OBJECTIVES: To assess the cost-effectiveness of dapagliflozin, the first-in-class sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared to the dipeptidyl peptidase-4 inhibitor (DPP4i) class, when used as triple oral therapy in combination with metformin and a sulphonylurea (met+SU) for the treatment of patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled on met+SU alone. METHODS: The validated CARDIFF diabetes model was used. Clinical inputs for the model were sourced from a systematic review and network meta-analysis (NMA) in triple therapy that found clinically relevant differences between dapagliflozin and DPP4i’s. A UK healthcare perspective was used for costs, and quality-adjusted life years (QALYs) were calculated from utility data sourced from the published literature. The cost-effectiveness was reported as an incremental cost-effectiveness ratio (ICER). To assess uncertainty, univariate deterministic and multivariate probabilistic sensitivity analyses (PSA) were performed.  RESULTS: Compared to the DPP4i class, dapagliflozin was associated with 0.023 incremental QALYs (95% CI: -0.058, 0.105), at an additional cost of £253 (95% CI: -£302, £741). This resulted in an ICER of £10,995 per QALY gained. The incremental cost associated with dapagliflozin was primarily due to the additional drug acquisition cost, whereas the QALY gain estimated was associated with superior weight reduction and its impact on health-related quality of life for dapagliflozin relative to the DPP4i’s. Univariate analyses demonstrated that the ICER was most sensitive to varying the weight change parameter for the comparator DPP4i’s according to the 95% credible intervals in the NMA, giving ICER estimates ranging from £3,937 to £16,727. Dapagliflozin had a 59% probability of being cost-effective versus DPP4i’s at a willingness-to-pay threshold of £20,000 per QALY gained. CONCLUSIONS: Dapagliflozin as triple therapy in combination with met+SU was shown to be a cost-effective treatment option from a UK healthcare perspective for patients with T2DM who are inadequately controlled on met+SU.