The first cardiovascular (CV) safety trial conducted with a sodium-glucose cotransporter (SGLT)-2 inhibitor, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients—Removing Excess Glucose (EMPA-REG OUTCOME), reported not only remarkable risk reductions in CV outcome, but also impressive improvements in renal outcome. Changes in renal hemodynamics could be involved in the benefit of SGLT2 inhibitors on renal outcomes. Considering that all patients of EMPA-REG OUTCOME had established atherosclerotic CV disease at baseline, many patients were also treated with several CV drugs at baseline, including RAS blockers, diuretics, calcium-channel blockers, and nonsteroidal anti-inflammatory drugs. These drugs also impact renal physiology and possibly renal outcome, which could cause relevant drug–drug interactions. This topic is addressed in this issue of Kidney International by Mayer and colleagues. In their manuscript, the impact of empagliflozin on kidney function, renal outcome, and renal safety is presented with stratification for background therapy. Although the beneficial effects of empagliflozin and its safety profile are consistent among all groups, we wonder, do we really understand the renal effects of all these drugs in type 2 diabetes (T2D) patients as studied in the large outcome trials?