BACKGROUND: Intensification of metformin monotherapy with additional glucose-lowering drugs is often required in patients with type 2 diabetes (T2D). This study evaluated changes in HbA1c and weight, as well as treatment persistence, associated with different second-line therapies used in UK clinical practice. METHODS: The UK Clinical Practice Research Datalink was used to identify patients with T2D who initiated second-line therapy after metformin monotherapy between 1 August 2013 and 14 June 2016. Treatment persistence and changes in HbA1c and weight were assessed at 6-month intervals up to 18 months. RESULTS: In total, 9097 patients (mean age 61.2 years, 57.2% men, mean [standard deviation] HbA1c 9.0% [1.8]/ 75 mmol/mol [19.7]) were included in the analysis, with a median 2.3 years between initiating metformin monotherapy and initiating second-line therapy. Patients were stratified according to second-line therapy: metformin in combination with sulfonylurea (SU; n = 4655 [51.2%]), a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor; n = 2899 [31.9%]), or a sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor; n = 441 [4.9%]) or other therapies (all other second-line treatments; n = 1102 [12.1%]). At 18 months, the cumulative proportion of patients changing treatment was lowest for those who received metformin plus an SGLT-2 inhibitor (42.3%), followed by patients on metformin plus SU or metformin plus a DPP-4 inhibitor (46.8%). HbA1c reductions were seen with all second-line therapies, with an overall mean (standard error) reduction of -1.23% (0.05)/-13.4 mmol/mol (0.5). Changes were directly, but not linearly, related to baseline HbA1c and were greater in those with higher HbA1c at baseline. Weight loss from baseline was greatest in patients treated with metformin plus either an SGLT-2 inhibitor (-4.2 kg) or a DPP-4 inhibitor (-1.5 kg). The highest proportion of patients who achieved the composite outcome of HbA1c reduction ≥ 0.5%, body weight loss ≥ 2.0 kg and treatment persistence for 18 months was observed in those receiving metformin plus an SGLT-2 inhibitor (36.5%). CONCLUSIONS: In this population-based cohort, all second-line therapies added to metformin monotherapy improved glycaemic control, but the lowest treatment change/discontinuation rate and most sustained weight loss was seen with patients receiving metformin plus an SGLT-2 inhibitor.