SGLT-2is, GLP-1RAs cut risk of COPD flare-ups

In adults with type 2 diabetes (T2D) and active chronic obstructive pulmonary disease (COPD), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) may also reduce the risk of COPD exacerbations, according to a study.

Analysis of data from three propensity score–matched cohort studies that emulated three target trials showed that both SGLT-2is and GLP-1RAs were associated with a 14–19 percent reduction in the risk of moderate or severe COPD exacerbation, the primary outcome, as compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) (hazard ratio [HR], 0.81, 95 percent confidence interval [CI], 0.76-0.86 and HR, 0.86, 95 percent CI, 0.81–0.91, respectively). Meanwhile, in a head-to-head comparison, SGLT-2is were associated with a 6-percent risk reduction relative to GLP-1RAs (HR, 0.94, 95 percent CI, 0.89–1.00). [JAMA Intern Med 2025;doi:10.1001/jamainternmed.2024.7811]

For the secondary outcome of severe exacerbation, the results followed a similar pattern as those for the primary outcome. The risk of severe exacerbation decreased by 29 percent with SGLT-2is vs DPP-4is (HR, 0.71, 95 percent CI, 0.65–0.78), by 18 percent with GLP-1RAs vs DPP-4is (HR, 0.82, 95 percent CI, 0.76–0.89), and by 7 percent with SGLT-2is vs GLP-1RAs (HR, 0.93, 95 percent CI, 0.85–1.01).

Sensitivity and subgroup analyses yielded consistent results.

“These findings suggest that SGLT-2is and GLP-1RAs may be preferable to DPP-4is when deciding among glucose-lowering medications for patients with T2D and active COPD,” according to the investigators.

How SGLT-2is and GLP-1RAs lower the risk of COPD flare-ups remains unclear, they said. However, some studies suggest that GLP-1RAs help reduce bronchial hyper-responsiveness through downregulation of interleukin 13 and interleukin 33. As for SGLT-2is, one theory is that their effect on glucose in the urine may aid carbon dioxide expulsion. Furthermore, these drugs tend to reduce fluid, which could benefit COPD patients with congestive heart failure. [Clin Exp Allergy 2023;53:469-473; Allergy 2021;76:3433-3445; Med Hypotheses 2020;139:109631; Qual Manag Health Care 2017;26:152-159]

“Finally, GLP-1RAs and SGLT-2is promote weight loss, which might also be associated with reduced COPD exacerbation risk, although evidence on this association remains conflicting,” the investigators noted. [J Am Pharm Assoc 2021;61:772-777; Chronic Obstr Pulm Dis 2024;11:524-533]

RCTs essential for definitive answers

In an accompanying editorial, experts stressed that while the study “provides intriguing and novel observational evidence about a potential off-target effect of SGLT-2is and GLP-1RAs,” further investigation is needed, given that emulating a target trial is not equivalent to conducting a randomized controlled trial (RCT). [JAMA Intern Med 2025;doi:10.1001/jamainternmed.2024.7812]

“Considering the high prevalence of comorbid diabetes and COPD, the widespread availability of SGLT-2is and GLP-1RAs, and the potential for unmeasured confounding, which cannot be fully controlled in a trial emulation, evidence from RCTs remains essential before more definitive conclusions are reached about the association of glucose-lowering drugs and COPD observed in this study,” wrote Drs Nathan Stall from the University of Toronto, Timothy Anderson from University of Pittsburgh, and Kenneth Covinsky from University of California-San Francisco.

The study included 27,991, 32,107, and 36,218 pairs in the SGLT-2i vs DPP-4i (mean age 70.8 years, 49.3 percent female), GLP-1RA vs DPP-4i (mean age 70.4 years, 54.9 percent female), and SGLT-2i vs GLP-1RA (mean age 69.8 years, 52.0 percent female) propensity score–matched cohorts, respectively. Around 11 percent of participants were in Global Initiative for Obstructive Lung Disease group E across all cohorts.

A moderate or severe COPD exacerbation occurred at 9.26 per 100 person-years with SGLT-2is vs 11.4 per 100 person-years with DPP-4is over a median follow-up time on treatment of 145 vs 147 days; at 9.89 per 100 person-years with GLP-1RAs vs 11.49 per 100 person-years with DPP-4is over a median follow-up time on treatment of 142 vs 156 days; and at 9.47 per 100 person-years with SGLT-2is vs 10.00 per 100 person-years with GLP-1RAs over a median follow-up time on treatment of 141 vs 139 days.

Exacerbation was defined as a filled prescription for oral glucocorticoids in association with an outpatient COPD visit or hospitalization for COPD.