Efinopegdutide beats semaglutide at reducing liver fat in NAFLD patients

Treatment with the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide results in a greater decrease in liver fat content (LFC) relative to the GLP-1 receptor agonist semaglutide in patients with nonalcoholic fatty liver disease (NAFLD), results of a phase IIa trial have shown.

“Treatment with efinopegdutide was also generally well tolerated, with a tolerability profile similar to that of semaglutide,” the researchers said.

LFC was determined by performing a magnetic resonance imaging-estimated proton density fat fraction assessment at screening and week 24. One hundred forty-five NAFLD patients with an LFC ≥10 percent at screening were randomly assigned to receive either efinopegdutide 10 mg (n=72) or semaglutide 1 mg (n=73), both administered subcutaneously once weekly for 24 weeks.

The researchers then stratified participants according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week period.

Of the NAFLD patients, 33.1 percent had T2DM. Their mean LFC at baseline was 20.3 percent, while the mean BMI was 34.3 kg/m². [J Hepatol 2023;79:888-897]

At week 24, the least squares (LS) mean relative reduction in LFC from baseline was significantly greater with efinopegdutide (72.7 percent, 90 percent confidence interval [CI], 66.8‒78.7; p<0.001) than with semaglutide (42.3 percent, 90 percent CI, 36.5‒48.1 percent). Both medications achieved an LS mean percent decrease in body weight from baseline at week 24.

“The substantial benefit of therapy with efinopegdutide on reducing liver fat is likely due to the complementary dual mechanisms of action of GLP-1 and glucagon receptor agonism, which together lead to improvements in the core pathophysiologic defects associated with NAFLD,” the researchers said.

However, the incidence of adverse events (AEs) and treatment-related AEs were slightly higher with efinopegdutide than with semaglutide, most of which were associated with an imbalance in gastrointestinal AEs.

These findings supported two previous phase II studies examining the use of efinopegdutide in obese patients with and without T2DM, which also reported dose-dependent gastrointestinal AEs (ie, nausea and vomiting). [Clin Obes 2021;11e12432; Clin Obes 2021;11e12433]

“There were otherwise no meaningful differences between the two treatment groups in the incidence of overall, serious, or drug-related AEs, including AEs that led to discontinuation,” the researchers said.

NASH

It should be noted that the current study was initiated prior to the availability of the higher-dose semaglutide (2.4 mg weekly), which has been approved for the treatment of obesity and is being evaluated in a phase III study as a potential treatment for patients with nonalcoholic steatohepatitis (NASH), according to the researchers.

Earlier studies with higher doses of semaglutide showed reductions in liver fat ranging from 36 percent to 46 percent at 6 months. The minimum threshold for histologic response in NASH patients is 30 percent. [Aliment Pharmacol Ther 2021;54:1150-1161; J Hepatol 2022;77:607-618; J Hepatol 2022;77:S10; Gut 2022;71:983-990]

“The substantial proportion of participants achieving over 50 percent and over 70 percent reduction in liver fat in the efinopegdutide group, with approximately two-thirds of the population normalizing their liver fat concentration, suggests that robust effects on steatohepatitis may be achievable with co-agonists that target both the GLP-1 receptor and the glucagon receptor,” the researchers said.

“Further studies are needed to evaluate the effects of efinopegdutide on histologic endpoints in patients with NAFLD/NASH,” they added.