Objective: To assess the cost-effectiveness of exenatide 2mg once-weekly (EQW) compared to dulaglutide 1.5 mg QW, liraglutide 1.2mg and 1.8mg once-daily (QD), and lixisenatide 20 g QD for the treatment of adult patients with type 2 diabetes mellitus (T2DM) not adequately controlled on metformin. Methods: The Cardiff Diabetes Model was applied to evaluate cost-effectiveness, with treatment effects sourced from a network meta-analysis. Quality-adjusted life years (QALYs) were calculated with health-state utilities applied to T2DM-related complications, weight changes, hypoglycemia, and nausea. Costs (GBP ) included drug treatment, T2DM-related complications, severe hypoglycemia, nausea, and treatment discontinuation due to adverse events. A 40-year time horizon was used. Results: In all base-case comparisons, EQW was associated with a QALY gain per patient; 0.046 vs dulaglutide 1.5 mg; 0.102 vs liraglutide 1.2 mg; 0.043 vs liraglutide 1.8 mg; and 0.074 vs lixisenatide 20 g. Cost per patient was lower for EQW than for liraglutide 1.8mg (-2,085); pound therefore, EQW dominated liraglutide 1.8 mg. The cost difference per patient between EQW and dulaglutide 1.5mg, EQW and liraglutide 1.2 mg, and EQW and lixisenatide 20 g was 27 pound, 103 pound, and 738 pound, respectively. Cost per QALY gained with EQW vs dulaglutide 1.5mg, EQW vs liraglutide 1.2mg, and EQW vs lixisenatide 20g was 596 pound, 1,004 pound, and 10,002 pound, respectively. In the probabilistic sensitivity analysis, the probability that EQW is cost-effective ranged from 76-99%. Conclusion: Results suggest that exenatide 2mg once-weekly is cost-effective over a lifetime horizon compared to dulaglutide 1.5mg QW, liraglutide 1.2mg QD, liraglutide 1.8mg QD, and lixisenatide 20g QD for the treatment of T2DM in adults not adequately controlled on metformin alone.