Exploring the possibility of a predictable precision therapy of COPD with inclusion of glycopyrronium responsiveness: A real-world experience

Abstract

Background:

The advent of glycopyrronium responsiveness has opened the prospect of selective responsiveness-based prescription of bronchodilators-β2-agonists or anti-muscarinic agents (AMA) for COPD. Such a concept needs ratification through clinical trials.

Methods:

Stable COPD patients [post-bronchodilator FEV₁/FVC <0.7] underwent serial glycopyrronium responsiveness [≥100 ml FEV₁-improvement] after salbutamol before universal prescription of LABA-LAMA ± ICS as per guideline recommendation. At real-world follow-up, we noted the adverse and serious adverse events (exacerbations and hospitalizations) and, whenever possible, repeated spirometry in the similar fashion. Based on the initial glycopyrronium responsiveness, we divided the patients into glycopyrronium-sensitive and non-sensitive groups and compared the impact of treatment between them using spirometric variables (FEV₁, FVC, FEV₁/FVC and FEF_25-75). We compared the ‘trough’-FEV₁ and ‘total’-FEV₁ (difference from the initial pre-bronchodilator to final post-dual-bronchodilator values) along with the frequency of exacerbation and hospitalization in each group.

Results:

The glycopyrronium-responsive and non-responsive groups (n = 30 for each) were similar demographically and on initial spirometry (pre-bronchodilator and post-salbutamol values). They received treatment for 162.4 ± 134.8 and 212 ± 118.1 days, respectively. The glycopyrronium-sensitive patients displayed significant improvement in both trough-FEV₁ [0.17 ± 0.29 vs. 0.02 ± 0.2; (P = 0.0308)], total-FEV₁ [0.32 ± 0.29 vs. 0.17 ± 0.21; (P = 0.0273) litres], in addition to trough FEF_25-75 (P = 0.0204), total FEV₁/FVC (0.0174) and total FEF_25-75 (P = 0.0322). The exacerbations (P = 0.0056) were significantly lower in glycopyrronium-responsive patients.

Conclusion:

The glycopyrronium-responsive COPD patients show a significantly better overall improvement including the significant change in trough and total FEV₁ with significantly reduced exacerbations in the real-world observation. The revelation demands more research.

INTRODUCTION

COPD is a condition of chronic and progressive airflow limitation with airway and systemic inflammation.[1] It imparts deleterious impact on the functional capacity, quality of life and survival prospect of the sufferers with or without considering comorbidities.[2,3,4,5,6] Inhaled bronchodilators [combination of long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs)] with or without inhaled corticosteroid (ICS) form the cornerstone of COPD treatment[7,8] while no strong recommendation to treat the pathophysiology of the condition exists.[9] The guideline recommends treatment of airway inflammation with ICS when the absolute eosinophil count (AEC) turns >300/ml in peripheral blood suggesting Th2 inflammation.[10] The LABA-LAMA combination that enhances bronchodilation, ensures better symptom management, reduces exacerbations and improves exercise tolerability.[11,12,13]

The responsiveness to a drug means the likely effectiveness of the agent for an indication under consideration. Hence, the information of responsiveness remains essential for initiating any ‘precision’ therapy. For an airway disease (asthma, COPD or overlap), such precision therapy, though cherished, could not be accomplished because of the lack of pre-emptive assessment of both the class-specific [β2-agonist and anti-muscarinic agents (AMA)] bronchodilator responsiveness (BDR) in office practice. The quick onset of action of salbutamol makes it possible to test the responsiveness to β2-agonists,[14] and the test is integrated into routine practice of spirometry globally.[15] However, such a simple and feasible responsiveness assessment of an AMA has not been possible until the recent publication of the feasibility and acceptability of inhaled glycopyrronium responsiveness test.[16,17] Glycopyrronium allows a good bronchodilation by 30 minutes as a relatively quick onset and long-acting inhaled bronchodilator.[18] These pharmacokinetic characteristics enable one to measure independently the class-specific responsiveness to inhaled AMA. Thus, the glycopyrronium responsiveness assessment has opened the prospect of precision bronchodilator therapy in an obstructive airway disease.[19]

High AEC, serum IgE and fractional exhaled nitric oxide (FENO) as markers of Th2 inflammation indicate responsiveness of a patient of airflow obstruction to ICS.[20,21,22,23] The GOLD guideline has already adopted the concept of pharma-co-responsiveness guided treatment through the recommendation of add-on ICS to LAMA-LABA with AEC >300 in peripheral blood.[7] The prospect of precision bronchodilator therapy in an OAD is now open with the availability of knowledge regarding the independent responsiveness to both AMA and β2-agonists. The impact of such treatment in the light of such responsiveness demands longitudinal trial. The present manuscript represents an effort to generate a real-world evidence favouring pharma-co-responsiveness-based precision therapy in COPD.

MATERIALS AND METHODS

The key elements of the study design include a comparison of an open, longitudinal, guideline-based treatment of COPD patients on spirometric lung function change with or without responsiveness of the subjects to glycopyrronium tested before starting the therapy. The institutional ethics committee approved the retrieving data from prospectively prepared practice archival in real world where the interventions, the follow-ups and the repeat spirometric assessments were done uniformly in all the patients. The study protocol allowed accomplishing a comparison on reaching the inclusion of a statistically acceptable number for each group on treatment.

The sample size was calculated using finite population formula. Previous study revealed that 40% of COPD are responsive to glycopyrronium.[24] Accordingly, global burden of disease reports 2019 COPD population in India is 49.2 million.[25,26] Therefore, the sample size should be at least 369. However, we decided to include any number, be it more than that, which will be enough to include a minimum of 30 subjects in each group.

The institutional ethics committee had earlier approved the integration of the BDR to glycopyrronium in our spirometry practice at the institute. The test (glycopyrronium-BDR) is done immediately serial to test salbutamol responsiveness in all patients with suspected or confirmed airflow limitation as a part of their spirometric exercise. COPD was diagnosed on finding the post-bronchodilator FEV₁/FVC as 0.7 with evidence of no other significant lung disease present concomitantly.

The act of serving the purpose of a meaningful observation in real world included multiple stakeholders. The physician concerned prescribed with LABA-LAMA (formoterol-glycopyrronium) ±ICS through metered dose inhaler (MDI) (using spacer device) uniformly in all the patients observing the recommendation of the GOLD guideline.[27] We requested the patients to follow up at least once in every three months and repeat spirometry at least once within six months of the beginning of the treatment. In the real-world scenario, repeating the spirometry was left to the desire and convenience of the patients. The physician used to make a routine enquiry on the events happening in between each patient especially and categorically regarding the adverse events such as exacerbations and hospitalizations at every interaction. We maintained records of such events conveyed on telephone calls requesting emergency consultation/support as a part of our practice protocol. We preserved all the prescriptions and follow-up records were preserved. The first follow-up point with repeat spirometry formed the endpoint of the duration of observation [Figure X].

Figure X.

The Flowchart-X elaborates the algorithm of diagnosis and treatment of obstructive airway diseases offered at the institute that enabled the authors to extract data for statistical analysis

Our practice and archival protocol allowed us to identify the patients with repeat spirometry from the spirometry registry. We entrusted an assistant cum research fellow to collect the registration numbers of such patients (performing repeat spirometry at follow-up visits) at regular intervals starting after 3 months of the initiation of the observation. He subsequently retrieved all the prescriptions and follow-up records of these patients from our archive. We applied the inclusion-exclusion criteria here to select the patients eligible for inclusion. In the next step, we looked for the initial glycopyrronium/LAMA responsiveness (FEV₁ change of 100 ml) in the selected lot to divide them into two groups with or without glycopyrronium responsiveness [see Figure Y]. This 100 ml of change in FEV₁ was taken to define responsiveness because this volume is regarded to be the minimal clinically significant difference (perceptible difference) of FEV₁ for a patient of COPD.[28] Our routine practice protocol for diagnosis and care for COPD and archiving the record on a uniform mode at the institute helped us to serve the purpose of the observation. The strategy adopted by us for the observation is presented in [see Figure Z].

Figure Y.

Flowchart-Y delineates the consort showing the final inclusion of the patients after going through the screening procedure

Figure Z.

Flowchart-Z elaborates the strategy to actually select the patients with repeat spirometry and finally calculating the impact of treatment statistically based on presence or absence of the initial glycopyrronium responsiveness

At this point of inclusion (discussed above), we excluded patients based on pre-defined criteria that included general considerations (as non-availability of consent, age ranging below 40 or above 75 years) and issues related to performing spirometry (inability to perform or unacceptable spirometry). Other reasons for exclusion were patient-related issues as history of exacerbation or hospitalization from any cause at or within the preceding 8 weeks of the initial visit, co-presence of any lung disease or systemic disease of significant dimension concomitant to COPD, and if a subject has been pregnant or lactating. We upfront excluded the patients on LAMA or oral corticosteroid at the time of inclusion, or having any contraindication to the use of glycopyrronium. Finally, subjects having history of exacerbation within the preceding 6 weeks of the date of performing the second (first repeat spirometry) spirometry were not included. To maintain uniformity, we excluded patients who joined formal rehabilitation programme or taking any other medicines (viz., homoeopathy).

We included the parameters as FVC, FEV₁, FEV₁/FVC and FEF_25-75 of initial and the follow-up spirometry for analysis. We noted the change in the trough values of FEV₁ and other parameters and a proposed a ‘total’ value for them meaning the change from the initial pre-bronchodilator value to the post-dual-bronchodilator (salbutamol-and-glycopyrronium) value at follow-up.

On reaching the target number of inclusion, we stopped the further collection of data and initiated the statistical exercise. The categorical variables were represented in frequency and the continuous variables were used for comparison of both inter and intragroup changes using the Mann–Whitney’s test for non-parametric variables accepting the P < 0.05 as significant. GraphPad Prism version 8 and Microsoft Excel were used to draw bar charts and trend lines, respectively.

RESULTS

We collected the records of 30 patients in each group for the statistical analysis and compared their demographic and spirometric variables [Table 1 with consort chart]. The duration of treatment and the changes on follow-up in each group for all spirometric variables at baseline, after salbutamol, and glycopyrronium inhalations are elaborated for both the glycopyrronium non-responsive and responsive patients in Table 2. The trough and the total improvement [measuring the dual-bronchodilator effect (salbutamol with add-on glycopyrronium) in follow-up compared to the initial pre-bronchodilator status] of the spirometric variables in both the groups of patients are detailed in Table 3. The treatment was tolerated well in both the groups; we recorded multiple exacerbations [noted in Table 3] and one hospitalization (serious adverse event) in glycopyrronium non-sensitive group [Table 3]. The improvement in ‘trough’ and ‘total’ FEV₁ is separately depicted in Figure 1. The trend lines depict the relatively better result in glycopyrronium-responsive group [Figure 2]. There is improvement in ‘trough’ FEV₁ and was found higher (1.24 ± 0.56 to 1.41 ± 0.57 vs 1.12 ± 0.61 to 1.15 ± 0.56) in the initial glycopyrronium-responsive group [Table 2, Figures 1 and 2].

Table 1.

Displays the initial spirometric measurements at the baseline along with responsiveness following salbutamol and glycopyrronium serially in patients with or without glycopyrronium responsiveness (add-on change after glycopyrronium inhalation)

		Glycopyrronium non-responsive (n=30)		Glycopyrronium responsive (n=30)		P
Demography
Age		64.77±8.5		57.93±14.33		0.0604
BMI		23.97±4.05		25.06±4.6		0.3352
Male: Female		5		4
FEV1
Pre-bronchodilator		1.12±0.61		1.24±0.56		0.3189
Post-salbutamol		1.22±0.66		1.37±0.61		0.1960
Post-glycopyrronium		1.25±0.65		1.53±0.61		0.0328
FVC
Pre-bronchodilator		2.16±0.85		2.34±0.83		0.2462
Post-salbutamol		2.29±0.84		2.49±0.84		0.2257
Post-glycopyrronium		2.34±0.86		2.68±0.82		0.0528
FEV1/FVC
Pre-bronchodilator		0.5±0.12		0.53±0.11		0.2826
Post-salbutamol		0.51±0.13		0.54±0.11		0.3144
Post-glycopyrronium		0.52±0.13		0.56±0.12		0.1883
Reversibility
Salbutamol induced		95±91.34		137.3±140.8		0.3473
From add-on Glycopyrronium		26±62.34		152.7±44.33		<0.0001
FEF25-75
Pre-bronchodilator		0.47±0.36		0.6±0.39		0.1237
Post-salbutamol		0.53±0.44		0.63±0.45		0.2037
Post-glycopyrronium		0.55±0.46		0.76±0.53		0.0276

Table 2.

Intragroup comparison of spirometric lung function parameters tests in stable COPD patients without or with glycopyrronium sensitivity

Glycopyrronium non-responsive, LAMA given (n=30)								Change: (follow-up–initial)		Glycopyrronium responsive, LAMA given (n=30)						Change: (follow-up–initial)		P (between change)
		Baseline		Follow-up		P		212±118.1 days		Baseline		Follow-up		P		165.3±131.9 days		0.1542
FVC
Pre-bronchodilator		2.16±0.85		2.23±0.77		0.2660		0.07±0.31		2.34±0.83		2.47±0.75		0.0584		0.18±0.36		0.2344
Post-salbutamol		2.29±0.84		2.38±0.78		0.0868		0.08±0.23		2.49±0.84		2.59±0.75		0.0831		0.12±0.26		0.4846
Post-glycopyrronium		2.34±0.86		2.46±0.82		0.0140		0.11±0.23		2.68±0.82		2.68±0.78		0.9516		0.04±0.25		0.2197
FEV1
Pre-bronchodilator		1.12±0.61		1.15±0.56		0.6894		0.02±0.2		1.24±0.56		1.41±0.57		0.0045		0.17±0.29		0.0308
Post-salbutamol		1.22±0.66		1.25±0.63		0.6012		0.03±0.18		1.37±0.61		1.5±0.6		0.0040		0.12±0.25		0.0217
Post-glycopyrronium		1.25±0.65		1.3±0.61		0.1993		0.05±0.22		1.53±0.61		1.56±0.61		0.3109		0.03±0.25		0.8005
FEV1 Reversibility
Salbutamol induced		95±91.34		105±119.3		0.6811		8.66±96.62		137.3±140.8		96±124.5		0.2580		–41.33±144		0.2806
From add-on Glycopyrronium		26±62.34		46.33±78.98		0.2407		20.33±92.98		152.7±44.33		61.6±100.8		<0.0001		–91±100.2		<0.0001
FEV1/FVC
Pre-bronchodilator		0.5±0.12		0.5±0.1		0.8056		–0.003±0.06		0.53±0.11		0.56±0.12		0.0429		0.03±0.07		0.0829
Post-salbutamol		0.51±0.13		0.51±0.12		0.9544		0.0008±0.05		0.54±0.11		0.58±0.11		0.0016		0.03±0.05		0.0446
Post-glycopyrronium		0.52±0.13		0.51±0.12		0.6776		–0.004±0.06		0.56±0.12		0.58±0.11		0.0704		0.02±0.05		0.1161
FEF25-75
Pre-bronchodilator		0.47±0.36		0.46±0.34		0.707		–0.009±0.16		0.6±0.39		0.7±0.44		0.0389		0.09±0.35		0.0204
Post-salbutamol		0.53±0.44		0.56±0.55		0.4654		0.03±0.29		0.63±0.45		0.76±0.53		0.0057		0.13±0.31		0.0021
Post-glycopyrronium		0.55±0.46		0.56±0.46		>0.999		0.01±0.26		0.76±0.53		0.81±0.54		0.1333		0.05±0.35		0.0971

Table 3.

Elaborates the change in lung function from initial to follow-up (post-treatment) in terms of trough (pre-BD) and total differences (post-dual BD at follow-up–pre-BD at baseline) spirometric variables. The table also includes adverse events (AEs) and serious adverse events (SAEs) during the follow-up in each group; all the SAEs were hospitalization unrelated to interventions and all the AEs are exacerbations

Change in		Glycopyrronium non-responsive		Glycopyrronium responsive		P		Change in		Glycopyrronium non-responsive		Glycopyrronium responsive		P
Trough FVC		0.07±0.31		0.18±0.36		0.2344		Total FVC		0.03±0.33		0.38±0.31		0.3170
Trough FEV1		0.02±0.2		0.17±0.29		0.0308		Total FEV1		0.17±0.21		0.32±0.29		0.0273
Post-salbutamol FEV1		0.03±0.18		0.12±0.25		0.0217		Total FEV1 with Salbutamol		0.13±0.19		0.26±0.3		0.0271
Trough FEV1/FVC		–0.003±0.6		0.03±0.07		0.0846		Total FEV1/FVC		0.01±0.05		0.04±0.07		0.0174
Trough FEF25-75		–0.009±0.16		0.09±0.35		0.0204		Total FEF25-75		0.09±0.2		0.21±0.41		0.0322
AE		10		1		0.0056		SAE		3		0		0.2373

Figure 1.

(a) elaborated the change in trough FEV₁ from initial to the follow-up in both glycopyrronium non-sensitive and sensitive groups; the dark bar represents the initial pre-bronchodilator FEV₁ while the hazy bar represents the same at follow up. (b) Comparison of Salbutamol and Dual Bronchodilator response between two groups (in glycopyrronium non-sensitive and sensitive patients)

Figure 2.

Elaborates the comparison of trends in Trough FEV₁ (a) and Total FEV₁ (b) changes in glycopyrronium non-responsive and responsive patients

DISCUSSION

The results appear interesting. At the initial visit, the two groups of patients (glycopyrronium non-sensitive or responsive/sensitive) were similar demographically and on spirometric lung function measurements (both the pre- and post-salbutamol values). The significantly higher post-glycopyrronium values of FEV₁, FEF_25-75 and FEV₁ reversibility [Table 1] in the glycopyrronium-sensitive group are evident from the add-on effect of the drug (glycopyrronium).

Post-treatment, there is improvement in spirometric lung function parameters in both the groups. However, it appears more impressive and statistically significant in the glycopyrronium-sensitive group both as regards the baseline (pre-bronchodilator) and the post-salbutamol values of FEV₁ (P = 0.0045 and 0.0040), FEV₁/FVC (P = 0.0429 and 0.0016) and FEF_25-75 (P = 0.0389 and 0.0057), respectively [see Table 2].

The trough-FEV₁ is significantly improved in glycopyrronium-responsive group (P = 0.0045) alone compared to the non-responsive group (P = 0.6894) [Figures 1a and 2a]. There is no difference between the glycopyrronium non-responsive and responsive patients in standard BDR (salbutamol responsiveness) [Figures 1b and 2b]. However, the glycopyrronium-sensitive group shows a significant improvement (P = 0.0022) in response to dual bronchodilator on follow-up [Figure 1b (ii)]. The observed adverse events are significantly less in glycopyrronium-responsive patients [Table 3]. The improvement in the ‘trough’ and the ‘total’ values of the other spirometric parameters [trough FEV₁ and FEF_25-75] show a uniform trend of betterment in significant terms in the glycopyrronium-responsive cohort, especially in terms of the ‘total’ change [Table 3].

The results, thus, reveal the prediction of a better response with dual bronchodilators based on the results of the initial glycopyrronium responsiveness in COPD. The significant ‘total’ improvement in FEV₁/FVC (P = 0.0174) and FEF_25-75 (P = 0.0322) with dual bronchodilators in the glycopyrronium-sensitive patients [Table 3] is predictive of reduction in obstruction and improvement in airflow limitations at the small airways. They suggest a more impressive improvement in glycopyrronium-responsive patients with use of dual bronchodilators. We can expect a better functional state and quality of life or even a better survival in the better responders and, therefore, customize our attention to the demand of each group separately.

The manuscript stands as a classic example of real-world research that, incidentally and spontaneously, meets the expectations of a randomized trial without any ethical conflict. The glycopyrronium responsiveness was performed in all our patients at the initial and follow-up visits. There is no question of bias at recruitment since the criteria of diagnosis were same for all and all the patients received a common treatment as per the GOLD guideline recommendation.[27] Although requested to observe a flexible schedule, the patients enjoyed the freedom to follow-up and perform a repeat spirometry. The physician just framed an inclusion-exclusion protocol and engaged an assistant to collect the records of patients with double spirometry (initial and at follow-up) until a statistically relevant number in each group was qualified for inclusion prospectively. Thus, our observation stands as a real-world surrogate of a randomized trial. In the real-world logistics of ours, a fixed protocol-based universal follow-up with performance of repeat spirometry was neither possible nor feasible. Hence, strategically, the targeted treatment duration until the first repeat spirometry appeared the most convenient to achieve.

We selected ≥100 ml change in FEV₁ to define glycopyrronium responsiveness; this is regarded as the minimum required value for a patient to perceive a change/improvement.[28,29] The glycopyrronium non-responsive patients demonstrated some glycopyrronium responsiveness (61.60 ± 100.80 ml) at follow-up [see Table 2]. This observation demands research since it either questions the compliance or indicates a possible variability of glycopyrronium responsiveness from time to time.

As per our observation, the betterment of lung function matches the observed initial BDR and appears to result in lower chance of exacerbation. It, thus, paves the foundation of a novel pharmacoresponsiveness-based predictive, precision therapy. Counting the individual and combined responsiveness to β2-agonist and AMA classes of bronchodilators can help framing prescription even in glycopyrronium non-responsiveness patients with a predictable prospect of improvement. We have already forwarded that a pre-treatment performance of responsiveness (to both bronchodilators and ICS) will be prudent for precision treatment of OAD.[19] Of late, we have found that roughly 40% of the patients of both COPD and asthma are glycopyrronium responsive with on-the-spot-spirometry in office practice.[24] The identification of these 40% of patients appears important as a sensible and ethical act. Since they have high parasympathetic receptor activation in airways, it’s inhibition can help in bronchodilation.[30] In addition, the application of anticholinergics (LAMA) has additional anti-inflammatory, anti-remodelling, mucus modifying and anti-cough properties to benefit the COPD patients.[31] Apart from initiating a precision therapy, a predicable reduction in exacerbation may be possible translating our work with further research. Exacerbations have negative influence on disease progression, lung function and survival.[32,33]

In addition to our already published LAMA responsiveness, we have included a novel ‘total change’ with the existing concept of ‘trough change’.[34] While the trough FEV₁ represents the difference in the baseline (pre-bronchodilator) value of FEV₁ from pre- to post-treatment states, the proposed ‘total FEV₁ change’ accommodates the change from initial (baseline) pre-bronchodilator to the final post-bronchodilator values of any measurement. It helps to set a target of treatment where, in an ideal situation, the gap between the trough and the total change is likely to lessen on improvement with treatment longitudinally. Airway obstruction is dynamic, and the responsiveness to bronchodilators in a single person may vary from time to time.[35] We need more research to establish the role of these parameters (the ‘total change’ and the ‘total to trough difference of changes’) to appreciate the compliance and the efficacy of treatment of airway diseases. A simultaneous measurement of the airway inflammation in all the visits can help to evolve more insight into the issue. We are leaving them for future to research and comprehend.

Since every COPD patient received the same treatment, the only job of the physician concerned was to make the prescription and note the adverse events at the initial and the follow-up visits. There was no chance of bias on his part. The selection starts from looking at the spirometry registry followed by inclusion and taking an account of the exacerbations and hospitalizations in each included patient and, thereafter, identification of the glycopyrronium responsiveness at initial spirometry [see Table 3]. This kept the assistant remain blind regarding the group-specific results. All the patients were educated uniformly regarding regularly taking the prescribed medications and the inhalation technique on a common protocol. The physiotherapist at the rehabilitation department had no knowledge that the record of the patients may be later included in real-world research. We excluded patients who joined the formal rehabilitation program to avoid any additional influence of the non-pharmacological treatment. Thus, the real-world process excluded the possibility of bias maximally. The compiling of data and the statistical analysis was initiated once both the groups (with or without glycopyrronium responsiveness) reached the pre-decided number in order to avoids any bias. When we reached the actual targeted total number (30 for each group), there was, incidentally, no scope of an extra inclusion to any of the groups.

There are several weaknesses in the study. Firstly, the number of the recruited subjects is small. Secondly, the glycopyrronium responsiveness is itself a new proposition; the act based on a single point glycopyrronium responsiveness testing also demands ratification on a bigger trial. Thirdly, the results are shown only in terms of lung functional change and number of adverse and serious adverse events. The impact of such novel mode of intervention needs to be shown in terms of other parameters such as health status, quality of life, functional ability and time to first exacerbation. Finally, we have not looked for the impact of the strategy in the different etiological subcategories of COPD (smoking, biomass smoke, pollution, etc.); the revelation in this front may be interesting and it demands planned research in future. In fact, four of our patients in the glycopyrronium-sensitive group and one in the non-sensitive group had asthma-defining FEV₁-reversibility (200 ml + 12%) but their FEV₁/FVC ratio <0.7 allowed us to exercise the guideline practice of LABA-LAMA considering them as symptomatic patients of stable COPD.[36,37] This may have influenced the result a bit in favour of the glycopyrronium-sensitive patients, but we have watched that the improvement seems more in the same group even after excluding those patients (see Supplementary File). This small possible caveat gives a clue that the patients with asthma defining reversibility to salbutamol also should be considered for dual bronchodilator therapy even if they belong to early stages according to the GINA guideline that preserves LAMA only for the uncontrolled and moderate to severe asthma[38] and recommends LAMA before initiating biologics.[39] This appears too late according to our observation. This too opens another frontier of clinical research.[40]

Supplementary File.

The intragroup comparison of spirometric lung function parameters tests in stable COPD patients without or with glycopyrronium sensitivity

Glycopyrronium non-responsive, LAMA given (n=29)								Change (Follow-up – (Baseline)		Glycopyrronium responsive, LAMA given (n=26)						Change (Follow-up – (Baseline)		P (Between Change)
		Baseline		Follow Up		P		212±118.1 days		Baseline		Follow Up		P		165.3±131.9 days		0.1542
FVC
Pre Bronchodilator		2.05±0.62		2.14±0.58		0.1102		0.093±0.30		2.23±0.71		2.35±0.63		0.1030		0.12±0.36		0.7628
Post Salbutamol		2.19±0.61		2.27±0.56		0.0549		0.08±0.23		2.34±0.73		2.45±0.63		0.0692		0.11±0.30		0.7132
Post Glycopyrronium		2.23±0.6		2.35±0.59		0.0071		0.12±0.23		2.53±0.74		2.55±0.68		0.8079		0.01±0.27		0.1022
FEV1
Pre Bronchodilator		1.05±0.47		1.09±0.45		0.4895		0.03±0.2		1.16±0.49		1.29±0.45		0.0372		0.12±0.29		0.2132
Post Salbutamol		1.14±0.49		1.17±0.47		0.4910		0.03±0.19		1.26±0.49		1.37±0.45		0.0390		0.11±0.26		0.2223
Post Glycopyrronium		1.16±0.48		1.23±0.48		0.1075		0.06±0.21		1.41±0.5		1.44±0.47		0.6393		0.02±0.24		0.4873
FEV1 Reversibility
Salbutamol induced		87.33±80.9		89.31±84.17		0.9025		1.37±87.94		92.69±82.29		78.85±120.4		0.5706		-13.85±122.8		0.9101
From add-on glycopyrronium		24.14±62.59		53.79±68.79		0.0263		31.03±131.9		157.2±45.02		68.08±84.52		<0.0001		-104.6±141.9		0.0002
FEV1/FVC
Pre Bronchodilator		0.5±0.12		0.49±0.1		0.8453		-0.002±0.06		0.53±0.12		0.55±0.12		0.2402		0.017±0.07		0.3006
Post Salbutamol		0.5±0.13		0.51±0.12		0.9052		0.001±0.05		0.53±0.11		0.56±0.12		0.0130		0.029±0.055		0.0156
Post Glycopyrronium		0.51±0.13		0.51±0.12		0.6736		-0.005±0.06		0.56±0.12		0.57±0.12		0.2248		0.014±0.05		0.2505
FEF25-75
Pre Bronchodilator		0.42±0.26		0.42±0.27		0.9106		-0.002±0.16		0.56±0.36		0.61±0.34		0.5004		0.04±0.34		0.1351
Post Salbutamol		0.47±0.29		0.5±0.45		0.5602		0.03±0.30		0.56±0.34		0.67±0.42		0.0267		0.11±0.33		0.0155
Post Glycopyrronium		0.49±0.33		0.51±0.36		0.8759		0.02±0.26		0.69±0.43		0.71±0.43		0.2942		0.02±0.36		0.2218

CONCLUSION

Pharma-co-responsiveness-based precision therapy of COPD seems better than blanket guideline treatment. The interpretations and implications of this small observation stand enormous as it implies to be the first pharma-co-responsiveness-based precision therapy in COPD.

Author contributions

PB: Concepts, design, definition of intellectual content, literature search, clinical studies, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review, guarantor. SG: Literature search, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing. SS: Data acquisition. DD: Manuscript editing, manuscript review. SSG: Data acquisition. SB: Data acquisition. AK: Manuscript review. DS: Data acquisition.

Conflicts of interest

There are no conflicts of interest.

Abbreviations

• COPD: chronic obstructive pulmonary disease

• FEV₁: forced expiratory volume in (first) 1 second

• FEF_25-75: forced expiratory flow in 25–75% of forced vital capacity

• BDR: bronchodilator reversibility

• BD: bronchodilator

• LAMA: long-acting anti-muscarinic agent

• LABA: long-acting β2-agonist

• ICS: inhaled corticosteroid.

Funding Statement

Nil.