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Understanding how long-acting ?2 -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update.

ABSTRACT: In moderate-to-severe asthma, adding an inhaled long-acting ?2 -adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti-inflammatory/anti-asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid-induced genes. Other genes, including dual-specificity phosphatase 1(DUSP1) in human airways smooth muscle (ASM) and epithelial cells, are up-regulated additively by both drug classes. Synergy may also occur for LABA-induced genes, as illustrated by the bronchoprotective gene, regulator of G-protein signalling 2 (RGS2) in ASM. Such effects cannot be produced by either drug alone and may explain the therapeutic efficacy of ICS/LABA combination therapies. While the molecular basis of synergy remains unclear, mechanistic interpretations must accommodate gene-specific regulation. We explore the concept that each glucocorticoid-induced gene is an independent signal transducer optimally activated by a specific, ligand-directed, GR conformation. In addition to explaining partial agonism, this realization provides opportunities to identify novel GR ligands that exhibit gene expression bias. Translating this into improved therapeutic ratios requires consideration of GR density in target tissues and further understanding of gene function. Similarly, the ability of a LABA to interact with a glucocorticoid may be suboptimal due to low ?2 -adrenoceptor density or biased ?2 -adrenoceptor signalling. Strategies to overcome these limitations include adding-on a phosphodiesterase inhibitor and using agonists of other Gs-coupled receptors. In all cases, the rational design of ICS/LABA, and derivative, combination therapies requires functional knowledge of induced (and repressed) genes for therapeutic benefit to be maximized.

SUBMITTER: Newton R

PROVIDER: S-EPMC5120156 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Understanding how long-acting β<sub>2</sub> -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update.

Newton Robert R Giembycz Mark A MA

British journal of pharmacology 20161109 24

In moderate-to-severe asthma, adding an inhaled long-acting β<sub>2</sub> -adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti-inflammatory/anti-asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid-induced genes. Other genes, including dual-specificity phosphatase 1(DUSP1) in human airw ...[more]

PMID: 27646470

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Project description:BackgroundSuboptimal adherence to maintenance medication has been associated with poor outcomes in asthma. This study examined single-inhaler inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) adherence and asthma-related outcomes.MethodsThis retrospective observational study of patients with asthma initiating ICS/LABA used data from IQVIA PharMetrics Plus (1 January 2014-31 March 2019). Patients included were ⩾18 years old and had ⩾12 months continuous eligibility before, and ⩾180 days follow-up after, the index date. Adherence was measured as proportion of days covered ([PDC] adherent ⩾ 0.8; non-adherent <0.8) each quarter, with outcomes measured each subsequent quarter. Endpoints were asthma-related overall and severe (inpatient/emergency department [ED] visit) exacerbations, rescue medication use, and asthma-related healthcare resource utilization and costs. Regression models evaluated associations between adherence and outcomes, controlling for repeated measures and differences in baseline characteristics.ResultsOverall, 50,037 patients were included (mean age 45.3 years; mean follow-up 23.3 months). Adherent patients were less likely to experience asthma-related overall (adjusted odds ratio [aOR] 95% confidence interval [CI]: 0.942 [0.890, 0.998]; p = 0.041), or severe exacerbations (aOR [95% CI]: 0.778 [0.691, 0.877]; p < 0.001) per quarter versus non-adherent patients. Adherent patients had lower severe exacerbation rates (adjusted rate ratio [aRR] [95% CI]: 0.792 [0.702, 0.893]; p < 0.001) but similar overall exacerbation rates (aRR [95% CI]: 0.993 [0.945, 1.044]; p = 0.783) versus non-adherent patients. The odds of rescue medication use were lower per 20% PDC increase (aOR [95% CI] short-acting β2 agonist: 0.991 [0.985, 0.996]; p = 0.001; oral corticosteroid: 0.988 [0.982, 0.995]; p < 0.001). Adherent patients were less likely to visit EDs per quarter (aOR [95% CI]: 0.775 [0.680, 0.883]; p < 0.001) and odds of hospitalization were lower per 20% PDC increase (aOR [95% CI]: 0.930 [0.881, 0.982]; p = 0.009). Across most measures, adherent patients incurred lower costs.ConclusionThis real-world study highlights the short-term clinical and economic benefits of ICS/LABA adherence in asthma, particularly in reducing severe exacerbations.

Project description:BackgroundThe Risk of Bias (RoB) tool is used to assess internal validity of randomized controlled trials (RCTs). Our objectives were to: 1) evaluate inter-rater agreement of the RoB tool; 2) determine the time to access supplemental study information; 3) compare the RoB tool with the Jadad scale and Schulz allocation concealment (AC); and 4) examine the relationship between RoB and effect estimates.MethodsWe conducted a systematic review of long-acting beta agonists (LABA) combined with inhaled corticosteroids (ICS) for adults with persistent asthma. Two reviewers independently assessed 107 trials using RoB, Jadad, and AC. One reviewer searched for study protocols. We assessed inter-rater agreement using weighted Kappa (?) and the correlation between tools using Kendall's Tau (?). Mean differences in effect sizes for RCTs with different RoB were calculated using inverse variance method and random effects model.ResultsTrials had good Jadad scores (median 4, IQR 3-4); however, 85% had unclear AC and 87% high RoB. The factor that most influenced RoB was the potential inappropriate influence of study sponsors (95% industry funded). Agreement on RoB domains was fair (??=?0.40) to almost perfect (??=?0.86), and moderate for overall RoB (??=?0.41). Median time to complete RoB assessments was 21 minutes (IQR 14-27) and 12 minutes (IQR 9-16) to search for protocols. Protocols were identified for 5/42 studies (12%); in 3 cases the assessment of selective outcome reporting changed. There was low correlation between overall RoB vs. Jadad (??=?0.04, p?=?0.3) and AC (??=?-0.02, p?=?0.7). Analyses comparing effect estimates and risk showed no important patterns.ConclusionsInter-rater agreement on RoB assessments was better than previously reported suggesting that review-specific guidelines are important. The correlation between RoB and Jadad was low suggesting measurement of different constructs (risk of bias vs. quality of reporting). The extensive involvement of the pharmaceutical industry in this LABA/ICS research should raise concerns about potential overestimates of treatment effects.

Project description:There are several new treatment options for patients whose asthma remains uncontrolled on free-dose and fixed-dose combinations of inhaled corticosteroids plus long-acting β2-agonists (ICS+LABA). In order to evaluate the likely impact of these treatments, we assessed the effect of uncontrolled asthma on healthcare and patient burden within the UK among adult patients treated with ICS+LABA. Data obtained from 2010-2011 UK National Health and Wellness Surveys identified 701 patients treated with ICS+LABA. Patients with not well-controlled asthma (Asthma Control Test™ score <20) were compared with well-controlled asthma (score ≥ 20) patients on multiple measures. Cost burden was calculated using healthcare resource utilisation models and work productivity and impairment questionnaire. Overall, 452 and 249 patients reported not well-controlled and well-controlled asthma, respectively. A greater proportion of not well-controlled patients visited the accident & emergency department (21 vs. 14%, P = 0.016), were hospitalised (13 vs. 8%, P = 0.022) and had lower mental and physical health-related quality of life (P < 0.001) and impaired work productivity and activity scores: presenteeism (23 vs. 11%, P < 0.001), work impairment (29 vs. 17%, P < 0.001) and activity impairment (46 vs. 24%, P < 0.001). Calculated direct and indirect yearly costs/person doubled among not well-controlled compared to well-controlled asthma patients (£6592 vs. £3220). Total cost to society was estimated at £6172 million/year (direct costs, £1307 million; indirect costs, £4865 million). In conclusion, not well-controlled asthma is common among UK adults treated with ICS+LABA, resulting in impairments across a number of important health outcomes and represents a significant unmet need and resource burden.AsthmaDRUG COMBO LEAVES MANY WITH UNCONTROLLED DISEASE: Many people who take inhaled steroids combined with long-acting β2-agonist drugs still have poorly controlled asthma. A team led by Ian Pavord from the University of Oxford, UK, identified 701 people from the 2010-2011 UK National Health and Wellness Surveys who were taking this drug combination for their asthma. The researchers found that nearly two-thirds of these individuals had poorly controlled asthma associated with more visits to the emergency room, worse quality of life (both mentally and physically), impaired productivity and other health problems. The calculated direct and indirect costs per person with poorly controlled asthma were about double that for someone whose asthma was under control. The authors conclude that better treatment and management is needed to reduce costs and address the unmet medical need for people with persistent uncontrolled asthma.

Dataset Information

Understanding how long-acting ?2 -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update.

Publications

Understanding how long-acting β<sub>2</sub> -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update.

Similar Datasets

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