Novel antidiabetic agents and the risk of respiratory diseases: a systematic review and meta-analysis of 27 randomized controlled trials

Introduction: Patients with type 2 diabetes (T2D) are at increased risk of respiratory diseases, but the effects of novel glucose-lowering drugs on respiratory diseases remain unclear. Method: We conducted a systematic review and meta-analysis of 27 large randomized controlled trials (202,727 participants) assessing sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is). Prespecified outcomes included pneumonia, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary edema, pulmonary embolism, respiratory failure, and asthma. Pairwise and network meta-analyses were performed to estimate odds ratios (ORs) with 95% confidence intervals (CIs). This review was prospectively registered in PROSPERO (CRD420251158592). Result: Compared with placebo, SGLT2is significantly reduced the risk of six respiratory diseases: pneumonia (OR 0.84, 95% CI 0.77-0.92), bronchitis (OR 0.59, 95% CI 0.44-0.79), COPD (OR 0.76, 95% CI 0.64-0.90), pulmonary edema (OR 0.51, 95% CI 0.39-0.67), respiratory failure (OR 0.77, 95% CI 0.64-0.91), and asthma (OR 0.55, 95% CI 0.38-0.85). Benefits were broadly consistent in patients with and without T2D. GLP-1RAs were neutral in T2D but reduced pneumonia, respiratory failure, and asthma risk in obese populations. DPP-4is were largely neutral but increased asthma risk (OR 1.70, 95% CI 1.03-2.82). Conclusion: SGLT2 inhibitors showed robust respiratory protection that appeared largely independent of diabetes status, GLP-1 receptor agonists may provide benefit in obesity, and DPP-4 inhibitors offered limited advantage with a potential asthma risk. Our findings should be viewed as hypothesis generating, with concepts requiring validation in future studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251158592, identifier PROSPERO (CRD420251158592).