Retatrutide: Evidence Grade B | Trials and Sources

Evidence grade: B — reviewed September 2026

Controlled human trials: 8 completed or reported (1 Phase 1b, 2 Phase 2, 5 Phase 3: three peer-reviewed, two topline only), 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).

Corrected September 15, 2026: an earlier version of this page said no Phase 3 result had been peer-reviewed. TRANSCEND-T2D-1 was published in The Lancet on June 6, 2026, and TRIUMPH-1 was presented in full at the ADA Scientific Sessions the same day. The grade is unchanged; the reasoning below is corrected.

Updated September 29, 2026: TRIUMPH-2 full results published in The Lancet and TRIUMPH-1 in NEJM the same day. Grade unchanged; stats and rationale updated.

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 only three of five Phase 3 results (TRANSCEND-T2D-1 and TRIUMPH-2 in The Lancet, TRIUMPH-1 in NEJM) have been through peer review; the rest are company topline releases, 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; three peer-reviewed, two 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 topline; Lancet Jun 2026	16.8% at 40 weeks
TRIUMPH-1	Obesity, no diabetes, n=2,339	May 2026 topline; NEJM Sep 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 topline; Lancet Sep 2026	20.8% at 80 weeks
TRIUMPH-3	Obesity + cardiovascular disease	Jul 2026	22.6% at 80 weeks

In TRIUMPH-1 (NEJM, September 29, 2026), the intention-to-treat result was 17.6%, 23.7% and 25.0% weight loss at 4, 9 and 12 mg vs 3.9% on placebo; the efficacy estimand, which assumes everyone stayed on drug, was 19.0%, 25.9% and 28.3%. Lilly’s May topline and most headlines use the second figure. On 12 mg, 36.9% lost 30% or more and 57.1% ended below the BMI 30 line. The 4 mg dose stopped drug for adverse events at 4.1% vs 4.6% on placebo. Knee osteoarthritis pain and sleep apnea events were also reduced in the nested cohorts.

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 (NEJM) was 4.1%, 6.5% and 11.2% at 4, 9 and 12 mg vs 4.6% on placebo. Orthostatic hypotension occurred in 8.8% at 12 mg vs 0.9%. No medullary thyroid cancer was reported.

Two signals are specific to this molecule and worth watching:

Dysesthesia (abnormal skin sensation, tingling, heightened sensitivity) in 12.3% at 9 mg and 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 no regulator has reviewed the safety dataset.

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

Two results are still press releases. TRIUMPH-3 and TRIUMPH-4 are known only from Lilly topline announcements. TRANSCEND-T2D-1, TRIUMPH-1 and TRIUMPH-2 are now peer-reviewed. Topline numbers have historically held up for Lilly’s incretin trials, but those two wait for their papers.
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%.

Common questions

How much weight did participants lose in the retatrutide trials?
In TRIUMPH-1 (NEJM, September 2026), the 12 mg dose produced 25.0% weight loss at 80 weeks by intention-to-treat, against 3.9% on placebo. The 28.3% figure in most headlines is the efficacy estimand, which assumes everyone stayed on the drug.

Is retatrutide approved?
No, not in any country. Lilly has said it plans to file with the FDA in the first quarter of 2027, which puts a decision in late 2027 at the earliest.

How is it different from semaglutide and tirzepatide?
Semaglutide activates one receptor (GLP-1), tirzepatide two (GLP-1 and GIP), and retatrutide three, adding glucagon. No head-to-head result exists yet. TRIUMPH-5, against tirzepatide, has not reported.

What adverse events did the trials report?
In TRIUMPH-1 at 12 mg: nausea 42%, diarrhea 32%, constipation 26% and vomiting 25%. Discontinuation for adverse events was 4.1%, 6.5% and 11.2% at 4, 9 and 12 mg vs 4.6% on placebo (NEJM). Two signals are specific to this molecule: abnormal skin sensation in 12.5% against 0.9%, and a rise in heart rate.

Is the retatrutide sold online the same as the trial drug?
No. Lilly’s material is available only to trial participants. Anything sold under the name is a research-grade synthetic from another manufacturer, and a UV-Vis certificate cannot confirm its identity. Mass spectrometry is the minimum for a credible identity claim.

Do people regain weight after stopping?
Unknown for retatrutide, because the maintenance trial has not reported. Every earlier drug in this class has shown substantial regain on stopping.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 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 now has the first in part: three of five reported Phase 3 results are published (TRANSCEND-T2D-1 and TRIUMPH-2 in The Lancet, TRIUMPH-1 in NEJM). It does not have the second; the BLA is planned for the first quarter of 2027. The grade will be revisited when the remaining Phase 3 results publish and when a regulator has reviewed the safety file.

See also: Tirzepatide (grade A; the dual GIP/GLP-1 comparator in TRIUMPH-5) and the Grade Key.

Key references

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