OBJECTIVES: To assess the cost-effectiveness of the novel SGLT2is empagliflozin 10mg and 25mg compared to other SGLT2is (canagliflozin 100mg, canagliflozin 300mg, and dapagliflozin 10mg) when administered as an add-on to metformin for the treatment of patients with T2DM in the UK. METHODS: A micro-simulation model was developed, based on the United Kingdom Prospective Diabetes Study (UKPDS68) and the Januvia Diabetes Economic (JADE) model, to estimate long-term diabetes-related complications, QALYs and costs in a cohort of T2DM patients initiating dual therapy. The model was populated with the results of a network meta-analysis that estimated the comparative efficacy and safety across SGLT2is. Data gaps were completed with information derived from published sources, including previous cost-effectiveness analyses. The UK National Health Service (NHS) perspective was considered to estimate costs and QALYs over a patients’ lifetime. RESULTS: There were small differences in efficacy and safety across SGLT2is, which resulted in minor QALY and cost differences across treatment combinations. On average, empagliflozin 25mg obtained incremental QALYs of 0.029 versus dapagliflozin 10mg and 0.019 versus canagliflozin 100mg, and incremental costs of £178 and £86, respectively, whereas both canagliflozin 300mg and empagliflozin 10mg were dominated by empagliflozin 25mg. This resulted in an incremental cost-effectiveness ratio (ICER) of £4,858 per QALY gained with empagliflozin 25mg vs. canagliflozin 100mg. However, the differences across treatments were not significant when 95% percentile confidence intervals were considered. These results were robust to a number of sensitivity analyses including a 10-year time horizon, BMI impact, discount rates and parameter values related to utilities, disutilities, adverse events, and discontinuation rates. CONCLUSIONS: Overall, differences in QALYs and costs were minor between SGLT2is used as add-on to metformin in UK T2DM patients. On average, empagliflozin 25mg was the most cost-effective strategy, with an ICER of £4,858 per QALY gained vs. canagliflozin 100mg.