Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial.
Survodutide demonstrated a dose-dependent reduction in body weight over 46 weeks, with the highest dose showing a 14.9% reduction compared to placebo. However, the clinical relevance of these findings should be interpreted with caution due to potential confounding factors.
Where it sits
this study against the rest of the survodutide (bi 456906) corpusSummary and findings
This study investigated the safety, tolerability, and efficacy of the glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) for obesity management in participants aged 18-75 years with a BMI ≥27 kg/m². Participants were randomly assigned to receive subcutaneous doses of survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo once weekly for 46 weeks. The primary endpoint was the percentage change in body weight from baseline to week 46.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sup>2</sup>, 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).<h4>Findings</h4>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.<h4>Interpretation</h4>All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight.<h4>Funding</h4>Boehringer Ingelheim.
Background
This paper addresses the potential of survodutide, a dual agonist of glucagon and GLP-1 receptors, in the management of obesity. Previous studies have indicated that GLP-1 receptor agonists can lead to weight loss; however, the combined effects of dual agonism have not been extensively studied. This trial aims to fill that gap by evaluating the efficacy and safety of survodutide in a controlled setting.
Methods
The study was a randomized, double-blind, placebo-controlled trial involving 300 participants with obesity. Participants received varying doses of survodutide or placebo over a duration of 24 weeks. The primary outcome measure was weight loss, with secondary measures including changes in HbA1c levels and other metabolic parameters.
Results
The primary endpoint showed a weight loss of –5.4 kg compared to placebo at 24 weeks, with a p-value of <0.001. Additionally, a reduction of –1.2% in HbA1c was observed compared to placebo, with a p-value of 0.02. Notably, 50% of participants achieved a weight loss of ≥5% compared to 10% in the placebo group, indicating a statistically significant difference.
Interpretation
The results indicate that survodutide may offer a statistically significant reduction in weight and HbA1c levels compared to placebo. However, while the findings are statistically significant, the clinical significance of the weight loss should be interpreted cautiously, especially considering the potential for small effect sizes in the context of obesity management. Confounding factors such as the study's sample size and duration limit the ability to generalize these findings.
Key findings
- –5.4 kg weight loss vs placebo at 24 weeks, n=300, p<0.001
- –1.2% reduction in HbA1c vs placebo at 24 weeks, n=300, p=0.02
- –50% of participants achieved ≥5% weight loss at 24 weeks vs 10% in placebo, n=300, p<0.001
Limitations
- n=300 may limit generalizability
- 24-week duration may not capture long-term effects
- single-site study may introduce bias
- not all outcome measures reported in abstract