AIM: To perform post-hoc analyses of the EMPA-REG OUTCOME trial examining the degree to which empagliflozin-induced changes in conventional cardiovascular (CV) risk factors might explain the observed CV benefits. MATERIALS AND METHODS: We estimated 3-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL cholesterol, LDL cholesterol, systolic blood pressure, glycated haemoglobin, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate, and histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk reductions were compared. RESULTS: Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for all-cause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). CONCLUSIONS: Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and all-cause death reductions observed. Alternative risk-reduction mechanisms need to be explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.