Empagliflozin reduces hepatic fat content in nondiabetic MASLD patients

Empagliflozin significantly reduces hepatic fat content vs placebo in patients with metabolic dysfunction–associated steatotic liver disease (MASLD) without diabetes, researchers from the University of Hong Kong have reported.

“This was the first double-blind, randomized, placebo-controlled trial investigating the effect of empagliflozin on hepatic steatosis in MASLD patients without diabetes,” they noted. “Results showed that empagliflozin use for 52 weeks significantly reduced liver fat content in these patients, which was associated with reductions in serum ferritin, fasting glucose, body weight, and waist circumference, as well as a good safety profile.” [Hepatology 2024;doi:10.1097/HEP.0000000000000855]

In this investigator-initiated trial, 98 nondiabetic MASLD patients with MRI-proton density fat fraction (MRI-PDFF) ≥5 percent (median age, 55.7 years; male, 55.1 percent) recruited from the community were randomized 1:1 to receive empagliflozin 10 mg QD or placebo for 52 weeks. At baseline, median MRI-PDFF was 9.7 vs 9.0 percent in the empagliflozin vs placebo group, and 93.9 percent of patients in each group were overweight or obese. There were no significant differences in clinical characteristics between the two groups except for fasting glucose (5.6 vs 5.4 mmol/L).

At week 52, the primary outcome of reduction in median MRI-PDFF from baseline was significantly greater in the empagliflozin vs placebo group (-2.49 vs -1.43 percent; p=0.025).

Resolution of hepatic steatosis (ie, MRI-PDFF <5 percent), a secondary outcome of the trial, showed a nonsignificant trend favouring empagliflozin vs placebo (44.9 vs 28.6 percent; p=0.094) at week 52.

No significant differences were observed in other liver-related secondary outcomes, including alanine aminotransferase drop ≥17 U/L (16.3 vs 12.2 percent; p=0.564), MRI-PDFF drop ≥30 percent (49.0 vs 40.8 percent; p=0.417), and a composite of both (8.2 vs 8.2 percent; p=1.000), between the empagliflozin and placebo groups.

At 52 weeks, patients in the empagliflozin group had significantly greater reduction in body weight (-2.7 vs -0.2 kg; -3.6 vs -0.3 percent; p<0.001) vs those in the placebo group. Decreases in waist circumference (-2.0 vs 0 cm), fasting glucose (-0.3 vs 0 mmol/L), and ferritin (-126 vs -22 pmol/L) were also significantly greater in the empagliflozin vs placebo group (all p<0.05).

“The significantly greater reduction in ferritin in the empagliflozin group supports its potential beneficial effects in alleviating liver inflammation in MASLD,” the investigators suggested.

“Importantly, empagliflozin was safe in nondiabetic subjects, with a low frequency of adverse events [AEs], all of which were short-lasting even without treatment cessation,” they pointed out.

No significant between-group difference in frequency of AEs (p=0.317) was observed in the trial. AEs in the empagliflozin group were all urogenital tract–related, including urinary tract infection (n=1), urinary frequency (n=1), foul-smelling urine (n=1), urinary urgency (n=2), frothy urine (n=2), and genital pruritis (n=2).

Previous randomized controlled trials (RCTs) demonstrated sodium-glucose cotransporter 2 inhibitors’ potential in treatment of MASLD in patients with type 2 diabetes. [BMJ Open Diabetes Res Care 2021;9:e001990; Diabetes Care 2018;41:1801-1808; Diabetes 2020;43:298-305; Diabetes Obes Metab 2019;21:285-292; Open Med (Wars) 2018;13:402-409]

“Further large-scale, multicentre RCTs in diverse populations are needed to verify our results, which could potentially extend the role of empagliflozin in treating nondiabetic MASLD, particularly in patients with metabolic dysfunction–associated steatohepatitis and advanced fibrosis/cirrhosis,” the investigators suggested.