Antidiabetic drug and chronic respiratory disease in type 2 diabetes: a network meta-analysis and Mendelian randomization analysis

Background: Multimorbidity management is crucial in aging populations, particularly for chronic respiratory diseases (CRDs) and diabetes. Their coexistence increases exacerbation and mortality risks. Antidiabetic drugs may differentially impact respiratory outcomes. Objectives: To evaluate the effects of antidiabetic drugs on CRDs in individuals with type 2 diabetes (T2D). Design: Systematic review with conventional and network meta-analyses (NMAs). Data sources and methods: We conducted a systematic review with conventional meta-analysis, NMA for drug comparisons, and two-sample Mendelian randomization for genetic evidence. We assessed nine antidiabetic drug classes for associations with CRD exacerbations, incidence, and all-cause mortality in individuals with T2D. Results: = 939,064) found that glucagon-like peptide-1 receptor agonists (GLP1RAs) offered the strongest protection against acute exacerbations (hazard ratio vs insulin: 0.40, 95% credible interval 0.29-0.56) and had the highest first-rank probability (72.95%), followed by sodium-glucose cotransporter-2 inhibitors (SGLT2is; 46.19%). Thiazolidinediones reduced incident CRD by 21% (odds ratio (OR) 0.79, 0.69-0.91), while metformin lowered all-cause mortality risk by 16% (OR 0.84, 0.74-0.95). Mendelian randomization confirmed GLP1R expression was associated with reduced asthma risk (OR 0.9987, 0.9979-0.9996). Conclusion: GLP1RAs provide the strongest protection against CRD exacerbations in T2D patients, with SGLT2is as the second-most effective option. These findings highlight the potential for personalized antidiabetic therapy in multimorbidity management. Further studies should validate these findings and elucidate underlying mechanisms. Trial registration: PROSPERO (ID: CRD42024542379).