OBJECTIVES To determine the clinical (compliance, metabolic control, hypoglycaemia and cardiovascular events [CVE]) and economic (resources and costs) impact of metformin in combination with dipeptidyl peptidase-4 inhibitors (DPP4-I) or sulfonylureas in patients with type 2 diabetes. METHODS Design: Multicentre, observational retrospective study. Patients aged ≥ 30 years under treatment with metformin who initiated a second oral antidiabetic treatment in 2008-2009 were evaluated. Two study groups were established: a) metformin + DPP4-I, b) metformin + sulfonylureas. Main measures: comorbidity, metabolic control (HbA1c < 7%), compliance and complications (hypoglycaemia, CVE). Patients were followed for 2 years. The cost model considered direct (primary/specialised care) and indirect (productivity) healthcare costs. Statistical analysis: logistic regression models and ANCOVA, p <0.05. RESULTS We recruited 1,405 patients (men age 67.1 years, 56.2% male) of whom 37% initiated a second treatment with DPP4-I and 63% with sulfonylureas. At 2 years follow-up, patients treated with DPP4-I showed better compliance (70.3% vs 60.6%), better metabolic control (64.3% vs 60.6%), and a lower proportion of hypoglycaemia (13.9% vs 40.4%) (p <0.05). The mean unit costs of the total adjusted costs were € 2,341 vs € 2, 512, respectively; p = 0.038. Rates of CVE and renal failure were 3.7% vs 6.4%; p = 0.027. Vildagliptin was the most commonly used DPP4-I. CONCLUSIONS Sulfonylureas were the most frequently used drugs for the treatment of diabetes. Patients treated with DPP4-I had better compliance and control of diabetes, with lower rates of hypoglycaemia and CVE, resulting in reduced healthcare costs.