Survodutide
Also known as: BI 456906, BI-456906
5 notable studies · 5 references
TLDR
Survodutide is an investigational once-weekly GLP-1/glucagon dual-receptor agonist with Phase 3 evidence for weight reduction and particularly notable Phase 2 evidence for histological improvement in MASH, but its long-term cardiovascular, liver, and safety outcomes remain under investigation. PubMed
Research Supports
- Studied for weight reduction through dual GLP-1/glucagon receptor agonism
- Investigated for histological improvement in MASH and liver fibrosis
- Examined for effects on hepatic metabolism, including FGF21 and amino-acid changes
- Studied in adults with obesity and type 2 diabetes
Observations Reported in Research
- Produced up to 18.7% average weight reduction at 46 weeks in the Phase 2 obesity trial (le Roux et al., 2024)
- SYNCHRONIZE-1: -12.2% and -13.0% weight change at 76 weeks for 3.6 mg and 6.0 mg vs -5.4% placebo (2026)
- Produced significantly greater histological MASH improvement than placebo over 48 weeks (Sanyal et al., 2024)
- Early multiple-dose cohort showed placebo-corrected weight reduction of 13.8% at 16 weeks, with biomarker evidence of GLP-1R/GCGR engagement (Jungnik et al., 2023)
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Long-acting acylated peptide; dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist
Survodutide is an investigational once-weekly peptide that simultaneously activates the glucagon receptor and GLP-1 receptor. Its mechanism therefore resembles mazdutide at a high level: Survodutide → GLP-1 + glucagon Mazdutide → GLP-1 + glucagon But they are separate molecules with different receptor pharmacology, development programs, clinical datasets, and potentially different therapeutic profiles. Survodutide is being developed by Boehringer Ingelheim in collaboration with Zealand Pharma. Its clinical development has focused particularly on two areas: obesity/weight management and metabolic dysfunction-associated steatohepatitis (MASH). Phase 2 obesity research reported average weight reductions reaching 18.7% at 46 weeks in the 4.8-mg group under the trial's planned-treatment analysis. PubMed More recently, the Phase 3 SYNCHRONIZE-1 trial enrolled 725 adults with obesity without diabetes. At 76 weeks, average weight changes under the treatment-regimen estimand were −12.2% with 3.6 mg, −13.0% with 6.0 mg, and −5.4% with placebo. PubMed Survodutide remains investigational and is not FDA-approved.
What Is Survodutide?
Survodutide is an engineered peptide based conceptually on the biology of oxyntomodulin, an endogenous intestinal hormone capable of activating both GLP-1 and glucagon receptors. Natural oxyntomodulin has a short biological half-life. Survodutide was engineered as a long-acting dual agonist and contains a C18 fatty-acid modification that prolongs exposure sufficiently to support once-weekly administration. PubMed Its pharmacological strategy combines two potentially complementary signals. GLP-1 receptor activation can reduce food intake and improve glucose regulation. Glucagon-receptor activation can influence hepatic metabolism, lipid metabolism, amino-acid metabolism and energy expenditure. Preclinical experiments indicate that survodutide's weight effects involve both reduced food intake and increased energy expenditure, rather than GLP-1 signaling alone. PubMed
What Are Researchers Studying?
Obesity and body-weight regulation
Obesity is one of survodutide's principal clinical-development targets. The Phase 2 obesity trial enrolled adults with BMI ≥27 kg/m² without diabetes across 43 centers in 12 countries. Participants received weekly survodutide at several doses or placebo for 46 weeks. At the 4.8-mg dose, average body-weight reduction reached as much as 18.7%, versus 2.3% with placebo under the planned-treatment analysis. PubMed This established survodutide as one of the more clinically advanced GLP-1/glucagon dual agonists.
Metabolic dysfunction-associated steatohepatitis (MASH)
MASH is arguably the most scientifically distinctive part of survodutide's development program. A 48-week Phase 2 trial enrolled adults with biopsy-confirmed MASH and fibrosis stages F1–F3. The primary outcome was histological improvement in MASH without worsening of fibrosis. Survodutide produced substantially greater rates of MASH improvement than placebo, providing direct histological evidence rather than relying only on blood biomarkers or imaging. PubMed This finding helped move survodutide into Phase 3 development for MASH.
Liver fibrosis
Researchers are also investigating whether survodutide affects fibrosis itself rather than simply reducing liver fat or MASH activity. The Phase 2 MASH trial included improvement of fibrosis by at least one stage without worsening of MASH as an important secondary histological outcome. PubMed This distinction matters because: less liver fat ≠ MASH resolution ≠ fibrosis regression. Aminodex should treat these as separate outcomes. Whether survodutide ultimately prevents cirrhosis, liver failure, transplantation, or liver-related mortality remains unknown.
Hepatic metabolism
Glucagon-receptor activation gives survodutide a particularly interesting relationship with the liver. The glucagon receptor is strongly expressed in hepatic tissue and influences: • Glucose production • Lipid oxidation • Amino-acid metabolism • Ketogenesis • Energy metabolism • FGF21 signaling During preclinical development, researchers used changes in FGF21, circulating amino acids, and hepatic NNMT expression as evidence of glucagon-receptor engagement. PubMed This hepatic biology is one reason dual GLP-1/glucagon agonists are being investigated for metabolic liver disease rather than simply obesity.
Type 2 diabetes
Survodutide is also being studied in people with obesity or overweight and type 2 diabetes. On October 1, 2026, Boehringer Ingelheim reported positive Phase 3 SYNCHRONIZE-2 results. At 76 weeks, average weight loss reached 13.1% under the efficacy estimand, compared with 3.1% with placebo. Up to 79.3% of survodutide-treated participants achieved at least 5% weight reduction versus 32.7% with placebo. Boehringer Ingelheim Because these results are extremely recent, this section should be updated when the complete peer-reviewed report and detailed metabolic outcomes are incorporated into Aminodex.
Energy expenditure
One of the central hypotheses behind GLP-1/glucagon dual agonism is that weight reduction may involve both sides of the energy-balance equation. GLP-1 signaling can substantially reduce energy intake. Glucagon signaling may additionally increase energy expenditure and alter substrate metabolism. In preclinical models, survodutide produced greater weight reduction than maximally effective semaglutide exposure, and experimental analyses supported contributions from both decreased food intake and increased energy expenditure. PubMed Whether glucagon-mediated increases in energy expenditure contribute substantially to the magnitude of human weight reduction remains less certain.
How Does It Work?
Survodutide activates two G-protein-coupled receptors: GLP-1 receptor GLP-1R activation can: • Reduce appetite • Reduce food intake • Increase glucose-dependent insulin secretion • Influence glucagon secretion • Delay gastric emptying, particularly early in treatment • Improve glycemic control Glucagon receptor GCGR activation can: • Increase hepatic glucose production • Increase lipid oxidation • Alter amino-acid metabolism • Influence hepatic fat metabolism • Increase FGF21 signaling • Potentially increase energy expenditure Phase 1 research found reductions in circulating amino acids and glucagon consistent with engagement of both GLP-1 and glucagon pathways. PubMed The pharmacological challenge is balance. Too much glucagon activity could theoretically worsen glucose regulation. Too little might eliminate the metabolic advantages researchers hope to gain by adding GCGR activity to a GLP-1 drug. Survodutide was selected from a series of candidate dual agonists partly by evaluating this receptor balance and biomarkers of engagement. PubMed
What Does the Research Show?
Human research
Survodutide now has substantial human evidence spanning Phase 1 through Phase 3. Phase 1 Early studies included 24 participants in a single-rising-dose trial and 125 participants in multiple-rising-dose studies. In one 16-week multiple-dose cohort, placebo-corrected average weight reduction reached 13.8%. Researchers also documented biomarker evidence of both GLP-1R and GCGR engagement. PubMed Phase 2 obesity The international Phase 2 trial demonstrated dose-dependent weight reduction over 46 weeks, with reductions reaching as much as 18.7% at the highest planned dose. PubMed Phase 2 MASH Biopsy-based research demonstrated significant histological improvement in MASH and generated evidence regarding fibrosis outcomes. PubMed Phase 3 obesity SYNCHRONIZE-1 randomized 725 adults. At week 76, treatment-regimen-estimand average weight changes were: 3.6 mg: −12.2% 6.0 mg: −13.0% Placebo: −5.4% At least 5% weight reduction occurred in approximately 72% of participants assigned survodutide versus 46% receiving placebo. PubMed Gastrointestinal events were common: 80.9% at 3.6 mg and 89.7% at 6.0 mg versus 47.9% with placebo, generally mild-to-moderate. PubMed That Phase 3 result is worth emphasizing because it is notably more modest than the headline 18.7% figure from Phase 2. Aminodex should display both rather than quietly allowing the earlier, larger number to become the compound's permanent headline.
Animal research
Animal studies played an important role in establishing survodutide's dual mechanism. Researchers evaluated: • Food intake • Body weight • Energy expenditure • Glucose tolerance • Gastric emptying • Hepatic metabolism • FGF21 • Amino-acid metabolism In obesity models, survodutide produced strong reductions in body weight through a combination of decreased energy intake and increased energy expenditure. PubMed Animal studies also helped establish biomarkers subsequently used to confirm glucagon-receptor engagement in clinical development.
In-vitro research
Survodutide was characterized using cell systems expressing human GLP-1R and GCGR. Researchers measured receptor-mediated cAMP signaling to quantify potency at each receptor. Candidate selection research compared survodutide with other dual agonists and combined cellular receptor assays with animal biomarkers to identify a receptor balance suitable for clinical development. PubMed This is important because two compounds can both be called GLP-1/glucagon dual agonists while having meaningfully different relative activity at each receptor.
Notable Studies
Phase I Studies of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Dual Glucagon Receptor/Glucagon-Like Peptide-1 Receptor Agonist BI 456906
humanResearchers conducted single- and multiple-rising-dose trials in healthy volunteers and adults with overweight or obesity. The multiple-dose program demonstrated substantial early weight reduction, reaching a maximum placebo-corrected mean reduction of 13.8% at week 16 in one dosing schedule. Changes in amino acids and glucagon provided evidence of glucagon- and GLP-1-receptor target engagement. PubMed
Limitations: These were small, early-stage studies designed primarily for pharmacology, safety, and dose selection. Adverse-event-related discontinuation was substantial in some cohorts.
View publication →Glucagon and GLP-1 Receptor Dual Agonist Survodutide for Obesity: A Randomised, Double-Blind, Placebo-Controlled, Dose-Finding Phase 2 Trial
humanAdults with overweight or obesity without diabetes received several weekly survodutide doses or placebo for 46 weeks. The trial demonstrated substantial dose-dependent weight reduction, reaching up to approximately 18.7% in the 4.8-mg group under the planned-treatment analysis. PubMed
Limitations: Treatment discontinuation and gastrointestinal tolerability affected interpretation of the higher-dose groups. The study did not establish cardiovascular outcomes, mortality benefit, or multi-year durability.
View publication →A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
humanAdults with biopsy-confirmed MASH and F1–F3 fibrosis received weekly survodutide or placebo for 48 weeks. The primary endpoint was histological improvement in MASH without worsening of fibrosis. Survodutide produced substantially greater rates of histological MASH improvement than placebo and also generated encouraging fibrosis findings. PubMed
Limitations: The trial lasted 48 weeks and was not designed to establish prevention of cirrhosis, liver failure, transplantation, cardiovascular events, or death. Histological surrogate outcomes should not be equated with demonstrated long-term clinical benefit.
View publication →Survodutide Once Weekly for the Treatment of Adults With Obesity
humanResearchers randomized 725 adults with obesity without diabetes to survodutide 3.6 mg, survodutide 6.0 mg, or placebo. At 76 weeks, average weight changes under the treatment-regimen estimand were: 3.6 mg: −12.2% 6.0 mg: −13.0% Placebo: −5.4% Both survodutide groups produced statistically greater weight reduction than placebo. PubMed
Limitations: Gastrointestinal adverse events were frequent and treatment discontinuation affects the difference between treatment-regimen and efficacy-estimand results. The trial did not establish cardiovascular or mortality benefit.
View publication →SYNCHRONIZE-2 Phase 3 Trial of Survodutide in Adults With Obesity or Overweight and Type 2 Diabetes
humanAdults with obesity or overweight and type 2 diabetes received survodutide or placebo for 76 weeks. Boehringer Ingelheim reported average weight reduction reaching 13.1% using the efficacy estimand, versus 3.1% with placebo. Up to 79.3% of survodutide-treated participants achieved ≥5% weight reduction compared with 32.7% receiving placebo. Boehringer Ingelheim
Limitations: These results are extremely recent. The full dataset should be incorporated from the peer-reviewed primary publication rather than relying indefinitely on topline company reporting.
View publication →What We Still Don't Know
Important unresolved questions include: • Long-term cardiovascular outcomes • Effects on cardiovascular mortality • Whether MASH histological improvement prevents liver-related clinical events • Whether fibrosis improvements persist with longer treatment • Multi-year safety • Durability of weight reduction • Weight regain after discontinuation • Long-term consequences of glucagon-receptor stimulation • Effects on lean mass and body composition • Optimal GLP-1R-to-GCGR receptor balance • Whether glucagon agonism provides clinically meaningful advantages over GLP-1-only therapy • Comparative efficacy versus mazdutide • Comparative efficacy versus tirzepatide and retatrutide • Whether the liver benefits are fully explained by weight loss or include meaningful direct hepatic effects • Eventual FDA and other regulatory decisions
Related Compounds
Recent publications
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Sources & References
- Jungnik A, Arrubla Martinez J, Plum-Mörschel L, et al. Phase I Studies of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Dual Glucagon Receptor/GLP-1 Receptor Agonist BI 456906. Diabetes, Obesity and Metabolism. 2023;25:1011–1023.
- Zimmermann T, Thomas L, Baader-Pagler T, et al. BI 456906: Discovery and Preclinical Pharmacology of a Novel GCGR/GLP-1R Dual Agonist With Robust Anti-Obesity Efficacy. Molecular Metabolism. 2022.
- le Roux CW, Steen O, Lucas KJ, et al. Glucagon and GLP-1 Receptor Dual Agonist Survodutide for Obesity: A Randomised, Double-Blind, Placebo-Controlled, Dose-Finding Phase 2 Trial. Lancet Diabetes & Endocrinology. 2024;12:162–173.
- Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine. 2024.
- le Roux CW, Wharton S, Startseva E, et al.; SYNCHRONIZE-1 Investigators. Survodutide Once Weekly for the Treatment of Adults With Obesity. New England Journal of Medicine. 2026;395:776–787.
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