Clinical Perspectives of Updated Management Strategies for COPD

AJMC®: The 2025 update of the GOLD Report (Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Prevention, Diagnosis and Management of COPD) (GOLD 2025) recommends the medications dupilumab and ensifentrine as treatment options for patients with chronic obstructive pulmonary disease (COPD). Can you describe the clinical need that led to these medications and the ways that they may be differentially applied in clinical practice?

Dr Panettieri: A recent focus in managing COPD has been an emphasis on reducing exacerbation frequency. This came about after data emerged showing that just a single hospitalization in a patient with COPD reduced their 5-year life expectancy to only 50%.

Out of this focus emerged the medications ensifentrine and dupilumab, both of which are highlighted in the GOLD 2025 as treatment options for patients who remain symptomatic despite triple therapy. These drugs’ differing mechanisms of action mean their clinical application is in differing patient populations, although there may be some overlap.

Dupilumab, which has already been used in other conditions (eg, atopic dermatitis, nasal polyps, and asthma), received FDA approval for COPD in September 2024. Its role is in patients with type-2 inflammation, identified by elevated blood eosinophil levels. For patients who continue to have exacerbations despite triple therapy, dupilumab is an appropriate choice when eosinophil counts are above 300 cells/µL.

Ensifentrine, by contrast, is the first inhaled, nebulized PDE3/4 inhibitor. Unlike dupilumab, it provides both bronchodilation (through PDE3 inhibition in airway smooth muscle) and anti-inflammatory effects (through PDE4 inhibition in neutrophils). In the past, clinicians used the oral PDE4 inhibitor roflumilast to manage chronic bronchitis in COPD; ensifentrine is distinct, because it is nebulized, and it targets both PDE3 and PDE4.

Because of these differing mechanisms, a question emerges whether dupilumab and ensifentrine can be used together. This has not yet been formally examined in peer-reviewed literature. Real-world data will be informative as these medications gain traction to determine whether they may have synergistic effects when used together. For now, my choice of one or the other depends on patients’ inflammation and BEC (blood eosinophil count).

AJMC®: Of the new medications highlighted in GOLD 2025, which are most likely to gain real-world traction, and what hurdles could affect their adoption?

Dr Panettieri: I think both dupilumab and ensifentrine will gain traction. Dupilumab has already been used safely in thousands of patients across other diseases, so I have little concern about off-target effects. For ensifentrine, the experience base is smaller, but the nebulized formulation appears to avoid the gastrointestinal adverse events, such as diarrhea and weight loss, we often see with the oral PDE4 inhibitor roflumilast. That makes ensifentrine much more attractive in practice.

The biggest hurdle for both therapies will be managed care approval. I expect both will require prior authorizations from payers, and payer reimbursement mechanisms will be critical determinants of access.

For ensifentrine specifically, its method of administration through a nebulizer adds another practical consideration, because patients will need to learn how to properly use the device. There had been similar conjecture regarding dupilumab, since it is self-injected, but these concerns have diminished in the last decade and a half or so. The introduction of GLP-1 agonists seems to have changed attitudes from patients and providers alike regarding injections. In fact, I now encounter many patients who prefer a monthly injection rather than a daily pill or inhaler.

AJMC®: In terms of initiating treatment, GOLD 2025 categorizes patients by exacerbation frequency and symptom burden using an ABE schema. Formerly, the categorization was ABCD. How has this change affected clinical decision-making?

Dr Panettieri: The shift to the ABE framework has streamlined decision-making.ABCD groupings were good conceptually; in practice, they required frequent respiratory function tests that were difficult to broadly implement, particularly in primary care settings, where most patients with COPD receive most of their care. The ABE schema removed respiratory function tests as a central factor to characterize disease severity, instead emphasizing exacerbation history. This is much easier to assess during an office visit, because care providers can simply ask patients how often they have had flare-ups in the last year.

Another benefit of the shift is that it elevates symptoms to a central role, strengthening shared decision-making efforts. Patients are sensitive to their own symptoms, and ABE creates a patient-centered approach that prioritizes symptom relief, functional status, and overall quality of life. Those are exactly the reasons patients seek care in the first place.

AJMC®: Have you encountered any new complexities when initiating treatment under the ABE schema?

Dr Panettieri: I have not encountered any. In fact, the streamlined nature of ABE has reduced complexity. We’re no longer distracted by treating numbers; instead, the focus is squarely on patient-centered outcomes—quality of life, functional status, and symptom relief.

I still perform spirometry at each visit, and patients often ask whether their results are better or worse. But by the time I see the test, I usually already know the answer based on their symptoms: whether shortness of breath has improved, whether daily activities are easier, and whether exacerbations are under control. Sometimes, spirometry may decline while symptoms and exacerbations improve, in which case I view spirometry as less sensitive or even superfluous for guiding treatment decisions. The shift to ABE reflects that reality, making management more practical and aligned with patient needs.

AJMC®: Where does the use of new medications such as dupilumab, ensifentrine, or mepolizumab fall within the GOLD 2025 ABE schema?

Dr Panettieri: All of these new medications are reserved forpatients with refractory COPD—those who continue to have exacerbations or experience uncontrolled symptoms despite optimized triple therapy. They’re not intended for patients with nonexacerbating COPD. Instead, they will most often be used in patients with more advanced disease.

AJMC®: What role do you think spirometry or other objective measures should still play in guiding treatment selection?

Dr Panettieri: Spirometry remains essential for diagnosis. At initial presentation, it confirms whether a patient has obstructive lung disease, which helps distinguish COPD from conditions such as asthma or interstitial lung disease. I also rely on spirometry when a previously stable patient develops new or worsening symptoms. If spirometry is unchanged or improved, that often points to another cause, such as cardiac disease, which is common in older patients with smoking histories.

Beyond spirometry, patient-reported outcomes are also very valuable. Tools like the COPD Assessment Test (CAT) provide validated, reliable measures of symptoms and exacerbation history. Tracking these longitudinally in the electronic health record allows me to follow patients’ quality of life and functional status over time.

AJMC®: Can you describe challenges you face when treating COPD patients with complex comorbidities?

Dr Panettieri: COPD patients often have multiple comorbidities, including cardiac disease, endocrine disorders, and metabolic syndrome. Caring for these patients requires attention not just to the lungs but to the broader context of their health. Secondary pulmonary hypertension is common in COPD, but it’s often less severe than primary pulmonary hypertension or pulmonary hypertension from other causes, such as pulmonary emboli.

Close coordination with other specialists is essential. These clinicians need to know whether a patient’s COPD is stable or unstable, as it can impact cardiac outcomes and overall management. Additionally, patients with cardiac comorbidities may not be referred for pulmonary function tests (PFTs) early, since care often focuses on the heart. Early PFTs are critical to confirm or rule out COPD and involve a pulmonologist, when appropriate. Team-based management is key to optimizing outcomes in these complex patients.

AJMC®: Do you know of any complex care scenarios wherein the COPD guidelines conflict with those of comorbid conditions?

Dr Panettieri: If there are conflicts between these guidelines, they are not intended. I think what often happens is a medication that treats 1 comorbidity may worsen the symptoms of another. An example that comes immediately to mind is β-blockers prescribed for cardiac comorbidities. Theoretically, they could worsen airflow obstruction by blocking β₂ receptors. In practice, selective β-blockers or alternatives such as ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) often mitigate this concern.

In my experience, it is more common that treating comorbidities will improve patients’ COPD outcomes. For example, controlling hypoxemia, weight, or sleep apnea in patients with chronic bronchitis can make COPD management easier. Given that nearly 50% of patients may not survive 5 years after their first COPD exacerbation, coordinated, team-based care is critical. The internist or primary care provider can act as the quarterback to ensure all comorbidities are addressed alongside COPD.

AJMC®: In practice, how do you differentiate between patients with eosinophilic COPD who are more appropriate for biologic therapy vs those with comorbid asthma and COPD who may benefit from inhaled corticosteroid (ICS)-based regimens?

Dr Panettieri: The terms asthma and COPD are imperfect; both describe spectrums of clinical syndromes rather than rigidly defined disease states. Complicating matters, asthma can overlap with smoking-related disease, and smoking itself is a major risk factor for COPD. Therefore, asthma is a risk factor for COPD in the context of smoked tobacco.

In the US, we almost exclusively recognize COPD as a consequence of smoking. To inform our treatment approach, we ascertain patients’ BECs and determine whether they have an eosinophilic phenotype characterized by type-2 inflammation. This occurs in about 40% of patients with COPD, whereas about 60% to 70% of patients with asthma have type-2 inflammation driven by high eosinophil counts. Accordingly, we use a cutoff value of at least 300 eosinophils/µL as a biomarker of type-2 inflammation. This allows us to be somewhat imperfect in our differential diagnosis of asthma or COPD, because the biologics approved for refractory COPD are also approved for refractory asthma. That is, the treatment path depends less on rigid disease labels and more on inflammation markers and clinical features.

That said, it is still best practice to follow the guidelines for biologics and ICS-based regimens. When patients with COPD exceed the 300 eosinophil/µL threshold and experience exacerbations, the first-line intervention is to escalate LAMA/LABA (long-acting muscarinic antagonist/long-acting β₂-agonist) therapy to triple therapy with LAMA/LABA/ICS. We would only use biologics in these patients if they continue to experience exacerbations despite triple therapy.