Dose-response effects on HbA<sub>1c</sub> and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial.
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.
Why this grade: This is a Phase II randomised, double-blind, placebo-controlled trial in humans (n=413), but its short duration (16 weeks), exploratory dose-ranging design, open-label active comparator arm, and Phase II scope limit the strength of evidence to moderate rather than strong.
Aims/hypothesis The aim of this study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA 1c levels and bodyweight reduction. Methods This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA 1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m 2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA 1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. Results A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA 1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA 1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. Conclusions/interpretation Survodutide reduced HbA 1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. Trial registration ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. Funding Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
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