OBJECTIVES: Canagliflozin, an agent that inhibits sodium glucose co-transporter 2, decreases glucose levels by lowering the renal threshold for glucose excretion, thereby increasing urinary glucose excretion (UGE). Increased UGE lowers glucose and reduces body weight and systolic blood pressure (SBP). In contrast, dipeptidyl peptidase-4 inhibitors such as sitagliptin lower glucose but are not associated with weight loss or SBP reduction, and sulfonylureas (glimepiride) are associated with weight gain and hypoglycaemia risk. The objective of this analysis was to assess the treatment costs of canagliflozin versus glimepiride or sitagliptin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin from the Italian National Health Service perspective. METHODS: Two CMAs were conducted to compare the mean annual direct costs of a patient with T2DM receiving canagliflozin (100 or 300 mg) or glimepiride (5,6 mg) or sitagliptin (100 mg). Both analyses estimated 12-month annual patient costs. Treatment effects and adverse event rates were sourced from head-to-head studies (ie, direct comparisons) in dual therapy with background metformin in the canagliflozin Phase 3 program RESULTS: Canagliflozin 100 and 300 mg showed lower expected costs (€2.785,46 and €2.979,52, respectively) versus glimepiride (€3.167,90). Canagliflozin 100 and 300 mg also showed lower expected costs (€2.820,05 and €3.013,96, respectively) versus sitagliptin (€3.030,38). CONCLUSIONS: This CMA showed that canagliflozin (100 or 300 mg) is a cost-saving strategy compared with glimepiride or sitagliptin in the treatment of patients with T2DM inadequately controlled with metformin from the perspective of the Italian National Health Service.