Survodutide
BI 456906
Survodutide (BI 456906) is an investigational, acylated peptide dual agonist of the glucagon receptor (GCGR) and GLP-1 receptor, developed by Boehringer Ingelheim for obesity and metabolic dysfunction-associated steatohepatitis (MASH/NASH). It is given as a once-weekly subcutaneous injection and is not approved by the FDA or EMA; all human data come from Phase 1 and Phase 2 trials. It causes substantial weight loss (up to roughly 15% over ~46 weeks in obesity trials) and improves liver histology in MASH. The main risks are dose-dependent and frequently gastrointestinal: nausea, vomiting, and diarrhea affect the majority of users and drive discontinuations, with risk of dehydration. The glucagon component and GLP-1 activity raise heart rate, and Phase 1 data recorded cardiac/vascular adverse events severe enough to cause discontinuations. As a GLP-1-class agent it carries class concerns (pancreatitis signal via amylase/lipase elevations, gallbladder disease, and a theoretical thyroid C-cell tumor concern extrapolated from other incretins). Long-term safety, cardiovascular outcome, and mortality data do not exist. This is not a bodybuilding or performance drug; using it outside medical supervision, without dose titration and clinician monitoring, materially increases the risk of severe GI illness, dehydration, and undetected pancreatic/cardiac events.
Mechanism of action
Pharmacokinetics
Not precisely defined in the abstracts reviewed; the C18 fatty-acid acylation and albumin binding produce a multi-day terminal half-life consistent with once-weekly dosing. Do not assume rapid clearance for washout purposes.
Pharmacodynamic effects (appetite suppression, delayed gastric emptying, weight/HbA1c effect) persist across a weekly dosing interval; slow dose escalation over 16-24 weeks is used in trials to limit GI toxicity.
Subcutaneous injection, once weekly (twice-weekly regimens were also tested in some Phase 2 diabetes cohorts).
As an acylated peptide it is expected to undergo proteolytic catabolism to amino acids and small peptide fragments rather than CYP450 metabolism; exposure increased dose-proportionally in Phase 1. This monitoring/washout information is for clinical safety, not for evading any test.
For monitoring and washout planning, not drug-test evasion.
Physiological & performance effects
- Dose-dependent body weight reduction: mean up to about -14.9% at 4.8 mg over 46 weeks in a Phase 2 obesity trial (placebo -2.8%)
- In MASH with fibrosis (F1-F3), histologic improvement of MASH without worsening fibrosis in 47-62% across doses vs 14% placebo over 48 weeks
- Reduction in liver fat content by >=30% in 57-67% of treated participants vs 14% placebo
- HbA1c reduction in type 2 diabetes comparable to semaglutide at lower doses and greater weight loss than semaglutide at higher doses
- Reduced appetite and food intake; delayed gastric emptying (transient)
- Reduction in plasma glucagon and amino acids reflecting dual target engagement
Adverse effects by system
Increased heart rate is expected from both glucagon and GLP-1 receptor agonism. In Phase 1 multiple-rising-dose testing, cardiac or vascular adverse events were the most common reason for discontinuation in one cohort (about 7.5%). No cardiovascular outcome trial exists; long-term cardiovascular safety is unknown.
No signal of drug-induced liver injury; survodutide instead improved liver histology and reduced liver fat in a Phase 2 MASH trial. It is being developed as a liver-directed therapy, not a hepatotoxin.
No direct effect on the hypothalamic-pituitary-gonadal (HPTA) axis has been studied or reported; survodutide is not an androgen, SERM, or aromatase modulator and has no described mechanism of gonadal suppression. Any hormonal changes would be indirect via substantial weight loss/caloric deficit. No adequate human data on sex-hormone effects.
No reproductive or fertility data in humans. GLP-1-class agents are generally advised to be avoided in pregnancy; no survodutide-specific human pregnancy data exist. Improved fertility from weight loss is possible but unstudied for this drug.
No specific psychiatric adverse-effect signal reported in the reviewed trials. Data are insufficient to exclude mood effects; incretin-class agents are under ongoing pharmacovigilance for neuropsychiatric events. No adequate human data specific to survodutide.
No direct nephrotoxicity reported. The principal renal risk is indirect: severe nausea, vomiting, and diarrhea can cause volume depletion and acute kidney injury, a recognized concern across the GLP-1 class.
No clinically significant hematologic toxicity reported in the reviewed trials; no adequate data suggesting an effect on blood counts.
Injection-site reactions are expected with subcutaneous dosing; no notable systemic dermatologic toxicity reported in the reviewed trials.
HPTA suppression & recovery
Suppression: None described / not applicable by mechanism
Survodutide has no known direct suppressive effect on the hypothalamic-pituitary-gonadal axis and is not an anabolic steroid or SERM, so single-SERM 'recovery' frameworks do not apply. Any hormonal shifts would be secondary to large weight loss and caloric deficit. Anyone with concerns about testosterone, menstrual, or fertility changes during rapid weight loss should consult an endocrinologist rather than self-managing hormones. No adequate human data.
Monitoring
Cadence: Clinician-supervised titration with review at each dose-escalation step (escalation over ~16-24 weeks in trials); ongoing periodic labs and vitals thereafter. This is a physician-directed drug, not a self-managed one.
- Severe or persistent vomiting/diarrhea with signs of dehydration (dizziness, reduced urination)
- Severe, persistent abdominal pain radiating to the back (possible pancreatitis) - stop and seek emergency care
- Right-upper-quadrant pain, fever, or jaundice (possible gallbladder disease)
- Sustained resting tachycardia, palpitations, chest pain, or shortness of breath
- A neck mass, hoarseness, or trouble swallowing (thyroid class precaution)
- Signs of hypoglycemia if combined with insulin or sulfonylureas
Contraindications
- Personal or family history of medullary thyroid carcinoma or MEN2 (class-based precaution extrapolated from GLP-1 receptor agonists; theoretical, not survodutide-specific)
- History of pancreatitis or unexplained elevated pancreatic enzymes
- Pregnancy and breastfeeding (no human data; class caution)
- Severe gastrointestinal disease including gastroparesis (delayed gastric emptying may worsen it)
- Active gallbladder disease
- Not established as safe in any population outside supervised clinical trials; not FDA/EMA approved for any use
Interaction profile
- ModerateWith a thermogenic stimulant: Additive cardiovascular strain
- MajorWith insulin: Metabolic / glucose
- ModerateWith another GLP-1 / incretin agonist: Metabolic / glucose
- ModerateWith metformin: Metabolic / glucose
- ModerateWith growth hormone: Metabolic / glucose
- ContraindicatedWith DNP: Additive cardiovascular strain
Check a specific combination in the interaction checker.
Reducing harm & when to stop
- Survodutide is investigational and not approved; there is no established safe self-administered protocol and no long-term safety data. The only responsible use is within medical supervision.
- Slow, clinician-guided dose escalation is the single most important measure to reduce severe nausea, vomiting, and diarrhea - trials escalated over 16-24 weeks for this reason.
- Stop and seek urgent care for severe persistent abdominal pain radiating to the back (possible pancreatitis), signs of dehydration, or jaundice/right-upper-quadrant pain.
- Maintain hydration during any GI upset; volume depletion from vomiting/diarrhea can cause acute kidney injury.
- Do not combine with insulin or sulfonylureas without clinician oversight due to hypoglycemia risk; monitor for palpitations or sustained elevated heart rate.
- This drug is not a tool for maximizing leanness or performance; higher doses increase GI and discontinuation risk without an established safety justification outside trials.
- Avoid in pregnancy, and consult an endocrinologist for any hormonal, fertility, or thyroid concerns rather than self-managing.
Citations (6)
Every clinical claim above is tied to a primary source. Overall evidence grade A — graded to the best available evidence for its core claims.
- 01
Survodutide (BI 456906) is a dual glucagon receptor / GLP-1 receptor agonist, acylated with a C18 fatty acid for once-weekly dosing, producing weight loss via increased energy expenditure and reduced food intake; greater than semaglutide in mice.
PreclinicalPMID 36356832 ↗
- 02
In a 48-week Phase 2 RCT (n=293) in biopsy-confirmed MASH with F1-F3 fibrosis, once-weekly survodutide 2.4/4.8/6.0 mg improved MASH without worsening fibrosis (47-62% vs 14% placebo) and reduced liver fat >=30% (57-67% vs 14%); nausea 66%, diarrhea 49%, vomiting 41%; serious AEs 8% vs 7% placebo.
- 03
In a Phase 2 dose-finding obesity RCT (n=387), once-weekly survodutide reduced body weight dose-dependently up to -14.9% at 4.8 mg vs -2.8% placebo over 46 weeks; adverse events in 91% of recipients, primarily gastrointestinal (75%).
- 04
In a Phase 2 RCT in type 2 diabetes (n=413), survodutide reduced HbA1c comparably to semaglutide at lower doses and produced greater weight loss (up to -8.7%) at higher doses; adverse events (mainly gastrointestinal) in ~78% of survodutide participants; GI AEs mitigated by slower escalation.
- 05
Phase 1 single- and multiple-rising-dose studies showed placebo-corrected weight loss up to 13.8% at week 16; drug-related AEs increased with dose; cardiac or vascular AEs were the most common cause of discontinuation in one cohort (~7.5%); target engagement shown by reduced plasma amino acids and glucagon.
- 06
Phase 1 study in Japanese men with overweight/obesity: placebo-corrected weight loss up to -12.4% over 16 weeks; decreased appetite in 66.7%, one case of amylase increase; transient delayed gastric emptying demonstrated by paracetamol absorption.
Last reviewed 2026-07-06 · Verified against PubMed · Educational, not medical advice