Retatrutide

What it is

Retatrutide is a single synthetic peptide that activates three receptors at once: GLP-1, GIP, and glucagon. Semaglutide hits one of those. Tirzepatide hits two. Retatrutide adds glucagon receptor agonism on top - and that third arm is the interesting part, because glucagon raises energy expenditure rather than only suppressing intake.

You will see it called "GLP-3" in forums and on vendor sites. There is no such thing as GLP-3. The name appears to have been invented by analogy - first-generation, second-generation, therefore third - and it stuck because it is easy to say. Retatrutide is a triple agonist, not a third GLP.

Mechanism

Each receptor arm does something different, and the combination is why the weight-loss numbers separate from the rest of the class:

• GLP-1 - slows gastric emptying, increases satiety, improves glucose-dependent insulin secretion. This is the appetite lever.
• GIP - potentiates insulin response and appears to improve tolerability of GLP-1 agonism, blunting nausea relative to GLP-1 alone.
• Glucagon - increases resting energy expenditure and drives hepatic fat mobilisation. This is the arm that adds "burn more," not just "eat less."

The glucagon arm is also the source of the class's open questions. Glucagon raises blood glucose in isolation; retatrutide's GLP-1 component offsets that, but the balance is dose-dependent, and it is why hepatic and glycaemic endpoints are watched closely in the phase 3 programme.

What the evidence shows

The phase 2 trial (338 adults with obesity, 48 weeks, published in NEJM in 2023) is the foundational human dataset. Least-squares mean change in body weight at 48 weeks:

At 24 weeks the 12 mg arm was already at roughly -17.5%. Crucially, the curves had not flattened by week 48 - weight was still coming off when the trial ended, which is unusual and is a large part of why the compound attracted the attention it did.

Phase 3 (TRIUMPH programme) readouts have since reported figures in the same territory - on the order of 28% mean reduction at 68-80 weeks in the higher-dose arms, the largest reported in any phase 3 obesity trial. Filing and approval timelines remain speculative; treat any specific date you read online as a guess.

A separate phase 2a trial in MASLD (fatty liver disease) found substantial reductions in liver fat content, consistent with the glucagon-driven hepatic mechanism.

What is not established: long-term safety beyond trial duration, effects of the years-long continuous use that real-world weight maintenance implies, and outcomes in anyone the trials excluded.

How it is dosed in trials

Trial protocols started low and escalated every 4 weeks - 2 mg or 4 mg for the first four weeks, stepping up toward the target dose over roughly 12 weeks. The trial explicitly compared a 2 mg start against a 4 mg start and found the lower start materially reduced GI adverse events. This is the single most transferable finding in the dataset: escalation speed drives tolerability far more than the final dose does.

Discontinuation due to adverse events ran 6-16% across retatrutide arms, versus zero on placebo.

Use the reconstitution calculator to convert a vial into syringe units.

Practical notes

• Protein and resistance training are not optional. Appetite suppression at these doses is profound, and weight lost without a protein floor and a lifting stimulus includes a meaningful fraction of lean mass. This is the most consistent regret reported across the entire GLP class.
• Hydration and electrolytes. Most acute problems on incretins are dehydration wearing a costume.
• Do not stack with another incretin. Retatrutide already covers GLP-1 and GIP. Adding tirzepatide or semaglutide on top adds side effects, not results.
• Sudden stops mean appetite returns. Nothing about the drug rewires long-term set point on its own.

Sourcing reality

Retatrutide has never been sold as a finished pharmaceutical product to anyone, anywhere. There is no legitimate consumer supply. Everything available is grey-market material labelled "not for human consumption," where identity, purity, sterility, and actual milligram content are unverified unless a third-party assay says otherwise - and vendor-supplied certificates are frequently recycled, stale, or for a different batch. See safety and sourcing for how to read a COA and what independent testing actually covers.

Side effects and warning signs

Commonly reported

• Nausea - 14% at 1 mg rising to 60% at 12 mg in phase 2
• Vomiting, diarrhoea and constipation, concentrated during dose escalation
• Resting heart rate up ~4-6 bpm at the top dose, peaking near week 24 then declining
• Appetite suppression severe enough that under-eating protein becomes the real risk
• Fatigue and dizziness, usually tied to inadequate food and fluid intake

Stop and get medical help

• Vomiting that prevents keeping fluids down - dehydration is the most common reason people end up in an ER on incretins
• Severe, persistent abdominal pain radiating to the back - the classic pancreatitis presentation
• Resting heart rate persistently above ~100 bpm, or palpitations with chest pain
• Personal or family history of medullary thyroid carcinoma or MEN2 - a contraindication across the whole GLP-1 class

Sources

1. Jastreboff et al., Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial, NEJM 2023trial
2. Phase 2 trial record (PubMed 37366315)trial
3. Eli Lilly - phase 2 results announcementregulatory
4. Retatrutide for MASLD - randomised phase 2a trialtrial

From the community

Discussion for this compound concentrates in r/Peptidesource, r/PeptideForum and r/Biohackers.

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