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

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. Graphical Abstract Supplementary Information The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-023-06053-9.

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.

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.

Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as liraglutide and semaglutide, have been developed for the treatment of both type 2 diabetes and obesity. These therapies have produced placebo-corrected bodyweight decreases of up to 5.4% (liraglutide 3 mg) [ 1 ] and 12.4% (semaglutide 2.4 mg), and HbA 1c reductions of –12.0 to –17.5 mmol/mol (–1.1 to –1.6%) (liraglutide 1.8 mg and semaglutide 1 mg, respectively) in adults with type 2 diabetes [ 2 , 3 ]. Apart from the well-characterised gastrointestinal (GI) adverse events (AEs), GLP-1R agonists are generally well tolerated [ 2 – 4 ]. However, dual agonists, such as glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R and glucagon receptor (GCGR)/GLP-1R dual agonists, have the potential for enhanced therapeutic efficacy and improved tolerability compared with GLP-1R mono-agonists, owing to their multiple mechanisms of action [ 5 , 6 ]. In addition to the glucose-lowering effects associated with GLP-1R agonism, GCGR agonism, via receptors in the liver, may lead to increased energy expenditure [ 7 , 8 ]. This effect can be seen at doses that do not activate the sympathetic nervous system, thereby avoiding potentially harmful effects on the cardiovascular system [ 7 ]. GCGR signalling also leads to stimulation of hepatic glucose production (via glycogenolysis and gluconeogenesis), stimulation of lipolysis and amino acid breakdown, and suppression of hepatic fat accumulation [ 9 ]. The efficacy of GCGR/GLP-1R dual agonism has been demonstrated by oxyntomodulin, an endogenous proglucagon derivative [ 10 ]. Oxyntomodulin has been shown to reduce bodyweight and food intake in rodents and humans [ 11 , 12 ] and to increase energy expenditure in people with obesity [ 13 ], via activity at both receptors. However, oxyntomodulin requires frequent dosing owing to its very short half-life; therefore, research into longer acting GCGR/GLP-1R dual agonists is warranted. Survodutide (BI 456906) is a novel subcutaneous GCGR/GLP-1R dual agonist in development for the treatment of people with type 2 diabetes, obesity and non-alcoholic steatohepatitis (NASH). Addition of a C18 fatty acid into the acylated peptide, as a half-life-extending principle, allows for weekly administration of survodutide [ 14 ]. Preclinical studies of survodutide in murine models showed that survodutide simultaneously engages the GLP-1R and GCGR to produce reductions in bodyweight, gastric emptying and energy intake, increasing energy expenditure and improving glucose tolerance [ 14 ]. In Phase I studies (ClinicalTrials.gov NCT03175211 , NCT03591718 ), survodutide was generally well tolerated and showed no unexpected safety or tolerability concerns in healthy volunteers and people with overweight/obesity; multiple ascending doses of survodutide over 16 weeks produced mean bodyweight decreases of up to 14.1% (2.4 mg survodutide twice weekly [biw] vs −0.3% with placebo) [ 15 ]. Here we report the results of a Phase II study (ClinicalTrials.gov NCT04153929 ) assessing the effects on HbA 1c levels and bodyweight of multiple rising doses of survodutide compared with placebo and open-label weekly semaglutide in participants with type 2 diabetes. The safety and tolerability of survodutide were also assessed. As a proof-of-clinical concept study, this trial aimed to demonstrate that survodutide lowers HbA 1c levels and bodyweight and to examine the dose–response relationship in this participant population to inform the design of further studies.

Randomisation to survodutide or placebo was in a 5:1 ratio within DGs (planned randomisation: survodutide, n =50 per DG; placebo, n =60); it was planned to randomise 50 participants to the semaglutide group. The trial was double-blind within DG1–6. Further details of randomisation and blinding are provided in the ESM Methods .

After completion of the 16 week treatment period, all participants had an end-of-treatment (EoT) visit (week 17). Participants then entered a 4-week follow-up period and completed the study. Details of treatment administration are provided in the ESM Methods . HbA 1c was assessed at screening, weeks 1, 5, 8, 12 and 16, EoT and follow-up and analysed centrally. Bodyweight was measured at every visit (screening, weeks 1–8, 12 and 16, EoT and follow-up). Waist circumference was measured at screening, weeks 1 and 6 and EoT. Waist circumference was measured at the midpoint between the lowest rib and the iliac crest. Participants were provided with a glucose monitoring device for weekly use at home during the study. Participant-reported outcomes (Three-Factor Eating Questionnaire [TFEQ-R18 V2], Patient Global Impression of Severity [PGI-S] and a hunger visual analogue scale [VAS]) were assessed at weeks 1, 5 and 8 and EoT in a fasted state. Blood sampling for pharmacokinetics was carried out at every visit (weeks 1–8, 12 and 16, EoT and follow-up) and blood sampling for exploratory biomarkers was carried out at weeks 1, 5, 8 and 12, EoT and follow-up. Safety assessments are described in the ESM Methods .

This trial was approved by the relevant institutional review boards, independent ethics committees and competent authorities, according to national and international regulations. The study was conducted in compliance with ethical principles laid down in the Declaration of Helsinki, in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice (ICH GCP). All participants provided written informed consent, according to the ICH GCP and regulatory and legal requirements of the participating countries.

Study participants and compliance Participants were recruited between 9 June 2020 and 7 June 2021; the last participant completed the trial on 5 November 2021. In total, 669 people were screened, 413 were randomised and 411 were treated (DGs 1, 2 and 4, n =50 each; DG3, n =52; DG5, n =51; DG6, n =49; semaglutide up to 1.0 mg qw, n =50; placebo, n =59; ESM Fig. 2 ). Of the 411 participants treated, 80 (19.5%) prematurely discontinued treatment, 53 (12.9%) owing to an AE. Important protocol deviations were reported for 62 of all randomised participants (15.0%), with two-thirds ( n =41) due to restricted medication use. All 411 participants treated were analysed for efficacy (full analysis set: all randomised participants who received one or more dose of the study drug and had analysable data for one or more efficacy endpoint) and safety (treated set: all randomised participants who received one or more dose of the study drug). Baseline characteristics and demographics were similar between DGs ( N =411); 83.7% of participants were White and mean ± SD age was 57.3±9.8 years, BMI 33.9±6.0 kg/m 2 and HbA 1c 64.7±9.2 mmol/mol (8.1±0.8%) (Table 1 ). The population included in this study was representative of a large study population of people with type 2 diabetes with respect to age and HbA 1c levels [ 17 ]; however, most participants were White and had a higher bodyweight, due to the inclusion criteria of this trial. Table 1 Participant baseline characteristics and demographics Characteristic DG1: Survodutide 0.3 mg qw ( n =50) DG2: Survodutide 0.9 mg qw ( n =50) DG3: Survodutide 1.8 mg qw ( n =52) DG4: Survodutide 2.7 mg qw ( n =50) DG5: Survodutide 1.2 mg biw ( n =51) DG6: Survodutide 1.8 mg biw ( n =49) Semaglutide 1.0 mg qw ( n =50) Placebo ( n =59) Total ( N =411) Sex Male 26 (52.0) 28 (56.0) 27 (51.9) 33 (66.0) 27 (52.9) 27 (55.1) 34 (68.0) 31 (52.5) 233 (56.7) Race and ethnicity White 42 (84.0) 44 (88.0) 42 (80.8) 43 (86.0) 41 (80.4) 42 (85.7) 43 (86.0) 47 (79.7) 344 (83.7) Asian 4 (8.0) 5 (10.0) 8 (15.4) 4 (8.0) 5 (9.8) 3 (6.1) 5 (10.0) 8 (13.6) 42 (10.2) Black or African American 3 (6.0) 1 (2.0) 2 (3.8) 2 (4.0) 4 (7.8) 3 (6.1) 2 (4.0) 3 (5.1) 20 (4.9) American Indian or Alaska Native 1 (2.0) 0 0 0 0 1 (2.0) 0 0 2 (0.5) Native Hawaiian or Other Pacific Islander 0 0 0 0 0 0 0 1 (1.7) 1 (0.2) Missing 0 0 0 1 (2.0) 1 (2.0) 0 0 0 2 (0.5) Age, years 56.1±10.2 58.2±9.6 55.3±10.3 59.6±8.5 58.3±8.8 57.7±9.4 55.8±10.5 57.5±10.5 57.3±9.8 HbA 1c , mmol/mol 64.9±8.3 62.8±8.8 65.5±9.4 65.9±10.6 65.1±10.3 63.6±7.8 64.3±9.2 65.6±9.2 64.7±9.2 HbA 1c , % 8.09±0.76 7.89±0.80 8.14±0.86 8.18±0.97 8.11±0.94 7.97±0.71 8.03±0.82 8.15±0.85 8.07±0.84 Time from type 2 diabetes diagnosis, years 6.1±4.7 7.7±7.3 7.0±5.6 7.9±5.7 8.8±7.1 7.4±5.3 7.9±4.7 7.9±5.6 7.6±5.8 Weight, kg 97.6±19.7 100.1±19.8 95.9±22.8 96.6±22.8 95.0±22.1 98.3±24.4 96.7±20.0 93.0±21.0 96.6±21.6 BMI, kg/m 2 33.8±6.1 34.9±5.2 33.6±5.8 34.0±6.8 33.0±5.0 34.9±7.0 33.4±6.1 33.4±5.9 33.9±6.0 Waist circumference, cm 110.6±12.8 111.5±15.6 107.2±20.0 110.7±16.4 109.0±18.2 115.1±28.7 108.1±13.5 110.4±16.5 110.3±18.2 Data are presented as n / N (%) or mean ± SD. Sex and race were self-reported

The relative and absolute reduction from baseline in bodyweight was greater with increasing survodutide dose, with bodyweight loss seen in all survodutide DGs in a dose-dependent manner (Fig. 2 , ESM Fig. 4 ). After 16 weeks of treatment, the relative decrease in bodyweight from baseline (key secondary endpoint) for DG2–6 was significantly greater than for placebo ( p <0.001), with a maximum adjusted mean (95% CI) MMRM estimate for relative bodyweight reduction of −8.7% (−10.1, −7.3; DG6, n =37; Fig. 2 ). Survodutide doses of ≥1.8 mg qw produced greater adjusted mean (95% CI) bodyweight reductions than semaglutide up to 1.0 mg qw (DG3 [ n =36] vs semaglutide [ n =45]: −6.6% [−7.9, −5.3] vs –5.3% [−6.6, −4.1]). Results of the multiple contrast test showed that all predefined dose–response models were significant in terms of non-flat dose–response for the relative change from baseline in bodyweight at a one-sided α=0.025. A significant dose–response was seen in the final MCPMod averaging model and did not reach a plateau (ESM Fig. 4 a). Descriptive statistics of the relative change from baseline in bodyweight were similar to the MMRM analysis (ESM Fig. 4 b). The adjusted mean (95% CI) MMRM estimates for absolute changes from baseline in bodyweight after 16 weeks’ treatment were consistent with the relative changes, with favourable results seen for DG3–6 (up to −8.4 kg [−9.7, −7.1]; DG6, n =37) compared with semaglutide ( n =45) up to 1.0 mg qw (−5.2 kg [−6.4, −4.0]) (ESM Fig. 4 c). Fig. 2 MMRM estimates for the relative change in bodyweight from baseline to EoT. a Semaglutide arm was open label Analysis of additional secondary endpoints showed that the proportion of participants with ≥5% and ≥10% reductions in bodyweight after 16 weeks’ treatment increased dose-dependently with survodutide (Table 2 ). In DG6, 57.1% of participants ( n =28) had ≥5% and 34.7% ( n =17) had ≥10% bodyweight reductions; this compares with 6.8% ( n =4) and 0%, respectively, for placebo and 38.0% ( n =19) and 16.0% ( n =8), respectively, for semaglutide up to 1.0 mg qw. The probability of achieving ≥5% or ≥10% bodyweight loss was significantly greater in DG2–6 for ≥5% loss (OR [95% CI] DG2, 7.92 [2.43, 25.74]; DG3, 17.68 [5.21, 60.03]; DG4, 25.87 [7.31, 91.55]; DG5, 21.75 [6.57, 72.04]; DG6, 35.00 [9.84, 124.47]) and DG3–6 for ≥10% loss (DG3, 25.17 [1.35, 470.86]; DG4, 33.00 [1.78, 613.20]; DG5, 42.43 [2.37, 761.05]; DG6, 84.51 [4.71, >999]) compared with placebo (Table 2 ). Table 2 Proportion of participants achieving ≥5% and ≥10% bodyweight reductions Bodyweight reduction DG1: Survodutide 0.3 mg qw ( n =50) DG2: Survodutide 0.9 mg qw ( n =50) DG3: Survodutide 1.8 mg qw ( n =52) DG4: Survodutide 2.7 mg qw ( n =50) DG5: Survodutide 1.2 mg biw ( n =51) DG6: Survodutide 1.8 mg biw ( n =49) Semaglutide 1.0 mg qw ( n =50) Placebo ( n =59) ≥5%, n (%) 4 (8.0) 19 (38.0) 22 (42.3) 23 (46.0) 29 (56.9) 28 (57.1) 19 (38.0) 4 (6.8) Vs placebo – OR 1.22 7.92 17.68 25.87 21.75 35.00 8.22 – (95% CI) (0.28, 5.20) (2.43, 25.74) (5.21, 60.03) (7.31, 91.55) (6.57, 72.04) (9.84, 124.47) (2.52, 26.79) – ≥10%, n (%) 1 (2.0) 3 (6.0) 7 (13.5) 8 (16.0) 13 (25.5) 17 (34.7) 8 (16.0) 0 Vs placebo – OR 3.67 7.97 25.17 33.00 42.43 84.51 22.44 – (95% CI) (0.14, 95.68) (0.39, 163.48) (1.35, 470.86) (1.78, 613.20) (2.37, 761.05) (4.71, >999) (1.22, 413.13) – Waist circumference decreased from baseline with both survodutide and semaglutide treatment, but data were highly variable and associated with wide 95% CIs (ESM Fig. 5 ). The maximum adjusted mean ± SEM MMRM estimate for decrease in waist circumference from baseline was observed after 16 weeks’ treatment in DG6 (−10.5±1.7 cm; n =36). Adjusted mean ± SEM MMRM estimates for the placebo-corrected absolute change from baseline after 16 weeks’ treatment were significant for DG4 (−4.6±2.25 cm; n =35; p =0.041) and DG6 (−8.4±2.24 cm; n =36; p =0.0002).

A total of 77.8% of participants ( n =235) treated with survodutide reported at least one treatment-emergent adverse event (TEAE); 52.5% of those receiving placebo ( n =31) and 52.0% receiving semaglutide ( n =26) also reported TEAEs (Table 3 ). Of these, severe AEs were reported by 16 participants treated with survodutide (5.3%), four receiving placebo (6.8%) and none receiving semaglutide; these were mostly GI disorders ( n =8/16 [50%] for survodutide; n =1/4 [25%] for placebo). Serious AEs were reported by 3.6% of participants receiving survodutide ( n =11: DG1, n =1; DG2, n =4; DG3, n =3; DG4, n =2; DG5, n =1) and 5.1% receiving placebo ( n =3) (Table 3 , ESM Table 3 ). AEs led to treatment discontinuation in 15.9% of participants receiving survodutide ( n =48), 5.1% receiving placebo ( n =3) and 4.0% receiving semaglutide ( n =2). Most of these discontinuations occurred within the first 6 weeks of the study ( n =38/53, 71.7%), coinciding with the dose-escalation period, and were mainly due to GI disorders (survodutide: n =36/48, 75.0%; placebo n =1/3, 33.3%; semaglutide: 0) such as nausea and vomiting. More discontinuations due to AEs were observed in those with baseline bodyweight <100 kg than those with bodyweight ≥100 kg. GI disorders were the most frequently reported AEs across all DGs, occurring in 55.3% of participants receiving survodutide, 22.0% receiving placebo and 28.0% receiving semaglutide. Table 3 Summary of AEs AE DG1: Survodutide 0.3 mg qw ( n =50) DG2: Survodutide 0.9 mg qw ( n =50) DG3: Survodutide 1.8 mg qw ( n =52) DG4: Survodutide 2.7 mg qw ( n =50) DG5: Survodutide 1.2 mg biw ( n =51) DG6: Survodutide 1.8 mg biw ( n =49) Semaglutide 1.0 mg qw ( n =50) Placebo ( n =59) Total survodutide ( n =302) Any TEAE 33 (66.0) 38 (76.0) 42 (80.8) 41 (82.0) 39 (76.5) 42 (85.7) 26 (52.0) 31 (52.5) 235 (77.8) Investigator-defined, drug-related AEs a 25 (50.0) 26 (52.0) 33 (63.5) 29 (58.0) 28 (54.9) 36 (73.5) 19 (38.0) 13 (22.0) 177 (58.6) Nausea 10 (20.0) 13 (26.0) 24 (46.2) 20 (40.0) 14 (27.5) 22 (44.9) 6 (12.0) 5 (8.5) 103 (34.1) Vomiting 6 (12.0) 7 (14.0) 12 (23.1) 13 (26.0) 6 (11.8) 10 (20.4) 2 (4.0) 1 (1.7) 54 (17.9) Diarrhoea 11 (22.0) 5 (10.0) 8 (15.4) 7 (14.0) 8 (15.7) 9 (18.4) 4 (8.0) 5 (8.5) 48 (15.9) Dyspepsia 4 (8.0) 3 (6.0) 3 (5.8) 4 (8.0) 3 (5.9) 6 (12.2) 1 (2.0) 0 23 (7.6) Decreased appetite 6 (12.0) 7 (14.0) 5 (9.6) 9 (18.0) 8 (15.7) 15 (30.6) 3 (6.0) 2 (3.4) 50 (16.6) Headache 2 (4.0) 5 (10.0) 3 (5.8) 0 3 (5.9) 2 (4.1) 0 1 (1.7) 15 (5.0) Severe AEs b 3 (6.0) 1 (2.0) 4 (7.7) 3 (6.0) 2 (3.9) 3 (6.1) 0 4 (6.8) 16 (5.3) Nausea 1 (2.0) 0 1 (1.9) 0 0 1 (2.0) 0 0 3 (1.0) Vomiting 2 (4.0) 0 0 0 2 (3.9) 0 0 0 4 (1.3) Dizziness 0 0 0 0 0 2 (4.1) 0 0 2 (0.7) Serious AEs 1 (2.0) 4 (8.0) 3 (5.8) 2 (4.0) 1 (2.0) 0 0 3 (5.1) 11 (3.6) Drug-related serious AEs 1 (2.0) 1 (2.0) 1 (1.9) 1 (2.0) 0 0 0 0 4 (1.3) AEs leading to treatment discontinuation 5 (10.0) 5 (10.0) 11 (21.2) 15 (30.0) 4 (7.8) 8 (16.3) 2 (4.0) 3 (5.1) 48 (15.9) Data are presented as n (%) a Drug-related AEs reported by preferred term in ≥10% of participants b Severe AEs reported by preferred term in two or more participants in all survodutide DGs Of participants treated with survodutide, 58.6% ( n =177) reported drug-related AEs, compared with 22.0% receiving placebo ( n =13) and 38.0% of those receiving semaglutide ( n =19) (Table 3 ). The majority of AEs were GI disorders (nausea, vomiting, diarrhoea and dyspepsia), which were reported for 50.0% ( n =151) receiving survodutide. Drug-related AEs were classed as serious for 1.3% of participants receiving survodutide ( n =4); DG1 (abdominal pain and vomiting), DG2 (mouth ulceration, autoimmune disorder and pharyngeal ulceration), DG3 (dehydration) and DG4 (diarrhoea) ( n =1 each; Table 3 , ESM Table 3 ). Mean heart rate was slightly increased from baseline in all treatment groups; the mean increase after 16 weeks was 2.3–7.3 beats per min (bpm) across the survodutide DGs, 5.9 bpm for semaglutide and 1.67 bpm for placebo. The mean increases in heart rate from baseline were below 10 bpm at all time points except for two in DG4 (10.3 bpm at week 7; 10.1 bpm at week 16). There were no new onsets reported in the QTcF (QT interval corrected for heart rate using the method of Fridericia) interval categories >480–500 msec or >500 msec; one participant each from DG3 (2.0%) and the placebo group (1.7%) reported an increase in QTcF interval of >60 msec. The changes from baseline in QTcF interval were considered minor and no increased risk of cardiovascular events was identified.

GLP-1R agonists such as semaglutide have been approved for the treatment of type 2 diabetes and obesity [ 18 ]. Recent data on the efficacy of tirzepatide demonstrate that incretin dual agonists have the potential to more effectively reduce HbA 1c and bodyweight than GLP-1R agonists alone [ 5 ]. Therefore, development of incretin dual agonists such as the novel GCGR/GLP-1R dual agonist survodutide is an important step towards the more effective treatment of people with type 2 diabetes and obesity. In this study, survodutide dose-dependently reduced HbA 1c after 16 weeks’ treatment (by up to −18.72 mmol/mol [−1.71%]). The efficacy of survodutide was compared with open-label semaglutide (up to 1.0 mg qw); survodutide was shown to be equally efficacious at lowering HbA 1c at low doses (−1.46% for DG2 vs −1.47% for semaglutide). Furthermore, survodutide at doses ≥1.8 mg qw induced greater bodyweight reductions than semaglutide after 16 weeks’ treatment (up to −8.7% [8.4 kg] DG6 vs −5.3% [5.2 kg] semaglutide). In addition to semaglutide, other GLP-1R agonists now approved for the treatment of type 2 diabetes have been investigated in combination with background metformin therapy. In the LEAD-2 study, liraglutide treatment for 26 weeks produced HbA 1c reductions of up to –10.9 mmol/mol (–1.0%) and bodyweight reductions of up to –2.8 kg from baseline [ 19 ]. These results are relatively similar to those seen with dulaglutide in the AWARD-5 study, which produced reductions of –12.0 mmol/mol (−1.1%) and –3.1 kg for HbA 1c and bodyweight, respectively, after 52 weeks of treatment [ 20 ]. The maximum reductions in HbA 1c and bodyweight observed in the current study (−18.72 mmol/mol [−1.71%] and −8.4 kg, respectively) exceeded those of the above studies, after a shorter treatment duration of only 16 weeks. Furthermore, a Phase II dose-finding study of the weekly GIPR/GLP-1R dual agonist tirzepatide found reductions in HbA 1c and bodyweight that were in line with the results of the present study; tirzepatide treatment up to 15 mg qw reduced HbA 1c by up to −21.9 mmol/mol (−2.0%) and bodyweight by up to −5.7 kg after 12 weeks [ 21 ]. This highlights the suggested additional efficacy of incretin dual agonists over GLP-1R mono-agonists. Another GCGR/GLP-1R dual agonist, cotadutide, has been developed for the treatment of type 2 diabetes and obesity. In a Phase IIa trial in participants receiving metformin background therapy, cotadutide treatment for 49 days led to a significant reduction in blood glucose ( p <0.001) and bodyweight reductions of –3.41% from baseline vs placebo [ 22 ]. A Phase IIb study comparing cotadutide with the GLP-1R mono-agonist liraglutide showed that, after 54 weeks, cotadutide produced similar HbA 1c reductions (cotadutide vs liraglutide: −13.0 mmol/mol vs −12.8 mmol/mol [−1.19% vs −1.17%]) but greater bodyweight reductions than liraglutide (−5.02% vs −3.33%) [ 6 ]. Although these studies also showed the potential of dual GCGR/GLP-1R agonism, the current study of survodutide produced greater HbA 1c and bodyweight reductions after a shorter treatment duration than the Phase II studies of cotadutide, again highlighting the potential greater therapeutic efficacy of survodutide. The overall tolerability profile of survodutide was as expected for an incretin dual agonist. Most of the reported TEAEs with survodutide treatment were GI disorders such as nausea; drug-related AEs were reported by 58.6% of those receiving survodutide, with half of these participants reporting drug-related GI disorders. The occurrence of GI disorders is common in people treated with GLP-1R agonists [ 23 , 24 ] and can be linked to the central effects of GLP-1R agonism and delayed gastric emptying [ 25 , 26 ]. Although participants receiving semaglutide up to 1.0 mg qw reported fewer AEs than those receiving survodutide, these were also primarily GI-related AEs ( n =14/26, 53.8%). The lower overall occurrence may be linked to the slower dose-escalation scheme for those in the semaglutide group, per approved prescribing information. Most of the AEs observed in participants receiving survodutide occurred during the rapid dose-escalation period of the study, and therefore the frequency of AEs (particularly GI AEs) may be mitigated by the implementation of a slower escalation scheme in future studies. In addition, the proportion of participants discontinuing treatment due to AEs was higher in those receiving survodutide than in those receiving placebo or semaglutide (15.9% vs 5.1% vs 4.0%, respectively). The discontinuations in the survodutide groups were again mostly due to GI AEs (nausea and vomiting) that occurred during the rapid dose-escalation phase. This is in line with Phase II study results for semaglutide treatment in participants with type 2 diabetes, with 11% of total participants withdrawing from the trial due to AEs (vs 12.9% in the present study), primarily due to GI AEs in the first month of treatment [ 16 ]. The