The Potential Impact of GLP-1 Receptor Agonists on Exacerbation Risk in Patients with COPD and Type 2 Diabetes: A Real-World Population-Based Observational Study

Introduction

Chronic Obstructive Pulmonary Disease (COPD) and type 2 diabetes mellitus (T2D) are prevalent chronic diseases that frequently coexist, particularly in older adults. The coexistence of these two conditions is more than coincidental, as both share pathophysiological pathways involving systemic inflammation, and metabolic dysfunction and obesity.^1,2 Individuals with both COPD and T2D experience worse clinical outcomes than those with either disease alone, including higher exacerbation rates, increased hospitalization risk, and elevated mortality.^3,4

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications primarily used in the management of T2D. These agents, including liraglutide, semaglutide, and dulaglutide, have demonstrated cardiovascular and kidney benefits beyond glycemic control.⁵ Emerging evidence suggests potential anti-inflammatory and pulmonary benefits in terms of exacerbation reduction of GLP-1 RAs compared to other T2D treatments.^6,7

Experimental data indicate that GLP-1 RAs may exert protective effects on the respiratory system by attenuating airway inflammation, improving lung mechanics, and reducing weight, which may be especially relevant in patients who are overweight or living with obesity with COPD.^8,9 Recently published data also suggest that patients receiving GLP-1 RAs for diabetes also experienced improved lung function in asthma populations¹⁰ Given the growing use of GLP-1 RAs in clinical practice, particularly in patients with cardiometabolic comorbidities, it is crucial to evaluate their potential benefits in populations beyond glycemic control.¹¹ While prior studies have suggested potential benefits of GLP-1 RAs on respiratory outcomes, robust real-world evidence in patients with established COPD remains scarce.

The present study aims to investigate whether the initiation of GLP-1 RA therapy in patients with both COPD and T2D is associated with lower COPD exacerbations and related outcomes, using real-world data from the UK-based Optimum Patient Care Research Database (OPCRD).

Materials and Methods

Study Design

This was a retrospective cohort study utilizing anonymized patient-level data from the Optimum Patient Care Research Database (OPCRD), a large UK primary care database that includes diagnostic, prescription, and consultation data from general practices.

Study Population

The study population included adults aged ≥40 years with a documented diagnosis of both COPD and T2D. Patients were included if they had at least 12 months of continuous data prior to the index date and at least one COPD-related consultation within the baseline year.

GLP-1 RA users (cases) were identified as patients who received a new prescription of a GLP-1 RA (eg, dulaglutide, liraglutide, semaglutide, etc). The index date was defined as the date of their first GLP-1 RA prescription. Each case was matched 1:1 with a control patient (GLP-1 naïve) based on age (±1 year), sex, smoking status, COPD treatment class (LABA, LAMA, ICS), and exacerbation history in the prior year (0, 1, 2, or ≥3 exacerbations). The index date for the controls was the date of a COPD related consultation within 186 days of the index date for each individually matched GLP1-RA user.

Inclusion and Exclusion Criteria

Inclusion criteria were: (1) age ≥40 years at index; (2) ≥12 months of medical records prior to index; (3) diagnosis of both COPD and T2D; (4) active COPD treatment during baseline. Exclusion criteria included prior GLP-1 RA use in the control group or insufficient follow-up data.

Outcomes

The primary outcome was the number of COPD exacerbations during the 12 months following the index date. Exacerbations were classified using two definitions: specific (recorded diagnosis of COPD or chest infection plus an OCS or antibiotic) and sensitive (prescription of OCS or antibiotic alone, with or without a diagnostic code).

Secondary outcomes included the number of oral corticosteroid (OCS) prescriptions and hospital resource utilization (HCRU), including COPD-related hospital visits or admissions.

Statistical Analysis

Descriptive statistics were used to summarize baseline characteristics. Poisson regression models adjusted for BMI and other potential confounders were used to estimate adjusted incidence rate ratios (aIRRs) for primary and secondary outcomes. Robust variance estimates and sensitivity analyses using negative binomial models were applied to account for potential overdispersion, Time to first OCS prescription was analyzed using Kaplan-Meier curves and Log rank tests.

All analyses were conducted using STATA (version 14.2) and adhered to a predefined statistical analysis plan.

Results

Study Population

A total of 4479 patients were included in each group (GLP-1 RA users and matched controls). Baseline characteristics, including age, sex, BMI, smoking status, COPD treatment, and exacerbation history, were ‘generally well balanced, although small differences remained (SMD > 0.1 for some variables) (Table 1). No significant differences were observed in the number of COPD exacerbations or oral corticosteroid (OCS) prescriptions in the year prior to the index date. Hospitalization rates were slightly lower in the GLP-1 RA group during the baseline year (Table 2).

Table 1 Baseline Characteristics of the Exposed and Unexposed

Table 2 COPD Control Outcomes

Primary Outcome

During the 12-month follow-up period, patients treated with GLP-1 RAs had significantly fewer COPD exacerbations compared to matched controls. The adjusted incidence rate ratio (aIRR) for total COPD exacerbations was 0.84 (95% CI: 0.79–0.89, p < 0.001) (Table 2). The reduction was consistent for both specific and sensitive exacerbation definitions.

Secondary Outcomes

GLP-1 RA users had a significantly lower number of OCS prescriptions compared to controls (aIRR 0.86, 95% CI: 0.77–0.95, p = 0.002) (Table 2). The time to first OCS prescription was significantly delayed in the GLP-1 RA group, as demonstrated by Kaplan-Meier analysis (log-rank p < 0.001) (Figure 1). Hospital resource utilization, including COPD-related hospital admissions, were also lower among those prescribed GLP-1 RA vs those not (aIRR 0.61, 95% CI: 0.51–0.74, p < 0.001).

Figure 1 Time to first OCS following GLP1-RA initiation.

Sensitivity Analyses

Sensitivity analyses restricted to patients without an active asthma (n = 3901) yielded similar results, confirming the robustness of the primary and secondary outcomes. No significant interaction effects were observed for age, sex, or smoking status.

Discussion

This real-world study provides new evidence that GLP-1 receptor agonist (RA) therapy might be associated with a lower risk for COPD exacerbations in patients with comorbid type 2 diabetes. Using a large UK primary care database with over 29 million patients, we observed that patients initiating GLP-1 RA therapy experienced fewer COPD exacerbations and OCS prescriptions, with a significant delay in time to first exacerbation event. These findings suggest a potential protective effect of GLP-1 RAs on respiratory health and provide a rationale for future randomised clinical trials.

Our results align with emerging mechanistic data indicating that GLP-1 RAs may exert anti-inflammatory effects in the lungs, modulate immune responses, and improve pulmonary function.^10,12 Although previous studies have focused on cardiovascular and metabolic outcomes, the potential respiratory benefits of GLP-1 RAs are gaining attention.¹³ Notably, GLP-1 receptors are expressed in airway epithelial and smooth muscle cells, and animal models have demonstrated reduced airway hyperresponsiveness and eosinophilic inflammation with GLP-1 RA therapy.¹⁴ Since nearly all GLP-1RAs lower weight to modest or greater extents, a potential contribution of weight loss to lower excerbations risks cannot be excluded.

The magnitude of risk reduction reported in this study, with an approximately 20% lower risk for exacerbations and corticosteroid prescriptions, is clinically meaningful, especially in a population with high multimorbidity burden. These findings, if replicated in randomised trials, may inform treatment strategies for patients with both COPD and T2D, particularly in those with frequent exacerbations or systemic inflammation.¹⁵

However, several limitations should be considered. This was an observational study, and although we employed rigorous matching and adjusted for key confounders, residual confounding cannot be excluded. The definitions of exacerbation were based on coding and prescription patterns and may not fully capture all clinically relevant events. Lung function data and biomarkers of inflammation were not available in the database, limiting mechanistic interpretation.Despite these limitations, the strength of our study lies in the large, well-characterized cohort, the real-world setting, and the consistency of findings across sensitivity analyses. Our results extend previous studies in the field of COPD suggesting a role for GLP-1RA in exacerbation prevention.^6,13,16 As compared to other T2D therapies,¹⁷ GLP-1 RA may provide a benefit in terms of exacerbation reduction.⁷ These findings should be interpreted with caution, and independent replication would strengthen confidence in these results.

Future research should aim to validate these findings in randomized clinical trials. Additionally, mechanistic investigations into the pulmonary actions of GLP-1 RAs could further elucidate their role in respiratory disease modification.¹⁸

Conclusions

GLP-1 RA therapy was associated with lower risk for COPD exacerbations and systemic corticosteroid use in patients with comorbid COPD and T2D. These results warrant further mechanistic and interventional randomised trials to explore the potential role of GLP-1 RAs in COPD management. ‘These results, derived from a UK primary-care cohort, may not directly extrapolate to other healthcare systems or populations.