Why it matters: According to Zealand Pharma, the November 9 SYNCHRONIZE-CVOT results complete the registrational Phase 3 program intended to support Boehringer’s planned regulatory submissions for obesity. Boehringer describes it as “the first and only global cardiovascular safety trial of a glucagon/GLP-1 dual agonist to date.”
In the company’s press release, trial principal investigator Biykem Bozkurt of Baylor College of Medicine emphasized the need for obesity treatments that address not only weight loss but also metabolic dysfunction “while maintaining cardiovascular safety.”
Zealand’s shares closed 5.2% higher at DKK245 on Monday and extended their gains on Tuesday, trading at DKK247.80, up another 1.1%, at noon in Copenhagen.
However, the results have also prompted questions about survodutide’s tolerability and competitiveness. “The GI adverse event rates are higher compared with GLP-1 RA such as semaglutide or dulaglutide or even GLP-1RA/GIP agonist tirzepatide,” Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles who has served on US Food and Drug Administration advisory committees, told European Biotechnology.
“All 3 of these agents have approved indication for reducing CV outcomes in patients with diabetes (Ozempic, Trulicity, Mounjaro), CKD (Ozempic), obesity or overweight (Wegovy). With availability of proven therapies, it is not clear to me what unique attribute does this GLP-1RA/Glucagon receptor agonist offer!” Kaul added.
(Kaul disclosed consulting work for Novo Nordisk, the maker of semaglutide, in a September 2026 journal publication.)
“These trials differ in their populations, design, endpoints and statistical objectives, so direct cross-trial comparisons are not appropriate,” Boehringer Ingelheim responded in comments to European Biotechnology. “What matters is the breadth and totality of evidence.” The company pointed to SYNCHRONIZE-1 substudy results showing up to a 34% relative reduction in visceral fat, with lean mass accounting for no more than 11.3% of the change in total tissue mass at the highest dose.
By the numbers: The trial, published in The Lancet and presented at the American Heart Association’s Scientific Sessions, randomized 5,530 adults with overweight or obesity and established cardiovascular disease, chronic kidney disease or multiple cardiovascular risk factors. Of these, 5,507 received at least one dose of survodutide, at 3.6 mg or 6.0 mg weekly, or placebo.
The primary cardiovascular endpoint, combining cardiovascular death, nonfatal heart attack or stroke, coronary revascularization and heart failure events, occurred in 136 of 3,671 patients (3.7%) receiving survodutide, compared with 76 of 1,836 (4.1%) receiving placebo. The hazard ratio was 0.89, with a 95% confidence interval of 0.67 to 1.18. Although the result met the trial’s prespecified noninferiority margin of 1.65, it did not establish cardiovascular superiority.
Weight loss reached 13.7% at 72 weeks, compared with 2.0% on placebo, in a supplementary analysis estimating the effect expected with continued treatment. In the same analysis, survodutide also reduced systolic blood pressure and waist circumference compared with placebo.
How it works: Survodutide, licensed from Zealand, combines GLP-1 receptor activation to help regulate appetite and food intake with glucagon receptor activation, which Boehringer associates with effects on energy expenditure and liver metabolism. The company says the combination could provide metabolic benefits beyond weight loss, although its Phase 3 obesity trials have not established superiority over GLP-1-only treatments.
Glucagon receptor activation can also increase heart rate. Bozkurt told Pharmacy Times that the mechanism’s potential cardiovascular effects made dedicated safety testing important.
Reality check: Gastrointestinal tolerability remains a significant obstacle. Nausea affected 48% to 49% of survodutide recipients and vomiting 31.7% to 34%, compared with 12.1% and 4.8%, respectively, on placebo.
Such adverse events caused 19.3% of patients receiving 3.6 mg and 20.8% receiving 6.0 mg to discontinue treatment, versus 1.9% on placebo. The rates are close to the 19% and 18% reported in two earlier Phase 3 trials. Serious adverse events overall, however, were not more frequent with survodutide than placebo.
Boehringer said the trial’s strict titration protocol, which limited slower dose escalation, dose adjustments and temporary interruptions, contributed to discontinuations, explaining: “In several cases, patients were required per protocol to discontinue rather than adjust treatment.” The company said current and upcoming studies, including LIVERAGE, SYNCHRONIZE-T2D, SYNCHRONIZE-START, SYNCHRONIZE-HERA and ELEVATE LIVER, will use more flexible dosing strategies, although evidence that these will substantially reduce discontinuations is not yet available.
Moreover, cardiovascular safety is not the same as demonstrated cardiovascular benefit. The European Medicines Agency recognized evidence in 2024 that Novo Nordisk’s Wegovy reduces major cardiovascular events in people with established cardiovascular disease and a body mass index of at least 27, although it did not grant a separate prevention indication. The US FDA approved such an indication for Wegovy in March 2024.
What’s next: Boehringer is preparing regulatory submissions for obesity, with a company executive telling Fierce Biotech that it aims to file in 2027.
Survodutide is also being evaluated in two Phase 3 trials for metabolic dysfunction-associated steatohepatitis (MASH): LIVERAGE, targeting patients with moderate or advanced liver fibrosis, and LIVERAGE-Cirrhosis, targeting those with compensated cirrhosis. These studies could help establish whether the drug’s effects on liver metabolism provide a meaningful advantage beyond weight loss.
Update (10 November 2026): This article has been updated to include comments from Boehringer Ingelheim received after publication.
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