BACKGROUND: The effects of oral antihyperglycemic drugs (OADs) for T2DM on outcomes of co-existing COPD patients have been less concerned. We examined the association of combinational OADs and risk of AECOPD in T2DM patients with co-existing COPDMETHODS: A nested case-control study was conducted using data from the National Health Insurance Research Database of Taiwan. Among new-onset COPD-T2DM patients, 65,370 were prescribed with metformin and 2nd line OADs before the date of COPD onset. Each AECOPD case was matched to 4 randomly selected controls according to the propensity score estimated by patient’s baseline characteristics. Conditional logistic regression analysis was performed to estimate the association between AECOPD risk and OADs use. RESULTS: Among COPD-T2DM patients, 3,355 AECOPD cases and 13,420 matched controls were selected. All COPD-T2DM patients with a double combination of oral OADs (n=12,916), AECOPD patients were less likely to be exposed to SU and thiazolidinediones (TZD) compared to the patients received metformin (MET) and sulfonylurea (SU), with an adjusted odds ratio (OR) of 0.69 (95% confidence interval [CI]: 0.51–0.94, P=0.02). Of the patients with a triple combination of oral OADs (n=3,859), we found that MET, SU and TZD had a lower risk of AECOPD (adjusted OR=0.81 (0.68-0.96, P=0.01) compared to a combination of MET, SU and a-glucosidase inhibitors (AGI) regardless the level of COPD complexity. CONCLUSION: Combination therapies with TZD were associated with reducing risk of AECOPD in advanced T2DM patients with co-existing COPD.