Retatrutide

LY3437943, "triple G" agonist

Metabolic & weight

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Retatrutide is an investigational medicine in late-stage trials, not an approved product and not a research chemical with any established community dosing. Anything sold under this name outside a clinical trial is unverified. This page explains the published science.

Summary

Class: Triple agonist of the GIP, GLP-1 and glucagon receptors; 39-amino-acid synthetic peptide based on the GIP sequence with a C20 fatty-diacid side chain
Mechanism: Combines the appetite and insulin effects of GLP-1/GIP agonism with glucagon-receptor activation, which raises energy expenditure and liver fat burning
Routes studied: Subcutaneous once-weekly (trials)
Dose range reported: Phase 2: 1, 4, 8 and 12 mg weekly, with escalation steps over 4–12 weeks (starting doses 2 or 4 mg for the higher arms). Phase 3 (TRIUMPH programme) is testing up to 12 mg weekly. No approved dose; community-reported doses mirror the trial arms and have no validation
Half-life: ~6 days, supporting weekly dosing †
Storage: Trial product is a refrigerated solution. Lyophilised grey-market product: refrigerate, follow the label; stability data are not public
Regulatory status: Not approved anywhere; Phase 3 trials in obesity, type 2 diabetes, knee osteoarthritis, obstructive sleep apnoea and cardiovascular outcomes under way, with first results expected 2025–2026

Doses are as reported in studies or by the community — never recommendations.

1What it is

Retatrutide is Eli Lilly's successor to tirzepatide. Where tirzepatide activates two incretin receptors, retatrutide activates three: GIP, GLP-1 and the glucagon receptor. Adding glucagon sounds counter-intuitive — glucagon raises blood sugar — but at the receptor it also increases energy expenditure, promotes fat burning in the liver and reduces appetite, and the incretin components appear to offset the glucose-raising effect. The molecule is fully synthetic.

It attracted attention in 2023 when Phase 2 results showed the largest average weight loss ever reported for a medicine, with the curves still falling at the end of the study. As of this review it remains investigational: the Phase 3 TRIUMPH programme is in progress, and no regulator has approved it. Because it has never been manufactured for sale, any vial labelled "retatrutide" outside a trial is of unknown origin and content.

2How it's thought to work

GLP-1 receptor. appetite suppression, glucose-dependent insulin release, slowed gastric emptying.

GIP receptor. additional insulin release, possible improvement in tolerability and fat-tissue metabolism, as with tirzepatide.

Glucagon receptor. increased resting energy expenditure, hepatic fat oxidation and lipolysis; the likely reason retatrutide produces more weight loss than tirzepatide and its very large reductions in liver fat.

Balance of activity. retatrutide is a weaker GLP-1 than native GLP-1 and a partial glucagon agonist; the ratio was tuned so that glucose control is preserved despite glucagon activity.

Heart rate. glucagon-receptor agonism raises heart rate more than GLP-1 agonism alone, a known class effect under scrutiny.

Three receptors at once: GIP and GLP-1 for insulin and appetite, plus the glucagon receptor, which raises energy expenditure and fat burning in the liver.Schematic — not to scale

3What the research shows

Graded A (Phase 2)

Weight loss in people with obesity

A 48-week Phase 2 (n=338, obesity without diabetes) reported mean weight change of −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg) and −24.2% (12 mg) vs −2.1% with placebo, with weight still declining at 48 weeks in the higher arms (Jastreboff 2023, NEJM). Among people with a BMI of 35 or more, mean loss on 12 mg exceeded 26%. [1]

Graded A (Phase 2)

Type 2 diabetes

A 36-week Phase 2 RCT (n=281) showed HbA1c reductions of up to about 2.0 percentage points and weight loss of up to ~17% at 12 mg, compared with dulaglutide 1.5 mg and placebo (Rosenstock 2023, Lancet). [2]

Graded A (Phase 2 sub-study)

Liver fat

In participants with MASLD, liver fat fell by more than 80% from in the 8 and 12 mg arms at 48 weeks, with the great majority reaching normal liver fat (<5%) (Sanyal 2024, Nat Med). [3]

Graded A (Phase 3, 2025)

Knee osteoarthritis

TRIUMPH-4 in people with obesity and knee osteoarthritis reported ~28% weight loss at 68 weeks on the highest dose and significant pain improvement vs placebo, per the sponsor's 2025 announcement; full publication pending †.

Not gradedin progress

Cardiovascular, kidney, sleep apnoea outcomes

TRIUMPH-Outcomes and other Phase 3 trials are ongoing. No outcome data yet.

Community use

No data; anecdotal reports of grey-market product largely mirror the trial side-effect profile but cannot be tied to a verified compound.

4Reported side effects and interactions

Literature-reported

Common (literature). nausea, diarrhoea, vomiting, constipation — dose-related, mostly during escalation, and more frequent with faster escalation. Discontinuation for adverse events was 6–16% across active arms in Phase 2.

Class-level warnings expected on any eventual label. gallbladder disease, pancreatitis, thyroid C-cell tumours in rodents, delayed gastric emptying with aspiration risk under anaesthesia, acute kidney injury from dehydration, hypersensitivity.

Of specific note. heart rate rose by up to about 6 beats per minute at higher doses, peaking around 24 weeks and declining thereafter; a dose-dependent rise in some participants' blood pressure was not seen (blood pressure fell). Skin sensitivity and dysaesthesia (tingling or altered skin sensation) were reported more than with placebo and are being tracked. Transient rises in liver enzymes and in lipase/amylase occurred in some participants. Hypoglycaemia was uncommon in people without diabetes.

Muscle mass. body-composition sub-study data are limited; lean-mass loss alongside fat is expected as with other incretin drugs.

Grey-market product risks. retatrutide has never been commercially manufactured, so no vial sold online is a legitimate pharmaceutical product. Identity, purity, dose and sterility are unverified. Unit confusion (mg vs ml vs "units") applies as for other incretin peptides.

Interactions. additive hypoglycaemia with insulin or sulfonylureas; slowed absorption of oral medicines; not for use in pregnancy. Interaction data are not yet published in full.

Markers researchers commonly monitor

Marker	Why it's watched
Body weight and body composition	primary endpoint in trials; lean-mass tracking matters given the magnitude of loss.
Resting heart rate	the glucagon component raises it; an explicit safety endpoint in the Phase 3 programme.
HbA1c and fasting glucose	glucagon agonism could in principle raise glucose; trials show the opposite but it remains a watch item.
Liver enzymes (ALT, AST)	both improvement (less liver fat) and transient rises have been reported.
Lipase/amylase	elevations were seen; only clinically meaningful with symptoms.
Creatinine/eGFR and electrolytes	dehydration from GI effects.
Lipids and blood pressure	generally improve.
Skin sensation symptoms	a trial-specific signal under observation rather than a lab marker.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

No approved product exists. grey-market vials, if encountered, require the same milligram-level care as semaglutide and tirzepatide: small volumes, high concentrations, and easy ten-fold errors. Use the calculator and double-check units.

Open in calculator, pre-loaded →

6Commonly studied alongside

Dulaglutide (comparator in the diabetes Phase 2), tirzepatide and semaglutide (indirect comparisons only). Lilly's lean-mass programme (bimagrumab) is being studied with incretin drugs separately. No published combination trials.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Investigational; not FDA-approved. Not eligible for compounding
European Union	Investigational; not authorised
United Kingdom	Investigational; not licensed
Australia	Investigational; not approved
South Africa	Investigational; not registered
Sport (WADA)	Not specifically listed; as a non-approved pharmacological substance it falls under S0 (non-approved substances) †

8Open questions

Does the extra weight loss over tirzepatide translate into better cardiovascular and metabolic outcomes, and at what cost in heart rate?
Where does weight plateau — Phase 2 curves had not levelled off at 48 weeks.
What fraction of loss is lean mass, and does glucagon agonism change that?
Long-term safety of chronic glucagon-receptor activation in humans.

9References

1Jastreboff AM et al. (2023). Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. PubMed · DOI
2Rosenstock 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-controlled, parallel-group, phase 2 trial. Lancet. PubMed · DOI
3Sanyal AJ et al. (2024). Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. PubMed · DOI
4Coskun T et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. PubMed · DOI
5Urva S et al. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet. PubMed · DOI
6Eli Lilly (2025). TRIUMPH-4 topline results announcement (knee osteoarthritis and obesity) — press release, to be replaced with the peer-reviewed publication. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

25 Oct 2026Profile published — awaiting medical review

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