OBJECTIVES:  Maintaining glycemic control is the key treatment target for patients with type two diabetes mellitus but the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be associated with other favorable treatment characteristics, such as avoidance of weight gain and reduced risk of hypoglycemia compared to traditional diabetes interventions. The aim of the present analysis was to compare the long-term cost-effectiveness of two GLP-1 RAs, liraglutide 1.8mg and lixisenatide 20μg both administered once daily, in the treatment of patients with type 2 diabetes failing to achieve glycemic control on metformin monotherapy in the Italian setting. METHODS:  The IMS CORE Diabetes Model was used to project costs (accounted in 2015 EUR) and clinical outcomes over patient lifetimes in a cohort with baseline characteristics from the LIRA-LIXI^TM trial of liraglutide 1.8mg versus lixisenatide (NCT01973231). Treatment effect data (including changes in glycated hemoglobin [HbA1c], systolic blood pressure, serum lipids, body mass index and hypoglycemic event rates) were taken from the 26-week primary endpoint of the LIRA-LIXI^TM study. Future outcomes were discounted at 3% annually and sensitivity analyses were performed. RESULTS:  Liraglutide 1.8mg was associated with improved discounted life expectancy (14.07 versus 13.96 years) and discounted quality-adjusted life expectancy (9.18 versus 9.06 quality-adjusted life years [QALYs]) compared with lixisenatide. These improvements resulted from a greater reduction in HbA1c with liraglutide 1.8mg, leading to reduced incidence and increased time to onset of diabetes-related complications. Liraglutide 1.8mg was associated with increased total costs over patient lifetimes (EUR 41,623 versus EUR 41,380), but lower costs of treating diabetes-related complications (EUR 26,682 versus EUR 27,476). Liraglutide 1.8mg was associated with an incremental cost-effectiveness ratio of EUR 2,001 per QALY gained versus lixisenatide. CONCLUSIONS:  Based on long-term projections, liraglutide 1.8mg is likely to be considered cost-effective compared to lixisenatide for treatment of patients with type 2 diabetes in Italy.