OBJECTIVES Poor control of type 2 diabetes (T2D) results in substantial morbidity and economic burden to the healthcare system. Studies of new T2D treatments are rarely designed to assess mortality, complication rates and costs. We sought to estimate long-term consequences of liraglutide and rosiglitazone both as add-on to glimepiride. METHODS To estimate clinical and economic consequences, we used the CORE diabetes model, a validated cohort model that uses data from long-term clinical trials to simulate morbidity, mortality and costs of T2D. Clinical data were extracted from the randomized double-blinded placebo-controlled LEAD 1 trial evaluating two doses (1.2 mg and 1.8 mg) of a once daily human GLP-1 analog liraglutide, or rosiglitazone 4 mg, added to glimepiride. The CORE diabetes model was calibrated to the LEAD 1 baseline patient characteristics. Survival, cumulative incidence of cardiovascular, ocular and renal events and costs were estimated over three periods: 10, 20 and 30 years. RESULTS In a cohort of 5000 patients per treatment followed for 30 years, liraglutide 1.2 mg and 1.8 mg had higher survival compared to the group treated with rosiglitazone (15.0% and 16.0% vs. 12.6% after 30 years), and fewer cardiovascular, renal, and ocular events. Cardiovascular deaths after 30 years were 69.7%, 68.4% and 72.5%, for liraglutide 1.2 mg, 1.8 mg, and rosiglitazone, respectively. First and recurrent amputations were lower in the rosiglitazone group compared to both doses of liraglutide (number of events: 565, 529 and 507 for liraglutide 1.2 mg, 1.8 mg, and rosiglitazone, respectively). CONCLUSIONS Overall cumulative costs per patient were lower in both liraglutide groups compared to rosiglitazone mainly driven by the costs of cardiovascular events (US$38,963, $39,239, and $40,401 for liraglutide 1.2 mg, 1.8 mg, and rosiglitazone, respectively). Projected survival and long term outcomes favored liraglutide 1.2 mg and 1.8 mg over rosiglitazone both added to glimepiride.