Two drugs adding glucagon to the GLP-1 formula
Most of the weight-loss drugs people know target GLP-1. Semaglutide hits that one receptor. Tirzepatide adds GIP. Survodutide and mazdutide take a different second target: the glucagon receptor. That single design choice changes how these molecules behave and why researchers are testing them in liver disease alongside obesity.
Both are still investigational. Survodutide is not approved anywhere. Mazdutide won approval in China in 2025 but is not cleared by the FDA or EMA. Nothing here is medical advice or a prescription protocol. This is a research and educational comparison of what the published trials actually show.
You can run reconstitution and dose math with our survodutide calculator and mazdutide calculator. For how these compare to the more established agents, see our semaglutide vs tirzepatide comparison and the tirzepatide, semaglutide, and retatrutide comparison.
Why glucagon is the interesting part
Glucagon has a reputation as the hormone that raises blood sugar, which sounds like the last thing you would want in a metabolic drug. The logic behind pairing it with GLP-1 is more subtle. Glucagon receptor activation appears to increase energy expenditure and push the liver to burn and clear fat. The GLP-1 component suppresses appetite, slows gastric emptying, and offsets glucagon's tendency to raise glucose. The two signals are meant to balance each other while stacking their metabolic benefits.
That hepatic effect is why both drugs are being studied in MASH (metabolic dysfunction-associated steatohepatitis), a liver condition tightly linked to obesity. The tradeoff is that glucagon agonism has to be dosed carefully, since too much of that signal without enough GLP-1 counterweight could work against glucose control. This is a large part of why the trials titrate so slowly.
Survodutide (BI 456906)
Survodutide is being developed by Boehringer Ingelheim in partnership with Zealand Pharma. It is a synthetic peptide with a C18 fatty acid chain attached (acylation), the same general trick used in semaglutide to slow clearance and extend the half-life to roughly 6 to 7 days. That is what allows once-weekly injection. It activates the glucagon receptor and the GLP-1 receptor with a balance tuned for metabolic effect.
Mazdutide (IBI362 / LY3305677)
Mazdutide is a GLP-1/glucagon dual agonist originally discovered by Eli Lilly and licensed to Innovent Biologics for development in China. Structurally it is based on oxyntomodulin, a natural gut hormone that already hits both receptors, which makes it a slightly different starting point than survodutide's design. It is also a once-weekly subcutaneous injection.
Dosing and titration in the trials
Both drugs follow the same broad playbook that the GLP-1 class established: start low, step up on a fixed schedule, and let the gut adapt at each level. Gastrointestinal side effects (nausea, vomiting, diarrhea, constipation) are the main reason for slow titration, and they were the most common adverse events in both programs. In the survodutide obesity trial, GI events occurred in roughly 75% of drug recipients versus 42% on placebo (le Roux 2024, Lancet Diabetes Endocrinol, PMID 38330987).
Survodutide titration (phase 2 obesity trial)
The dose-finding trial titrated survodutide from a low starting dose up to one of several maintenance targets over about 20 weeks, then held that dose to week 46. The starting point was 0.6 mg weekly, and the maintenance arms studied were 2.4 mg, 3.6 mg, and 4.8 mg.
| Phase | Approximate dose | Frequency |
|---|---|---|
| Start | 0.6 mg | Weekly |
| Step-up | Increasing every few weeks | Weekly |
| Maintenance arms | 2.4 mg / 3.6 mg / 4.8 mg | Weekly |
The trial used a fairly rapid escalation to reach the 4.8 mg target, and how well people tolerated that pace fed directly into the phase 3 design. These are investigational research doses, not a prescription schedule.
Mazdutide titration (phase 2 and phase 3 trials)
Mazdutide trials also titrated weekly toward the maintenance doses under study, principally 4 mg and 6 mg. The phase 2 trial in Chinese adults ran 24 weeks (Ji 2023, Nat Commun, PMID 38092790), while the phase 3 GLORY-1 trial extended to 48 weeks (Ji 2025, NEJM, PMID 40421736).
| Phase | Approximate dose | Frequency |
|---|---|---|
| Start | Low starting dose | Weekly |
| Step-up | Increasing on schedule | Weekly |
| Maintenance arms | 4 mg / 6 mg | Weekly |
The general principle for both drugs is the same one that governs semaglutide and tirzepatide: do not rush the titration. Skipping ahead is the most common reason people get hit hard by nausea and stop.
What the weight-loss data shows
Survodutide
In the phase 2 obesity trial, survodutide reduced body weight in a dose-dependent way across all arms. At the top 4.8 mg dose over 46 weeks, mean weight loss was about 14.9% under the treatment-policy estimand and up to roughly 18.7% under the trial-product estimand (le Roux 2024, Lancet Diabetes Endocrinol, PMID 38330987). The two numbers are not a contradiction. Treatment-policy counts everyone regardless of whether they stayed on the drug, while trial-product estimates the effect if people had stayed on treatment as intended. Notably, weight loss had not plateaued at week 46, so longer dosing might have gone further. Over half of the 4.8 mg group lost at least 15% of their body weight.
The MASH trial is the other pillar of the survodutide story. Over 48 weeks in people with biopsy-confirmed steatohepatitis and fibrosis, up to 62% of survodutide participants achieved MASH improvement without worsening fibrosis, compared with 14% on placebo (Sanyal 2024, NEJM, PMID 38847460). That is the glucagon-driven liver effect showing up in a hard clinical endpoint, and it is why survodutide is being pursued in liver disease as well as obesity.
Mazdutide
The phase 2 trial in Chinese adults reported placebo-adjusted weight loss up to about 12.3% at the 6 mg dose over 24 weeks (Ji 2023, Nat Commun, PMID 38092790). The phase 3 GLORY-1 trial extended the picture: at 6 mg over 48 weeks, mean weight loss was roughly 14%, with about half of that group losing at least 15% of their body weight (Ji 2025, NEJM, PMID 40421736). GLORY-1 is the trial that supported mazdutide's regulatory filing in China.
One caveat worth keeping front of mind: the mazdutide trials were run in Chinese populations, while the survodutide obesity trial enrolled a broader international population. Baseline body weight, diet, and genetics all shift these numbers, so lining up a percentage from one trial against a percentage from another is not a fair head-to-head.
Head-to-head comparison
| Factor | Survodutide (BI 456906) | Mazdutide (IBI362) |
|---|---|---|
| Mechanism | GLP-1 / glucagon dual agonist | GLP-1 / glucagon dual agonist |
| Developer | Boehringer Ingelheim + Zealand Pharma | Innovent (licensed from Eli Lilly) |
| Structure | Acylated peptide, C18 fatty acid | Oxyntomodulin-based peptide |
| Dosing frequency | Once weekly subcutaneous | Once weekly subcutaneous |
| Half-life | ~6-7 days | Supports weekly dosing |
| Trial stage | Phase 3 (SYNCHRONIZE ongoing) | Phase 3 complete (GLORY-1); approved in China |
| Approval | Not approved anywhere | China NMPA 2025; not FDA/EMA |
| Headline weight loss | ~14.9% (treatment-policy) to ~18.7% (trial-product) at 4.8 mg, 46 wks | ~14% at 6 mg, 48 wks (GLORY-1) |
| Other lead indication | MASH / liver fibrosis | Obesity, type 2 diabetes |
On mechanism: these two are the closest thing to true peers in this guide. Both drop the GIP arm that tirzepatide uses and swap in glucagon. The practical difference is in how each molecule was built and tuned, not in the receptors they target.
On development stage: mazdutide is further along in the regulatory sense, with a Chinese approval in hand. Survodutide is still fully investigational but has the more advanced liver disease data, thanks to the phase 2 MASH trial.
How they compare to tirzepatide and semaglutide
For context, the established agents produced these figures in their pivotal obesity trials: semaglutide 2.4 mg reached about 14.9% over 68 weeks in STEP 1, and tirzepatide 15 mg reached about 20.9% over 72 weeks in SURMOUNT-1 (treatment-policy). The dual-glucagon drugs land in a broadly similar zone on the weight number, but that is not the whole point. The reason to develop them is the glucagon-driven metabolic and hepatic effects that GLP-1 and GIP do not deliver, which is why the survodutide MASH data matters as much as the weight figures. Retatrutide, a triple agonist that adds glucagon on top of GLP-1 and GIP, sits in the same conceptual family and is covered in our triple agonist comparison.
Practical and safety notes
- Both are investigational. Survodutide is not approved anywhere. Mazdutide is approved only in China. Any use outside a clinical trial or an approved market is not a validated protocol.
- GI side effects dominate. Nausea, vomiting, and diarrhea were the most common adverse events in both programs, and they track with how fast the dose is escalated.
- Glucagon needs the counterweight. The glucagon component is what makes these drugs interesting and also what makes careful titration and glucose monitoring important, especially in people with diabetes.
- Trial numbers are not interchangeable. Different populations, different trial lengths, and different estimands all move the reported percentages. Read each figure with its trial attached.
- Long-term data is still thin. These are newer molecules. Safety and durability beyond the trial windows are not yet established the way they are for semaglutide.
Bottom line
Survodutide and mazdutide represent the glucagon-inclusive branch of the incretin drug family. Mazdutide is the more regulated of the two right now, with a Chinese approval and phase 3 data behind it. Survodutide carries the stronger liver disease case through its phase 2 MASH results and is working through phase 3 for obesity. Both remain investigational in the US and Europe, and both should be understood as research compounds rather than options you can pick up at a pharmacy. If you are tracking where obesity pharmacology is heading, these two are the drugs that show what adding glucagon to GLP-1 can and cannot do.
References
- le Roux CW et al. "Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial." Lancet Diabetes Endocrinol, 2024. PMID 38330987. https://pubmed.ncbi.nlm.nih.gov/38330987/
- Sanyal AJ et al. "A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis." N Engl J Med, 2024. PMID 38847460. https://pubmed.ncbi.nlm.nih.gov/38847460/
- Ji L et al. "A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity." Nature Communications, 2023. PMID 38092790. https://pubmed.ncbi.nlm.nih.gov/38092790/
- Ji L et al. "Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight (GLORY-1)." N Engl J Med, 2025. PMID 40421736. https://pubmed.ncbi.nlm.nih.gov/40421736/