Survodutide (also called BI 456906) is being developed by Boehringer Ingelheim as a treatment for obesity, type 2 diabetes, and a serious form of fatty liver disease called MASH (metabolic dysfunction-associated steatohepatitis). It has moved through phase 1 safety studies, several phase 2 trials, and is now in phase 3 - the last stage before a drug can be approved. It is not an approved medicine anywhere yet; every result here comes from supervised clinical trials, not from real-world prescribing. It sits in the same family as semaglutide and tirzepatide, but adds an extra hormone target (glucagon) on top of the GLP-1 effect that those drugs use.
How strong is the evidence?
This is strong, human-based evidence. Of the 40 papers on file, more than a dozen are randomized, placebo-controlled human trials - phase 1 through phase 3 - covering well over 2,000 participants across obesity, type 2 diabetes, fatty liver disease, and cirrhosis. Two phase 3 trials with full results are already published: one in obesity (SYNCHRONIZE-1) and one in obesity with fatty liver disease (SYNCHRONIZE-MASLD). Other phase 3 trials are still underway - the diabetes trial (SYNCHRONIZE-2) has so far only reported who enrolled, not results, and a large cardiovascular outcomes trial is still recruiting. The rest of the file is mostly reviews and meta-analyses that pool this trial data, plus a handful of mouse and lab studies that explain how the drug works at a molecular level. The evidence is clinical-trial strength, but survodutide itself is still investigational - not yet an approved medicine.
Uses
What people use it for
Weight loss in adults with obesity
Human trialsThe most heavily studied use. A large phase 2 trial and a completed phase 3 trial (SYNCHRONIZE-1) both show substantial, dose-dependent weight loss over close to a year of treatment.
Blood sugar control in type 2 diabetes
Human trialsA phase 2 trial in people with type 2 diabetes on metformin showed meaningful drops in HbA1c (the 2-3 month blood sugar average) alongside weight loss, and a phase 3 trial (SYNCHRONIZE-2) in this population is underway.
Fatty liver disease (MASH and MASLD)
Human trialsA phase 2 trial in biopsy-confirmed MASH and a completed phase 3 trial (SYNCHRONIZE-MASLD) both show survodutide reducing liver fat and improving the disease on liver scans and biopsies, not just body weight.
Use in people with cirrhosis
Some human dataA phase 1 trial specifically tested survodutide in people with liver cirrhosis (including more advanced, decompensated cirrhosis) and found it was generally tolerated and didn't need special dose adjustments, though this is early safety data, not proof of benefit in cirrhosis itself.
Potential benefits
What it may help with
Substantial, dose-dependent weight loss in obesity
Human trialsIn a 46-week phase 2 trial, average weight loss ranged from -6.2% at the lowest dose to -14.9% at the highest dose (4.8 mg/week), versus -2.8% on placebo. The phase 3 SYNCHRONIZE-1 trial confirmed this at scale: over 76 weeks, average weight loss was -12.2% (3.6 mg) and -13.0% (6.0 mg) versus -5.4% on placebo, with about 72% of treated participants losing at least 5% of their body weight versus 46% on placebo.
Outperformed semaglutide on weight loss in a head-to-head trial
Human trialsIn a phase 2 trial in people with type 2 diabetes, survodutide at doses of 1.8 mg/week or higher produced greater weight loss (up to -8.7%) than open-label semaglutide (-5.3%) over 16 weeks, while lowering HbA1c by a similar amount to semaglutide at matched low doses.
Studies:38095657Meaningful blood sugar improvement in type 2 diabetes
Human trialsThe same 16-week trial showed HbA1c drops of roughly 1.5 to 1.7 percentage points at most doses, and a pooled analysis across multiple trials found an average HbA1c reduction of about 0.66 percentage points versus placebo, with bigger effects at higher weekly doses.
Reduces liver fat and improves MASH (fatty liver disease with inflammation)
Human trialsIn a 48-week phase 2 trial in people with biopsy-confirmed MASH, 43-62% of survodutide-treated participants (depending on the dose) had their MASH improve without their fibrosis (liver scarring) getting worse, versus 14% on placebo, and 57-67% had at least a 30% drop in liver fat versus 14% on placebo. The phase 3 SYNCHRONIZE-MASLD trial confirmed this on liver MRI scans: 84% of treated participants had at least a 30% reduction in liver fat versus 24% on placebo, alongside meaningful weight loss.
Ranked among the most effective drugs for reversing MASH in a network comparison
Human trialsA meta-analysis comparing many MASH drugs against each other ranked survodutide as one of the top two most effective treatments (alongside pegozafermin) for achieving MASH resolution without worsening fibrosis, ahead of semaglutide and close to tirzepatide.
Studies:39903735Generally tolerated in people with liver cirrhosis, with liver improvements seen
Some human dataIn a phase 1 trial specifically in people with cirrhosis (including more severe, decompensated cases), 28 weeks of survodutide was generally tolerable and did not require special dose adjustment, and was associated with reductions in liver fat, liver stiffness (a marker of scarring), liver volume, and body weight.
Studies:38857788
What to watch for
Side effects & risks
- Moderate
Nausea, vomiting, and diarrhea
By far the most common side effects, and they climb with the dose. In the phase 2 MASH trial, nausea hit 66% (vs 23% placebo), diarrhea 49% (vs 23%), and vomiting 41% (vs 4%). In the phase 3 obesity trial, gastrointestinal symptoms occurred in 81-90% of treated participants versus 48% on placebo, though most were described as mild to moderate.
- Mild
- Moderate
Higher rate of stopping treatment because of side effects
A meta-analysis of survodutide trials found that people on the drug were significantly more likely to stop treatment because of side effects than those on placebo, and that this got worse at higher doses - mostly driven by gastrointestinal symptoms. The same analysis found side effects overall were about 3 to 5 times more common on the drug than on placebo, though it did not put a specific number on the discontinuation rate itself.
- Serious
Cardiac or vascular side effects leading some people to stop treatment in early trials
In a phase 1 multiple-dose trial, 7.5% of participants in one part of the study discontinued survodutide because of a cardiac or vascular adverse event - the most common reason for stopping in that group. A review of the drug also notes modest increases in heart rate as a known effect.
- Mild
Serious adverse events overall similar to placebo
In the phase 2 MASH trial, serious adverse events occurred in 8% of people on survodutide versus 7% on placebo - a reassuring sign that, aside from the gastrointestinal symptoms, the drug hasn't shown a clear excess of serious harm in trials so far. No deaths were reported in the phase 3 obesity trial.
Dosing
Dosing — what studies used
There's no approved dose because survodutide isn't an approved medicine yet - it's still in phase 3 testing. Everything below is what researchers used in clinical trials, not a prescription. Every trial used once-weekly injections under the skin, and doses were always ramped up slowly over months (not started at full strength) specifically to reduce nausea and vomiting. Doses tested have ranged from as low as 0.3 mg to as high as 6.0 mg per week, with 3.6 mg and 6.0 mg being the two doses carried forward into the phase 3 trials for obesity.
Weight loss, phase 2 dose-finding trial in obesity
Human trial0.6, 2.4, 3.6, or 4.8 mg
Once weekly · 46 weeks (20-week dose escalation, then 26-week maintenance) · Subcutaneous injection
Weight loss increased with dose, topping out at -14.9% average loss on the 4.8 mg dose versus -2.8% on placebo.
Weight loss, phase 3 pivotal trial (SYNCHRONIZE-1)
Human trial3.6 mg or 6.0 mg
Once weekly · 76 weeks · Subcutaneous injection
These are the two doses carried into phase 3 testing after the phase 2 dose-finding trial. Average weight loss was 12.2% and 13.0% respectively versus 5.4% on placebo.
Type 2 diabetes, blood sugar and weight control
Human trialUp to 2.7 mg once weekly, or 1.2-1.8 mg twice weekly
Once or twice weekly (studied both ways) · 16 weeks · Subcutaneous injection
Compared against open-label semaglutide; survodutide matched or beat it on blood sugar and weight, with more gastrointestinal side effects.
MASH (fatty liver disease with inflammation), phase 2 trial
Human trial2.4, 4.8, or 6.0 mg
Once weekly · 48 weeks (24-week escalation, then 24-week maintenance) · Subcutaneous injection
All three doses beat placebo on liver improvement; the middle 4.8 mg dose had the best results in this trial.
Fatty liver disease, phase 3 trial (SYNCHRONIZE-MASLD)
Human trial6.0 mg
Once weekly · 48 weeks · Subcutaneous injection
The single highest dose tested was used here and produced large reductions in liver fat alongside weight loss.
Cirrhosis, safety and pharmacokinetics
Human trialSingle 0.3 mg dose, then escalated from 0.3 mg up to 6.0 mg
Once weekly (after the initial single dose) · 24-week escalation plus 4-week maintenance (28 weeks total) · Subcutaneous injection
Designed to check the drug behaves the same way in people with cirrhosis as in healthy people, and confirmed it does not need dose adjustment for liver disease.
Every trial ramps the dose up gradually over many weeks - nobody starts at the target dose - specifically because doing so up front causes much worse nausea and vomiting. Slower dose escalation was shown in one trial to help with tolerability.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
After you eat, your gut and pancreas release hormones that manage hunger and blood sugar. One of them, GLP-1, slows down digestion, makes you feel full, and helps insulin work better. Another, glucagon, is usually thought of as insulin's opposite - it can raise blood sugar - but it also revs up how many calories your body burns. Survodutide is a lab-made molecule that turns on both of these hormone signals at once with a single weekly shot. In animal studies, this combination produced greater weight loss than turning on the GLP-1 signal alone, because the drug both reduces how much people eat and increases how much energy their body burns at rest. In the liver, engaging the glucagon signal appears to directly help burn off stored fat, which is likely why survodutide performs strongly in fatty liver disease trials, not just weight-loss trials.
Who should avoid it
- Anyone who is pregnant, trying to become pregnant, or breastfeeding, since it hasn't been tested for safety in these groups
- Children and teenagers, since all trials on file enrolled only adults
- People with type 1 diabetes, since trials only studied type 2 diabetes and obesity/overweight without diabetes
- Anyone outside a clinical trial or licensed prescription, since this is still an investigational drug with no approved use anywhere as of this literature
Interactions to know
- Insulin or other blood-sugar-lowering medicines may need dose adjustments, since survodutide already lowers blood sugar and stacking it with other diabetes drugs raises the risk of blood sugar going too low
- Because it slows down stomach emptying (shown directly in trials via slower absorption of a test drug, paracetamol), it can change how fast other oral medicines are absorbed, which matters most for pills with a narrow safe-dose window
- Trials to date have mostly studied it alongside metformin in people with diabetes; combining it with other GLP-1 or weight-loss injections hasn't been studied and isn't how it's used in any trial on file
The papers that matter most
Key studies
The dose-finding trial that established survodutide's weight-loss effect in obesity: up to -14.9% average weight loss over 46 weeks at the highest dose, clearly dose-dependent.
Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial
The pivotal 725-person phase 3 trial: over 76 weeks, survodutide produced 12-13% average weight loss versus 5.4% on placebo, with about 72% of treated participants losing at least 5% of body weight.
Survodutide Once Weekly for the Treatment of Adults with Obesity
In 293 people with biopsy-confirmed fatty liver disease, survodutide improved the disease in up to 62% of participants versus 14% on placebo, with gastrointestinal side effects being the main drawback.
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
Confirmed the liver benefit at phase 3 scale: 84% of treated participants had at least a 30% drop in liver fat on MRI versus 24% on placebo, over 48 weeks.
Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD
Head-to-head against semaglutide in type 2 diabetes: survodutide matched it on blood sugar control at low doses and beat it on weight loss at higher doses, with more GI side effects.
Dose-response effects on HbA1c and bodyweight reduction of survodutide...compared with placebo and open-label semaglutide
Showed survodutide behaves the same way in people with cirrhosis as in healthy people and is generally tolerated, with liver fat and stiffness improving over 28 weeks.
Efficacy, tolerability and pharmacokinetics of survodutide...in cirrhosis
Bottom line
Survodutide has real, strong clinical trial evidence behind it - multiple phase 2 and completed phase 3 trials show 12-15% average weight loss, meaningful blood sugar improvement, and some of the best fatty-liver-disease results of any drug in its class. The tradeoffs are dose-dependent nausea, vomiting, and diarrhea that drive a meaningful share of people to stop treatment, and the fact that it isn't an approved medicine anywhere yet - so it isn't available through a normal prescription, and anyone hearing about it should treat it as still experimental, not as something to seek out on the gray market.
Research papers
Studies we have on file for Survodutide. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.
Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear. In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage. A total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo. Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).
Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.
The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1-based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders.
Emerging pharmacotherapies for obesity: A systematic review.
The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.
Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial.
Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management. In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI ≥27 kg/m2, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37). Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (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 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6·2% (-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; 4·8 mg); -2·8% (-4·9 to -0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients. All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight. Boehringer Ingelheim.
Weight management treatment in obesity.
Obesity is a chronic and relapsing disease associated with medical complications and mortality. Our improved understanding of the relevance of the gut-brain axis in regulating appetite and body weight has encouraged research into nutrient-stimulated gastroenteropancreatic hormones as a new therapeutic arsenal for the treatment of people living with obesity. Beyond the necessary lifestyle changes, this new era with second-generation drugs has been able to achieve weight loss of 15-25%, close to that of bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists (RA), used as weekly injectable monotherapy or daily oral (semaglutide), achieve weight loss of 15-17%, with a good safety profile. The synergistic combination with other hormones (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, or amylin) will allow to increase weight loss, as well as improve cardiometabolic variables. Tirzepatide (a dual GLP-1/GIP receptor agonist) achieves weight loss of up to 22.5% at the highest doses. In this same range of weight loss, it is expected that it can be achieved with the combination of Cagrisema (cagrilintide 2.4mg plus semaglutide 2.4mg), combinations of GLP-1 RAs - glucagon agonists or with the triple combination of GLP-1 RAs-GIP-Glucagon (Retatrutide). In this review, we will examine the efficacy and safety of the drugs marketed and others under ongoing clinical trials for the treatment of persons with obesity, as well as the main challenges faced by both healthcare professionals and patients in maintaining long-term treatment.
BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy.
Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.
The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation.
Similar to bariatric surgery, incretin receptor agonists have revolutionized the treatment of obesity, achieving up to 15-25 % weight loss in many patients, i.e., at a rate approaching that achieved with bariatric surgery. However, over 25 % of total weight lost from both surgery and pharmacotherapy typically comes from fat-free mass, including skeletal muscle mass, which is often overlooked and can impair metabolic health and increase the risk of subsequent sarcopenic obesity. Loss of muscle and bone as well as anemia can compromise physical function, metabolic rate, and overall health, especially in older adults. The myostatin-activin-follistatin-inhibin system, originally implicated in reproductive function and subsequently muscle regulation, appears to be crucial for muscle and bone maintenance during weight loss. Activins and myostatin promote muscle degradation, while follistatins inhibit their activity in states of negative energy balance, thereby preserving lean mass. Novel compounds in the pipeline, such as Bimagrumab, Trevogrumab, and Garetosmab-which inhibit activin and myostatin signaling-have demonstrated promise in preventing muscle loss while promoting fat loss. Either alone or combined with incretin receptor agonists, these medications may enhance fat loss while preserving or even increasing muscle and bone mass, offering a potential solution for improving body composition and metabolic health during significant weight loss. Since this dual therapeutic approach could help address the challenges of muscle and bone loss during weight loss, well-designed studies are needed to optimize these strategies and assess long-term benefits. For the time being, considerations like advanced age and prefrailty may affect the choice of suitable candidates in clinical practice for current and emerging anti-obesity medications due to the associated risk of sarcopenia.
Therapeutic horizons in metabolic dysfunction-associated steatohepatitis.
Metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, is now a leading cause of chronic liver disease worldwide. Driven by obesity and type 2 diabetes, MASH significantly increases the risk of cirrhosis, hepatocellular carcinoma, and liver failure. While public health interventions remain essential, therapeutic strategies targeting metabolic dysfunction, inflammation, and fibrosis are urgently needed. This Review focuses on pharmacological treatments in advanced development, including incretin-based therapies (GLP-1, dual, and triple agonists), metabolic modulators (PPAR, FGF21, and THR-β agonists), and novel agents such as fatty acid synthase inhibitors. Current regulatory approval is based on histological end points, with increasing interest in noninvasive biomarkers and personalized treatment approaches. Recent trials with agents such as semaglutide, tirzepatide, survodutide, lanifibranor, pegozafermin, and resmetirom demonstrate substantial promise in resolving MASH and improving fibrosis, but unresolved issues remain regarding treatment duration, response heterogeneity, and long-term adherence. Genetic variants (e.g., PNPLA3 polymorphisms) and emerging molecular biomarkers may enhance stratification, while artificial intelligence is beginning to shape trial design and drug development. As the field moves toward combination therapies and precision medicine, the definition of therapeutic success will likely evolve to reflect both histological improvement and patient-reported outcomes. This Review provides a timely synthesis of the landscape, challenges, and future directions in MASH therapeutics.
Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial.
Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index ≥27 kg/m2 and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864).
GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis.
The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated at 32.4%, reflecting its growing clinical significance. MASLD, which includes MASLD and metabolic dysfunction-associated steatohepatitis (MASH) has been linked to increased metabolic, cardiovascular, and malignant morbidity. Progression into fibrotic stages of MASLD is also strongly associated with liver-related mortality. The past few years have seen a heightened focus on creating innovative therapeutic strategies for MASH management. GLP-1 receptor agonists (RA) have also emerged as a potential treatment option. Studies on GLP-1 agonists, such as liraglutide and semaglutide, have demonstrated efficacy in MASH management, albeit with limited histological improvement of fibrosis. However, recent investigations into GLP-1/GIP RA (tirzepatide) and Glucagon/GLP-1 RA (survodutide) have shown even more encouraging results, with higher rates of MASH resolution and fibrosis improvement. The tolerability of these medications due to their gastrointestinal side effects remains a major concern. Future research should focus on optimizing drug regimens, identifying patients most likely to benefit, and balancing efficacy with tolerability. The evolving landscape of MASH therapeutics suggests a bright future, with the potential for combination therapies to further enhance patient outcomes.
Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.
The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.
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.
The aim of this study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction. This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. Survodutide reduced HbA1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis.
Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. With the advent of multiple therapeutic targets in late-phase clinical drug development for MASH, there is a knowledge gap to better understand the comparative efficacy of various pharmacological agents. We conducted an updated network meta-analysis to evaluate the relative rank order of the different pharmacological agents for both fibrosis regression and MASH resolution. We searched PubMed and Embase databases from January 1, 2020 to December 1, 2024, for published randomized controlled trials comparing pharmacological interventions in patients with biopsy-proven MASH. The co-primary endpoints were fibrosis improvement ≥1 stage without MASH worsening and MASH resolution without worsening fibrosis. We conducted surface under the cumulative ranking curve (SUCRA) analysis. A total of 29 randomized controlled trials (n=9324) were included. Pegozafermin, cilofexor + firsocostat, denifanstat, survodutide, obeticholic acid, tirzepatide, resmetirom, and semaglutide were significantly better than placebo in achieving fibrosis regression without worsening MASH. Pegozafermin (SUCRA: 79.92), cilofexor + firsocostat (SUCRA: 71.38), and cilofexor + selonsertib (SUCRA: 69.11) were ranked the most effective interventions. Pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E + pioglitazone, resmetirom, semaglutide, pioglitazone, denifanstat, semaglutide, and lanifibranor were significantly better than placebo in achieving MASH resolution without worsening fibrosis. Pegozafermin (SUCRA: 91.75), survodutide (SUCRA: 90.87), and tirzepatide (SUCRA: 84.70) were ranked the most effective interventions for achieving MASH resolution without worsening fibrosis. This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design.
Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.
Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. NCT05296733.
Survodutide for treatment of obesity: Baseline characteristics of participants in a randomized, double-blind, placebo-controlled, phase 3 trial (SYNCHRONIZE™-1).
Survodutide, a novel glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor dual agonist, elicited significant weight loss in a phase 2 trial in individuals with obesity without type 2 diabetes (T2D). Two multinational phase 3 trials are investigating survodutide for obesity management in individuals with or without T2D. We report the baseline characteristics of participants in the SYNCHRONIZE-1 trial in adults with obesity without T2D (ClinicalTrials.gov: NCT06066515). Participants aged ≥18 years with BMI ≥30 or ≥27 kg/m2 with ≥1 obesity complication without T2D were randomized 1:1:1 to double-blind, once-weekly, subcutaneous injections of survodutide (up-titrated to 3.6 or 6.0 mg) or placebo for 76 weeks. The primary endpoints are percent body weight change and achievement of body weight reduction ≥5% from baseline to Week 76. Efficacy and safety analyses will include all randomized and treated participants. At baseline, participants (n = 725 from 14 countries) had a mean age of 47.1 years, BMI 37.9 kg/m2, and waist circumference 115.2 cm. Most participants (59.4%) were female; 47.3% were from North America, 21.0% from Europe, and 20.0% from East Asia. Obesity complications included hypertension (40.0%), dyslipidaemia (33.7%), and prediabetes (30.2%). Mean haemoglobin A1c was 5.5%, estimated glomerular filtration rate 93.0 mL/min/1.73 m2, systolic/diastolic blood pressure 127.0/82.7 mmHg, and low-density lipoprotein cholesterol 116.4 mg/dL; 21.8% were taking lipid-lowering drugs. SYNCHRONIZE-1 will determine the efficacy, safety, and tolerability of survodutide, a glucagon receptor/GLP-1 receptor dual agonist, for weight loss in a representative cohort of people with obesity without T2D.
Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE™-1 and -2).
The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2). In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.6 or 6.0 mg, and dose flexibility is permitted. Participants (n = 726) in SYNCHRONIZE-1 (NCT06066515) have a baseline BMI ≥ 30 kg/m2 or ≥27 kg/m2 with at least one obesity-related complication but without T2D; participants (n = 755) in SYNCHRONIZE-2 (NCT06066528) have a baseline BMI ≥ 27 kg/m2 and T2D. The primary endpoints are percentage change in body weight and proportion of participants achieving ≥5% body weight reduction from baseline to week 76. Secondary endpoints include change in systolic blood pressure and measures of glycemia. A SYNCHRONIZE-1 substudy is evaluating changes in body composition and liver fat content using magnetic resonance imaging. These trials are designed to provide robust evaluation of the efficacy, safety, and tolerability of survodutide for the treatment of obesity in the presence or absence of T2D.
Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities.
Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).
The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection.
To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP-1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in-depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15- to 17-fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight-lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%-0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.
Beyond weight loss: multisystem benefits of obesity medications.
Obesity is increasingly managed with medications as disease-modifying therapies, reflecting its role as a gateway disease driving metabolic, cardiovascular, reproductive, neuropsychiatric, and mechanical conditions. This Review synthesises evidence from randomised controlled trials and high-quality meta-analyses on approved and late-stage investigational obesity medications, including phentermine-topiramate, naltrexone-bupropion, glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide, semaglutide, subcutaneously and orally), and newer GLP-1 receptor agonist-based agents (eg, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). We evaluated the effects of obesity medications across major obesity-related conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea syndrome, polycystic ovary syndrome (recently named polyendocrine metabolic ovarian syndrome), osteoarthritis, muscle mass, depression, quality of life, and food cravings, along with binge-eating disorders, substance use disorders, and neurodegenerative diseases. Overall, GLP-1-based and multiagonist therapies show beneficial effects across these comorbid conditions. While many benefits of obesity medications are mediated by weight loss, accumulating evidence indicates important weight loss-independent effects, particularly with GLP-1 receptor agonist-based therapies. A broader understanding of these pleiotropic effects is essential to inform personalised obesity management and optimise long-term clinical outcomes.
Review Article: GLP-1 Receptor Agonists and Glucagon/GIP/GLP-1 Receptor Dual or Triple Agonists-Mechanism of Action and Emerging Therapeutic Landscape in MASLD.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies. This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis. GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.
Survodutide Once Weekly for the Treatment of Adults with Obesity.
Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide, an investigational glucagon receptor-GLP-1 receptor dual agonist, led to substantial weight reduction in a phase 2 trial involving adults with obesity without diabetes. In this phase 3, double-blind trial, we randomly assigned adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), in a 1:1:1 ratio to receive once-weekly survodutide administered subcutaneously at a dose adjusted up to 3.6 mg or 6.0 mg or placebo, in addition to counseling for lifestyle modification. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. The primary efficacy analysis was conducted according to the treatment-regimen estimand, which incorporates the effects of any early discontinuation of survodutide or placebo, the use of protocol-prohibited obesity medications, and a prolonged dose-escalation period. Among 725 participants (241 in the 3.6-mg survodutide group, 242 in the 6.0-mg survodutide group, and 242 in the placebo group), the mean age was 47.1 years; 294 participants (40.6%) were men. At baseline, the mean BMI was 37.9, and the mean body weight was 108.8 kg. At week 76, the mean change in body weight from baseline according to the treatment-regimen estimand was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo). The most common adverse events were gastrointestinal symptoms (typically mild to moderate), which occurred in 80.9% of the participants in the 3.6-mg group, in 89.7% of those in the 6.0-mg group, and in 47.9% of those in the placebo group. No deaths were reported. Survodutide led to significantly greater reductions in body weight than placebo in adults with obesity without diabetes. (Funded by Boehringer Ingelheim; SYNCHRONIZE-1 ClinicalTrials.gov number, NCT06066515.).
Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction-associated Steatohepatitis: A Systematic Review and Meta-analysis.
New therapies are urgently needed for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We conducted this systematic review and meta-analysis to evaluate the therapeutic effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on MASLD/MASH. We searched PubMed, Embase, and Cochrane Library databases to identify randomized controlled trials (RCTs) that compared GLP-1RAs with placebo or active agents with respect to the efficacy in patients with MASLD/MASH. The effects of GLP-1RAs on liver fat content (LFC) by imaging, liver histology, serum liver enzymes, and noninvasive fibrosis indexes [Fibrosis-4, nonalcoholic fatty liver disease fibrosis score, cytokeratin 18, procollagen III, and liver stiffness) were evaluated. Mean differences and risk ratios with 95% confidence intervals were pooled using a random-effect model. Twenty-five RCTs involving 2600 patients who used GLP-1RAs including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide were included. Overall, GLP-1RAs treatment for a median of 24 weeks demonstrated a significant reduction in LFC by 5.21%, with retatrutide displaying the most obvious treatment effects. GLP-1RAs treatment induced significant histological improvements in steatosis, hepatocellular ballooning, and lobular inflammation but nonsignificantly improved fibrosis, with the evidence for tirzepatide more robust than that for semaglutide and liraglutide. GLP-1RAs treatment significantly decreased serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase compared with control. GLP-1RAs also significantly improved liver stiffness, with semaglutide displaying the most obvious treatment effect. No drug-related adverse effects involving the liver were observed. GLP-1RAs decreased liver fat deposition and improved histological steatosis, hepatocellular ballooning, and lobular inflammation, without worsening of fibrosis in MASLD and MASH.
Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.
The pleiotropic effects of glucagon-like peptide-1 receptor agonists in patients with metabolic dysfunction-associated steatohepatitis: a review for gastroenterologists.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) or glucagon receptor agonists have emerged as promising agents to treat metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Although the beneficial effects of GLP-1RAs on glycemic control and weight are well-established, clinicians may be unfamiliar with other potential benefits of this class. We examined the pleiotropic effects of GLP-1RAs and how they relate to gastroenterologists for MASLD/MASH treatment. Our narrative review of English articles included four GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide, and efpeglenatide), a dual GLP-1/GIP agonist (tirzepatide), a dual GLP-1/glucagon receptor agonist (survodutide), MASLD/MASH, related disorders, clinical management, treatment outcomes and landscape. In Phase I - III trials, GLP-1RAs are associated with clinically relevant hepatic improvements including MASH resolution, liver fat reduction, and preventing worsening fibrosis. Effects on cardiometabolic parameters align with type 2 diabetes/obesity Phase III data, comprising substantial improvements in glycemic, weight, and cardiovascular outcomes. Promising data also suggest benefits in common comorbidities, including obstructive sleep apnea, polycystic ovary syndrome, chronic kidney disease, and heart failure with preserved ejection fraction.GLP-1RAs represent a valuable pharmacotherapeutic option for gastroenterologists managing individuals with MASLD/MASH and cardiometabolic comorbid conditions.
Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A Bayesian NMA.
To compare the efficacy and safety of GLP-1 receptor agonists (GLP-1RAs), dual agonists (GLP-1RAs/GIP or GCGR), and retatrutide (GLP-1/GIP/glucagon) for weight loss in adults with overweight or obesity. We conducted a systematic review and Bayesian network meta-analysis (NMA) of 19 randomized controlled trials (RCTs) including 29,506 adults (BMI ≥ 25 kg/m2), assessing liraglutide, semaglutide, survodutide, tirzepatide, retatrutide, and placebo. Outcomes included mean weight loss, achievement of ≥ 5%, ≥ 10%, and ≥ 15% weight loss, waist circumference (WC), BMI, and adverse events (AEs) at ≥ 36 weeks. Subgroup and meta-regression analyses evaluated the impact of diabetes status, sex, age, and BMI. Retatrutide and dual agonists achieved equivalent mean weight loss (-11.0 kg), surpassing GLP-1RAs (-9.0 kg), with retatrutide excelling at achieving ≥ 15% weight loss (OR 54.6). Dual agonists and GLP-1RAs followed (OR 16.4 and 9.0, respectively). Retatrutide had the highest AE risk. Meta-regression showed type 2 diabetes mellitus (T2DM) reduced weight loss by 4.338 kg for GLP-1RAs and 5.016 kg for dual agonists, with enhanced outcomes in female-dominant or high-BMI cohorts. Retatrutide offers superior weight loss efficacy but with a higher AE risk. Dual agonists provide a favorable efficacy-safety balance. Personalized treatment selection based on patient characteristics is recommended.
Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide.
Nutrient-stimulated gut hormone peptide YY3-36 (PYY3-36) selectively activates the neuropeptide Y2 receptor (NPY2R) and reduces energy intake in humans. We describe the discovery and pharmacology of the long-acting NPY2R agonist BI 1820237 and its potential bodyweight-lowering efficacy alone and in combination with the glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist survodutide. BI 1820237 dose-dependently reduced food intake and gastric emptying in lean mice. Significant bodyweight reductions were not observed with BI 1820237 alone in diet-induced obese mice, however combination with survodutide led to bodyweight reduction of 22% which was significantly (p < 0.01) greater than the 17% bodyweight reduction with survodutide alone. Regression-based interaction analysis demonstrated that BI 1820237 increased the efficacy of survodutide by 265% at an ED50 of 11.7 nmol/kg over a range of dose combinations. Synergistic NPY2R and GCGR/GLP-1R agonism provides an attractive mode of action for clinically relevant weight loss in patients with obesity.
Survodutide in MASH: bridging the gap between hepatic and systemic metabolic dysfunction.
Glucagon-like peptide-1 receptor (GLP-1 R) agonists have demonstrated remarkable effectiveness in the treatment of obesity and type 2 diabetes. Although these agents provide beneficial effects for metabolic dysfunction-associated steatohepatitis (MASH) through their glucose-lowering and weight-reducing properties, their efficacy in promoting fibrosis regression remains unproven. Survodutide, an investigational dual agonist that simultaneously targets both the glucagon receptor (GCGR) and GLP-1 R, has emerged as a promising therapeutic candidate for the comprehensive management of obesity and MASH. By engaging these two critical receptors, this drug has the potential to offer a broad spectrum of metabolic benefits, addressing multiple pathogenic mechanisms underlying these interrelated disorders. This review examines the pharmacological profile, clinical efficacy, and safety data of survodutide derived from phase 1 and 2 clinical trials. Survodutide's dual agonism of the GCGR and GLP-1 R may surpass the efficacy of selective GLP-1 R agonists, demonstrating significant potential in resolving MASH and promoting fibrosis regression. The drug is generally well tolerated, with primarily manageable gastrointestinal adverse effects. As survodutide progresses through phase 3 clinical development, its potential to provide a more effective and holistic approach to treating MASH and its comorbidities may significantly improve patient outcomes and quality of life.
Survodutide: A Dual GLP-1/Glucagon Agonist Reshaping Cardiometabolic Care.
Cardiovascular disease remains the leading cause of mortality worldwide, with obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) serving as major upstream drivers. Current therapies largely address downstream risk factors, leaving a need for agents that modify the metabolic contributors to cardiovascular disease. Survodutide, a dual glucagon and glucagon-like peptide-1 receptor agonist, represents an emerging therapy with broad metabolic effects, including potent weight reduction, glycemic control, hepatic fat reduction, and anti-inflammatory activity. Phase 2 trials have demonstrated weight loss up to 18.7% and HbA1c reductions up to -1.71%, outperforming semaglutide for weight outcomes while maintaining comparable glycemic efficacy. In MASH, survodutide achieved significant improvements in liver fat and fibrosis, offering potential cardiovascular protection through reductions in systemic inflammation and fibrosis-related remodeling. Its mechanistic profile suggests benefits for visceral and epicardial adiposity, with implications for heart failure with preserved ejection fraction. Early signals of renal benefit further underscore its role in cardiorenal syndromes. Adverse events, primarily gastrointestinal intolerance and modest heart rate increases, remain important limitations, contributing to discontinuation rates higher than comparator agents. The ongoing Survodutide for the treatment of obesity study (SYNCHRONIZE-CVOT) trial will clarify whether these robust metabolic effects translate into reduced cardiovascular events and long-term safety. Survodutide has the potential to reshape cardiometabolic care by addressing multiple converging pathways that drive cardiovascular disease. Confirmation of its safety and efficacy in outcomes trials could establish dual agonism as a cornerstone therapeutic strategy for patients with obesity, type 2 diabetes, MASH, and cardiorenal disease.
A review of survodutide: a new dual acting agonist.
Survodutide represents an innovative approach to obesity management and metabolic-associated fatty liver disease (MAFLD). These conditions, often closely linked with type 2 diabetes (T2DM) and cardiovascular diseases, demand effective treatment strategies. Survodutide acts by targeting both GLP-1 and glucagon receptors. This new dual agonist offers potential transformative benefits, with early clinical trials showcasing significant weight loss and improvements in metabolic markers. Survodutide's mechanism of action includes appetite regulation, enhanced glucose metabolism, and increased energy expenditure, making it a promising option for those struggling with obesity and related health issues. This review assesses Survodutide's pharmacology, efficacy, and safety in MASH and obesity, while also outlining its broader metabolic and cardiovascular benefits. It compares Survodutide's dual-agonist mechanism and clinical performance with single-target incretin therapies to clarify its potential role in the evolving treatment landscape. While the initial results are promising, the review emphasizes the importance of continued research to fully understand Survodutide's long-term safety and effectiveness. Ongoing trials will provide critical insights into its overall impact, side effects, patient response, and cost considerations. This article highlights Survodutide's potential in the treatment of obesity and metabolic disordersand evaluates its place in therapy for seeking improved outcomes.
Efficacy and Safety of Twincretin Survodutide, a Dual Glucagon-Like Peptide-1 and Glucagon Receptor Agonist as an Anti-Obesity and Anti-Diabetes Medication: A Systematic Review and Meta-Analysis.
Survodutide is a twincretin having dual glucagon-like peptide-1 and glucagon receptor agonist activity, conceptually based on endogenous peptide oxyntomodulin. This systematic review and meta-analysis (SRM) holistically analyzed the body weight lowering, glycemic efficacy, and safety of survodutide. Electronic databases were searched for RCTs involving diabetes and/or obesity patients receiving once-weekly subcutaneous survodutide in intervention arm and placebo/active comparator in control arm. Co-primary outcomes were the percent changes in body weight and HbA1c. Secondary outcomes were to evaluate absolute changes in absolute weight, blood pressure, fatty-liver disease parameters, and adverse events (AEs). Data from 3 RCTs (1088 patients) having follow-up duration ranging from 4-11 months were analyzed. Survodutide at 2.4 mg [MD (mean difference) -7.79% (95% confidence interval [CI]: -11.54, -4.07); I2 = 98%; P < 0.01] and 3.6 mg [MD - 9.08% (95% CI: -11.63, -6.54); I2 = 96%; P < 0.001] was associated with significantly greater percent reductions in body weight compared to placebo. The corresponding absolute body-weight reduction with survodutide 2.4 mg and 3.6 mg was - 9.14 kg (95% CI: -13.76, -4.53) and - 10.23 kg (95% CI: -15.43, -5.04), respectively. Survodutide of 2.4 mg was associated with significant HbA1c reduction [MD: -0.88% (95% CI - 1.72, -0.05); I2 = 99%; P = 0.040]. Survodutide of 2.4 mg [odds ratio (OR): 2.93 (95% CI: 1.66, 5.18); I2 = 0%; P < 0.001] and 3.6 mg [OR: 4.61 (95% CI: 2.33, 9.12); I2 = 0%; P < 0.001] was associated with significantly higher treatment-emergent AEs, compared to placebo, although severe AEs were not increased. Gastrointestinal AEs were the predominant AEs and were dose dependent. Treatment discontinuation due to AEs was significantly higher with survodutide and was dose dependent. Survodutide demonstrates impressive weight and glucose-lowering properties over short-term clinical use. The optimal dose for clinical use ranges from 2.4 to 4.8 mg/week.
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.
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. 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). 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. 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.
Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial.
Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist under investigation for treating obesity and related diseases. The SYNCHRONIZE-MASLD phase 3, randomized, double-blind, placebo-controlled trial included 216 adults (131 female and 85 male) with obesity (defined as a body mass index ≥30 kg m-2 or ≥27 kg m-2 with at least one obesity complication) and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD), defined by MASLD with evidence of liver inflammation and/or fibrosis by noninvasive tests (NITs) or biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH). Participants were randomized (2:1) and treated with once-weekly subcutaneous injections of survodutide 6.0 mg (n = 146) or placebo (n = 70). The co-primary endpoints, ≥30% reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF)-assessed liver fat content (LFC) and percentage change in body weight (both baseline to week 48), were met. In total, 84.2% of survodutide-treated patients versus 24.3% of placebo-treated patients had ≥30% reduction in LFC using the efficacy estimand (P < 0.0001; treatment regimen estimand: 68.5% versus 28.6%, respectively; P < 0.0001). Mean percentage change in body weight was -12.2% with survodutide and -1.0% with placebo using the efficacy estimand (P < 0.0001; treatment regimen estimand: -8.7% versus -1.4%, respectively; P < 0.0001). The most frequently reported adverse events with survodutide were gastrointestinal, commonly occurring during dose escalation, and were generally of mild-to-moderate severity. In adults with obesity and at-risk MASLD, survodutide treatment was statistically and clinically superior to placebo for reductions in MRI-PDFF-assessed LFC and body weight. Limitations included short trial duration (48 weeks) and limited global reach (participants recruited in the United States and Spain).
Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906.
To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity. A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20-<30 kg/m2 . A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27-40 kg/m2 . In the SRD study (N = 24), mean body weight decreased with increasing BI 456906 dose. In the MRD study, the maximum decreases in placebo-corrected mean body weight were at week 6 (-5.79%, dosage schedule [DS] 1; Part A) and week 16 (-13.8%, DS7; Part B). BI 456906 reduced plasma amino acids and glucagon, indicating target engagement at GCGRs and GLP-1Rs. Drug-related adverse events (AEs) increased with BI 456906 dose. The most frequent drug-related AE with SRDs was decreased appetite (n = 9, 50.0%), and two subjects (8.3%) did not complete the trial because of AEs (nausea and vomiting). During MRD Part A (N = 80), 10 subjects (12.5%) discontinued BI 456906, most commonly because of a cardiac or vascular AE (n = 6, 7.5%); during Part B (N = 45), eight subjects (17.8%) discontinued BI 456906, mainly because of AEs (n = 6, 13.3%), most commonly gastrointestinal disorders. BI 456906 produced a placebo-corrected body weight loss of 13.8% (week 16), highlighting its potential to promote clinically meaningful body weight loss in people with overweight/obesity.
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.
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). 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. 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. 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.
Efficacy and safety of survodutide on glycemic control and weight loss in adults: A systematic review and meta-analysis.
This meta-analysis aimed to evaluate the efficacy and safety of survodutide on glycemic control and weight loss in adults. We systematically searched PubMed, Embase, the Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) evaluating the efficacy and safety of survodutide up to 12 July 2025. The primary outcomes were changes in glycated haemoglobin (HbA1c), fasting glucagon levels, body weight, waist circumference, along with the incidence of adverse events (AEs). Secondary outcomes included body mass index (BMI), lipid profiles, and blood pressure. Six RCTs involving 1272 participants were included in this meta-analysis. Compared with placebo, survodutide significantly reduced HbA1c (weighted mean difference [WMD]: -0.66%, 95% confidence interval [CI] [-1.08, -0.23], p = 0.002) and fasting glucagon levels (WMD: -7 pmol/L, 95% CI [-10.3, -3.69], p = 0.016). Greater reductions were observed in the subgroup receiving a total weekly dose of >2.4 mg compared with the subgroup receiving ≤2.4 mg weekly. Survodutide also significantly decreased body weight (WMD: -6.7 kg, 95% CI [-10.0, -3.4], p < 0.001) and waist circumference (WMD: -7.09 cm, 95% CI [-9.44, -4.47], p < 0.001), with enhanced effects observed at higher total weekly doses (>2.4 mg) and longer treatment durations (>16 weeks). Additionally, significant reductions were observed in BMI, and modest reductions were noted in total cholesterol, triglycerides, and blood pressure. However, survodutide was associated with a higher risk of treatment discontinuation due to AEs, with gastrointestinal AEs being the most common, although there was no significant increase in the incidence of serious AEs. Survodutide significantly reduced HbA1c, body weight, and waist circumference. A greater reduction in HbA1c was specifically associated with a higher total weekly dose (>2.4 mg), while more pronounced effects on body weight and waist circumference were observed with both higher doses and longer treatment durations (>16 weeks). However, it is crucial to highlight the significant increase in gastrointestinal AEs and the associated risk of treatment discontinuation. Further large-scale, multicentre, long-term, and high-quality RCTs are necessary to validate these results in diverse populations.
A randomized Phase I study of the safety, tolerability, pharmacokinetics and pharmacodynamics of BI 456906, a dual glucagon receptor/glucagon-like peptide-1 receptor agonist, in healthy Japanese men with overweight/obesity.
To report a Phase I study of subcutaneous glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist BI 456906 versus placebo in healthy Japanese men with overweight/obesity. We investigated multiple rising doses of BI 456906 escalated over 16 weeks (maximum doses: 1.8 mg once weekly [dose group {DG} 1], 4.8 mg once weekly [DG 2] and 2.4 mg twice weekly [DG 3]) in Japanese men with a body mass index of 23 to 40 kg/m2 . Thirty-six participants were treated (n = 9 per DG and placebo). Overall, 10 participants (37.0%) treated with BI 456906 withdrew from dose escalation due to adverse events (amylase increase, n = 1; decreased appetite, n = 9), and the proportion of participants was higher in DG 2 (n = 6, 66.7%) versus DGs 1 and 3 (both n = 2, 22.2%). No participants receiving placebo withdrew from dose escalation. BI 456906 exposure increased with dose and dose escalation in each DG. Treatment with BI 456906 decreased placebo-corrected bodyweight after 16 weeks (placebo +1.06%): DG 1, -5.57%; DG 2, -12.37%; DG 3, -9.62%. Paracetamol absorption decreased in Week 1 for DGs 2 and 3, indicating transient delayed gastric emptying. BI 456906 reduced plasma alanine and glucagon levels, indicating indirect target engagement at GCGRs and GLP-1Rs. Drug-related adverse events were reported for all participants receiving BI 456906 and four receiving placebo, the most frequent being decreased appetite (n = 24, 66.7%). BI 456906 showed no unexpected tolerability concerns and it reduced placebo-corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks of treatment.
Harnessing GLP-1 Receptor Agonists for Obesity Treatment: Prospects and Obstacles on the Horizon.
Obesity has emerged as a pressing global health challenge, and therapies based on glucagon-like Peptide 1 receptor agonists (GLP-1RAs) have transformed its management. Currently, liraglutide, semaglutide, and tirzepatide are FDA-approved for obesity treatment, while other agents are used off-label. These drugs not only provide unprecedented efficacy and acceptable safety in weight reduction and glycemic control for patients with obesity and Type 2 diabetes but also hold promise in broader indications, including neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular conditions. This narrative review examined the therapeutic applications of GLP-1RAs for obesity, emphasizing their efficacy, safety profile, challenges with patient adherence, and limitations. The review also explored emerging innovations such as ultralong-acting formulations, combination therapies, and the integration of digital health and artificial intelligence in advancing antiobesity drug development. GLP-1RAs represent a paradigm shift in the treatment of obesity and metabolic diseases, with rapidly expanding indications and global uptake. Recent evidence highlights improvements in tolerability, global accessibility, and the potential of novel technologies to optimize patient outcomes. By 2025, GLP-1RAs are anticipated to receive FDA approval for new indications, such as chronic kidney disease, heart failure with preserved ejection fraction, and metabolic dysfunction-associated steatohepatitis. Novel agents including CagriSema and higher dose oral semaglutide are advancing through clinical trials, while pivotal trial results for orforglipron, mazdutide, retatrutide, and survodutide are anticipated to further expand the therapeutic landscape. At the same time, the arrival of generic liraglutide and evolving insurance coverage are reshaping access and affordability. The convergence of pharmacological innovation, digital health strategies, and equitable care initiatives is expected to revolutionize obesity therapeutics in the coming decade. Priorities for future research include sustaining long-term weight loss, establishing disease-modifying potential in nonmetabolic disorders, and addressing health equity concerns to ensure broader global benefit.
Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.
Diabetes is a chronic illness that can become debilitating owing to its microvascular and macrovascular complications. Its prevalence is increasing and so is its cost. Diabetes, particularly type 2, appears to have a very close relationship with obesity. While lifestyle modifications, exercises, and current therapeutics have substantially improved clinical outcomes, the need for new therapeutics and regimens continue to exist. Several new medications and regimens for diabetes, obesity, and diabesity are showing promising results in advanced clinical trials. For type 1 diabetes mellitus (T1DM), they include teplizumab, ustekinumab, jakinibs, and cell therapies, whereas for type 2 diabetes mellitus (T2DM), they include once-weakly insulin, tirzepatide, high oral dose of semaglutide, orforglipron, retatrutide, CagriSema, and survodutide. Given their structural and mechanistic diversity as well as their substantial efficacy and safety profiles, these medications and regimens are paradigm shifting and promise a brighter future. They will likely enable better disease prevention and management. This review will provide details about each of the above strategies to keep the scientific community up to date about progress in the fields of diabetes and obesity.
Approved and Emerging Hormone-Based Anti-Obesity Medications: A Review Article.
Obesity is a heterogeneous, complex, and chronic disease that has a detrimental impact on disability-adjusted life years across the globe. Recent advancements in our understanding of gut-brain communication at the molecular level have driven the development of next-generation anti-obesity medications (AOMs). Glucagon-like peptide-1 receptor agonists (GLP1RAs) remain the front-runners in this rapidly evolving landscape of hormone-based AOMs. Two GLP1RAs, namely Liraglutide and Semaglutide, have been approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) for use in clinical practice for weight loss. Three oral GLP1RAs, namely Semaglutide, Danuglipron, and Orforglipron, are undergoing advanced clinical trials in individuals with obesity. Amylin receptor agonist (AMYRA) Cagrilintide, when used alone or in combination with Semaglutide, has demonstrated substantial weight reduction in clinical trials. Tirzepatide, a dual agonist for the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, has been observed to be associated with a significant placebo-subtracted weight reduction of 17.8% in a 72-week randomized controlled trial. Novel approaches targeting glucagon signalling have also yielded promising preliminary results. Three long-acting GLP1R/glucagon receptor (GCGR) dual agonists, namely Survodutide, Mazdutide, and Pemvidutide, exhibited significant weight loss in clinical trials. Retatrutide, a GLP1R/GCGR/GIPR tri-agonist, has been associated with a placebo-subtracted weight reduction of -22.1% in a 48-week phase-II trial. As a note of caution, long-term data on such medications' safety and cardiovascular benefits is yet to be ascertained. Our review provides a comprehensive overview of the approved and emerging hormone-based AOMs, highlighting the diversity of options that might become available in the near future.
Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials.
Glucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity. PubMed, Cochrane, Embase, and Scopus databases were systematically searched. Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis. Random-effects models were applied to assess mean differences (MD) in weight change, both absolute and percent changes, HbA1c, adverse events, and discontinuation due to adverse events. Heterogeneity was quantified using the I2 statistic. Retatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]), followed by survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]) and mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]). Cotadutide showed the smallest and nonsignificant effect (MD -3.41 kg; 95% CI [-11.63, 4.81]). Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance. In terms of safety, mazdutide demonstrated the most favourable tolerability profile, whereas retatrutide and cotadutide were associated with comparatively lower tolerability. Retatrutide and survodutide exhibit the most favourable efficacy profiles for obesity and T2DM, with acceptable safety. These findings support their potential clinical use and highlight the need for future head-to-head trials.
Quick links (PubMed)
- PMID 38847460 — 2024 · A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.
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