Empagliflozin effectively reduces liver fat content in type 2 diabetes

Type 2 diabetes (T2D) associates with non-alcoholic fatty liver disease (NAFLD), which contributes to insulin resistance and cardiovascular risk of diabetes. Currently, there is no established therapy for NAFLD in T2D. This trial examined whether treatment with the sodium glucose transporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (HCL, primary outcome). T2D patients (n = 84; BMI 32.2 ± 4.5 kg/m2; HbA1c 6.6 ± 0.5%) were randomly assigned to 24-week treatment with either EMPA 25 mg per day or placebo (PLAC). HCL was measured by magnetic resonance (MR) methods (1 H-MR spectroscopy, STEAM); MR imaging, IDEAL). Statistical analysis was done by ANCOVA adjusted for the respective baseline value, age, sex and BMI. After treatment, HCL was reduced compared to baseline (relative change, RC: EMPA -33%[95% confidence interval -43;-23], p < 0.0001; PLAC -14[-23;-3]%, p = 0.014) and different between the two interventions (p = 0.007). Body weight decreased with EMPA, but not with PLAC (least square means (LSM): -2.7 ± 0.4 kg, p < 0.0001, vs. 0.06 ± 0.5 kg) and contributed to reduction of HCL as shown by causal mediation analysis. Serum uric acid decreased (LSM: -81 ± 13 mmol/l, p < 0.0001, vs. -4 ± 11 mmol/l), while serum adiponectin rose with EMPA only (RC: 27[15;40]%, p < 0.0001, vs. -5[-16;9]%) and correlated only in EMPA (p = 0.038). Furthermore, the changes in adiponectin inversely associated with changes in serum cytokeratin-18 M30 fragment in the EMPA group only (p = 0.005). In conclusion, empagliflozin effectively reduces HCL in well-controlled T2D patients and increases serum adiponectin with beneficial effects on hepatocellular integrity. Thus, empagliflozin may improve NAFLD via distinct different mechanisms.