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24th May 2023
The rate of exacerbations in COPD patients with type 2 inflammation is lowered by treatment with dupilumab, according to the findings of a recent randomised, placebo trial.
Patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation experience a lower annualised rate of moderate to severe disease exacerbations when dupilumab is added to standard triple therapy, the BOREAS clinical trial group found.
Published in the New England Journal of Medicine, the study looked at COPD patients with type 2 inflammation, based on an elevated eosinophil count (≥300 cells/µL), who were in receipt of standard triple therapy. They were randomised them to either dupilumab 300 mg or placebo, given subcutaneously once every two weeks.
The primary endpoint was the annualised rate of moderate or severe exacerbations of COPD. Secondary outcomes included the change in the prebronchodilator FEV1 and the St. George’s Respiratory Questionnaire (SGRQ) for which lower scores indicated a better quality of life. In addition, the Evaluating Respiratory Symptoms in COPD (E-RS–COPD) scale was used, with, again, lower scores indicative of less severe symptoms.
A total of 939 patients were included and randomised to either dupilumab (468) or placebo. The mean baseline absolute blood eosinophil count was 401.
The annualised rate of moderate or severe exacerbations was 0.78 (95% CI 0.64 – 0.93) for those given dupilumab and 1.10 (95% CI 0.93 to 1.30) with placebo (rate ratio, RR = 0.70, 95% CI 0.58 to 0.86, p < 0.001).
For the secondary outcomes, the prebronchodilator FEV1 increased from baseline to week 12 by a mean of 160 ml with dupilumab and 77 ml with placebo (p < 0.001) and this difference was sustained through to week 52. Similarly, both the SGRQ and E-RS–COPD scores were significantly lower in those receiving dupilumab at week 52.
The authors concluded that the use of dupilumab in COPD patients with a type 2 inflammation phenotype, experience a lower annualised rate of moderate to severe exacerbations, improved quality of life and better lung function.
COPD exacerbations are linked to an accelerated decline in lung function, especially in patients with eosinophil counts greater than 350 cells/µL and not using inhaled corticosteroids.
Type 2 inflammation is present in a sub-set of COPD patients, with one study finding a prevalence of 37%, and such individuals show a better response to systemic corticosteroids such as prednisolone. Type 2 inflammation is characterised by increased eosinophil counts together with elevated levels of various interleukins including interleukin-5, interleukin-4 and interleukin-13.
Monoclonal antibody treatment targeting interleukin-5 with a view to reducing disease exacerbations has, to date, produced mixed results. For instance, use of benralizumab was not associated with a lower annualised rate of COPD exacerbations. In contrast, treatment with mepolizumab, did lower the annual rate of moderate or severe exacerbations. An alternative, yet untested therapeutic approach, is the use of dupilumab, which blocks two other interleukins elevated in those with the type 2 inflammation phenotype, namely, interleukin-4 and 13.
16th February 2023
While prior work has revealed a heightened capsaicin cough reflex sensitivity in those with COPD, Japanese researchers have observed the opposite and found that this reduced sensitivity is associated with an increased risk of both an acute exacerbation or community-acquired pneumonia requiring hospitalisation.
According to the World Health Organisation, COPD was the third highest global cause of death in 2020. Moreover, community-acquired pneumonia (CAP) can often co-exists in patients hospitalised with an acute exacerbation of COPD. Typically patients with COPD experience cough, sputum and dyspnoea and it is know that the presence of both cough and sputum production are associated with frequent disease exacerbations leading to hospitalisation. Previous studies in animals, suggest that patients with COPD have a heightened response to stimulation with capsaicin, leading to a greater number of coughs. Such heightened responses have an important role in helping to protect the airways from particles although other work has identified a reduced capsaicin cough response in those with recurrent pneumonia.
In the present study, the Japanese team speculated that among those with COPD, rather than being more sensitive, as seen in previous work, the capsaicin cough reflex sensitivity would actually be lower due to the fact that many exacerbations occur alongside a co-existent CAP infection. The team prospectively recruited COPD patients and performed a number of baseline tests that included various lung and cardiac function tests, blood eosinophil counts as well as the capsaicin cough reflex sensitivity. These patients were then monitored over the next 12 months for cases of an acute exacerbation or CAP infections leading to hospitalisation.
Capsaicin cough reflex sensitivity and COPD exacerbations
A total of 68 patients with a mean age of 74 years (85.3% male) were included in the study and during the 12 month follow-up, 8 patients (3 with an exacerbation of COPD and 5 with CAP) were hospitalised.
Capsaicin cough reflex sensitivity scores were lower among those hospitalised and using multivariate regression analysis, the researchers identified that a decreased cough sensitivity was significantly associated with an acute exacerbation or CAP infection requiring hospitalisation (odds ratio, OR = 2.19, 95% CI 1.08 – 4.44, P = 0.029). In addition, an eosinophil count ≥300 µL was also significantly associated with hospitalisation (OR = 45.9, 95% CI 1.09 – 1934, P = 0.045).
The authors concluded that use of the capsaicin cough reflex sensitivity in those with COPD, may have a role in the prevention of severe acute exacerbations or pneumonia that require hospitalisation.
Citation
Kanemitsu Y et al. Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD. BMJ Open Respir Res 2023
15th February 2023
US researchers have developed a CT biomarker based model that is able to predict exacerbations in patients with chronic obstructive pulmonary disease (COPD) and which could ultimately be used to identify those at risk of such exacerbations.
Chronic obstructive pulmonary disease is associated with a high level of morbidity, disability and mortality, affecting around 10.3% of the world’s population aged between 30 and 79. The condition is associated with disease exacerbations which contribute to a decline in lung function over time and often result in hospitalisation. In recent years, computed tomography (CT) has been used to identify the phenotypic abnormalities in COPD that can be seen and quantitatively evaluated such as airway wall thickening which contributes to airflow limitations. Nevertheless, the value of using these CT derived markers to help predict exacerbations in COPD has not been explored and was the subject of the current study. The US team hypothesised that a CT biomarker model that included measures such as parenchymal texture and airway wall thickness could be used to predict disease exacerbations. They retrospectively examined patient data obtained from the SIROMICS cohort study, which sought to better understand COPD exacerbations. The team used 3-year follow-up data to develop their models for predicting exacerbations and which together CT-based measure of density gradient texture and airway structure also included several variables such as age, gender, exacerbation history. The performance of the model was assessed using the receiver operating characteristics curve (AUC) and compared to models based on exacerbation history and the exercise capacity (BODE) index.
CT biomarker model prediction of exacerbations
A total of 1956 participants with a mean age of 63.1 years (52%) completed the 3-year follow-up and were included in the analysis.
The CT biomarker model had an AUC of 0.854 for prediction of at least one severe exacerbation within 3 years and 0.93 for consistent exacerbations (defined as at least one acute episode in each of the three years. This was higher than models based on either exacerbation history (AUC = 0.823) or using the BODE index (AUC = 0.812).
In a further analysis using an external cohort of nearly 7,000 participants, the CT biomarker model had an AUC of 0.768 for at least one severe exacerbation.
The authors suggested that CT biomarker models could in the future, potentially be used to investigate the underlying disease mechanisms that lead to an exacerbation.
Citation
Chaudhary MFA et al. Predicting severe chronic obstructive pulmonary disease exacerbations using quantitative CT: a retrospective model development and external validation study. Lancet Digit Health 2023
19th January 2023
Dupilumab add-on therapy in severe asthma improves the exacerbation rate and disease control according to the findings of a real-world study.
Dupilumab add-on treatment in patients with severe asthma is associated with significant improvements in the exacerbation rate, asthma control, pulmonary function and quality of life, according to the findings of a real-world study by Dutch researchers.
Severe asthma occurs when adequate control cannot be achieved by high-dose treatment with inhaled corticosteroids and additional agents (i.e. long-acting inhaled beta 2 agonists, montelukast, and/or theophylline) or by oral corticosteroid treatment, for at least six months per year.
Although it is generally considered that 5% and 10% of all asthmatic patients have severe disease, a 2015 Dutch study of asthmatic adults, found that only 3.6% qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants.
There are currently several biological agents used to treat severe asthma including mepolizumab, benralizumab and dupilumab, with the latter agent binding to the interleukin-4-receptor-α and therefore targeting interleukin-4 and interleukin-13, both of which are key cytokines in type-2 (T2) inflammation.
Moreover, the prevalence of type 2 asthma in severe, uncontrolled disease has been found to be present in the majority (89%) of cases.
Dupilumab add-on therapy is therefore an appropriate treatment option in severe asthma and effective, as shown in randomised, controlled trials.
Nevertheless, while effective in clinical trials, some evidence has shown, especially with mepolizumab, that a large proportion of real-world mepolizumab-treated population with severe asthma, would be excluded from the clinical trial population, raising concerns over the generalisability of trial findings.
In the present study, the Dutch team set out to assess the efficacy and safety of dupilumab add-on therapy for severe asthma in a real-world cohort.
The team retrospectively examined the impact of subcutaneously administered dupilumab, either at hospital or by self-administration at home, at a dose of 200 mg every 14 days, or 300 mg in patients with other type 2 co-morbidities.
The primary endpoint was the annually exacerbation-rate (AER), whereas secondary outcomes included asthma control, pulmonary function and quality of life and the changes were assessed by comparing baseline to 12 month values.
A total of 148 patients with a median age of 52.5 years (57% male) were included in the study, of whom 73% had allergic asthma (which includes the type 2 form).
The AER reduced from 3.00 at baseline to 1.00 at 12 months with dupilumab use (p < 0.001). In fact, after 12 months of treatment, 46% of dupilumab add-on therapy patients remained completely exacerbation-free.
Similarly, asthma-controlled-questionnaire-5 scores reduced over time, from a median of 3.00 at baseline to 1.40 after 12 months of dupilumab use (p < 0.001). Furthermore, lung function (based on FEV1) also improved, increasing from a median of 2.21 at baseline to 2.51 at 12 months (p < 0.001) in the dupilumab group.
The authors concluded that dupilumab add-on therapy in severe asthma was associated with significant improvements in the exacerbation rate, asthma control and pulmonary function, which was in line with findings observed in previous Phase III trials.
Citation
Thelen JC et al. Efficacy and safety of dupilumab as add-on therapy for patients with severe asthma: A real-world Dutch cohort study. Respir Med 2023.
15th November 2022
The use of the anti-diabetic agents, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transport-2 (SGLT-2) inhibitors, gave rise to a significant reduction in the risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes compared to sulfonylureas, according to an analysis by Canadian researchers. In contrast, a third group, the dipeptidyl peptidase 4 (DPP-4) inhibitors, produced only a modest and non-significant reduction in the risk of exacerbations.
The oral anti-diabetic agents, GLP-1 receptor agonists and DPP-4 inhibitors have become well established treatments in the management of type 2 diabetes. In addition, the newest class of drugs, the SGLT-2 inhibitors, in addition to providing diabetic control, also appear to have some positive benefits on cardiovascular endpoints. In addition, to the anti-diabetic agents, there is emerging evidence to suggest that drugs within these classes also have the potential for a positive impact on lung function. For example, animal studies have revealed how the GLP-1 receptor agonists have potential therapeutic value in the treatment of obstructive pulmonary diseases. Similarly, given that dipeptidyl peptidase 4 expression is increased in the lungs of those with COPD, leading to inflammation, the DPP-4 inhibitors have a possible role in the disease through a reduction in lung inflammation. Finally, as COPD is characterised by increased retention of alveolar CO2 and given how SGLT-2 inhibitors lower serum glucose levels, reducing its availability for, there is also a commensurate reduction in the endogenous production of CO2. It is conceivable therefore that SGLT-2 inhibitors may be beneficial for patients with diabetes and concomitant pulmonary disease who retain CO2.
In practice however, the extent to which these purported benefits actually reduce COPD exacerbations is unknown and was the subject in the present study. The Canadian team undertook a population cohort study in which they linked a clinical and hospital episode database to explore whether prescription of each of the three oral anti-diabetic drug classes was associated with a reduced risk of COPD exacerbations in patients with both type 2 diabetes and COPD. The primary outcome was the time to the first episode of a severe COPD exacerbation during follow-up and patients prescribed drugs from each of the different classes were matched with patients prescribed sulfonylureas.
Oral anti-diabetic drugs and COPD exacerbations
A total of 1252 participants prescribed GLP-1 receptor agonists were followed for a median of 1 year. The use of GLP-1 agonists was associated with a 30% lower risk of a severe COPD exacerbation compared to sulfonylureas (Hazard ratio, HR = 0.70, 95% CI 0.49 – 0.99) and a 37% reduced risk of a moderate exacerbation (HR = 0.63, 95% CI 0.43 – 0.94).
After propensity matching, participants prescribed DPP-4 inhibitors had a reduced, but non-significant reduction in severe (HR = 0.91, 95% CI 0.82 – 1.02) and moderate COPD exacerbations (HR = 0.93, 95% CI 0.82 – 1.07).
For SGLT-2 inhibitors, the mean reduction in severe exacerbations was 38% lower (HR = 0.62, 955 CI 0.48 – 0.81) but the reduction for moderate severity exacerbations was non-significant (HR = 1.02, 95% CI 0.83 – 1.27).
The authors concluded that the use of both GLP-1 receptor agonists and SGLT-2 inhibitors were associated with a significantly reduced risk of severe exacerbations compared with sulfonylureas in patients with chronic obstructive pulmonary disease and type 2 diabetes. In contrast, while exacerbations rates were reduced with DPP-4 inhibitors, these reductions were not statistically significant.
Citation
Pradham R et al. Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study. BMJ 2022
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