Survodutide Reduces Visceral and Liver Fat in Phase 3 Obesity and MASLD Trials

Boehringer Ingelheim announced full results from two phase 3 trials of survodutide (BI 456906), an investigational glucagon/glucagon-like peptide-1 (GLP-1) receptor dual agonist.¹ The trials, SYNCHRONIZE-1 and SYNCHRONIZE-MASLD, were published simultaneously in the New England Journal of Medicine and Nature Medicine, respectively.^2,3 The company presented the results at the American Diabetes Association 2026 Scientific Sessions.

Both trials met their primary endpoints, with SYNCHRONIZE-1 demonstrating up to 16.6% body weight reduction at 76 weeks in adults with obesity or overweight without type 2 diabetes. SYNCHRONIZE-MASLD showed up to 84.2% of participants achieving at least 30% relative liver fat reduction at 48 weeks in adults with metabolic dysfunction-associated steatotic liver disease (MASLD) with evidence of inflammation or fibrosis.¹

"There is an urgent need for treatments that go beyond weight loss to also address these related conditions," said Lee Kaplan, MD, PhD, director of The Obesity and Metabolism Institute, Boston, and chair of the SYNCHRONIZE program executive committee. "These data reveal that the glucagon/GLP-1 dual agonism of survodutide offers a promising approach for people with obesity and for those with obesity-associated metabolic liver diseases including MASLD [metabolic dysfunction-associated steatotic liver disease] and MASH [metabolic dysfunction-associated steatohepatitis]."

What did the SYNCHRONIZE-1 trial show regarding body composition and metabolic fat outcomes?

SYNCHRONIZE-1 (NCT06066515) was a 76-week, double-blind, placebo-controlled phase 3 trial enrolling 725 adults with obesity or overweight without type 2 diabetes, randomized to weekly subcutaneous survodutide at 3.6 mg or 6.0 mg, or placebo. Using the efficacy estimand, survodutide produced sustained weight loss of up to 16.6% from baseline versus 3.2% with placebo (p<0.0001).

In a prespecified magnetic resonance imaging (MRI) sub-study, survodutide achieved a relative reduction of up to 34.0% in visceral fat volume. Lean mass accounted for no more than 10.8% of total tissue mass change at the highest dose, indicating that weight loss was predominantly driven by fat mass reduction. A prespecified analysis within the same sub-study demonstrated liver fat reduction of up to 63.1% relative to baseline, a finding with potential implications for the prevention of obesity-associated hepatic disease progression.

What did the SYNCHRONIZE-MASLD trial demonstrate in patients with liver disease and obesity?

SYNCHRONIZE-MASLD (NCT06309992) was a 48-week, double-blind, placebo-controlled phase 3 trial that enrolled 218 adults with overweight or obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) with evidence of inflammation or fibrosis, both with and without type 2 diabetes. The participants were randomized to weekly survodutide 6.0 mg or placebo.

The trial met both co-primary endpoints, in which up to 84.2% of survodutide-treated participants achieved at least 30% relative liver fat reduction versus 24.3% with placebo (p<0.0001), and relative body weight reduction reached up to 12.2% versus 1.0% with placebo (p<0.0001). A secondary endpoint showed that 61.0% of survodutide-treated patients reached liver fat normalization (liver fat content <5%) at week 48 versus 5.7% with placebo. Positive trends were observed in alanine aminotransferase levels, a biomarker of hepatic inflammation, across secondary endpoint analyses.

What is the clinical context and unmet need in obesity-associated metabolic liver disease?

More than 1 billion people worldwide are currently living with obesity, a figure projected to exceed 2 billion by 2030.⁴ Up to 75% of individuals with obesity develop MASLD, and approximately 1 in 3 of these patients progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatic inflammation and fibrosis that can advance to cirrhosis and liver failure.⁵ In the United States, MASH cases are projected to rise 63% between 2015 and 2030, from 16.5 million to 27.0 million.⁵

Approved pharmacological options specifically targeting the hepatic manifestations of obesity-related metabolic disease remain limited. Resmetirom (Rezdiffra) received FDA approval for non-cirrhotic MASH with moderate to advanced fibrosis in 2024, but the landscape for combination metabolic benefit, meaning simultaneous weight reduction and hepatic fat clearance, remains largely unaddressed.⁶

What is survodutide's mechanism of action, and how does dual agonism differ from GLP-1 monotherapy?

Survodutide simultaneously activates glucagon and GLP-1 receptors, both of which regulate metabolic function through complementary but distinct pathways.⁷ GLP-1 receptor agonism decreases appetite and increases satiety, consistent with the mechanisms of approved agents such as semaglutide and tirzepatide. Glucagon receptor agonism is hypothesized to act directly on the liver to reduce hepatic fat accumulation, regulate metabolic function, resolve inflammation, and improve fibrosis, effects not attributable to GLP-1 receptor activation alone.⁷

This hepatic-directed mechanism may explain the degree of liver fat reduction observed in both trials relative to body weight change, though the relative contributions of each receptor pathway to clinical outcomes have not been fully delineated. Survodutide is licensed to Boehringer Ingelheim from Zealand Pharma, with Boehringer solely responsible for global development and commercialization. FDA granted survodutide fast track designation in May 2021 and breakthrough therapy designation in September 2024 for MASH with fibrosis.¹

What limitations apply to these results, and what further data are anticipated?

Survodutide remains investigational and has not received approval by any regulatory authority to date. Gastrointestinal (GI) adverse events, including nausea, vomiting, diarrhea, and constipation, were the most common treatment-related events in both trials, which are consistent with GLP-1-based class effects.

Treatment discontinuation due to GI events occurred in 19.0% of survodutide-treated patients in SYNCHRONIZE-1 versus 2.9% with placebo, a rate that could warrant careful attention in broader clinical use. The SYNCHRONIZE-MASLD trial was powered for surrogate endpoints, liver fat content and body weight, rather than histological resolution of MASH or fibrosis regression, which will require biopsy-confirmed outcomes from other ongoing phase 3 trials (LIVERAGE).¹ Additional phase 3 programs in women's health (SYNCHRONIZE-HERA), cardiac function in MASLD (ELEVATE-LIVER), and real-world titration (SYNCHRONIZE-START) are expected to initiate later in 2026.

References

1. Boehringer Ingelheim. Boehringer Ingelheim’s survodutide Phase III trial showed targeted 34% visceral and 63% liver fat reduction, while minimizing lean mass loss in pre-specified analysis, supporting improved metabolic health in people living with obesity. Published June 7, 2026. Accessed June 9, 2026. https://www.boehringer-ingelheim.com/human-health/crm-health/metabolic-health/survodutide-phase-3-fat-loss-obesity-dual-agonist-data
2. le Roux CW, Wharton S, Startseva E, et al. Survodutide once weekly for the treatment of adults with obesity. N. Engl. J. Med. 2026. doi:10.1056/NEJMoa2600751
3. Kaplan LM, Startseva E, le Roux CW, et al. Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 2026. doi:10.1038/s41591-026-04479-3
4. World Obesity Federation. World Obesity Atlas 2023. World Obesity Federation, 2023. Accessed June 9, 2026. https://www.worldobesity.org
5. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431
6. Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
7. Ambery P, Parker VE, Stumvoll M, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes. Lancet. 2018;391(10140):2607-2618. doi:10.1016/S0140-6736(18)30726-8