|Year : 2023 | Volume
| Issue : 1 | Page : 5-12
Newer therapeutic options in chronic obstructive pulmonary disease
Jesin Kumar Chakkamadathil
Department of Pulmonary Medicine, Karuna Medical College, Palakkad, Kerala, India
|Date of Submission||12-Jul-2022|
|Date of Acceptance||01-Aug-2022|
|Date of Web Publication||27-Dec-2022|
Dr. Jesin Kumar Chakkamadathil
Shivam, Guruvayur Road, Punkunnam, Thrissur - 680 002, Kerala
Source of Support: None, Conflict of Interest: None
Chronic respiratory diseases, particularly chronic obstructive pulmonary disease (COPD), are the third leading cause of death worldwide behind only cardiovascular deaths (ischemic heart disease and stroke) and cancers. The issues of misdiagnosis and suboptimal management in COPD are evident from the global disease burden and disability-adjusted life years due to COPD. One of the many reasons for this could be a lack of awareness of the newer treatment modalities among the treating physicians. The recent years have seen the introduction of many new molecules for the treatment of COPD. Many of these drugs are extremely potent bronchodilators which, when used, can reduce overreliance on inhaled corticosteroids (ICSs). On the contrary, we need not refrain from the use of ICS particularly in cases where they are indicated. Targeted therapy of COPD is also coming up in a big way and is a sphere of medicine to watch out for in the future. Through this review, an attempt is made to summarize some of these recent advances in management of COPD.
Keywords: Bronchodilators, chronic obstructive pulmonary disease, corticosteroids, targeted therapy
|How to cite this article:|
Chakkamadathil JK. Newer therapeutic options in chronic obstructive pulmonary disease. J Adv Lung Health 2023;3:5-12
| Introduction|| |
Chronic obstructive pulmonary disease (COPD) and asthma are the predominant chronic respiratory diseases in India with COPD contributing 75.6% of the total disability-adjusted life years (DALYs). COPD is also one of the leading causes of disease burden and mortality in India. The percentage of global DALYs due to COPD is also disproportionately high at 32%. It proves that there are various pitfalls in the diagnosis and management of COPD at present, which needs to be addressed.
The widespread use of biomass fuel for cooking in rural areas, especially in developing nations, has resulted in the emergence of nonsmoker COPD group with a high number of female COPD patient populations. This group is often misdiagnosed or diagnosed at a later stage with majority (56.94%) of these patients being diagnosed at stage 2 of the disease. This can also be attributed to the poor awareness among the population and due to the stigma associated with the disease. These factors also result in frequent exacerbations which accelerate the progression of the disease.
Overuse of inhaled corticosteroids (ICSs) is another issue faced by COPD patients. Many physicians resort to this due to coexisting bronchial asthma in many of these patients. However, many of them are also left with no option due to the inadequate bronchodilation achieved by the currently available, commonly used bronchodilators. These issues can be addressed by using the newer modalities of treatment available now. Knowledge and awareness of these novel therapies among physicians need to be enhanced in order to make proper use of them.
| Pharmacotherapy in Chronic Obstructive Pulmonary Disease|| |
A summary of the pharmacokinetic properties of various drugs used in COPD is provided in [Table 1] and scientific rationale behind their use is summarized in [Figure 1].
| Bronchodilators|| |
Inhaled bronchodilators are central to the treatment of COPD because they alleviate bronchial obstruction and airflow limitation, reduce hyperinflation, and improve emptying of the lung and exercise performance. Both long-acting muscarinic antagonists (LAMAs) and long-acting β2-adrenergic agonist (LABAs) are long-lasting bronchodilators, widely used as first-line treatments in patients with stable COPD. The results of a recent meta-analysis suggested that LAMAs are associated with a lower risk of acute exacerbations and lower incidence of adverse events compared with LABA, but there were no significant differences between LAMA and LABA in terms of lung function, symptom score, and health status. These findings indicate that LAMA may be preferable to LABA in patients with stable COPD, especially in those at risk of frequent exacerbations.
| Muscarinic Antagonists|| |
Muscarinic acetylcholinergic receptors are present in the airway smooth muscle cells, glandular cells, and inflammatory cells of the airways and lung tissues. Acetylcholine released via the activation of the motor vagal fibers binds to these receptors, and results in bronchoconstriction and increase in mucus secretion. There are five types of muscarinic receptors in the airways (M1-M5). Among them, only M2 and M3 have significant effects on the airways. The activation of M2 receptors, which are auto-receptors, inhibits further release of acetylcholine from the nerve terminal. M3 receptors mediate the parasympathetic effects in large airways. Hence, an anti-muscarinic with selective M3 receptor blockade would be an ideal agent for treatment of patients with chronic respiratory ailments. Until recently, tiotropium was the only available LAMA. Tiotropium mediates effects on the M2 receptors which has raised concerns regarding its cardiovascular safety profile. These concerns were further reiterated by the meta-analysis conducted by Singh et al. Fortunately, newer agents have been made available which has helped to allay few of our apprehensions regarding muscarinic antagonists.
| Glycopyrronium Bromide|| |
Glycopyrronium is a potent antagonist at M1, M2, and M3 receptors with preferential activity at M1 and M3 receptors over M2 receptors. The dissociation rate of glycopyrronium from the M2 receptors is also faster when compared to that from M1 and M3 receptors. The safety and efficacy of glycopyrronium has been extensively studied and proven beyond doubt in the GLOW (glycopyrronium bromide in COPD airways) series of clinical studies. GLOW is a series of 6 studies where the efficacy, safety, and tolerability of glycopyrronium (GLOW1 and GLOW2); effect of glycopyrronium on exercise endurance (GLOW3); long-term safety and tolerability of glycopyrronium in Japanese patients (GLOW4); efficacy, safety, and tolerability of glycopyrronium versus tiotropium (GLOW5); and the efficacy, safety, and tolerability of co-administration of glycopyrronium with indacaterol (GLOW6) were evaluated. The study showed that this compound has similar efficacy to tiotropium, but a faster onset of action. GLOW3 also reiterated the fact that COPD patients on glycopyrronium have superior exercise tolerance which significantly improves their adherence to rehabilitation programs and hence would improve their quality of life (QOL) in the long run. More importantly, GLOW1 and GLOW2 showed a significant reduction (34%) in the rate of moderate and severe exacerbations in COPD patients, thus preserving their lung function and reducing health-care expenditure.,
| Umeclidinium|| |
Umeclidinium, as a LAMA, has proven to be a safe and effective agent for the management of obstructive airway diseases. It has a long t1/2 (>27 h) which is not affected by the renal and hepatic function of patients. It is found to improve forced expiratory volume in 1 second (FEV1) and reduce dyspnea and the time to first exacerbation in respiratory patients. Its efficacy has been comparable to tiotropium and it is reported to have fewer side effects like dry mouth.
| Aclidinium|| |
Aclidinium is a LAMA that has recently been approved for the treatment of COPD patients. Even though not many head-to-head comparison trials with tiotropium have been conducted, the results of placebo-controlled trials have been promising. It has been shown to improve the QOL and FEV1 of patients. It has also been shown to reduce the occurrence of exacerbations requiring hospitalization. It is however approved for use at a dose of 400 μg twice daily making it unsuitable for patients who would prefer once-daily dosing.
| β2-adrenoreceptor Agonists|| |
β2-adrenoreceptor agonist stimulates the G-protein-coupled β2-adrenoreceptors which in turn cause relaxation of the airway smooth muscles and increase airflow into the lungs. Upon activation, these β2-receptors stimulate G protein which in turn increases the levels of 3'-5' cyclic adenosine monophosphate (cAMP) via the activation of adenylyl cyclase. cAMP then attenuates myosin regulatory light chain kinase activity and phosphorylates Ca2+-dependent K+ channels. Both these mechanisms then result in airway smooth muscle relaxation.
| Indacaterol|| |
Indacaterol is the first once-daily LABA approved for the treatment of COPD. It is also considered an "ultra-LABA," a title that has been bestowed on it due to its rapid onset and long duration of action. Its onset of action (10 min) is comparable to salbutamol and formoterol. Its duration of action (529 ± 99 min) is significantly longer than its counterparts, formoterol, and salmeterol. This longer duration does not come at an expense of its bronchodilatory properties as was proven in the INTEGRAL study in which patients on indacaterol had a superior inspiratory capacity compared to patients on twice-daily salmeterol. The side effect profile was also similar to formoterol as evaluated in the INDORSE study and comparable to those receiving placebos. Worsening of COPD, nasopharyngitis, and cough were the most frequent among them.
| Vilanterol Trifenate|| |
Vilanterol was developed via modification of salmeterol in order to create a more potent compound with higher intrinsic activity at the β2-adrenoreceptor. Pharmacological studies have reported a significant improvement in FEV1 with no significant adverse effects. The drug, however, is not available as a single-dose agent and is only available in fixed-dose combinations with either umeclidinium or fluticasone furoate.
| Olodaterol|| |
Olodaterol is a selective agonist of β2-adrenergic receptor with a high affinity for the receptor. It forms a stable complex with the receptor which renders it a long 24-h bronchodilatory effect. Patients on olodaterol have demonstrated improvement in lung function, QOL, and exercise endurance. Its adverse effect profile has also been generally favorable without any bothersome cardiovascular or respiratory effects. This property together with its convenient once-daily dosing, makes it an ideal agent for maintenance therapy in patients with obstructive airway diseases.
| Abediterol|| |
Abediterol is a novel LABA that has a high affinity for the β2-adrenoreceptor. It is usually marketed in combination with an anti-inflammatory agent for the treatment of both asthma and COPD. This compound possesses superior β2-selectivity and bronchodilatory potency when compared to its counterparts like formoterol, indacaterol, salmeterol, vilanterol, and olodaterol. It is a safe and well-tolerated bronchodilator with a long duration of action (t1/2 – 24.3 h) making it ideal for maintenance therapy. These results have been consistent in patients with asthma and COPD resulting in a significant improvement in their QOL.
| Dual Bronchodilators|| |
Combination therapy with two bronchodilators including a β2-agonist and muscarinic antagonist is the currently accepted treatment in COPD patients. The benefits of this strategy can be manifold. Since both these agents have distinct and complimentary mechanisms for inducing bronchodilation, their effects are found to be synergistic. Patients also often tend to demonstrate varied responses to different classes of bronchodilators. Since individualizing treatment for all such patients might not be feasible, combining both these agents would be a more practical solution. This strategy also enables us to use a smaller dose of each component, thus improving their side effect profile. Many researchers are of the opinion that the way forward in management of COPD patients would be to elucidate the role of LABA/LAMA dual therapy beyond symptom control and determine its long-term outcomes such as those on disease progression. This, along with a more accurate diagnostic distinction from asthma, would help curtail the unnecessary prescription of ICSs. Newer and more effective such combinations can help in this regard and a better understanding of such therapies would be of paramount importance.
| Glycopyrronium + Formoterol|| |
Glycopyrronium/formoterol is a useful addition which has extended treatment options for COPD patients. The PINNACLE studies were conducted in order to assess the efficacy of this combination. PINNACLE-1, PINNACLE-2, and PINNACLE-4 were three phase III multicenter, randomized, double-blind, parallel-controlled trials. PINNACLE-1 was conducted in the USA, Australia, and New Zealand. PINNACLE-2 was conducted in the USA and PINNACLE-4 across Asia, Europe, and the USA. The studies reported improvements in FEV1, dyspnea score, QOL, symptom burden, and need for rescue medications when compared to monotherapy. Studies like the AERISTO trial have found this combination to be noninferior to umeclidinium/vilanterol fixed-dose combinations (FDCs). Its twice-daily dosing also ensures better control of the circadian variability of symptoms in these patients.
| Indacaterol + Glycopyrronium|| |
Indacaterol/glycopyrronium is a new and emerging combination in the management of COPD patients. Its effects have been evaluated in 14 controlled trials of COPD patients. The POWER study (The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium with indacatERol combination in the management of COPD) is one such study conducted in Canada. In this study, moderate-to-severe COPD patients on LAMA monotherapy or ICS/LABA therapy were switched to indacaterol/glycopyrronium and the results were analyzed. Patients on indacaterol/glycopyrronium demonstrated significant improvements in dyspnea indices, CAT scores, and QOL. The combination was also well tolerated. Studies like SHINE and ARISE evaluated the efficacy of this combination in Asian populations as well and found these patients to have a better reduction in FEV1 and improvement in dyspnea indices and QOL.
| Tiotropium + Olodaterol|| |
Tiotropium/olodaterol, a potent combination for maintenance therapy in COPD patients, has recently been approved for treatment in the USA, Japan, China, and some countries of the EU. Its efficacy has been evaluated in various trials including the TOviTO, OTEMTO, VIVACTO, ENERGITO, TORRACTO, and PHYSACTO trials. Most trials demonstrated an improvement in lung function in comparison to its individual components and these improvements were sustained over 52 weeks. This also translated into better compliance, reduced need for rescue medications, and improvement in the QOL of patients. Even though cardiovascular adverse effects like increased heart rate, BP, and ECG changes have been reported; its tolerability has been found to be similar to its individual components. Most of them were also of mild or moderate severity.
| Umeclidinium + Vilanterol|| |
Umeclidinium/vilanterol is another novel combination that caters to the needs of COPD patients preferring once-daily dosing of medications. This combination has demonstrated a wide range of benefits in COPD patients. The improvement in pulmonary function, dyspnea, need for rescue medications, exacerbations, QOL, and exercise endurance have been superior to each of its individual components, tiotropium monotherapy, and twice-daily combinations of ICS/LABA. It is also noteworthy that the adverse effects are minimal with headache and nasopharyngitis being the most commonly reported ones. On head-to-head comparisons with other LABA/LAMA combinations, like tiotropium/olodaterol, umeclidinium/vilanterol was found to be noninferior. It was also found to be superior in improvements of lung function, CAT score, and need for rescue medications.
| Aclidinium + Formoterol|| |
Aclidinium/formoterol is being marketed in the USA and UK as dry powder inhalers. It is a potent combination that has helped reduce the need for staring ICS in COPD patients. Studies like the ACLIFORM COPD and AUGMENT COPD have demonstrated a significant improvement in the lung function in patients across various subgroups when compared with monotherapy with each of its components. The AMPLIFY study has also demonstrated an improvement when compared with tiotropium in the exercise endurance time, daily step count, and levels of daily physical activity. This also translates into an improvement in the QOL of these patients. A significant reduction in the number of exacerbations and clinically important deteriorations was also noted. With regard to the tolerability of this combination, the ASCENT-COPD study has demonstrated that this combination was noninferior to placebo for the risk of major cardiovascular adverse effects making it a viable option in COPD patients with concomitant cardiovascular diseases.
| Muscarinic β2-agonists|| |
Bifunctional muscarinic β2-agonist agents are a novel approach to "dual" bronchodilator therapy that combines muscarinic antagonism and β2-agonism in a single molecule. It may offer several advantages over combination therapy with two separate drug entities. However, one limitation is that the ratio of muscarinic antagonism and β2-agonism activities cannot be adjusted as needed and this may limit dosing flexibility. Consequently, it still remains to be established if their use would offer any clinical benefits relative to the existing LAMA/LABA combinations. It has been postulated that their significance is more likely to stem from their use in combination with an ICS where only two drugs need to be co-formulated, rather than three.
| Inhaled Corticosteroids|| |
ICSs are only recommended as a last resort in COPD patients, particularly in those with severe disease, frequent exacerbations, high eosinophil count, and asthma-COPD overlap. The long-term use of ICS in COPD patients has been postulated to increase the risk of significant side effects such as pneumonia, osteoporosis, and mycobacterial disease. Hence, studies such as the SUNSET study have recommended de-escalating patients on triple-drug combinations to a potent LABA/LAMA combination. On the contrary, studies like the one conducted by Maltais et al. demonstrated no significant worsening of bone mineral density by the addition of an ICS to the regimen. Hartley et al. also allayed the apprehensions regarding ICS-induced pneumonia by stating that the history of exacerbations was a more significant indicator of the future risk of exacerbations. Thus, ICS-containing regimens might prove to beneficial in COPD patients by reducing frequent exacerbation-induced lung decline. The lung deflation study conducted by Stone et al. also reported that the reduction in hyperinflation through effective bronchodilation, mediated by ICS-containing regimens, has consistent beneficial and plausible effects in cardiac function. Hence, our hesitancy in staring ICS in COPD patients where it is warranted is often not justified.
| Triple-drug Combinations|| |
As per the current Global Initiative of Obstructive Lung Diseases guidelines, dual bronchodilators may be escalated to triple-drug combinations containing LABA, LAMA, and ICS if indicated. Three such combinations have recently been approved as FDCs for such patients. These include beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide, fluticasone furoate/umeclidinium/vilanterol, and budesonide/glycopyrronium bromide/formoterol fumarate. Such FDCs provide a convenient means to provide these medications significantly improving the outcome of COPD patients. The effects of these FDCs were evaluated in various trials including the TRILOGY, TRIBUTE, TRINITY, ETHOS, KRONOS, FULFIL, and IMPACT trials. These studies have consistently demonstrated an improvement in dyspnea indices and frequent exacerbations, thus improving patients' QOL. Studies like the WISDOM trial have also gone on the state that the risk of exacerbations increases on discontinuation of ICS in patients with severe COPD. Hence, a significant mortality benefit has been demonstrated in patients on triple-drug combinations. The risk of pneumonia has been shown to be minimal and dose dependent.
| Novel Classes of Bronchodilators|| |
Novel classes of bronchodilators have proved difficult to develop, but there is still a continued interest in generating new bronchodilators that act via emerging targets, particularly given the concerns over the long-term safety of β2-agonists. Potassium channel openers, vasoactive intestinal peptide analogs, rho kinase inhibitors, brain natriuretic peptide and analogs, nitric oxide donors, E-prostanoid receptor 4 agonists, and bitter taste receptor agonists are considered potential new classes of bronchodilators. Unfortunately, the development of many of them is delayed or blocked because of limited efficacy and/or safety problems. An alternative approach is to develop molecules designed to have two distinct primary pharmacological actions based on distinct pharmacophores, i.e., bifunctional drugs, which might be able to deliver complementary pharmacological activities for the treatment of patients with asthma or COPD. Currently, the first bifunctional bronchodilator/anti-inflammatory drugs (phosphodiesterase [PDE] 3/PDE4 inhibitors) are in clinical development.
| Future Directions|| |
COPD can result from several different mechanisms. The better understanding of the pathogenesis of COPD in recent years has enabled us to formulate new treatment strategies targeting those specific molecular pathways and stop inflammation. The strategies currently being evaluated include antioxidants, protease inhibitors, chemokine inhibitors, adhesion molecule inhibitors, epidermal growth factor receptor and transforming growth factor inhibitors, PDE-4 inhibitors like roflumilast, endothelin inhibitors like bosentan, vasoactive intestinal peptides, adenosine A2a receptor agonists, anti-inflammatory drugs like macrolides, PPAR agonists like thiazolidinediones and fenofibrate, NF-κB inhibitors, p38MAPK inhibitors, P13K inhibitors, and thioredoxin. In addition, the importance of disease phenotyping in COPD and its role in the personalized treatment strategy in disease management is increasingly being highlighted. These newer treatments targeting specific phenotypes are called biological drugs. Some people with COPD have a large number of eosinophils, the eosinophilic COPD phenotype. Anti-interleukin-5 (IL-5) molecules like mepolizumab and benralizumab, target airway inflammation caused by eosinophils. These drugs may limit or reduce the number and/or activity of blood eosinophils, providing relief from COPD and reducing eosinophilic airway inflammation. Currently, IL-5 drugs are approved for the treatment of severe asthma, but none are approved to treat COPD.
Stem cell therapy
Clinical trials are also evaluating the use of mesenchymal stem cell therapy for the treatment of COPD. Researchers believe that stem cells could be used to create new alveolar cells, responsible for the exchange of air and gasses in the lungs. Stem cells are undifferentiated cells that are fed into the body to become specialized to a specific need – in this case, regenerating lung tissue and reversing lung damage. The FDA has approved stem cell therapy for COPD in human clinical trials, but it is not currently available as a treatment. If approved in the future, this type of treatment could be used to regenerate lung tissue and reverse lung damage.
| Conclusion|| |
New combinations of bronchodilators can help reduce our overreliance on ICS. However, complete abstinence from using ICS might not always be justified, particularly in cases where there is an overlap of asthma, high eosinophil count, and severe disease. New and emerging therapies can prove to be beneficial in the coming years for the treatment of COPD. Even though many of these treatment options molecules are under research or currently unavailable in India, a thorough understanding of these agents would enable us to make better use of them in the future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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