Survodutide: Glucagon/GLP-1 Dual Agonist, Trials and Status

Key facts

• Compound type: synthetic peptide carrying a C18 fatty acid to extend its half-life; a dual receptor agonist.
• Developer: Boehringer Ingelheim, under licence from Zealand Pharma; Boehringer is solely responsible for global development.
• Receptors: glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R).
• Highest stage (October 2026): phase 3, with three phase 3 trials published in 2026.
• Approval status (October 2026): not approved anywhere; described by its developer as investigational.
• CAS number: 2805997-46-8 (FDA Global Substance Registration System).
• Molecular formula: C192H289N47O61 (PubChem).

The best-known weight-loss medicines of recent years act on the GLP-1 receptor, alone or with a second gut hormone receptor. Survodutide picks a different partner: the glucagon receptor, which is concentrated in the liver. That choice is why it is being tested in fatty liver disease as well as obesity.

How does survodutide work?

GLP-1 receptor agonists such as semaglutide act mainly on appetite and blood glucose: they increase fullness, slow stomach emptying and raise insulin release when glucose is high. Our guide to GLP-1 peptides covers that class. Tirzepatide adds a second receptor, the GIP receptor, which is also involved in insulin release. Survodutide adds the glucagon receptor instead.

Glucagon is best known for raising blood glucose, which sounds like the wrong direction for a metabolic drug. Its other actions are the reason for the interest. Oxyntomodulin, a natural hormone made in the gut, already activates both the GLP-1 and glucagon receptors (Holst et al., 2018), and Boehringer Ingelheim's discovery paper cites it as the biological precedent. In that paper, survodutide reduced body weight in mice more than semaglutide at its maximally effective level, through a mix of lower food intake and higher energy expenditure. Markers of glucagon receptor activity appeared in the liver and blood, and experiments in mice lacking the GLP-1 receptor confirmed it acts on both targets (Zimmermann et al., 2022). These are rodent findings.

In the first human studies, survodutide lowered plasma amino acids and glucagon, read by the authors as signs that both receptors were engaged (Jungnik et al., 2023). Boehringer Ingelheim describes the glucagon component as acting directly on the liver to reduce fat there, and suggests that the balance between the two receptor activities may help preserve glucose control.

What did the phase 2 trials show?

Obesity. The phase 2 obesity trial randomised 387 adults with a BMI of 27 or more and no diabetes, at 43 centres in 12 countries, to one of four survodutide strengths or placebo for 46 weeks (le Roux et al., 2024, The Lancet Diabetes & Endocrinology). In the primary analysis by assigned treatment, mean body weight fell by between 6.2% and 14.9% across the survodutide groups, larger at higher strengths, compared with 2.8% on placebo. Only about 60% of participants in each arm completed the 46 weeks, which limits how far these figures can be pushed.

MASH. The phase 2 MASH trial randomised 293 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stages F1 to F3 to three survodutide strengths or placebo for 48 weeks (Sanyal et al., 2024, New England Journal of Medicine). The primary end point, improvement in MASH on biopsy without worsening of fibrosis, was reached by 47%, 62% and 43% in the three survodutide groups against 14% on placebo. A fall in liver fat of at least 30% occurred in 57% to 67% against 14%. Fibrosis improved by at least one stage in 34% to 36% against 22%, a secondary end point. The trial was not designed to measure clinical outcomes such as progression to cirrhosis.

A 16-week phase 2 trial in 413 people with type 2 diabetes found lower HbA1c and body weight, with more weight loss than open-label semaglutide at the higher strengths (Blüher et al., 2024). An open-label phase 1 study in people with cirrhosis found drug exposure similar to that in people without cirrhosis, with liver fat and stiffness generally lower after 28 weeks (Lawitz et al., 2024). The diabetes trial was short and its semaglutide arm unblinded; the cirrhosis study was small, open-label and had no placebo group.

On the liver data, the US FDA granted survodutide Fast Track designation for MASH in May 2021 and Breakthrough Therapy designation in September 2024, and the European Medicines Agency accepted it into its PRIME scheme in November 2023, according to Boehringer Ingelheim (1 October 2026). None of these is an approval.

Where does the phase 3 programme stand in October 2026?

Two analysis methods explain why different headline numbers circulate. The treatment-regimen estimand counts everyone as randomised, whether or not they stopped treatment or started other medicines; it is the more conservative figure and the primary analysis in the journal papers. The efficacy estimand estimates what would have happened had everyone stayed on treatment, and gives the larger figures used in company announcements.

• SYNCHRONIZE-1 randomised 725 adults with obesity, or overweight with a related complication, and no diabetes, for 76 weeks alongside lifestyle counselling. By the treatment-regimen estimand, mean weight change was 12.2% and 13.0% in the two survodutide groups against 5.4% on placebo, and 72.6% and 71.9% lost at least 5% against 46.3% (le Roux et al., 2026, NEJM). By the efficacy estimand, Zealand Pharma's April 2026 announcement reported up to 16.6% against 3.2%.
• SYNCHRONIZE-2 randomised 752 adults with type 2 diabetes and a BMI of 27 or more for 76 weeks. By the treatment-regimen estimand, weight fell 8.2% and 9.8% against 3.9% on placebo, and HbA1c fell 0.9 and 0.8 percentage points from a baseline of 7.4%, against 0.2 (Wharton et al., 2026, NEJM). Boehringer Ingelheim reported up to 13.1% against 3.1% by the efficacy estimand, noting that weight loss is typically harder in type 2 diabetes.
• SYNCHRONIZE-MASLD randomised 216 adults with obesity and at-risk fatty liver disease, two to survodutide for every one to placebo, for 48 weeks. A fall in MRI-measured liver fat of at least 30% occurred in 68.5% against 28.6% by the treatment-regimen estimand (84.2% against 24.3% by the efficacy estimand), with mean weight loss of 8.7% against 1.4% (Kaplan et al., 2026, Nature Medicine). Participants came only from the US and Spain, and liver fat on MRI is a marker, not a biopsy outcome.

Still pending as of October 2026: SYNCHRONIZE-CVOT, an event-driven cardiovascular safety trial in people with obesity and raised cardiovascular risk (Kosiborod et al., 2024), enrolled 5,531 people and is listed as completed in June 2026 on ClinicalTrials.gov. Boehringer said on 1 October 2026 that it expects to present results later this year. LIVERAGE (about 1,800 adults with MASH and F2 to F3 fibrosis) and LIVERAGE-Cirrhosis (about 1,590 adults with compensated MASH cirrhosis) were still recruiting, with estimated primary completion in December 2031 and June 2029 (NCT06632444, NCT06632457). Regional phase 3 trials in Japan and China are listed as completed, with only design and baseline papers published so far, and a newer SYNCHRONIZE-T2D trial is recruiting. We found no announcement of a marketing application as of mid-October 2026.

What side effects were reported?

Gastrointestinal effects dominate every trial so far, as with other drugs acting on the GLP-1 receptor. As reported:

• Phase 2 obesity: adverse events in 91% on survodutide against 75% on placebo, mainly gastrointestinal (75% against 42%).
• Phase 2 MASH: nausea 66% against 23%, diarrhoea 49% against 23%, vomiting 41% against 4%; serious adverse events 8% against 7%.
• SYNCHRONIZE-1: gastrointestinal events in 80.9% and 89.7% against 47.9%, typically mild to moderate; no deaths.
• SYNCHRONIZE-2: gastrointestinal events in 72.8% and 77.7% against 38.6%. Boehringer reported that 18% on survodutide stopped because of them, against 1.2% on placebo, mostly early in treatment.
• Phase 1b: in the faster-escalation part, the commonest reason for stopping was a cardiac or vascular adverse event (6 of 80 people) (Jungnik et al., 2023).
• SYNCHRONIZE-MASLD: 41.1% on survodutide and 40.0% on placebo stopped treatment early, according to a published author correction.

How does it compare with mazdutide and retatrutide?

Mazdutide is the other glucagon and GLP-1 dual agonist in late development (see our mazdutide overview). Retatrutide adds a third target, the GIP receptor (see retatrutide vs tirzepatide). The last row takes one published phase 3 obesity trial for each, with mean weight change as reported in the journal paper.

Sources: le Roux et al., 2026; Ji et al., 2025; Jastreboff et al., 2026; Innovent, June 2025; Innovent, September 2025.

These rows are not a head-to-head comparison. The trials differ in length, population (GLORY-1 enrolled Chinese adults with lower BMI thresholds) and analysis method, and no trial has compared any two of these compounds. Retatrutide's larger figures, also seen in its phase 2 trial (up to 24.2% at 48 weeks, Jastreboff et al., 2023), may reflect trial design as well as the drug.

What is not known yet?

• Cardiovascular outcomes. SYNCHRONIZE-CVOT results had not been presented as of mid-October 2026.
• Liver outcomes. The biopsy evidence is one 48-week phase 2 trial. LIVERAGE, which will look at liver histology and, later, clinical events, is years from reporting.
• Direct comparisons. No phase 3 trial has compared survodutide with semaglutide or tirzepatide; the only active comparison is a 16-week phase 2 trial with an open-label semaglutide arm.
• Durability. No published data beyond 76 weeks, or on what happens after stopping.
• Body composition. Boehringer reported that muscle made up no more than 10% of tissue lost in a 75-person SYNCHRONIZE-1 sub-study; that is a small group and a company-reported figure.
• Tolerability. Boehringer says newer trials allow more flexible escalation; whether that cuts the gastrointestinal dropouts is not yet shown.

The bottom line

Survodutide now has three published phase 3 trials showing reductions in weight and liver fat against placebo, with gastrointestinal effects the main cost. Its distinctive claim, a direct effect on the liver, rests so far on a phase 2 biopsy trial and MRI liver fat; the LIVERAGE histology results and the cardiovascular outcomes trial will decide much of its standing. As of October 2026 it is not approved anywhere. Research-grade material is listed on the survodutide compound page.

References

1. Blüher M, et al. (2024). Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial. Diabetologia. PubMed 38095657
2. Holst JJ, et al. (2018). Oxyntomodulin: Actions and role in diabetes. Peptides. PubMed 29412831
3. Jastreboff AM, et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. New England Journal of Medicine. PubMed 37366315
4. Jastreboff AM, et al. (2026). Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. New England Journal of Medicine. PubMed 42814954
5. Ji L, et al. (2025). Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. New England Journal of Medicine. PubMed 40421736
6. Jungnik A, et al. (2023). Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906. Diabetes, Obesity and Metabolism. PubMed 36527386
7. Kaplan LM, et al. (2026). Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial. Nature Medicine. PubMed 42252333
8. Kosiborod MN, et al. (2024). Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial. JACC: Heart Failure. PubMed 39453356
9. Lawitz EJ, et al. (2024). Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis. Journal of Hepatology. PubMed 38857788
10. le Roux CW, et al. (2024). Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. The Lancet Diabetes & Endocrinology. PubMed 38330987
11. le Roux CW, et al. (2026). Survodutide Once Weekly for the Treatment of Adults with Obesity. New England Journal of Medicine. PubMed 42253238
12. Sanyal AJ, et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine. PubMed 38847460
13. Wharton S, et al. (2026). Survodutide Once Weekly in Adults with Obesity and Type 2 Diabetes. New England Journal of Medicine. PubMed 42820639
14. Zimmermann T, et al. (2022). BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular Metabolism. PubMed 36356832