Survodutide: Research Overview & Study Index

Q: What is survodutide, in one sentence?

An investigational once-weekly peptide from Boehringer Ingelheim and Zealand Pharma that activates both the glucagon receptor and the GLP-1 receptor, studied in obesity, type 2 diabetes, MASH, and liver fibrosis [1].

Q: How does it differ from tirzepatide and retatrutide?

All are multi-receptor agonists, but the second targets differ: tirzepatide pairs GLP-1 with GIP (a second incretin), survodutide pairs GLP-1 with glucagon (adding hepatic energy expenditure and direct liver activity), and retatrutide combines all three [1][5].

Q: How much weight loss has been reported in trials?

Up to 14.9% at 46 weeks in phase 2 [3] and, in the phase 3 SYNCHRONIZE-1 trial at 76 weeks, 13.0% by the all-randomized analysis and up to 16.6% among participants who adhered to treatment, versus 5.4% and 3.2% respectively for placebo [7][12].

Q: What did the MASH research show?

In a biopsy-based phase 2 trial, up to 62% of participants had improvement in MASH without worsening of fibrosis versus 14% on placebo, and roughly a third had fibrosis improve by at least one stage [4]; analyses suggest much of the fibrosis effect was independent of weight loss [5].

Q: Is survodutide FDA-approved?

No. It is an investigational compound in phase 3 development; it holds FDA Breakthrough Therapy designation for non-cirrhotic MASH with moderate or advanced fibrosis, which expedites review but is not an approval [13].

Q: What were the most common adverse events in trials?

Dose-related gastrointestinal events — nausea, diarrhea, vomiting — reported by a majority of participants at higher doses, mostly mild to moderate and concentrated during dose escalation [3][4][7].

Q: What major readouts are still ahead?

SYNCHRONIZE-2 in obesity with type 2 diabetes (expected late 2026) [14], the SYNCHRONIZE-CVOT cardiovascular outcomes trial [10], and the biopsy-based LIVERAGE and LIVERAGE-Cirrhosis MASH trials [13].

Survodutide is an investigational peptide developed by Boehringer Ingelheim and Zealand Pharma that activates two metabolic hormone receptors simultaneously — the glucagon receptor and the GLP-1 receptor. In a 46-week phase 2 obesity trial, the highest dose produced an average body-weight reduction of 14.9% versus 2.8% with placebo [3], and the phase 3 SYNCHRONIZE-1 trial published in 2026 reported reductions of up to 16.6% at 76 weeks among participants who stayed on treatment [7][12]. The compound has drawn particular research attention for its liver findings: in a biopsy-based phase 2 trial in metabolic dysfunction-associated steatohepatitis (MASH), up to 62% of participants showed histologic improvement without worsening of fibrosis, versus 14% on placebo [4], a result that earned survodutide FDA Breakthrough Therapy designation for non-cirrhotic MASH [13]. Survodutide remains an investigational compound: it is not approved by the FDA for any use, and this article is a summary of the published scientific literature, not medical guidance.

What Is Survodutide?

Survodutide, known during development as BI 456906, is a glucagon-derived peptide engineered for balanced dual agonism at the human glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R), administered once weekly by subcutaneous injection in clinical trials [1]. It originated in the long-running peptide collaboration between Zealand Pharma and Boehringer Ingelheim, with Boehringer leading clinical development [12].

Its development history:

Preclinical candidate selection (published 2024). Boehringer scientists described how survodutide was chosen from 19 dual GCGR/GLP-1R agonists using biomarker-based profiling — glucose-tolerance testing for GLP-1 receptor engagement and FGF21/hepatic gene-expression markers for glucagon receptor engagement — selecting the molecule whose weight-lowering efficacy in obese mice exceeded that of selective GLP-1 agonists while retaining comparable glucose-lowering [1].
Phase 2 in type 2 diabetes (published 2023–2024). A 16-week dose-response trial in 413 adults on metformin, published in Diabetologia, with open-label semaglutide as an active comparator [2].
Phase 2 in obesity (2024). A 46-week dose-finding trial in 387 adults without diabetes, published in The Lancet Diabetes & Endocrinology [3].
Phase 2 in MASH (2024). A 48-week, biopsy-confirmed trial in 293 adults with MASH and fibrosis stages F1–F3, published in the New England Journal of Medicine [4].
Phase 3 (2023–ongoing). The SYNCHRONIZE program in obesity (SYNCHRONIZE-1, -2, -CVOT, -MASLD, plus regional trials in Japan and China) [9][10] and the LIVERAGE program in MASH and MASH cirrhosis [13]. SYNCHRONIZE-1 and SYNCHRONIZE-MASLD read out in 2026 and were published in the New England Journal of Medicine and Nature Medicine, respectively [7][8].

Mechanism of Action

Survodutide engages two receptors with complementary effects on energy balance:

GLP-1 receptor. Activation enhances glucose-dependent insulin secretion, slows gastric emptying, and reduces appetite — the mechanism of semaglutide and the appetite-suppressing "energy-in" side of the incretin class.
Glucagon receptor. Glucagon receptor agonism increases hepatic energy expenditure and lipid oxidation, adding an "energy-out" mechanism and acting directly on the liver — the organ most affected in MASH. Because glucagon signaling alone can raise blood glucose, the molecule was engineered so that GLP-1 receptor activity counterbalances this effect; the preclinical program specifically screened for a ratio of activities that preserved glucose-lowering while maximizing weight-lowering [1].

This design places survodutide in a distinct position among multi-receptor agonists. Tirzepatide is also a dual agonist but pairs GLP-1 with GIP — a second incretin that amplifies insulin secretion and appears to act on adipose tissue — rather than glucagon. Survodutide's second target instead adds a catabolic, liver-centered mechanism. Retatrutide combines all three (GLP-1, GIP, and glucagon). The glucagon component is the leading hypothesis for the strong liver signals seen with survodutide: a 2026 mediation analysis of the phase 2 MASH trial estimated that only 36.3% of the fibrosis-improvement effect was mediated by weight reduction — implying that most of it was weight-independent — whereas steatosis endpoints such as MRI-measured liver fat were predominantly weight-mediated [5].

Research Findings by Area

Weight and metabolic outcomes

The phase 2 obesity trial randomized 386 treated adults (BMI ≥27, without diabetes) to once-weekly survodutide 0.6, 2.4, 3.6, or 4.8 mg or placebo for 46 weeks, including a 20-week dose-escalation period [3]. Mean weight change at week 46 by planned treatment was −6.2% (0.6 mg), −12.5% (2.4 mg), −13.2% (3.6 mg), and −14.9% (4.8 mg), versus −2.8% with placebo. Adverse events were primarily gastrointestinal (75% of survodutide recipients versus 42% on placebo), and only 60.4% of participants completed the 46-week period — a limitation the phase 3 program addressed with slower, more flexible dose escalation [3][9]. Post hoc analyses of the same trial reported improvements in systolic blood pressure among survodutide-treated adults [11].

In phase 3, SYNCHRONIZE-1 (NCT06066515) randomized 725 adults with obesity, or overweight plus at least one weight-related complication (excluding diabetes), to survodutide up-titrated to 3.6 mg or 6.0 mg or placebo for 76 weeks [7]. By the treatment-regimen estimand — which counts everyone randomized, including those who stopped treatment — mean weight change was −12.2% (3.6 mg) and −13.0% (6.0 mg) versus −5.4% with placebo; 72.6% and 71.9% of survodutide participants achieved at least 5% weight reduction versus 46.3% on placebo (p<0.001 for all comparisons) [7]. By the efficacy estimand, which reflects participants who adhered to treatment, weight loss reached an average of 16.6%, per the companies' April 2026 topline announcement [12]. Gastrointestinal adverse events remained the most common finding (80.9% at 3.6 mg and 89.7% at 6.0 mg versus 47.9% with placebo), mostly mild to moderate; no deaths were reported [7].

Glycemic outcomes

The phase 2 type 2 diabetes trial randomized 413 adults (baseline HbA1c 7.0–10.0% on metformin) across survodutide doses up to 2.7 mg once weekly or 1.8 mg twice weekly, placebo, or open-label semaglutide up to 1.0 mg, for 16 weeks [2]. HbA1c fell by up to 1.71 percentage points (1.8 mg once weekly), with the 0.9 mg dose matching semaglutide (−1.46 vs −1.47 points). Body weight decreased dose-dependently by up to 8.7%, exceeding the 5.3% observed with semaglutide over the same 16 weeks — an early signal that the glucagon component adds weight-lowering without sacrificing glycemic control [2]. The trial was short and used an open-label comparator, so these comparisons are hypothesis-generating rather than definitive.

The phase 3 counterpart, SYNCHRONIZE-2 (NCT06066528; 755 adults with BMI ≥27 and type 2 diabetes), completed enrollment with percentage weight change and ≥5% weight reduction at 76 weeks as primary endpoints [9]. Results had not been published at the time of writing; Zealand Pharma's half-year 2026 report indicates they are expected for presentation at the EASD annual meeting in late 2026 [14].

Liver outcomes: MASH and fibrosis

This is where survodutide's data most stand out among incretin-class compounds. The phase 2 MASH trial (NCT04771273) randomized 293 adults with biopsy-confirmed MASH and fibrosis stage F1–F3 to survodutide 2.4, 4.8, or 6.0 mg or placebo for 48 weeks [4]. Histologic improvement in MASH with no worsening of fibrosis — the primary endpoint, assessed by paired biopsy — occurred in 47% (2.4 mg), 62% (4.8 mg), and 43% (6.0 mg) of participants versus 14% on placebo (p<0.001). A liver-fat reduction of at least 30% occurred in up to 67% of survodutide participants versus 14% on placebo, and fibrosis improved by at least one stage in 34–36% versus 22% [4]. Nausea (66% vs 23%), diarrhea (49% vs 23%), and vomiting (41% vs 4%) were more frequent with survodutide; serious adverse events were similar between arms (8% vs 7%) [4].

The 2026 mediation analysis of this trial, discussed above, found that inflammation- and fibrosis-related improvements were predominantly weight-independent, consistent with direct glucagon receptor activity in the liver [5]. A separate phase 1 trial in people with cirrhosis (Child-Pugh A–C) found that survodutide's pharmacokinetics were similar to those in healthy individuals, that no dose adjustment for hepatic impairment appeared necessary, and that liver fat, liver stiffness, and body weight were generally reduced after 28 weeks in participants with compensated or decompensated cirrhosis [6].

On the strength of the phase 2 histology data, the FDA granted survodutide Breakthrough Therapy designation for non-cirrhotic MASH with moderate or advanced fibrosis in October 2024, and Boehringer initiated two phase 3 trials: LIVERAGE (~1,800 adults with MASH and F2–F3 fibrosis, with histologic endpoints at 52 weeks and long-term liver outcomes over ~7 years) and LIVERAGE-Cirrhosis (~1,590 adults with compensated MASH cirrhosis, following end-stage liver-disease outcomes over ~4.5 years) [13].

In 2026, the phase 3 SYNCHRONIZE-MASLD trial (216 adults with obesity and at-risk MASLD) reported that 84.2% of survodutide-treated participants achieved a ≥30% reduction in MRI-measured liver fat at 48 weeks versus 24.3% on placebo by the efficacy estimand (68.5% vs 28.6% by treatment-regimen estimand; both p<0.0001), with mean weight change of −12.2% versus −1.0% [8]. This trial used imaging and noninvasive tests rather than biopsy; the biopsy-based verdict belongs to LIVERAGE.

Cardiovascular outcomes

Beyond the blood-pressure improvements observed in phase 2 [11], hard cardiovascular evidence is pending. SYNCHRONIZE-CVOT (NCT06077864) is an event-driven trial enrolling a planned 4,935 adults with BMI ≥27 and established cardiovascular disease, chronic kidney disease, or multiple risk factors, with time to first five-point major adverse cardiovascular event as the primary endpoint — the first trial designed to determine the cardiovascular safety and efficacy of a glucagon/GLP-1 dual agonist in this population [10].

Limitations & Open Questions in the Literature

No approved indication. Survodutide is investigational in every studied condition. All figures above describe supervised clinical-trial settings with structured dose escalation and monitoring.
Estimand gap. In SYNCHRONIZE-1, average weight loss was 13.0% counting all randomized participants but 16.6% among those adhering to treatment [7][12] — a reminder that discontinuation and tolerability materially affect real-world expectations.
Head-to-head data are thin. The only randomized comparison with another agent is the 16-week phase 2 diabetes trial against open-label semaglutide 1.0 mg [2]. No trial has directly compared survodutide with tirzepatide or retatrutide.
Tolerability. Gastrointestinal adverse events were the dominant finding in every trial and were dose-related; in the phase 2 obesity trial only ~60% of participants completed 46 weeks [3], and in SYNCHRONIZE-1 nearly 90% of the 6.0 mg group reported gastrointestinal events [7].
Weight-loss magnitude versus triple agonists. Cross-trial comparisons are unreliable, but survodutide's phase 3 weight-loss figures are numerically lower than those reported for retatrutide in phase 3; its differentiation case rests more on the liver data than on maximal weight reduction.
Biopsy-confirmed phase 3 liver outcomes are pending. SYNCHRONIZE-MASLD used imaging endpoints [8]; histologic and hard liver outcomes await LIVERAGE and LIVERAGE-Cirrhosis, which run for years [13].
Hard cardiovascular outcomes unknown. SYNCHRONIZE-CVOT is ongoing [10]; glucagon receptor agonism can raise heart rate and energy expenditure, and its long-term cardiovascular net effect is precisely what the trial exists to answer.
Durability and discontinuation. Published trials extend to 76 weeks [7]; what happens to weight and liver endpoints after stopping has not been characterized for survodutide.

Frequently Asked Questions

What is survodutide, in one sentence? An investigational once-weekly peptide from Boehringer Ingelheim and Zealand Pharma that activates both the glucagon receptor and the GLP-1 receptor, studied in obesity, type 2 diabetes, MASH, and liver fibrosis [1].

How does it differ from tirzepatide and retatrutide? All are multi-receptor agonists, but the second targets differ: tirzepatide pairs GLP-1 with GIP (a second incretin), survodutide pairs GLP-1 with glucagon (adding hepatic energy expenditure and direct liver activity), and retatrutide combines all three [1][5].

How much weight loss has been reported in trials? Up to 14.9% at 46 weeks in phase 2 [3] and, in the phase 3 SYNCHRONIZE-1 trial at 76 weeks, 13.0% by the all-randomized analysis and up to 16.6% among participants who adhered to treatment, versus 5.4% and 3.2% respectively for placebo [7][12].

What did the MASH research show? In a biopsy-based phase 2 trial, up to 62% of participants had improvement in MASH without worsening of fibrosis versus 14% on placebo, and roughly a third had fibrosis improve by at least one stage [4]; analyses suggest much of the fibrosis effect was independent of weight loss [5].

Is survodutide FDA-approved? No. It is an investigational compound in phase 3 development; it holds FDA Breakthrough Therapy designation for non-cirrhotic MASH with moderate or advanced fibrosis, which expedites review but is not an approval [13].

What were the most common adverse events in trials? Dose-related gastrointestinal events — nausea, diarrhea, vomiting — reported by a majority of participants at higher doses, mostly mild to moderate and concentrated during dose escalation [3][4][7].

What major readouts are still ahead? SYNCHRONIZE-2 in obesity with type 2 diabetes (expected late 2026) [14], the SYNCHRONIZE-CVOT cardiovascular outcomes trial [10], and the biopsy-based LIVERAGE and LIVERAGE-Cirrhosis MASH trials [13].

References

Thomas L, et al. The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection. Diabetes Obes Metab. 2024;26(6):2368–2378. doi:10.1111/dom.15551. PMID: 38560764
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: a randomised clinical trial. Diabetologia. 2024;67(3):470–482. doi:10.1007/s00125-023-06053-9. PMID: 38095657
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. doi:10.1016/S2213-8587(23)00356-X. PMID: 38330987
Sanyal AJ, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024;391(4):311–319. doi:10.1056/NEJMoa2401755. PMID: 38847460
Noureddin M, et al. Weight reduction-dependent/-independent effects of survodutide on liver endpoints: Mediation analysis of a phase 2 trial in MASH. Hepatology. 2026 (online ahead of print). doi:10.1097/HEP.0000000000001825. PMID: 42545725
Lawitz EJ, et al. Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis. J Hepatol. 2024;81(5):837–846. doi:10.1016/j.jhep.2024.06.003. PMID: 38857788
le Roux CW, et al. Survodutide Once Weekly for the Treatment of Adults with Obesity. N Engl J Med. 2026;395(8):776–787. doi:10.1056/NEJMoa2600751. PMID: 42253238
Kaplan LM, et al. Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2026;32(8):2948–2958. doi:10.1038/s41591-026-04479-3. PMID: 42252333
Wharton S, et al. Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE™-1 and -2). Obesity (Silver Spring). 2025;33(1):67–77. doi:10.1002/oby.24184. PMID: 39495965
Kosiborod MN, et al. Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial. JACC Heart Fail. 2024;12(12):2101–2109. doi:10.1016/j.jchf.2024.09.004. PMID: 39453356
le Roux CW, et al. Survodutide, a glucagon receptor/glucagon-like peptide-1 receptor dual agonist, improves blood pressure in adults with obesity: A post hoc analysis from a randomized, placebo-controlled, dose-finding, phase 2 trial. Diabetes Obes Metab. 2025;27(2):993–996. doi:10.1111/dom.16052. PMID: 39582349
Zealand Pharma / Boehringer Ingelheim. Zealand Pharma announces Boehringer Ingelheim's novel glucagon/GLP-1 dual agonist survodutide achieved significant weight loss of 16.6% delivering meaningful metabolic improvement in people with obesity or overweight in Phase 3 trial (SYNCHRONIZE-1). Press release, April 2026. https://www.biospace.com/press-releases/zealand-pharma-announces-boehringer-ingelheims-novel-glucagon-glp-1-dual-agonist-survodutide-achieved-significant-weight-loss-of-16-6-delivering-meaningful-metabolic-improvement-in-people-with-obesity-or-overweight-in-phase-3-trial
Boehringer Ingelheim. Boehringer receives U.S. FDA Breakthrough Therapy designation and initiates two phase III trials in MASH for survodutide (LIVERAGE; LIVERAGE-Cirrhosis). Press release, October 2024. https://www.biospace.com/press-releases/boehringer-receives-u-s-fda-breakthrough-therapy-designation-and-initiates-two-phase-iii-trials-in-mash-for-survodutide
Zealand Pharma. Zealand Pharma Announces Financial Results for the First Half of 2026. Press release, August 13, 2026. https://www.globenewswire.com/news-release/2026/08/13/3344209/0/en/zealand-pharma-announces-financial-results-for-the-first-half-of-2026.html

This article summarizes published scientific literature for educational purposes only. Survodutide is an investigational compound not approved for human use. Nothing here constitutes medical advice, and no statement has been evaluated by the FDA.