Survodutide

What it is

Survodutide is a 29-amino acid peptide derived from glucagon that acts as a dual agonist at both the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). It contains a C18 diacid moiety that mediates albumin binding, prolonging its half-life to enable once-weekly subcutaneous dosing. GLP-1R agonism reduces appetite and stimulates insulin secretion, while GCGR agonism increases energy expenditure and hepatic fat oxidation, providing complementary mechanisms for weight loss and metabolic improvement. In the brain, survodutide accesses circumventricular organs (CVOs) and adjacent hypothalamic and hindbrain nuclei without uniformly crossing the blood-brain barrier, activating multiple nuclei associated with food intake control; the intake-suppressive effects appear GLP-1R-dependent. Preclinically, survodutide was selected from 19 dual agonists based on balanced GCGR/GLP-1R pharmacology, demonstrating robust body-weight lowering via both decreased energy intake and increased energy expenditure. Survodutide also significantly improved beta-cell function (HOMA-β) and insulin sensitivity (HOMA-IR), and reduced glucagon levels, with effects that were largely independent of body weight changes. Mediation analysis of a Phase 2 MASH trial suggests that improvements in hepatic inflammation and fibrosis are predominantly weight-reduction-independent, consistent with a direct glucagon receptor agonist effect in the liver.

Class: Dual glucagon receptor (GCGR) / glucagon-like peptide-1 receptor (GLP-1R) agonist; investigational peptide therapeutic

What it's studied for

• Obesity (without type 2 diabetes) Human RCT
  • Phase 2 trial (n=387, BMI ≥27 kg/m², no diabetes, 46 weeks). Mean bodyweight change from baseline: -6.2% (0.6 mg), -12.5% (2.4 mg), -13.2% (3.6 mg), -14.9% (4.8 mg) vs -2.8% (placebo). All survodutide doses tolerated; gastrointestinal AEs were most common. PMID 38330987 le Roux et al. (2024). Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol.
  • Phase 3 SYNCHRONIZE-1 trial (n=725, BMI ≥30 or ≥27 with complication, no diabetes, 76 weeks). Mean body weight change: -12.2% (3.6 mg), -13.0% (6.0 mg) vs -5.4% (placebo). Achievement of ≥5% weight loss: 72.6%, 71.9% vs 46.3% (P<0.001). No deaths reported. Gastrointestinal AEs in 80.9%/89.7% survodutide vs 47.9% placeb PMID 42253238 le Roux et al. (2026). Survodutide Once Weekly for the Treatment of Adults with Obesity. N Engl J Med.
  • Phase 2 subgroup analysis: females had greater reductions in bodyweight and waist circumference than males; lower baseline BMI was associated with greater proportional bodyweight reductions. Nausea was the most frequently reported gastrointestinal AE across all subgroups. PMID 39821928 le Roux et al. (2025). Subgroup analysis by sex and baseline BMI in the phase 2 trial of survodutide. Diabetes Obes Metab.
• Obesity with type 2 diabetes Human RCT
  • Phase 2 trial (n=413, T2D on metformin, 16 weeks). HbA1c decreased dose-dependently across survodutide groups (DG1–6: -0.91% to -1.68%); bodyweight decreased up to -8.7% (DG6). Survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3%). GI AEs in 77.8% survodutide vs 52.5% placebo. PMID 38095657 Blüher et al. (2024). Dose-response effects on HbA1c and bodyweight reduction of survodutide vs placebo and open-label semaglutide in people with T2D: a randomised clinical trial. Diabetologia.
  • Phase 3 SYNCHRONIZE-2 (n=752, BMI ≥27 + T2D, 76 weeks, ongoing). Primary endpoints: percentage change in body weight and ≥5% BW reduction at Week 76. Results pending. PMID 41216778 Wharton et al. (2026). Baseline characteristics in the SYNCHRONIZE-2 randomized phase 3 trial of survodutide for obesity in people with T2D. Diabetes Obes Metab.
• Metabolic dysfunction-associated steatohepatitis (MASH) / MASLD Human RCT
  • Phase 2 trial (n=293, biopsy-confirmed MASH F1–F3, 48 weeks). MASH improvement with no worsening of fibrosis: 47% (2.4 mg), 62% (4.8 mg), 43% (6.0 mg) vs 14% (placebo; P<0.001). Liver fat reduction ≥30%: 63%, 67%, 57% vs 14%. Fibrosis improvement ≥1 stage: 34%, 36%, 34% vs 22%. AEs: nausea (66% vs 23%), diarrhea (49% v PMID 38847460 Sanyal et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med.
  • Phase 3 SYNCHRONIZE-MASLD (n=216, obesity + at-risk MASLD, 48 weeks). ≥30% LFC reduction: 84.2% survodutide vs 24.3% placebo (P<0.0001). Mean BW change: -12.2% vs -1.0% (P<0.0001). Most frequent AEs: gastrointestinal, mild-to-moderate, during dose escalation. PMID 42252333 Kaplan et al. (2026). Survodutide in adults with obesity and MASLD: SYNCHRONIZE-MASLD phase 3 trial. Nature Medicine.
  • Post hoc mediation analysis of Phase 2 MASH trial (n=170, F2–F3). Weight reduction mediated 66.7% of MASH resolution, 71.8% of MASH improvement, but only 36.3% of fibrosis improvement — suggesting a direct, weight-independent glucagon receptor effect on fibrosis. For NIT-based inflammation/fibrosis endpoints, <50% of e PMID 42545725 Noureddin et al. (2026). Weight reduction-dependent/-independent effects of survodutide on liver endpoints: Mediation analysis. Hepatology.
• Beta-cell function and insulin sensitivity improvement Human RCT
  • Post hoc analysis of two Phase 2 trials. In T2D participants, survodutide significantly increased HOMA-β and decreased HOMA-IR, glucagon, and fasting plasma glucose. In overweight/obese normoglycaemic participants, significant decreases in HOMA-IR, glucagon, C-peptide, fasting insulin, and FPG, and increased HMW adipon PMID 42331726 Ekinci et al. (2026). Dual Glucagon and GLP-1 Receptor Agonist Survodutide Improves Biomarkers of Beta-Cell Function and Insulin Sensitivity. Diabetes Obes Metab.
• MASH in cirrhosis (pharmacokinetics and tolerability) Human observational
  • Phase 1 open-label study in Child-Pugh A/B/C cirrhosis (n=41 single-dose; n=41 multiple-dose). PK (AUC and Cmax) was similar in cirrhosis vs healthy individuals — no PK-related dose adjustment required. Drug-related AEs: 82.4%–87.5% with multiple doses. Liver fat, stiffness, volume, and body weight generally reduced af PMID 38857788 Lawitz et al. (2024). Efficacy, tolerability and pharmacokinetics of survodutide in cirrhosis. J Hepatol.
• Cardiovascular outcomes (safety/efficacy trial ongoing) Human RCT
  • SYNCHRONIZE-CVOT: Phase 3, randomized, event-driven CV safety study in adults with BMI ≥27 kg/m² and established CVD or CKD and/or ≥2 weight-related complications. Primary endpoint: time to first 5-point MACE. Target n=4,935. Currently enrolling; results pending. PMID 39453356 Kosiborod et al. (2024). Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial. JACC Heart Fail.
• Combination with NPY2R agonist for obesity (preclinical) Animal studies only
  • In diet-induced obese mice, survodutide alone produced ~17% bodyweight reduction; combined with NPY2R agonist BI 1820237, reduction increased to ~22% (p<0.01). BI 1820237 increased survodutide efficacy by 265% at an ED50 of 11.7 nmol/kg over a range of dose combinations. PMID 40619099 Augustin et al. (2025). Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with survodutide. Mol Metab.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• High frequency of gastrointestinal adverse events (nausea, vomiting, diarrhea): nausea 66% (survodutide) vs 23% (placebo); vomiting 41% vs 4%; diarrhea 49% vs 23% in Phase 2 MASH trial. PMID 38847460
• Gastrointestinal AEs in 80.9% (3.6 mg) and 89.7% (6.0 mg) survodutide groups vs 47.9% placebo in Phase 3 SYNCHRONIZE-1; typically mild to moderate severity. PMID 42253238
• Higher risk of treatment discontinuation due to AEs with survodutide vs placebo; gastrointestinal AEs are the most common cause, with no significant increase in serious AEs in meta-analysis. PMID 40922121
• Adverse events (primarily gastrointestinal) in 91% of survodutide recipients vs 75% of placebo recipients in Phase 2 obesity trial. PMID 38330987
• Potential cardiovascular safety signals associated with GCGR agonism: increased heart rate to a similar extent as GLP-1R monoagonists observed with survodutide and mazdutide. At least one other GCGR/GLP-1R dual agonist was discontinued partly due to unacceptably large increases in heart rate and QT prolongation; cardiovascular effects of survodutide are being evaluated in SYNCHRONIZE-CVOT. PMID 42535526
• Drug-related AEs occurred in 82.4%–87.5% of participants with cirrhosis receiving multiple subcutaneous doses escalated to 6.0 mg in a Phase 1 study. PMID 38857788
• No deaths were reported in the Phase 3 SYNCHRONIZE-1 trial (n=725, 76 weeks). PMID 42253238
• Serious adverse events occurred in 8% of survodutide-treated participants vs 7% placebo in the Phase 2 MASH trial. PMID 38847460
• Durability of beta-cell function improvements after treatment cessation is unknown. PMID 42331726

Contraindications

• Type 2 diabetes was an exclusion criterion in the SYNCHRONIZE-1 Phase 3 trial and the Phase 2 obesity dose-finding trial; individuals with T2D were studied separately (SYNCHRONIZE-2). PMID 42253238
• Participants with decompensated cirrhosis are typically excluded from clinical trials of investigational drugs; however, survodutide was specifically evaluated in a Phase 1 study in Child-Pugh A/B/C cirrhosis with no PK-based dose adjustment required, though safety monitoring is warranted. PMID 38857788
• No additional explicit contraindications are stated in the reviewed literature beyond standard trial exclusion criteria. Formal contraindication data from regulatory labeling are not available, as survodutide is investigational. PMID 41187967