Retatrutide

Evidence grade: B — reviewed September 2026

Controlled human trials: 8 completed or reported (1 Phase 1b, 2 Phase 2, 5 Phase 3 topline), roughly 5,800 participants in the Phase 3 program alone Pilot or open-label human studies: 1 (Phase 2a liver substudy) Animal studies: yes (mouse, rat, and monkey pharmacology in the discovery program)

Also known as: LY3437943, “GGG tri-agonist,” “triple G,” GLP-3 and GLP-3 RT (vendor slang)

Sequence: 39-amino-acid synthetic peptide with a C20 fatty diacid on lysine-17; based on the GIP backbone with substitutions that add GLP-1 and glucagon receptor activity. Lilly has not published the full sequence in a form suitable for reproduction here.

One-line rationale: The largest weight-loss effect ever recorded in an obesity drug trial, replicated across five Phase 3 studies. It stays a B, not an A, because every Phase 3 number below is from a company press release; none has been through peer review, and no regulator has reviewed the safety file.

What it is

Retatrutide is Eli Lilly’s investigational once-weekly injectable that activates three receptors at once: GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and the glucagon receptor. Semaglutide hits one of those. Tirzepatide hits two. Retatrutide is the first molecule to reach Phase 3 hitting all three, and the third one, glucagon, is what makes it different.

It was first described in 2022 as LY3437943 and reached its first Phase 3 readout in December 2025.

Proposed mechanism

GLP-1 and GIP agonism do what they do in tirzepatide: slow gastric emptying, reduce appetite through the brain, and improve insulin secretion. Both reduce how much people eat.

Glucagon receptor agonism is the new lever. On its own, glucagon raises blood sugar, which is why it was long considered the wrong target for a metabolic drug. But it also increases energy expenditure and drives fat oxidation in the liver. Paired with GLP-1 and GIP, which keep glucose under control, the theory is that glucagon adds an “energy out” effect on top of the “energy in” reduction. The very large liver-fat reductions in the Phase 2a substudy are the clearest support for that theory in humans.

What the human evidence shows

Phase 1b (2022, Lancet). 72 people with type 2 diabetes, 12 weeks. Established once-weekly pharmacokinetics and dose-dependent reductions in glucose and body weight. Heart rate rose with dose.

Phase 2 obesity (2023, NEJM). 338 adults with obesity, 48 weeks, placebo-controlled. Mean weight loss of 24.2% at 12 mg vs. 2.1% on placebo. At the time this exceeded anything published for semaglutide or tirzepatide at matched duration.

Phase 2 type 2 diabetes (2023, Lancet). 281 adults, 36 weeks, placebo and dulaglutide controlled. A1C reductions up to about 2 percentage points and weight loss up to 16.9%, both larger than the active comparator.

Phase 2a liver substudy (2024, Nature Medicine). 98 participants from the obesity trial with elevated liver fat. At 48 weeks the 12 mg dose reduced liver fat by 86% and about 9 in 10 participants normalized. This is the strongest single-drug liver-fat result reported for any therapy and is the main evidence that the glucagon component does something GLP-1/GIP alone don’t.

Phase 3 program (TRIUMPH and TRANSCEND, 2025–2026, topline only).

Trial	Population	Readout	Weight loss at highest dose
TRIUMPH-4	Obesity + knee osteoarthritis, n=445	Dec 2025	28.7% at 68 weeks
TRANSCEND-T2D-1	Type 2 diabetes	Mar 2026	16.8% at 40 weeks
TRIUMPH-1	Obesity, no diabetes, n=2,339	May 2026	28.3% at 80 weeks; 30.3% at 104 weeks in the BMI ≥35 extension
TRIUMPH-2	Obesity + type 2 diabetes, n=1,152	Jul 2026	20.8% at 80 weeks
TRIUMPH-3	Obesity + cardiovascular disease	Jul 2026	22.6% at 80 weeks

In TRIUMPH-1, 45% of participants on 12 mg lost 30% or more of their body weight, a threshold usually only reached by bariatric surgery, and 65% ended below the BMI 30 obesity line. The 4 mg dose, reached with a single escalation step, produced 19% loss with a discontinuation rate no worse than placebo.

Still outstanding: TRIUMPH-5 (head-to-head against tirzepatide), a weight-maintenance study, MASH/liver outcome trials, and a roughly 10,000-participant cardiovascular outcomes trial that will run for years.

Safety signals

The adverse-event profile is the incretin-class profile, but heavier at the top doses. In TRIUMPH-1 at 12 mg: nausea 42%, diarrhea 32%, constipation 26%, vomiting 25%, versus 15%, 14%, 11%, and 5% on placebo. Discontinuation for adverse events was 11.3% at 12 mg vs. 4.9% placebo.

Two signals are specific to this molecule and worth watching:

Dysesthesia (abnormal skin sensation, tingling, heightened sensitivity) in 12.5% at 12 mg vs. 0.9% placebo. Lilly reports most cases were mild and resolved on treatment. It is not a known GLP-1 or GIP effect and is presumed to come from the glucagon component.
Heart rate increase, seen from Phase 1b onward. Magnitude and long-term meaning await the outcomes trial.

Urinary tract infections were also modestly more frequent. No new serious safety signal has been reported to date, with the caveat that the full safety dataset has not been published or reviewed by any regulator.

Regulatory status

Not approved anywhere. Lilly has said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027. On a standard review that puts a decision in late 2027 at the earliest. Retatrutide is, in Lilly’s words, “legally available only to participants in Lilly’s clinical trials.”

Anything sold today under the name retatrutide is a research-grade synthetic made by someone other than Lilly. It has no connection to the trial material, no manufacturer-controlled identity, and none of the safety monitoring above applies to it. Identity and purity testing of such material is a genuine problem: standard UV-Vis certificates cannot confirm that a 39-residue peptide with a fatty-acid side chain is the right molecule, and mass spectrometry is the minimum for a credible identity claim.

Gaps and caveats

Press releases are not papers. Every Phase 3 figure on this page comes from Lilly topline announcements. Peer-reviewed publication of TRIUMPH-1 is expected but had not appeared as of this review. Topline numbers have historically held up for Lilly’s incretin trials, but the grade waits for the paper.
No regulator has seen the safety file. The dysesthesia and heart-rate findings will get their real evaluation in the FDA review and the outcomes trial.
Head-to-head data is missing. TRIUMPH-5 will answer whether the extra receptor beats tirzepatide directly; cross-trial comparisons of percentages are suggestive, not proof.
Durability unknown. Every incretin drug so far shows substantial weight regain on stopping. Nothing suggests retatrutide is different, and the maintenance trial hasn’t reported.
Dose matters enormously. The 30% headline is the 12 mg arm in people who tolerated escalation to it. The 4 mg arm, which many participants stayed on, delivered 19%.

Why it’s a B and not an A

On effect size and trial scale, this is the best-supported compound in the library by a wide margin, and it is the only one with multiple placebo-controlled Phase 3 trials in thousands of people. An A on this scale means peer-reviewed pivotal data and a regulatory safety review. Retatrutide has neither yet. It will likely have both within 18 months, and the grade will be revisited when the TRIUMPH-1 paper publishes.

Key references

Peptide Briefs is an independent reference on peptides as they appear in the scientific literature. Nothing here is medical advice or a recommendation to use any compound.