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Efinopegdutide Cuts Liver Fat More Than Semaglutide in 24 Weeks
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EASL Congress 2023, June 21-24, Vienna
Mark Mascolini
Efinopegdutide, a glucagon-like peptide (GLP)-1/glucagon dual receptor agonist designed to lower liver fat, helped people with nonalcoholic fatty liver disease (NAFLD) lose significantly more liver fat content than semaglutide, a licensed drug that stimulates only the GLP-1 receptor, in a 145-person, 24-week randomized comparison [1].
By activating GLP-1 receptors and glucagon receptors, efinopegdutide and pemvidutide trim liver fat in several ways: They reduce caloric intake and weight, increase energy expenditure, stimulate fatty acid oxidation, and reduce lipogenesis. Another study presented at EACS and reviewed separately by NATAP found large drops in liver fat content with pemvidutide over 12 to 24 weeks [2]. If either drug gets licensed, it would be the first therapy approved for nonalcoholic steatohepatitis (NASH), a severe form of NAFLD.
This phase 2a open-label trial of efinopegdutide recruited men and women 18 to 70 years old who had NAFLD with liver fat content at or above 10% by MRI-PDFF scan [3] and a body mass index (BMI) from 25 to 50 kg/m2 with stable weight [1,4]. Researchers randomized 145 people to efinopegdutide or to semaglutide, a GLP-1 agonist licensed to manage diabetes and obesity. Both medications were given subcutaneously once weekly. Starting doses of 2.4 mg for efinopegdutide and 0.25 mg for semaglutide were raised to 5.0 and 0.5 mg at week 4, and to 10.0 and 1.0 mg at week 8.
Researchers assigned 72 people to efinopegdutide and 73 to semaglutide. Men made up 55% of the study group, 86% were white, 10% Asian, and 35% Hispanic. One third of each group had type 2 diabetes. BMI averaged 35.2 kg/m2 in the efinopegdutide group and 33.5 kg/m2 in the semaglutide group, while respective liver fat content averaged 21.1% and 19.4%
The trial's primary efficacy endpoint-least squares mean relative reduction in liver fat content from baseline to week 24-was significantly greater with efinopegdutide than with semaglutide (-72.7% vs -42.3%, difference -30.4%, 90% confidence interval -38.7% to -22.1%, P < 0.001). Median relative 24-week reduction in liver fat content also proved greater with efinopegdutide than with semaglutide (-83.8% vs -44.4%).
Higher proportions of people randomized to efinopegdutide than to semaglutide had 24-week relative reductions in liver fat content at or above 30% (81.9% vs 67.1%), at or above 50% (77.8% vs 43.8%), and at or above 70% (70.8% vs 12.3%). And a bigger fraction of people assigned efinopegdutide than semaglutide reached normal liver fat content (below 5%) at week 24 (66.7% vs 17.8%).
Week-24 least squares mean relative reduction in body weight was marginally (but not significantly) greater with efinopegdutide than with semaglutide (-8.5% and -7.1%, P = 0.085). Relative reduction in liver fat content at 24 weeks by weight-loss category (at or below 5%, above 5% to at or below 10%, and above 10%) always proved greater with efinopegdutide (-52.4%, -76.6%, and -86.2%) than with semaglutide (-13.4%, -39.6%, and -64.2%).
Declines in liver enzymes ALT and AST through 24 weeks were similar in the two study arms. A higher proportion taking efinopegdutide than semaglutide (63.9% vs 47.9%) had drug-related adverse events, but only 1 person in each study arm had a serious adverse event, and none in either arm had a drug-related serious adverse event. Three people randomized to efinopegdutide (4.2%) and none randomized to semaglutide stopped treatment because of a drug-related adverse event. Gastrointestinal adverse events (usually nausea or diarrhea) affected 56.9% randomized to efinopegdutide and 52.1% randomized to semaglutide
A phase 2b trial of efinopegdutide is planned to begin in mid-2023 [5].
References
1. Romero Gomez M, Lawitz E, Shankar RR, et al. A phase 2a, randomized, active-comparator-controlled, open-label study to evaluate the efficacy and safety of efinopegdutide in individuals with non-alcoholic fatty liver disease. EASL Congress 2023, June 21-24, Vienna. Abstract OS-060.
2. Harrison S, Tomah S, Suschak J, et al. Pemvidutide, a GLP-1/glucagon dual receptor agonist, significantly reduces liver fat, fibro-inflammation, and body weight in patients with non-alcoholic fatty liver disease: a 24-week multicenter, randomized, double-blind, placebo-controlled trial. EASL Congress 2023, June 21-24, Vienna. Abstract OS-063.
3. Caussy C, Reeder SB, Sirlin CB, Loomba R. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018;68:763-772. doi: 10.1002/hep.29797. https://journals.lww.com/hep/Abstract/2018/08000/Noninvasive,_Quantitative_Assessment_of_Liver_Fat.32.aspx
4. ClinicalTrials.gov. A study of efinopegdutide (MK-6024) in participants with nonalcoholic fatty liver disease (NAFLD) (MK-6024-001). ClinicalTrials.gov identifier NCT04944992. https://classic.clinicaltrials.gov/ct2/show/NCT04944992
5. ClinicalTrials.gov. A study of efinopegdutide (MK-6024) in participants with precirrhotic nonalcoholic steatohepatitis (NASH) (MK-6024-013). ClinicalTrials.gov identifier NCT05877547. https://classic.clinicaltrials.gov/ct2/show/NCT05877547
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