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 takes this approach further than any approved drug.

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.

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
• Reducing appetite through additional slowing of gastric emptying
• Potential effects on fat metabolism, though the precise role of GIP in weight loss is still an active area of research

Adding GIP to GLP-1 is what allowed tirzepatide to outperform semaglutide in head-to-head trials. Retatrutide includes this receptor as well.

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:

• Increases energy expenditure, particularly by promoting thermogenesis (heat production) in brown adipose tissue — in other words, you burn more calories at rest
• Induces lipolysis — the breakdown of stored fat for energy
• Decreases lipogenesis — reduces the creation of new fat
• Reduces gastrointestinal motility, contributing to satiety

The glucagon component is what sets retatrutide apart conceptually. Semaglutide and tirzepatide work primarily by making you eat less. Retatrutide does that too, but also increases the rate at which your body burns energy. It attacks obesity from both sides of the energy balance equation.

How Retatrutide Compares to Existing Drugs

Each generation has roughly added 5-10 percentage points of weight loss over the previous one. The addition of the glucagon receptor appears to be a meaningful step forward, though direct head-to-head trials between retatrutide and tirzepatide have not been published.

Key Clinical Results So Far

Phase 2 Trial — Obesity (48 Weeks)

The 24.2% weight loss at the highest dose exceeded what any obesity drug had achieved in a clinical trial at the time.

Phase 2 Trial — Type 2 Diabetes (36 Weeks)

• HbA1c reduction of up to -2.02 percentage points
• Weight loss of up to -16.94% in people with type 2 diabetes
• Strong glucose control across all dose levels

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: Safety and pharmacokinetics established. Published in The Lancet in 2022 (Coskun 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, if granted, is most likely in 2027.

Retatrutide does not yet have a brand name. Eli Lilly will announce one closer to the approval date.

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). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1, randomised, double-blind, placebo-controlled and active comparator-controlled 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