Survodutide (BI 456906): How a Glucagon/GLP-1 Dual Agonist Was Chosen and Tested

Survodutide, Boehringer Ingelheim's development code BI 456906, is a lipidated peptide that activates two receptors: the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) (Zimmermann 2022). This Vial Post explainer covers how it was chosen from a panel of candidates, what the preclinical pharmacology showed, and what two phase 2 trials reported.

Nothing here is guidance on use in people or animals. The Vial Post covers survodutide only as a subject of laboratory and literature research.

Identity Check

• Names: PubChem lists Survodutide, BI-456906 and CAS number 2805997-46-8 under CID 171378821 (PubChem: Survodutide).
• Formula and mass: PubChem gives C192H289N47O61 and a computed molecular weight of about 4,232 g/mol (PubChem: Survodutide).
• Half-life feature: the discovery paper describes BI 456906 as an acylated peptide carrying a C18 fatty acid as its half-life-extending element (Zimmermann 2022).

The Oxyntomodulin Idea

The design starts from a natural gut peptide. Oxyntomodulin activates both GCGR and GLP-1R, and the discovery team notes that it lowers bodyweight by raising energy expenditure and cutting energy intake (Zimmermann 2022). Survodutide was built to engage the same two receptors with a long-acting, engineered molecule.

Picking One Molecule From Nineteen

A 2024 paper in *Diabetes, Obesity and Metabolism* describes how the developers chose survodutide over its siblings (Thomas 2024):

• They started with 19 dual GCGR/GLP-1R agonists and measured how strongly each raised cyclic AMP in CHO-K1 cells expressing the human receptors.
• They used biomarkers in mice to read out each receptor separately: improved oral glucose tolerance for GLP-1R, and liver nicotinamide N-methyltransferase (NNMT) mRNA and plasma FGF21 for GCGR.
• Those biomarkers correlated significantly with the in vitro potencies across all 19 compounds.
• Three molecules (survodutide, BI 456908 and BI 456897) went forward for in-depth profiling. Survodutide was selected for its balanced dual pharmacology.

The point of the exercise was the balance between the two receptors. Too little glucagon activity would make the molecule look like an ordinary GLP-1 agonist; the team was looking for GCGR engagement that added bodyweight effects in rodents while keeping glucose effects comparable to selective GLP-1R agonism (Thomas 2024).

What the Mouse Work Showed

The 2022 *Molecular Metabolism* discovery paper reported (Zimmermann 2022):

• greater bodyweight reductions in mice than maximally effective doses of the GLP-1R agonist semaglutide;
• that this came from both higher energy expenditure and lower food intake;
• engagement of GLP-1R shown through glucose tolerance, food intake and gastric emptying tests, and of GCGR through liver NNMT expression and circulating amino acids and FGF21;
• confirmation of the dual activity using GLP-1R knockout mice, transgenic reporter mice and an ex vivo bioactivity assay.

In the follow-up selection paper, survodutide lowered bodyweight from baseline by 25% in diet-induced obese mice and significantly lowered glycated haemoglobin in diabetic db/db mice (Thomas 2024).

Two Phase 2 Readouts

Obesity trial. le Roux and colleagues ran a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial at 43 centres in 12 countries, enrolling 387 adults without diabetes. The primary endpoint was percentage change in bodyweight at week 46. Mean changes in the survodutide groups ranged from −6.2% to −14.9%, against −2.8% with placebo (planned-treatment analysis). Adverse events were reported in 91% of survodutide recipients and 75% of placebo recipients (le Roux 2024).

Liver trial. Sanyal and colleagues ran a 48-week phase 2 trial in adults with biopsy-confirmed MASH (metabolic dysfunction-associated steatohepatitis) and fibrosis stages F1 to F3, with 293 participants treated (Sanyal 2024). The reported results:

• the primary endpoint, improvement in MASH with no worsening of fibrosis, occurred in 43% to 62% of the survodutide groups versus 14% on placebo;
• a liver-fat reduction of at least 30% occurred in 57% to 67% of survodutide groups versus 14% on placebo;
• fibrosis improved by at least one stage in 34% to 36% of survodutide groups versus 22% on placebo;
• nausea, diarrhoea and vomiting were more frequent with survodutide than with placebo.

The authors concluded the results warranted phase 3 trials (Sanyal 2024). Thomas and colleagues noted in 2024 that survodutide was being investigated in phase 3 trials (Thomas 2024).

Frequently Asked Questions

What does "dual agonist" mean here? That a single molecule activates both the glucagon receptor and the GLP-1 receptor (Zimmermann 2022).

Why include glucagon activity at all? In the mouse studies, the GCGR arm was linked to higher energy expenditure, which added to the food-intake effect of the GLP-1R arm (Zimmermann 2022; Thomas 2024).

What mass should a COA show? PubChem's computed molecular weight is about 4,232 g/mol (PubChem: Survodutide). Mass spectrometry should match the expected mass for the stated form; see our explainer on HPLC versus mass spec.

For research and educational use only. This article is not medical advice and does not describe dosing or human use.