Retatrutide is investigational. As of early 2026 it is in Phase 3 trials and is not approved by any regulator, which means there is no licensed product, no pharmacy supply and no prescriber who can legitimately dispense it. Everything sold under the name is unlicensed material of unverified identity and purity. That is a materially different proposition from semaglutide or tirzepatide, which are approved medicines, and no amount of trial data changes it.
What it is
A single peptide engineered to activate three receptors at once: GLP-1, GIP and glucagon. Developed by Eli Lilly, given as a once-weekly subcutaneous injection, with a half-life around six days.
The generational framing is straightforward. Semaglutide hits one receptor and produces around 15% average weight loss. Tirzepatide hits two and produces around 20%. Retatrutide hits three, and in Phase 2 produced 24.2% at 48 weeks.
| Receptor | What activating it does |
|---|---|
| GLP-1 the semaglutide target |
Insulin release when glucose rises, slower gastric emptying, less hepatic glucose output, and a hypothalamic signal that reduces background interest in food |
| GIP added by tirzepatide |
Further insulin response after meals, steadier glucose, and nutrient partitioning — directing fat and muscle cells to take up what is circulating |
| Glucagon the new one |
Tells the liver to oxidise fat, raises resting energy expenditure, and promotes lipolysis. This is the expenditure side of the equation rather than the intake side |
That third receptor is the whole argument. GLP-1 and GIP drugs work almost entirely by making you eat less. Adding glucagon means the compound also increases what you burn, which is why the numbers step up rather than creeping.
Why appetite suppression feels weaker
A design trade-off that surprises people coming off semaglutide. One molecule cannot be maximally potent at three receptors, so the potencies were deliberately unbalanced: retatrutide is reported as far more potent at GIP than native GIP, and only around 40% as potent at GLP-1 as semaglutide.
So hunger is more present than people expect, and they conclude it is not working. That inference is wrong, and the reason is worth stating plainly: hunger is a sensation and hepatic fat oxidation is not. The glucagon arm produces no felt signal at all. Judging this compound by appetite alone measures the weakest of its three mechanisms.
What the trials show
Retatrutide has more published data behind it than any other investigational obesity drug — Phase 1, Phase 2 across three populations, and the first Phase 3 readout.
| Weekly dose | Weight loss |
|---|---|
| Placebo | 2.1% |
| 1 mg | 8.7% |
| 4 mg | 17.1% |
| 8 mg | 22.8% |
| 12 mg | 24.2% |
Phase 2 obesity trial, 338 adults, 48 weeks (Jastreboff et al., NEJM 2023). Weight was still falling at week 48.
Note the shape rather than the peak. Going from 4 to 8 mg buys about five further percentage points; going from 8 to 12 mg buys around one and a half, while side effects keep climbing. The curve flattens well before the top dose.
| Outcome | Finding | Evidence |
|---|---|---|
| Weight loss | 24.2% at 48 weeks (Phase 2); 28.7% at 68 weeks at 12 mg in the first Phase 3 readout | B |
| Liver fat | 82.4% relative reduction at 24 weeks; 86% of participants reached normal liver fat versus 0% on placebo | B |
| Glycaemic control | HbA1c down about 2.0 percentage points at 12 mg in type 2 diabetes | B |
| Blood pressure and lipids | Systolic pressure down roughly 10 mmHg; non-HDL cholesterol and triglycerides reduced | B |
| Knee osteoarthritis pain | WOMAC pain scores down substantially in TRIUMPH-4 | C |
| Lean mass preservation | Proportion of lean mass lost similar to other agents, despite greater total loss | C |
| Long-term safety and durability | Unknown. Longest published follow-up is 68 weeks | D |
Not because the effect is doubted. Multiple randomised trials point the same way and the effect sizes are large and consistent. The reservations are structural: every trial so far is sponsored by the manufacturer, there is no independent replication, and the Phase 3 figures have been announced by the company rather than published in full. Grade A on this site requires independent replication. That will very likely come; it has not yet.
The liver fat result deserves separate mention because it is the most striking number in the whole file. An 82% relative reduction, with most participants reaching genuinely normal liver fat while none did on placebo, is a larger effect than anything else on record for that condition.
Side effects
Dose-dependent, and predominantly gastrointestinal. In the Phase 3 readout at the top dose, roughly 43% reported nausea, 33% diarrhoea and 21% vomiting. Discontinuation for adverse events ran at about 12% at 9 mg and 18% at 12 mg — which is to say roughly one in six people at the top dose stopped because of how it felt.
One effect is genuinely distinctive and worth knowing about in advance:
Altered skin sensation, where ordinary touch reads as uncomfortable — tingling, sensitivity to pressure and temperature, an awareness of clothing against skin. Frequently worse at night. Strongly dose-dependent: around 8.8% at 9 mg and 20.9% at 12 mg, against 0.7% on placebo. Thought to involve GLP-1 receptors in nervous tissue. It is the most commonly reported reason people reduce the dose.
Also reported: feeling cold persistently, an increase in resting heart rate of roughly 10 bpm which peaked around week 24 and then declined, injection site reactions, and fatigue. Hair thinning turns up frequently in user reports and tracks with rapid weight loss and under-eating rather than with the drug itself. One case of pancreatitis in Phase 2 resolved without intervention. No thyroid cancers and no severe hypoglycaemia were reported.
Who should not use it
| Absolute | Caution, with clinical oversight |
|---|---|
| Personal or family history of medullary thyroid carcinoma | History of pancreatitis |
| Multiple endocrine neoplasia type 2 | Gallbladder disease — rapid weight loss raises gallstone risk |
| Pregnancy, breastfeeding, or trying to conceive | Type 1 diabetes; diabetic retinopathy |
| Known hypersensitivity to the compound | Arrhythmia; gastroparesis; any active eating disorder |
Interactions that matter
- Insulin and sulfonylureas. Additive glucose lowering. Doses commonly need reducing, and this is not a self-managed adjustment.
- Any oral medication. Slowed gastric emptying changes absorption. Relevant for narrow-margin drugs and for oral contraceptives, particularly during dose escalation.
- SGLT2 inhibitors. Raised ketoacidosis risk in combination, more so on a low-carbohydrate diet. The Phase 3 programme carries a ketoacidosis warning.
- Other GLP-1 agonists. Stacking semaglutide or tirzepatide on top is pharmacologically redundant — retatrutide already occupies that receptor — and adds side-effect burden without a matching benefit.
What is not known
- What happens after 68 weeks. That is the longest published follow-up. Durability, and what happens on stopping, are unstudied.
- Whether the weight returns. With every drug in this class it largely does, absent sustained behaviour change. There is no reason to expect this one to differ, and no data either way.
- Long-term glucagon-agonism safety. Chronically raising a catabolic hormone signal is novel at scale. Trials so far are reassuring and short.
- Whether combining it with an amylin analogue helps. Widely discussed; never trialled.
- What is actually in unlicensed vials. No regulator is checking. This is not a minor caveat given everything above describes pharmaceutical-grade material.
What this page does not include
The source material for this entry carried a week-by-week titration schedule, a dosing schedule for pairing retatrutide with cagrilintide, and self-treatment suggestions for the skin sensitivity. None of those are reproduced here.
The trial doses are reported above, in full, because they are the evidence — a dose-response curve published in the New England Journal of Medicine is a finding. Packaging those same numbers as a schedule to follow is a different act: it converts reporting into prescribing, for an unapproved drug, without knowing the reader. The cagrilintide pairing is worse, because that combination has never been tested in a trial at all — the original says so itself while supplying a titration table for it. And the suggested remedies for dysesthesia were, by the source's own admission, never studied for it.
If you are considering this compound, the dose question belongs with a clinician who can see your bloods, not with a website.
Sourcing
Protocol Index has a financial relationship with Nalu Labs, and that link is commercial. Grades on this page were assigned from the published trials before any commercial consideration; see independence and funding.
Two things are worth saying plainly alongside it. Retatrutide is an unapproved investigational drug, so any vendor selling it is selling unlicensed material. And the trial results on this page were produced with pharmaceutical-grade compound of known identity and purity — they do not automatically transfer to a vial from any other source. Apply the third-party testing standard, and treat a supplier who cannot produce batch analysis as disqualifying.
Before you act on any of this
This is a summary of published research on an investigational drug, not a recommendation to use it and not a protocol. It deliberately contains no dosing schedule. Retatrutide is not approved anywhere, it interacts significantly with common medications including insulin, and it is contraindicated outright in several conditions listed above. Anyone considering it needs a clinician who knows their history — and should know that asking one about an unapproved compound may get a refusal rather than supervision.
References
- Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine, 2023;389(6):514–526.
- Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a phase 2 trial. The Lancet, 2023;402(10401):529–544.
- Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomised phase 2a trial. Nature Medicine, 2024;30(7):2037–2048.
- Coskun T, et al. Effects of retatrutide on body composition in people with type 2 diabetes. The Lancet Diabetes & Endocrinology, 2025;13(8):674–684.
- Abouelmagd AA, et al. Efficacy and safety of retatrutide: a systematic review and meta-analysis. Baylor University Medical Center Proceedings, 2025;38(3):291–303.
- Li W, et al. Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discovery, 2024;10(1):77.
- Finan B, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nature Medicine, 2015;21(1):27–36.
- Giblin K, et al. Retatrutide for obesity, obstructive sleep apnoea and knee osteoarthritis: rationale and design of the TRIUMPH trials. Diabetes, Obesity and Metabolism, 2026;28(1):83–93.
- Eli Lilly and Company. First Phase 3 (TRIUMPH-4) results, company announcement, December 2025.
Phase 2 figures are drawn from the peer-reviewed publications above. Phase 3 figures come from the sponsor's announcement and had not been published in full at the time of review, which is reflected in the grades.