Frailty-stratified effectiveness of SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 receptor agonists on pulmonary outcomes in type 2 diabetes: a nationwide cohort study.

Abstract

<h4>Background</h4>The coexistence of type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD) poses significant clinical challenges, particularly in aging populations. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) show promise for pulmonary protection, their effectiveness compared to other newer antidiabetic agents across different frailty levels remains unknown.<h4>Methods</h4>In this population-based cohort study using Taiwan's National Health Insurance database, we identified adults aged ≥40 years with coexisting T2D and COPD who initiated SGLT2i or comparator drugs (dipeptidyl peptidase-4 inhibitors [DPP-4i] or glucagon-like peptide-1 receptor agonists [GLP-1 RA]) between January 1, 2017, and December 31, 2020. We classified participants overall and stratified by frailty status using the multimorbidity frailty index. After propensity score matching, we estimated subdistribution hazard ratios (sHR) and incidence rate differences (IRD) for a composite pulmonary endpoint (first hospitalization for COPD exacerbation or pneumonia) and for each outcome separately, with follow-up through December 31, 2021. We also assessed all-cause hospitalization and all-cause mortality as secondary outcomes.<h4>Findings</h4>Among 14,787 propensity-score-matched pairs of SGLT2i versus DPP-4i users (7606 fit/mild, 3834 moderate, 3347 severe frailty), SGLT2i use was associated with a lower risk of the composite pulmonary endpoint (sHR 0.83 [95% CI 0.77-0.90]; IRD -28.0 per 1000 person-years [95% CI -36.0 to -20.0]), a reduced risk of COPD hospitalization in the fit/mild subgroup (sHR 0.82 [0.69-0.98]), decreased pneumonia hospitalization across all frailty strata (sHR range 0.65-0.85), and lower risks of all-cause hospitalization (sHR 0.91 [0.86-0.95]) and all-cause mortality (sHR 0.60 [0.53-0.68]). In 4815 matched SGLT2i versus GLP-1RA pairs (2101 fit/mild, 1294 moderate, 1420 severe frailty), SGLT2i use showed no significant differences for any outcomes.<h4>Interpretation</h4>Compared with DPP-4i, SGLT2i reduced the composite pulmonary endpoint overall, prevented COPD hospitalizations primarily in fit or mildly frail patients, and conferred protection against pneumonia admissions across most frailty strata, while showing comparable benefits to GLP-1 RA. These findings suggest that both SGLT2i and GLP-1 RA may be preferred options for T2D patients with COPD, with effectiveness influenced by frailty status.<h4>Funding</h4>National Science and Technology Council, Taiwan.