Articles

Glucagon and GLP-1 receptor dual agonist survodutide for

obesity: a randomised, double-blind, placebo-controlled,
dose-finding phase 2 trial
Carel W le Roux, Oren Steen, Kathryn J Lucas, Elena Startseva, Anna Unseld, Anita M Hennige

Summary
Lancet Diabetes Endocrinol Background Obesity is a widespread and chronic condition that requires long-term management; research into
2024; 12: 162–73 additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety,
Published Online tolerability, and efficacy of glucagon receptor–GLP-1 receptor dual agonist survodutide (BI 456906) in obesity
February 5, 2024
management.
https://doi.org/10.1016/
S2213-8587(23)00356-X
See Comment page 150
Methods In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in
Diabetes Complications
12 countries, we enrolled participants (aged 18–75 years, BMI ≥27 kg/m², without diabetes) and randomly assigned
Research Centre, University them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or
College Dublin, Dublin, Ireland 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary
(Prof C W Le Roux MD); LMC endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified
Diabetes and Endocrinology,
Toronto, ON, Canada
intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial
(O Steen MD); Diabetes and medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at
Endocrinology Consultants, randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity
Morehead City, NC, USA analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment
(K J Lucas MD); Boehringer
Ingelheim International GmbH,
data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with
Ingelheim, Germany ClinicalTrials.gov (NCT04667377) and EudraCT (2020–002479–37).
(E Startseva MD); Boehringer
Ingelheim Pharma GmbH,
Findings Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated
Biberach an der Riß, Germany
(A Unseld MSc); Boehringer (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
Ingelheim International GmbH, 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed
Biberach an der Riß, Germany according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were −6·2%
(A M Hennige MD)
(−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;
Correspondence to: 4·8 mg); −2·8% (−4·9 to −0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%)
Anita M Hennige, Boehringer
Ingelheim International GmbH,
of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of
Biberach (Riß) 88400, Germany 77 placebo recipients.
anita.hennige@boehringer-
ingelheim.com Interpretation All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight.

Funding Boehringer Ingelheim.

Copyright © 2024 Elsevier Ltd. All rights reserved.

Introduction the efferent and satiety pathways in the brain alters energy
Obesity is a chronic, relapsing, and progressive disease homoeostasis in favour of bodyweight loss, by reducing
that requires long-term management.1,2 Currently, life­ food intake and delaying gastric emptying, and improves
style modifications remain the most common treat­ glucose tolerance by stimulating insulin secretion.4,5
ment modality.2 However, if obesity is not managed In phase 3 randomised controlled trials examin­ ing
effectively by lifestyle modifications alone then treat­ obesity, liraglutide 3·0 mg and semaglutide 2·4 mg
ment with pharmacotherapy is recommended in showed sustained, clinically relevant reductions in body­
individuals with a BMI of 27 kg/m² or greater in the weight of up to 8·0% (vs 2·6% with placebo) following
presence of one or more concurrent conditions.2 56 weeks of treatment with liraglutide 3·0 mg and 14·9%
Bariatric surgery is an option for individuals with a BMI (vs 2·4% with placebo) following 68 weeks of treat­
of 35 kg/m² or greater, or a BMI of 30 kg/m² or greater ment with semaglutide 2·4 mg.6,7 However, long-term
and type 2 diabetes.2,3 treat­ment options are still required, with weight regain
Currently, there are five pharmacological agents approved follow­ing treatment discontinuation remaining a key
by the US Food and Drug Administration for the treatment chal­lenge with current therapies.8 Therefore, research
of obesity, two of which are GLP-1 receptor agonists into additional targets for the treatment of obesity
(semaglutide and liraglutide).2 GLP-1 receptor agonists in remains a priority.9

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Research in context
Evidence before this study for participants receiving survodutide 4.8 mg versus placebo
GLP-1 receptor agonists, such as liraglutide and semaglutide, when analysed by planned treatment, and almost 7 times
have been approved for the treatment of obesity, promoting greater when analysed according to actual treatment.
weight loss by altering energy homoeostasis. Survodutide Furthermore, over half of the participants receiving
(BI 456906) is a glucagon receptor–GLP-1 receptor dual agonist survodutide 4·8 mg reached bodyweight reductions of 15%
currently being investigated as a treatment for obesity and or more. The tolerability profile of survodutide was in line
non-alcoholic steatohepatitis. with what would be expected based on its mechanism of
We searched PubMed on July 4, 2023, for publications from the action, with participants most frequently reporting
past 5 years, using the terms “obesity”, “glucagon-like peptide-1 gastrointestinal adverse events.
receptor agonist”, “GLP-1 receptor agonist”, “glucagon receptor”, Implications of all the available evidence
“bodyweight”, “body weight”, and “randomised clinical trial”. Preclinical data and data from earlier phase trials have
Phase 3 trials of semaglutide 2·4 mg in participants with obesity demonstrated clinically meaningful reductions in bodyweight.
without diabetes have reported bodyweight reductions from In this phase 2 clinical study, survodutide significantly reduced
baseline of up to 14·9% (vs 2·4% with placebo) after 68 weeks. bodyweight relative to placebo. These results show the
A number of agents with dual and triple mechanisms of action potential of survodutide to induce greater bodyweight loss
are now under investigation, as these have potential for than the approved GLP-1 receptor mono-agonist semaglutide.
enhanced therapeutic efficacy in the treatment of obesity. Survodutide appears to be a promising new anti-obesity
Added value of this study treatment, and warrants further investigation in phase 3 trials.
In adults with BMI of 27 kg/m² or greater without diabetes, Survodutide could offer the potential for greater therapeutic
survodutide once weekly produced significant decreases in efficacy compared with GLP-1 receptor agonism alone, and
bodyweight versus placebo from baseline to week 46. Mean warrants further investigation in phase 3 trials.
reductions in bodyweight were approximately 5 times greater

Pharmacological agents targeting multiple pathological −5·3% [−6·6 to −4·1]).15 In a phase 1b study in adults
pathways that alter energy homoeostasis might improve with a BMI of 27–40 kg/m² (n=125), survodutide
bodyweight loss efficacy versus currently approved GLP-1 treatment escalated over 6 (Part A; n=80) or 16 (Part B;
receptor mono-agonists.9 In a phase 3 trial in adults with n=45) weeks resulted in mean bodyweight reductions
obesity (n=2539), the glucose-dependent insulinotropic of up to −6·7% at week 6 (survodutide 0·45 mg
polypeptide–GLP-1 receptor dual agonist tirzepatide once daily; vs −0·9% with placebo) and −14·1% at week
significantly reduced bodyweight relative to placebo 16 (survodutide 2·4 mg once per week; vs −0·3% with
(p<0·001). Following 72 weeks of once-weekly treatment, placebo). These results highlight the potential of
the mean percentage change from baseline in bodyweight survodutide to induce greater bodyweight loss than
ranged from −15·0% to −20·9% with tirzepatide approved GLP-1 receptor mono-agonists.16
(5–15 mg) versus −3·1% with placebo.10 Here, we report the results of a phase 2, randomised,
Survodutide (BI 456906) is a glucagon receptor–GLP-1 dose-finding, double-blind, placebo-controlled, parallel-
receptor dual agonist derived from glucagon, with group trial of survodutide in adults with a BMI of
a C18 fatty diacid incorporated to enable once-weekly 27 kg/m² or greater, which aimed to characterise the
dosing.11 Preclinical studies of survodutide showed that dose–response relationship of survodutide in obesity
treatment reduced bodyweight in murine models to management to facilitate selection of the optimal dose
a greater extent than maximally effective semaglutide for future phase 3 trials.
via simultaneous engagement of the glucagon receptor
and GLP-1 receptor.11 The improved efficacy of survo­ Methods
dutide compared with semaglutide was partly attributed Study design and participants
to increased energy expenditure, resulting from We performed a multicentre, randomised, double-blind,
glucagon receptor agonism in the liver and adipose parallel-group, and placebo-controlled phase 2 trials
tissue to stimulate gluconeogenesis, glycogenolysis, and involv­ing 43 sites in 12 countries (USA, Australia,
lipolysis,11–14 in addition to reductions in gastric emptying Belgium, Canada, China, Germany, South Korea,
and energy intake.11 In a 16 week phase 2 study in adults Netherlands, New Zealand, Poland, Sweden, and UK).
with type 2 diabetes (n=413), treatment with survodutide Clinical sites where the study was conducted comprised
at doses of up to 1·8 mg twice per week escalated over research units, dedicated weight management clinics,
5−9 weeks, produced greater mean (95% CI) bodyweight independent research units and university hospitals. The
reductions than semaglutide 1·0 mg once weekly trial protocol was approved by the relevant Independent
(survodutide, −8·7% [−10·1 to −7·3]; semaglutide, Ethics Committees or Institutional Review Boards for the

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See Online for appendix participating centres (appendix p 6). The trial was the dose-escalation phase did not continue titration to the
conducted in accordance with the principles of the next step, but had the option to receive a lower available
Declaration of Helsinki, the International Conference on survodutide dose and continue with the new scheme for
Harmonization Good Clinical Practice, applicable the dose-maintenance phase. Participants who still did not
regulatory requirements, and standard operating tolerate treatment due to gastrointestinal adverse events,
procedures of the trial sponsor. including at the lowest tested dose (0·6 mg), were
Participants were adults (aged ≥18 to <75 years) with discontinued from treatment.
a BMI of 27 kg/m² or greater, a stable bodyweight of 70 kg In addition to their assigned treatment or placebo, all
or greater (females) or 80 kg or greater (males), and with participants received dietary and physical activity
HbA1c less than 6·5% (without diabetes) at screening. counselling (approximately 500 kcal/day energy deficit
Patients must have undergone at least one previous and 150–300 min per week of moderate-intensity aerobic
unsuccessful nonsurgical weight-loss attempt. A complete and strength exercises) every 4 weeks between weeks 1
list of the inclusion and exclusion criteria is provided in and 40, at week 46, and at the end-of-treatment visit, by
the appendix (p 3). All participants provided written a dietician and site staff member, respectively. All
informed consent prior to participation in the trial. participants who completed the treatment period had an
end-of-treatment visit at week 46, followed by a 3-week
Randomisation and masking follow-up period that ended in an end-of-study visit.
After the assessment of all inclusion and exclusion If treatment was discontinued early, the end-of-treatment
criteria, eligible participants were randomly assigned by visit was conducted 7 days after administration of the last
interactive response technology 1:1:1:1:1 (using a block dose of survodutide or placebo. All efforts were made to
size of 10) to receive survodutide (0·6, 2·4, 3·6, or conduct the week 46 visit for all participants, including
4·8 mg) or placebo; randomisation was stratified by sex. those who discontinued treatment prematurely.
Randomisation lists were generated using a validated
system involving a pseudorandom number generator. Outcomes
Access to the randomisation codes were kept restricted The primary endpoint was the percentage change in
until final analysis. The trial was double blind; partic­ bodyweight from baseline to week 46, assessed to
ipants, investigators, central reviewers, and everyone characterise the dose–response relationship for
involved in the trial conduct or analysis were blinded to survodutide. Secondary endpoints were the achievement
the randomised treatment assignments until after of bodyweight reductions of 5% or greater, 10% or
database lock. Primary outcome assessors were blinded greater, and 15% or greater at week 46, and absolute
with respect to the study treatment. Participants in all changes in bodyweight, waist circumference, systolic
dose groups received treatment (survodutide or placebo) blood pressure, and diastolic blood pressure from
in pre-filled syringes in a blinded manner with baseline to week 46. Bodyweight, waist circumference,
the solution looking similar for the active drug and the and blood pressure were assessed at screening, baseline,
placebo. and every visit (once every 2 weeks) to week 18;
bodyweight and blood pressure were then assessed
Procedures at weeks 20, 24, 28, 32, 36, 40, 46, and end-of-treatment,
Eligible participants were randomly assigned to receive and waist circum­ference at weeks 24, 32, 40, 46, and end-
subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or of-treatment. Safety was assessed by the occurrence of
placebo once weekly for 46 weeks. Participants assigned to adverse events and vital signs; adverse events were
receive survodutide followed one of four dose-escalation assessed from the signing of informed consent until the
schemes (appendix p 4). The treatment period comprised end of the study. Safety parameters were assessed at
a 20-week rapid dose-escalation phase, with doses every visit (once every 2 weeks to week 20 then every
escalated every 2–4 weeks (fixed dosing, weeks 1 to 10; 4 weeks to end-of-treatment), with a physical examination
flexible dosing, weeks 11 to 20) followed by a 26-week every other visit (every 4 weeks). Assessments of further
dose-maintenance phase. For the first 10 weeks of dose exploratory endpoints are detailed in the appendix (p 2;
escalation, all participants received treatment according to effect on survodutide on levels of plasma triglyceride,
the dosing scheme assigned to them at randomisation, cholesterol levels, HbA1c, glucagon, alanine amino­
with no dose adjustments permitted (appendix p 4); transferase concentrations, and change from baseline
between weeks 11 and 20, adjustments to the dosing in BMI).
scheme were allowed, in a blinded manner, based on the
tolerance of gastrointestinal adverse events. Dosing was Statistical analyses
not flexible during the dose-maintenance phase (from Sample size calculation was performed using simulations
week 21 until end of study), with all participants receiving in R software.17 Based on an assumed placebo effect size of
one of the four planned survodutide doses (0·6, 2·4, 3·6, zero and a maximum effect size in the highest dose group
or 4·8 mg) or placebo. Participants who did not tolerate of –10·0% (SD 7·0%18), a sample size of 70 participants
treatment due to gastrointestinal adverse events during per trial group gave 80% or greater probability of success

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520 patients screened

133 not randomised

120 inclusion or exclusion
criteria not met
2 lost to follow-up
11 withdrawal by participant

387 participants randomised

1 not treated
1 withdrawal by participant

77 assigned to placebo 78 assigned to survodutide 78 assigned to survodutide 77 assigned to survodutide 77 assigned to survodutide
0·6 mg 2·4 mg 3·6 mg 4·8 mg

77 participants treated 77 participants treated 78 participants treated 77 participants treated 77 participants treated

20 prematurely stopped 22 prematurely stopped 18 prematurely stopped 18 prematurely stopped 22 prematurely stopped
medication medication medication medication medication
6 lack of perceived 13 adverse events 11 adverse events 14 adverse events 18 adverse events
efficacy 3 other 3 other 2 other 2 protocol deviation
5 burden of study 2 protocol deviation 2 protocol deviation 1 burden of study 1 burden of study
procedures 2 burden of study 1 burden of study procedures procedures
3 adverse events procedures procedures 1 change of residence 1 other
3 other 2 no reason available 1 no reason available
2 no reason available
1 protocol deviation

57 completed dose 55 completed dose 60 completed dose 59 completed dose 55 completed dose
escalation escalation escalation escalation escalation

11 prematurely stopped 8 prematurely stopped 15 prematurely stopped 11 prematurely stopped 8 prematurely stopped
medication medication medication medication medication
6 other 2 adverse events 9 adverse events 5 adverse events 4 adverse events
1 adverse events 2 other 2 lack of perceived 4 other 3 other
1 lack of perceived 1 protocol deviation efficacy 1 lack of perceived 1 burden of study
efficacy 1 burden of study 2 burden of study efficacy procedures
1 change of residence procedures procedures 1 no reason available
1 no reason available 1 no reason available 1 change of residence
1 protocol deviation 1 missing 1 no reason available
1 missing

46 completed dose 47 completed dose 45 completed dose 48 completed dose 47 completed dose
maintenance maintenance maintenance maintenance maintenance

59 completed study 60 completed study 60 completed study 62 completed study 67 completed study

Figure 1: Trial profile

Completed study refers to patients who prematurely discontinued treatment but completed the week 46 visit.

for all assumed dose−response models. The maximum participants at ran­domisation (planned treatment). The
effect size of −10·0% was not based on previous data but modified intention-to-treat population was defined as all
was considered a reasonable assumption at the time of randomly assigned participants who received at least one
trial design. An overall significance level of 2·5% (one- dose of trial treatment and who had analysable data
sided) for the contrast test of the null hypothesis of a flat (observed baseline and post-baseline value) for at least
dose–response was assumed. one efficacy endpoint. The primary analysis included all
The primary analysis of the primary endpoint was data (on-treatment and off-treatment) censored for
performed using the modified intention-to-treat popu­ COVID-19−related treatment discontinuations. Sensitivity
lation and based on the maintenance dose assigned to analysis of the primary endpoint performed using the

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Survodutide dose group Placebo (n=77) Total (N=384)

0·6 mg (n=77) 2·4 mg (n=78) 3·6 mg (n=76) 4·8 mg (n=76)
Sex
Female 51 (66%) 54 (69%) 51 (67%) 53 (70%) 53 (69%) 262 (68%)
Male 26 (34%) 24 (31%) 25 (33%) 23 (30%) 24 (31%) 122 (32%)
Age, years 48·6 (12·6) 49·0 (13·1) 50·3 (11·8) 47·6 (13·5) 50·0 (13·5) 49·1 (12·9)
Race
White 59 (77%) 60 (77%) 63 (83%) 59 (78%) 60 (78%) 301 (78%)
Asian 8 (10%) 9 (12%) 9 (12%) 7 (9%) 7 (9%) 40 (10%)
Black or African American 10 (13%) 8 (10%) 3 (4%) 8 (11%) 8 (10%) 37 (10%)
Multiple 0 1 (1%) 1 (1%) 0 1 (1%) 3 (1%)
Native Hawaiian or Pacific Islander 0 0 0 1 (1%) 1 (1%) 2 (1%)
American Indian or Alaska Native 0 0 0 1 (1%) 0 1 (<1%)
BMI, kg/m² 37·8 (6·3) 37·6 (7·3) 37·0 (5·7) 37·6 (6·0) 35·8 (5·0) 37·1 (6·1)
Weight, kg 107·0 (18·7) 106·6 (23·0) 104·7 (19·6) 105·9 (17·4) 104·3 (23·0) 105·7 (20·4)
Waist circumference, cm 115·3 (13·4) 115·3 (17·0) 112·8 (13·9) 112·8 (13·0) 110·4 (14·6) 113·4 (14·5)
Systolic blood pressure, mm Hg 125·0 (13·4) 125·4 (13·3) 127·4 (13·2) 122·6 (12·3) 127·5 (14·2) 125·6 (13·4)
Diastolic blood pressure, mm Hg 80·5 (7·5) 80·7 (7·4) 81·8 (8·1) 80·8 (7·6) 82·4 (8·6) 81·3 (7·8)
Pulse rate, beats per minute 70·8 (9·4) 71·4 (10·1) 71·2 (9·6) 70·9 (9·0) 70·7 (9·4) 71·0 (9·5)

Modified intention-to-treat population. Data are mean (SD) or n (%).

Table 1: Baseline characteristics

modified intention-to-treat population was based on the 5% or greater or 10% or greater body weight loss from
actual dose per protocol that participants received during baseline to 16 weeks was analysed using logistic
the dose-maintenance phase (actual treatment) and regression and descriptive statistics. Details on statistical
included on-treatment data only (collected from the date analysis methods are provided in the appendix (p 2).
of administration of the first dose of survodutide or A Data Monitoring Committee assessed the progress of
placebo until 28 days after the administration of the last the clinical trial, including an unblinded safety review at
dose of survodutide or placebo). A reduced dose could specified intervals, and a recommendation to the sponsor
have been received by participants who did not tolerate whether to continue, stop, or modify the trial.
treatment due to gastrointestinal adverse events during This trial is closed, completed, and registered
the dose-escalation phase. Furthermore, if the participant with ClinicalTrials.gov (NCT04667377) and EudraCT
was known to have discontinued treatment during the (2020–002479–37).
dose-escalation phase, actual treatment was defined as
the next planned maintenance dose up from the last dose Role of the funding source
taken before discontinuation. Analysis of continuous The funder was involved in the study design, data
secondary endpoints was performed on the modified collection, and analysis, oversaw its conduct, monitored
intention-to-treat population including on-treatment data. trial sites, and were given the opportunity to review this
For analysis of the primary endpoint, a mixed model manuscript for medical and scientific accuracy, as well as
for repeated measures was used to generate estimates of intellectual property considerations. Investigators were
mean percentage changes from baseline in bodyweight responsible for the trial-related medical decisions and
at week 46 for each dose group. The mixed model for data collection. This article was drafted under the
repeated measures analysis included a fixed effect for guidance of the authors, with medical writing and
baseline bodyweight as a continuous covariate. Analysis editorial support paid for by the funder.
of the dose−response relationship was performed using
multiple comparison procedure and modelling (MCP- Results
Mod) techniques. Adverse events were analysed in the Participants were recruited between March 8, 2021 and
treated set, comprising all randomly assigned participants Nov 11, 2021; the last participant completed the trial on
who received at least one dose of trial treatment, and Oct 7, 2022. In total, 520 participants were screened for
based on planned treatment; key safety analyses (eg, eligibility, and 387 participants were randomly assigned
treatment discontinuations) were also performed based (approximately 77 per trial arm), of whom 386 received
on actual treatment. Absolute change in bodyweight and survodutide or matched placebo during the dose-escalation
waist circumference were analysed using a mixed model phase, and 286 during the dose-maintenance phase
for repeated measures. The percentage of patients with (approximately 57 per trial arm). Overall, 308 (80%) of

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A B
0

–2 −2·3
−2·8

–4
body weight from baseline (%, 95% CI)
Adjusted mean percentage change in

−6·2
–6 −6·8

–8

–10

–12 −12·5
−13·6
–14 −13·2

–16 −14·9 −16·7

Placebo
Survodutide 0·6 mg
–18
Survodutide 2·4 mg
Survodutide 3·6 mg −18·7
–20
Survodutide 4·8 mg
–22
Base- 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 46 Base- 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 46
line Week line Week
Number of participants
Survodutide 0·6 mg 76 75 73 71 69 65 63 63 60 59 58 55 52 53 50 52 56 88 88 81 79 74 68 67 67 64 63 62 58 54 52 50 50 51
once weekly
Survodutide 2·4 mg 78 76 76 72 70 71 64 65 56 65 66 64 64 62 60 58 58 92 90 91 88 81 80 68 61 54 57 58 54 53 53 52 47 43
once weekly
Survodutide 3·6 mg 76 76 73 75 68 67 64 64 59 64 62 64 60 57 59 58 61 71 71 71 71 71 71 70 70 64 64 59 59 57 51 52 50 50
once weekly
Survodutide 4·8 mg 76 76 75 75 74 74 70 68 65 62 60 63 60 62 60 58 64 54 54 54 54 54 54 53 53 54 53 53 52 50 49 48 47 45
once weekly
Placebo 77 75 72 72 72 70 65 65 63 62 59 59 56 55 55 54 54 76 75 72 72 70 69 64 64 62 60 58 57 53 52 50 48 46

C D 96·0
100 Survodutide 0·6 mg (n=56) 95·3 97·8 Survodutide 0·6 mg (n=51)
Survodutide 2·4 mg (n=58) Survodutide 2·4 mg (n=43)
90 82·0 82·8 82·0 82·2 Survodutide 3·6 mg (n=50)
81·0 Survodutide 3·6 mg (n=61) 79·1
80 Survodutide 4·8 mg (n=64) Survodutide 4·8 mg (n=45)
Percentage of participants (%)

65·5 68·8 Placebo (n=54) Placebo (n=46)

66·7
70 65·6
60·7 60·0 66·7
60 54·7
45·9 46·5
50
37·9 37·3 40·0 37·8
40 33·9 32·8
25·9 29·5 26·1
30 25·6
20·7
20 15·7
11·1 12·5 10·9
10 5·6 4·3
2·0
0·0 0·0 0·0
0
≥5 ≥10 ≥15 ≥20 ≥5 ≥10 ≥15 ≥20
Percentage bodyweight reduction (%) Percentage bodyweight reduction (%)

Figure 2: Comparison of bodyweight parameters

Change from baseline in bodyweight to week 46; mixed model for repeated measures estimates for percentage changes in bodyweight from baseline to week 46 according to planned treatment
(A) and actual treatment received during the dose-maintenance phase (B; modified intention-to-treat population). Percentage of participants achieving 5% or more, 10% or more, 15% or more, and
20% or more bodyweight reductions over time according to planned treatment (C) and actual treatment received during the dose-maintenance phase (D; modified intention-to-treat population).

386 participants completed the trial, which included (92%) randomly assigned to the survodutide 2·4 mg dose
participants who prematurely discontinued the trial received that same dose during the maintenance phase. In
medication but completed the week 46 visit (249 [81%] of the highest survodutide dose group (4·8 mg), 70% of the
309 receiving survodutide; 46 [77%] of 77 receiving placebo), participants received the maintenance dose as assigned at
with 233 (60%) of 386 completing the 46-week treatment randomisation (appendix p 7).
period (187 [61%] of 309 receiving survodutide; 46 [60%] of Mean age at trial entry was 49·1 years (SD 12·9),
77 receiving placebo; figure 1). The treated set comprised approximately two-thirds of participants were female
386 participants and the modified intention-to-treat (n=262, 68%) and 301 (78%) of participants were White.
population comprised 384 participants; two participants Mean (SD) BMI was 37·1 kg/m² (6·1), waist circumference
did not provide any post-baseline efficacy data. Analyses was 113·4 cm (14·5), systolic blood pressure was
based on planned treatment and actual treatment were 125·6 mm Hg (13·4), and diastolic blood pressure
predefined for this trial. The majority of the participants was 81·3 mm Hg (7·8; table 1).

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Change from baseline to week 46 Comparison versus placebo

Survodutide Survodutide Survodutide Survodutide Placebo Survodutide Survodutide Survodutide Survodutide
0·6 mg 2·4 mg 3·6 mg 4·8 mg 0·6 mg 2·4 mg 3·6 mg 4·8 mg
Planned treatment
Primary endpoint 56/76 58/78 61/76 64/76 57/77 56/76 58/78 61/76 64/76
(all data), n/N
Bodyweight, % −6·2 −12·5 −13·2 −14·9 −2·8 −3·4 −9·7 −10·4 −12·1
(−8·3 to −4·1) (−14·5 to −10·5) (−15·3 to −11·2) (−16·9 to −13·0) (−4·9 to −0·7) (−6·3 to −0·4) (−12·6 to − 6·8) (−13·3 to −7·5) (−15·0 to −9·2)
p value ·· ·· ·· ·· ·· 0·026 <0·0001 <0·0001 <0·0001
Secondary endpoints 47/75 45/78 50/76 47/76 46/76 47/75 45/78 50/76 47/76
(on-treatment)
Bodyweight, kg −7·2 −14·8 −15·6 −18·5 −2·7 −4·5 −12·1 −13·0 −15·8
(−9·3 to −5·1) (−16·8 to −12·7) (−17·7 to −13·6) (−20·5 to −16·4) (−4·7 to −0·6) (−7·4 to −1·6) (−14·9 to −9·2) (−15·9 to −10·1) (−18·7 to −12·9)
p value ·· ·· ·· ·· ·· 0·0025 <0·0001 <0·0001 <0·0001
Waist circumference, −8·3 −15·0 −15·0 −16·0 −4·0 −4·4 −11·0 −11·0 −12·1
cm (−10·7 to −5·9) (−17·4 to −12·6) (−17·3 to −12·6) (−18·4 to −13·7) (−6·3 to −1·6) (−7·7 to −1·0) (−14·4 to −7·7) (−14·3 to −7·7) (−15·4 to −8·7)
p value ·· ·· ·· ·· ·· 0·012 <0·0001 <0·0001 <0·0001
Systolic blood −6·2 −8·1 −8·7 −8·6 −2·5 −3·7 −5·6 −6·2 −6·2
pressure, mm Hg (−9·1 to −3·3) (−11·0 to −5·2) (−11·5 to −5·8) (−11·5 to −5·7; (−5·3 to 0·4; (−7·8 to 0·4) (−9·7 to −1·5) (−10·2 to −2·2) (−10·3 to −2·1)
(n=48) (n=47)
p value ·· ·· ·· ·· ·· 0·073 0·0072 0·0027 0·0033
Diastolic blood −3·3 −4·4 −4·3 −4·8 −1·9 −1·4 −2·5 −2·4 −2·9
pressure, mm Hg (−5·1 to −1·5) (−6·1 to −2·6) (−6·0 to −2·6) (−6·6 to −3·1; (−3·6 to −0·1; (−3·9 to 1·1) (−5·0 to 0·0) (−4·9 to 0·0) (−5·4 to −0·5)
(n=48) (n=47)
p value ·· ·· ·· ·· ·· 0·257 0·050 0·051 0·020
Actual treatment
Primary endpoint 51/88 43/92 50/71 45/54 46/76 51/88 43/92 50/71 45/54
(on-treatment), n/N
Bodyweight, % −6·8 −13·6 −16·7 −18·7 −2·3 −4·6 −11·3 −14·4 −16·4
(−8·7 to −5·0) (−15·4 to −11·7) (−18·6 to −14·8) (−20·8 to −16·6) (−4·2 to −0·4) (−7·2 to −1·9) (−14·0 to −8·7) (−17·1 to −11·7) (−19·3 to −13·6)
p value ·· ·· ·· ·· ·· 0·0009 <0·0001 <0·0001 <0·0001
Secondary endpoints 51/88 43/92 50/71 45/54 46/76 51/88 43/92 50/71 45/54
(on-treatment), n/N
Bodyweight, kg −7·2 −13·8 −17·1 −19·5 −2·7 −4·5 −11·1 −14·4 −16·8
(−9·2 to −5·3) (−15·8 to −11·9) (−19·1 to −15·1) (−21·7 to −17·2) (−4·7 to −0·7) (−7·4 to −1·7) (−14·0 to −8·3) (−17·3 to −11·5) (−19·8 to −13·8)
p value ·· ·· ·· ·· ·· 0·0018 <0·0001 <0·0001 <0·0001
Waist circumference, −8·6 −14·6 −15·2 −16·6 −4·0 −4·6 −10·6 −11·3 −12·7
cm (−10·9 to −6·3) (−17·0 to −12·2) (−17·5 to −12·9) (−19·1 to −14·2) (−6·3 to −1·6) (−7·9 to −1·3) (−14·0 to −7·2) (−14·6 to −8·0) (−16·1 to −9·2)
p value ·· ·· ·· ·· ·· 0·0061 <0·0001 <0·0001 <0·0001
Systolic blood −6·3 −8·0 −9·2 −8·3 −2·5 −3·8 −5·5 −6·7 −5·8
pressure, mm Hg (−9·0 to −3·5) (−10·9 to −5·1) (−12·0 to −6·4) (−11·3 to −5·3; (−5·4 to 0·4; (−7·8 to 0·2) (−9·6 to −1·4) (−10·8 to −2·7) (−10·0 to −1·6)
(n=46) (n=47)
p value ·· ·· ·· ·· ·· 0·063 0·0086 0·0011 0·0066
Diastolic blood −3·4 −4·4 −4·3 −4·7 −1·9 −1·6 −2·5 −2·4 −2·8
pressure, mm Hg (−5·1 to −1·8) (−6·2 to −2·6) (−6·0 to −2·5) (−6·5 to −2·9; (−3·6 to −0·1; (−4·0 to 0·9) (−5·0 to −0·0) (−4·8 to 0·1) (−5·4 to −0·3)
(n=46) (n=47)
p value ·· ·· ·· ·· ·· 0·20 0·048 0·056 0·028

Data are given as mean (95% CI), unless otherwise stated, for the modified intention-to-treat population. N numbers per dose group are given as n at week 46/n at baseline. No confirmatory hypothesis testing
was performed. The p values reported are considered nominal. Planned treatment was defined as the maintenance dose assigned at randomisation, and included all data censored for COVID-19-related
treatment discontinuations. Actual treatment was defined as the actual dose participants received during the dose maintenance phase, and included on-treatment data only.

Table 2: Mixed model for repeated measures estimates for the primary and secondary endpoints from baseline to week 46 by planned and actual treatment

The therapeutic effect of survodutide versus placebo participants were analysed according to the planned
was shown by a non-flat dose−response curve of survodutide treatment, mean changes in bodyweight
percentage change in bodyweight from baseline to from baseline to week 46 (mixed model for repeated
week 46, indicative of continued bodyweight loss. measures estimates) ranged from −6·2% (95% CI
Significant bodyweight reductions were observed at all −8·3 to −4·1; survodutide 0·6 mg) to −14·9% (−16·9 to
tested doses (0·6 mg, p=0·026; ≥2·4 mg, p<0·0001) −13·0; survodutide 4·8 mg) versus −2·8% (−4·9 to −0·7)
compared with placebo (figure 2, table 2). When for placebo; this range increased to −6·8% (−8·7 to −5·0;

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survodutide 0·6 mg) to −18·7% (−20·8 to −16·6; Treatment with survodutide led to reductions in plasma
survodutide 4·8 mg) when participants were analysed triglyceride levels, VLDL, HbA1c, and alanine amino­
according to the actual treatment (−2·3% [−4·2 to −0·4] transferase concentrations (appendix p 8). Changes from
for placebo). baseline in BMI and clinical obesity staging were
At week 46, bodyweight losses of 5% or greater, 10% consistent with the primary endpoint results, and no
or greater, and 15% or greater were achieved by 53 (83%; changes from baseline were observed in the use of anti-
≥5% bodyweight loss), 44 (69%; ≥10% bodyweight loss), hypertensive and lipid-lowering medications. The changes
and 35 (55%; ≥15% bodyweight loss) of 64 participants from baseline in plasma glucagon and amino acids were
who were randomly assigned to receive survodutide consistent with target engagement of the glucagon
4·8 mg, and by 14 (26%), six (11%), and three (6%) of receptor and GLP-1 receptor. Further exploratory results
54 participants who were randomly assigned to are described in the appendix (p 2).
placebo (planned treatment; figure 2C). Consistently, The incidence of treatment-emergent adverse events
bodyweight losses were achieved by 44 (98%; was higher with survodutide (all doses pooled; 281 [91%]
≥5% bodyweight loss), 37 (82%; ≥10% bodyweight loss), of 309 participants) compared with the placebo group
and 30 (67%; ≥15% bodyweight loss) of 45 participants (58 [75%] of 77 participants; table 3). However,
who received survodutide 4·8 mg for the duration of the incidence of serious (defined in accordance with
the dose-maintenance phase, and 12 (26%), 5 (11%), good clinical practice; assessed by the investigator as
and 2 (4%) of 46 participants who received placebo medically significant or requiring hospitalisation, or
(actual treatment; figure 2D). Additionally, bodyweight resulting in death, persistent disability, or is life
reductions of 20% or greater were assessed at week 46. threatening) treatment-emergent adverse events was
By planned treatment, up to one third of partici­ lower among participants receiving survodutide than
pants receiving survodutide 4·8 mg (21 [33%] of those receiving placebo (survodutide 13 [4%] of 309,
64 participants) and 3·6 mg (18 [30%] of 61 participants) placebo 5 [7%] of 77). Gastrointestinal disorders were the
achieved bodyweight losses of 20% or more; this most common treatment-emergent adverse event,
increased to 17 (38%) of 45 participants receiving occurring in 232 [75%] of 309 participants receiving
survodutide 4·8 mg for the duration of the dose- survodutide and 32 [42%] of 77 participants receiving
maintenance phase (actual treatment), and 20 (40%) placebo; these were primarily nausea (survodutide,
of 50 receiving survodutide 3·6 mg (figure 2). No 174 [56%] of 309 vs placebo, 15 [20%] of 77), vomiting
participants receiving placebo achieved bodyweight (83 [27%] of 309 vs 4 [5%] of 77), diarrhoea (69 [22%] of
reductions of 20% or more. 309 vs 8 [10%] of 77), and constipation (65 [21%] of 309 vs
At week 46, all tested survodutide doses resulted in 4 [5%] of 77). There were no treatment-emergent adverse
substantial absolute reductions in bodyweight and events of special interest (pancreatitis and hepatic injury),
waist circumference from baseline, with greatest mean life-threatening treatment-emergent adverse events, or
reductions observed in participants receiving survodutide deaths in the trial. There was a higher rate of investigator-
4·8 mg (95% CI −18·5 kg [−20·5 to −16·4; bodyweight] defined, drug-related adverse events in the survodutide
and −16·0 cm [−18·4 to −13·7; waist circumference]; group (77% of all dose groups, n=237/309 [0·6 mg, 61%;
placebo: −2·7 kg [−4·7 to −0·6] and −4·0 cm [−6·3 to 2·4 mg, 85%; 3·6 mg, 81%; 4·8 mg, 81%]) compared
−1·6]; planned treatment; table 2). Substantial reductions with the placebo group (38%, n=29/77), mostly
in blood pressure were also achieved at week 46; the gastrointestinal-related adverse events. Serious drug-
greatest mean reductions were −8·7 mm Hg (95% CI related adverse events were reported by two participants,
−11·5 to −5·8) for systolic blood pressure (with survo­ one receiving survodutide 0·6 mg (nausea, vomiting,
dutide 3·6 mg; vs −2·5 mm Hg [−5·3 to 0·4] with dehydration, and renal failure) and one receiv­ing survo­
placebo; planned treatment) and −4·8 mm Hg (−6·6 to dutide 3·6 mg (angioedema). No unexpected tolerability
−3·1) for diastolic blood pressure (with survodutide concerns were identified.
4·8 mg; vs −1·9 mm Hg [−3·6 to −0·1] with placebo; Adverse events led to treatment discontinuation in
planned treatment; table 2). When participants were 76 (25%) of 309 participants receiving survodutide and
analysed according to actual treatment received, greatest three (4%) of 77 participants receiving placebo. These
mean absolute reductions in bodyweight and waist adverse events were most commonly gastrointestinal
circum­ference were observed at week 46 with survodutide disorders (51 [67%] of 76 patients who discontinued
4·8 mg (−19·5 kg [−21·7 to −17·2] and −16·6 cm survodutide due to adverse events; one [33%] of
[−19·1 to −14·2]; placebo: −2·7 kg [−4·7, −0·7] and three patients that discontinued placebo due to adverse
−4·0 cm [−6·3 to −1·6]; table 2). The mean reductions in events) and occurred primarily during the rapid dose-
blood pressure at week 46 by actual treatment were escalation phase. In participants receiving survodutide,
similar, if not slightly lower in the survodutide 4·8 mg 56 (74%) of 76 discontinuations due to adverse events
group compared with planned treatment (systolic blood occurred during rapid dose-escalation (appendix p 10).
pressure, –8·3 mm Hg [−11·3 to −5·3]; diastolic When analysed by planned treatment, the proportion of
blood pressure, −4·7 mm Hg [−6·5 to −2·9]; table 2). participants discontinuing treatment due to adverse

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Placebo Survodutide dose group Survodutide

(n=77) total (n=309)
0·6 mg (n=77) 2·4 mg (n=78) 3·6 mg (n=77) 4·8 mg (n=77)
Any treatment-emergent adverse event 58 (75%) 70 (91%) 70 (90%) 71 (92%) 70 (91%) 281 (91%)
Gastrointestinal disorders 32 (42%) 44 (57%) 67 (86%) 58 (75%) 63 (82%) 232 (75%)
Nausea* 15 (20%) 26 (34%) 51 (65%) 48 (62%) 49 (64%) 174 (56%)
Vomiting* 4 (5%) 7 (9%) 23 (30%) 26 (34%) 27 (35%) 83 (27%)
Diarrhoea* 8 (10%) 14 (18%) 22 (28%) 18 (23%) 15 (20%) 69 (22%)
Constipation* 4 (5%) 9 (12%) 17 (22%) 19 (25%) 20 (26%) 65 (21%)
Infections and infestations 33 (43%) 34 (44%) 29 (37%) 35 (46%) 33 (43%) 131 (42%)
Coronavirus disease (COVID-19)* 17 (22%) 16 (21%) 11 (14%) 16 (21%) 10 (13%) 53 (17.2%)
Leading to treatment discontinuation 3 (4%) 15 (20%) 20 (26%) 19 (25%) 22 (29%) 76 (25%)
Gastrointestinal disorders 1 (1%) 5 (7%) 13 (17%) 13 (17%) 20 (26%) 51 (17%)
Nausea† 0 3 (4%) 12 (15%) 8 (10%) 9 (12%) 11 (4%)
Vomiting† 0 1 (1%) 4 (5%) 9 (12%) 10 (13%) 24 (8%)
Infections and infestations 0 4 (5%) 3 (4%) 3 (4%) 1 (1%) 11 (4%)
Coronavirus disease (COVID-19)† 0 4 (5%) 2 (3%) 2 (3%) 1 (1%) 9 (3%)
Serious‡ 5 (7%) 1 (1%) 2 (3%) 6 (8%) 4 (5%) 13 (4%)
Requiring or prolonging 4 (5%) 0 1 (1%) 3 (4%) 4 (5%) 8 (3%)
hospitalisation
Other medically important serious 1 (1%) 1 (1%) 1 (1%) 3 (4%) 0 5 (2%)
event
Life-threatening 0 0 0 0 0 0
Leading to death 0 0 0 0 0 0
Investigator defined, drug related 29 (38%) 47 (61%) 66 (85%) 62 (81%) 62 (81%) 237 (77%)
Serious‡ 0 0 0 2 (3%) 0 2 (1%)

Data are n (%). Safety was analysed in the treated set, comprising all randomised participants who received at least one dose of trial treatment, and based on planned
treatment. *Treatment-emergent adverse events listed according to Medical Dictionary for Regulatory Activities preferred term occurred in 20% or more participants in any
one study group. †Treatment-emergent adverse events leading to treatment discontinuation events listed according to Medical Dictionary for Regulatory Activities preferred
term occurred in 5% or more participants in any one study group. ‡Assessed by the investigator based on pre-defined definition of serious adverse events.

Table 3: Summary of treatment-emergent adverse events

events was highest in the survodutide 4·8 mg group Discussion

compared with the other dose groups (4·8 mg, 22 [29%] In this phase 2 trial, all tested survodutide doses
of 77; 0·6 mg, 15 [20%] of 77; 2·4 mg, 20 [26%] of 78; significantly reduced bodyweight in a dose-dependent
3·6 mg, 19 [25%] of 77). However, when analysed by manner relative to placebo in participants with a BMI of
actual treatment received, less than 10% of participants 27 kg/m² or greater (0·6 mg, p=0·026; ≥2·4 mg,
in the survodutide 4·8 mg group reported adverse events p<0·0001). Survodutide doses 2·4 mg or greater resulted
leading to treatment discontinuation (n=5/54, 9·3%; in substantial, clinically relevant bodyweight losses of
appendix p 11). The difference here is due to discon­ 5%19 or more in over half of participants within 8 weeks
tinuations mostly occurring during the dose-escalation of treatment initiation. The effect of survodutide on
phase, before the maintenance dose of 4·8 mg was bodyweight was sustained throughout the treatment
reached, but still being reported with the 4·8 mg dose period. According to the planned treatment, participants
when analysed by planned treatment. In participants receiving survodutide reached a maximum mean body­
receiving 4·8 mg survodutide, 18 of 22 discontinuations weight reduction from baseline of −14·9% at week 46,
due to adverse events occurred during the rapid dose which increased to −18·7% when participants were
escalation phase (figure 1). analysed according to the actual treatment dose received.
The mean heart rate was higher on average in This corresponded to absolute bodyweight reductions of
participants receiving survodutide than those receiving up to –19·5 kg with survodutide 4·8 mg (actual
placebo (appendix p 14). At week 46, the mean increase in treatment, on-treatment data only) and –18.5 kg (planned
heart rate from baseline was 2·7 (SD 9·1) bpm for treatment).
survodutide (all doses pooled) and 0·1 (7·1) bpm In a study of the GLP-1 receptor agonist semaglutide
for placebo; the mean increases from baseline did (2·4 mg weekly), mean changes in bodyweight after
not exceed 10 bpm in any survodutide dose groups 68 weeks of treatment received reached up to −16·9% (vs
for the duration of the trial. −2·4% with placebo) for the trial product estimand.8 This

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shows the potential enhanced bodyweight lowering In people with obesity, hypertension and hypercholes­
efficacy of targeting both glucagon receptor and GLP-1 terolaemia are associated with an increased risk of
receptor with survodutide. Furthermore, the proportion cardiovascular disease.22 In this trial, survodutide
of participants receiving survodutide 4·8 mg who treatment substantially reduced systolic and diastolic
reached clinically significant bodyweight reductions of blood pressure, and other cardiovascular risk factors in
5% or greater, 10% or greater, and 15% or greater at week adults with a BMI of 27 kg/m² or greater. GLP-1 receptor
46 (actual on-treatment: 97·8% [≥5%], 82·2% [≥10%], agonists are known to provide cardiovascular benefits,
and 66·7% [≥15%]) was numerically greater in the particularly in patients with type 2 diabetes.23 Multiple
current study compared with those seen following cardiovascular outcome trials have been performed for
68 weeks treatment with semaglutide (on-treatment: GLP-1 receptor agonists, with reductions in three-point
92·4%, 74·8%, and 54·8%).8 In the current study, up to major adverse cardiovascular events observed for
40% of participants (3·6 mg) in the actual treatment liraglutide,24 semaglutide,25 albiglutide,26 dulaglutide,27
set, also achieved at least 20% body­ weight reduc­ and efpeglenatide,28 when tested in people with obesity
tion, a greater proportion than that seen in the phase 3 and type 2 diabetes. The phase 3 trials of liraglutide
semaglutide study (34·8%).8 As the dose–response and semaglutide in obesity have shown reductions in
curves in the current phase 2 trial suggest that partici­ blood pressure;6,7 however, few trials directly assessing
pant bodyweight loss did not reach a plateau at week 46, cardiovascular outcomes have been performed in
it is possible that further bodyweight reductions might people with obesity without diabetes. The recently
be seen in the phase 3 survodutide trials with longer published results of the SELECT study examining
treatment durations. semaglutide 2·4 mg in people with obesity with pre-
The potential for increased bodyweight lowering existing cardiovascular disease found that semaglutide
efficacy has been investigated with other glucagon was superior to placebo in reducing incidence of major
receptor–GLP-1 receptor dual agonists, such as NN1177, adverse cardiovascular events.29
which was discontinued following safety concerns The tolerability profile of survodutide was similar to that
associated with treatment.20 Across three phase 1 trials, of GLP-1 receptor mono-agonists and glucose-dependent
treatment with NN1177 showed bodyweight decreases insulinotropic polypeptide–GLP-1 receptor dual agonists,
of up to 12·6% (NN1177 4200 µg), but was accompanied with gastrointestinal disorders being the most frequent
by increases in heart rate, inflammatory markers, drug-related adverse events.7,10 Treatment discontinuation
and liver enzymes (eg, alanine transaminase), and due to adverse events was more frequent in participants
decreases in glucose tolerance and levels of most receiving survodutide than those receiving placebo. These
amino acids to below the lower limit of normal.20 were most frequent in the first 10 weeks of the trial,
Despite the similar mode of action of survodutide and coinciding with the initial part of the dose escalation
NN1177, these safety signals were not observed with phase. The dose-escalation schemes used in this trial were
survodutide treat­ment. Furthermore, previous studies rapid, with dose increases mostly occurring up to every
of survodutide have shown improvements in glucose 2 weeks. Although treatment discontinuations in this trial
tolerance and decreases in HbA1c in participants with occurred at a higher rate than seen in phase 3 trials of
type 2 diabetes.15 The disparities observed between GLP-1 receptor mono-agonists and glucose-dependent
these treatments is likely due to differences in target insulinotropic polypeptide–GLP-1 receptor dual ago­
engagement, with NN1177 showing a receptor ratio of nists,7,10 the differences in study design and duration
approximately 1:3 compared with a ratio of 1:8 for between the current phase 2 trial and phase 3 trials means
survodutide.11,20 This suggests that the balance of recep­ that direct comparisons are not possible. For example, in
tor ratios of survodutide may be more favourable for the phase 3 trials, dose escalations occurred every 4 weeks
a glucagon receptor–GLP-1 receptor agonist in clinical due to the increased length of the trials (68 and 72 weeks,
development. respectively), while faster escalations were done in the
In a recent phase 2 study of the glucose-dependent current phase 2 trial, which could explain the differences
insulinotropic polypeptide/GLP-1 receptor/glucagon observed.7,10 This suggests that adjustments to the dose-
receptor triple agonist retatrutide, participants receiving escalation phase in future studies might help to minimise
the highest dose (12 mg) achieved a mean weight loss rates of treatment discontinuation. In addition, when
of −24·2% after 48 weeks of treatment, with 83% of analysed by actual treatment, the discontinuation rate in
participants achieving at least 15% weight loss.21 These the highest survodutide dose group (4·8 mg) was in line
results exemplify the potential for therapies targeting with the rates seen in phase 3 trials of other incretin
multiple pathways to have improved efficacy over current agonists7,10 and lower than observed with the highest dose
GLP-1 receptor agonists.9 Treatments promoting weight of retatrutide (9·3% vs 16·1%).21 This suggests that in
loss of this magnitude are likely required for people with participants who reach the target maintenance dose of
class III obesity (a BMI of 40 or greater) or those who 4·8 mg survodutide, the discontinuation rate is similar
need substantial weight loss to improve the complications to other GLP-1 receptor-based therapies. Overall, no
of obesity. unexpected tolerability concerns were identified.

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There are several limitations that should be Bayer, Eli Lilly, Novo Nordisk, and Sanofi. ES, AMH, and AU are
considered when interpreting these results. The employees of Boehringer Ingelheim. KJL declares no competing
interests.
relatively short duration of this phase 2 trial did not
permit long term assessment of efficacy, safety, and Data sharing
To ensure independent interpretation of clinical study results and enable
outcomes; thus, phase 3 studies are planned to eval­ authors to fulfil their role and obligations under the ICMJE criteria,
uate the long-term effects of survodutide. Obesity is Boehringer Ingelheim grants all external authors access to relevant
a chronic and progressive disease that requires long- clinical study data. In adherence with the Boehringer Ingelheim Policy
term management,1,2 and therefore long-term assess­ on Transparency and Publication of Clinical Study Data, scientific and
medical researchers can request access to clinical study data after
ments of potential pharmacotherapies are required. publication of the primary manuscript and secondary analyses in
The STEP 5 trial of semaglutide 2·4 mg assessed the peer-reviewed journals and regulatory and reimbursement activities are
effects of treatment over 2 years in participants with completed, normally within 1 year after the marketing application has
obesity, showing that weight loss of up to −15·2% been granted by major Regulatory Authorities. Researchers should use
the https://vivli.org/ link to request access to study data, and visit
was sustained over longer treatment periods, provided https://www.mystudywindow.com/msw/datasharing for further
the medications were continued.30 An extension of the information.
STEP 1 phase 3 trial of semaglutide 2·4 mg showed Acknowledgments
that participants regained two-thirds of their previous The authors would like to acknowledge the contributions of Michele Brun
weight loss 1 year after treatment withdrawal, and (clinical trial lead, Boehringer Ingelheim) and Robert Toorawa (trial
weight regain had not reached a plateau at the end of statistician, Boehringer Ingelheim) to this study. The authors thank the
study participants, and the investigators and study site staff who
the observation period.30 This effect reversal was also contributed to the study. Medical writing support in the preparation of
observed for the car­diometabolic improvements seen this manuscript was provided by Susie Eaton, and Anna Wydra, of
with 68 weeks’ treat­ ment, proving the chronicity of Callisto, OPEN Health Communications (London, UK), and was funded
by Boehringer Ingelheim. Survodutide was co-invented with Zealand
obesity.8
Pharma. Under the terms of the glucagon/GLP-1 licensing agreement,
Other limitations include the fact that participants Boehringer Ingelheim funds all research, development, and
with complications associated with obesity, such as commercialisation activities.
diabetes or non-alcoholic steatohepatitis, were excluded References
from the current trial; therefore, the efficacy of 1 Bray GA, Kim KK, Wilding JPH. Obesity: a chronic relapsing
survodutide in people with these conditions requires progressive disease process. A position statement of the World
Obesity Federation. Obes Rev 2017; 18: 715–23.
further investigation. In addition, 78% of participants 2 Cornier MA. A review of current guidelines for the treatment of
in this trial were White and 68% were female; increased obesity. Am J Manag Care 2022; 28 (suppl): S288–96.
diversity of the trial population will be a focus in 3 Eisenberg D, Shikora SA, Aarts E, et al. 2022 American Society
of Metabolic and Bariatric Surgery (ASMBS) and International
future studies. The results from this phase 2 trial build Federation for the Surgery of Obesity and Metabolic Disorders
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AMH and ClR designed the trial. OS and KJL were trial investigators 7 Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly
and enrolled participants. AU, ES, and ClR analysed the data. AMH, AU, semaglutide in adults with overweight or obesity. N Engl J Med 2021;
ES, and ClR interpreted the data. AU and ES accessed and verified the 384: 989–1002.
underlying manuscript data. This article was drafted under the guidance 8 Wilding JPH, Batterham RL, Davies M, et al. Weight regain and
of the authors, with medical writing and editorial support paid for by the cardiometabolic effects after withdrawal of semaglutide: the
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funder. All authors were permitted access to the study data, contributed
to manuscript writing (assisted by a medical writer paid for by the 9 Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor
co-agonists for treating metabolic disease. Mol Metab 2021;
funder), approved the final version of the manuscript, and vouch for data
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accuracy and fidelity to the protocol.
10 Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once
Declaration of interests weekly for the treatment of obesity. N Engl J Med 2022; 387: 205–16.
The authors meet criteria for authorship as recommended by the 11 Zimmermann T, Thomas L, Baader-Pagler T, et al. BI 456906:
International Committee of Medical Journal Editors (ICMJE) and did Discovery and preclinical pharmacology of a novel GCGR/GLP-1R
not receive payment related to the development of this manuscript. dual agonist with robust anti-obesity efficacy. Mol Metab 2022;
ClR has received personal fees from Boehringer Ingelheim, Eli Lilly, 66: 101633.
GI Dynamics, Gila Pharmaceuticals, Herbalife, Johnson & Johnson, 12 Jiang G, Zhang BB. Glucagon and regulation of glucose
Keyron, Novo Nordisk, and Zealand Pharma outside the submitted metabolism. Am J Physiol Endocrinol Metab 2003; 284: E671–78.
work. OS has received research support from Alnylam, Anji, 13 Pereira MJ, Thombare K, Sarsenbayeva A, et al. Direct effects of
AstraZeneca, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, glucagon on glucose uptake and lipolysis in human adipocytes.
Gilead, Janssen, Kowa, Medicago, Moderna, Novartis, Novo Nordisk, Mol Cell Endocrinol 2020; 503: 110696.
Pfizer, Sanofi, ViaCyte, and Zucara Therapeutics; speaker bureau fees 14 Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases
from Amgen, AstraZeneca, Bausch Health, HLS Therapeutics, Janssen, energy expenditure independently of brown adipose tissue
activation in humans. Diabetes Obes Metab 2016; 18: 72–81.
LMC, Novo Nordisk, and Sanofi; and consultancy fees from Amgen,

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