GLP-1/GIP/GCG Agonist / SubQ / 1-12mg weekly
Retatrutide
Retatrutide (LY3437943) is Eli Lilly's triple incretin-receptor agonist: one 39-amino-acid peptide, engineered on the GIP backbone, that activates the GIP, GLP-1, and glucagon receptors. The 2023 phase 2 result, 24.2% mean weight loss at 48 weeks, was the largest reported for any obesity drug candidate at the time, and grey-market use took off years before any approval.
In plain words
Retatrutide is a single lab-made peptide, engineered at Eli Lilly, that acts on three hormone receptors at once: the two gut-hormone receptors other weight-loss drugs use, GIP and GLP-1, plus the glucagon receptor, which in mice added weight loss by raising energy output. A fatty tail on the molecule makes it last roughly six days, which is what makes a weekly injection workable. The published evidence is striking but still early-stage: a 48-week phase 2 trial in adults with obesity reported an average 24.2 percent weight loss against 2.1 percent on placebo, and one phase 3 trial in type 2 diabetes has been published, while four other completed phase 3 trials had not reported results as of August 2026. Retatrutide is investigational and has never been approved anywhere, for anything; the vials people buy are grey-market, and community use runs years ahead of any approval. In the trials, the common problems were gastrointestinal side effects and a dose-related rise in resting heart rate that peaked around week 24 and then fell back.
At a glance
| Half-life | 6.14 days |
|---|---|
| Tmax | 1.68 days |
| Route(s) | SubQ |
| Published dosing range | 1-12mg weekly |
| Vial strengths | 10, 5, 15, 20 mg |
Reference data from the DosePlot canon -- not a protocol recommendation.
Serum curve
Single 6.5 mg dose by SubQ, rendered from the same engine that powers the interactive chart. Relative levels, not lab values.
What does the evidence show?
Two things are labeled separately here because they answer different questions. The tier is how a study was built. The distance chips are whether that study touched this molecule, by this route, in a population resembling the reader. A randomized trial of a different molecule keeps its tier and still says nothing about this compound.
| Finding | Tier | Distance from use | Study |
|---|---|---|---|
| In a 48-week phase 2 trial in 338 adults with obesity or overweight (without diabetes), once-weekly retatrutide 12 mg produced a mean body-weight reduction of 24.2%, versus 2.1% with placebo; every participant on the 8 mg and 12 mg doses lost at least 5% of body weight. | rct | not recorded | Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.New England Journal of Medicine 389(6):514-526, 2023 |
| In a phase 2 trial in 281 adults with type 2 diabetes, weekly retatrutide lowered HbA1c and body weight versus placebo, in a design that also carried an active dulaglutide 1.5 mg comparator arm. | rct | not recorded | Rosenstock J, et al. 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 conducted in the USA.Lancet 402(10401):529-544, 2023 |
| In the first published phase 3 trial (TRANSCEND-T2D-1), 537 adults with type 2 diabetes inadequately controlled by diet and exercise alone were randomly assigned to retatrutide 4 mg, 9 mg, 12 mg, or placebo once weekly for 40 weeks. For the treatment-regimen estimand, HbA1c fell by up to 1.94 percentage points at the 12 mg dose versus 0.81 with placebo, and body weight by up to 15.3% versus 2.6% with placebo. | rct | not recorded | Bajaj HS, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.Lancet 407(10546):2402-2413, 2026 |
| In a randomized substudy of adults with MASLD (metabolic dysfunction-associated steatotic liver disease) and obesity, 24 weeks of retatrutide 8 mg or 12 mg cut liver-fat content by a mean of 81-82% relative to baseline, versus essentially no change with placebo, and 86% of the 12 mg group reached normal liver fat (below 5%). | rct | not recorded | Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.Nature Medicine 30(7):2037-2048, 2024 |
| Side effects track dose: gastrointestinal events were the most common adverse events in the obesity trial, and resting heart rate rose dose-dependently, peaking around week 24 and declining thereafter. | rct | not recorded | Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.New England Journal of Medicine 389(6):514-526, 2023 |
| In the first human study, a single dose reduced body weight measurably for six weeks (out to day 43), and the pharmacokinetics, with a half-life of roughly six days, supported once-weekly injection. | clinical | not recorded | Coskun T, et al. 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 Metabolism 34(9):1234-1247, 2022 |
| The glucagon-receptor arm adds an energy-output mechanism: in obese mice, GCGR activity raised energy expenditure and produced additional weight loss on top of the reduced food intake driven by the GIP and GLP-1 receptor arms. | preclinical | not recorded | Coskun T, et al. 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 Metabolism 34(9):1234-1247, 2022 |
| Community reports describe appetite suppression stronger than users experienced on semaglutide or tirzepatide, weight loss broadly in line with trial rates, and a noticeable rise in resting heart rate; grey-market use runs years ahead of any approval. | anecdotal | not recorded | community reports aggregated from reddit, MESO-Rx, and similar forumsno study |
How did it get here?
- preclinicallate 2010s
- Engineered at Eli Lilly as LY3437943: a single 39-amino-acid peptide built on the GIP backbone, with GLP-1 and glucagon receptor activity designed into the same chain and a fatty-acid tail for a roughly six-day half-life. In obese mice, the glucagon arm added energy-expenditure-driven weight loss on top of the intake reduction from the two incretin arms.
- first-human2019-2022
- First-in-human single-ascending-dose study, then a phase 1b multiple-ascending-dose trial in type 2 diabetes. A single dose cut body weight measurably for six weeks, and the kinetics confirmed once-weekly injection was workable.
- clinical-adoption2023
- The phase 2 readouts land weeks apart: 24.2% mean weight loss at 48 weeks in obesity (New England Journal of Medicine) and glucose plus weight reductions in type 2 diabetes against an active dulaglutide comparator (Lancet). Lilly moves the molecule into a broad phase 3 program spanning obesity, diabetes, sleep apnea, and osteoarthritis.
- grey-market2023-2024
- Within months of the phase 2 publications, grey-market peptide vendors are listing retatrutide as lyophilized vials, and forum protocols appear that copy the trial titration. An unapproved compound in phase 3 becomes one of the most used peptides in the community, entirely outside medical supervision.
- clinical-adoption2025-2026
- The first phase 3 trials complete, with more of the program still running. The public trial registry records TRIUMPH-4 (obesity with knee osteoarthritis, 445 participants) reaching primary completion in November 2025, TRIUMPH-1 (2335 participants) in April 2026, TRIUMPH-3 (severe obesity with cardiovascular disease, 1946 participants) in April 2026, and TRIUMPH-2, the type 2 diabetes trial in that series (1152 participants), in June 2026. None of the four has posted results to the registry. The one peer-reviewed phase 3 report so far is TRANSCEND-T2D-1, published in the Lancet in June 2026. As of late August 2026 retatrutide holds no approved application in the FDA drug approval database; Lilly has opened a pre-approval expanded-access program for individual patients (NCT07629401), a mechanism that exists for drugs their sponsor is carrying toward approval.
How is it made?
Retatrutide is a fully synthetic peptide; nothing about it is extracted or fermented. Production happens in three stages.
1. Building the chain. The 39-amino-acid backbone is assembled by solid-phase peptide synthesis: the chain grows one protected amino acid at a time on resin beads. The sequence is a re-engineered version of the gut hormone GIP, with GLP-1 and glucagon receptor activity built into the same chain, and with non-natural residues, such as aminoisobutyric acid at position 2, placed where the blood enzyme DPP-4 normally cuts. Native GIP survives minutes in circulation; that substitution is much of why retatrutide survives days.
2. Attaching the fat tail. A 20-carbon fatty diacid is bonded through a short linker to the lysine at position 17. After injection the tail binds serum albumin, so the peptide rides a carrier protein instead of being cleared - this is what stretches the half-life to roughly six days and makes once-weekly injection work.
3. Cleaving, purifying, filling. The finished peptide is cleaved from the resin, stripped of its protecting groups, and purified by preparative chromatography. A synthesis this long accumulates deletion and truncation byproducts - chains missing a residue here or there - and only chromatography plus mass-spectrometry testing finds them. Pharmaceutical material is sterile-filtered and filled under GMP rules, with every batch tested for identity, potency, sterility, and endotoxins. The chemistry is demanding but standard; purification and sterile fill are the steps that vary most outside regulated manufacturing, and no vial label reveals either.
Worth knowing
The triple agonist is built on the backbone of GIP, long treated as the least interesting of the three hormones. Lilly's chemists found the GIP scaffold tolerant enough to carry engineered GLP-1 and glucagon activity in the same 39-amino-acid chain, so one peptide does all three jobs rather than three hormones sharing a vial.
Coskun T, et al. 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 Metabolism 34(9):1234-1247, 2022
Response in the phase 2 obesity trial was essentially universal at the top doses: 100% of participants on 8 mg and 12 mg lost at least 5% of body weight by 48 weeks, and 83% of the 12 mg group lost at least 15%.
Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.New England Journal of Medicine 389(6):514-526, 2023
Community shorthand for retatrutide is 'reta', and much of the grey market brands it 'GLP-3' - a name with no pharmacological meaning (GLP-2 exists as an unrelated gut hormone; there is no GLP-3), but it stuck as shorthand for the generation after semaglutide and tirzepatide.
community reports aggregated from reddit, MESO-Rx, and similar forumsno study
Reconstitution
Retatrutide ships lyophilized and is mixed before use; the published vial strengths are 10, 5, 15, 20 mg. The water volume you add sets the concentration, not the dose -- the calculator turns a vial size and a water volume into mg/mL, draw volume, and units on an insulin syringe.
Open in the reconstitution calculatorWritten and reviewed by Evan Marlow, developer of DosePlot · Updated 2026-08-27
Not medical advice. DosePlot is an informational tool, not a healthcare provider, and using it creates no provider-patient relationship. Do not start, stop, or change any protocol without the approval of a licensed healthcare professional.
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