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Jump to Key Points MILAN — The investigational glucagon/GLP-1 receptor dual agonist survodutide produced sustained weight loss and improved glycemic control in adults with obesity and type 2 diabetes (T2D) over approximately 18 months in the phase 3 SYNCHRONIZE-2 trial.
“We also saw improvements in other cardiometabolic parameters, with a safety profile consistent with therapies with GLP-1 receptor agonist activity,” said Sean Wharton, MD, PharmD, of McMaster University, Hamilton, and the University of Toronto, Toronto, both in Canada, who presented the results here at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting.
The study was simultaneously published online in The New England Journal of Medicine.
Survodutide is a once weekly dual agonist of the glucagon and GLP-1 receptors. As previously reported by Medscape Medical News, the investigational drug reduced body weight in people with obesity but without diabetes in the SYNCHRONIZE-1 trial.
- Survodutide 3.6/6.0 mg weekly met both primary endpoints in obesity + T2D.
- Week 76 weight loss: 13.1% with 6.0 mg vs 3.1% placebo.
- ≥5% weight loss: 57.6% (3.6 mg), 64.5% (6.0 mg) vs 35.1% placebo.
- A1c fell 0.8-0.9%; placebo-adjusted reduction 1.1-1.2 points.
- GI AEs common; discontinuation ~26% vs 8.8% placebo; tolerability limits use.
However, “we know that people living with type 2 diabetes generally lose less weight than people without type 2 diabetes,” Wharton said, highlighting the significance of the weight reductions achieved in SYNCHRONIZE-2.
Study Details, Weight Loss
The double-blind trial included 752 treated participants with T2D and a BMI of at least 27, who were randomly assigned to once-weekly subcutaneous survodutide 3.6 mg, survodutide 6.0 mg, or placebo. Treatment continued for 76 weeks alongside a reduced calorie diet and increased physical activity.
Participants had a mean age of 55.7 years, mean BMI of 36.5, a mean body weight of 104.1 kg, and a mean A1c level of 7.4% at baseline. Approximately 66% were White and 26% were Asian. The primary endpoints, assessed from baseline to week 76, were percentage change in body weight and the proportion of participants achieving at least 5% weight loss. Key secondary endpoints included the proportions achieving at least 10%, 15%, and 20% weight loss, as well as changes in A1c, waist circumference, systolic blood pressure, absolute body weight, and patient-reported eating behavior.
Both primary endpoints were met. In the treatment-regimen analysis, 57.6% of participants receiving 3.6 mg and 64.5% receiving 6.0 mg achieved at least 5% weight loss compared with 35.1% receiving placebo (P < .001 for both comparisons).
In addition, higher weight-loss thresholds were also reached more frequently with survodutide. With the 6.0-mg dose, 45.8% of participants lost at least 10% of their body weight, 25.5% lost at least 15%, and 11.2% lost at least 20% compared with 11.2%, 4.0%, and 1.6%, respectively, with placebo.
Wharton highlighted the sustained separation of the weight-loss curves in the efficacy analysis, in which mean weight loss at week 76 reached 13.1% with the 6.0-mg dose compared with 3.1% with placebo.
Glycemic Control
Survodutide also improved glycemic control. From a mean baseline of 7.4%, A1c levels decreased by 0.9 percentage points with 3.6 mg, and 0.8 percentage points with 6.0 mg under the treatment-regimen estimand, compared with 0.2 percentage points with placebo. In the efficacy analysis, the placebo-adjusted reductions were 1.2 and 1.1 percentage points, respectively.
Presenting an analysis according to baseline A1c levels, Wharton drew attention to the greater absolute reductions among participants starting with higher A1c levels. Among participants with a baseline A1c less than 8.5%, levels fell by 1.06 percentage points with both survodutide doses; among those starting with an A1c of 8.5% or higher, levels fell by approximately 2.0 percentage points.
This gives “an impression of what the molecule can do if you have an elevated A1c,” said Wharton.
The trial also showed improvements in several cardiometabolic measures. High-sensitivity C-reactive protein fell by 50.2% with survodutide 3.6 mg and 53.4% with 6.0 mg compared with 17.0% with placebo.
Adverse Events
Gastrointestinal adverse events were common, occurring in 72.8% and 77.7% of participants receiving survodutide 3.6 mg and 6.0 mg, respectively, compared with 38.6% receiving placebo. The most frequent gastrointestinal events were nausea, reported in 47.6% and 57.4% of participants receiving survodutide 3.6 mg and 6.0 mg, respectively, compared with 11.2% of participants receiving placebo; vomiting, reported in 34.4%, 39.0%, and 5.6%, respectively; and diarrhea, reported in 26.4%, 30.7%, and 12.4%, respectively.
Wharton noted that gastrointestinal events were generally mild to moderate and occurred “mainly during the dose-escalation period.”
However, adverse events led to discontinuation of study treatment in 26.4% and 25.9% of participants receiving the two survodutide doses compared with 8.8% of participants receiving placebo. Gastrointestinal adverse events specifically led to discontinuation in approximately 18% of participants in both survodutide groups compared with 1.2% of participants receiving placebo.
The investigators noted that the relatively strict dose-escalation schedule used for much of the trial may have contributed to the gastrointestinal adverse event burden, suggesting that slower and more flexible escalation could potentially improve tolerability and treatment adherence.
Substudy Results From SYNCHRONIZE-1: Efficacy Must Be Balanced Against Tolerability
Independent commentator Andreas L. Birkenfeld, MD, of the Helmholtz Munich at the University of Tübingen, Neuherberg, Germany, described survodutide as demonstrating “robust efficacy,” but identified tolerability as the key caveat, particularly given the gastrointestinal adverse events and treatment discontinuations seen in SYNCHRONIZE-2.
“Its ultimate role needs to be defined by the efficacy-tolerability balance, not by efficacy alone,” he said, adding that the drug’s “clinical positioning is still evolving.”
Birkenfeld also highlighted the body composition findings from the SYNCHRONIZE-1 substudy, calling them an “encouraging quality of weight loss.”
Survodutide remains investigational and has not been approved by regulatory agencies.
The trial was funded by Boehringer Ingelheim. Wharton reported receiving honoraria and/or serving on advisory boards for AbbVie, Amgen, AstraZeneca, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly, i2o Therapeutics, Merck, Metsera, NGX, Novo Nordisk, and Regeneron. He also reported receiving clinical trial funding from AstraZeneca, Amgen, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly, Merck, Metsera, Novo Nordisk, and York University. The SYNCHRONIZE-2 trial was funded by Boehringer Ingelheim. Birkenfeld reported receiving research support from AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo; serving as a principal investigator or in trial leadership roles for Novo Nordisk, Boehringer Ingelheim, Eli Lilly, and Bayer; and serving on advisory boards for AstraZeneca and Bayer. Kirsi H. Pietiläinen, MD, reported advisory board membership with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Vivus, and receiving presentation fees from AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Orion, and UCB. Editorial support for the presentation was contracted and funded by Boehringer Ingelheim, the study sponsor. Survodutide is licensed to Boehringer Ingelheim from Zealand Pharma.
Becky McCall is a UK-based medical journalist and researcher who writes for Medscape Medical News and other medical and scientific publications. Her research at University College London focuses on antimicrobial resistance and the use of digital storytelling in health research.
