Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial.
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.
Why this grade: This is a randomised, double-blind, placebo-controlled trial in humans, but it is a phase 2 dose-finding study with a relatively small sample size (~386 participants), a high dropout rate (~40%), and limited 46-week follow-up duration, precluding strong efficacy conclusions.
Background Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management. Methods In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI ≥27 kg/m 2 , without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37). Findings Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0·6 mg, n=77; 2·4 mg, n=78; 3·6 mg, n=77; 4·8 mg, n=77; placebo n=77) and 233 (60·4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6·2% (-8·3 to -4·1; 0·6 mg); -12·5% (-14·5 to -10·5; 2·4 mg); -13·2% (-15·3 to -11·2; 3·6 mg); -14·9% (-16·9 to -13·0; 4·8 mg); -2·8% (-4·9 to -0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients. Interpretation All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight. Funding Boehringer Ingelheim.
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