Moderate · human
The SYNCHRONIZE-MASLD trial investigated survodutide — a dual glucagon receptor/GLP-1 receptor agonist — in 216 adults with obesity and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD). Participants were randomized 2:1 to once-weekly subcutaneous survodutide 6.0 mg (n=146) or placebo (n=70) for 48 weeks. The trial had two co-primary endpoints: ≥30% reduction in MRI-assessed liver fat content (LFC) and percentage change in body weight from baseline to week 48. Both endpoints were met. The study found that 84.2% of survodutide-treated participants achieved ≥30% LFC reduction versus 24.3% on placebo. Mean body weight decreased by 12.2% with survodutide compared to 1.0% with placebo. The most common adverse events were gastrointestinal in nature, typically mild-to-moderate and concentrated during dose escalation. Key limitations include the relatively short 48-week duration, which precludes conclusions about long-term outcomes such as fibrosis regression or cardiovascular events, a modest sample size, and recruitment restricted to the United States and Spain, limiting generalizability. The study was funded by the manufacturer and used surrogate endpoints rather than hard clinical outcomes.
Nature medicine · Jun 2026DOI ↗ Moderate · human
This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy of pharmacological interventions—at specific dosages—for improving liver fibrosis in adults with metabolism-associated steatotic liver disease (MASLD) and fibrosis stages F1–F3. Researchers searched three databases through July 2025, identifying 13 randomized controlled trials encompassing 3,871 patients and 12 distinct drug regimens. Using both direct comparisons and network meta-analysis, the study found that six interventions—resmetirom (two doses), survodutide, and tirzepatide (three doses)—were significantly more effective than placebo at achieving NASH resolution without worsening fibrosis. Surface Under the Cumulative Ranking (SUCRA) analysis ranked survodutide 6 mg/week highest, followed by tirzepatide 15 mg/week; emricasan 10 mg/day ranked lowest. The authors concluded that survodutide, efruxiferimin, resmetirom, and denifanstat showed the most promise for this population, while emricasan was not supported. Limitations include the moderate number of included trials, potential heterogeneity across study populations and outcome definitions, and the indirect nature of many NMA comparisons, which may limit the precision of the relative effect estimates.
Journal of translational medicine · May 2026DOI ↗ Moderate · human
This network meta-analysis systematically evaluated the comparative efficacy and safety of four investigational glucagon receptor agonist (GRA)-based agents — retatrutide, cotadutide, mazdutide, and survodutide — in adults with type 2 diabetes, overweight, or obesity. Researchers searched PubMed, Cochrane, Embase, and Scopus, ultimately including 14 randomised controlled trials analyzed using frequentist network meta-analysis with random-effects models. Key outcomes included absolute and percent body weight change, HbA1c reduction, adverse events, and treatment discontinuation due to adverse events. The study found that retatrutide produced the greatest absolute weight reduction versus placebo (MD −13.44 kg), followed by survodutide (MD −10.74 kg) and mazdutide (MD −6.47 kg); cotadutide's effect did not reach statistical significance. Retatrutide also showed the largest HbA1c reduction, though only its effect was statistically significant among the agents. Regarding tolerability, mazdutide demonstrated the most favorable safety profile, while retatrutide and cotadutide were associated with comparatively lower tolerability. The authors acknowledge limitations inherent to network meta-analysis, including reliance on early- and mid-phase trial data and the absence of direct head-to-head comparisons between agents.
Endocrinology, diabetes & metabolism · Mar 2026DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from six randomized controlled trials (RCTs) involving 1,272 adults to evaluate the efficacy and safety of survodutide, a glucagon/GLP-1 receptor co-agonist peptide, for glycemic control and weight loss. Compared with placebo, the study found that survodutide was associated with statistically significant reductions in HbA1c, fasting glucagon levels, body weight, and waist circumference. Subgroup analyses suggested that higher total weekly doses and longer treatment durations (greater than 16 weeks) were associated with more pronounced effects on body weight and waist circumference, while greater HbA1c reductions were linked to higher doses. Secondary outcomes including BMI, total cholesterol, triglycerides, and blood pressure also showed modest reductions. On the safety side, survodutide was associated with a significantly higher risk of treatment discontinuation due to adverse events, with gastrointestinal events being the most frequently reported, though serious adverse events did not increase significantly. Limitations include the small number of included trials (six), limited participant diversity, and varying treatment durations across studies. The authors call for larger, longer, multicenter RCTs to confirm these findings across broader populations.
Diabetes, obesity & metabolism · Sep 2025DOI ↗ Moderate · human
This paper reports a prespecified subgroup analysis from a phase 2 randomized controlled trial examining how sex and baseline BMI influenced the efficacy and safety of survodutide, a dual glucagon/GLP-1 receptor agonist, in adults without diabetes who had a BMI ≥27 kg/m². A total of 387 participants were randomized to one of four once-weekly subcutaneous survodutide doses or placebo over 46 weeks, which included a 20-week dose-escalation phase followed by a 26-week maintenance phase. The study found that, across survodutide-treated groups, females experienced greater reductions in both bodyweight and waist circumference compared with males. Participants who started with a lower baseline BMI showed proportionally greater bodyweight reductions, while those with a higher baseline BMI showed greater absolute reductions in waist circumference. Adverse event rates were broadly comparable across sex and BMI subgroups, with nausea being the most common gastrointestinal side effect reported in all subgroups. Key limitations include the descriptive (non-inferential) nature of the subgroup analyses, the relatively modest sample size when subdivided by subgroup, and potential confounding from COVID-19-related treatment discontinuations. These findings suggest differential responses by sex and baseline BMI, but the subgroup design limits causal conclusions.
Diabetes, obesity & metabolism · Jan 2025DOI ↗ Moderate · human
This meta-analysis pooled data from 18 treatment arms across multiple randomized controlled trials (total n = 1,029 participants) to evaluate the effect of injectable survodutide — a dual glucagon and GLP-1 receptor agonist — on obesity-related outcomes. Searches were conducted across major databases through August 2024. Using a random-effects model, the authors found that survodutide was associated with statistically significant reductions in body weight (weighted mean difference: −8.33 kg), BMI (−4.03 kg/m²), and waist circumference (−6.33 cm) compared to control groups. Subgroup analyses suggested that longer intervention durations (more than 16 weeks) and higher doses were associated with greater reductions in weight and waist circumference, a pattern also supported by meta-regression. Key limitations include very high statistical heterogeneity for weight (I² = 99.6%) and waist circumference (I² = 99.5%), which may reflect substantial differences in study populations, doses, and durations across the included trials. The relatively small total participant count and the emerging nature of the evidence base for survodutide also limit the certainty of conclusions. The findings suggest a potential role for survodutide in weight management, but the high heterogeneity warrants cautious interpretation.
Diabetology & metabolic syndrome · Nov 2024DOI ↗ Moderate · human
This phase 2 randomised, double-blind, placebo-controlled trial investigated the safety, tolerability, and efficacy of survodutide (BI 456906), a glucagon receptor and GLP-1 receptor dual agonist, for weight management in adults with obesity but without diabetes. Across 43 centres in 12 countries, 386 participants (BMI ≥27 kg/m²) were assigned to one of four subcutaneous survodutide doses or placebo, administered once weekly for 46 weeks. The primary endpoint was percentage change in bodyweight from baseline to week 46. The study found dose-dependent reductions in bodyweight across all survodutide groups compared to placebo, ranging from approximately -6.2% to -14.9% versus -2.8% for placebo. Gastrointestinal adverse events were the most common side effects, occurring in 75% of survodutide recipients compared to 42% of placebo recipients. Notably, only about 60% of participants completed the full 46-week treatment period, and the study was not powered to establish definitive efficacy or compare doses head-to-head. As an industry-funded phase 2 dose-finding trial, these results are considered preliminary and intended to inform larger confirmatory studies.
The lancet. Diabetes & endocrinology · Feb 2024DOI ↗ Moderate · human
This Phase II randomised controlled trial evaluated survodutide (BI 456906), a dual glucagon receptor/GLP-1 receptor agonist, across six dose groups compared with placebo and open-label semaglutide (1.0 mg once weekly) in 413 adults with type 2 diabetes on metformin background therapy. Over 16 weeks, survodutide produced dose-dependent reductions in HbA1c and bodyweight. Higher dose groups achieved HbA1c reductions of approximately 17–19 mmol/mol (~1.6–1.7%), broadly comparable to semaglutide (~16 mmol/mol, ~1.5%), while lower doses showed smaller reductions. Bodyweight decreased dose-dependently, with the highest-dose groups producing greater reductions (up to ~8.7%) than semaglutide (~5.3%). Adverse events, predominantly gastrointestinal, were reported in ~78% of survodutide-treated participants versus ~52% in both the placebo and semaglutide groups. Limitations include the relatively short 16-week treatment duration, the open-label (non-blinded) design of the semaglutide comparator arm, and the Phase II exploratory nature of the trial, which was not powered for head-to-head superiority conclusions. The trial was funded by Boehringer Ingelheim.
Diabetologia · Dec 2023DOI ↗