What Is Retatrutide (GLP-3)?

How Retatrutide Works

Most weight loss drugs in the current generation work by mimicking gut hormones called incretins — hormones your body naturally releases after eating to regulate blood sugar and appetite. Retatrutide combines incretin receptor activity with glucagon receptor activity.

Structurally, retatrutide is a 39-amino acid peptide linked to a C20 fatty diacid moiety. The fatty acid chain extends the drug's half-life, allowing it to remain active in the body long enough for once-weekly dosing — the same pharmacological strategy used in semaglutide and tirzepatide.

What makes retatrutide different is its targets. Where semaglutide activates one receptor and tirzepatide activates two, retatrutide activates three. The original molecular study found reduced food intake and increased energy expenditure in obese mice. Human trials demonstrate weight loss, but they do not establish how much of that loss is caused by an increase in energy expenditure.

The Three Receptors, Explained

1. GLP-1 (Glucagon-Like Peptide-1)

GLP-1 is the receptor that made Ozempic and Wegovy household names. When activated, it:

• Reduces appetite by acting on hunger-regulating centers in the brain
• Increases insulin secretion in response to food, improving blood sugar control
• Slows gastric emptying, meaning food stays in the stomach longer, prolonging the feeling of fullness

This is the best-understood mechanism in the incretin drug class and the foundation that all three generations share.

2. GIP (Glucose-Dependent Insulinotropic Polypeptide)

GIP is the second receptor, also targeted by tirzepatide (Mounjaro/Zepbound). Its effects include:

• Stimulating insulin release from the pancreas, complementing GLP-1's effect on blood sugar
• Appetite regulation, with the precise contribution of GIP activity to retatrutide’s human weight-loss effect still being studied
• Potential effects on fat metabolism, though the precise role of GIP in weight loss is still an active area of research

Retatrutide includes GIP receptor activity, but comparing whole medicines cannot isolate the effect of one receptor.

3. Glucagon Receptor

This is the differentiator. Glucagon is a hormone most people associate with raising blood sugar — it signals the liver to release stored glucose. That might sound counterproductive in a diabetes or weight loss drug, but the glucagon receptor does more than regulate blood sugar:

• Energy expenditure: glucagon receptor activation contributed to increased energy expenditure in the obese-mouse experiments.
• Liver metabolism: glucagon signaling affects glucose and lipid metabolism. Retatrutide’s human liver-fat findings are measured outcomes, not proof that one receptor alone produced them.

The glucagon component is an important difference in the molecule’s design. Claims that it reliably makes a person burn a specific number of extra calories at rest go beyond the clinical evidence discussed here.

How Retatrutide Compares to Existing Drugs

Counting receptors does not predict a fixed increase in weight loss. Retatrutide’s placebo-controlled results are promising, but they do not establish superiority over semaglutide or tirzepatide.

Key Clinical Results So Far

Phase 2 Trial — Obesity (48 Weeks)

The highest-dose group lost an average of 24.2% at week 48, versus 2.1% with placebo. These are group averages, not a guaranteed outcome.

Phase 2 Trial — Type 2 Diabetes (36 Weeks)

• HbA1c reduction of up to 2.02 percentage points at 24 weeks
• Weight loss of up to 16.94% at 36 weeks in people with type 2 diabetes
• Different effects across the tested doses; not every dose showed the same benefit

Phase 3 TRIUMPH-4 (68 Weeks)

TRIUMPH-4 also demonstrated significant pain relief in participants with knee osteoarthritis, suggesting potential benefits beyond weight and metabolism.

The initial Phase 3 TRIUMPH program enrolled more than 5,800 participants. Lilly reported in July 2026 that five Phase 3 studies had produced positive results and that it was preparing a U.S. submission.

Current Status

• Phase 1 completed: Early safety, tolerability and pharmacokinetics characterized in small studies. Published in The Lancet in 2022 (Urva et al., NCT04143802).
• Phase 2 completed: Strong efficacy demonstrated in both obesity and type 2 diabetes.
• Phase 3 (TRIUMPH program) underway: Lilly has reported positive results from five studies, including TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4.
• U.S. filing: Lilly says it plans to submit retatrutide for U.S. approval in Q1 2027.
• FDA approval: A planned submission is not an approval decision or a guaranteed availability date.

Retatrutide does not yet have a brand name. No approval date is established in the sources reviewed here.

Where the Name "GLP-3" Comes From

If you arrived at this page searching for "GLP-3," you are not alone — but the term requires some clarification.

• "GLP-1" drugs (semaglutide) activate one receptor — they are single agonists
• "GLP-2" is sometimes used informally for dual agonists (tirzepatide), which activate two receptors — though this is not standard terminology either
• "GLP-3" follows the same logic for retatrutide, a triple agonist activating three receptors

The term was popularized in part by Andrew Huberman on his podcast, where he discussed the next generation of weight loss drugs. It has since spread through social media, health forums, and consumer health content.

Frequently Asked Questions

Sources

• Coskun, T., et al. (2022). Molecular pharmacology and Phase 1 single-dose results. Cell Metabolism.
• Lilly. (2026). TRIUMPH-1 and TRANSCEND-T2D-1 data at ADA. June 6 release.
• Qualitative Phase 2 follow-up. Participant interviews.
• Urva, S., et al. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, randomised, multiple-ascending-dose trial. The Lancet. DOI: 10.1016/S0140-6736(22)02033-5
• Jastreboff, A.M., et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. DOI: 10.1056/NEJMoa2301972
• Rosenstock, J., et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. DOI: 10.1016/S0140-6736(23)01053-X
• Eli Lilly and Company. (2025). Lilly's retatrutide achieved significant weight loss and pain relief in adults with obesity and knee osteoarthritis. Press release.
• Eli Lilly and Company. (2026). Retatrutide Phase 3 TRIUMPH-2 and TRIUMPH-3 results and planned U.S. submission. Press release.
• ClinicalTrials.gov: NCT04143802, NCT04881760, NCT04867785