GLP-1/Glucagon Co-agonists: Survodutide and Mazdutide

Glucagon is usually thought of as the hormone that raises blood glucose, so pairing it with a glucose-lowering GLP-1 signal can seem counter-intuitive. Yet dual agonism of the GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) has become a major research strategy, particularly for liver disease. This review covers the natural template for the approach, oxyntomodulin, and two of the most advanced synthetic co-agonists, survodutide and mazdutide.

Origin and discovery

Oxyntomodulin is a 37-residue peptide produced from proglucagon in intestinal L-cells, released with GLP-1 after meals. It consists of the full 29-residue glucagon sequence followed by an eight-residue C-terminal extension (intervening peptide-1). Oxyntomodulin activates both GLP-1R and GCGR, each with lower potency than the native ligand.

Human studies in the 2000s showed that oxyntomodulin reduced food intake in acute experimental settings (Cohen et al., 2003; Wynne et al., 2005). Its very short half-life, however, made it impractical as more than a physiological probe.

In 2009 two groups independently described stabilised GLP-1/glucagon co-agonist peptides that reduced body weight in obese rodents beyond what was seen with GLP-1R agonism alone, and attributed the difference partly to increased energy expenditure from glucagon receptor activation (Day et al., 2009; Pocai et al., 2009). These papers established the design principle behind today's co-agonists.

Survodutide (BI 456906) emerged from a collaboration between Boehringer Ingelheim and Zealand Pharma; its preclinical characterisation was published by Zimmermann et al. (2022). Mazdutide (LY3305677, also known as IBI362) was originally discovered at Eli Lilly and has been developed in China by Innovent Biologics.

Structure and chemistry

Both survodutide and mazdutide are acylated peptides built on glucagon-like sequences, with amino-acid substitutions that tune the balance between GLP-1R and GCGR activity and confer protease resistance. Fatty-acid modifications promote albumin binding and extend half-life from minutes to days.

The balance of receptor activity is the critical design variable. Too much glucagon activity risks raising glucose and increasing catabolism; too little loses the hepatic and energy-expenditure effects that justify the approach. Because glucagon and GLP-1 share substantial sequence similarity at their N-termini, relatively few substitutions can shift a peptide's preference between the two receptors, which makes the class a useful model for studying how single residues govern selectivity among class B GPCRs. Each sponsor has chosen a different ratio, and these ratios are measured in recombinant cell assays that may not fully reflect tissue-level receptor reserve.

Receptor pharmacology and mechanism studied

The two arms are studied for complementary roles:

• GLP-1R activation enhances glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying and reduces food intake via central pathways.
• GCGR is highly expressed in hepatocytes. Its activation increases fatty-acid oxidation, reduces de novo lipogenesis and promotes amino-acid catabolism and ureagenesis. In rodents it raises energy expenditure, an effect that may involve hepatic FGF21 signalling and other pathways.

The hepatic action of glucagon is the main reason these compounds are prominent in research on metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH). Unlike GLP-1R agonists, whose effects on liver fat are thought to be largely indirect, GCGR agonists act directly on hepatocytes.

Open mechanistic questions include whether glucagon receptor activity meaningfully raises energy expenditure in humans, how it affects lean tissue and amino-acid balance, and what the long-term consequences of increased hepatic amino-acid catabolism might be.

Research and clinical-trial landscape

Survodutide

• A phase 2 trial in adults with MASH and fibrosis evaluated histological improvement of MASH as the primary endpoint (Sanyal et al., 2024, NEJM).
• A phase 2 trial in adults with overweight or obesity evaluated body-weight endpoints (le Roux et al., 2024, Lancet Diabetes & Endocrinology).
• Phase 3 programmes are under way in obesity (SYNCHRONIZE) and in MASH (LIVERAGE). Registrations and readouts should be checked on ClinicalTrials.gov.

Mazdutide

• Phase 2 trials in Chinese adults with overweight or obesity and with type 2 diabetes evaluated body-weight and glycaemic endpoints (for example Ji et al., 2023).
• Phase 3 trials in China, including GLORY-1 in obesity and DREAMS trials in type 2 diabetes, evaluated body-weight and glycaemic endpoints, with liver-fat measurements as secondary assessments.

Other co-agonists have been studied, including cotadutide (AstraZeneca), whose development was discontinued, and further candidates such as pemvidutide and efinopegdutide, which have been evaluated mainly in liver-fat and MASH settings.

Across the class, gastrointestinal adverse events were the most commonly reported, and increases in heart rate have been noted in several programmes.

Evidence quality and open questions

• Histology versus imaging. MASH trials that use biopsy-based histology provide stronger evidence than those relying on MRI liver-fat measurements alone, but biopsy reading is itself variable.
• Endpoint choice. Trials relying on surrogate markers such as liver enzymes provide weaker evidence than those using histological endpoints accepted by regulators.
• Population generalisability. Most mazdutide data come from Chinese populations; replication in other populations is needed.
• Head-to-head comparisons. Co-agonists have not yet been compared in published phase 3 trials with selective GLP-1R agonists or GIP/GLP-1 agonists on liver endpoints.
• Glucagon-specific safety. Effects on amino-acid levels, lean mass, heart rate and glycaemia in people without diabetes need long-term characterisation.
• Translation from rodents. Energy-expenditure effects seen in mice may be smaller in humans, and the relative contribution of each receptor is hard to isolate clinically.

Regulatory and anti-doping status

Oxyntomodulin is an endogenous peptide and is not an approved medicine. Survodutide is investigational and not approved by the FDA, EMA or other major regulators at the time of writing. Mazdutide has been approved by Chinese regulators as a prescription medicine; it is not approved by the FDA or EMA. Research-grade material of any of these compounds is intended solely for in vitro and animal research.

None of these compounds is named on the WADA Prohibited List at the time of writing. Non-approved substances may fall under the S0 category; researchers working with athletes should consult the current list.

Summary table

	Oxyntomodulin	Survodutide	Mazdutide
Type	Endogenous proglucagon peptide	Synthetic acylated co-agonist	Synthetic acylated co-agonist
Code names	—	BI 456906	LY3305677 / IBI362
Developer	—	Boehringer Ingelheim / Zealand Pharma	Eli Lilly / Innovent Biologics
Receptors	GLP-1R + GCGR	GLP-1R + GCGR	GLP-1R + GCGR
Half-life	Minutes	Extended (albumin binding)	Extended (albumin binding)
Research focus	Physiology, appetite	MASH, obesity	Obesity, type 2 diabetes
Status	Endogenous; not approved	Investigational (phase 3)	Approved in China; investigational elsewhere

References

• Cohen MA, Ellis SM, Le Roux CW, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003;88(10):4696–4701.
• Wynne K, Park AJ, Small CJ, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54(8):2390–2395.
• Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009;5(10):749–757.
• Pocai A, Carrington PE, Adams JR, et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes. 2009;58(10):2258–2266.
• Zimmermann T, Thomas L, Baader-Pagler T, et al. BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Mol Metab. 2022;66:101633.
• Sanyal AJ, Bedossa P, Fraessdorf M, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311–319.
• le Roux CW, Steen O, Lucas KJ, 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;12(3):162–173.
• Ji L, Jiang H, Cheng Z, et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat Commun. 2023;14:8289.
• Ambery P, Parker VE, Stumvoll M, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018;391:2607–2618.