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 ↗ Insufficient
SYNCHRONIZE-CVOT is a phase 3, randomized, double-blind, placebo-controlled, event-driven cardiovascular (CV) outcomes trial evaluating survodutide — a dual glucagon and GLP-1 receptor agonist administered subcutaneously once weekly — in adults with obesity or overweight (BMI ≥27 kg/m²) who also have established CV disease, chronic kidney disease, and/or at least two weight-related complications or CV risk factors. The primary endpoint is time to first occurrence of a 5-point major adverse cardiovascular event (MACE) composite. The trial targets enrollment of 4,935 participants globally and is currently in the recruitment phase (NCT06077864). The paper describes the scientific rationale — that dual glucagon/GLP-1 receptor agonism may produce greater weight reduction than GLP-1 agonism alone — and outlines the trial design in detail. As a design/rationale publication, no efficacy or safety outcomes are yet available. Key limitations at this stage include the absence of results and the event-driven nature meaning the timeline is uncertain. This trial will be the first to formally assess CV safety and potential efficacy of survodutide in a high-risk obesity population.
JACC. Heart failure · Oct 2024DOI ↗ Review
This review article provides a comprehensive overview of approved and emerging hormone-based anti-obesity medications (AOMs), situating them within the broader context of obesity as a complex, chronic, global disease. The authors summarize the current regulatory landscape, noting that the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide have received FDA and EMA approval for weight management. The review also covers pipeline agents, including oral GLP-1RAs (semaglutide, danuglipron, orforglipron), the amylin receptor agonist cagrilintide (alone and in combination with semaglutide), and dual agonists such as tirzepatide (GIP/GLP-1), survodutide, mazdutide, and pemvidutide (GLP-1R/GCGR). The authors highlight tirzepatide's placebo-subtracted weight reduction of 17.8% in a 72-week RCT and retatrutide's (a GLP-1R/GCGR/GIPR tri-agonist) placebo-subtracted reduction of 22.1% in a 48-week phase-II trial. The review cautions that long-term safety and cardiovascular outcome data for many of these agents remain incomplete. As a narrative review, it does not conduct original research or meta-analysis, and conclusions are limited by the quality and heterogeneity of the underlying primary studies it synthesizes.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Animal only
This paper describes the preclinical pharmacological profiling and biomarker-guided selection process used to identify survodutide (BI 456906) as a clinical development candidate from a library of 19 dual glucagon receptor (GCGR)/GLP-1R agonists. Researchers assessed receptor potency using cAMP assays in CHO-K1 cells expressing human GCGR and GLP-1R, as well as in insulinoma (MIN6) cells and rat primary hepatocytes for endogenous receptor activity. In vivo target engagement was evaluated in lean mice using oral glucose tolerance tests (GLP-1R biomarker) and plasma FGF21 and liver NNMT mRNA expression (GCGR biomarkers). Efficacy was further tested in diet-induced obese (DIO) mice for body weight reduction and in diabetic db/db mice for glucose lowering. A strong correlation was found between in vitro and in vivo GCGR and GLP-1R biomarkers, enabling candidate ranking. Survodutide demonstrated balanced dual agonism, producing greater body weight reduction than selective GLP-1R agonists while maintaining comparable antidiabetic effects. Key limitations include that all efficacy data are from rodent models, and human pharmacological profiling is not reported in this paper. Survodutide is now in Phase 3 clinical trials for obesity.
Diabetes, obesity & metabolism · Apr 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 ↗