Four in five asthma deaths may be due to long acting β agonists
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PROVIDER: S-EPMC1482362 | biostudies-literature | 2006 Jun
REPOSITORIES: biostudies-literature
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Project description:Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.
| S-EPMC4659681 | biostudies-literature
Project description:Inhaled corticosteroids (ICS) plus long-acting β2-agonists (LABA) are recommended for maintenance-only or maintenance and reliever therapy (MART) in patients with asthma. However, real-world data on ICS/LABA as maintenance-only or MART are limited. This study characterized clinical, economic, and humanistic burdens of asthma in Canada, China, Europe, Japan, and the US, using data collected from patients and physicians via a cross-sectional survey (Asthma Disease Specific Programme). Patients were ≥18 years of age with physician-confirmed asthma and receiving fixed-dose ICS/LABA for ≥3 months. Mean physician-reported symptom-free days over the past 30 days ranged from 10.1-20.6 days, and 31.5-34.6% of ICS/LABA users self-reported not well-controlled asthma. SABA co-prescription was reported in 8.8-67.8% of patients. These findings highlight the continued disease burden among ICS/LABA users, with the high level of SABA co-prescription indicating potentially inappropriate prescribing of ICS/LABA as MART or detrimental reliance on SABA medication in addition to MART.
| S-EPMC11865622 | biostudies-literature
Project description:IntroductionInhaled β-agonists have been foundational medications for maintenance COPD management for decades. Through activation of cyclic adenosine monophosphate pathways, these agents relax airway smooth muscle and improve expiratory airflow by relieving bronchospasm and alleviating air trapping and dynamic hyperinflation improving breathlessness, exertional capabilities, and quality of life. β-agonist drug development has discovered drugs with increasing longer durations of action: short acting (SABA) (4-6 h), long acting (LABA) (6-12 h), and ultra-long acting (ULABA) (24 h). Three ULABAs, indacaterol, olodaterol, and vilanterol, are approved for clinical treatment of COPD.PurposeThis article reviews both clinically approved ULABAs and ULABAs in development.ConclusionIndacaterol and olodaterol were originally approved for clinical use as monotherapies for COPD. Vilanterol is the first ULABA to be approved only in combination with other respiratory medications. Although there are many other ULABA's in various stages of development, most clinical testing of these novel agents is suspended or proceeding slowly. The three approved ULABAs are being combined with antimuscarinic agents and corticosteroids as dual and triple agent treatments that are being tested for clinical use and efficacy. Increasingly, these clinical trials are using specific COPD clinical characteristics to define study populations and to begin to develop therapies that are trait-specific.
| S-EPMC7751789 | biostudies-literature
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.
| S-EPMC9434680 | biostudies-literature
Project description: Not available
| S-EPMC4170910 | biostudies-literature
Project description:In moderate-to-severe asthma, adding an inhaled long-acting β2 -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 β2 -adrenoceptor density or biased β2 -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.
| S-EPMC5120156 | biostudies-literature
Project description: Not available
| S-EPMC6513433 | biostudies-literature
Project description:BackgroundThe efficacy of inhaled corticosteroids (ICSs)/long-acting beta2-agonist (LABA) treatment in patients with asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) compared to patients with COPD alone has rarely been examined. This study aimed to evaluate the clinical efficacy for the improvement of lung function after ICS/LABA treatment in patients with ACOS compared to COPD alone patients.MethodsPatients with stable COPD were selected from the Korean Obstructive Lung Disease (KOLD) cohort. Subjects began a 3-month ICS/LABA treatment after a washout period. ACOS was defined when the patients had 1) a personal history of asthma, irrespective of age, and wheezing in the last 12 months in a self-reported survey and 2) a positive bronchodilator response.ResultsAmong 152 eligible COPD patients, 45 (29.6%) fulfilled the criteria for ACOS. After a 3-month treatment with ICS/LABA, the increase in forced expiratory volume in 1 second (FEV1) was significantly greater in ACOS patients than in those with COPD alone (240.2±33.5 vs 124.6±19.8 mL, P=0.002). This increase in FEV1 persisted even after adjustment for confounding factors (adjusted P=0.002). According to severity of baseline FEV1, the ACOS group showed a significantly greater increase in FEV1 than the COPD-alone group in patients with mild-to-moderate airflow limitation (223.2±42.9 vs 84.6±25.3 mL, P=0.005), whereas there was no statistically significant difference in patients with severe to very severe airflow limitation.ConclusionThis study provides clinical evidence that ACOS patients with mild-to-moderate airflow limitation showed a greater response in lung function after 3 months of ICS/LABA combination treatment.
| S-EPMC5108502 | biostudies-literature
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.
| S-EPMC3044729 | biostudies-literature
Project description:BackgroundLong-acting beta agonists (LABA) and leukotriene receptor antagonists (LTRA) are the major add-on treatments in older adults with persistent asthma when inhaled corticosteroids (ICS) fail to achieve adequate asthma control.ObjectivesTo evaluate the cost-utility of ICS + LABA treatment compared with ICS + LTRA treatment in older adults with asthma.MethodsA Markov model was used to estimate the incremental costs and quality-adjusted life expectancy associated with ICS + LABA treatment versus ICS + LTRA treatment in older adults with asthma in the United States from the health system perspective. The HCUPnet 2010 national statistics were used to extract the costs associated with asthma and cardiovascular hospitalizations, and inpatient mortality associated with these events. Event probabilities were predicted using Medicare 2009-2010 claims for older adults with asthma. Treatment costs were estimated on the basis of average wholesale drug price listings, and utility estimates were extracted from the literature. To account for uncertainty, one-way sensitivity analysis and probabilistic sensitivity analysis were performed.ResultsThe model predicted that, compared with ICS + LTRA treatment, ICS + LABA treatment costs $5,823 more while gaining 0.03 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of $209,090 per QALY. Hospitalization probabilities and posthospitalization utilities were the most influential parameters in the one-way sensitivity analysis. Probabilistic uncertainty analysis using Monte-Carlo simulations showed that the probabilities that ICS + LTRA treatment is cost-effective compared with ICS + LABA treatment are 77% and 62% at $50,000 and $100,000 per QALY gained willingness-to-pay thresholds, respectively.ConclusionsThe cost-effectiveness of ICS + LABA treatment is economically unfavorable in older adults when compared with LTRA as add-on treatment.
| S-EPMC7961838 | biostudies-literature