Baseline characteristics in the SYNCHRONIZE™‐2 randomized phase 3 trial of survodutide, a glucagon receptor/GLP‐1 receptor dual agonist, for obesity in people with type 2 diabetes

Abstract

Aims

Survodutide is an investigational glucagon receptor/glucagon‐like peptide‐1 receptor dual agonist that has shown promise for treating obesity and its complications in Phase 2 trials. Two double‐blind, randomized, global Phase 3 trials are designed to assess the efficacy and safety of survodutide for treatment of obesity—SYNCHRONIZE™‐1 in people with obesity without type 2 diabetes (T2D) and SYNCHRONIZE™‐2 in people with obesity and T2D. This paper describes the baseline characteristics of participants in SYNCHRONIZE‐2 (ClinicalTrials.gov identifier NCT06066528).

Materials and Methods

Participants aged ≥18 years with a body mass index (BMI) ≥27 kg/m² and T2D were randomized 1:1:1 to weekly subcutaneous survodutide (up‐titrated to 3.6 or 6.0 mg) or placebo with recommendations for modified diet and physical activity. The primary endpoints are the percentage change in body weight (BW) and achievement of BW reduction of ≥5% from baseline to Week 76.

Results

SYNCHRONIZE‐2 includes 752 treated participants from 133 sites across 19 countries. At baseline, participants had a mean age of 55.7 years, BMI 36.5 kg/m², BW 104.1 kg, waist circumference 115.5 cm and haemoglobin A1c 7.4%; 50.7% were female. Overall, 36.2% are from Europe, 32.8% from North America and 22.3% from East Asia. The most common obesity complications included hypertension (69.0%), dyslipidaemia (67.6%), obstructive sleep apnoea (17.3%) and arteriosclerotic cardiovascular disease (10.9%); 78.7% were treated with metformin, 34.2% with sodium‐glucose co‐transporter‐2 inhibitors and 58.6% with lipid‐lowering medications.

Conclusions

SYNCHRONIZE‐2 will determine the efficacy, safety and tolerability of survodutide for BW reduction in people with obesity and T2D, whose baseline characteristics suggest a representative, diverse cohort.

1. INTRODUCTION

Obesity, a chronic metabolic disease characterized by excess and/or ectopic adiposity, is one of the major contributors to the development of type 2 diabetes (T2D). ¹ , ² It is generally recommended that people with both diseases should undergo treatment for both the diabetes and the underlying obesity, ³ which is often defined as a body mass index (BMI) ≥30 or ≥ 27 kg/m² with at least one complication such as T2D. Weight loss in these individuals can substantially improve glycaemic control and reduce the need for glucose‐lowering medications. First‐line intervention for treating obesity is lifestyle modification, including changes in diet and physical activity. ³ , ⁴ , ⁵ , ⁶ While this approach may result in significant short‐term weight loss, most individuals will experience substantial, even complete, regain of the lost weight.

Obesity management medications (OMMs) typically yield more durable weight loss compared to lifestyle changes alone. Over the past 5 years, medications such as semaglutide and tirzepatide have demonstrated sustained weight loss in the range of 10%–22%. ⁷ , ⁸ Semaglutide is a glucagon‐like peptide‐1 (GLP‐1) receptor mono‐agonist whereas tirzepatide is a dual agonist of both the GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) receptors. ⁷ , ⁸ These compounds lead to a reduction in appetite and food intake. Although their therapeutic effects appear to work through the central nervous system, the precise neuroendocrine signalling pathways involved are less well defined. ⁹ , ¹⁰ Despite their overall greater efficacy for weight loss, most OMMs—if not all of them—induce substantially less weight loss in people with T2D than those without T2D. ⁷ , ⁸ , ¹¹ , ¹² While the reason for this difference in weight loss is unclear, there is a strong unmet need for medications that produce greater weight loss in people with T2D.

Molecules that combine GLP‐1 receptor agonism with agonism of the glucagon receptor are under investigation for the treatment of obesity and its complications. Although glucagon is classically known for its involvement in the regulation of glucose homeostasis, it also stimulates weight loss in animals and humans, suggesting a wider role in regulating metabolic health. Oxyntomodulin, a naturally occurring dual agonist of both GLP‐1 and glucagon receptors, ¹³ , ¹⁴ induces weight loss without adverse effects on glucose regulation, suggesting a potential therapeutic benefit in coordinately activating these two receptors.

Survodutide is a synthetic, long‐acting, unimolecular peptide with half‐maximal effective concentration (EC₅₀) values in vitro of approximately 8 and 1 nM for the human glucagon receptor and GLP‐1 receptor, respectively, indicating greater potency for the latter receptor. ¹⁵ In a Phase 2 clinical trial in people with both obesity and T2D, treatment with survodutide up to 2.7 mg once weekly or 1.8 mg twice weekly for 16 weeks induced up to an 8.7% mean reduction in BW, and up to a 1.71% (18.72 mmol/mol) mean reduction in haemoglobin A1c (HbA1c) from a mean baseline of 8.1% (64.7 mmol/mol). ¹⁶ In a separate Phase 2 trial, treatment with survodutide 4.8 mg once weekly for 46 weeks led to an average 18.7% weight loss in people with obesity without T2D (based on actual doses received after initial up‐titration). ¹⁷

Consequently, survodutide is being evaluated in the SYNCHRONIZE™ Phase 3 programme for the treatment of obesity. The SYNCHRONIZE programme includes a multinational trial for the treatment of people with obesity without T2D (SYNCHRONIZE™‐1), similar studies in China (SYNCHRONIZE™‐CN) and Japan (SYNCHRONIZE™‐JP), a multinational cardiovascular outcomes trial (SYNCHRONIZE™‐CVOT) ¹⁸ and a multinational Phase 3 trial for the treatment of people with obesity who also have T2D (SYNCHRONIZE™‐2).

This paper describes the baseline characteristics of participants in SYNCHRONIZE‐2.

2. MATERIALS AND METHODS

The SYNCHRONIZE‐2 trial design and methodology are summarized below and have been published previously. ¹⁹

2.1. Trial design

SYNCHRONIZE‐2 (ClinicalTrials.gov identifier: NCT06066528) is an ongoing, 76‐week, double‐blind, placebo‐controlled, Phase 3, randomized clinical trial of the efficacy, safety and tolerability of survodutide for the treatment of people with obesity and coexistent T2D. One hundred and thirty‐three sites worldwide have recruited participants from 19 countries (Australia, Belgium, Canada, China, Czechia, Denmark, Finland, Germany, Greece, Hungary, Japan, South Korea, Netherlands, New Zealand, Poland, Spain, Sweden, the United Kingdom and the United States). The ethics and administrative structure of the trial are described in Supporting Information S1.

2.2. Participants

Individuals were eligible to participate in the trial if, at baseline, they were ≥18 years old with BMI ≥27 kg/m², had been previously diagnosed with T2D, had HbA1c ≥6.5% and <10% (≥48 and <86 mmol/mol), and were being treated for their T2D with either diet and exercise alone or with medications other than insulin, amylin analogues, drugs with GLP‐1 receptor agonist activity (alone or in combination with GIP receptor agonist activity) or dipeptidyl peptidase‐4 (DPP‐4) inhibitors for ≥3 months prior to screening. Participants also had to report at least one previous unsuccessful dietary attempt to lose weight.

Individuals were excluded if they had received one or more OMMs or had experienced a BW change >5% in either direction within the previous 3 months, or if they had a demonstrated endocrinological, syndromic or genetic cause of obesity. They were also excluded if they had received treatment with medication for T2D other than those described above, or had a cardiovascular event (atherosclerotic or heart failure‐related) within the 3 months prior to screening.

Full inclusion and exclusion criteria for this study have been published previously. ¹⁹

2.3. Randomization and treatment

Participants were randomly assigned in a 1:1:1 ratio to receive double‐blind treatment with survodutide 3.6 mg, survodutide 6.0 mg or matching placebo, self‐administered once weekly by subcutaneous injection (Figure 1). These doses were selected based on Phase 2 trials in people with obesity, T2D and/or metabolic dysfunction‐associated steatohepatitis (MASH) that together encompassed each of these doses, ¹⁶ , ¹⁷ , ²⁰ as well as evidence from Phase 1, ²¹ animal and modelling studies.

FIGURE 1.

Study design of SYNCHRONIZE™‐2. This is a randomized, double‐blind, placebo‐controlled, multinational, Phase 3 clinical trial in people with obesity and type 2 diabetes to evaluate the efficacy, safety and tolerability of survodutide, as an adjunct to a reduced‐calorie diet and increased physical activity for reducing body weight. *The treatment period includes an initial dose‐escalation period that may be extended if one or two re‐escalation attempts are needed due to the occurrence of gastrointestinal symptoms. EOS, end of study; EOT, end of treatment. Adapted from fig. 1 in Wharton et al., ¹⁹ used under CC BY‐NC 4.0.

Trial drug is escalated to these target dosages with an up‐titration scheme aimed at mitigating trial drug‐related symptoms such as gastrointestinal events, ¹⁹ which are a common cause of discontinuation of medications containing GLP‐1 receptor agonist activity in clinical trials and clinical practice. ²² If counselling on dietary behaviours and medications to control adverse gastrointestinal symptoms do not sufficiently mitigate such symptoms, actions can include temporary interruption of treatment, followed by temporary dose reduction or delay of a scheduled up‐titration and a subsequent attempt to re‐escalate. Continuing onto maintenance therapy at a lower dose than assigned at randomization is allowed only (1) if the participant would otherwise discontinue the study drug, (2) if it is considered safe to do so and (3) at the discretion of the trial site investigator.

Throughout the trial, participants are assessed onsite or remotely every 2–4 weeks during the up‐titration period and every 6 weeks during the dose‐maintenance period. At randomization and onsite visits, all participants are counselled with regard to diet, including a recommended energy deficit of approximately 500 kcal/day, and physical activity, with a recommended minimum of 150 min of exercise per week, by dieticians or other healthcare professionals with similar qualifications.

2.4. Endpoints

The primary endpoints are percentage change in BW and achievement of BW reduction ≥5% (yes/no), each from baseline to Week 76. The key secondary endpoints are achievement of BW reduction ≥10%, ≥15% or ≥20% (yes/no), and absolute change from baseline to Week 76 in BW, HbA1c, waist circumference, systolic blood pressure, Capacity to Resist domain score of the Eating Behaviour Patient‐Reported Outcome (EB PRO) measure, ²³ and the EB PRO total score. Additional secondary endpoints and exploratory endpoints have been published previously. ¹⁹

Safety and tolerability will be assessed by analysing reported adverse events, laboratory tests (including changes in calcitonin, amylase and lipase levels), 12‐lead electrocardiograms, physical examinations and vital signs (including heart rate). Particular events of interest that will be closely monitored include those that are routinely monitored in all trials (e.g., drug‐induced liver injury) and those specific to medications that include GLP‐1 receptor agonist activity, including but not limited to gastrointestinal events, pancreatitis, acute gall bladder disease, pancreatic and thyroid malignancy, hypoglycaemia and worsening of diabetic retinopathy.

2.5. Statistical analysis

A sample size of approximately 600 randomized participants was planned, which would yield 99% power for the two primary endpoints as well as meet regulatory requirements for safety data (Supporting Information S1).

Analyses of efficacy and safety will be conducted for the treated set of participants (i.e., all randomized individuals who received ≥1 dose of study drug). The treatment regimen estimand will be used for the primary efficacy analysis and reflects the treatment effect including the effects of any premature treatment discontinuation, any prohibited OMM, any temporary stop of trial drug (for three or more consecutive administrations) or any prolonged dose‐escalation phase. The efficacy estimand will also be used, in order to capture the treatment effect expected if all participants had adhered to the prescribed treatment and had not received any prohibited OMM, including the effect of any prolonged dose escalation. In broad terms, the treatment regimen estimand measures how treatment might work in practice, whereas the efficacy estimand measures how treatment works in an ideal setting (that is, if all participants had adhered to trial protocol). Both estimands will be used to analyze the primary and key secondary endpoints. The analytical methods and models are detailed in Supporting Information S1.

The Medical Dictionary for Regulatory Activities (https://www.meddra.org/) will be used to code adverse events, which will be analyzed descriptively.

3. RESULTS

3.1. Trial status and participant disposition

Recruitment of participants for SYNCHRONIZE‐2 began in November 2023 and was completed in June 2024, with trial end (last visit for the last participant) estimated to occur in the second quarter of 2026. Seven hundred and fifty‐five participants have been randomized, of whom 752 have been treated with at least one dose of study drug (three were randomized in error due to eligibility criteria not being fulfilled, and were not included in the statistical analysis).

3.2. Baseline demographic and clinical characteristics

The demographic and clinical characteristics of the 752 randomized and treated participants at baseline are summarized in Table 1. Overall, participants had a mean age of 55.7 years and 50.7% are female; 36.2% are from Europe, 32.8% from North America and 22.3% from East Asia. The majority of participants are White (65.0%); 8.8% are Hispanic/Latino. At baseline, participants had a mean overall BMI, BW and waist circumference of 36.5 kg/m², 104.1 kg and 115.5 cm, respectively.

TABLE 1.

Demographic and clinical characteristics of participants at baseline.

Characteristic	Randomized and treated (n = 752) a
Age (years)	55.7 ± 11.2
Sex
Female	381 (50.7)
Male	371 (49.3)
Region
Europe	272 (36.2)
North America	247 (32.8)
East Asia	168 (22.3)
Other	65 (8.6)
Race
White	489 (65.0)
Asian	195 (25.9)
Black	43 (5.7)
Other	21 (2.8)
Missing	4 (0.5)
Ethnicity
Hispanic/Latino	66 (8.8)
Not Hispanic/Latino	686 (91.2)
Current nicotine user	139 (18.5)
Body weight (kg)	104.1 ± 21.4
BMI (kg/m2)	36.5 ± 6.5
BMI category
<27 kg/m2	6 (0.8) b
≥27 to <30 kg/m2	107 (14.2)
≥30 to <35 kg/m2	257 (34.2)
≥35 to <40 kg/m2	176 (23.4)
≥40 kg/m2	206 (27.4)
Waist circumference (cm)	115.5 ± 14.2
Waist‐to‐hip ratio	1.0 ± 0.1

Note: Data are presented as mean ± SD or n (%).

Abbreviation: BMI, body mass index.

^a n = 752 except for waist‐to‐hip ratio (n = 749) as hip circumference was not measured in three participants (waist circumference was measured for all 752 treated participants).

^b All participants in the BMI category <27 kg/m² at baseline fulfilled the inclusion criterion of BMI ≥27 kg/m² at screening.

3.3. Baseline vital signs, laboratory values and medications

The baseline vital signs, laboratory values and medications of participants are summarized in Table 2. Overall, mean HbA1c was 7.4% (57.4 mmol/mol), estimated glomerular filtration rate (eGFR) 89.7 mL/min/1.73 m² and urinary albumin‐to‐creatinine ratio (UACR) 45.3 mg/g. Mean low‐density lipoprotein cholesterol was 95.4 mg/dL, high‐density lipoprotein cholesterol 47.5 mg/dL and triglycerides 178.0 mg/dL, while mean high‐sensitivity C‐reactive protein level was 4.1 mg/L. Mean systolic and diastolic blood pressure was 129.8 and 81.5 mmHg, respectively.

TABLE 2.

Vital signs, laboratory values and medications at baseline.

	Randomized and treated (n = 752) a
HbA1c (%)	7.4 ± 0.9
HbA1c (mmol/mol)	57.4 ± 9.5
eGFR (CKD‐EPI) (mL/min/1.73 m2)	89.7 ± 19.1
eGFR (CKD‐EPI) category
<60 mL/min/1.73 m2	56 (7.4)
60 to <90 mL/min/1.73 m2	276 (36.7)
90 to <120 mL/min/1.73 m2	391 (52.0)
120 to <150 mL/min/1.73 m2	28 (3.7)
≥150 mL/min/1.73 m2	1 (0.1)
Urinary albumin‐to‐creatinine ratio (mg/g)	45.3 ± 140.3
Systolic blood pressure (mmHg)	129.8 ± 12.2
Diastolic blood pressure (mmHg)	81.5 ± 8.2
Heart rate (beats per min)	69.6 ± 10.5
Lipids (mg/dL)
Total cholesterol	177.5 ± 42.7
LDL cholesterol	95.4 ± 36.6
HDL cholesterol	47.5 ± 12.0
Triglycerides	178.0 ± 106.7
C‐reactive protein (mg/L)	4.1 ± 5.2
Liver enzymes (U/L)
Aspartate aminotransferase	24.2 ± 12.4
Alanine aminotransferase	31.0 ± 19.6
Platelets (×109/L)	257.5 ± 66.1
FIB‐4 score b	1.1 ± 0.6
Metformin	592 (78.7)
SGLT2 inhibitor	257 (34.2)
β‐blocker	154 (20.5)
ACE inhibitor	183 (24.3)
Angiotensin receptor blocker	244 (32.4)
Angiotensin receptor‐neprilysin inhibitor	3 (0.4)
Mineralocorticoid receptor antagonist	18 (2.4)
Loop diuretic	36 (4.8)
Diuretic, other than loop diuretic	160 (21.3)
Calcium channel blocker	218 (29.0)
Anticoagulant	25 (3.3)
Lipid‐lowering drug	441 (58.6)

Note: Data are presented as mean ± SD or n (%).

Abbreviations: ACE, angiotensin‐converting enzyme; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD‐EPI, Chronic Kidney Disease‐Epidemiology Collaboration creatinine equation; eGFR, estimated glomerular filtration rate; FIB, fibrosis; HbA1c, haemoglobin A1c; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; SGLT2, sodium‐glucose co‐transporter‐2.

^a n = 752 except for the following parameters: platelets (n = 751), heart rate (n = 749), FIB‐4 score (n = 739), LDL cholesterol (n = 734) and C‐reactive protein (n = 733).

^b FIB‐4 score is calculated as: (age [years] × AST [U/L])/(platelets [10⁹/L] × √ALT [U/L]). FIB‐4 scores are typically categorized as low risk for advanced liver fibrosis (<1.30), indeterminate risk (1.30–2.67) or high risk (>2.67).

Metformin was the most commonly taken medication at baseline (78.7% of participants), followed by lipid‐lowering drugs (58.6%) and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors (34.2%). Other baseline medications included angiotensin receptor blockers (32.4% of participants), calcium channel blockers (29.0%), angiotensin‐converting enzyme inhibitors (24.3%), non‐loop diuretics (21.3%) and β‐blockers (20.5%).

3.4. Baseline obesity complications

The most common complications at baseline included hypertension (69.0%), dyslipidaemia (67.6%), obstructive sleep apnoea (17.3%) and arteriosclerotic cardiovascular disease (ASCVD) (10.9%), defined as coronary artery disease, myocardial infarction, stroke or peripheral artery disease (Figure 2). MASH (7.7%), chronic kidney disease (5.7%), atrial fibrillation (2.3%) and chronic obstructive pulmonary disease (2.3%) were less common.

FIGURE 2.

Complications of obesity in the overall trial cohort at baseline. AFib, atrial fibrillation; ASCVD, arteriosclerotic cardiovascular disease (defined as coronary artery disease, myocardial infarction, stroke or peripheral artery disease); CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DLD, dyslipidaemia; HTN, hypertension; MASH, metabolic dysfunction‐associated steatohepatitis; OSA, obstructive sleep apnoea.

4. DISCUSSION

SYNCHRONIZE‐2 is a global Phase 3 trial of survodutide, a glucagon receptor/GLP‐1 receptor dual agonist, for treating obesity in people with concurrent T2D not taking insulin. This ongoing trial in 752 participants from 19 countries is designed to assess the efficacy of survodutide for weight reduction in people with both diseases, after it appeared to have potent weight‐reducing effects as well as antihyperglycaemic effects in Phase 2 trials. ¹⁶ , ¹⁷ It is intended that this dedicated trial in people with both obesity and T2D will help to determine the efficacy and safety of survodutide in this population, particularly as OMMs have been consistently observed to induce less weight loss in such individuals compared with those without T2D. ²⁴ The reason for this difference is not fully understood. Several potential contributors have been hypothesized, including glucose‐lowering drugs that cause weight gain, such as thiazolidinediones and sulphonylureas, and a hyperinsulinaemic response to insulin resistance in early T2D, but additional as‐yet‐unknown contributors are also suspected. ²⁴

The baseline characteristics of participants in SYNCHRONIZE‐2 suggest that the trial cohort is generally representative of people with obesity and T2D seen in clinical practice and diverse. The cohort includes participants from three Asian countries, Australia and New Zealand, several central, southern and western European countries and North America, and 35% of participants are non‐White. On average, participants had a BMI of 36.5 kg/m² (class 2 obesity) and a HbA1c level of 7.4% (indicative of moderate hyperglycaemia). The baseline HbA1c level is above the glycaemic goal of <7.0% generally recommended by the American Diabetes Association and the European Association for the Study of Diabetes ²⁵ and other professional societies, despite the high prevalence of treatment with glucose‐lowering medications such as metformin (78.7% of participants) and SGLT2 inhibitors (34.2%) at baseline. Although the majority of participants had normal kidney function at baseline (mean eGFR approximately 90 mL/min/1.73 m²), 7.4% had eGFR <60 and 5.7% had been previously diagnosed with chronic kidney disease. Furthermore, the average UACR (45 mg/g) may reflect the presence of undiagnosed early‐stage diabetic kidney disease. Unsurprisingly, there is a high prevalence of known cardiometabolic risk factors in the study population, including hypertension (69% of participants) and dyslipidaemia (68%). However, the prevalence of documented MASH (7.7%) was lower than recent estimates of its global prevalence in people with T2D (32% ²⁶ and 66% ²⁷ ), which may reflect underdiagnosis of this condition—a well‐documented phenomenon thought to reflect the asymptomatic nature of the disease ²⁸ —as it was determined by medical history rather than biopsy or non‐invasive tests. Similarly, only 10.9% of participants had ASCVD, compared with an estimated prevalence of at least one‐third in people with T2D seen in clinical practice, ²⁹ , ³⁰ , ³¹ which may be a consequence of excluding individuals with a recent cardiovascular event and those taking insulin.

There are some noteworthy similarities and differences between the baseline characteristics of the SYNCHRONIZE‐2 trial cohort and other Phase 3 trials of OMMs with GLP‐1 receptor agonist activity in participants with obesity and T2D (Table 3). ⁷ , ⁸ , ³² The mean BMI, BW and waist circumference were very similar in the STEP‐2 trial of the GLP‐1 receptor mono‐agonist semaglutide ⁷ and the SURMOUNT‐2 trial of the GLP‐1/GIP receptor dual agonist tirzepatide. ⁸ However, these weight‐related anthropometric measures were much lower in the DREAMS‐2 trial of mazdutide, ³² another glucagon receptor/GLP‐1 receptor dual agonist, which was conducted exclusively in China for improving glycaemic control in T2D patients with BMI ≥23 kg/m² (BMI ≥28 kg/m² is the cutpoint for defining obesity in China ³³ ). In June 2025, mazdutide was approved in China for chronic weight management in adults with overweight or obesity, based mainly on the results of the GLORY‐1 trial. ³⁴ Where reported, the rates of ASCVD, metabolic dysfunction‐associated steatotic liver disease/MASH, and obstructive sleep apnoea were generally similar in STEP‐2, SURMOUNT‐2 and SYNCHRONIZE‐2. However, glycaemic control at baseline was better in SYNCHRONIZE‐2 (mean HbA1c 7.4%) than in the other three trials (mean 8.0%–8.1%), the reason for which is unclear. Thus, comparison of the SYNCHRONIZE‐2 results with STEP‐2 and SURMOUNT‐2 may illuminate the efficacy and safety of survodutide in people with both obesity and T2D compared with a GLP‐1 receptor mono‐agonist or GLP‐1 receptor/GIP receptor dual agonist. However, between‐study comparisons should be interpreted cautiously, given the differences across trial cohorts, particularly in DREAMS‐2.

TABLE 3.

Baseline characteristics of participants in Phase 3 trials of obesity management medications with glucagon‐like peptide‐1 receptor agonist activity in people with obesity and type 2 diabetes (T2D).

	SYNCHRONIZE™‐2 (n = 752)	STEP‐2 (n = 1210) 7	SURMOUNT‐2 (n = 938) 8	DREAMS‐2 (n = 731) 32 , a
Compound	Survodutide	Semaglutide	Tirzepatide	Mazdutide
Mechanism	Glucagon receptor/GLP‐1R dual agonist	GLP‐1R mono‐agonist	GLP‐1R/GIPR dual agonist	Glucagon receptor/GLP‐1R dual agonist
Trial location	19 countries	12 countries	7 countries	1 country (China)
Year(s) of participant enrolment	2023–2024	2018	2021–2023	2023–2024
Age	55.7 years	55 years	54.2 years	51.8 years
Female	50.7%	50.9%	51%	39.5%
White	65.0%	62.1%	76%	Not reported
Black or African American	5.7%	8.3%	8%	Not reported
Hispanic/Latino	8.8%	12.8%	60%	Not reported
BMI	36.5 kg/m2	35.7 kg/m2	36.1 kg/m2	27.91 kg/m2
Body weight	104.1 kg	99.8 kg	100.7 kg	76.95 kg
Waist circumference	115.5 cm	114.6 cm	114.9 cm	Not reported
HbA1c	7.4%	8.1%	8.02%	8.22%
Hypertension	69.0%	70.1%	66%	Not reported
Obstructive sleep apnoea	17.3%	14.5%	8%	Not reported
ASCVD	10.9%	Not reported	10%	Not reported
MASH	7.7%	Not reported	Not reported	Not reported

Note: Data are presented as mean or %.

Abbreviations: ASCVD, arteriosclerotic cardiovascular disease; BMI, body mass index; GIPR, glucose‐dependent insulinotropic polypeptide receptor; GLP‐1R, glucagon‐like peptide‐1 receptor; HbA1c, haemoglobin A1c; MASH, metabolic dysfunction‐associated steatohepatitis.

^a DREAMS‐2 was not a dedicated obesity trial but, in addition to T2D, participants were required to have a BMI ≥23 kg/m² (cutpoints for overweight and obesity in China are ≥24 and ≥28, respectively).

Although the strengths and limitations of the design of SYNCHRONIZE‐2 have been discussed elsewhere, ¹⁹ some issues are worth reiterating here. This study assesses a diverse population of people with obesity and T2D. It will provide valuable insights into potential changes in hepatic enzymes and patient‐reported outcomes during treatment. As a limitation, this study may not be applicable to individuals with monogenic obesity, uncontrolled hypertension, recent cardiovascular events or suicidality, as people with these conditions were excluded. Also notable from the T2D perspective is the exclusion of participants taking insulin.

In conclusion, SYNCHRONIZE‐2 will study the efficacy, safety and tolerability of the investigational glucagon receptor/GLP‐1 receptor dual agonist survodutide as an OMM in participants with obesity and concomitant T2D not taking insulin. The SYNCHRONIZE‐2 cohort has overall demographic and clinical characteristics suggesting the results of this trial should be generally applicable to the broader population of people with both diseases. Thus, if survodutide demonstrates clinically meaningful improvements in BW, glycaemic markers and cardiometabolic risk factors in SYNCHRONIZE‐2, along with an acceptable tolerability and safety profile, it has the potential to emerge as a new therapeutic option for people with obesity and T2D.

AUTHOR CONTRIBUTIONS

Sean Wharton, Carel W. le Roux, Biykem Bozkurt, Elke Platz, Samina Ajaz Hussain, Martina Brueckmann, Elena Startseva, Isabel M. Kloer and Lee M. Kaplan were involved in the design and planning of the study. Gabriele Bleckert was involved in the statistical analyses. All authors contributed to developing the draft, critically reviewed and edited it and approved the final version of the manuscript. The authors meet criteria for authorship recommended by the International Committee of Medical Journal Editors as supported by Good Publication Practice (GPP) guidelines.

FUNDING INFORMATION

The study is supported and funded by Boehringer Ingelheim.

CONFLICT OF INTEREST STATEMENT

Sean Wharton reports research funding from Novo Nordisk and Bausch Health Canada. He reports honoraria for academic talks and advisory boards from Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Regeneron, Bausch Health Canada, Merck, iNova and Currax. Carel W. le Roux has received personal fees from Boehringer Ingelheim, GI Dynamics, Herbalife, Johnson and Johnson, Keyron, Eli Lilly and Novo Nordisk outside the submitted work. Biykem Bozkurt has received consulting fees from Abbott, Abiomed, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, Daiichi Sankyo, Johnson and Johnson, Lantheus, Liva Nova, Merck, Regeneron, Renovacor, Respicardia/Zoll, Roche, Sanofi‐Aventis and Vifor. Elke Platz's employer has received support from Novartis for consulting work, and she has consulted for scPharmaceuticals. She has received research support from the NIH and AstraZeneca, and she serves on the clinical trial steering committee of the SYNCHRONIZE™‐1 and ‐2 trials and SYNCHRONIZE™‐CVOT funded by Boehringer Ingelheim. Gabriele Bleckert is an employee of Staburo GmbH, which was contracted by Boehringer Ingelheim. Samina Ajaz Hussain, Martina Brueckmann, Elena Startseva and Isabel M. Kloer are employees of Boehringer Ingelheim. Lee M. Kaplan reports serving as a consultant to Altimmune, Amgen, AstraZeneca, Bain Capital, Boehringer Ingelheim, Cytoki, Gelesis, Gilead Sciences, Intellihealth, Johnson and Johnson, Kallyope, Eli Lilly, Metsera, Novo Nordisk, Optum Health, Perspectum, Pfizer, Sidekick Health, Skye Bioscience, Structure Therapeutics and Twenty30 Health.

Supporting information

Data S1. Supporting Information.

Wharton S, le Roux CW, Bozkurt B, et al. Baseline characteristics in the SYNCHRONIZE™‐2 randomized phase 3 trial of survodutide, a glucagon receptor/GLP‐1 receptor dual agonist, for obesity in people with type 2 diabetes. Diabetes Obes Metab. 2026;28(2):1490‐1498. doi: 10.1111/dom.70263

DATA AVAILABILITY STATEMENT

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