Survodutide (BI 456906)
Survodutide (BI 456906) — the GLP-1/glucagon dual agonist built for MASH: Phase 3 evidence

Class: peptide
Synonyms: Survodutide
development code BI 456906
Function tags: metabolic
weight loss
MASH / hepatic fat (the differentiator)
glycaemic
Overall evidence grade: B
WADA prohibited: no
Last updated: 2026-07-13

In brief: Survodutide is an investigational GLP-1 / glucagon dual-agonist peptide (weekly injection) from Boehringer Ingelheim and Zealand Pharma. What makes it distinct is the second receptor: instead of tirzepatide's GIP, survodutide adds glucagon-receptor activation, which raises energy expenditure (the liver burns more calories — a thermogenic effect GIP doesn't provide) and directly drives hepatic fat oxidation. That's why its MASH (fatty-liver) data are among the most striking in the field (Phase 2 MASH resolution ~83% at top dose), and why it's being developed as much for liver disease as for obesity. On weight, its Phase 3 SYNCHRONIZE-1 delivered −16.6% at 76 weeks — clinically meaningful, though numerically below tirzepatide's ~20.9% (no head-to-head trial exists). The glucagon arm is a double-edged sword: it adds fat-burning but, without GIP's insulin-releasing "safety net," and given glucagon's historic tendency to raise blood sugar, it demands careful GLP-1-balanced titration and carries transient liver-enzyme and heart-rate signals.

## Identity an investigational **peptide** engineered for **weekly subcutaneous** dosing via a **fatty-acid albumin-binding** strategy (the same long-acting trick as semaglutide and tirzepatide). Developed by **Boehringer Ingelheim** in partnership with **Zealand Pharma**. Its defining feature is **which two receptors it hits**: **GLP-1** *and* **glucagon** — deliberately *not* GIP. ## Mechanism (as proposed) survodutide co-activates two receptors. The **GLP-1** arm does the familiar work: **suppresses appetite**, slows gastric emptying, improves glycaemia. The **glucagon (GCGR)** arm is the differentiator: although glucagon is classically a *counter-regulatory* hormone that **raises** blood sugar, deliberately activating its receptor **increases hepatic energy expenditure** (the liver burns more calories processing nutrients — a **thermogenic** effect) and **directly promotes liver fat oxidation** (breaking down stored hepatic fat). The GLP-1 component is needed partly to **offset** glucagon's glucose-raising tendency. This is why survodutide targets the **fat accumulation that defines MASH** more directly than pure incretin drugs — but also why its safety requires **balancing** two opposing glucose effects.

Evidence grades by outcome:
outcome: Weight loss (obesity, no diabetes)
grade: B
base: Phase 3 SYNCHRONIZE-1 (2026): −16.6% at 76 wk vs 3.2% placebo, p<0.0001; 85.1% ≥5% loss. Phase 2 (2024): −14.9% at 46 wk
caveat: Strong, positive Phase 3 — but not yet approved (confirmatory/regulatory pending); below tirzepatide numerically (no direct comparison)
outcome: MASH resolution / hepatic fat
grade: B
base: Phase 2 MASH (Sanyal, NEJM 2024): resolution ~83% top dose vs ~18% placebo; dedicated Phase 3 LIVERAGE ongoing
caveat: Standout Phase 2 liver data (the glucagon-arm advantage); Phase 3 MASH histology outcomes still to confirm
outcome: Glycaemic control (T2D)
grade: C
base: SYNCHRONIZE-2 (obesity + diabetes) in Phase 3
caveat: In development; glucagon component makes glucose handling a balance rather than a pure win
outcome: Cardiovascular outcomes
base: SYNCHRONIZE-CVOT ongoing
caveat: Being formally tested; no outcome data yet; transient heart-rate increase is a class + glucagon consideration
outcome: Safety / tolerability
base: Phase 2/3 program
caveat: GI effects (nausea/diarrhea/vomiting — GLP-1 class); transient aminotransferase (liver-enzyme) elevations; small transient heart-rate rise (glucagon-mediated sympathetic activation); the missing-GIP "insulin safety net" makes titration more demanding

Legal status:
region: EU
status: Not approved
note: not approved anywhere (Phase 3, investigational). No EMA/FDA marketing authorisation; not a cosmetic; no compounding pathway.

Cosmetic claims:

Note: The glucagon arm of the incretin map — and the register's clearest "different second receptor, different job" story. Three points make this entry pop: (1) it's a GLP-1 / glucagon dual agonist — the glucagon half is what sets it apart from tirzepatide (#2, GLP-1/GIP), giving it a unique liver-fat-burning mechanism; (2) Phase 3 just read out (April 2026): −16.6% body weight at 76 weeks — real late-stage data, not hype; (3) it is being built as much for MASH (fatty-liver disease) as for obesity — a genuinely differentiated positioning in a crowded field.
Status note: fast-moving — additional SYNCHRONIZE and LIVERAGE read-outs expected through 2026; re-check obesity + MASH Phase 3 completeness and any regulatory filing

Sources:
Boehringer Ingelheim / Zealand Pharma — SYNCHRONIZE-1 Phase 3 topline (April 2026) and ADA-2026 presentation; published in NEJM (SYNCHRONIZE-1) and Nature Medicine (SYNCHRONIZE-MASLD).
le Roux CW, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: dose-finding Phase 2 trial. Lancet Diab Endocrinol. 2024;12:162–173.
Sanyal AJ, et al. A Phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311–319.
Zimmermann T, et al. BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist. Mol Metab. 2022;66:101633.
Trial registrations: NCT06066515 (SYNCHRONIZE-1), NCT06066528 (SYNCHRONIZE-2); LIVERAGE (MASH).