Type 2 diabetes (T2D) associates with nonalcoholic fatty liver disease (NAFLD), which itself contributes to both insulin resistance and excessive cardiovascular risk of diabetes. Nevertheless, there is currently 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) in metabolically well-controlled patients with short known disease duration. T2D patients (n=84; 63±8 years; body mass index (BMI) 32.2±4.5 kg/m2, HbA1c 6.6±0.5%, disease duration 38±27 months) were randomly assigned to 24-week treatment with either EMPA 25 mg per day or placebo (PLAC). HCL was measured by 1H-magnetic resonance (MR) spectroscopy (STEAM) and fat-selective 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 (BW) 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). Causal mediation analysis revealed that reduction of HCL was mainly driven by weight loss. Serum adiponectin levels rose markedly with EMPA only (LSM EMPA 458±102, p<0.0001; PLAC -63±105 ng/ml; EMPA vs. PLAC p=0.0008), whereas tumor necrosis factor α (TNFα) was unchanged in both groups (RC TNFα 0.1[-11.3;13.0] vs. -0.1[-8.1;8.6]%). Δadiponectin neither correlated with ΔHCL nor with ΔBW, but inversely correlated with changes in serum cytokeratin-18 (CK18) M30 fragment in the EMPA group only (β=-3.0, p=0.014).

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.


S. Kahl: None. S. Gancheva: None. K. Strassburger: None. C. Herder: None. J. Machann: None. H. Katsuyama: None. S. Kabisch: Research Support; Self; California Walnut Commission, Institute for Grain Processing, Nuthetal, J. Rettenmaier Söhne, Südzucker / Beneo. Other Relationship; Self; Berlin-Chemie AG, Sanofi. E. Henkel: None. S. Kopf: None. K. Kantartzis: None. Y. Kupriyanova: None. O. Kuss: None. J. Hwang: None. C. Kasperk: None. N. Stefan: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi. A.F. Pfeiffer: Advisory Panel; Self; Abbott, Berlin-Chemie AG, Novo Nordisk A/S. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG, Sanofi-Aventis Deutschland GmbH. A.L. Birkenfeld: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc.


Boehringer Ingelheim Pharma GmbH

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