Oxyntomodulin, GLP-1, and glucagon each reduced food intake by about 15% in healthy men, but combining GLP-1 and glucagon provided no additional benefit, challenging assumptions about dual-receptor weight loss strategies.
No additive effectGLP-1+glucagon combined reduced food intake by the same amount (~15%) as either peptide alone in 15 healthy men
What the researchers found
In a rigorous head-to-head comparison, oxyntomodulin, GLP-1, glucagon, and GLP-1+glucagon combined all reduced food intake by similar amounts compared to saline (roughly 15-17% reduction). However, combining GLP-1 and glucagon together did not produce an additive effect — the combination was no better than either peptide alone.
The mechanisms differed: oxyntomodulin, GLP-1, and GLP-1+glucagon slowed gastric emptying and reduced appetite scores, while glucagon reduced food intake without affecting either gastric emptying or appetite. No peptide infusion significantly changed resting energy expenditure compared to saline.
Why it matters
Oxyntomodulin activates both GLP-1 and glucagon receptors, and the drug industry has bet heavily on dual-agonists (like survodutide) that mimic this. This study challenges a key assumption: that activating both receptors simultaneously produces additive benefits. The finding that GLP-1+glucagon was no better than either alone at reducing food intake suggests oxyntomodulin's weight-loss mechanism may not be simply the sum of its receptor activities — there may be something else at play.
The numbers in context
n=15 healthy males · Age 22 (18-32) · BMI 23 (21-26) · GLP-1: 1 pmol/kg/min · Glucagon: 0.86 pmol/kg/min · Oxyntomodulin: 3 pmol/kg/min · Food intake (g): saline 811, GLP-1 669, glucagon 686, OXM 689, GLP-1+glucagon 688 · No REE changes
How the study worked
Double-blinded, randomized, crossover study in 15 healthy young men. Each participant received five 4-hour liquid meal tests during infusion of saline, GLP-1, glucagon, oxyntomodulin, or GLP-1+glucagon on separate occasions. Researchers measured resting energy expenditure (oxygen uptake), gastric emptying, composite appetite scores, and ad libitum food intake.
Who was studied
15 young healthy male volunteers, aged 18-32 years, BMI 21-26 kg/m²
What this study cannot tell us
Small sample size (n=15) of only young, lean, healthy men — results may differ in obese individuals or women. Acute infusion study (4 hours) may not reflect chronic effects relevant to weight management. The doses tested may not have been optimal to demonstrate additive effects. Only one dose combination of GLP-1+glucagon was tested.
How to read the evidence
This is a moderate-quality human study using a rigorous double-blind, randomized, crossover design — the gold standard for within-subject comparisons. Published in the Journal of Clinical Endocrinology & Metabolism (a top journal). However, the small sample (n=15) of healthy lean men and acute dosing protocol limit generalizability.
When this study was published
Published in 2015, this study predates the current wave of dual-agonist drugs in development. Its findings remain highly relevant as GLP-1/glucagon dual agonists advance through clinical trials.
The bigger picture
The pharmaceutical industry has invested billions in dual GLP-1/glucagon agonists (like survodutide, efinopegdutide, and mazdutide) based on the theory that hitting both receptors simultaneously produces superior metabolic effects. This study's finding that combining GLP-1 and glucagon infusions didn't produce additive appetite suppression complicates that narrative. It suggests the clinical benefits of dual agonists may come from mechanisms beyond simple receptor co-activation — perhaps from receptor interactions, timing, or downstream signaling differences.
Questions still open
- Would combining GLP-1 and glucagon show additive effects on food intake at different doses, in obese subjects, or over longer treatment durations?
- If oxyntomodulin's weight-loss effect isn't simply dual receptor activation, what additional mechanisms does it employ?
- Does glucagon's ability to reduce food intake without affecting appetite or gastric emptying suggest a distinct central mechanism?
Common questions
What is oxyntomodulin and why is it important for weight loss?
Why is it surprising that combining GLP-1 and glucagon wasn't more effective?
Read the original research
Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure.
The Journal of clinical endocrinology and metabolism, 100(12), 4541-52
Citation
Bagger, Jonatan Ising; Holst, Jens Juul; Hartmann, Bolette; Andersen, Birgitte; Knop, Filip Krag; Vilsbøll, Tina. (2015). Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure.. The Journal of clinical endocrinology and metabolism, 100(12), 4541-52. https://doi.org/10.1210/jc.2015-2335