Main Research Findings

1) Following 16 weeks of treatment with Survodutide, HbA1c levels were significantly reduced in participants with type 2 diabetes mellitus.

2) Survodutide was well tolerated in both healthy and cirrhotic participants, demonstrated consistent pharmacokinetics across groups, and elicited potential therapeutic benefits on liver fat, fibrosis markers, and body weight.

Selected Data
1) This clinical trial performed by Blüher et al was a multicentre, randomized, double-blind, placebo-controlled study designed to evaluate the safety, efficacy, and pharmacological properties of Survodutide, a dual glucagon and GLP-1 receptor agonist. The study implemented a parallel-group structure with six distinct dose-escalation schemes for Survodutide. Participants were randomized to one of six Survodutide dosing groups ranging from 0.3 mg, 0.9 mg, 1.8 mg, or 2.7 mg once weekly to 1.2 mg or 1.8 mg twice weekly, a placebo group, or semaglutide at doses up to 1.0 mg weekly. The trial was conducted across multiple clinical research centers, including hospitals and healthcare facilities, with oversight from a principal investigator at each site [1].
Eligible participants were adults aged 18 to 75 years who had been diagnosed with type 2 diabetes for at least six months. To qualify, individuals were required to have HbA1c levels between 7.0% and 10.0%, a BMI between 25 and 50 kg/m², and to be receiving a stable daily dose of at least 1000 mg of metformin, either immediate- or extended-release, for a minimum of three months before screening. A detailed list of exclusion criteria was provided in the supplementary materials. Randomization occurred at a 5:1 ratio of Survodutide to placebo within each dosing group, with approximately 50 participants per Survodutide group and 60 on placebo. Fifty participants were also planned for assignment to the semaglutide control arm. The study maintained a double-blind design within the six Survodutide groups, while semaglutide remained open-label [1].
The primary endpoint was the absolute change in HbA1c from baseline to week 16. Secondary efficacy outcomes focused on body weight, including relative and absolute weight change, changes in waist circumference, and the proportion of participants achieving at least 5% or 10% weight loss over the 16-week treatment period. Additional pharmacodynamic endpoints assessed exploratory biomarkers linked to liver function and fatty liver disease, such as plasma cytokeratin-18, Pro-C3, and enhanced liver fibrosis (ELF) scores. Investigators also measured markers of glucose metabolism including adiponectin, fasting insulin, and C-peptide, as well as amino acids and glucagon levels to evaluate target receptor engagement. Safety-related exploratory endpoints included non-invasive fibrosis scores relevant to NASH, such as Fibrosis-4 (Fib-4), aspartate aminotransferase/platelet ratio (APRI), and the NAFLD fibrosis score. Pharmacokinetic assessments examined dose proportionality and attainment of steady-state concentrations of Survodutide.
Following the 16-week treatment phase, participants attended an end-of-treatment visit at week 17, then completed a four-week follow-up period. Throughout the study, HbA1c values were centrally analyzed at baseline, weeks 16 and 17, and at follow-up. Bodyweight was measured consistently at screening, weekly through week 8, and again at weeks 12, 16, 17, and during follow-up. Waist circumference was recorded at screening, weeks 1 and 6, and at end-of-treatment, measured precisely at the midpoint between the lowest rib and iliac crest. Participants also used glucose monitoring devices weekly at home to track glycemic patterns. Patient-reported outcomes were incorporated into the trial design, including the Three-Factor Eating Questionnaire (TFEQ-R18 V2), the Patient Global Impression of Severity (PGI-S), and a hunger visual analogue scale (VAS), all assessed at weeks 1, 5, 8, and 17 in a fasted state. Blood samples for pharmacokinetic evaluation were taken at each study visit, while exploratory biomarkers were collected at weeks 1, 5, 8, and 12, as well as at end-of-treatment and follow-up [1].
2) Researchers Lawitz et al investigated the pharmacokinetics, safety, tolerability, and efficacy of subcutaneous Survodutide in participants with compensated or decompensated cirrhosis compared with those without cirrhosis. The trial began with a single-dose pharmacokinetic evaluation, followed by a 28-week open-label treatment phase.
In the pharmacokinetic component, participants received a single 0.3 mg subcutaneous injection of Survodutide. Cohorts were divided into healthy individuals without cirrhosis and participants with cirrhosis classified according to Child-Pugh class A, B, or C. Healthy participants were matched to cirrhosis cohorts based on age, sex, and weight to ensure demographic comparability. Eligible participants were at least 18 years old, had a BMI between 18.5 and 40.0 kg/m², and either no cirrhosis or cirrhosis confirmed by vibration-controlled transient elastography (VCTE) with liver stiffness greater than 15 kPa. Exclusion criteria varied by cohort but included hepatocellular carcinoma or recent malignancy, viral hepatitis or chronic liver disease in healthy controls, severe hepatic complications such as hepatorenal syndrome or recent gastrointestinal bleeding in cirrhosis cohorts, and biochemical evidence of acute hepatic dysfunction [2].
For the open-label treatment portion, eligible participants were required to be categorized as overweight or obese by a BMI ≥27 kg/m² and body weight >70 kg for females or >80 kg for males. They were stratified into cohorts without cirrhosis, with Child-Pugh A cirrhosis, or with Child-Pugh B cirrhosis. Exclusion criteria mirrored those of the pharmacokinetic trial. Participants received once-weekly subcutaneous Survodutide, beginning at 0.3 mg and gradually up-titrated to a maximum of 6.0 mg over 24 weeks, depending on tolerability, followed by 4 weeks at the maximum tolerated dose. Dose reductions were permitted if adverse effects occurred. Monitoring was performed weekly, with some visits conducted remotely and others on-site [2].
During the pharmacokinetic phase, participants were closely observed after dosing, staying at the site for three days before returning for daily visits on days 4 through 16. Blood samples were collected regularly for pharmacokinetic analysis, and adverse events were monitored throughout. Once sufficient pharmacokinetic comparisons between cirrhotic and non-cirrhotic participants had been completed, the open-label therapy phase was initiated.
The trial’s primary pharmacokinetic endpoints were the area under the plasma concentration-time curve and the maximum plasma concentration (Cmax) of Survodutide. For the open-label treatment portion, the primary endpoint was the occurrence of drug-related adverse events. Secondary and exploratory endpoints included changes from baseline to week 28 in liver fat content assessed by MRI-proton density fat fraction (MRI-PDFF) and FibroScan controlled attenuation parameter, liver stiffness measured by magnetic resonance elastography and FibroScan VCTE, liver volume determined by MRI, body weight, waist circumference, and blood-based biomarkers of fibrosis such as N-terminal type III collagen propeptide (Pro-C3) and the Enhanced Liver Fibrosis (ELF) score [2].
Screening assessments within two weeks of the first dose included laboratory tests of liver function, vital signs, weight, and imaging measures of liver fat, stiffness, and volume. These assessments were repeated at week 28 to evaluate treatment effects. Safety monitoring encompassed both clinical assessments and laboratory parameters throughout the study.
The sample size was not based on formal power calculations, as this was an exploratory early-phase study. For the single-dose pharmacokinetic portion, the planned enrollment was approximately 40 participants: 16 healthy controls and 8 in each cirrhosis cohort (Child-Pugh A, B, and C). This design was considered adequate to detect pharmacokinetic differences across groups and aligned with regulatory guidelines, which state that at least six individuals per cohort are sufficient for hepatic impairment trials. For the open-label treatment portion, the planned enrollment was also approximately 40 participants, with 16 each in the non-cirrhotic and Child-Pugh A cohorts, and 8 in the Child-Pugh B cohort. These numbers were chosen to provide about an 81.5% chance of identifying a common adverse event if the true incidence was at least 10% [2].
Pharmacokinetic analyses were performed by calculating the ratio of geometric means between cirrhosis cohorts and healthy controls, with two-sided 90% confidence intervals estimated using analysis of variance on log-transformed data. Descriptive statistics were also used to summarize outcomes in both study phases. Analyses of safety, efficacy, and pharmacokinetics were conducted on predefined data sets: the treated set, which included all participants who received at least one dose of Survodutide, and the pharmacokinetic analysis set, which included all treated participants with data for at least one pharmacokinetic endpoint.
In summary, this trial was designed to explore how hepatic impairment affects the pharmacokinetics of Survodutide, while also assessing the drug’s safety, tolerability, and preliminary efficacy in individuals with and without cirrhosis and with overweight or obesity. The study employed a stepwise approach beginning with pharmacokinetic evaluation before moving into a longer open-label treatment phase, with comprehensive safety and efficacy assessments [2].

Discussion
1) Participants included in the research study conducted by Blüher et al were allocated across six Survodutide dose groups, a semaglutide control arm, and placebo. Group sizes ranged from 49 to 52 participants in each Survodutide cohort, with 50 participants assigned to semaglutide and 59 to placebo. Baseline demographics were broadly similar across treatment groups, with participants averaging 57.3 years of age, a BMI of 33.9 kg/m², and HbA1c of 8.1% [1].
The primary endpoint of the study was the absolute change in HbA1c after 16 weeks of treatment. All Survodutide groups demonstrated significant reductions in HbA1c compared with placebo, though the lowest dose group receiving 0.3 mg weekly, showed a notably weaker effect. Analysis of dose–response modeling indicated that treatment efficacy plateaued at around 1.8 mg weekly, with no additional benefit at higher doses. After 16 weeks, mean HbA1c reductions from baseline ranged from –0.91% to –1.7% across the various treatment groups. By comparison, semaglutide reduced HbA1c by –1.47%, nearly identical to the reduction achieved with low-dose Survodutide at a dose of 0.9 mg weekly. Across all timepoints, HbA1c reductions in Survodutide groups were significantly greater than placebo for all but one early low-dose comparison. Descriptive statistics confirmed these findings, showing maximal mean HbA1c decreases of up to 1.88% with Survodutide in certain groups, reinforcing its efficacy across doses [1].
Secondary endpoints focused on weight loss outcomes, which showed clear dose-dependent effects. Participants receiving survodutide experienced progressively greater reductions in bodyweight with increasing doses, in contrast to the plateau seen for HbA1c. At the highest dose of 1.8 mg twice weekly, participants achieved an adjusted mean relative bodyweight reduction of –8.7%, compared with –5.3% in the semaglutide group and minimal loss with placebo. In absolute terms, this corresponded to weight reductions of up to –8.4 kg, compared with –5.2 kg in the semaglutide group. Statistical models confirmed a significant non-flat dose–response relationship for bodyweight, with no plateau evident, suggesting greater efficacy could be expected with dose escalation.
The proportion of participants achieving clinically meaningful weight loss further highlighted survodutide’s efficacy. In the highest dose group, 57.1% achieved at least 5% weight loss, and 34.7% achieved at least 10% weight loss after 16 weeks. By comparison, only 6.8% and 0% of placebo-treated participants, respectively, reached these thresholds. In the semaglutide group, 38% achieved ≥5% weight loss, and 16% achieved ≥10% weight loss. Odds ratios confirmed that survodutide treatment groups receiving 0.9 mg, 1.8 mg, or 2.7 mg once weekly and 1.2 mg or 1.8 mg twice weekly, significantly increased the likelihood of ≥5% weight reduction, and treatment groups receiving 1.8 mg, or 2.7 mg once weekly and 1.2 mg or 1.8 mg twice weekly significantly increased the likelihood of ≥10% reduction compared with placebo. Waist circumference decreased across all active treatment groups, though results were variable. The greatest mean reduction was —10.5 cm and occurred in the group administered 1.8 mg twice weekly, with statistically significant placebo-adjusted reductions observed with 2.7 mg once weekly and 1.8 mg twice weekly [1].
Exploratory efficacy endpoints included effects on blood glucose profiles, patient-reported outcomes, and biomarkers of liver health. Survodutide and semaglutide both reduced seven-point self-monitored blood glucose levels more effectively than placebo, with the most pronounced decreases observed post-meal. In groups administered 1.8 mg once weekly, mean blood glucose dropped by –3.03 mmol/L from baseline. Patient-reported outcomes, including measures of eating behavior, hunger, and global disease impression, showed only minor treatment effects.
Pharmacodynamic analyses examined biomarkers associated with NASH and liver fibrosis. Survodutide did not demonstrate clear dose-dependent effects on noninvasive fibrosis scores such as Fib-4, APRI, or NAFLD fibrosis score. However, reductions in Pro-C3, a biomarker of fibrogenesis, were observed in all survodutide groups, with the greatest decrease of –7.3 μg/L in DG5, compared with minimal change in placebo. Similarly, ELF scores decreased modestly in mid- and high-dose survodutide groups, while placebo showed increases, suggesting potential favorable effects on liver health.
Pharmacokinetic analyses confirmed dose-proportional increases in plasma exposure to Survodutide. Trough concentrations rose with increasing weekly or twice-weekly doses, with steady-state levels generally achieved by week 8 in most dose groups, and by week 12 in the highest dose group. Biomarker data also supported target receptor engagement. Plasma glucagon levels decreased in a dose-dependent manner across survodutide groups, particularly in groups administered 1.2 mg and 1.8 mg twice weekly, while no meaningful changes occurred in placebo or semaglutide groups. Additionally, reductions in plasma alanine levels were observed with administration of 1.8 mg twice weekly, further supporting glucagon receptor activity. These biomarker trends provided evidence of Survodutide’s dual receptor engagement and its mechanistic effects on metabolism [1].
In summary, this trial demonstrated that Survodutide significantly reduced HbA1c and bodyweight in adults with type 2 diabetes compared with placebo, with HbA1c effects plateauing at 1.8 mg weekly but weight loss continuing in a dose-dependent manner without plateau. Survodutide achieved comparable glycemic efficacy to semaglutide at low doses, while higher doses surpassed semaglutide in weight loss. Exploratory findings suggested possible benefits for liver health, supported by reductions in Pro-C3 and ELF scores, alongside clear pharmacokinetic and pharmacodynamic evidence of target engagement [1].
2) 41 participants took part in the single-dose pharmacokinetic study and open-label treatment arm conducted by researchers Lawitz et al. In the pharmacokinetic group, cohort allocation included 16 healthy participants matched to the cirrhosis cohorts, 8 with Child-Pugh A cirrhosis, 8 with Child-Pugh B cirrhosis, and 9 with Child-Pugh C cirrhosis. Among participants with Child-Pugh A and B cirrhosis in the treatment arm, metabolic dysfunction-associated steatohepatitis (MASH) was the underlying cause in 87.5% of cases. As expected, participants with cirrhosis exhibited lower baseline liver fat content but higher liver stiffness and fibrosis biomarkers compared with those without cirrhosis [2].
Pharmacokinetic analysis showed that Survodutide exposure, measured by the area under the concentration–time curve and maximum plasma concentration (Cmax), was similar across healthy participants and those with Child-Pugh A, B, or C cirrhosis. The 90% confidence intervals for geometric mean ratios all spanned unity, indicating no meaningful differences between groups. Other pharmacokinetic parameters were likewise comparable. Drug-related adverse events occurred in 25% of healthy participants and in 0%, 25%, and 0% of Child-Pugh A, B, and C participants, respectively. No adverse events were serious, fatal, or led to discontinuation, and no participants experienced hepatic injury [2] .
In the open-label treatment phase, Survodutide was escalated from 0.3 mg to a maximum of 6.0 mg weekly over 24 weeks, followed by 4 weeks of maintenance. Dose reductions due to tolerability occurred in three of eight participants without cirrhosis, two of eleven with Child-Pugh A, and none of six with Child-Pugh B cirrhosis. Drug-related adverse events were common, occurring in 82.4% of those without cirrhosis, 87.5% with Child-Pugh A, and 87.5% with Child-Pugh B cirrhosis. Gastrointestinal disorders, particularly nausea and vomiting, were the most frequent events and accounted for most discontinuations. Adverse events leading to discontinuation occurred in 47.1% of participants without cirrhosis, 18.8% with Child-Pugh A, and 25.0% with Child-Pugh B. Serious adverse events were reported in none of the participants without cirrhosis, but in 31.3% and 37.5% of those with Child-Pugh A and B, respectively. None were fatal or considered drug-related, except for one case of minimal hepatic encephalopathy, which did not necessitate discontinuation. Importantly, no cases of acute kidney injury were observed in participants experiencing vomiting or diarrhea [2].
Cardiac safety was closely monitored. Mean heart rate increased slightly by +4.1, +8.5, and +7.6 beats per minute in participants without cirrhosis, and with Child-Pugh A and B, respectively. No participant experienced a QTcF interval exceeding 500 ms or an increase greater than 60 ms from baseline, and no safety concerns for arrhythmia risk were identified.
Efficacy endpoints demonstrated consistent metabolic and hepatic benefits. At 28 weeks, reductions were observed in liver fat content by –43.29% in participants without cirrhosis and –51.59% in participants with Child-Pugh A cirrhosis. However, participants with Child-Pugh B experienced a –0.48% reduction in liver fat content. All cohorts exhibited reductions in liver stiffness by magnetic resonance elastography, ELF scores, and plasma Pro-C3 levels, indicating improvements in fibrosis markers. Additional improvements were seen in FibroScan liver fat and stiffness measures, liver volume reductions by MRI, and meaningful weight loss across groups by –14.80% in those without cirrhosis, –10.40% in Child-Pugh A, and –8.69% in Child-Pugh B. Liver enzymes generally decreased across cohorts, while changes in bilirubin and INR were minor and inconsistent [2].

Figure 1: Changes in liver fat content, liver stiffness, ELF scores, and Pro-C3 levels in participants without cirrhosis and participants with either Child-Pugh A or Child-Pugh B cirrhosis.

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

Citations

[1] Blüher M, Rosenstock J, Hoefler J, Manuel R, Hennige AM. Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial. Diabetologia. 2024;67(3):470-482. doi:10.1007/s00125-023-06053-9.

[2] Lawitz EJ, Fraessdorf M, Neff GW, et al. Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis. J Hepatol. 2024;81(5):837-846. doi:10.1016/j.jhep.2024.06.003

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