Dose-response effects on HbA1c 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

Abstract

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/m² 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.

Keywords: Bodyweight loss; Dual incretin agonist; Glucagon; Glucagon-like peptide-1; Obesity; Pharmacotherapy; Semaglutide; Survodutide; Type 2 diabetes.

Fig. 1

MMRM estimates for the absolute change in HbA_1c from baseline to EoT. ^aSemaglutide arm was open label

Fig. 2

MMRM estimates for the relative change in bodyweight from baseline to EoT. ^aSemaglutide arm was open label

Fig. 3

Change from baseline in 7-point SMBG. Blood glucose measurements were collected before each meal (assuming three meals a day), approximately 2 h after each meal and at bedtime on a single day during screening (baseline) and a single day between the last dose of study drug and EoT (week 16). Mean overall time points represent the mean per participant per visit of the seven blood glucose measurements at baseline and week 16. Data are presented per DG. The centre line denotes the median value, with the symbols within the boxes denoting the mean. The box boundaries mark the upper and lower quartile of the dataset. The whiskers indicate the variability of the data; whiskers are drawn to the nearest value within 1.5× the IQR of the upper and lower quartiles. Any observations outside of these values are plotted with symbols. ^aSemaglutide arm was open label