Retatrutide: LY3437943, triple-action weight-loss drug (GIP/GLP-1/glucagon)
An experimental once-weekly injection that activates three hunger-and-metabolism hormones at once, producing 23.7% weight loss in late-stage trials; not yet an FDA-approved drug.
- Class
- Triple GIP / GLP-1 / glucagon receptor agonist (investigational)
- Status
- Investigational drug; not FDA-, EMA-, MHRA-, Health Canada-, or TGA-approved as of the source date (April 2026). In Phase 3 development under Eli Lilly's TRIUMPH program.
- Best-supported effect
- Substantial body-weight reduction in adults with obesity at the 12 mg weekly subcutaneous dose, established in a Phase 2 trial (24.2% at 48 weeks) and reported again in the Phase 3 TRIUMPH-4 readout.
- Main caveat
- Most of the Phase 3 program is still reading out, long-term safety beyond ~88 weeks is uncharacterized, and the entire human evidence package comes from a single sponsor (Eli Lilly) with no completed independent replication.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
Lilly GMP manufacturing
Phase 3 clinical supply (TRIUMPH program)
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PMID:36354040
EC50 at GLP-1R, GIPR, GCGR in low-nM range (Coskun et al., Lancet 2022)
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What this is
Retatrutide (Eli Lilly code LY3437943) is an investigational once-weekly injectable peptide designed to activate three hormone receptors at the same time — the GLP-1 receptor, the GIP receptor, and the glucagon receptor. That triple combination sets it apart from earlier drugs in the same class: semaglutide targets only GLP-1, while tirzepatide (/card/pep-00017) targets GLP-1 and GIP. Adding the glucagon receptor introduces a distinct mechanism — increased energy expenditure and hepatic fat mobilisation — that neither single nor dual incretin agonists provide alone. Lilly describes it as a 39-residue peptide built on a modified GIP backbone; the raw stored sequence does not reflect a fatty-acid conjugation that accounts for the roughly six-day plasma half-life enabling once-weekly dosing (Jastreboff and colleagues, NEJM 2023). As of the available literature date (April 2026), retatrutide is not approved in any major jurisdiction; clinical exposure occurs only inside Lilly's Phase 3 TRIUMPH program.
History
Retatrutide's scientific premise built on tirzepatide's Phase 3 success and on decades of evidence that glucagon-receptor agonism increases energy expenditure and mobilises hepatic fat — an attractive therapeutic target that had been difficult to use in isolation because glucagon also raises blood glucose. The solution Lilly pursued was to pair glucagon-receptor activity with strong GLP-1 and GIP co-agonism, using the glucose-lowering effects of the incretin arms to neutralise the hyperglycaemic risk of the glucagon arm. The molecular design and first proof-of-concept data were published in 2022 (Coskun and colleagues described LY3437943 discovery through clinical proof of concept in Cell Metabolism that year). The landmark Phase 2 obesity trial published in NEJM (Jastreboff and colleagues, 2023) reported 24.2% mean body-weight reduction at 48 weeks at the 12 mg dose — the largest obesity-drug weight loss published at that time. A companion Phase 2 trial in type 2 diabetes (Rosenstock and colleagues, Lancet 2023) and a Phase 2a trial in metabolic dysfunction-associated steatotic liver disease (Sanyal and colleagues, Nature Medicine 2024) followed. Phase 3 development — the TRIUMPH program — began enrolling in 2022 across at least eight trials covering obesity, type 2 diabetes, MASH, obstructive sleep apnea, hypertension, and cardiovascular outcomes. TRIUMPH-4, a Phase 3 trial in adults with obesity and knee osteoarthritis (n=445), reported positive topline results in December 2025, with 23.7% mean weight loss at 12 mg at 68 weeks; a Phase 3 type 2 diabetes trial (TRANSCEND-T2D-1, n=537) reported positive topline results in March 2026. Most of the TRIUMPH program had not yet read out at the published literature date.
What it does
Retatrutide acts at three hormone receptors, each contributing a distinct metabolic effect. GLP-1 receptor activation reduces appetite by signalling satiety through hypothalamic and brainstem circuits and slows gastric emptying — the same mechanism shared with semaglutide (/card/pep-00016) and tirzepatide. GIP receptor activation adds complementary appetite suppression and improves insulin sensitivity. Glucagon receptor activation is the novel addition: it increases resting energy expenditure, drives lipolysis, and accelerates hepatic fatty-acid oxidation, thereby reducing liver fat — effects that the incretin arms alone do not produce. Together, the three pathways produce body-weight reductions in clinical trials that exceed what has been observed with approved single or dual incretin agents. In the Phase 2 MASH trial, the glucagon component is the proposed explanation for unusually large liver-fat reductions (Sanyal and colleagues, Nature Medicine 2024). The trade-off is that glucagon-receptor activation also produces a resting heart-rate elevation and, at higher doses, modest transient increases in fasting glucose that dual or single incretin agonists do not share.
Evidence
- Human: Strong Phase 2 evidence across three indications. Jastreboff and colleagues (NEJM 2023) reported 24.2% mean body-weight loss at 48 weeks in adults with obesity (n=338, Phase 2; 12 mg dose). Rosenstock and colleagues (Lancet 2023) reported HbA1c reductions up to 2.02 percentage points at 36 weeks in adults with type 2 diabetes (Phase 2). Sanyal and colleagues (Nature Medicine 2024) reported more than 80% relative liver-fat reduction at 48 weeks in adults with metabolic dysfunction-associated steatotic liver disease (Phase 2a). Phase 3 TRIUMPH-4 (obesity with knee osteoarthritis; December 2025 topline) reported 23.7% mean weight loss at 12 mg at 68 weeks and a WOMAC pain reduction of 75.8%; Phase 3 TRANSCEND-T2D-1 (type 2 diabetes; March 2026 topline) reported positive results. All human evidence originates with a single sponsor; no independent replication is in the available literature.
- Animal: The triple-agonism concept is described as well-supported in preclinical models; a comparative study in db/db mice examined effects on diabetic kidney disease relative to liraglutide and tirzepatide.
- In vitro: Receptor-level pharmacology of GIPR, GLP-1R, and GCGR activation is established through the broader incretin literature; assay-level data are not separately extracted in this card.
Known effects
- Body-weight reduction (obesity) — Phase 2 (NEJM 2023): 24.2% at 48 weeks, 12 mg; Phase 3 TRIUMPH-4 topline: 23.7% at 68 weeks, 12 mg. Curve was still descending at Phase 2 trial end, suggesting a higher plateau with longer treatment.
- HbA1c reduction (type 2 diabetes) — Phase 2 (Lancet 2023): up to 2.02 percentage points at 36 weeks, 12 mg.
- Liver-fat reduction (MASH/MASLD) — Phase 2a (Nature Medicine 2024): >80% relative reduction at 24–48 weeks, 12 mg. Substantial histologic resolution also reported in that trial.
- Knee osteoarthritis pain reduction — Phase 3 TRIUMPH-4 topline: WOMAC pain score reduced 75.8% at 68 weeks alongside the weight-loss endpoint.
- Resting energy expenditure increase — Attributed to glucagon-receptor agonism; quantified in trial pharmacology data but not separately extracted here.
- Heart-rate elevation — Phase 2 trials: mean +2 to +6 bpm at 12 mg; attributed to glucagon-receptor activation; under continued monitoring in Phase 3.
Safety signals
Gastrointestinal events — nausea, vomiting, diarrhea, constipation, and decreased appetite — were reported in Phase 2 and Phase 3 trials at rates described as broadly comparable to tirzepatide and concentrated at dose-escalation steps (Jastreboff and colleagues, NEJM 2023; Rosenstock and colleagues, Lancet 2023). Treatment discontinuation reached approximately 18% at the 12 mg dose in the Phase 2 obesity trial, described in available literature as higher than rates reported with semaglutide and tirzepatide at their respective top doses.
A signal not seen with other incretin drugs is dysesthesia — tingling, burning, or pin-and-needle sensations in the extremities — with an approximately 21% incidence at 12 mg in the Phase 2 obesity trial. Severity was described as variable and usually transient; the mechanism is uncharacterised in the available literature.
Heart-rate elevation of approximately +2 to +6 bpm at 12 mg is attributed to glucagon-receptor activation and is under continued Phase 3 monitoring. Modest fasting-glucose and HbA1c excursions at higher doses were reported in Phase 2 and attributed to the glucagon component.
For pancreatitis, thyroid neoplasia, and liver injury, available sources report no signal in published retatrutide trials. The class-level concerns from GLP-1 and incretin agonists — including the boxed-warning parallel for medullary thyroid carcinoma and Multiple Endocrine Neoplasia syndrome type 2 — are expected to apply to retatrutide based on shared rodent C-cell tumour findings in the class. Long-term safety beyond approximately 88 weeks is uncharacterised; dedicated Phase 3 cardiovascular outcome data had not read out at the available literature date.
Drug-interaction observations available in published literature are mechanism-inferred parallels to tirzepatide; no dedicated pharmacokinetic interaction studies are extracted.
Regulatory status
- US (FDA): Not approved. Investigational drug under Eli Lilly's IND, available only through TRIUMPH-program trial participation. No legal US compounding pathway exists: 503A compounding requires either an approved reference product or a validated bulk drug substance list entry, neither of which applies to retatrutide. Analyst projections described in available literature anticipate an NDA filing in 2026 with potential approval in late 2026 or 2027; these are not regulatory commitments.
- EU (EMA), UK (MHRA), Canada (Health Canada), Australia (TGA): Not approved. No major regulator has authorised retatrutide as a medicine per available sources.
- WADA: Not listed by name on the Prohibited List, but falls within the S0 category covering substances "not currently approved by any governmental regulatory health authority for human therapeutic use." Athletes subject to the WADA code should treat retatrutide as prohibited in and out of competition (per available sources; current list status not independently refreshed in this card).
Mechanism
Retatrutide is a 39-amino-acid peptide engineered for simultaneous agonist activity at the GIP receptor (GIPR), GLP-1 receptor (GLP-1R), and glucagon receptor (GCGR). All three receptors are class B G-protein-coupled receptors that signal through Gαs and the cAMP pathway; their individual pharmacology is well characterised from prior drug development.
GLP-1R agonism suppresses appetite via hypothalamic and brainstem satiety circuits, slows gastric emptying, and stimulates glucose-dependent insulin secretion. GIPR agonism provides complementary appetite suppression and improves insulin sensitivity; this pairing — the same combination present in tirzepatide (/card/pep-00017) — underlies the larger weight-loss magnitudes seen with dual compared with single incretin agonists. The retatrutide-specific addition is GCGR agonism, which drives lipolysis, increases hepatic fatty-acid oxidation, increases thermogenesis, and raises resting energy expenditure. In the context of simultaneous GLP-1R and GIPR activation, the hyperglycaemic effect ordinarily produced by isolated glucagon-receptor activation appears neutralised at studied doses, enabling the thermogenic and lipolytic benefits to be harnessed without net glycaemic destabilisation.
The glucagon-receptor arm is the proposed explanation for both retatrutide's incremental weight-loss magnitude beyond tirzepatide and the scale of liver-fat reduction in MASH trials (Sanyal and colleagues, Nature Medicine 2024). The glucagon arm is also the probable source of the drug's distinct safety signals: the approximately +2 to +6 bpm resting heart-rate elevation and the dysesthesia not shared with semaglutide or tirzepatide.
The approximately six-day plasma half-life — supporting once-weekly subcutaneous injection — is consistent with a fatty-acid conjugation enabling albumin binding; residue-level sequence detail beyond the backbone is not reported in the available literature.
Open questions
- Remaining TRIUMPH Phase 3 readouts. Of the eight planned Phase 3 trials, most outcomes — including dedicated cardiovascular, MASH Phase 3, obstructive sleep apnea, and hypertension endpoints — had not read out at the available literature date.
- TRIUMPH-4 weight-loss discrepancy. Available sources quote both 23.7% and 28.7% mean weight loss at 12 mg for the TRIUMPH-4 readout; the discrepancy is unresolved in the available literature.
- Long-term safety beyond ~88 weeks. All published and planned trials end at or before that duration; chronic multi-year safety data are absent.
- Dysesthesia mechanism. The approximately 21% dysesthesia incidence at 12 mg is not seen with other incretin drugs; the underlying mechanism is uncharacterised.
- Withdrawal and weight-regain kinetics. No Phase 3 discontinuation-arm data comparable to obesity-drug withdrawal studies is attached; regain timing and magnitude are inferred from class behaviour.
- Body composition at higher doses. Whether the larger absolute weight loss at 12 mg includes disproportionate lean-mass loss relative to tirzepatide or semaglutide remains under study.
- Head-to-head comparison with tirzepatide. No completed direct trial exists; comparative efficacy and tolerability rest on cross-trial indirect comparisons with their methodological limits.
- Independent replication. All human evidence in the available literature originates with Eli Lilly; no independent-program human replication is published.
Related peptides
- Tirzepatide (/card/pep-00017) — Eli Lilly's dual GIP/GLP-1 receptor agonist; the immediate structural predecessor to retatrutide in the same pipeline, FDA-approved for type 2 diabetes (Mounjaro) and obesity (Zepbound).
- Semaglutide (/card/pep-00016) — Novo Nordisk's GLP-1 receptor agonist; the most widely used comparator in cross-trial efficacy discussions; approved for type 2 diabetes and weight management.
- Dulaglutide (/card/pep-10881) — Eli Lilly's once-weekly GLP-1 receptor agonist fusion protein; an earlier entry in Lilly's GLP-1-based pipeline, FDA-approved for type 2 diabetes and cardiovascular risk reduction.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could this drug fix a dangerous liver condition even in people who barely lose weight on it?
Millions with fatty liver disease (MASH) fail to lose enough weight for current treatments to help them. If this hypothesis holds, retatrutide could treat their liver directly by triggering a fat-burning process called ketogenesis, meaning patients who do not slim down much might still see their liver recover.
Why do some patients on the highest dose feel tingling or burning sensations, and is it a warning for the whole drug class?
About one in five patients at the top dose reported strange skin sensations not seen with similar drugs. If this is confirmed to come from the glucagon part of the drug acting on sensory nerves, it could signal a shared risk for any future drug that targets the glucagon receptor, prompting researchers to redesign that component before it reaches more patients.
Could this drug ease arthritis pain directly in the joint, beyond what losing weight would account for?
Patients in one trial saw their knee pain fall by roughly three-quarters, which looks larger than what weight loss alone typically delivers. If the drug is also calming inflammation inside the joint, it could eventually help people with painful arthritis who are not overweight at all, a much larger group than those currently eligible.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.761703372001648 | openfold3-mlx |
| ranking score | 0.8307342529296875 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.712 | global PDE — lower = better |
| disorder | 0.145 | fraction disordered |
| chain pair ipTM (A, B) | 0.762 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| runtime | 489s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-14 |
▸citationbibtex
@peptide{pep00018,
sequence = {YAEGTFISDYSIAMDEIHQQDFVNWLLAQKGKKNDWKHNI},
target = {gcgr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}