Novel agents that act on multiple receptor pathways are showing potential in the management of fatty liver disease, according to data presented recently at the American Diabetes Association (ADA) 83rd Scientific Sessions.

Retatrutide, a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors, featured at the meeting for its potential in managing type 2 diabetes, obesity and NAFLD.

In a phase 2 study, concurrently published in The Lancet [link here], retatrutide delivered clinically meaningful improvements in glycaemic control in adults with type 2 diabetes and a BMI of 25–50 compared to dulaglutide.

A second phase 2 study, published in the NEJM [link here], found retatrutide led to a mean weight reduction of 24.2% after 48 weeks in participants with obesity (BMI ≥30) or overweight (BMI 27-30) with at least one weight-related condition. It found 92% of participants achieved a bodyweight reduction of ≥5%, 75% achieved ≥10% and 60% achieved ≥15%.

Professor Arun Sanyal, director of the Stravitz Sanyal Institute for Liver Disease and Metabolic Health at the Virginia Commonwealth University, also presented the results from a subset of patients with both obesity and NAFLD.

It found a relative liver fat reduction with all doses of retatrutide (1mg, 4mg, 8 mg, 12 mg) compared to placebo at weeks 24 and 48. The mean liver fat reduction was >80% with the higher doses of 8mg and 12mg.

The meeting also heard that 8mg and 12 mg retatrutide was associated with a relative liver fat reduction of ≥30% in all patients (both 100%), ≥50% in 95% and 100% of patients respectively, and ≥70% in 86% and 80% respectively.

Hepatic steatosis resolved (<5% fat) at week 48 in 89% of participants receiving 8mg retatrutide and 93% receiving the 12 mg dose.

The study also found that NASH biomarkers cytokeratin 18 (K-18) and the pro-peptide of type lll collagen (Pro-C3) decreased with the higher doses of retatrutide than placebo.

Retatrutide, the triple G, Glucagon-GIP-GLP-1 based triagonist produces substantial resolution of liver fat #NAFLD in PPL with #obesity #ADA2023 @ADA_DiabetesPro @AmDiabetesAssn #NASH trial coming pic.twitter.com/V2y4qZ6dEA

— Daniel J Drucker (@DanielJDrucker) June 26, 2023

The most frequently reported adverse events were mild to moderate gastrointestinal events including nausea, diarrhoea, vomiting, and constipation.

Another study presented at ADA 2023 and published in NEJM [link here], showed some promise with a long-acting glycopegylated fibroblast growth factor 21 (FGF21) analogue.

The phase 2b study randomised 222 patients with biopsy-confirmed NASH and stage F2 or F3 fibrosis to either subcutaneous pegozafermin (15 mg or 30 mg weekly or 44 mg once every 2 weeks) or placebo (weekly or every 2 weeks).

It found the percentage of patients with an improvement in fibrosis of at least one stage without worsening of NASH was significantly higher with pegozafermin than with placebo (22-27% v 7%).

As well, the percentage of patients with NASH resolution without worsening of fibrosis was 23-37% in the pegozafermin arms compared to 2% in the placebo arm.

The most frequent adverse events were nausea, diarrhoea, and injection-site erythema.

Meanwhile, the ADA has also updated its Standards of Care in Diabetes – 2023 [link here] to include new recommendations on NAFLD in the section on comorbidities. They include recommendations for:

• lifestyle changes that promote weight loss in people with diabetes, obesity and NAFLD
• consideration of a GLP-1 receptor agonist for people with diabetes, obesity and NAFLD
• metabolic surgery as an option in adults with type 2 diabetes and NASH

The retatrutide studies were funded by Eli Lilly; pegozafermin by 89bio.