Triple agonism GLP-1 + GIP + glucagon — how simultaneous pathway stimulation reshapes metabolism

Triple agonism is a pharmacological strategy based on the simultaneous stimulation of three hormone receptors that regulate metabolism: GLP-1, GIP and glucagon. Rather than acting on a single pathway, one molecule activates three in parallel — which in metabolism research is analysed as a qualitatively different approach from single or dual agonism. The most extensively studied triple agonist is retatrutide.

This article is educational in nature and constitutes a review of the published scientific literature. The substances described (semaglutide, tirzepatide, retatrutide) are investigational or approved medicines, examined here in a scientific context. It is neither medical advice nor a suggestion to use any substance.

From one receptor to three — escalating the strategy

The metabolic pharmacology of the past decade has followed a clear logic: adding successive points of engagement.

• Monoagonism (GLP-1). The starting point was agonism of the GLP-1 receptor — a single incretin pathway. It is represented by semaglutide.
• Dual agonism (GLP-1 + GIP). The next step was the addition of the GIP receptor, the second incretin. It is represented by tirzepatide.
• Triple agonism (GLP-1 + GIP + glucagon). The most recent stage is the addition of the glucagon receptor — represented by retatrutide.

The mechanisms of action of each of these three incretins in isolation — how GLP-1, GIP and glucagon regulate insulin secretion, satiety and energy balance — are described in detail in a separate article on incretins within this knowledge base. The focus here is something else: why combining them in a single molecule produces an effect different from the sum of its parts — and why adding glucagon, of all hormones, is the least obvious yet most interesting move.

The glucagon paradox — why add a hormone that raises blood sugar

Adding glucagon agonism to a molecule intended for metabolism research seems, at first glance, counterintuitive. Glucagon is, after all, a hormone antagonistic to insulin: in the liver it intensifies glucose release, raising its concentration in the blood. Why, then, should it feature in a molecule studied in the context of metabolic disorders?

The answer lies in glucagon’s other, less familiar actions. Beyond its effect on glucose, glucagon increases energy expenditure, intensifies lipolysis (the breakdown of fat) and the oxidation of fatty acids in the liver. It is precisely these effects that make it of interest to metabolic pharmacology.

The mechanism of triple agonism rests on the mutual balancing of pathways. The hyperglycaemic action of glucagon is offset by the strong, insulinotropic and glucose-dependent action of the GLP-1 and GIP components — which lower glycaemia. As a result, in models and clinical studies, the “cost” in the form of rising glucose is neutralised, while the “benefit” in the form of increased energy expenditure and lipolysis remains. This is the essence of crosstalk: the three pathways do not sum linearly but mutually modulate one another’s effects (Coskun et al., 2022).

Three receptors, three metabolic levers

Each of the three receptors brings a distinct mechanism to the molecule — and it is their complementarity, not their number alone, that lies at the heart of the strategy.

• GLP-1 — stimulates glucose-dependent insulin secretion, suppresses postprandial glucagon, slows gastric emptying and acts centrally on satiety (hypothalamic signalling).
• GIP — the second incretin; intensifies insulin secretion and influences adipose tissue metabolism and insulin sensitivity. Its role within the combination remains the subject of active research.
• Glucagon — adds the energy-expenditure dimension: it intensifies thermogenesis, lipolysis and hepatic fat oxidation.

In mechanistic terms, a monoagonist acts mainly “on the supply side” — reducing energy intake through satiety. Adding glucagon brings in the “expenditure side” — increasing energy use. A triple agonist therefore acts on both sides of the energy balance simultaneously, which is the theoretical basis for the hypothesis of its distinct metabolic profile (Coskun et al., 2022; Coskun et al., 2018 — for comparison with the dual agonist).

The role of GIP in this arrangement remains, moreover, the most contentious. Counterintuitively, the pharmacological literature is debating whether agonism or antagonism of the GIP receptor is more metabolically favourable — both strategies yield positive effects on body weight in models, probably through different routes. Tirzepatide is a GIP agonist, yet the fact that blocking the same receptor also produces an effect shows how ambiguous incretin biology is. In the context of a triple agonist, this means that simply “adding a receptor” does not settle the question of the molecule’s optimal profile.

The scale of the effect in studies — an escalation of clinical data

Comparing the results of clinical studies of the individual classes reveals a pattern of a metabolic effect that grows with the number of receptors stimulated. The figures below are results reported in human clinical studies — they describe scientific observations, not promises or recommendations.

The pattern is consistent with the mechanistic hypothesis: adding a receptor was associated in the studies with a greater observed metabolic change. Interpretative caution is warranted, however — these are separate studies with different protocols, populations and durations, not a direct head-to-head comparison within a single experiment. The results for retatrutide come from phase II; the full picture from phase III remains the subject of ongoing trials (Rosenstock et al., 2023 — data in type 2 diabetes).

Semaglutide is an approved medicine (Ozempic, Wegovy); tirzepatide is an approved medicine (Mounjaro, Zepbound); retatrutide remains in clinical trials and is not approved as a medicine. The results cited concern clinical studies conducted under medical supervision — they do not pertain to the use of research reagents.

What the studies have yet to settle

The triple-agonism strategy is mechanistically promising, yet a number of open questions remain in the literature:

• The optimal contribution of the individual receptors. Which ratio of GLP-1 : GIP : glucagon activity yields the best profile — this remains under investigation.
• The role of GIP. Whether agonism or antagonism of the GIP receptor is more favourable — this is still a debated question in incretin pharmacology.
• Long-term safety. The data for retatrutide come from phase II studies of limited duration.
• The glucagon component. The long-term effect of chronic glucagon-receptor stimulation on the liver and on carbohydrate metabolism requires further evaluation.

Receptor agonism is not the only combination strategy

It is worth noting that adding successive incretin receptors is not the only route in combinatorial metabolic pharmacology. A parallel strategy is the addition of an entirely different hormonal axis — amylin. The combination of a GLP-1 agonist (semaglutide) with an amylin analogue (cagrilintide), studied as CagriSema, acts not through a further incretin receptor but through the amylin/calcitonin system, which regulates satiety and gastric emptying via a separate route.

This shows that “combination” in metabolic pharmacology has at least two faces: extending incretin agonism (mono → dual → triple, up to retatrutide) and combining different hormonal axes (GLP-1 + amylin). Both strategies pursue the same goal — a stronger effect on body-weight regulation than a single mechanism — but do so via different biological routes. The mechanism of amylin itself and of the CagriSema combination is developed in a separate article within this knowledge base.

Research reagents in the field of incretin agonism

Substances from the incretin-agonist class are the subject of laboratory research into energy metabolism. The One-Peptides catalogue includes, among others:

• Retatrutide (retatrutide 5 mg) — a triple GLP-1/GIP/glucagon agonist, analysed as a reagent in metabolism research; all formats in the Triple G (retatrutide) category.
• GLP-1/GIP (GLP-1/GIP 5 mg) — a dual agonist.
• CagriSema (Sema+Cagri PEN, a semaglutide + cagrilintide blend) — a combination of a GLP-1 agonist with an amylin analogue.

All are chemical reagents intended exclusively for laboratory research (Research Use Only) — they are not medicines, supplements or products for human use, regardless of the fact that the active substances may be identical to investigational or approved medicines. The full mechanism of the individual incretins is described in the article on GLP-1, GIP and glucagon, and the profile of retatrutide itself in a dedicated analysis of the substance. The broader context of metabolic pharmacology is set out in the guide to GLP-1 peptides and metabolism.

Frequently asked questions

What is a triple agonist?

It is a molecule that simultaneously activates three metabolic receptors: GLP-1, GIP and glucagon. The most extensively studied example is retatrutide. The strategy differs from monoagonism (GLP-1 alone, e.g. semaglutide) and dual agonism (GLP-1 + GIP, e.g. tirzepatide) in the number and complementarity of the pathways stimulated.

The informal shorthand used for retatrutide in online searches is explained in a separate entry: an explanation of the term “reta”.

Why does a triple agonist contain glucagon, given that glucagon raises blood sugar?

Because, beyond its effect on glucose, glucagon increases energy expenditure, lipolysis and hepatic fat oxidation. Within the combination, its hyperglycaemic action is offset by the glucose-dependent, insulinotropic action of the GLP-1 and GIP components — while the benefit, in the form of increased energy expenditure, remains. This is the essence of the crosstalk mechanism.

How does retatrutide differ mechanistically from tirzepatide and semaglutide?

In the number of receptors stimulated. Semaglutide acts on one (GLP-1), tirzepatide on two (GLP-1 + GIP), retatrutide on three (GLP-1 + GIP + glucagon). The additional glucagon component in retatrutide brings in the energy-expenditure dimension. A detailed comparison of the substances is provided in dedicated articles.

Is triple agonism more effective?

In clinical studies, a metabolic effect that grows with the number of receptors was observed (semaglutide ~15%, tirzepatide ~21%, retatrutide ~24% body-weight reduction). These are, however, separate studies, not a direct comparison, and the data for retatrutide come from phase II. These are scientific observations, not recommendations.

Is retatrutide available as a medicine?

No. Retatrutide remains in clinical trials and is not approved as a medicine. Semaglutide and tirzepatide are approved. In the One-Peptides catalogue, retatrutide, GLP-1/GIP and CagriSema function as research reagents (RUO), not medicinal products.

Is triple agonism the only strategy for combining mechanisms?

No. Extending incretin agonism (mono → dual → triple) is one route. The other is combining different hormonal axes — for example, a GLP-1 agonist with an amylin analogue (studied as CagriSema). Both strategies pursue a stronger effect on body-weight regulation than a single mechanism, but they act via different biological routes.

What does “crosstalk” mean in the context of triple agonism?

It is the mutual modulation of the effects of three pathways. The actions of the receptors do not sum straightforwardly — the hyperglycaemic effect of glucagon is offset by the glucose-dependent action of GLP-1 and GIP, while the benefit, in the form of increased energy expenditure, remains. Crosstalk describes precisely this non-linear interaction, in which the final effect differs from the sum of the individual actions.

Summary

• Triple agonism is the simultaneous stimulation of the GLP-1, GIP and glucagon receptors by a single molecule — a strategy represented by retatrutide.
• The addition of glucagon, despite its hyperglycaemic action, brings in the dimension of energy expenditure and lipolysis; its effect on glucose is offset by the GLP-1/GIP components (the crosstalk mechanism).
• Three receptors bring three complementary levers: satiety and insulin (GLP-1), insulin and adipose tissue (GIP), energy expenditure (glucagon).
• In clinical studies, a metabolic effect that grows from the monoagonist through the dual agonist to the triple agonist was observed — as a study finding, not a recommendation.
• Many questions remain open: the optimal contribution of the receptors, the role of GIP, long-term safety.

This content is educational in nature and constitutes a review of the published scientific literature in the field of metabolic pharmacology. The substances mentioned are analysed in a scientific context. Semaglutide and tirzepatide are approved medicines, available solely on prescription under medical supervision; retatrutide remains in clinical trials and is not approved. The products in the One-Peptides catalogue (retatrutide, GLP-1/GIP, CagriSema) are chemical reagents intended exclusively for laboratory research (Research Use Only) — they are not medicines, dietary supplements or products for human consumption, regardless of the identity of the active substance with medicines. The clinical-study results cited describe scientific observations conducted under medical supervision and do not constitute advice or a suggestion to use any substance for the purpose of body-weight reduction.

References

1. Coskun T et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept
2. Jastreboff AM et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
3. Jastreboff AM et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)
4. Wilding JPH et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1)
5. Coskun T et al. (2018). LY3298176, a novel dual GIP and GLP-1 receptor agonist (tirzepatide) for the treatment of type 2 diabetes mellitus
6. Rosenstock J et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, in people with type 2 diabetes: a phase 2 trial

Bartosz BartczakPhysiotherapist, Personal Trainer

Physiotherapist with 20 years of clinical experience, graduate of Poznan University of Medical Sciences. Founder of One Peptides and lead author of clinical-perspective content.

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