EFFECT OF EMPAGLIFLOZIN ON LIVER FAT IN METABOLIC-DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE PATIENTS WITHOUT DIABETES MELLITUS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Background: While sodium-glucose cotransporter 2 inhibitors improves cardiovascular and renal outcomes irrespective of diabetes mellitus (DM) status, their effects in metabolic-dysfunction associated steatotic liver disease (MASLD) patients without diabetes mellitus (DM) are unknown.
Methods: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community between March 2021 and April 2022. Eligible subjects had magnetic resonance imaging-proton density fat fraction [MRI-PDFF] ≥5% but without DM (fasting plasma glucose <7mmol/L and HbA1c <6.5%). They were randomly allocated to receive empagliflozin 10mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. Exclusion criteria included DM, alcoholism, concurrent chronic liver diseases, decompensated cirrhosis, prior malignancy, pregnancy and contraindications to empagliflozin use and MRI. The primary outcome was the difference in changes of MRI-PDFF between two groups at EOT. Secondary outcomes were resolution of hepatic steatosis (MRI-PDFF <5%) and changes of anthroprometic and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis.
Results: Of 98 recruited subjects (median age 55.7years [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49; placebo:48) had MRI-PDFF repeated at EOT. The median MRI-PDFF at baseline was 9.7% and 9.0%, respectively. At EOT, empagliflozin group had a greater drop in median MRI-PDFF than placebo group (–2.49% vs –1.43%; p=0.025), with a trend of resolution of hepatic steatosis (44.9% vs 28.6%; p=0.094). Empagliflozin group had a greater drop in body weight (–2.7 vs –0.2kg; p<0.001), waist circumference (–2.0 vs –0.4cm; p=0.015), fasting glucose (–0.3 vs 0mmol/L; p<0.001) and ferritin (–126 vs –22pmol/L; p=0.030) compared with placebo group.
Conclusions: Treatment with empagliflozin for 52 weeks reduces hepatic fat content in MASLD subjects without DM, together with reduction in serum ferritin, fasting glucose and anthropometric parameters (body weight and waist circumference).

Funding: This work was funded by a research grant from the General Research Fund, Research Grant Council, The Government of the Hong Kong Special Administrative Region (Ref: 17110420).