What Is Oxyntomodulin? The Gut Peptide Behind Dual Agonists

Peptide science

Oxyntomodulin is a 37-amino-acid gut peptide that the body has been using as a dual receptor agonist for far longer than the pharmaceutical industry has had a name for the concept. It never became a drug. Its half-life is roughly twelve minutes, which meant the human trials that established its effects required three injections a day, before every meal. But the pharmacology it demonstrated — hit the GLP-1 receptor and the glucagon receptor at once and you lose more weight than either alone — became the design brief for an entire class of molecules now in late-stage development or, in one case, already approved.

What is oxyntomodulin?

Oxyntomodulin comes from proglucagon, the same 158-residue precursor that yields glucagon, GLP-1 and GLP-2. Which peptides actually appear depends entirely on which prohormone convertase is present in the cell — a clean illustration of the principle covered in prohormone processing.

In pancreatic alpha cells, PC2 cuts at the lysine-arginine sites and liberates glucagon as a free 29-residue peptide. In the enteroendocrine L-cells of the intestine, PC1/3 does the cutting instead, and one of its products is proglucagon residues 33 to 69: the 29 residues of glucagon with an eight-residue tail still attached. That is oxyntomodulin. It weighs roughly 4.4 kilodaltons. Extend the cut back to the start of the precursor and you get glicentin, residues 1 to 69.

The name is a fossil of how it was found. Early work showed that this gut-derived material inhibited acid secretion from the oxyntic (acid-producing) glands of the stomach — a modulator of the oxyntic gland, hence oxyntomodulin. A 1989 study in six volunteers confirmed it in humans: infused oxyntomodulin almost abolished basal gastric acid secretion, cut postprandial acid secretion by about 35 per cent, and roughly doubled the time taken to empty half of a meal from the stomach.

Why an eight-residue tail changes everything

Those eight extra residues do not create a new receptor — no oxyntomodulin-specific receptor has ever been identified, and everything oxyntomodulin does runs through the GLP-1 receptor and the glucagon receptor. What they do is change the balance. In cyclic AMP assays on cells expressing the human receptors, GLP-1 was about 17 times more potent than oxyntomodulin at the GLP-1 receptor, and glucagon about 7.8 times more potent than oxyntomodulin at the glucagon receptor. Oxyntomodulin is therefore a genuinely dual, and genuinely mediocre, agonist — which is exactly what makes it interesting as a template.

The two arms are dissociable, and this is the part that matters for drug design. Blocking the GLP-1 receptor abolishes the reduction in food intake but leaves the increase in oxygen consumption intact; remove glucagon-receptor activity and the energy-expenditure effect disappears. Appetite comes from one receptor, thermogenesis from the other.

What the human studies showed

The human evidence base for native oxyntomodulin is real but small, and it is worth being precise about its size.

• Acute infusion (2003). Thirteen healthy volunteers, randomised, double-blind, placebo-controlled crossover, 90 minutes of intravenous oxyntomodulin. Energy intake at a buffet meal fell 19.3 per cent, cumulative 12-hour intake fell 11.3 per cent, and preprandial ghrelin was substantially suppressed. Notably, it did not cause nausea or change how palatable the food was rated.
• Four weeks of self-injection (2005). Overweight and obese volunteers injected subcutaneously three times daily, 30 minutes before each meal, for four weeks. Body weight fell 2.3 kg on oxyntomodulin against 0.5 kg on saline. The appetite effect did not wear off over the month.
• Energy expenditure (2006). Fifteen overweight and obese participants, four days of pre-prandial dosing. Resting energy expenditure did not change; activity-related energy expenditure rose about 26 per cent and total energy expenditure about 9 per cent.

Three trials, dozens of participants, weeks rather than years. That is the entire clinical record for the native peptide.

Why it never became a drug

Pharmacokinetics killed it. Circulating oxyntomodulin has a half-life of about 12 minutes in humans. It is a substrate for DPP-4, it is cleared renally, and it is also attacked by other ectopeptidases. Nobody was going to take a three-times-daily pre-meal injection for chronic weight management, and the exposure achievable with that schedule was marginal.

The fixes are now standard practice in the field and are covered in more depth in our guide to peptide half-life extension: substitute the second residue with aminoisobutyric acid so DPP-4 cannot cleave the N-terminus, then attach a fatty acid so the molecule binds albumin and stops disappearing through the glomerulus. Do both and a twelve-minute peptide becomes a once-weekly injection.

The molecules that came out of it

Mazdutide is the one that has crossed the line. A long-acting GLP-1 and glucagon receptor dual agonist, it was approved by China’s National Medical Products Administration in June 2025 for chronic weight management in adults with overweight or obesity — described by its developer as the first dual glucagon/GLP-1 receptor agonist approved anywhere for weight loss.

Survodutide (Boehringer Ingelheim) is in Phase 3 development in the SYNCHRONIZE programme and is not approved. Cotadutide (AstraZeneca) reached Phase 2b in obesity with type 2 diabetes before the once-daily programme was discontinued in favour of a once-weekly successor. Efinopegdutide (Merck) was repositioned away from obesity toward metabolic dysfunction-associated steatohepatitis, where it holds FDA Fast Track designation but no approval.

Retatrutide takes the idea one step further by adding GIP receptor agonism, making it a triple agonist. As of Eli Lilly’s June 2026 disclosures it remains an investigational molecule, legally available only to clinical trial participants. Its Phase 3 TRIUMPH programme has reported substantial results — in TRIUMPH-1, 2,339 participants randomised over 80 weeks, mean weight reduction reached 28.3 per cent on the highest dose — but reported trial results are not a regulatory decision, and no approval exists. If you are comparing the current approved options instead, see semaglutide versus tirzepatide.

Frequently asked questions

Is oxyntomodulin a GLP-1 drug?

No. It is a proglucagon-derived peptide that happens to activate the GLP-1 receptor as one of two targets, and it is markedly weaker there than GLP-1 itself. It is not a GLP-1 analogue and it is not an approved drug of any kind.

Does oxyntomodulin have its own receptor?

None has been identified. All of its known signalling is accounted for by the GLP-1 receptor and the glucagon receptor.

If glucagon raises blood sugar, why add a glucagon receptor agonist?

Because in combination the incretin arm dominates glycaemic control while the glucagon arm contributes energy expenditure and hepatic lipid handling. The empirical answer is that these molecules lower rather than raise glucose in the trials that have measured it — mazdutide, a glucagon/GLP-1 dual agonist, is approved in China with glycaemic data behind it.

Why is it called oxyntomodulin rather than something to do with appetite?

Because it was characterised first as an inhibitor of gastric acid secretion from the oxyntic glands. The appetite and energy-expenditure work came later, and the name never caught up.

References

Informational only — not medical advice. Nothing here is a treatment recommendation or a dose for any person; prescribing information for linaclotide and plecanatide is linked above and should be read in full by anyone with a clinical question. Consult a qualified healthcare professional about your own care. Intended for readers 21 and over.