Survodutide
BI 456906, BI-456906
Survodutide is an investigational once-weekly dual agonist at the glucagon receptor and the GLP-1 receptor, developed for obesity and for metabolic dysfunction-associated steatohepatitis. It is one of the most advanced glucagon-containing multi-agonists, with a completed phase 3 obesity programme reporting in 2026. It is not approved for use anywhere.
Mechanism
Survodutide engages two receptors that pull metabolism in opposite directions and exploits the resulting balance. The GLP-1 receptor arm delivers the familiar incretin effects: glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying and central appetite reduction. The glucagon receptor arm adds a catabolic component that GLP-1 alone cannot provide: increased hepatic fatty acid oxidation, increased energy expenditure, enhanced lipolysis and, importantly for liver disease, direct reduction of hepatic triglyceride content. In preclinical characterisation survodutide behaves as a full agonist at the human GLP-1 receptor and a partial agonist at the human glucagon receptor, a deliberate asymmetry.
The obvious hazard of glucagon receptor agonism is hyperglycaemia, since glucagon's principal physiological job is to raise blood glucose through glycogenolysis and gluconeogenesis. The design solution is that the GLP-1 insulinotropic effect more than offsets the glucagon-driven hepatic glucose output at therapeutic exposures, so net glycaemic control improves rather than worsens. Structurally the molecule is glucagon-derived rather than GLP-1-derived, with an Ac4c residue at position 2 protecting against DPP-4 and a C18 diacid chain providing reversible albumin binding for weekly dosing. The theoretical appeal of adding glucagon is that weight loss driven partly by raised energy expenditure, rather than solely by reduced intake, may preserve more lean mass and act more directly on the liver. That remains a mechanistic hypothesis rather than a demonstrated clinical advantage.
What the research shows
The phase 2 obesity trial randomised 387 adults with a body mass index of at least 27 and without diabetes to survodutide at 0.6, 2.4, 3.6 or 4.8 mg weekly or placebo for 46 weeks across 43 centres in 12 countries. Mean body weight change at week 46 was -14.9% at the 4.8 mg dose against -2.8% on placebo, with intermediate results at lower doses (-6.2%, -12.5% and -13.2%). A figure close to 19% is widely quoted for this trial; that is the trial-product estimand, which models what would have happened had every participant remained on treatment throughout, and it should not be compared against treatment-policy results reported for other agents. A separate 48-week phase 2 trial in 293 adults with biopsy-confirmed steatohepatitis and stage F1-F3 fibrosis found histological improvement in steatohepatitis without worsening of fibrosis in 43% to 62% of participants across the 2.4, 4.8 and 6.0 mg doses against 14% on placebo. The dose-response was not monotonic: 47% at 2.4 mg, 62% at 4.8 mg and 43% at 6.0 mg, which weakens any claim of a clean dose-dependent histological effect.
The phase 3 SYNCHRONIZE-1 trial randomised 725 adults with obesity to survodutide 3.6 mg, 6.0 mg or placebo for 76 weeks. Mean body weight change was -12.2% at 3.6 mg and -13.0% at 6.0 mg against -5.4% on placebo, giving a placebo-adjusted difference of roughly 7.6 percentage points at the higher dose. Two observations temper enthusiasm. First, the placebo group itself lost 5.4%, so the headline percentage overstates the drug-attributable effect considerably. Second, gastrointestinal adverse events were near-universal on active treatment, reported by 80.9% at 3.6 mg and 89.7% at 6.0 mg against 47.9% on placebo, though these were characterised as mild to moderate and no deaths occurred. SYNCHRONIZE-MASLD reported reductions in liver fat and visceral adipose tissue over 48 weeks. No cardiovascular outcomes data are yet available.
Evidence assessment
High-quality evidence
Survodutide has replicated randomised controlled trials in humans, including two phase 2 trials with histological or imaging endpoints and a completed phase 3 obesity programme published in 2026 in the New England Journal of Medicine and Nature Medicine. The tier reflects the replication and quality of the randomised evidence, not regulatory status: survodutide is not approved anywhere, long-term safety data are limited, and no cardiovascular outcomes trial has yet reported. Note that several efficacy figures in circulation for this compound come from trial-product rather than treatment-policy estimands and overstate the effect; the figures given here are the primary reported results.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy Preclinical only
Characterised survodutide as a full agonist at the human GLP-1 receptor and a partial agonist at the human glucagon receptor, with weight loss in rodents exceeding that achieved by GLP-1 receptor agonism alone.
Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial Preclinical only
Mean body weight change at week 46 was -6.2% (0.6 mg), -12.5% (2.4 mg), -13.2% (3.6 mg) and -14.9% (4.8 mg) against -2.8% on placebo. Gastrointestinal adverse effects were frequent and dose-related.
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis Preclinical only
Histological improvement in steatohepatitis without worsening of fibrosis occurred in 47% (2.4 mg), 62% (4.8 mg) and 43% (6.0 mg) of participants against 14% on placebo (P<0.001). Nausea affected 66%, diarrhoea 49% and vomiting 41%.
Survodutide Once Weekly for the Treatment of Adults with Obesity Preclinical only
Mean body weight change at week 76 was -12.2% (95% CI -13.6 to -10.8) at 3.6 mg and -13.0% (95% CI -14.4 to -11.6) at 6.0 mg, against -5.4% (95% CI -6.9 to -4.0) on placebo; P<0.001 for both. Gastrointestinal adverse events affected 80.9%, 89.7% and 47.9% respectively, mostly mild to moderate. No deaths.
Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial Preclinical only
Survodutide reduced liver fat content and visceral adipose tissue relative to placebo, alongside body weight reduction.
Safety
Gastrointestinal adverse effects are frequent and dose-dependent, reported by roughly four in five participants at 3.6 mg and nine in ten at 6.0 mg in the phase 3 obesity trial, against about half on placebo. Nausea, vomiting, diarrhoea and constipation predominate and are concentrated during dose escalation. Increases in resting heart rate have been observed, consistent with both GLP-1 and glucagon receptor pharmacology, and the clinical significance over years of exposure is unknown. The glucagon receptor component raises theoretical concerns about hepatic glucose output, hepatic protein catabolism and blood pressure, none of which has emerged as a clear clinical problem in trials to date but all of which warrant longer observation. As an unapproved compound, survodutide has no established long-term safety record: there are no data on cardiovascular outcomes, malignancy, pancreatitis incidence at scale, or effects in pregnancy. Material obtained outside clinical trials carries the additional and substantial risks of unverified identity, purity and sterility.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Investigational. Survodutide has no MHRA marketing authorisation and is not available on prescription or through the NHS for any indication. UK sites have participated in the phase 3 programme. Supplying or selling it as a medicine outside a clinical trial would fall foul of the Human Medicines Regulations 2012. |
| United States | Investigational. Survodutide has no FDA approval for any indication. It has received FDA Breakthrough Therapy designation for adults with metabolic dysfunction-associated steatohepatitis and fibrosis. It is being studied in the SYNCHRONIZE phase 3 programme, which includes a dedicated cardiovascular outcomes trial. It may lawfully be supplied in the United States only within an authorised clinical trial. Material sold online as survodutide is unapproved and unregulated. |
| WADA (sport) | Not prohibited. Survodutide does not appear on the WADA Prohibited List, and dual GLP-1 and glucagon receptor agonists are not listed as a class. WADA's separate Monitoring Programme is revised annually and carries no sanctions; athletes should check the list in force for the relevant year, since monitoring status can change. |
Questions
Glucagon also increases energy expenditure and drives hepatic fat oxidation, which GLP-1 does not. At therapeutic exposures the GLP-1 insulinotropic effect offsets the glucose-raising effect, so net glycaemic control improves while the metabolic rate and liver fat benefits are retained.
No. As of August 2026 survodutide has no marketing authorisation in any jurisdiction. It holds FDA Breakthrough Therapy designation for steatohepatitis, which accelerates review but is not approval. Lawful access is through clinical trial participation only.
Mean body weight fell 13.0% at the 6.0 mg dose over 76 weeks, against 5.4% on placebo. Higher figures circulating for this compound, including one close to 19%, come from a different statistical estimand that assumes perfect adherence, and are not comparable with the headline results reported for other obesity drugs.
No head-to-head trials exist, so cross-trial comparison is unreliable and is made worse by the fact that different trials report different estimands. Survodutide's distinguishing claim is its effect on liver fat and steatohepatitis histology rather than weight alone.
The grading reflects the quality and replication of randomised human data, which now includes completed phase 3 trials published in major journals. It says nothing about approval, availability, or long-term safety, all of which remain open questions.