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. 2025 Jan 16;27(4):1773–1782. doi: 10.1111/dom.16167

Subgroup analysis by sex and baseline BMI in people with a BMI ≥27 kg/m2 in the phase 2 trial of survodutide, a glucagon/GLP‐1 receptor dual agonist

Carel W le Roux 1, Oren Steen 2, Kathryn J Lucas 3, Elena Startseva 4, Anna Unseld 5, Samina Ajaz Hussain 4, Anita M Hennige 6,✉
PMCID: PMC11885088  PMID: 39821928

Abstract

Aim

To explore the effects of sex and baseline body mass index (BMI) on the efficacy and safety of survodutide in people with a BMI ≥27 kg/m2.

Materials and Methods

Totally 387 people (aged 18–75 years, BMI ≥27 kg/m2, without diabetes) were randomized 1:1:1:1:1 to once‐weekly subcutaneous survodutide (0.6, 2.4, 3.6 or 4.8 mg) or placebo for 46 weeks (20‐week dose escalation; 26‐week dose maintenance). Participants were categorized according to sex and baseline BMI. Data were analysed descriptively for the full analysis set (FAS), according to dose assigned at randomization (planned treatment) using on‐treatment data or all data censored for COVID‐19‐related treatment discontinuations. (ClinicalTrials.gov number: NCT04667377).

Results

After 46 weeks of survodutide treatment, females had greater reductions in bodyweight and waist circumference than males. Participants with a lower baseline BMI had greater proportional reductions in bodyweight than those with a higher baseline BMI; the trend was reversed for reductions in waist circumference. Rates of adverse events (AEs) were comparable between subgroups for sex and baseline BMI. Nausea was the most frequently reported gastrointestinal AE in all subgroups.

Conclusions

In people with a BMI ≥27 kg/m2, survodutide was associated with clinically meaningful reductions in bodyweight and waist circumference when compared with placebo, in prespecified subgroups based on sex and baseline BMI, and was tolerated at all doses tested.

Keywords: antiobesity drug, effectiveness, GLP‐1, glucagon, obesity therapy, phase I‐II study

1. INTRODUCTION

Obesity is a chronic, complex and heterogeneous disease, 1 caused by an imbalance of energy intake and expenditure. 2 The global prevalence of obesity is increasing, and it is estimated that 1.2 billion people will be affected by obesity (defined as a body mass index [BMI] ≥30 kg/m2) by 2025. 3 In most countries, obesity is more prevalent in females than in males, 4 , 5 and the development of several obesity‐related complications shows sex‐specific differences. 4 , 6 , 7 , 8 Data suggest that weight reduction in females is greater than in males after receiving pharmacologic weight‐loss interventions for approximately 12 months (per analysis of data from the Semaglutide Treatment Effect in People with Obesity [STEP] and Satiety and Clinical Adiposity–Liraglutide Evidence in individuals with and without diabetes [SCALE] Obesity and Prediabetes, and Sibutramine Cardiovascular Outcomes [SCOUT] trials). 8 , 9

Several pharmacological targets have been proposed for the management of obesity, and a number of investigational compounds are currently in clinical development, mainly consisting of entero‐pancreatic hormone‐based agents. 10 Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R) agonists were initially developed for the treatment of type 2 diabetes (T2D), 11 and one of their main extra‐pancreatic effects is bodyweight reduction. 12 , 13 , 14 GLP‐1R mono‐agonists liraglutide and semaglutide, as well as glucose‐dependent insulinotropic polypeptide receptor (GIPR)/GLP‐1R dual agonist tirzepatide, are approved by the US Food and Drug Administration and the European Medicines Agency for the management of obesity. 15 , 16 , 17 , 18 , 19 , 20 However, given the complexity of obesity pathophysiology, the use of agents that target different physiological pathways may be necessary to obtain sustained and clinically relevant reductions in bodyweight. This approach may also help address the wider spectrum of cardio‐renal‐metabolic diseases associated with obesity and extend its management beyond just bodyweight reduction. Survodutide (BI 456906) is a glucagon receptor (GCGR)/GLP‐1R dual agonist in clinical development for the treatment of obesity, 21 and metabolic dysfunction‐associated steatohepatitis (MASH) with fibrosis. 22 GCGR/GLP‐1R dual agonism putatively targets energy expenditure (via the catabolic effect of glucagon in the liver) and energy intake (via the effects of GLP‐1, namely appetite regulation, food intake reduction, interference with counterregulatory metabolic adaptation and the slowing of gastric emptying). 21 , 23 , 24 , 25 , 26 , 27 In a multinational phase 2 clinical trial in adults with a BMI ≥27 kg/m2 without diabetes (ClinicalTrials.gov number, NCT04667377; EudraCT number, 2020–002479–37), once‐weekly survodutide (0.6, 2.4, 3.6 or 4.8 mg; subcutaneous injection) demonstrated significant reduction in bodyweight in a dose‐dependent manner relative to placebo in participants with a BMI ≥27 kg/m2 (survodutide: 0.6 mg, p = 0.026; ≥2.4 mg, p < 0.001). 28 Analyses were based on doses received during the maintenance period (actual treatment), or according to doses assigned at randomization (planned treatment). Mean percentage change in bodyweight at week 46 was −14.9% with survodutide 4.8 mg versus −2.8% with placebo when analysed by planned treatment (all data censored for COVID‐19‐related treatment discontinuations) and −18.7% for survodutide 4.8 mg versus −2.3% with placebo when analysed by actual treatment (on‐treatment data). 28 Furthermore, 54.7% participants receiving survodutide 4.8 mg reached at least 15% bodyweight reduction at week 46, compared with 5.6% of those receiving placebo. Also, at week 46, bodyweight reductions of at least 20% occurred in 32.8% and 29.5% participants receiving survodutide 4.8 and 3.6 mg, respectively, by planned treatment; none of the participants receiving placebo achieved bodyweight reductions of 20% or more. 28 The safety profile of survodutide was comparable to that of GLP‐1R mono‐agonists, and gastrointestinal disorders were the most frequent treatment‐emergent adverse events (AEs). 28

This subgroup analysis investigated the effect of sex and baseline BMI on the efficacy and safety outcomes of survodutide in people with a BMI ≥27 kg/m2.

2. MATERIALS AND METHODS

2.1. Trial overview

Data for this analysis were derived from a 46‐week randomized, double‐blind, placebo‐controlled, dose‐finding phase 2 trial of survodutide that was conducted at 43 centres in 12 countries (ClinicalTrials.gov number, NCT04667377; EudraCT number, 2020–002479–37). 28 Full details of the clinical trial (including the protocol and trial profile/flow diagram) have been published 28 and are summarized here.

In total, 387 adult participants (aged ≥18 to <75 years) with a BMI ≥27 kg/m2, a stable bodyweight of ≥70 kg (females) or ≥80 kg (males) and with HbA1c <6.5% (without diabetes) at screening, were randomized 1:1:1:1:1 to receive once‐weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or placebo for 46 weeks. The treatment period included a 20‐week dose‐escalation period when the dose could be adjusted for gastrointestinal tolerability, followed by a 26‐week dose‐maintenance period. 28 In addition to their assigned treatment or placebo, all participants received diet and physical activity counselling (~500 kcal/day energy deficit and ~150–300 min per week of moderate‐intensity aerobic and strength exercises) every 4 weeks between weeks 1 and 40, and at end‐of‐treatment. The primary endpoint was percentage change in bodyweight from baseline to week 46. Secondary endpoints included achievement of bodyweight reductions of ≥5%, ≥10% and ≥15% at week 46, as well as absolute changes in bodyweight, waist circumference and systolic and diastolic blood pressure from baseline to week 46. Safety was assessed by the occurrence of AEs and changes in vital signs. 28

2.2. Post hoc analysis

Participants were categorized according to sex and baseline BMI (<30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2) to assess the effect of these parameters on efficacy and safety outcomes. Subgroup analyses of the primary endpoint (percentage change in bodyweight from baseline to week 46) were prespecified before unblinding of the trial. All other presented efficacy and safety evaluations were performed as post hoc analyses.

2.3. Statistical analysis

Data were analysed descriptively for the full analysis set (FAS), defined as all randomized participants who received at least one dose of study treatment and who had analysable data for at least one efficacy endpoint, according to doses assigned at randomization (planned treatment). For the primary endpoint, results were given as descriptive statistics, including all data (on‐ and off‐treatment) censored for COVID‐19‐related treatment discontinuations. A frequency table describing categorical bodyweight reduction (≥5%, ≥10% and ≥15%) from baseline to week 46 (including all data [on‐ and off‐treatment] censored for COVID‐19‐related treatment discontinuations) was developed. Continuous secondary endpoints were presented as descriptive statistics, including on‐treatment data.

3. RESULTS

3.1. Participant demographics and baseline characteristics

A total of 387 participants were randomized (one participant withdrew). Of these, 386 participants received survodutide or matched placebo during the dose‐escalation phase, and 286 during the dose‐maintenance phase. 28 Two treated participants did not provide any post baseline efficacy data, leaving 384 participants in the FAS. Overall, baseline demographic and clinical characteristics were similar across treatment groups. Of 384 participants (FAS), 68.2% (262) were female and 31.8% (122) were male. At baseline, 9.9% (38), 30.5% (117), 31.8% (122) and 27.9% (107) had a BMI of <30, 30 to <35, 35 to <40 and ≥40 kg/m2, respectively. 28 In this analysis, baseline demographics and clinical characteristics were generally similar between males and females (Supplementary Table S1) and across BMI subgroups (Supplementary Table S2). Males weighed more than females at baseline (mean [standard deviation, SD]: 117.5 [21.7] kg vs. 100.2 [17.2] kg, respectively), and had a greater waist circumference (mean [SD]: 119.6 [14.7] cm vs. 110.4 [13.5] cm, respectively); BMI at baseline was comparable between males and females (mean [SD]: 36.7 [5.8] kg/m2 vs. 37.3 [6.3] kg/m2, respectively).

3.2. Percentage change in bodyweight from baseline to week 46 (analysed by planned treatment)

Across all survodutide doses, percentage change in bodyweight from baseline to week 46 was greater with survodutide versus placebo (Figure 1A). Percentage change in bodyweight was numerically higher in females versus males for most survodutide dose groups. With survodutide versus 4.8 mg, percentage change in bodyweight from baseline versus placebo was −11.9% versus −3.3% in males, and −17.0% versus −3.2% in females. In general, participants with a lower baseline BMI had a greater percentage change in bodyweight at week 46 than those with a higher baseline BMI (Figure 1B).

FIGURE 1.

FIGURE 1

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Percentage change in bodyweight from baseline to week 46 by (A) sex and (B) BMI category at baseline (full analysis set, planned treatment, all data censored for COVID‐19). BMI, body mass index; SD, standard deviation.

3.3. Absolute change in bodyweight from baseline to week 46 (analysed by planned treatment)

At week 46, absolute reductions in bodyweight were greater in females than in males (survodutide 4.8 mg vs. placebo; −15.9 vs. −4.2 kg in males and −22.0 vs. −3.0 kg in females; Figure 2A). With consideration of the small sample sizes and variability, change in mean absolute bodyweight at week 46 were similar across BMI subgroups (survodutide 4.8 mg vs. placebo: −21.3 vs. 1.4 kg, −16.2 vs. −3.3 kg, −22.2 vs. −7.5 kg and −19.9 vs. −1.6 kg in participants with a BMI <30, 30 to <35, 35 to <40 and ≥40 kg/m2, respectively; Figure 2B).

FIGURE 2.

FIGURE 2

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Absolute change in bodyweight from baseline to week 46 by (A) sex and (B) BMI category at baseline (full analysis set, planned treatment, on‐treatment data). BMI, body mass index; SD, standard deviation.

3.4. Achievement of bodyweight reductions of ≥5%, ≥10% and ≥15% at week 46 (analysed by planned treatment)

The proportion of participants achieving bodyweight reductions of ≥5% and ≥10% at week 46 was greater in females than in males for those receiving 2.4‐ and 3.6‐mg survodutide, but not for those receiving 4.8 mg. The proportion of participants achieving bodyweight reductions of ≥15% at week 46 was greater in females than in males for those receiving 2.4‐, 3.6‐ and 4.8‐mg survodutide; whereas the opposite trend was observed for those receiving 0.6‐mg survodutide (Figure 3A). In general, the proportion of participants achieving bodyweight reductions of ≥5%, ≥10% and ≥15% at week 46 was greater in participants with a lower baseline BMI compared with those with a higher baseline BMI. At least half of participants in each baseline BMI subgroup achieved bodyweight reductions of ≥15% with survodutide 4.8 mg compared with those receiving placebo (<30 kg/m2: 75.0% vs. 14.3%; 30 to <35 kg/m2: 57.9% vs. 4.5%; 35 to <40 kg/m2: 52.0% vs. 6.7%; ≥40 kg/m2: 50.0% vs. 0.0%, respectively; Figure 3B).

FIGURE 3.

FIGURE 3

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Percentage of participants achieving 5% or more, 10% or more and 15% or more bodyweight reductions at week 46 by (A) sex and (B) BMI category at baseline (full analysis set, planned treatment, all data censored for COVID‐19). BMI, body mass index; SD, standard deviation.

3.5. Absolute change in waist circumference from baseline to week 46 (analysed by planned treatment)

Overall, absolute reductions in waist circumference at week 46 were greater in females than in males (survodutide 4.8 mg vs. placebo; −17.9 vs. −4.9 cm in females and −12.8 vs. −1.7 cm in males, respectively; Figure 4A). In general, participants with a higher baseline BMI had greater reductions in waist circumference at week 46 than those with a lower baseline BMI (survodutide 4.8 mg vs. placebo: −8.4 vs. −2.6 cm, −14.3 vs. −6.4 cm, −17.5 vs. −5.0 cm and −17.2 vs. 3.3 cm in participants with BMI <30, 30 to <35, 35 to <40 and ≥40 kg/m2, respectively; Figure 4B).

FIGURE 4.

FIGURE 4

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Absolute change in waist circumference from baseline to week 46 by (A) sex and (B) BMI category at baseline (full analysis set, planned treatment, on‐treatment data). BMI, body mass index; SD, standard deviation.

3.6. Safety and tolerability

Rates of AEs were comparable between males (87.9% [87/99]) and females (92.4% [194/210]; Table 1). Gastrointestinal AEs for all survodutide doses pooled were experienced by more females (79.5%) than males (65.7%), and nausea was the most frequently reported gastrointestinal AE in females and males (62.4% and 43.4%, respectively). The frequency of AEs was similar across baseline BMI subgroups (86.7% [26/30] in <30 kg/m2; 92.2% [83/90] in 30 to >35 kg/m2; 91.8% [90/98] in 35 to >40 kg/m2; and 90.1% [82/91] in ≥40 kg/m2; Table 1). Participants with baseline BMI <30 kg/m2 experienced fewer gastrointestinal AEs (53.3% vs. 80.0%, 77.6%, and 74.7% in participants with baseline BMI 30 to <35, 35 to <40 and ≥40 kg/m2, respectively). Nausea was the most frequently reported gastrointestinal AE across all baseline BMI subgroups (46.7%, 64.4%, 57.1% and 50.5% for baseline BMI <30, 30 to <35, 35 to <40 and ≥40 kg/m2, respectively).

TABLE 1.

Summary of adverse events by sex and by BMI at baseline.

AEs, n (%) Male (n = 123) Female (n = 263) BMI < 30 kg/m2 (n = 39) BMI 30 to < 35 kg/m2 (n = 118) BMI 35 to < 40 kg/m2 (n = 122) BMI ≥ 40 kg/m2 (n = 107)
Survodutide pooled (n = 99) Placebo (n = 24) Survodutide pooled (n = 210) Placebo (n = 53) Survodutide pooled (n = 30) Placebo (n = 9) Survodutide pooled (n = 90) Placebo (n = 28) Survodutide pooled (n = 98) Placebo (n = 24) Survodutide pooled (n = 91) Placebo (n = 16)
Any AE 87 (87.9) 21 (87.5) 194 (92.4) 37 (69.8) 26 (86.7) 8 (88.9) 83 (92.2) 22 (78.6) 90 (91.8) 16 (66.7) 82 (90.1) 12 (75.0)
Gastrointestinal AEs 65 (65.7) 9 (37.5) 167 (79.5) 23 (43.4) 16 (53.3) 7 (77.8) 72 (80.0) 9 (32.1) 76 (77.6) 7 (29.2) 68 (74.7) 9 (56.3)
Nausea 43 (43.4) 2 (8.3) 131 (62.4) 13 (24.5) 14 (46.7) 4 (44.4) 58 (64.4) 5 (17.9) 56 (57.1) 3 (12.5) 46 (50.5) 3 (18.8)
Vomiting 15 (15.2) 0 (0.0) 68 (32.4) 4 (7.5) 9 (30.0) 2 (22.2) 29 (32.2) 0 (0.0) 22 (22.4) 0 (0.0) 23 (25.3) 2 (12.5)
Diarrhoea 20 (20.2) 1 (4.2) 49 (23.3) 7 (13.2) 1 (3.3) 2 (22.2) 23 (25.6) 3 (10.7) 26 (26.5) 1 (4.2) 19 (20.9) 2 (12.5)
Constipation 19 (19.2) 1 (4.2) 46 (21.9) 3 (5.7) 2 (6.7) 0 (0.0) 16 (17.8) 1 (3.6) 25 (25.5) 1 (4.2) 22 (24.2) 2 (12.5)
AEs leading to discontinuation 25 (25.3) 0 (0.0) 51 (24.3) 3 (5.7) 5 (16.7) 1 (11.1) 22 (24.4) 0 (0.0) 22 (22.4) 2 (8.3) 27 (29.7) 0 (0.0)
Gastrointestinal AEs leading to discontinuation 13 (13.1) 0 (0) 38 (18.1) 1 (1.9) 2 (6.7) 1 (11.1) 18 (20.0) 0 (0.0) 18 (18.4) 0 (0.0) 13 (14.3) 0 (0.0)
Serious AEs 4 (4.0) 1 (4.2) 9 (4.3) 4 (7.5) 0 (0.0) 1 (11.1) 3 (3.3) 1 (3.6) 4 (4.1) 2 (8.3) 6 (6.6) 1 (6.3)
Investigator defined, drug‐related AEs 72 (72.7) 8 (33.3) 165 (78.6) 21 (39.6) 16 (53.3) 6 (66.7) 76 (84.4) 8 (28.6) 78 (79.6) 7 (29.2) 67 (73.6) 8 (50.0)
Serious, investigator defined, drug‐related AEs 1 (1.0) 0 (0.0) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (2.2) 0 (0.0)
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Note: Data shown are for all randomized participants who received at least one dose of trial treatment, including on‐treatment data only.

Abbreviations: AE, adverse event; BMI, body mass index.

4. DISCUSSION

This subgroup analysis investigated the effect of sex and baseline BMI on the efficacy and safety outcomes of survodutide in people with a BMI ≥27 kg/m2. After 46 weeks of treatment with survodutide, females had a greater reduction in bodyweight and waist circumference than males. In general, participants with a lower baseline BMI had a greater proportional reduction in bodyweight than those with a higher baseline BMI. Conversely, participants with a higher baseline BMI had a greater reduction in waist circumference than those with a lower baseline BMI.

These results require further insight and analysis from larger data sets (i.e., from ongoing phase 3 clinical trials), as there may be underlying differences in the baseline characteristics of the participants other than sex that would explain these results. The mechanism behind the differential weight loss observed in females versus males is also unclear at present, but may be related to differences in plasma concentrations of survodutide. A population pharmacokinetic analysis of survodutide data from three phase 1 and two 2 trials that included people with a range of BMIs (from 20 to 50 kg/m2) with and without T2D demonstrated that only bodyweight had a relevant effect on the steady‐state exposure of survodutide and that heavier individuals were less exposed than lighter people in terms of area under the concentration–time curve during a dosing interval at steady‐state and maximum concentration during a dosing interval at steady state. 29 Furthermore, the observed magnitude of the covariate effects alongside the flexible dose‐escalation scheme suggested that no dose adjustments were warranted for survodutide. 29 (The survodutide exposure–response analysis will be published separately).

The tolerability profile of survodutide was consistent with that reported for GLP‐1R mono‐agonists and GIPR/GLP‐1R dual agonists. 28 Gastrointestinal events were the most frequently reported treatment‐emergent AEs in participants receiving survodutide, 28 and occurred more frequently in females (80%) than males (66%). AEs leading to treatment discontinuation occurred in approximately 25% of male and female participants receiving survodutide. The vast majority (74% [56/76]) of treatment discontinuations due to AEs in participants receiving survodutide occurred during the 20‐week rapid dose‐escalation phase. 28 Data suggest that the discontinuation rate for participants reaching the target maintenance dose of 4.8‐mg survodutide is similar to that for other GLP‐1R‐based therapies. 28

Cumulative evidence indicates that weight reduction with GLP‐1R agonists is more pronounced in females compared with males. 30 Exposure–response analyses of liraglutide (doses 1.2, 1.8, 2.4 and 3.0 mg) in people with a BMI ≥27 kg/m2 with and without T2D reported that greater weight loss was associated with increasing drug exposure. Women had greater weight loss than men at similar exposure, and this was additional to the extra weight loss expected in women from a 32% higher exposure than men of a similar bodyweight. 31 Sex differences with semaglutide treatment were explored in a review of data from the STEP phase 3 trial programme, 32 in which greater weight reduction occurred in females than in males in three of the trials (STEP 1, 2 and 4). 32 , 33 , 34 , 35 In STEP 1 and STEP 4 (semaglutide 2.4 mg; participants with a BMI ≥27 kg/m2 without T2D), estimated treatment difference in weight reduction compared with placebo was 14% in females versus 8% in males, and 16.2% in females versus 9.3% in males, respectively; in STEP 2 (semaglutide 1.0 or 2.4 mg; participants with a BMI ≥27 kg/m2 with T2D) weight reduction was 7.5% in females versus 4.6% in males. 32 A prespecified subgroup analysis from the semaglutide and cardiovascular outcomes trial in obesity without diabetes (SELECT; ClinicalTrials.gov number NCT03574597; N = 17 604), reported that semaglutide (2.4 mg once‐weekly, subcutaneous injection) significantly reduced the risk of the primary composite cardiovascular endpoint versus placebo in males (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.70 to 0.90), females (HR 0.84; 95% CI 0.66 to 1.07) and participants with various categories of baseline BMI (<30 kg/m2: HR 0.74; 95% CI 0.60 to 0.91; ≥30 to <35 kg/m2: HR 0.76; 95% CI 0.64 to 0.91; ≥35 to <40 kg/m2: HR 0.93; 95% CI 0.74 to 1.18; ≥40 to <45 kg/m2: HR 0.83; 95% CI 0.55 to 1.26; ≥45 kg/m2: HR 0.92; 95% CI 0.51 to 1.65). 36 A post hoc subgroup analysis of tirzepatide data from the SURPASS clinical trial programme, in which the participants had T2D, reported that the efficacy of tirzepatide in reducing bodyweight was independent of sex. 37 Lastly, a phase 2 trial of GLP‐1R/GIPR/GCGR triple agonist retatrutide (ClinicalTrials.gov number, NCT04881760; N = 338) in participants with a BMI ≥27 mg/m2 reported that females had a higher mean weight reduction than males (8 mg: 28.5% vs. 19.8%; 12 mg: 26.6% vs 21.9%, respectively). 38

The following limitations should be considered regarding the results reported here. The trial population was predominantly White; thus, the impact of ethnicity on the findings is unknown. Lack of ethnic diversity may hinder understanding and prediction of drug outcomes across populations. Also, the trial duration was relatively short; therefore, no long‐term assessment of outcomes was possible. These points will be addressed by larger phase 3 trials that are currently in progress (namely, SYNCHRONIZE™‐1, NCT06066515; SYNCHRONIZE™‐2, NCT06066528; and SYNCHRONIZE™‐CVOT, NCT06077864). In addition, the small number of participants in some of the subgroups may limit the significance and generalizability of the conclusions; for example, the subgroup for baseline BMI <30 kg/m2 was considerably smaller than the other baseline BMI subgroups (N = 38 vs. >100, respectively).

Survodutide was tolerated at all doses tested and was associated with clinically meaningful reductions in bodyweight and waist circumference, when compared with placebo, in prespecified subgroups based on sex and baseline BMI. After 46 weeks of survodutide treatment, females appeared to lose more bodyweight and had a greater reduction in waist circumference than males. Participants with a lower BMI at baseline had proportionally greater reduction in bodyweight than those with a higher baseline BMI whereas the trend was reversed for the observed reduction in waist circumference. Plasma concentrations of survodutide will be investigated as one of the possible explanations for the differential weight loss between males and females, and between the highest and lowest baseline BMI subgroups. Data sets from the larger numbers of participants in ongoing phase 3 trials will provide further insights into the observed outcomes. In conclusion, bodyweight reduction associated with survodutide occurred across a range of participant subgroups, and the observed effects of survodutide in modifying cardiometabolic parameters, 22 , 28 suggest wider population benefit, but females and those with a lower BMI may achieve more weight loss with survodutide.

AUTHOR CONTRIBUTIONS

Carel W. le Roux and Anita M. Hennige designed the trial. Oren Steen and Kathryn J. Lucas were trial investigators and enrolled participants. Carel W. le Roux, Elena Startseva and Anna Unseld analysed the data. Carel W. le Roux, Elena Startseva, Anna Unseld and Anita M. Hennige interpreted the data. Elena Startseva and Anna Unseld accessed and verified the underlying manuscript data. Samina Ajaz Hussain accessed and interpreted the safety data. All authors contributed to manuscript writing (assisted by a medical writer funded by the sponsor), approved the final version of the manuscript and vouched for data accuracy and fidelity to the protocol.

FUNDING INFORMATION

This study was supported and funded by Boehringer Ingelheim.

CONFLICT OF INTEREST STATEMENT

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of this manuscript. Carel W. le Roux has received personal fees from Boehringer Ingelheim, Eli Lilly, GI Dynamics, Gila Pharmaceuticals, Herbalife, Johnson & Johnson, Keyron, Novo Nordisk and Zealand Pharma outside the submitted work. Oren Steen has received research support from Alnylam, Anji, AstraZeneca, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Gilead, Janssen, Kowa, Medicago, Moderna, Novartis, Novo Nordisk, Pfizer, Sanofi, ViaCyte and Zucara Therapeutics; speaker bureau fees from Abbott, Amgen, AstraZeneca, Bausch Health, Boehringer Ingelheim, Eli Lilly, Janssen, LMC, Novo Nordisk and Sanofi; and consultancy fees from Amgen, Bayer, Eli Lilly, Novo Nordisk and Sanofi. Kathryn J. Lucas has nothing to disclose. Elena Startseva, Anna Unseld, Samina Ajaz Hussain and Anita M. Hennige are employees of Boehringer Ingelheim.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16167.

Supporting information

Table S1. Baseline demographics and characteristics by sex.

Table S2. Baseline demographics and characteristics by BMI at baseline.

DOM-27-1773-s001.docx (26.8KB, docx)

ACKNOWLEDGEMENTS

The authors thank the study participants, investigators and study site staff. Medical writing support in the preparation of this manuscript was provided by Kayleigh Walker, PhD, and Debra Brocksmith, MB ChB, PhD, of Elevate Scientific Solutions LLC, a member of the Envision Pharma Group, and was funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Survodutide is licensed to Boehringer Ingelheim from Zealand Pharma, with Boehringer Ingelheim solely responsible for development and commercialization globally. Zealand has a co‐promotion right in the Nordic countries.

le Roux CW, Steen O, Lucas KJ, et al. Subgroup analysis by sex and baseline BMI in people with a BMI ≥27 kg/m2 in the phase 2 trial of survodutide, a glucagon/GLP‐1 receptor dual agonist. Diabetes Obes Metab. 2025;27(4):1773‐1782. doi: 10.1111/dom.16167

DATA AVAILABILITY STATEMENT

To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically, one year after the approval has been granted by major Regulatory Authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Baseline demographics and characteristics by sex.

Table S2. Baseline demographics and characteristics by BMI at baseline.

DOM-27-1773-s001.docx (26.8KB, docx)

Data Availability Statement

To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically, one year after the approval has been granted by major Regulatory Authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

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