OBJECTIVES: Exenatide once-weekly (EQW) is a GLP-1 receptor agonist that controls glucose in patients with type 2 diabetes (T2DM) and is associated with weight loss and improvement in cardiovascular risk factors such as blood pressure and lipids.  We estimated the long-term clinical and financial benefits of EQW compared to sitagliptin or pioglitazone in the US. Pending US approval and EQW price, we conducted a cost-consequence analysis that excluded pharmacy costs.  METHODS: We used the CORE Diabetes Model, a validated computer simulation model of diabetes progression and treatment, to project lifetime clinical outcomes and complication costs. Patient characteristics (mean age 52.5y; diabetes duration 6y; HbA1c 8.51%; body mass index 32.12 kg∙m-2) and clinical data were derived from a phase 3 clinical trial comparing EQW to sitagliptin or pioglitazone against metformin background. Compared to sitagliptin and pioglitazone patients, trial patients on EQW had HbA1c improvement (0.63% and 0.32% points, respectively) and BMI reduction (0.51 kg∙m-2 and 1.77 kg∙m-2). Health outcomes and complication costs were discounted at 3% per year. Sensitivity analyses were performed to determine how changes in estimated values affected results. RESULTS: Compared to sitagliptin and pioglitazone, EQW increased life expectancy by 0.31 years (13.80±0.18 versus 13.50±0.16) and 0.14 years (13.80±0.18 versus 13.66±0.18), respectively, and quality-adjusted life years (QALY) by 0.30 (9.49±0.12 versus 9.20±0.11) and 0.21 (9.49±0.12 versus 9.28±0.12). EQW was also associated with lower complication costs: Compared to sitagliptin and pioglitazone, EQW saved US$1,654 (US$55,385±1,781 versus US$57,039±1,848) and US$573 (US$55,385±1,781 versus US$55,958±1,838) lifetime direct cost per patient. In both cases, cost savings resulted mainly from lower cumulative incidence of cardiovascular diseases and neuropathic complications (e.g. ulcer, amputation). CONCLUSIONS: Over a patient’s lifetime, EQW is projected to improve health and decrease complication costs compared with sitagliptin or pioglitazone. Incremental cost-effectiveness ratios will depend upon EQW price.