The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest
different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum
creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a
rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/
R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+empagliflozin (10 mg/kg/day). Glucose excretion was
comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate
markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in
the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R +
canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the
placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas
canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved
inflammatory score (p =0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and
empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a
excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This
study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin
might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of
inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.