Retatrutide

Three receptors instead of two. It cuts intake and raises energy burn, and it has the largest weight-loss numbers in its class.

Evidence: BHuman trials what's this?
Grade B. Strong Phase 2 trials and a reported Phase 3, but not yet approved anywhere.
Also known as: LY3437943 · sometimes nicknamed "GLP-3" (not a real hormone)
Class: Triple GIP + GLP-1 + glucagon receptor agonist. Investigational, Eli Lilly.

The 30-second version

WhatA once-weekly peptide that activates GIP, GLP-1 and glucagon receptors at the same time.

ResultsUp to 24.2% weight loss at 48 weeks in Phase 2, and about 28.7% at 68 weeks in a Phase 3 topline.

The honest catchIt is still investigational. Long-term safety and approval are both still open.

What it is

Semaglutide activates one gut-hormone receptor and tirzepatide activates two. Retatrutide, from Eli Lilly, adds a third: glucagon. It's a single peptide with a fatty-acid tail that gives it a half-life of about six days, so like the others it's injected once a week.

The results are why it matters. Phase 2 produced the largest average weight loss reported for any incretin drug at the time, and the Phase 3 TRIUMPH topline in December 2025 reported about 28.7% average body-weight loss over 68 weeks³. It is not approved yet. Legitimate access is through clinical trials only.

How it works

GLP-1 arm. Reduces hunger in the brain and slows stomach emptying, so you eat less.

GIP arm. Adds insulin release and appetite signalling, and may soften nausea.

Glucagon arm. The new part. Raises resting energy expenditure and burns stored fat, especially in the liver.

Balance. Glucagon alone would raise blood sugar. The other two arms and the weight loss more than cancel that out.

Outcome. Less coming in and more going out. Weight, liver fat, glucose and lipids all improve.

The glucagon arm explains both of retatrutide's standout features: the dramatic drop in liver fat, and a heart-rate rise that is larger than with the other incretin drugs.

What the research shows

Phase 2 obesity trial (Jastreboff, NEJM 2023): weight loss rose with dose, reaching 24.2% at 48 weeks on 12 mg, with better blood pressure, lipids and glucose. 72% of participants with prediabetes went back to normal glucose levels¹.

Liver-fat substudy (Nature Medicine 2024): liver fat fell by up to 82% at 24 weeks, and more than 90% of the top-dose group reached normal liver-fat levels².

Phase 3 (TRIUMPH): the topline reported about 28.7% average loss at 68 weeks. Full peer-reviewed publication is still pending³.

Its effect is not in doubt. What is still open is whether it gets approved, and whether a vial from outside a trial actually contains the trial drug.

Evidence at a glance

Use	Grade	Best evidence	Main gap	Read
Weight loss	BHuman trials	24.2% (Ph 2) and ~28.7% (Ph 3 topline)^1,3	Not yet approved	Largest in class
Liver fat	BHuman trials	Up to 82% reduction²	Phase 2a size	Striking
Glucose, prediabetes	BHuman trials	72% reverted to normal glucose¹	Not approved	Strong

Dosing: what has been reported

Not a recommendation. These figures describe what was studied or what circulates in practice, kept separate so you can see how solid each one is. Speak with a qualified clinician before acting on any of it.

Setting	Figure	Route	Grade
Trial protocol	Start 2 mg, step up about every 4 weeks; arms of 4, 8 and 12 mg; strongest effect at 8–12 mg¹	Subcutaneous, weekly	B
Clinical	No approved protocol, because the drug is investigational	—	—
Community	Copies the trial titration, starting at 1–2 mg	Subcutaneous, weekly	D

Trial step	Weekly dose	What to watch
1	2 mg	The first and biggest nausea wave. A tolerance step, not a weight-loss dose.
2	4 mg	A new GI wave; start checking heart rate
3	8 mg	Strong appetite suppression. Make sure protein intake keeps up.
4	12 mg	Highest studied dose. Many people do well below it.

Heart rate is the extra checkpoint with retatrutide. Check it before every step up, and hold or step back if it climbs or you feel palpitations. Slower half-steps (2 → 4 → 6 → 8 mg) are used when the standard steps are rough.

Preparing & storing

Trial supply is a refrigerated, ready-made injectable. Lyophilised research material is reconstituted with bacteriostatic water, swirled gently, kept at 2–8 °C and away from light. Inject on the same weekday each week into the abdomen, thigh or upper arm, rotating sites.

Reported side effects

Nausea (about 43% in trials), diarrhoea (about 33%), vomiting, constipation, all worst during step-ups
Heart-rate increase, dose-dependent, from the glucagon arm
Injection-site reactions; some skin-sensitivity reports
Class effects: gallbladder problems, a pancreatitis signal, muscle loss during rapid weight loss

Who should avoid it

Personal or family history of medullary thyroid cancer or MEN2
History of pancreatitis or serious GI disease
Pregnancy and breastfeeding
Significant heart disease (discuss the heart-rate effect with a doctor)
Do not combine with semaglutide, tirzepatide or other incretin drugs
Insulin and sulfonylurea doses need medical review

Regulatory status checked Oct 2026

Body	Status	Detail
FDA (US)	Not approved	Phase 3 reported; submission expected. Available through trials only.
EMA (EU)	Not approved	Investigational.
CDSCO (India)	Not approved	Investigational.
WADA	Not named	Not on the prohibited list. Athletes should check the current status.

The NexGen read

The most powerful compound in this guide, still in development

Retatrutide works on intake and expenditure at once, and the trial numbers reflect that. It still needs slow titration, heart-rate checks and plenty of protein. Its long-term safety record is still being built. With an investigational drug, independent testing of every batch matters even more.

References

Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972
Sanyal AJ, Kaplan LM, Frías JP, et al. Triple hormone receptor agonist retatrutide for MASLD: a randomized phase 2a trial. Nat Med. 2024. doi:10.1038/s41591-024-03018-2
Eli Lilly. TRIUMPH Phase 3 topline results, December 2025: about 28.7% mean weight reduction at 68 weeks. Full publication pending.