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AIMS To describe the characteristics and treatment of patients with type 2 diabetes mellitus initiating a second-line glucose-lowering therapy in the global DISCOVER study programme. METHODS DISCOVER comprises two similar 3-year prospective observational studies (NCT02322762 and NCT02226822), involving 15,992 patients initiating a second-line glucose-lowering therapy in 38 countries across six regions (Africa, Americas, South-East Asia, Eastern Mediterranean, Europe and Western Pacific). RESULTS Overall, 54.2% of patients were male (across region range [ARR]: 37.7-58.6%). At baseline, mean age and time since diagnosis of type 2 diabetes mellitus were 57.2 (ARR: 53.1-61.9)and 5.6 (ARR: 4.6-6.9) years, respectively. Median glycated haemoglobin (HbA1c) was 63.9 mmol/mol (8.0%; ARR: 7.6-8.3%). Microvascular and macrovascular complications were reported in 18.9% (ARR: 14.5-23.5%) and 12.7% (ARR: 5.0-26.6%) of patients, respectively. First-line treatments were mostly metformin monotherapy (55.6%; ARR: 42.5-83.6%) and combinations of metformin with a sulfonylurea (14.4%; ARR: 5.8-31.1%). The most commonly prescribed second-line therapies were combinations of metformin with a dipeptidyl peptidase-4 inhibitor (23.5%; ARR: 2.2-29.6%) or a sulfonylurea (20.9%; ARR: 13.6-57.1%). CONCLUSIONS DISCOVER demonstrates considerable global variation in the treatment of type 2 diabetes mellitus, and a need for more aggressive risk factor control.