Glucagon and its receptor agonists explained

How glucagon drives the liver, glucose production and energy expenditure, and what trials with survodutide, mazdutide and retatrutide show.

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ARTICLE · METABOLIC & MITOCHONDRIAL · BASICS

Glucagon switches the liver on and raises energy expenditure. Paired with GLP-1, only those effects are meant to remain. What trials with survodutide, mazdutide and retatrutide show.

MVMichel van der Veen — Registered Nurse · Science Editor, Peptalis Sources checked via PubMed · 17 referencesReviewed September 2026 · 12 MIN READ

Illustration after the structure PDB 6LMK (Qiao et al., Science 2020): glucagon bound to the glucagon receptor. The G protein in the structure is not shown.

Glucagon is insulin's counter-hormone. It sets the liver to making and releasing glucose, and it raises energy expenditure. That first effect is exactly what long made it unsuitable as a target for obesity drugs: activate the glucagon receptor and blood glucose goes up. The solution worked out over the past fifteen years is to pair glucagon with GLP-1, which absorbs the rise in glucose, and so keep only the effects on liver, fat and expenditure. Whether that arithmetic holds has now been tested in phase 2 and phase 3 trials in people.

The body's own hormone

Glucagon is a 29-amino-acid peptide from the alpha cells of the islets of Langerhans. It comes from the same precursor as GLP-1, proglucagon, but the pancreas cuts a different piece from it than the gut does. Release rises as blood glucose falls, during exercise and after a protein-rich meal, and is suppressed by glucose, insulin and GLP-1.

The liver is the target organ. Glucagon binds its receptor on the liver cell, raises cAMP, and sets two processes going: the breakdown of glycogen into glucose and the synthesis of new glucose from amino acids and other building blocks. Between meals this keeps blood glucose up; it is why an injection of glucagon reverses a severe hypoglycaemia within minutes. The review by Habegger and colleagues (2010) and the extensive review by Müller and colleagues (2017) also describe what else the liver does under glucagon: less fat synthesis, more fatty acid oxidation and more ketone production.

Amino acids play a role of their own. Glucagon sets the liver to break amino acids down and convert them into urea. When the liver responds poorly to glucagon, as in fatty liver disease, amino acids accumulate and stimulate the alpha cells to release more glucagon. This feedback loop, the liver-alpha cell axis, is described by Wewer Albrechtsen and colleagues (2019) and explains why people with a fatty liver often have raised glucagon without the liver responding to it properly.

How central glucagon is to the derangement of diabetes shows in a mouse experiment from Unger's group. Mice without a glucagon receptor received a double dose of streptozotocin, which destroys the insulin-producing beta cells. Ordinary mice became severely hyperglycaemic, developed ketones, wasted away and had to be killed after six weeks. The mice without the receptor showed none of those signs, with normal fasting glucose and normal glucose tolerance, despite equal destruction of beta cells (Lee 2011). Without glucagon action, insulin deficiency in mice does not lead to diabetes.

Energy expenditure: the effect that makes the combinations interesting

That glucagon raises energy expenditure has been measured directly in people. Tan and colleagues at Imperial College London gave ten volunteers with overweight or obesity, without diabetes, four infusions in random order: placebo, GLP-1 alone, glucagon alone and both together. GLP-1 did not change resting expenditure. Glucagon raised it clearly, and the combination did so to the same degree. Glucagon alone let plasma glucose rise; as soon as GLP-1 was added, that rise quickly disappeared through amplified insulin release (Tan 2013). One experiment thus contains the whole reasoning behind the dual agonists: glucagon supplies the expenditure, GLP-1 neutralises the glucose.

Where that expenditure comes from is less clear. Salem and colleagues from the same group compared, in eleven healthy men, a glucagon infusion of 50 ng per kg per minute with cold exposure. Both raised expenditure by about 15 percent. Cold activated brown fat, visible on a PET scan and in a higher skin temperature at the neck; glucagon did not, and did not raise noradrenaline either (Salem 2016). Glucagon does raise expenditure in people, but not through brown fat. The liver itself, with its higher oxygen consumption under glucagon, is the most likely source, and that has not been measured directly in people.

What a receptor agonist does differently, and why always in combination

The glucagon receptor is a G-protein-coupled receptor from the same family as the GLP-1 and GIP receptors. A selective glucagon agonist exists as an emergency drug for hypoglycaemia, and beyond that it does not: chronic activation of this receptor alone would raise blood glucose. The clinically studied compounds are therefore all dual or triple agonists, in which glucagon activity is built in next to GLP-1 activity, and in retatrutide next to GIP activity as well.

The design goes back to the work of Day and colleagues in 2009. They modified the glucagon molecule so that it lost its selectivity and began to activate the GLP-1 receptor too. Two variants, differing only in their degree of glucagon activity, were given weekly to obese mice. Fat mass and glucose tolerance normalised, through less food intake and more expenditure at once (Day 2009). The lesson of that study is that the ratio between the two receptor activities decides the result: too little glucagon adds nothing, too much drives glucose up.

The drugs that followed differ in exactly that ratio. Cotadutide, survodutide and mazdutide are GLP-1/glucagon agonists with different balances; retatrutide adds GIP. What the investigators look for in each of these compounds is an extra effect on liver and expenditure on top of what GLP-1 already does.

What the studies in people show

Liver

The liver studies are the most specific test of the glucagon component. Cotadutide was given daily for 54 weeks to 834 adults with overweight and type 2 diabetes, at 100, 200 or 300 µg, alongside placebo and an open-label arm with liraglutide 1.8 mg. HbA1c and weight fell relative to placebo. At 300 µg, liver enzymes, the propeptide of type III collagen and two fibrosis scores improved as well, while with liraglutide they did not. Weight loss with 200 µg was comparable to liraglutide and with 300 µg greater. Nausea occurred in 35 percent and vomiting in 17 percent, decreasing over time (Nahra 2021). The liver improvement was an ad hoc analysis, not a prespecified endpoint.

Survodutide was then tested in a trial with liver biopsies. 293 adults with proven MASH and fibrosis stage F1 to F3 received 48 weeks of weekly 2.4, 4.8 or 6.0 mg or placebo. Improvement in MASH without worsening of fibrosis occurred in 47, 62 and 43 percent, against 14 percent on placebo. A decrease in liver fat of at least 30 percent was reached by 63, 67 and 57 percent against 14 percent. Improvement in fibrosis by at least one stage: 34, 36 and 34 percent against 22 percent. Nausea occurred in 66 percent against 23, diarrhoea in 49 against 23 and vomiting in 41 against 4 percent; serious events in 8 against 7 percent (Sanyal 2024). This is human evidence at tissue level, and it is phase 2.

Weight

Survodutide was given weekly for 46 weeks to 387 participants with a BMI of 27 or higher and no diabetes, at doses from 0.6 to 4.8 mg. Weight fell by 6.2, 12.5, 13.2 and 14.9 percent, against 2.8 percent on placebo. Of the 386 treated participants, 60.4 percent completed the 46 weeks. Adverse events occurred in 91 percent on survodutide and 75 percent on placebo, mainly gastrointestinal complaints in 75 against 42 percent (le Roux 2024).

Mazdutide was tested in a phase 3 trial in China: 610 adults with a BMI of 28 or higher, or 24 with a comorbidity, received 48 weeks of weekly 4 or 6 mg or placebo. After 48 weeks, weight was 11.00 and 14.01 percent lower, against a rise of 0.30 percent on placebo. Discontinuation for adverse events: 1.5, 0.5 and 1.0 percent (Ji 2025).

Retatrutide, the triple compound, has the largest numbers. In the phase 2 trial, 338 adults with obesity received 48 weeks of weekly 1, 4, 8 or 12 mg or placebo. Weight fell by 8.7, 17.1, 22.8 and 24.2 percent, against 2.1 percent on placebo. In the 12 mg group, 83 percent reached at least 15 percent weight loss. Gastrointestinal complaints were dose-dependent and decreased with a lower starting dose of 2 rather than 4 mg. Heart rate rose dose-dependently, with a peak at 24 weeks and a decline thereafter (Jastreboff 2023).

The phase 3 results appeared in 2026. TRIUMPH-1, the largest published trial, randomised 2339 adults with obesity without diabetes to weekly 4, 9 or 12 mg retatrutide or placebo for 80 weeks. Weight fell by 17.6, 23.7 and 25.0 percent, against 3.9 percent on placebo, a difference of 21.0 percentage points at the highest dose. In the 574 participants with knee osteoarthritis the pain score fell by 3.4, 3.9 and 4.1 points against 2.5 on placebo; in the 243 participants with obstructive sleep apnoea the number of breathing pauses per hour fell by 22.8, 34.3 and 32.1 against 9.6 (Jastreboff 2026). TRIUMPH-2 randomised 1152 adults with obesity and type 2 diabetes to weekly 4, 9 or 12 mg retatrutide or placebo for 80 weeks. Weight fell by 11.9, 16.8 and 18.8 percent, against 5.1 percent on placebo, a difference of 13.8 percentage points at the highest dose with an interval of 11.8 to 15.8. Diarrhoea occurred in 27, 34 and 34 percent against 13 percent, nausea in 14, 21 and 28 percent against 8 percent. Two adverse events that do not stand out with the other incretin drugs were more frequent here: low blood pressure in 1, 5 and 6 percent against less than 1 percent, and dysaesthesia, an altered sensation of the skin, in 4, 6 and 7 percent against 1 percent. Permanent discontinuation for adverse events ran at 4, 12 and 8 percent, against 5 percent on placebo (Bellido 2026). TRANSCEND-T2D-1 tested retatrutide as sole therapy in 537 people with type 2 diabetes inadequately controlled by diet and exercise, for 40 weeks. HbA1c fell by 1.69, 1.86 and 1.94 percentage points against 0.81 on placebo; weight by 11.5, 13.9 and 15.3 percent against 2.6 percent. No severe hypoglycaemia occurred (Bajaj 2026).

What the glucagon component contributes to this

None of these trials compares the drug with a version lacking glucagon activity. The direct comparison with a GLP-1 agonist in the same trial exists only for cotadutide, where the liver improvement appeared at 300 µg and did not with liraglutide. That is the strongest human indication that the glucagon component does something of its own in the liver. For weight and expenditure, the contribution of glucagon in people has not been isolated; Tan's infusion study shows the effect on expenditure exists, not how large it is after a year of weekly injections.

Adverse events and limitations

The gastrointestinal complaints of these drugs are the same in kind as with GLP-1 agonists, and in the survodutide trials higher in frequency. Retatrutide adds the rise in heart rate, the low blood pressure and the dysaesthesia, whose mechanism has not been clarified. In the survodutide obesity trial, 40 percent did not complete treatment, which complicates the reading of the weight outcome.

The mirror-image approach teaches what else glucagon does in the liver. Guzman and colleagues gave 65 patients with type 2 diabetes six months of 20 mg of the glucagon receptor antagonist LY2409021, alongside 68 on placebo and 41 on sitagliptin. HbA1c fell 0.77 percentage points more than with placebo. But the liver fat fraction on MRI rose by 4.44 percentage points relative to placebo, ALT by 10.7 U/l, systolic blood pressure by 4.3 mmHg, and weight and total cholesterol increased. All effects were reversible (Guzman 2017). Block the glucagon receptor and glucose falls while liver fat rises. That makes it plausible that activating does the opposite, and it is why the antagonists were abandoned and the agonists went on.

The largest limitation is the missing dissection. The animal studies show that the ratio of glucagon to GLP-1 activity decides the result; in people that ratio is fixed per drug and has not been varied. What the trials need is a comparison of two molecules that differ only in glucagon activity, with liver fat, expenditure and body composition as endpoints. Until it exists, the evidence for the glucagon component stays convincing in the liver, plausible for expenditure, and inseparable from GLP-1 for weight.

Retatrutide is available from Peptalis as a research compound. What stands above are outcomes of clinical trials with the pharmaceutical drug in the populations and regimens described; it says nothing about the product as such, and Peptalis makes no statements about that.

About the authorMVMichel van der VeenRegistered Nurse · Science Editor, Peptalis

Registered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.

Sources checked via PubMed · 17 references

Compound profilesEvidence reviewsQualityIN THIS ARTICLE
  • The body's own hormone
  • Energy expenditure: the effect that makes the combinations interesting
  • What a receptor agonist does differently, and why always in combination
  • What the studies in people show
  • Adverse events and limitations
SCIENTIFIC REFERENCESView all references →RELATED COMPOUNDRetatrutide →RELATED ARTICLES

Compounds in this article

For laboratory research use only. Not for human use.

SCIENTIFIC REFERENCES

These references are provided for informational and research purposes only. They do not constitute medical advice.

  1. 01ReviewThe metabolic actions of glucagon revisited.Habegger KM, et al. Nat Rev Endocrinol. 2010.View on PubMed →DOI →
  2. 02ReviewThe New Biology and Pharmacology of Glucagon.Müller TD, et al. Physiol Rev. 2017.View on PubMed →DOI →
  3. 03ReviewThe Liver-α-Cell Axis and Type 2 Diabetes.Wewer Albrechtsen NJ, et al. Endocr Rev. 2019.View on PubMed →DOI →
  4. 04Preclinical · animalGlucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice.Lee Y, et al. Diabetes. 2011.View on PubMed →DOI →
  5. 05Human RCTCoadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia.Tan TM, et al. Diabetes. 2013.View on PubMed →DOI →
  6. 06Human studyGlucagon increases energy expenditure independently of brown adipose tissue activation in humans.Salem V, et al. Diabetes Obes Metab. 2016.View on PubMed →DOI →
  7. 07Preclinical · animalA new glucagon and GLP-1 co-agonist eliminates obesity in rodents.Day JW, et al. Nat Chem Biol. 2009.View on PubMed →DOI →
  8. 08Human RCTEffects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study.Nahra R, et al. Diabetes Care. 2021.View on PubMed →DOI →
  9. 09Human RCTA Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.Sanyal AJ, et al. N Engl J Med. 2024.View on PubMed →DOI →
  10. 10Human RCTGlucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial.le Roux CW, et al. Lancet Diabetes Endocrinol. 2024.View on PubMed →DOI →
  11. 11Human RCTOnce-Weekly Mazdutide in Chinese Adults with Obesity or Overweight.Ji L, et al. N Engl J Med. 2025.View on PubMed →DOI →
  12. 12Human RCTTriple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial.Jastreboff AM, et al. N Engl J Med. 2023.View on PubMed →DOI →
  13. 13Human RCTRetatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial.Rosenstock J, et al. Lancet. 2023.View on PubMed →DOI →
  14. 14Human RCTRetatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial.Bellido V, et al. Lancet. 2026.View on PubMed →DOI →
  15. 15Human RCTEfficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.Bajaj HS, et al. Lancet. 2026.View on PubMed →DOI →
  16. 16Human RCTTreatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.Guzman CB, et al. Diabetes Obes Metab. 2017.View on PubMed →DOI →
  17. 17Human RCTRetatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity.Jastreboff AM, et al. N Engl J Med. 2026.View on PubMed →DOI →

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