Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is approaching a global epidemic with an estimated prevalence of 32.4%. Sodium glucose cotransporter-2 (SGLT2) inhibitors are effective in treating MASLD patients with diabetes mellitus (DM) and also improve outcomes in patients with heart failure and chronic kidney disease regardless of DM status, no randomized controlled trial has explored the role of SGLT2 inhibitors specifically in MASLD patients without DM.

Aim

To investigate the effect of empagliflozin on hepatic steatosis in MASLD patients without DM

Patient Profile

• 98 MASLD patients with magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥5% and without DM (fasting plasma glucose <7mmol/L and glycosylated hemoglobin, HbA1c <6.5%)

  Method

  Study Design

• Randomized, double-blind, placebo-controlled trial
• Patients received empagliflozin 10 mg daily or placebo till the end of treatment (EOT) at 52 weeks
• Liver fat content was measured by MRI-PDFF at baseline and at EOT

Endpoints

• Primary outcome: difference in the change of liver fat content between the two groups at EOT
• Secondary outcomes: hepatic steatosis resolution (MRI-PDFF <5%), ALT drop >17U/L, MRI-PDFF decline >30%, combination of both (ALT drop >17U/L and MRI-PDFF decline >30%)
• Other outcomes: change in serial anthropometric parameters (body weight, BMI, waist circumference and blood pressure), ferritin, serial liver function parameters, serial creatinine, and serial metabolic parameters

Results

Efficacy

• Empagliflozin achieved greater reduction in the liver fat content as compared to placebo (change in median MRI-PDFF by ITT analysis –2.49% vs –1.43%; p=0.025 and by PP analysis –2.49% vs –1.47; p=0.033) (Figure 1)

   

  Figure 1: Effect of empagliflozin in comparison with placebo on liver fat content

  

• Empagliflozin significantly reduced the liver fat content among patients aged ≥60 years (–2.40% vs –0.89%; p=0.025), female subjects (–2.76% vs –0.97%; p=0.012), OWOB subjects (–2.47% vs –1.10%; p=0.019) and those with baseline ALT ≤30 U/L (–2.46% vs –1.09%; p=0.005)

• A non-significant resolution of hepatic steatosis was observed with empagliflozin (44.9% vs 28.6%; p=0.094)
• No significant difference observed in ALT drop >17U/L (16.3% vs 12.2%; p=0.564), MRI-PDFF drop >30% (49.0% vs 40.8%; p=0.417), and composite outcome (8.2% vs 8.2%; p=1.000)
• Empagliflozin led to greater reduction in body weight (–2.7 vs – 0.2 kg; p<0.001), waist circumference (–2.0 vs 0 cm), fasting glucose (–0.3 vs 0 mmol/L, p<0.001) and ferritin levels (–126 vs –22 pmol/L; p=0.035), in which a significant difference was seen as early as week 12 (–91.0 vs –4.0pmol/L; p=0.007)
• At EOT, a significant reduction in ALP between two groups was observed (–2.0 vs 1.0U/L; p=0.034)

Safety 

• No significant difference seen in frequency of known empagliflozin-related side effects (p=0.317)
• Adverse events that occurred in empagliflozin group were all urogenital tract-related, including urinary tract infection, urinary frequency, foul-smelling urine, urinary urgency, frothy urine and genital pruritis (all p>0.05)
• No serious adverse events or suspected unexpected serious adverse reactions were reported

Conclusion

• Empagliflozin treatment for 52 weeks significantly reduced liver fat content to a greater degree than placebo in non-diabetic MASLD patients, which was associated with reduction in serum ferritin, fasting glucose and anthropometric parameters
• Empagliflozin was safe even in non-diabetic subjects, with a low frequency of short-term AEs, without treatment cessation
• This was the first randomized, double-blind, placebo-controlled trial investigating the effect of empagliflozin on hepatic steatosis in MASLD patients without DM

Hepatol 2024 doi:10.1097/hep.0000000000000855