The glucagon/GLP-1 dual agonist hit both weight loss endpoints in phase 3, though gastrointestinal discontinuations and competitor data temper the readout.
Survodutide, an investigational glucagon/glucagon-like peptide-1 (GLP-1) receptor dual agonist, met both co-primary endpoints in the phase 3 SYNCHRONIZE-2 trial in adults with overweight or obesity and type 2 diabetes. Results were presented Oct. 1 at the European Association for the Study of Diabetes annual meeting in Milan and published in The New England Journal of Medicine.1,2
The readout advances the program, but its weight loss figures and an 18% discontinuation rate tied to gastrointestinal events will shape positioning in a crowded incretin market.1,3
“Obesity and type 2 diabetes are deeply intertwined, with excess weight increasing the risk of [type 2 diabetes (T2D)]. For people living with these conditions, sustained weight loss is often a biological struggle rather than a lack of willpower,” said Sean Wharton, MD, PharmD, the trial’s coordinating investigator. “These results are encouraging because, in obesity medicine, clinicians increasingly recognize the opportunity to address multiple interconnected health conditions together. Seeing improvements in glycemic control and insulin sensitivity alongside weight loss provides evidence that tackling obesity can positively influence broader metabolic health. This brings new optimism to people seeking more effective ways to improve their overall health.”1
The double-blind trial randomly assigned 755 adults to weekly survodutide 3.6 mg or 6.0 mg, or placebo, for 76 weeks. Co-primary endpoints were percentage change in body weight and the share of participants losing at least 5% of body weight.1
Under the efficacy estimand, which assumes participants stayed on treatment, mean weight loss reached up to 13.1% vs 3.1% with placebo, and up to 79.3% of treated participants lost at least 5% vs 32.7%. The sponsor notes those P values are nominal.1 The journal publication emphasizes the treatment-regimen estimand, which counts outcomes regardless of discontinuation; on that basis, weight loss was 9.8% with 6.0 mg and 8.2% with 3.6 mg vs 3.9% with placebo.3
From a baseline hemoglobin A1c of 7.4%, levels fell by up to 1.21 percentage points vs 0.03 with placebo, and up to 29.5% of treated participants reverted to normoglycemia vs 4.0%, under the efficacy estimand.1
Nausea, vomiting, diarrhea, and constipation were the most frequent adverse events and were mostly mild to moderate. Gastrointestinal events led 18% of survodutide recipients to discontinue vs 1.2% on placebo, usually during dose escalation. The sponsor attributed this partly to a rigid titration protocol and said newer trials allow more flexibility.1
More than 1 billion people live with obesity, a central risk factor for type 2 diabetes.1 Pharmacologic weight loss is generally smaller in people with diabetes, which is why sponsors test the 2 populations separately. Other incretin-based candidates presented at the same meeting produced greater weight loss.3
Glucagon typically raises blood glucose. The rationale for survodutide is that a specific balance of glucagon and GLP-1 receptor agonism, combined with liver fat reduction, may preserve glycemic control while driving weight loss.1 An imaging substudy of 75 participants in the companion SYNCHRONIZE-1 trial reported preferential loss of visceral and liver fat, with muscle accounting for no more than 10% of tissue lost.
In a phase 2 dose-finding trial in adults without diabetes, survodutide 4.8 mg produced up to 14.9% weight loss over 46 weeks vs 2.8% with placebo.4 SYNCHRONIZE-1 later reported up to 16.6% vs 3.2% at 76 weeks.3 Survodutide also holds US Breakthrough Therapy and European Medicines Agency PRIME status for metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis.
Boehringer Ingelheim licensed the molecule from Zealand Pharma in 2011. Zealand shares fell more than 8% in Copenhagen after the release, extending a decline that followed the SYNCHRONIZE-1 data in June.3
The trial used only a placebo comparator, so performance against approved incretin therapies is unknown. The gap between estimands and the discontinuation rate bear directly on real-world durability. Survodutide is not approved in any market.
“The growing body of evidence from our SYNCHRONIZE Phase III program continues to strengthen our understanding of survodutide’s potential in people living with obesity, including those with type 2 diabetes. The SYNCHRONIZE-2 results demonstrate meaningful weight loss alongside improvements in glycemic control and other key markers of metabolic health, reinforcing our belief that obesity should be addressed as a complex chronic disease with interconnected health consequences,” said Shashank Deshpande, chairman of the board of managing directors and head of human pharma at Boehringer Ingelheim. “We remain committed to advancing innovative treatment approaches that address the diverse needs of people living with obesity across different stages of disease and risk profiles.”1
Cardiovascular outcomes data from SYNCHRONIZE-CVOT are expected later this year, and phase 3 trials in glycemic control and MASH are ongoing.1
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