Oxyntomodulin: The Dual Agonist Your Gut Makes
Glucagon Biology
37 amino acids
Oxyntomodulin is a 37-amino-acid gut hormone that activates both GLP-1 and glucagon receptors, reducing food intake and increasing energy expenditure through distinct receptor-dependent pathways.
Baggio et al., Gastroenterology, 2004
Baggio et al., Gastroenterology, 2004
View as imageYour gut already produces a molecule that does what the newest weight loss drugs are designed to do: activate two metabolic receptors at once. Oxyntomodulin (OXM) is a 37-amino-acid peptide secreted by intestinal L-cells after meals that simultaneously engages the GLP-1 receptor and the glucagon receptor. It reduces appetite through one pathway and increases energy expenditure through the other. Native OXM breaks down in minutes, which limited its direct clinical utility. But OXM's dual-receptor pharmacology became the blueprint for a new class of drugs, including survodutide (BI 456906), which achieved up to 18.7% body weight loss in a phase 2 trial.[1] OXM sits at the intersection of gut hormone biology and modern metabolic drug design. This article covers the peptide itself, how it works, what human studies have shown, and where the OXM-inspired drug pipeline stands.
Key Takeaways
- Oxyntomodulin is a 37-amino-acid proglucagon-derived peptide that activates both GLP-1 and glucagon receptors, with appetite suppression mediated through GLP-1R and energy expenditure through GCGR (Baggio et al., Gastroenterology, 2004)
- Native OXM infusion in humans reduced ad libitum food intake by 19.3% and suppressed ghrelin levels, with weight loss of 2.3 kg over 4 weeks versus 0.5 kg for placebo (Bagger et al., JCEM, 2015)
- An OXM analogue increased resting energy expenditure specifically through glucagon receptor activation, with no energy expenditure increase when GCGR activity was blocked (Scott et al., Peptides, 2018)
- Survodutide, a GLP-1/glucagon dual agonist inspired by OXM's pharmacology, produced up to 18.7% weight loss at 46 weeks in a phase 2 obesity trial (le Roux et al., Lancet Diabetes Endocrinol, 2024)
- Native OXM improved insulin secretion rates independent of weight loss in obese humans with and without type 2 diabetes (Shankar et al., Diabetes, 2018)
- Combined subcutaneous GLP-1, OXM, and PYY infusion mimicking post-bariatric hormone profiles produced 4.4 kg weight loss over 4 weeks versus 2.5 kg for placebo (Behary et al., Diabetes Care, 2019)
What Is Oxyntomodulin?
Oxyntomodulin is a product of the proglucagon gene (GCG), the same gene that encodes glucagon and GLP-1. The proglucagon precursor contains 160 amino acids and is processed differently depending on the tissue. In pancreatic alpha cells, prohormone convertase 2 (PC2) cleaves it to produce glucagon. In intestinal L-cells, prohormone convertase 1/3 (PC1/3) cleaves it to produce GLP-1, GLP-2, and OXM.[2]
Structurally, OXM consists of glucagon's full 29-amino-acid sequence plus an 8-amino-acid C-terminal extension called intervening peptide 1 (IP-1). This octapeptide tail changes the molecule's receptor pharmacology. While glucagon acts primarily through the glucagon receptor (GCGR) and GLP-1 acts through the GLP-1 receptor (GLP-1R), OXM activates both, though with lower affinity than either native ligand at its respective receptor.[3]
No dedicated OXM receptor has been identified despite decades of searching. The current consensus is that OXM's biological effects arise entirely from partial agonism at two known receptors rather than through a unique receptor of its own.[3]
L-cells in the jejunum and ileum secrete OXM into the circulation after meals, alongside GLP-1 and PYY. Circulating OXM levels rise within 15-30 minutes of eating and peak at approximately 30-60 minutes. The peptide has a plasma half-life of roughly 12 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) and other peptidases. This short half-life means endogenous OXM acts as a brief postprandial signal rather than a sustained hormonal influence.[2]
How Oxyntomodulin Reduces Appetite
The appetite-suppressing effects of OXM are mediated predominantly through the GLP-1 receptor. Baggio and colleagues demonstrated this in 2004 using knockout mice: OXM's anorectic effects were completely abolished in GLP-1R-knockout mice but fully preserved in glucagon receptor-knockout mice.[4] Central administration of OXM activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract, the same appetite-regulating centers activated by the GLP-1R agonist exendin-4.
There is one important difference from GLP-1 itself. While both OXM and the GLP-1R agonist exendin-4 reduced food intake when administered directly into the brain (intracerebroventricular injection), only exendin-4 reliably reduced food intake after peripheral (intraperitoneal) administration at comparable doses.[4] This suggests OXM may access central appetite circuits differently than GLP-1R agonists do, potentially requiring higher peripheral concentrations to produce equivalent central effects.
In human studies, OXM infusion reduced ad libitum food intake at a buffet meal and suppressed circulating ghrelin levels. Bagger et al. (2015) conducted a double-blinded, randomized crossover study comparing intravenous infusions of OXM, glucagon, GLP-1, and combined glucagon + GLP-1 in healthy volunteers. OXM infusion reduced food intake and hunger scores, and the combined glucagon + GLP-1 infusion most closely replicated OXM's appetite and energy expenditure effects, consistent with OXM functioning as a natural dual agonist.[5]
How Oxyntomodulin Increases Energy Expenditure
The energy expenditure side of OXM's profile works through the glucagon receptor. Scott et al. (2018) tested an OXM analogue designed to have varying ratios of GLP-1R to GCGR activity and found that the increase in energy expenditure depended specifically on glucagon receptor activation. When GCGR activity was eliminated, there was no increase in energy expenditure, even though the appetite-suppressing effect (via GLP-1R) remained intact.[6]
This division of labor is central to OXM's appeal as a drug design template. GLP-1 receptor agonists like semaglutide reduce body weight primarily by decreasing caloric intake. Adding glucagon receptor activation on top of GLP-1R activation provides an additional weight loss mechanism: increased energy expenditure. Human studies with subcutaneous OXM have shown a 26% increase in activity-related energy expenditure and a 9.4% increase in total energy expenditure.[7]
The glucagon receptor contribution also explains why OXM-based dual agonists may be particularly effective for liver fat reduction. Glucagon receptor activation stimulates hepatic lipid oxidation and decreases lipogenesis. Glucagon receptor antagonists lower blood glucose but tend to increase liver fat, providing indirect evidence that glucagon receptor activation does the opposite.[8]
OXM and Blood Sugar Regulation
Native OXM has glucoregulatory effects that extend beyond what weight loss alone would explain. Shankar et al. (2018) evaluated intravenous OXM infusion during graded glucose infusions in obese humans with and without type 2 diabetes. OXM increased insulin secretion rates in a glucose-dependent manner, meaning it enhanced insulin release when glucose was elevated but did not cause hypoglycemia at normal glucose levels. These effects occurred acutely, before any weight loss could occur.[9]
This glucose-dependent insulinotropic effect is characteristic of GLP-1R activation and is one of the safety advantages of incretin-based therapies: they amplify the insulin response to glucose without triggering insulin release independently.
OXM may also serve as a metabolic biomarker. Zwierz et al. (2025) evaluated circulating OXM levels in adults with obesity and found that OXM concentrations correlated with metabolic risk stratification, suggesting the peptide's endogenous levels may carry diagnostic information beyond its pharmacological potential.[10]
The Combined Gut Hormone Approach
One of the most interesting lines of OXM research involves using it alongside other gut hormones to replicate the hormonal profile seen after bariatric surgery. Roux-en-Y gastric bypass dramatically increases postprandial secretion of GLP-1, OXM, and PYY. Behary et al. (2019) tested whether subcutaneous infusion of all three hormones ("GOP") could reproduce these effects without surgery.[11]
In obese patients with prediabetes or type 2 diabetes, 4 weeks of GOP infusion produced 4.4 kg mean weight loss versus 2.5 kg for placebo. The combination also improved glycemic control: HbA1c fell by 0.6% in the GOP group. While 4 weeks is a short duration, this study provided proof of concept that multi-hormone therapy mimicking the post-bariatric endocrine milieu could produce meaningful metabolic improvements.
Nielsen et al. (2020) found that pre-operative OXM and glicentin levels predicted the degree of weight loss and changes in food preferences after bariatric surgery, suggesting that baseline gut hormone profiles may help identify which patients will respond most favorably to surgical or pharmacological interventions.[12]
From Oxyntomodulin to Survodutide
OXM's short half-life (~12 minutes) made it impractical as a therapeutic agent in its native form. Drug developers instead used OXM's dual-receptor pharmacology as a blueprint. The goal: build molecules that activate both GLP-1R and GCGR with long enough half-lives for weekly or monthly dosing.[13]
Survodutide (BI 456906, developed by Boehringer Ingelheim and Zealand Pharma) is the most advanced OXM-inspired dual agonist. It activates both GLP-1R and GCGR with a ratio designed to balance appetite suppression, energy expenditure, and hepatic fat reduction.
In a phase 2, randomized, double-blind, placebo-controlled trial, survodutide produced dose-dependent weight loss in adults with obesity (BMI 27 or higher). At the highest dose (4.8 mg weekly), participants lost a mean of 14.9% of body weight at 46 weeks. The 6.0 mg dose (tested with a slower titration) achieved 18.7% weight loss.[1] For context, this is comparable to the weight loss seen with tirzepatide, the dual GLP-1/GIP agonist, but through a different receptor combination.
Survodutide has also shown promise for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). In a phase 2 trial in patients with MASH, survodutide achieved MASH resolution without worsening of fibrosis in a significantly higher proportion of treated patients compared to placebo, with dose-dependent reductions in liver fat content.[14] Glucagon receptor activation drives hepatic lipid oxidation directly, which may explain why GLP-1/glucagon dual agonists appear to have stronger liver-specific effects than GLP-1R-only agonists.
The most common side effects of survodutide in clinical trials were gastrointestinal: nausea, diarrhea, and vomiting, similar to the side effect profile of GLP-1 receptor agonists as a class. These events were generally mild to moderate and decreased over time with dose titration.[1]
Survodutide is currently in phase 3 trials (the SYNCHRONIZE program) for both obesity and MASH. The SYNCHRONIZE-1 trial enrolled participants with a mean BMI of 38.2 kg/m2, and the SYNCHRONIZE-2 trial focuses on people with obesity and type 2 diabetes. Efficacy data from these pivotal trials are pending.[15]
Other OXM-Inspired Programs
Survodutide is not the only molecule built on the OXM template. Several other GLP-1/glucagon dual agonists are in various stages of development:
DA-1726 (NeuroBo Pharmaceuticals) is a novel OXM analogue that received FDA IND clearance in 2024, with a phase 1 trial initiated for obesity treatment. Early preclinical data suggested favorable receptor binding ratios.
OPKO/Entera Bio announced a collaboration in 2025 to develop an oral GLP-1/glucagon dual agonist combining OPKO's long-acting OXM analogue with Entera's oral delivery technology (N-Tab). A phase 1 study with the subcutaneous formulation is expected to report data by late 2026.
The broader pipeline also includes triple agonists (GLP-1/GIP/glucagon) like retatrutide, which add GIP receptor activation to the dual agonist framework.[16] All of these programs owe an intellectual debt to OXM: the observation that a single natural peptide activating two receptors could outperform single-receptor activation launched an entire field of multi-agonist drug design. These multi-receptor approaches all trace their conceptual origins back to OXM's demonstration that activating two metabolic receptors simultaneously produces effects greater than either alone. For a complete overview of the glucagon receptor's role in this pharmacology, see our glucagon pillar article.
Limitations and Open Questions
OXM research has several gaps that are worth noting honestly.
No OXM-specific receptor. After decades of research, no unique OXM receptor has been found. If all of OXM's effects are mediated through GLP-1R and GCGR, then synthetic dual agonists designed for those receptors may replicate or exceed OXM's effects. This makes OXM scientifically interesting but potentially redundant as a drug candidate in its native form.
Short-duration human trials. The clinical trials with native OXM (Wynne, Cohen, Bagger) lasted 4 weeks or less. Whether OXM's weight loss effects are sustained over longer durations with native peptide is unknown, though the survodutide trials provide indirect evidence that the dual-agonist concept works long-term.
Glucagon receptor activation carries theoretical risk. Glucagon raises blood glucose. While the GLP-1R component of dual agonists counterbalances this, individuals with insulin resistance or brittle diabetes could theoretically experience glucose dysregulation. Phase 2 survodutide data showed no increase in clinically significant hyperglycemia, but real-world safety with diverse patient populations remains to be established.
Most mechanistic data comes from rodents. The elegant GLP-1R-knockout and GCGR-knockout mouse studies that dissected OXM's receptor dependencies may not fully translate to human physiology, where receptor expression patterns and metabolic regulation differ.
How Gut Peptide Alterations Connect to Metabolic Disease
Recent work has examined how endogenous gut peptide levels, including OXM, change in metabolic disease states. In type 2 diabetes and obesity, the postprandial secretion profile of gut peptides is altered: GLP-1 and OXM responses are blunted, while ghrelin suppression is impaired.[17] Tzeravini et al. (2026) reviewed these alterations across multiple studies and found consistent patterns of reduced incretin and OXM secretion in metabolically unhealthy obesity compared to metabolically healthy obesity, even at similar BMI levels. This creates a hormonal environment that favors continued overeating and reduced energy expenditure. Understanding these alterations provides rationale for why replacing or supplementing these hormones pharmacologically can produce metabolic benefit. It also explains part of why bariatric surgery, which physically reroutes food to maximize L-cell exposure, produces such dramatic hormonal changes and sustained weight loss. The counter-regulatory response also depends on intact peptide signaling to prevent hypoglycemia during these interventions.
The Bottom Line
Oxyntomodulin is a 37-amino-acid gut hormone that naturally activates both GLP-1 and glucagon receptors, suppressing appetite through one and increasing energy expenditure through the other. While native OXM degrades too quickly for direct therapeutic use, its dual-receptor pharmacology inspired survodutide and other GLP-1/glucagon dual agonists now in phase 3 trials. The evidence from native OXM studies and OXM-inspired drugs consistently shows that dual receptor activation produces metabolic benefits, including weight loss, glucose regulation, and liver fat reduction, that exceed what GLP-1R activation alone achieves.