319-OR: Effects of Empagliflozin on Markers of Liver Steatosis and Fibrosis and Their Relation to Cardiorenal Outcomes in the EMPA-REG OUTCOME Trial

Abstract

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of >50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS >0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p<0.001; placebo-corrected change -0.13±0.03 at 164 weeks) and also in the subgroup at high steatosis risk. Despite comparable overall NFS over time in EMPA and PLAC groups, NFS was lower in the EMPA-treated advanced fibrosis subgroup at weeks 12, 28 and 108 (placebo-corrected changes -0.08±0.03, -0.11±0.03 and -0.11±0.04, all timepoints p<0.01 vs. PLAC). Of note, effects of EMPA on cardiorenal and mortality outcomes were consistent across high and low fibrosis risk groups. In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category. Disclosure S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck & Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.