Survodutide

Survodutide (BI 456906) is a next-generation dual glucagon/GLP-1 receptor agonist that has demonstrated remarkable efficacy in clinical trials for weight loss, type 2 diabetes management, and metabolic dysfunction-associated steatohepatitis (MASH). Phase 2 trials have shown weight reductions of up to 18.7–20.9% from baseline over 46–48 weeks, positioning it among the most potent obesity treatments in development. This investigational peptide has gained significant attention among researchers, biohackers, and individuals seeking advanced metabolic interventions. Typical dosing in clinical studies ranges from 0.6 mg to 4.8 mg administered once weekly via subcutaneous injection, with treatment durations spanning 16 to 52 weeks depending on the indication.

What Is Survodutide?

Survodutide, also known by its development code BI 456906, is an investigational dual agonist peptide that simultaneously activates both the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). Developed through a partnership between Boehringer Ingelheim and Zealand Pharma, this compound is derived from native glucagon with a C18 fatty diacid modification that enables once-weekly dosing.

What distinguishes survodutide from other incretin-based therapies is its dual mechanism. While semaglutide (Ozempic/Wegovy) acts solely on GLP-1 receptors and tirzepatide targets GLP-1 and GIP receptors, survodutide uniquely combines GLP-1 with glucagon receptor activation. This approach mimics oxyntomodulin, a naturally occurring gut hormone that influences both pathways.

The primary human-use benefits observed in clinical research include:

• Substantial body weight reduction (up to 20.9% in phase 2 trials)
• Significant HbA1c reduction in type 2 diabetics
• Improvement in liver fat content and MASH resolution
• Reduction in waist circumference
• Potential cardiovascular benefits currently under investigation

How It Works

GLP-1 Receptor Activation

The GLP-1 receptor component of survodutide's mechanism provides appetite suppression through central nervous system signaling. When activated, GLP-1 receptors in the hypothalamus reduce hunger signals and increase satiety. Additionally, GLP-1 receptor activation slows gastric emptying, prolonging the feeling of fullness after meals and naturally reducing caloric intake.

GLP-1 also directly acts on pancreatic β-cells to enhance glucose-dependent insulin secretion while suppressing glucagon release from α-cells during hyperglycemic states. This dual pancreatic action improves glycemic control without the hypoglycemia risk associated with insulin secretagogues.

Glucagon Receptor Activation

The glucagon receptor component differentiates survodutide from pure GLP-1 agonists. Glucagon receptor activation increases energy expenditure through enhanced thermogenesis and directly stimulates lipolysis, particularly in hepatic tissue. This metabolic boost helps counteract the adaptive reduction in energy expenditure that typically accompanies weight loss.

The glucagon component also promotes hepatic fat oxidation, which is particularly relevant for individuals with fatty liver disease. Clinical data has shown survodutide reduces liver fat content by at least 30% in 63–67% of treated participants.

Balanced Receptor Agonism

The therapeutic concept behind survodutide involves carefully balanced receptor agonism. The GLP-1 activity provides appetite suppression and glycemic control, while the glucagon activity enhances energy expenditure and hepatic fat metabolism. Importantly, the GLP-1 component helps offset the hyperglycemic potential of glucagon, creating a synergistic effect that maximizes weight loss while maintaining glucose homeostasis.

Dosage Protocols

Clinical trials have employed dose-escalation protocols to minimize gastrointestinal side effects. Based on published research:

For obesity (Phase 2 data):

• Starting dose: 0.6 mg once weekly
• Escalation: Gradual increases every 4 weeks
• Target doses studied: 2.4 mg, 3.6 mg, and 4.8 mg once weekly
• Treatment duration: 46 weeks in the primary obesity trial

For MASH (Phase 2 data):

• Doses studied: 2.4 mg, 4.8 mg, and 6.0 mg once weekly
• Treatment duration: 48 weeks
• The 4.8 mg dose showed optimal efficacy-to-tolerability ratio

For type 2 diabetes:

• Doses ranged from 0.3 mg to 2.7 mg once weekly
• Some protocols tested twice-weekly dosing at 1.2 mg and 1.8 mg
• Treatment duration: 16 weeks in phase 2

Slower dose escalation has been associated with improved gastrointestinal tolerability. Researchers have noted that extending the escalation period reduces the incidence and severity of nausea and vomiting.

How to Use / Administration

Survodutide is administered via subcutaneous injection once weekly. In clinical trials, participants self-administered the medication using prefilled injection devices. The injection sites typically include the abdomen, thigh, or upper arm, with rotation recommended to prevent injection site reactions.

The timing of administration should remain consistent each week, though it does not need to be taken with food. If a dose is missed, standard incretin therapy protocols suggest taking it as soon as remembered if within a few days, then resuming the regular schedule.

Results Timelines

Based on clinical trial data, users can expect the following general timeline:

Weeks 1–4: Initial adaptation period with potential gastrointestinal effects; modest weight changes as dose escalation begins.

Weeks 4–12: Noticeable appetite suppression; weight loss typically becomes apparent; HbA1c improvements begin in diabetic individuals.

Weeks 12–24: Significant weight reduction observed; phase 2 data showed approximately 12–15% weight loss by this point at higher doses.

Weeks 24–46: Continued weight loss with plateau approaching; maximum efficacy observed. The 4.8 mg dose achieved 18.7% weight reduction at 46 weeks, while the 6.0 mg dose in MASH trials showed 20.9% reduction.

Liver fat reduction in MASH patients showed significant improvements by week 24, with continued benefits through week 48.

Research Evidence

The clinical evidence base for survodutide includes multiple randomized controlled trials:

Phase 2 Obesity Trial (Roux 2024): This multinational study of 384 participants demonstrated dose-dependent weight loss. The 4.8 mg dose achieved 18.7% weight reduction versus 2.8% with placebo over 46 weeks. Participants achieving ≥10% weight loss: 83% in the 4.8 mg group versus 22% with placebo.

Phase 2 MASH Trial (Sanyal 2024): Published in the New England Journal of Medicine, this study showed 83% of participants on the 4.8 mg dose achieved MASH resolution without worsening fibrosis, compared to 18.2% with placebo. Fibrosis improvement occurred in 52.3% of the 4.8 mg group.

Type 2 Diabetes Trial (Blüher 2024): Demonstrated HbA1c reductions of up to 2.1% and body weight reductions of up to 8.7% over 16 weeks compared to placebo.

A systematic review and meta-analysis published in 2025 confirmed significant relative body weight reduction (SMD: −1.5; P

Stacking

Currently, there is limited published research on combining survodutide with other peptides or compounds. Clinical trials have studied survodutide as monotherapy or in combination with metformin for type 2 diabetes.

Theoretical considerations suggest caution when combining with other GLP-1 agonists due to overlapping mechanisms and potential for additive gastrointestinal effects. Combining with compounds that affect glucose metabolism requires careful monitoring for hypoglycemia.

Some researchers have noted potential synergy with lifestyle interventions, as all clinical trials incorporated dietary and exercise counseling alongside pharmacotherapy.

Reconstitution, Storage & Preparation

For research-grade survodutide obtained as lyophilized powder:

Storage (unreconstituted):

• Long-term: −80°C for up to 6 months
• Short-term: −20°C for up to 1 month
• Keep sealed, away from moisture and light

Reconstitution:

• Allow peptide vial to reach room temperature (approximately 30 minutes)
• Use bacteriostatic water for reconstitution
• Add water slowly along the vial wall to prevent foaming
• Gently swirl—do not shake vigorously
• Allow 15–30 minutes for complete dissolution
• Solution should be clear; discard if cloudy or particulate matter is present

Storage (reconstituted):

• Refrigerate at 2–8°C (36–46°F)
• Use within 4 weeks of reconstitution
• Protect from light
• Do not freeze reconstituted solution

Side Effects

The most commonly reported adverse events in clinical trials are gastrointestinal in nature:

Common (>10% incidence):

• Nausea (40–60% of participants)
• Vomiting (27% in some studies)
• Diarrhea (significantly higher than placebo; RR: 1.89)
• Decreased appetite
• Dyspepsia

Less common:

• Constipation
• Abdominal pain
• Abdominal distention
• Headache
• Early satiety
• Injection site reactions

Discontinuation rates: Survodutide was associated with higher treatment discontinuation due to adverse events compared to placebo (RR: 4.53; P

Importantly, meta-analysis of available trials found no deaths reported in survodutide groups, suggesting a favorable safety profile compared to some other dual agonists. Slower dose escalation protocols have been shown to mitigate gastrointestinal side effects.

Legal Status / FDA

Survodutide is currently an investigational drug and has not received FDA approval for any indication. Key regulatory milestones include:

• Breakthrough Therapy Designation: The FDA granted survodutide Breakthrough Therapy designation for the treatment of adults with non-cirrhotic MASH, facilitating expedited development and review.
• Phase 3 Trials: Multiple phase 3 programs are underway:
  • SYNCHRONIZE-1 and SYNCHRONIZE-2 for obesity (completion expected December 2025)
  • SYNCHRONIZE Cardiovascular Outcomes Trial for cardiovascular safety
  • LIVERAGE trial for MASH with fibrosis
• Projected Approval: Industry analysts anticipate potential FDA and EMA approval around 2027–2028 if phase 3 trials are successful.

As an unapproved investigational compound, survodutide is not legally available for prescription use. Research-grade material may be obtained for legitimate research purposes in accordance with applicable regulations.

Sports / WADA Status

GLP-1 receptor agonists, including semaglutide, are currently on WADA's Monitoring Program rather than the Prohibited List. This means they are being tracked to determine whether they should be banned but are not currently prohibited for competitive athletes.

Survodutide, as a dual GLP-1/glucagon agonist, falls into a similar category. As of the 2026 Prohibited List, GLP-1 agonists remain under monitoring rather than outright prohibition.

However, athletes should note:

• Some natural bodybuilding federations have implemented their own bans on GLP-1 substances
• WADA continues to study whether these compounds enhance performance or violate the spirit of sport
• Regulations may change; athletes should verify current status before use

Conclusion

Survodutide represents a significant advancement in metabolic pharmacotherapy, offering a unique dual-agonist approach that addresses multiple pathways involved in obesity, diabetes, and fatty liver disease. Clinical evidence demonstrates impressive efficacy, with weight loss approaching 20% and remarkable MASH resolution rates exceeding 80% at optimal doses.

While gastrointestinal side effects remain the primary tolerability concern, these appear manageable with appropriate dose escalation and are consistent with the incretin class. The absence of reported deaths in clinical trials and the FDA's Breakthrough Therapy designation underscore the compound's promising safety-efficacy profile.

As phase 3 trials progress toward completion, survodutide may emerge as a leading option for individuals with complex metabolic conditions requiring multi-target intervention. Those considering research use should carefully weigh the available evidence, understand proper handling and administration, and remain informed about evolving regulatory status.

FAQ

What makes survodutide different from semaglutide or tirzepatide?
Survodutide is a dual GLP-1/glucagon receptor agonist, whereas semaglutide targets only GLP-1 receptors and tirzepatide targets GLP-1/GIP receptors. The glucagon component in survodutide increases energy expenditure and promotes liver fat oxidation, potentially offering advantages for MASH treatment and enhanced weight loss.

How much weight loss can be expected with survodutide?
Phase 2 clinical trials demonstrated weight loss of 14.9% at the 2.4 mg dose and up to 18.7–20.9% at higher doses (4.8–6.0 mg) over 46–48 weeks, compared to approximately 2–3% with placebo.

Is survodutide FDA approved?
No, survodutide remains an investigational drug. It has received FDA Breakthrough Therapy designation for MASH treatment, and phase 3 trials are ongoing. Potential approval is anticipated around 2027–2028.

What are the most common side effects?
Gastrointestinal effects predominate, including nausea (40–60%), vomiting (27%), diarrhea, and decreased appetite. These typically occur during dose escalation and may improve with continued use or slower titration.

How is survodutide administered?
Survodutide is given as a once-weekly subcutaneous injection. Clinical trials used prefilled devices for self-administration in the abdomen, thigh, or upper arm.

Can survodutide help with fatty liver disease?
Yes, phase 2 trials showed 83% of participants achieved MASH resolution at the 4.8 mg dose, with 52% showing fibrosis improvement. Liver fat reduction of ≥30% occurred in approximately two-thirds of treated participants.

Is survodutide banned in sports?
GLP-1 agonists including survodutide are not currently on WADA's Prohibited List but are on the Monitoring Program. Athletes should verify current regulations with their governing body before use.

How should research-grade survodutide be stored?
Lyophilized powder should be stored at −80°C for long-term storage (up to 6 months) or −20°C for shorter periods. Once reconstituted with bacteriostatic water, store refrigerated at 2–8°C and use within 4 weeks.

References

1. Awad AA, et al. Evaluating the efficacy and safety of survodutide for obesity: A systematic review and meta-analysis of randomized controlled trials. Proc (Bayl Univ Med Cent). 2025;38(4):514-522. https://pmc.ncbi.nlm.nih.gov/articles/PMC12184113/
2. Sanyal AJ, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024;391(4):311-319. https://www.nejm.org/doi/full/10.1056/NEJMoa2401755
3. Le Roux CW, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 2024;12(3):162-173. https://www.sciencedirect.com/science/article/abs/pii/S221385872300356X
4. Blüher M, et al. 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. Diabetologia. 2024;67(3):470-482. https://pmc.ncbi.nlm.nih.gov/articles/PMC11542446/
5. Boehringer Ingelheim. Survodutide US FDA Breakthrough Therapy phase 3 trials MASH. https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/survodutide-us-fda-breakthrough-therapy-phase-3-trials-mash
6. FDA Grants Survodutide Breakthrough Therapy Designation for Treatment of Adults with MASH. Pharmacy Times. https://www.pharmacytimes.com/view/fda-grants-survodutide-breakthrough-therapy-designation-for-treatment-of-adults-with-mash
7. World Anti-Doping Agency. 2026 Prohibited List. https://www.wada-ama.org/en/resources/world-anti-doping-code-and-international-standards/prohibited-list
8. MedChemExpress. Survodutide (BI 456906) Product Information. https://www.medchemexpress.com/survodutide.html
9. Medpace. World Obesity Day 2025: Recent Developments and the Road Ahead. https://www.medpace.com/blog/world-obesity-day-2025-recent-developments-and-the-road-ahead/
10. ClinicalTrials.gov. NCT04771273 - A Study to Test Safety and Efficacy of BI 456906 in Patients with NASH. https://www.clinicaltrials.gov/study/NCT04771273