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Retatrutide

Also known as Reta, LY3437943, triple-G agonist

Experimental triple agonist of the GIP, GLP-1 and glucagon receptors for obesity.

early-clinical Metabolic & weight research chemical

At a glance

Category
Metabolic & weight
Status
research chemical
Route
subcutaneous, once a week
Half-life
about 6 days in humans (from phase 1 pharmacokinetics), consistent with weekly dosing
Onset
weight loss from a few weeks onwards; in studies weight was still falling after 48 weeks
Molecular weight
about 4731 g/mol
Sequence
39-amino acid peptide based on the GIP sequence, with Aib substitutions and a C20 fatty diacid chain; full sequence not published in standardised public form

Not registered. In phase 3 research (Eli Lilly's TRIUMPH programme) for obesity, type 2 diabetes, MASH and knee osteoarthritis. The FDA states that retatrutide cannot be used in compounding under federal law, is not a component of any FDA-approved drug, and has not been found safe and effective for any condition; it has warned telehealth companies marketing it, API distributors selling it to compounders, and outsourcing facilities repackaging it 3. Powders sold online as a 'research chemical' are not a medicine and are not checked for identity, purity or sterility.

Doping status: Prohibited (WADA S0, non-approved substances)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Retatrutide activates three receptors simultaneously: the GIP receptor, the GLP-1 receptor and the glucagon receptor. The first two deliver the same effects as with tirzepatide: glucose-dependent insulin secretion, inhibition of glucagon release, delayed gastric emptying and central appetite suppression.

The added glucagon receptor agonist component is the distinguishing element. Glucagon receptor activation in the liver increases energy expenditure, stimulates lipolysis and fatty acid oxidation and reduces hepatic steatosis. This adds a catabolic, expenditure-side component to the predominantly intake-suppressing effect of GLP-1 and GIP.

The combination is pharmacologically delicate: glucagon in itself raises blood glucose, which theoretically works against the desired antidiabetic effect. In the molecule the glucagon receptor activity is therefore relatively attenuated compared with the GLP-1 component, so that the glucose-raising effect is offset. Whether this balance remains safe in the long term has not yet been established.

What the research shows

The evidence consists of phase 1 and phase 2 studies with a few hundred participants in total; phase 3 outcomes had not been fully published at the time this text was written. The reported effect sizes are the largest so far reported for a pharmacological obesity treatment, but without long-term safety data and without a cardiovascular outcomes trial the risk-benefit balance has not been established.

Research in humans

The phase 2 study by Jastreboff et al. (NEJM 2023, n=338 adults with obesity without diabetes) reported a mean weight loss of up to about 17.5% after 24 weeks and up to about 24.2% after 48 weeks at the highest dose (12 mg per week), versus about 2.1% with placebo 1. A separate phase 2a study in MASLD showed a substantial reduction in liver fat content. Phase 2 data in type 2 diabetes have also been published.

Animal and lab research

Preclinical models support the additive effect of glucagon receptor agonism on energy expenditure and hepatic fat accumulation. As is usual for the class, thyroid C-cell effects have been studied in rodents; these findings are the basis for the class warning.

Caveats. All published studies were funded and carried out by Eli Lilly. The phase 2 study was not designed to detect rare side effects. Weight loss had not yet levelled off at 48 weeks, so the eventual plateau is unknown. There are signals of a dose-dependent increase in heart rate and of raised blood glucose at higher doses in some subgroups. Not a single published study has examined long-term safety or cardiovascular outcomes.

What it is used for

  • Studied for obesity and overweight with comorbidity
  • Studied for type 2 diabetes mellitus
  • Studied for MASH/MASLD (hepatic steatosis)
  • Studied for obesity-related knee osteoarthritis and obstructive sleep apnoea
  • Used outside trials via the grey market; this use is unregulated and unchecked

Dosing

Dose
1 mg to 12 mg per week (doses as used in the phase 2 study)
Frequency
once a week
Route
Subcutaneous
Duration
48 weeks in the phase 2 study; the optimal treatment duration has not been established
  • In the phase 2 study titration started at 2 mg per week with increases every 2 or 4 weeks; the arms with higher final doses (8 and 12 mg) used slower escalation schedules to limit gastrointestinal side effects.
  • There is no approved dosing schedule. What is set out here is a description of study doses, not instructions for use.
  • Doses circulating in online user protocols are not clinically validated and the strength of unregistered product is unknown.
  • The optimal dose in the phase 3 programme has not yet been publicly established.
  • Retatrutide is the compound in this group with the widest gap between what is licensed and what circulates. Nothing is approved anywhere, trial participants receive a sponsor-prepared solution, and yet lyophilised powder is sold in vials online and is reconstituted and self-injected. The FDA states that retatrutide cannot lawfully be used in compounding, is not a component of any approved drug, and has not been found safe and effective for any condition; it has issued warnings to telehealth companies marketing it, to active pharmaceutical ingredient distributors selling it to compounders, and to outsourcing facilities repackaging it 3.
  • The milligram-versus-microgram trap is the single most likely way someone is harmed with this compound. Doses are expressed in milligrams; insulin syringes are marked in units, and one unit is a volume (0.01 ml), not a dose, so the same unit count means a different milligram amount at every concentration. The FDA's compounding risk alert of 26 July 2024, written about semaglutide but describing the identical failure mode with vials and syringes, records patients administering five to twenty times the intended dose after confusing millilitres, milligrams and 'units' — patients told to inject 5 units injected 50 instead 4. Retatrutide vials circulate at strengths from 10 mg to 60 mg, so the scope for that error is wider here than for any approved incretin.
  • Grey-market powder carries no guarantee of identity, purity, sterility or actual milligram content, so the number on the label may not be the number in the vial, and any calculation is only as good as that label. For retatrutide this is sharper than for the approved molecules: there is no legitimate finished product anywhere in the world to compare a vial against, and no regulator has ever verified a batch of it intended for human use.
  • The phase 2 escalation schedules exist because gastrointestinal effects are dose-limiting — the arms reaching 8 and 12 mg used deliberately slower escalation than the lower-dose arms for exactly that reason. Starting at a high dose rather than escalating is how people end up vomiting for days and dehydrated. With a half-life of about six days, an overdose does not resolve overnight.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Phase 2 obesity trial, 12 mg arm (NCT04881760)

published trial

Source: ClinicalTrials.gov record NCT04881760 (phase 2, Eli Lilly)

Starting dose2 mg subcutaneously once weekly
Second step4 mg once weekly
Third step8 mg once weekly
Target dose12 mg once weekly

The registry records the sequence of doses, not how many weeks are spent at each; treatment ran once weekly for 48 weeks in total. The trial deliberately compared starting doses — separate arms reached 4 mg and 8 mg from either a 2 mg or a 4 mg start — and the published report states that gastrointestinal effects were partially mitigated by the lower 2 mg start.

Grey-market powder, four-week ladder to 12 mg

user protocol — not validated

Source: Pattern circulating among users and sellers of unlicensed retatrutide powder

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Weeks 1-42 mg once weekly
Weeks 5-84 mg once weekly
Weeks 9-128 mg once weekly
Week 13 onward12 mg once weekly

This is the phase 2 twelve-milligram arm rebuilt on four-week steps and applied to powder bought online. Only the dose sequence has a source; the four-week spacing, the vial strength and the contents of the vial do not. Vials circulate anywhere between 10 mg and 60 mg, so an identical syringe reading is a different dose from one vial to the next, and no regulator has ever verified a batch of this compound intended for human use.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
10 mg, 15 mg, 20 mg, 30 mg, 60 mg
Solvent
bacteriostatic water (0.9% benzyl alcohol)
Storage
No approved storage instruction exists, because there is no approved product. Sellers typically advise storing the powder frozen and protected from light and refrigerating the reconstituted solution, but no stability data for this material have been published, and the FDA has received complaints of GLP-1 products arriving warm or inadequately cooled.

Worked example

Keep the two supply routes apart. In the clinical trials a sponsor-prepared, ready-to-use solution is used and participants reconstitute nothing; there is no registered product and no validated reconstitution protocol. What circulates online is lyophilised powder, reconstituted and measured by the buyer, and the arithmetic for such a vial runs: 10 mg vial + 2 ml bacteriostatic water = 5 mg/ml. A 2 mg dose is 0.4 ml, which is 40 units on a U100 insulin syringe; a 1 mg dose is 20 units. Reconstitute a 30 mg vial with the same 2 ml and the concentration is 15 mg/ml, at which those same 40 units deliver 6 mg — three times the intended dose, from an identical-looking vial and an identical syringe reading.

Vial strengths are not standardised between sellers: 10, 15, 20, 30 and 60 mg all circulate, a sixfold spread, so concentration must be recalculated for every vial and a unit figure copied from someone else's protocol is meaningless. The worked example above is descriptive arithmetic, not a protocol, and it changes nothing about the starting material: identity, purity, sterility and actual milligram content of grey-market retatrutide are unverified, and unlike semaglutide or tirzepatide there is no licensed equivalent anywhere against which a vial could even in principle be compared.

Work it out for Retatrutide

Safety

Side effects

  • Nausea, vomiting, diarrhoea and constipation — the most reported side effects, dose-dependent and most pronounced during titration
  • Reduced appetite, dyspepsia, abdominal pain
  • Dose-dependent increase in heart rate (in phase 2 an average of a few beats per minute, peaking around week 24)
  • Increased blood glucose at higher doses in some participants, attributed to the glucagon component
  • Injection site reactions
  • Loss of fat-free mass with rapid weight loss
  • Class effects of GLP-1 agonists (pancreatitis, gallbladder disorders, gastroparesis) are to be expected but cannot be reliably quantified in the limited study population
  • Rare and late side effects are unknown because of the limited duration of exposure
  • Overdose from a dosing error with reconstituted powder: the adverse events the FDA recorded for this failure mode were gastrointestinal effects, fainting, headache, migraine, dehydration, acute pancreatitis and gallstones, some requiring hospitalisation 4. With a half-life of about six days, the effects of a tenfold error persist for days rather than hours
  • Injection-site infection and abscess from non-sterile technique or non-sterile starting material

Do not use if

  • Personal or family history of medullary thyroid carcinoma (MTC) — class contraindication for incretin agents
  • Multiple endocrine neoplasia type 2 (MEN2)
  • History of pancreatitis
  • Pregnancy, breastfeeding and a wish to conceive
  • Serious gastrointestinal disorders including gastroparesis
  • Existing cardiac arrhythmias or tachycardia — given the observed increase in heart rate
  • Use outside clinical trials: there is no body guaranteeing the identity, strength or sterility of the product, and the FDA has warned companies selling retatrutide falsely labelled 'for research purposes' or 'not for human consumption' directly to consumers with dosing instructions 3
  • Reconstituting and measuring unregulated powder without being able to do the milligram-to-unit conversion reliably. Tenfold errors at this step are the most frequently documented mechanism of harm with drugs in this class, and the FDA has recorded adverse events, some requiring hospitalisation, from them 4
  • Any assumption that a grey-market vial contains what its label states. For retatrutide there is no licensed product anywhere, so there is no verified reference material and the label is the only claim that exists

Interactions

Not systematically studied. On the basis of the mechanism of action, the same points of attention are to be expected as with registered incretin agents: delayed gastric emptying can affect the absorption of oral medication, and combination with insulin or sulfonylureas increases the risk of hypoglycaemia. Combination with other GLP-1 or GIP agonists has not been studied and overlaps pharmacologically in full.

Common questions

What is retatrutide, or “reta”?
An experimental triple agonist that activates the GIP, GLP-1 and glucagon receptors. It is in phase 3 trials for obesity and is not an approved medicine.
Is retatrutide approved or legal to buy?
No. It is not approved anywhere, so it cannot be prescribed or sold as a drug. Powder sold online as “reta” is an unapproved research chemical — see the legal status.
How does retatrutide compare with tirzepatide and semaglutide?
Its early-phase weight-loss figures have been the most dramatic of the three, but it is the least far along and unapproved. The comparison page sets them side by side.

Sources