What people mean by "GLP-3": retatrutide and triple agonists

Where the term 'GLP-3' comes from

In human physiology, the proglucagon gene gives rise to several peptides through tissue-specific processing, including glucagon, GLP-1 and GLP-2. GLP-2 is a recognised hormone involved in intestinal growth and is the basis of the approved drug teduglutide, used for short bowel syndrome. There is no naturally occurring, peer-reviewed 'GLP-3' in this family.

The term appears to have emerged informally, largely in online and commercial contexts, as a way of signalling that a compound goes 'beyond GLP-1' by acting on additional receptors. It is not a designation used in FDA labelling, in peer-reviewed pharmacology literature, or by the companies developing these molecules, which instead use precise mechanistic descriptions such as 'GIP/GLP-1/glucagon receptor triple agonist'.

GLPWiki uses the phrase in this article only because readers search for it, and it is important to explain clearly what it does and does not mean rather than let an inaccurate label go unaddressed.

What the term is generally used to describe

When people use 'GLP-3' colloquially, they are almost always referring to retatrutide, an investigational peptide developed by Eli Lilly that simultaneously activates the receptors for GLP-1, GIP and glucagon. It is the most advanced 'triple agonist' in clinical development and the most frequently discussed compound in this context.

Retatrutide is chemically a single peptide engineered to bind three distinct G-protein-coupled receptors rather than a naturally circulating hormone. Describing it as a hormone, or as a fourth entrant in a 'GLP' numbering series, is a simplification that does not reflect its actual pharmacology or regulatory status.

The rationale for triple receptor agonism

GLP-1 receptor activation contributes appetite suppression and glycaemic benefits, as described in GLPWiki's GLP-1 explainer. GIP receptor activation is thought to enhance these effects and may improve tolerability when combined with GLP-1 agonism, a principle already demonstrated clinically with the dual agonist tirzepatide.

The added third target in retatrutide is the glucagon receptor. Glucagon is best known for raising blood glucose by stimulating hepatic glucose output, which seems counterintuitive in a weight or diabetes drug. However, glucagon receptor activation also increases energy expenditure and hepatic fat oxidation in preclinical and early human studies, and developers have balanced this glucagon agonism against the glucose-lowering, insulin-sensitising effects of concurrent GLP-1 and GIP agonism.

The hypothesis being tested in clinical trials is that this three-way combination produces greater weight loss than agonism at one or two of these receptors alone, by combining appetite suppression with a modest increase in energy expenditure.

Human trial evidence for retatrutide

The key published clinical evidence for retatrutide comes from a Phase 2, randomised, double-blind, placebo-controlled trial reported in the New England Journal of Medicine in 2023. In participants with obesity, higher doses of retatrutide were associated with mean weight reductions of roughly 24% of body weight at 48 weeks, among the largest reductions reported for an injectable peptide in a placebo-controlled trial at that stage of development.

Adverse events reported in that trial were predominantly gastrointestinal — nausea, diarrhoea, vomiting and constipation — broadly consistent with the tolerability profile seen across the wider incretin drug class, with rates that increased with dose during the escalation phase.

As of the most recent public information, retatrutide has been progressed into Phase 3 clinical trials for obesity and related metabolic conditions, but it had not received marketing approval from the FDA or other major regulators. This means confirmatory efficacy and long-term safety data, including any cardiovascular outcome trial results, are not yet fully established in the peer-reviewed literature.

Why the distinction between real and informal terminology matters

Referring to any triple agonist as 'GLP-3' risks two kinds of confusion. First, it implies the existence of a natural hormone analogous to GLP-1 and GLP-2, which does not exist under that name in the endocrinology literature. Second, it can blur the very real differences in regulatory status, trial size, and duration of follow-up between an FDA-approved medicine and an investigational compound still in trials.

Readers evaluating claims about any peptide should check whether it has completed Phase 3 trials, whether results are published in a peer-reviewed journal, and whether a regulator such as the FDA has approved it for a specific indication, rather than relying on informal naming conventions.