Aims In the EMPA‐REG OUTCOME® trial, the sodium‐glucose cotransporter 2 inhibitor empagliflozin when given in addition to standard care improved cardiovascular (CV) and renal outcomes, and reduced mortality. Trial participants were on a variety of glucose‐lowering therapies at baseline, some of which could potentially affect CV risk. This analysis investigated whether the use of background diabetes therapy affected the risk of CV death, hospitalizations for heart failure, and progression of chronic kidney disease, among patients treated with empagliflozin. Materials and methods Patients meeting inclusion and exclusion criteria were randomized to placebo, empagliflozin 10 mg or empagliflozin 25 mg; glucose‐lowering therapy was to remain unchanged for 12 weeks and then adjusted to achieve glycaemic control according to local guidelines. Differences in risk of cardio‐renal outcomes between empagliflozin and placebo by baseline use of metformin, sulphonylurea (SU) and insulin were assessed using a Cox proportional hazards model. Results Of 7020 eligible patients, 74% were receiving metformin, 43% SU and 48% insulin at baseline (each alone or in combination); the most common regimens were metformin plus SU (20%) and metformin plus insulin (20%). Empagliflozin reduced the risk of CV death irrespective of the use of: metformin with: hazard ratio (HR) 0.71 (95% confidence interval, CI, 0.54–0.94); without: 0.46 (0.32–0.68); Pinteraction = 0.07; SU with: HR 0.64 (0.44–0.92); without: 0.61 (0.46–0.81); Pinteraction = 0.85; or insulin with: HR 0.63 (0.46–0.85); without: 0.61 (0.44–0.85); Pinteraction = 0.92. Reductions in three‐point major adverse CV events, hospitalizations for heart failure, and all‐cause mortality were consistent across subgroups of baseline therapies. Empagliflozin reduced the risks of incident or worsening nephropathy versus placebo irrespective of the use of SU or insulin at baseline (Pinteraction > 0.05), but there was a greater reduction in this risk for patients not using metformin HR 0.47 (95% CI 0.37–0.59) versus those using metformin HR 0.68 (95% CI 0.58–0.79) at baseline (Pinteraction = 0.01). Conclusions The addition of empagliflozin to antihyperglycaemic regimens of patients with type 2 diabetes and CV disease consistently reduced their risks of adverse CV outcomes and mortality irrespective of baseline use of metformin, SU or insulin. For chronic kidney disease progression, there may be a larger benefit from empagliflozin in those patients who are not using metformin.