Association of GLP-1 Receptor Agonists with Chronic Obstructive Pulmonary Disease Exacerbations among Patients with Type 2 Diabetes

Abstract

Rationale: Patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D) have worse clinical outcomes compared with patients without metabolic dysregulation. GLP-1 (glucagon-like peptide 1) receptor agonists (GLP-1RAs) reduce asthma exacerbation risk and improve FVC in patients with COPD. Objectives: To determine whether GLP-1RA use is associated with reduced COPD exacerbation rates, and severe and moderate exacerbation risk, compared with other T2D therapies. Methods: A retrospective, observational, electronic health records-based study was conducted using an active comparator, new-user design of 1,642 patients with COPD in a U.S. health system from 2012 to 2022. The COPD cohort was identified using a previously validated machine learning algorithm that includes a natural language processing tool. Exposures were defined as prescriptions for GLP-1RAs (reference group), DPP-4 (dipeptidyl peptidase 4) inhibitors (DPP-4is), SGLT2 (sodium-glucose cotransporter 2) inhibitors, or sulfonylureas. Measurements and Main Results: Unadjusted COPD exacerbation counts were lower in GLP-1RA users. Adjusted exacerbation rates were significantly higher in DPP-4i (incidence rate ratio, 1.48 [95% confidence interval, 1.08-2.04]; P = 0.02) and sulfonylurea (incidence rate ratio, 2.09 [95% confidence interval, 1.62-2.69]; P < 0.0001) users compared with GLP-1RA users. GLP-1RA use was also associated with significantly reduced risk of severe exacerbations compared with DPP-4i and sulfonylurea use, and of moderate exacerbations compared with sulfonylurea use. After adjustment for clinical covariates, moderate exacerbation risk was also lower in GLP-1RA users compared with DPP-4i users. No statistically significant difference in exacerbation outcomes was seen between GLP-1RA and SGLT2 inhibitor users. Conclusions: Prospective studies of COPD exacerbations in patients with comorbid T2D are warranted. Additional research may elucidate the mechanisms underlying these observed associations with T2D medications.

Keywords: health services research; obesity; obstructive lung diseases; type 2 diabetes mellitus.

Figure 1.

Electronic health record patient cohort selection. COPD = chronic obstructive pulmonary disease; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1RA = glucagon-like peptide 1 receptor agonist; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2D = type 2 diabetes.

Figure 2.

Incidence rate ratios of chronic obstructive pulmonary disease exacerbations and the association with GLP-1RAs or comparator treatments by six months after treatment initiation. (A and B) Negative binomial regression models adjusted for (A) clinical covariates (clinical model) and (B) metabolic covariates at baseline (metabolic model). The x-axes for both models are plotted on a log scale. CI = confidence interval; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1RA = glucagon-like peptide 1 receptor agonist; ref = reference group; SGLT2i = sodium-glucose cotransporter 2 inhibitor.

Figure 3.

(A and B) Unadjusted Kaplan-Meier survival curves indicating the time to onset of (A) moderate COPD exacerbations and (B) severe exacerbations. COPD = chronic obstructive pulmonary disease; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1RA = glucagon-like peptide 1 receptor agonist; SGLT2i = sodium-glucose cotransporter 2 inhibitor.

Figure 4.

Incidence rate ratios of chronic obstructive pulmonary disease exacerbations and the association with GLP-1RAs or comparator treatments by 12 months after treatment initiation. (A and B) Negative binomial regression models adjusted for (A) clinical covariates (clinical model) and (B) metabolic covariates at baseline (metabolic model). The x-axes are plotted on a log scale. For definition of abbreviations, see Figure 2.

Figure 5.

(A and B) Exploratory analysis of changes in BMI and HbA_1c on incidence rate ratios of chronic obstructive pulmonary disease exacerbations and the association with GLP-1RAs or comparator treatments by (A) 6 months and (B) 12 months after treatment initiation. Negative binomial regression models were adjusted for all covariates in the metabolic model and change in BMI and change in HbA_1c over the study period to generate estimates of the direct controlled effect of the changes in those parameters on the outcome. The x-axes are plotted on a log scale. BMI = body mass index; CI = confidence interval; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1RA = glucagon-like peptide 1 receptor agonist; ref = reference group; SGLT2i = sodium-glucose cotransporter 2 inhibitor.