-adrenoceptors on airway smooth muscle and inflammatory cells, where such receptors are expressed (Box 2). The first clinical study to address this issue evaluated salmeterol (or placebo) as an add-on therapy to ICS for one month in moderate persistent asthmatics; it showed that, even 36 h after stopping the administration of salmeterol, there was a persistent reduction in the number of ex vivo peripheral blood mononuclear cells, which was also associated with blunting of the acute bronchodilator response to repeated doses of inhaled salbutamol [14]. In the same study, the peak flow response (a measure of airway calibre) to salmeterol was maintained over the four weeks. Similar findings were subsequently reported with formoterol as an add-on therapy to ICS [15]. To mimic more closely the clinical scenario in acute asthma, it is more informative to examine what happens in the setting of acetylcholine-induced airway constriction by measuring the degree of bronchoprotection (i.e. www.sciencedirect.com
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Box 2. Tachyphylaxis of the b2-adrenoceptor-mediated response An intrinsic defect of b2-adrenoceptors that results in impaired function of airway smooth muscle was originally hypothesized as being one of the possible mechanisms underlying the asthmatic condition. This defect, in turn, results in bronchial smooth muscle constriction because of an imbalance between sympathetic (bronchorelaxation) and acetylcholine-mediated (bronchoconstriction) airway tone. Continuous, twice-daily exposure to an exogenous LABA such as salmeterol results in reduced receptor numbers (i.e. downregulation) on bronchial smooth muscle and inflammatory cells, together with uncoupling of the b2-adrenoceptor from the G protein adenylyl cyclase. This, in turn, produces progressive diminution of the agoniststimulated response (i.e. tachyphylaxis or subsensitivity of response). In addition, 24-h occupancy of receptors by regular exposure to twice-daily LABAs results in the relative antagonism of salbutamol when the latter is used for rescue treatment of acute episodes of bronchoconstriction.
functional antagonism) conferred against a standardized bronchial challenge test. Subjects inhale cumulative doses of the acetylcholine receptor agonist methacholine to produce a 20% reduction in the forced expiratory volume in 1 s (FEV1). Studies with salmeterol twice daily as an add-on to ICS have demonstrated loss of protection against methacholine challenge after three repeated doses, compared with placebo [16]. Similar results were reported after regular exposure to salmeterol following four weeks of treatment, showing loss of protection against exerciseinduced bronchoconstriction [17]. For formoterol given as an add-on to ICS, loss of protection against methacholine occurred with doses of 6 mg or 24 mg twice daily or 12 mg once daily, when comparing first with last doses, such that the residual protection was not significantly better than that obtained with placebo [18]. Moreover, with both salmeterol and formoterol, this loss of protection against methacholine cannot be overcome by administering eight times the usual recommended dose of salbutamol (i.e. 1200 mg) [19]. Cross-tachyphylaxis between LABAs and salbutamol in the presence of increased airway tone has been demonstrated in other studies [16,20,21]. These findings all indicate that concomitant administration of ICS does not protect against tachyphylaxis of response to LABAs or against cross-tachyphylaxis to salbutamol, although a bolus high dose of systemic corticosteroid might increase the number of b2-adrenoceptors and resensitize them ex vivo and in vivo in asthmatics [22]. Another possible mechanism is prolonged receptor occupancy by LABAs resulting in relative antagonism of salbutamol [23]. There is evidence to support this from a study in which a single dose of salmeterol or formoterol (compared with placebo) attenuated salbutamol-induced bronchorelaxation in methacholine-constricted airways of asthmatics in vivo [24]. The obvious question is whether this interaction between LABAs and salbutamol as reliever therapy might, in part, explain the findings of the SMART study, in terms of delaying recovery from episodes of acute bronchoconstriction, and whether susceptible individuals might be
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genetically predisposed to such adverse effects of LABAs. Unfortunately, no information on salbutamol use or genotype was collected in the SMART study. Genetic variation of b2-adrenoceptors Several polymorphisms of the b2-adrenoceptor have potential functional consequences for ligand–receptor interactions. Of these polymorphisms, most attention has been focused on allelic variants at position 16 of the b2-adrenoceptor, where a single nucleotide polymorphism results in an amino acid substitution of glycine (Gly) for arginine (Arg) [25]. The allelic frequencies are 36% and 64% for Arg and Gly polymorphisms, respectively, with genotypic frequencies of 14%, 42% and 44% for homozygous Arg16, homozygous Gly16 and heterozygote, respectively [26]. In vitro experiments using b2-adrenoceptors expressed in airway smooth muscle cells cultured from humans showed that agonist-promoted reductions in receptor number occur to a greater degree with Gly16 than with Arg16 receptors [27]. However, this does not take into account the potential influence of exogenous circulating catecholamines that occurs in vivo. The putative effect of catecholamines in vivo is to reduce the number of b2-adrenoceptors so that there are fewer Gly-form receptors than there are Arg-form receptors before exposure to an exogenous agonist. The result is that further reduction in receptor numbers by an exogenous agonist would be expected to be relatively greater in individuals expressing the Arg polymorphism than in those expressing the Gly polymorphism [28]. However, there is contradictory evidence from a study in which ex vivo peripheral blood mononuclear cells, taken from asthmatic patients, that were washed-out of exogenous b2-adrenoceptor agonists showed no difference in the numbers of b2-adrenoceptors or adenylyl cyclase activity when different b2-adrenoceptor polymorphisms or extended haplotypes were compared [29]. There are important racial differences in the prevalence of extended haplotypes, which might explain the ethnic differences in adverse events seen in the SMART study in African Americans [25], who have an increased frequency of the homozygous Arg16 genotype [30]. One study indicated that the Arg–Cys19 polymorphism in the b-upstream peptide of the b2-adrenoceptor, but not the Arg–Gly16 polymorphism, might have a role in salbutamol bronchodilator responsiveness in African American subjects [31]. This, in turn, raises the issue of whether a possible increased rate of severe deterioration in asthma symptoms and/or death in African Americans receiving salmeterol, as documented in the SMART study, is related to an ethnicspecific pharmacogenetic difference. In this regard, b2adrenoceptor agonists produce dose-related prolongation of cardiac repolarization, and genetic polymorphisms in African Americans might have been a contributory cause of death in the SMART study [32–34]. A retrospective genotyped analysis of data from steroid-treated asthmatics exposed to regular LABAs or placebo showed loss of bronchoprotection between first and last doses in Gly16 and Arg16 genotypes, with the degree of protection being significantly less in Arg16 than in Gly16 genotypes [35]. Moreover, the level of protection from www.sciencedirect.com
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LABAs in Arg16 patients was lower than that from placebo for both first and last doses. In susceptible Arg16 patients, the protection afforded by formoterol was significantly less than that obtained with salmeterol after first and last doses. These findings were supported by other retrospective genotyped data in which the peak flow response to salmeterol (compared with placebo) over four months was worse in homozygous Arg than in homozygous Gly genotypes, irrespective of concomitant ICS use [36]. A post hoc genotype analysis of a study in which a fluticasone–salmeterol combination was given for three months showed no difference in peak flow response between Arg and Gly genotypes, although it was not possible to distinguish the effects that were attributable to the ICS and LABA moieties because there was no LABA placebo arm for comparison [37]. Moreover, the study was biased towards b2-adrenoceptor responders because, at initial screening, the degree of bronchodilator response to salbutamol was large for all genotypes at position 16. Because salbutamol and salmeterol both act on the same b2-adrenoceptor, it is perhaps not surprising that the results also showed such an excellent response to salmeterol for all genotypes at position 16. In 164 asthmatic children taking ICS plus salmeterol, there was a 3.4-fold (95% CI 1.19–9.4) increased risk of asthma exacerbation over six months when comparing Arg16 and Gly16 patients [38]. However, data regarding 108 adult asthmatics showed no difference in exacerbations over one year when comparing genotypes at position 16 [39]. Another relevant issue is whether the interaction between LABAs and salbutamol is genotype dependent. In a prospective randomized controlled crossover trial, patients selected with either the Arg or the Gly genotype received a fluticasone–salmeterol or a budesonide–formoterol combination [40]. The acute salbutamol recovery after a standardized methacholine challenge, when comparing first and last doses, was significantly delayed to a similar degree by both combinations in both genotypes. Furthermore, after the last dose of each combination, there were no differences between genotypes in pre-challenge FEV1 or in the degree of protection conferred by LABAs against methacholine challenge (as the 20% threshold value). These findings raise the issue of whether the adverse effects of LABAs on exacerbations and lung function can be explained by enhanced cross-tachyphylaxis of b2-adrenoceptors. The way forward There is clearly a potential problem with LABAs whereby worsening asthma control might result in life-threatening exacerbations. The subgroup analysis from the SMART study was inadequate for drawing valid conclusions, but it has been used in some circles to make the point that physicians should not be concerned about using LABAs, as long as they are prescribed for Caucasians and for use in combination inhalers in conjunction with ICSs, which have beneficial anti-inflammatory activity and putative protective effects against tachyphylaxis. This assumption about ICSs is misguided because other data clearly indicate that concomitant administration of ICS does not prevent LABAinduced tachyphylaxis or prevent cross-tachyphylaxis
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between LABAs and salbutamol. Pointedly, the FDA imposed the product label warning on all LABAs, including combination inhalers, on the basis that the data from the SMART study did not conclusively show that adverse effects were confined to patients taking unopposed LABAs without ICSs. The dilemma for clinicians is to know which patients are most at risk when taking LABAs. On the one hand, LABAs are effective second-line bronchodilator controller agents that improve airway calibre and quality of life, and reduce salbutamol reliever use but, on the other hand, they might also increase the risk of hospitalization and asthmarelated death in certain situations. It is tempting to attribute all harmful effects of LABAs to the 15% of patients who have the Arg16 homozygous genotype. Although some data indicate that such patients might fare worse with regular exposure to LABAs, the situation is far from clear-cut. The Long-acting bAgonist Response by Genotype (LARGE) study, run by the Asthma Clinical Research Network (http://www. acrn.org/), is underway in the USA to evaluate prospectively the effects of ICSs plus LABAs or placebo in Arg versus Gly homozygous genotypes, looking at effects on peak flow over 18 weeks. However, until there are longerterm (i.e. longer than one year) prospective studies that look at exacerbations (rather than airway calibre, as measured by peak flow) in genotyped patients, we will be no closer to resolving this issue. With the current evidence, it would be unethical to withhold LABAs on the basis of genetic screening. However, it might be equally unethical to prescribe LABAs on the basis of genetic screening because there are no real assurances that any subgroup of patients is immune to the adverse effects. It would be hard to imagine a twofoldincreased risk of asthma hospitalization in pooled data solely related to increased events in the 15% of patients with the homozygous Arg genotype. Therefore, the proposal to provide genotyping of individuals to help with decision making might not result in fewer serious adverse events. In my opinion, a more pragmatic approach would be to consider stopping the use of pre-existing LABAs in patients who experience a severe exacerbation, particularly with lifethreatening features, and in those who have increasing salbutamol use or for whom salbutamol is no longer effective as a reliever. Such susceptible patients would, therefore, be effectively risk stratified, and a cogent case could then be made for genotyping with informed consent to aid decision making. It should also be pointed out that, in these circumstances, there are effective alternatives for secondline controllers that, unlike LABAs, are not bronchodilators but, instead, exhibit non-steroidal anti-inflammatory activity, such as anti-leukotrienes, theophylline or antiIgE. The possible role of long-acting acetylcholine receptor antagonist drugs such as tiotropium, instead of LABAs, as a second-line bronchodilator therapy for more-severe asthma that is not controlled by ICSs is worthy of further investigation [41]. It is also worth emphasizing that ICSs should always be used as a first-line anti-inflammatory therapy for all asthmatics and that LABAs should never be used as a monotherapy, in keeping with present guidelines [2]. www.sciencedirect.com
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Concluding remarks The dilemma for clinicians will increase because LABAs are likely to become more prevalent in a market driven by an ever-increasing number of proprietary and generic combination inhalers. Moreover, the imminent availability of ultra-long-acting once-daily drugs means that b2-adrenoceptors might be exposed to continuous 24-h occupancy by a high-efficacy, high-affinity agonist that would be expected to induce an even more profound tachyphylaxis. In this regard, opinion leaders need to take a step sideways to appraise the situation more critically and to refine the position of LABAs in asthma management guidelines so that the blanket use of combination inhalers for all severities of asthma can be avoided. This problem will persist and it is now down to clinicians to work in a responsible fashion with the pharmaceutical industry and the regulatory authorities to ensure that LABAs are prescribed in a safe and responsible fashion. Disclosure statement B.J.L. and the Asthma and Allergy Research Group have received funding support for performing clinical trials, consulting activity, advisory work, giving postgraduate educational talks and departmental meetings from companies that make LABA and ICS, including AstraZeneca, GlaxoSmithKline, Altana, Sanofi-Aventis, Ivax, Schering Plough, Noelab, Cipla, Novartis, Innovata and Verus. References 1 Szentivanyi, A. (1968) The b-adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 42, 203–232 2 Global Initiative for Asthma (2006) Global strategy for asthma management and prevention (http://www.ginasthma.org) 3 Masoli, M. et al. (2005) Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 60, 730–734 4 Gibson, P.G. et al. (2007) Differential effects of maintenance long-acting b-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J. Allergy Clin. Immunol. 119, 344–350 5 Cazzola, M. et al. (2005) Ultra long-acting b2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs 14, 775–783 6 Nelson, H.S. et al. (2006) The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129, 15–26 7 Sears, M.R. (2006) The Salmeterol Multicenter Asthma Research Trial. Chest 130, 928–929 8 Nelson, H.S. and Dorinsky, P.M. (2006) The Salmeterol Multicenter Asthma Research Trial. Chest 130, 928–929 9 Castle, W. et al. (1993) Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 306, 1034–1037 10 Salpeter, S.R. et al. (2006) Meta-analysis: effect of long acting bagonists on severe asthma exacerbations and asthma related deaths. Ann. Intern. Med. 144, 904–912 11 US Food and Drug Administration (2003) Labelling changes for drug products that contain salmeterol. FDA Talk Paper (www.fda.gov/bbs/ topics/ANSWERS/2003/ANS01248.html) 12 US Food and Drug Administration (2005) FDA Public Health Advisory. Serevent, Advair, Foradil (http://www.fda.gov/cder/drug/advisory/ LABA.htm) 13 Medicines and Healthcare Products Regulatory Agency (2007) MHRA review of formoterol and salmeterol in asthma and chronic obstructive pulmonary disease (http://www.mhra.gov.uk/home/idcplg?IdcService= SS_GET_PAGE&nodeId=1016) 14 Grove, A. and Lipworth, B.J. (1995) Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 346, 201–206
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