Loading ...

NEW ORLEANS — Survodutide, an investigational glucagon receptor/GLP-1 receptor dual agonist, produced significant weight loss along with reductions in visceral fat and liver fat in two phase 3 trials. 

“What we’re seeing here is a drug that has a very good effect on obesity, [and a] very good effect on liver disease,” said Lee Kaplan, MD, PhD, director of the Obesity, Metabolism, & Nutrition Institute in Boston, who presented the results of one of the trials, SYNCHRONIZE-MASLD, here at the American Diabetes Association (ADA) 2026 Scientific Sessions. 

The data from the trial of survodutide in adults with obesity or overweight who had metabolic dysfunction-associated steatotic liver disease (MASLD) with evidence of inflammation and/or fibrosis, both with and without type 2 diabetes (T2D), were simultaneously published in Nature Medicine. 

The drug’s “GLP‑1 agonism decreases appetite while increasing fullness and satiety, while its glucagon agonism is thought to directly act on the liver to reduce hepatic fat, regulate metabolic function, resolve inflammation, and improve fibrosis,” said Kaplan, who is also the SYNCHRONIZE program executive committee chair. 

This could be a favored therapy for patients with obesity and liver disease,” he told Medscape Medical News.

The results from the SYNCHRONIZE-1 trial of survodutide in adults with obesity without diabetes were also presented at the meeting, and concurrently published online in the New England Journal of Medicine. 

Weight and Visceral Fat Loss in People With Obesity

In the SYNCHRONIZE-1 trial, 725 adults with obesity or overweight without T2D were randomly assigned to receive weekly injections of survodutide in doses of 3.6 mg (n = 241) or 6.0 mg (n = 242), or placebo (n = 242) for 76 weeks. All received counseling on nutrition and physical activity, and were encouraged to follow a reduced-calorie diet (with a deficit of 500 kcal/day relative to total daily energy expenditure) and engage in at least 150 minutes per week of moderate intensity exercise. 

The efficacy and safety results for the trial were presented at the meeting by lead author Carel le Roux, MBChB, PhD, professor of experimental pathology, Conway Institute, Diabetes Complications Research Centre, University College, Dublin, Ireland.

For the treatment-regimen estimand, mean weight loss at week 76 was 12.2% with 3.6 mg survodutide, and 13.0% with the 6.0 mg dose, compared to 5.4% with placebo. Both differences were statistically significant (P < .001). More than 70% of those in both treatment groups had body weight reductions of at least 5% at 76 weeks compared with 46.3% with placebo (odds ratio [OR], 3.1 and 3.0 for the two doses, respectively; P < .001 for both), le Roux reported. 

Among 25 participants in each group who underwent MRI body composition analysis, the 6.0-mg survodutide group showed reductions of 27.8% in total body fat, 34.0% in visceral fat, 63.1% in liver fat, and 9.8% in lean body volume, vs reductions of 9.5%, 11.8%, 24.5%, and 2.9%, respectively, with placebo. 

The overall trial population had reductions in waist circumference, A1c and fasting plasma glucose levels, and cardiometabolic risk factors, and also showed improvements in Eating Behavior Patient-Reported Outcome scores. 

As with all GLP-1-based therapies, gastrointestinal adverse events were more common with survodutide than placebo. These occurred mostly during dose escalation and were mild to moderate in severity. Serious adverse events occurred in 8.3% in the 3.6 mg group, 8.3% in the 6.0 mg group, and in 6.2% in the placebo group. Discontinuation due to gastrointestinal adverse events occurred in 17.8% of the 3.6 mg group and 20.2% with 6.0 mg, vs 2.9% with placebo, he said. 

No severe hypoglycemia was reported, and hyperglycemia was less common in the survodutide groups than in the placebo group.

SYNCHRONIZE-MASLD

In the SYNCHRONIZE-MASLD trial, 218 adults with obesity/overweight and MASLD with evidence of inflammation and/or fibrosis were randomly assigned to weekly injections of 6.0 mg survodutide (n = 146) or placebo (n = 70; two participants were not treated) for 48 weeks. All participants also received the same lifestyle counseling as in SYNCHRONIZE-1. 

Based on the efficacy estimand, 84.2% of participants treated with survodutide had a 30% or greater reduction in liver fat content, as assessed by MRI-proton density fat fraction (MRI-PDFF) at week 48, compared with 24.3% in the placebo group (OR, 17.3; P < .0001), Kaplan reported. 

Using the efficacy estimand, 75.3% of participants had a reduction of liver fat content of 50% or greater with 6.0-mg survodutide vs just 8.6% with placebo, while 55.5% in the survodutide group had liver fat content reductions of 70% or greater, vs 2.9% in the placebo group (P < .0001 for both). In addition, the proportions with liver fat content of < 5% at week 48 were 61.0% with survodutide vs 5.7% with placebo (P < .0001). The mean relative change in liver fat content was a drop of 58.7% with 6.0-mg survodutide vs 9.5% with placebo (P < .0001). 

At week 48, the mean change in body weight was a reduction of 12.2% with survodutide vs just 1.0% with placebo (P < .0001). More than three fourths of participants (79.1%) had a body weight reduction of ≥ 5% with survodutide treatment vs 14.3% in the placebo group. 

As in SYNCHRONIZE-1, most gastrointestinal events (predominantly nausea, vomiting, diarrhea, and constipation) occurred primarily during the dose-escalation period and were mild to moderate in intensity. They resulted in treatment discontinuation in 19.9% of participants receiving survodutide vs 4.3% of the placebo group. The incidence of serious adverse events was higher in the placebo group (11.4%) than in the survodutide treatment group (9.6%), Kaplan noted. 

Boehringer Ingelheim is conducting two other global phase 3 trials of survodutide: SYNCHRONIZE-2 in adults with T2D, and SYNCHRONIZE-CVOT in patients with cardiovascular disease, chronic kidney disease, or with risk factors for cardiovascular disease. Other SYNCHRONIZE trials are taking place in China and Japan. 

Additional phase 3 trials, LIVERAGE and LIVERAGE-Cirrhosis, will investigate the efficacy and safety of survodutide in adults with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stages 2 or 3, and in those with compensated MASH cirrhosis (fibrosis stage 4), respectively.

Looking Beyond Weight Loss

Asked to comment, ADA Senior VP of Medical Affairs Joshua J. Neumiller, PharmD, CDCES, told Medscape Medical News, “There are definitely a lot of various combinations, triple dual agonists in the pipeline, but this one’s a little unique compared to what we currently have with that GLP-1/glucagon co-agonist mechanism.

“The glucagon appears to have very good effects on visceral fat restructuring and certainly on the MASH/MASLD landscape,” and the data showed good weight loss, added Neumiller, a professor of pharmacotherapy at Washington State University College of Pharmacy and Pharmaceutical Sciences in Spokane.

“I like how these studies are looking beyond just the weight loss to the more comprehensive addressing of cardiovascular and other metabolic risk factors,” he said.

Neumiller pointed out that semaglutide (Wegovy) is already provisionally approved for the treatment of MASH with fibrosis but not cirrhosis. 

The various approaches are moving things closer to a personalized medicine approach, “where we’re going to have to look at the various risk factors for an individual,” he noted, while acknowledging that it was “kind of early in the story.” 

“As the data evolve, we’re going to have to see how these various agents work within the larger framework. They may have niche areas based on the data. I think that’s to be determined,” he concluded. 

Kaplan has served as a scientific and medical consultant to Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Dexligo, Dil Figaro, Eli Lilly, Helicore, Johnson & Johnson, Kallyope, The Last Food Fight, MetaVia, Neurogastrx, Novo Nordisk, Optum Health, Oxford Medical Products, Perspectum, Pfizer, Roche/Genentech, Skye Bioscience, State 4 Therapeutics, Structure Therapeutics, and Wave Life Sciences. 

Le Roux serves on advisory panels for Novo Nordisk, Lilly, Amgen Inc., Boehringer Ingelheim International GmbH, Pfizer Inc., AstraZeneca, Roche Pharmaceuticals, Herbalife International of America, Inc., Arrowhead Pharmaceuticals, Inc., and Medtronic. 

Neumiller is an employee of ADA with no further disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social