Association between sodium-glucose cotransporter 2 inhibitors and the risk of chronic lower respiratory disease in type 2 diabetes mellitus: findings from two target trial emulations

Abstract Background Research on the association between sodium‑glucose cotransporter 2 inhibitors (SGLT-2i) and chronic lower respiratory diseases (CLRDs) in patients with type 2 diabetes (T2DM) remains limited. This study aimed to investigate this association and examine the potential modifying effects such as age, sex, and diabetes severity. Methods Using the Shenzhen Public Health Data Platform, we conducted two independent target trial emulations with a new‑user active comparator design, comparing SGLT‑2i with glucagon‑like peptide‑1 receptor agonists (GLP-1RA) and dipeptidyl peptidase‑4 inhibitors (DPP‑4i), respectively. The primary outcome was incident CLRD; secondary outcomes included five subtypes—bronchitis, bronchiectasis, asthma, chronic obstructive pulmonary disease, and emphysema. Overlap-weighted Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Results During a median follow-up of 1.76 years, 349 (7.95%) and 397 (9.04%) new CLRD cases occurred in SGLT-2i and GLP-1RA users, respectively. Compared with GLP-1RA, SGLT-2i use was associated with a lower CLRD incidence (HR 0.87, 95% CI 0.79–0.96), primarily driven by reduced risk of bronchitis (HR: 0.89; 95% CI: 0.79-1.00) and asthma (HR: 0.77; 95% CI: 0.58–1.01); no significant associations were found for other subtypes. Compared with DPP-4i, SGLT-2i use showed a trend toward lower CLRD risk (HR: 0.95; 95% CI: 0.91–0.99), with significant reductions for bronchitis (HR: 0.95; 95% CI: 0.91-1.00), bronchiectasis (HR: 0.86; 95% CI: 0.75-1.00), and asthma (HR: 0.87; 95% CI: 0.77–0.98). Subgroup analyses indicated significant interactions for bronchiectasis by sex ( P interaction = 0.001). Conclusion Compared with GLP-1 RA, SGLT-2i were associated with a significantly lower risk of CLRDs, driven predominantly by bronchitis; versus DPP-4i, the risk reduction was primarily observed for bronchitis, bronchiectasis, and asthma. The protective association between SGLT-2i use and bronchiectasis was more pronounced in females than in males relative to DPP-4i.