Survodutide (BI 456906)
Survodutide (BI 456906); dual glucagon receptor (GCGR) / glucagon-like peptide-1 receptor (GLP-1R) agonist
Survodutide is an investigational dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist peptide developed by Zealand Pharma and licensed to Boehringer Ingelheim for the treatment of obesity, type 2 diabetes, and MASH. A Phase 2 RCT demonstrated MASH resolution in up to 62% of patients vs 14% placebo (DOI: 10.1056/NEJMoa2401755).
Last updated: 2026-03-13
Safety Summary
Gastrointestinal adverse events are the predominant safety concern with survodutide and are a class effect of GLP-1R agonism, compounded by GCGR activity. Incidence is dose-dependent and highest during dose-escalation phases. Titration strategies are used in all clinical protocols to mitigate GI tolerability. Overall AE rates were 91% survodutide vs 75% placebo in one dose-finding trial. SAE rates (4-8%) were similar to placebo. Treatment discontinuation due to AEs was 15-25%, predominantly due to GI events. No clinically important immunogenicity (anti-drug antibody) signal was reported (PMC12184113). Preclinical carcinogenicity studies showed thyroid C-cell tumors in rodents (class effect for GLP-1R agonists) at high exposures; no signal in non-rodent species (monkey), and no human pharmacovigilance cancer signal through early 2026 (PMC9679702; FAERS data). Preclinical monkey studies showed mild myocardial changes (vacuolation) at supratherapeutic doses with identified NOAEL (PMC9679702). No clinical QT signal reported. Pharmacodynamic drug interaction risk: delayed gastric emptying may alter absorption of narrow-therapeutic-index oral drugs (DrugBank DB18989; PMC12052016). Long-term tolerance: sustained efficacy through Week 76 without clear tachyphylaxis (PMC12803687; dom DOI 10.1111/dom.70196). Withdrawal: no dedicated discontinuation trials; class-level evidence suggests metabolic/weight rebound after stopping GLP-1 therapy (Lancet eClinicalMedicine DOI S2589-5370(25)00614-5) (NEJM DOI 10.1056/NEJMoa2401755; PMC10844353; PMC9679702; PMC12184113).
Known Side Effects
Very common (up to 66% in MASH trial vs 23% placebo; dose-dependent)
Very common (up to 49% in MASH trial vs 23% placebo)
Common (up to 41% in MASH trial vs 4% placebo)
Common
Common (pharmacological effect)
Uncommon; reported in phase 2 data and community reports
Common (dose-dependent; ~-8.6 mmHg systolic at highest dose)
Rare (2 cases reported across trials)
Rare (1 case reported)
Who Should NOT Use This
Preclinical rodent carcinogenicity studies showed thyroid C-cell tumors. This is a standard contraindication for all GLP-1R agonists (PMC9679702)
History of chronic or acute pancreatitis was an exclusion criterion in survodutide trials. GLP-1R agonists have theoretical pancreatic safety concerns.
Not studied in pregnant/breastfeeding women. Women of childbearing potential required to use effective contraception in all trials. Standard exclusion in all trials
Standard trial exclusion.
Excluded from trials due to potential alteration of drug absorption and GI physiology.
Excluded from clinical trials. No dose adjustment data available for severe renal impairment.
Phase I PK study in cirrhosis (PMID 38857788) showed tolerable PK in compensated/decompensated cirrhosis without need for dose adjustment based on PK alone, but advanced hepatic disease beyond studied stages was excluded.
Excluded from MASH and obesity trials.1056/NEJMoa2401755)
Survodutide's GLP-1R-mediated delayed gastric emptying may alter absorption of orally administered drugs. Monitoring recommended. A DDI study with oral contraceptives (ethinylestradiol/levonorgestrel) was conducted (NCT05896384).
Talk to Your Doctor
Before considering Survodutide (BI 456906), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-15]
Evidence Assessment
Survodutide has completed multiple phase 2 randomized, double-blind, placebo-controlled trials (obesity n=386, MASH n=293, T2D n=413) with robust efficacy results published in NEJM, Lancet, and Diabetologia. An extensive phase 3 program (SYNCHRONIZE) is actively enrolling >10,000 participants across 5+ trials including a cardiovascular outcomes trial. A completed Phase 3 trial in China (NCT06214741, n=307) has finished. FDA Breakthrough Therapy designation for MASH was granted October 2024. Meta-analyses confirm efficacy (PMC11542446; PMC12184113). While no FDA approval exists yet (investigational), the breadth and scale of human clinical data place this firmly at Tier 2 (Phase III+ human data available).
1Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trialNCT04667377PMID 38330987
Le Roux CW, Hannige AM, et al. - Lancet Diabetes & Endocrinology (2024) - Phase 2 RCT (dose-finding) - 386
Dose-dependent weight loss: -6.2% (0.6 mg) to -14.9% (4.8 mg) vs -2.8% placebo at 46 weeks. Responder rates at 4.8 mg: >=5% weight loss 83%, >=10% 73%, >=15% 55%. GI adverse events were the most common.
Limitations: Industry-sponsored (Boehringer Ingelheim), 46-week duration limits long-term safety assessment, dose-finding not powered for rare events.
2A Phase 2 Randomized Trial of Survodutide in MASH and FibrosisNCT04771273PMID 38847460
Sanyal AJ, et al. - New England Journal of Medicine (2024) - Phase 2 RCT - 293
MASH improvement without worsening fibrosis: 2.4 mg 47%, 4.8 mg 62%, 6.0 mg 43% vs placebo 14% (dose-response P<0.001). Liver fat >=30% reduction: 63-67% vs 14% placebo. Fibrosis improvement >=1 stage: 34-36% vs 22%. Nausea up to 66%, diarrhea 49%, vomiting 41%.
Limitations: Industry-sponsored, 48-week duration, histologic endpoints require liver biopsy, high GI AE rates with potential for unblinding.
3Dose-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: a randomised clinical trial
Bluher M, Hennige AM, et al. - Diabetologia (2024) - Phase 2 RCT (T2D) - 413
HbA1c reduction up to -1.68% at highest dose; weight loss up to -8.7% vs placebo at 16 weeks. Superior to semaglutide 1 mg for weight loss at some doses. Overall AEs 91% vs 75% placebo.
Limitations: Industry-sponsored, short duration (16 weeks), open-label semaglutide comparator arm.
4Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosisPMID 38857788
Not specified in raw data - Journal of Hepatology (2024) - Phase 1 PK study - Small (PK study in cirrhosis vs healthy controls)
AUC and Cmax similar between cirrhosis patients and healthy controls. No dose adjustment needed based on PK. Tolerable in compensated/decompensated cirrhosis. Half-life ~6 days. >99% albumin binding.
Limitations: Small sample size, PK-focused, limited efficacy assessment.
5Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE-1 and -2)NCT06066515PMID 39495965
Wharton S, et al. - Obesity (Silver Spring) (2024) - Phase 3 design publication - Planned enrollment >10,000 across SYNCHRONIZE program
Design publication describing SYNCHRONIZE-1 (obesity without T2D, NCT06066515) and SYNCHRONIZE-2 (obesity with T2D, NCT06066528). Primary endpoint: percentage change in body weight at ~76 weeks.
Limitations: Design paper only - no efficacy results yet reported.
6The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection
Thomas L, et al. - Diabetes, Obesity and Metabolism (2024) - Preclinical/Translational - Preclinical (in vitro and animal models)
Characterized survodutide receptor potency (GCGR EC50 0.52 nM, GLP-1R EC50 0.60 nM in human CHO-K1 cAMP assays), albumin binding, PK profile in mouse (MRT 24-28h), bioavailability (82-123% SC in mouse). DPP-4 resistance confirmed.
Limitations: Preclinical data; human translation requires confirmation in clinical studies.
7BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy
Not specified in raw data - PMC (2022) - Preclinical discovery - Preclinical
2-year rodent carcinogenicity: thyroid C-cell hyperplasia/adenomas/carcinomas (GLP-1R agonist class effect). No thyroid tumors in monkeys. Negative genotoxicity. Myocardial vacuolation in monkeys at supratherapeutic doses. NOAEL identified.
Limitations: Preclinical data only. Rodent thyroid findings may not translate to humans.
8Effect of survodutide, a glucagon and GLP-1 receptor dual agonist, on weight loss: a meta-analysis of randomized controlled trials
Wan X, et al. - Diabetology & Metabolic Syndrome (2024) - Meta-analysis - Pooled from multiple RCTs (~1000+ across treatment arms)
Pooled mean weight reduction approximately -8.33 kg across RCTs. Confirmed dose-dependent efficacy and consistent GI adverse event profile.
Limitations: Limited by heterogeneity of included trials (different doses, populations, durations).
9Evaluating the efficacy and safety of survodutide for obesity: a systematic review and meta-analysis of randomized controlled trials
Not specified in raw data - PMC (2025) - Systematic review and meta-analysis - Pooled from RCTs
Confirmed efficacy for weight loss and acceptable safety profile. No clinically important anti-drug antibody signal. SAE rates similar to placebo.
Limitations: Limited by available trial data at time of analysis.
10SYNCHRONIZE-CVOT: Cardiovascular Outcomes Trial of SurvodutideNCT06077864
Boehringer Ingelheim (sponsor) - ClinicalTrials.gov (2023) - Phase 3 CVOT (ongoing) - Large (planned completion 2027)
Designed to assess major adverse cardiovascular events in adults with obesity. Active, recruiting. Will provide definitive CV safety and efficacy data.
Limitations: No results yet. Completion estimated 2027.
11LIVERAGE: Phase 3 Trial of Survodutide in MASH with FibrosisNCT06309992
Boehringer Ingelheim (sponsor) - ClinicalTrials.gov (2024) - Phase 3 (ongoing) - Large (event-driven design)
Phase 3 trial for MASH with moderate-to-advanced liver fibrosis (F2-F3). FDA Breakthrough Therapy designation supports expedited review.
Limitations: No results yet.
12Phase 3 Study of Survodutide in Chinese Participants With Overweight or ObesityNCT06214741
Boehringer Ingelheim (sponsor) - ClinicalTrials.gov (2024) - Phase 3 RCT (completed) - 307
Completed January 2026. Tested 3.6 mg and 4.8 mg vs placebo in Chinese adults. Primary endpoints: percentage change in body weight and achievement of >=5% weight loss at 52 weeks. Results not yet published.
Limitations: Results pending publication. Population-specific (Chinese adults with different BMI thresholds).
13Phase 1 Drug Interaction Study: Survodutide Effect on Oral Contraceptive PKNCT05896384
Boehringer Ingelheim (sponsor) - ClinicalTrials.gov (2023) - Phase 1 DDI - 32
Completed March 2025. Evaluated effect of multiple doses of survodutide on single-dose PK of ethinylestradiol and levonorgestrel (Microgynon). Results pending.
Limitations: Results not yet reported.
14Survodutide acts through circumventricular organs in the brain and activates neuronal regions associated with appetite regulation
Not specified in raw data - PMC (2025) - Preclinical/Mechanistic - Preclinical
Survodutide accesses the brain via circumventricular organs (area postrema, NTS, ARH) without uniform BBB penetration. Activates neuronal appetite regulation regions.
Limitations: Animal study; human brain penetration not directly confirmed.
15Survodutide improves blood pressure in adults with obesity: A post hoc analysis from a randomized phase 2 trial
Not specified in raw data - Diabetes, Obesity and Metabolism (2024) - Post-hoc analysis of Phase 2 RCT - From obesity phase 2 cohort
Dose-dependent blood pressure reductions: ~-8.6 mmHg systolic and ~-4.8 mmHg diastolic at highest dose vs placebo.
Limitations: Post-hoc analysis, not pre-specified primary endpoint.