Next-Gen Metabolic Peptides: Survodutide, Mazdutide & Cagrilintide
Beyond semaglutide and tirzepatide: next-generation metabolic peptides including survodutide, mazdutide, and cagrilintide. Mechanisms, trials, and current research status.
Semaglutide and tirzepatide set the current reference point for incretin-based weight-loss therapy. The next wave of metabolic peptides is testing whether broader pathway combinations, or pairing GLP-1 with non-incretin satiety signals, can extend those results into obesity, type 2 diabetes, and liver disease.
Three programs are often discussed together but work in different ways: survodutide, mazdutide, and cagrilintide. Two are GLP-1/glucagon dual agonists, while cagrilintide is an amylin analog being developed mainly as part of CagriSema with semaglutide.
Research Use Only
This article discusses compounds in clinical development and, in some cases, approved use in specific regions. Regulatory status varies by molecule and market. The content is educational and is not medical advice.
Survodutide (BI 456906): The GLP-1/Glucagon Dual Agonist
Survodutide is a dual GLP-1 and glucagon receptor agonist developed by Boehringer Ingelheim under license from Zealand Pharma. It combines appetite and gastric-emptying effects associated with GLP-1 signaling with glucagon-receptor activity that may support hepatic lipid oxidation and energy expenditure.
Why Add Glucagon?
Glucagon receptor activation can raise glucose, but it is also linked to changes in liver fat handling and energy balance. That is why GLP-1/glucagon dual agonists are being studied not only for obesity, but also for MASH and related liver endpoints.
This makes survodutide relevant for researchers following metabolic dysfunction-associated steatotic liver disease (MASLD) and, more specifically, metabolic dysfunction-associated steatohepatitis (MASH).
Clinical Trial Data
Survodutide has produced Phase 2 data in obesity and MASH:
- Weight loss: In obesity studies, the highest-dose groups reported approximately 18-19% body weight reduction over 46 weeks.
- Liver endpoints: In Boehringer's Phase 2 MASH communication, up to 83.0% of treated adults showed improvement in MASH versus placebo, and up to 64.5% of adults with F2/F3 fibrosis achieved fibrosis improvement without worsening of MASH after 48 weeks. The same update reported up to 64.3% relative reduction in liver fat content, and that 87.0% of adults achieved at least a 30% relative reduction in liver fat. (Boehringer, June 7 2024)
- Phase 3 program: Boehringer's obesity program includes the SYNCHRONIZE studies. For liver disease, the company announced the LIVERAGE and LIVERAGE-Cirrhosis Phase 3 trials in October 2024. (Boehringer, October 8 2024)
- Breakthrough Therapy designation: The U.S. FDA granted Breakthrough Therapy designation for survodutide in adults with non-cirrhotic MASH and moderate or advanced fibrosis in September 2024, according to Boehringer's October 2024 announcement. (Boehringer, October 8 2024)
Development Focus
Survodutide is being studied for both weight loss and liver-disease endpoints, unlike GLP-1 programs focused mainly on obesity and glycemic control.
Mechanism Summary
| Target | Effect |
|---|---|
| GLP-1 receptor | Appetite reduction, insulin secretion, gastric slowing |
| Glucagon receptor | Increased energy expenditure, hepatic fat oxidation, reduced liver lipid storage |
Mazdutide (IBI362 / LY3305677): A Parallel GLP-1/Glucagon Program
Mazdutide is also a dual GLP-1/glucagon receptor agonist. Innovent describes it as in-licensed from Lilly, not the other way around. Innovent's 2025 interim materials list the program rights as Mainland China, Hong Kong, Taiwan, and Macau. (Innovent 2024 interim results, Innovent 2025 interim results)
Development Timeline
Mazdutide's late-stage development split obesity and type 2 diabetes into separate programs:
- Obesity/overweight: Innovent reported that the first mazdutide NDA, for chronic weight management in adults with obesity or overweight, was accepted by China's NMPA in February 2024. (Innovent 2024 interim results)
- Type 2 diabetes: Innovent reported that a second mazdutide NDA, for T2D, was accepted by China's NMPA in August 2024. (Innovent 2024 interim results)
- Approval status: Innovent's 2025 interim presentation later listed mazdutide as approved in Mainland China, Hong Kong, Taiwan, and Macau for obesity (4/6 mg) and T2DM (4/6 mg). (Innovent 2025 interim results)
The trial names also need to be kept separate. GLORY-1 was an obesity/overweight Phase 3 study. DREAMS-1, DREAMS-2, and DREAMS-3 were the Phase 3 diabetes studies. That means it is not accurate to describe GLORY-1 as a T2D trial.
Clinical Results
The available Innovent materials support a more cautious summary:
- Obesity: Innovent reported that GLORY-1 met its primary and all secondary endpoints in adults with obesity or overweight. In the company's June 2024 ADA update, mazdutide 6 mg produced 14.4% placebo-adjusted weight loss at week 48. (Innovent 2024 interim results)
- Liver fat: In the same update, Innovent reported 80.2% reduction in liver fat content at week 48 in GLORY-1 participants with baseline liver fat content of at least 10%. (Innovent 2024 interim results)
- Type 2 diabetes: Innovent stated in 2024 that DREAMS-1 and DREAMS-2 had met study endpoints, with DREAMS-3 ongoing. (Innovent 2024 interim results)
- Broader program: Innovent's 2025 materials show additional development in obesity, obesity with OSA, obesity with MAFLD, MASH, HFpEF, and adolescent obesity. (Innovent 2025 interim results)
Lilly's Involvement
The collaboration structure matters because it is often misstated. Based on Innovent's own disclosures, mazdutide is a Lilly-originated GCG/GLP-1 program that Innovent in-licensed for its regional rights.
Dual Agonist Field
Survodutide and mazdutide both target GLP-1 and glucagon receptors, but the public data packages, regional rights, and development priorities differ. Cross-trial comparisons should be treated cautiously.
Cagrilintide: The Amylin Analog Approach
Cagrilintide takes a different path. It is a long-acting amylin analog developed by Novo Nordisk, not a GLP-1 peptide. Amylin is co-secreted with insulin and contributes to satiety signaling, gastric emptying, and post-meal glucagon regulation.
Why Amylin?
Amylin works through neural pathways that overlap only partly with GLP-1 signaling. That is why cagrilintide has been developed mainly as a combination partner for semaglutide, rather than as a direct substitute for GLP-1 receptor agonists.
CagriSema: The Combination Program
The main late-stage story is CagriSema, a fixed-dose combination of cagrilintide and semaglutide 2.4 mg.
The Phase 3 REDEFINE program supports a more precise summary:
- Weight loss: In REDEFINE-1, the estimated mean change in body weight at week 68 was -20.4% with CagriSema versus -3.0% with placebo under one estimand reported in the Phase 3 publication summary. (ACC summary of NEJM publication, July 2 2025)
- Comparison with components: The same report states that CagriSema produced greater weight loss than cagrilintide alone, semaglutide alone, or placebo in REDEFINE-1, and a similar pattern was reported in REDEFINE-2 for adults with obesity and T2D. (ACC summary of NEJM publication, July 2 2025)
- Responder rates: ACC's summary notes that more CagriSema recipients reached >=5%, >=20%, >=25%, and >=30% weight-loss thresholds versus placebo in REDEFINE-1. (ACC summary of NEJM publication, July 2 2025)
- Estimands matter: Reported REDEFINE-1 weight-loss figures can differ because the trial reported more than one estimand. Figures such as -20.4% and -22.7% reflect different analysis frameworks from the same Phase 3 dataset rather than a contradiction.
Cagrilintide Alone
As monotherapy, cagrilintide also showed independent activity in Phase 2. The Lancet trial indexed on PubMed reported 6.0% to 10.8% mean weight reduction at week 26, depending on dose, with 10.8% at the 4.5 mg dose. (PubMed / Lancet phase 2 trial)
Combination Logic
CagriSema is a combination strategy, not a broader receptor profile in one molecule. Its rationale is to pair GLP-1 signaling with amylin-pathway satiety effects.
How They Compare: Dual Agonists, Amylin Analogs & Triple Agonists
These programs are often grouped together because they all sit beyond first-generation GLP-1 monotherapy, but they do not solve the same problem in the same way.
Mechanism Comparison
| Peptide | Targets | Developer | Main distinction |
|---|---|---|---|
| Survodutide | GLP-1 + Glucagon | Boehringer Ingelheim / Zealand Pharma | Advanced MASH and obesity program |
| Mazdutide | GLP-1 + Glucagon | Innovent / Lilly | Regional approvals reported by Innovent plus broad metabolic pipeline |
| Cagrilintide | Amylin receptor | Novo Nordisk | Main role is combination with semaglutide |
| Retatrutide | GLP-1 + GIP + Glucagon | Eli Lilly | Triple-agonist clinical program |
Key Takeaways
Survodutide and mazdutide are both GLP-1/glucagon dual agonists, but their public development narratives differ. Survodutide is strongly associated with MASH and fibrosis endpoints, while mazdutide's public disclosures emphasize obesity, T2D, and a widening cardiometabolic program in Greater China.
Cagrilintide belongs in the same broader metabolic discussion, but not in the narrow category of GLP-1 peptides. Its value is as an amylin analog that can be paired with semaglutide.
Retatrutide is relevant as a reference point because it represents the triple-agonist strategy, but it is a different molecule and development program from the three covered here.
What's Next for GLP-1 Research
Several themes are shaping the next stage of metabolic peptide development:
Oral Formulations
Oral semaglutide showed that peptide-based obesity and diabetes treatment does not have to remain injection-only. Newer oral programs are trying to improve exposure, convenience, and dosing flexibility, though injectable formulations still dominate late-stage pipelines.
Combination Approaches
CagriSema is one example of combining complementary pathways rather than adding more receptor activity into one molecule. Similar logic is being explored with other metabolic hormones and appetite-regulating signals.
Liver-Targeted Peptides
The survodutide data kept attention on liver-related endpoints such as MASH resolution and fibrosis improvement without worsening of MASH. That has increased interest in agents that may affect both adiposity and hepatic disease biology.
Body Composition
As greater weight loss becomes more achievable, more programs are being judged not only by total weight reduction but also by effects on lean mass, cardiometabolic markers, and long-term tolerability.
Evolving Field
This area changes quickly. Trial status, approved indications, and published endpoints should be checked against primary company disclosures, trial registries, and peer-reviewed publications.
Selected Sources
- Boehringer Ingelheim: survodutide Phase 2 MASH/fibrosis update (June 7, 2024)
- Boehringer Ingelheim: FDA Breakthrough Therapy designation and Phase 3 MASH program (October 8, 2024)
- Innovent Biologics interim results 2024
- Innovent Biologics interim results 2025
- ACC summary of REDEFINE-1 and REDEFINE-2 / NEJM publication context (July 2, 2025)
- PubMed entry for the cagrilintide Phase 2 Lancet trial
Frequently Asked Questions
This article is provided for educational purposes. It discusses published clinical-development and regulatory information, but status can change over time and differs by region. For the most current information, consult primary company disclosures, trial registries, and peer-reviewed literature.