Survodutide reduces body weight in phase 2 dose-finding trial for overweight/obesity

Treatment with the dual glucagon/GLP-1 receptor agonist survodutide for 46 weeks dose-dependently reduced body weight up to 12% compared with placebo in individuals with BMI ≥27 kg/m² but no diabetes. Gastrointestinal disorders were the most frequently reported adverse events.

This summary is based on the publication of Le Roux CW, Steen O, Lucas KJ, 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 Mar;12(3):162-173. doi: 10.1016/S2213-8587(23)00356-X

Introduction and methods

Background

Although the GLP-1RAs liraglutide and semaglutide have shown clinically relevant reductions in body weight of up to 12% compared with placebo [1,2], weight regain after treatment discontinuation remains a problem [3]. Therefore, additional targets for the treatment of obesity need to be explored. Survodutide (BI 456906) is a dual glucagon/GLP-1 receptor agonist that has demonstrated greater weight reductions than semaglutide in T2D patients with BMI 25–50 kg/m² in a head-to-head comparison, 16-week, phase 2 trial [4].

Aim of the study

The study aim was to investigate the efficacy, safety, and tolerability of survodutide in individuals with overweight or obesity.

Methods

In an international, multicenter, double-blind, placebo-controlled, parallel-group, dose-finding, phase 2 RCT, 386 participants (aged 18–74 years) with BMI ≥27 kg/m² but no diabetes were included. Using interactive response technology, they were randomized in a 1:1:1:1:1 ratio (stratified by sex) to subcutaneous survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo once weekly for 46 weeks (comprising a 20-week dose-escalation phase and 26-week dose-maintenance phase), in addition to dietary and physical activity counselling.

Outcomes

The primary efficacy endpoint was the percentage change in body weight from baseline to 46 weeks. Secondary efficacy endpoints were the achievement of body weight reductions of ≥5%, ≥10%, and ≥15% at 46 weeks and absolute changes in body weight, waist circumference, systolic blood pressure, and diastolic blood pressure from baseline to 46 weeks. Safety analysis included vital sign assessment and the frequency of adverse events.

Main results

Efficacy

• In the modified intention-to-treat population (i.e., all randomized participants who had received ≥1 trial medication dose and had analyzable data for ≥1 efficacy endpoint), mean relative changes in body weight from baseline to 46 weeks were –6.2% (95%CI: –8.3% to –4.1%) for survodutide 0.6 mg, –12.5% (95%CI: –14.5% to –10.5%) for survodutide 2.4 mg, –13.2% (95%CI: –15.3% to –11.2%) for survodutide 3.6 mg, –14.9% (95%CI: –16.9% to –13.0%) for survodutide 4.8 mg, and –2.8% (95%CI: –4.9% to –0.7%) for placebo.
• Hence, the placebo-corrected mean relative change in body weight ranged from −3.4% (95%CI: −6.3% to −0.4%; P=0.026) for survodutide 0.6 mg to −12.1% (95%CI: −15.0% to −9.2%; P<0.0001) for survodutide 4.8 mg.
• Among 64 participants receiving survodutide 4.8 mg, 53 (83%) achieved body weight loss ≥5% at 46 weeks, 44 (69%) showed body weight reduction ≥10%, and 35 (55%) achieved body weight loss ≥15%, compared with 14 (26%), 6 (11%), and 3 (6%), respectively, of the 54 placebo-treated participants.
• In the survodutide 4.8-mg dose group, significant placebo-corrected mean absolute changes from baseline to 46 weeks were also observed for body weight (−15.8 kg; 95%CI:−18.7 to −12.9; P<0.0001), waist circumference (−12.1 cm; 95%CI:−15.4 to −8.7; P<0.0001), systolic blood pressure (−6.2 mmHg; 95%CI:−10.3 to −2.1; P=0.0033), and diastolic blood pressure (95%CI:−2.9 mmHg; −5.4 to −0.5; P=0.020).

Safety and tolerability

• Treatment-emergent adverse events occurred in 281 of 309 (91%) survodutide-treated participants (all doses pooled) and 58 of 77 (75%) placebo recipients, most of which were gastrointestinal disorders (75% vs. 42%).
• The incidence of adverse events leading to treatment discontinuation was 25% in the combined survodutide group and 4% in the placebo group; they were also mostly gastrointestinal disorders. 
• In contrast, the frequency of serious treatment-emergent adverse events was lower in survodutide-treated participants (4%) than placebo-treated participants (7%).

Conclusion

This phase 2 RCT showed that 46-week treatment with survodutide dose-dependently reduced body weight up to 12% compared with placebo in individuals with BMI ≥27 kg/m² but no diabetes. A majority (55%) of the participants receiving survodutide 4.8 mg achieved ≥15% body weight loss. The tolerability profile of survodutide was similar to that of GLP-1RAs, with gastrointestinal disorders being the most frequently reported adverse events.

Find this article online at Lancet Diabetes Endocrinol.

References

1. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3·0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11–22.

2. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989–1002.

3. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022; 24: 1553–64.

4. Blüher M, Rosenstock J, Hoefler J, Manuel R, Hennige AM. Dose-response effects on HbA1c and bodyweight reductions with a dual glucagon/GLP-1 receptor agonist, survodutide, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial. Diabetologia 2023; published online Dec 14. https://doi.org/10.1007/s00125-023-06053-9.