Coleman RL, Gray AM, Broedl UC, et al. - Since EMPA-REG OUTCOME trial showed a significant decline in cardiovascular (CV) outcomes in T2D patients given empagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, researchers conducted post-hoc analyses of this trial investigating the degree to which empagliflozin-induced changes in conventional CV risk factors might explain the observed CV benefits. The EMPA-REG OUTCOME trial treated 7,020 individuals randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or to placebo with a median follow-up of 3.1 years between September 2010 and April 2013. According to findings, empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME tend to explain only a small proportion of the observed decrease in the CV and all-cause mortality. Alternative risk-reduction mechanisms must be investigated to determine if other causes, or possibly a direct drug-specific effect, can explain the observed CV risk changes.