OBJECTIVES: To assess the cost-effectiveness of the SGLT2is empagliflozin 10mg and 25mg compared to other SGLT2is (canagliflozin 100mg and canagliflozin 300mg) when administered as an add-on to MET+SU in patients with T2DM in the UK. METHODS: Long-term diabetes-related complications, QALYs, and costs were estimated for T2DM patients failing MET+SU. A micro-simulation model was developed based on the United Kingdom Prospective Diabetes Study (UKPDS68) and the Januvia Diabetes Economic (JADE) model. A network meta-analysis comparing efficacy and safety across SGLT2is was used to populate the model. Data gaps were completed with information derived from published sources, including previous cost-effectiveness models. Costs and QALYs were estimated over a patients’ lifetime from the UK National Health Service perspective. RESULTS: Empagliflozin 10mg attained the highest QALYs (6.991, compared to 6.98 for canagliflozin 100mg, 6.978 for empagliflozin 25mg and 6.976 for canagliflozin 300mg) due to slightly better HbA1c, SBP and weight control, and a small number of non-severe hypoglycaemias, compared to higher doses. Canagliflozin 300mg was the most costly strategy (£32,087, vs. £31,217 for canagliflozin 100mg, £31,409 for empagliflozin 10mg and £31,557 for empagliflozin 25mg). Therefore, empagliflozin 10mg dominated both canagliflozin 300mg and empagliflozin 25mg, and resulted in an incremental cost-effectiveness ratio of £17,445 per QALY gained vs. canagliflozin 100mg. However, incremental QALY and cost differences were not significant based on 95% percentile confidence intervals. These results remained robust when sensitivity analyses were conducted, including utilities, adverse events, discontinuation, modelling of weight, impact of BMI, duration of effect, time horizon and discount rates. CONCLUSIONS: Differences in QALYs and costs between SGLT2is as add-ons to MET+SU were minor. On average, empagliflozin 10mg resulted to be the most cost-effective option for T2DM patients failing MET+SU when commonly accepted thresholds in the UK were considered, with an incremental cost per QALY of £17,445 compared to canagliflozin 100mg.