01 Identity
| Common name | Retatrutide |
|---|---|
| Developmental code | LY3437943 |
| Class | Single peptide (fatty-diacid conjugated); triple agonist of GIP, GLP-1 and glucagon receptors |
| Route studied | Once-weekly subcutaneous injection |
| Developer | Eli Lilly and Company |
| CAS number | 2381089-83-2 · FDA UNII NOP2Y096GV |
Relative to endogenous ligands, in vitro retatrutide is less potent at the glucagon and GLP-1 receptors (about 0.3× and 0.4×) and more potent at GIP (about 8.9×). The glucagon component is the feature most often cited to explain its effects on energy expenditure and hepatic fat.
02 Regulatory status
Retatrutide holds no marketing authorisation anywhere. It is not approved by the FDA, EMA, or MHRA, is not available on the NHS or by private prescription, and is not an approved medicine in any market as of the review date. It is an investigational compound, lawfully available only within sponsor-run clinical trials.
It is therefore neither a licensed prescription medicine nor a conventionally scheduled controlled substance; material offered for sale outside a registered trial is not a regulated pharmaceutical product. Re-check at each review as the Phase 3 programme reports.
03 Mechanism of action
Retatrutide is a single peptide that simultaneously agonises three receptors:
GLP-1 receptor — incretin effect, slowed gastric emptying, central appetite suppression. Well-characterised drug-class mechanism.
GIP receptor — incretin and appetite effects; contribution to clinical outcomes debated within the class. Mechanistic; not isolated in humans.
Glucagon receptor — proposed to raise energy expenditure and reduce hepatic fat; the differentiating component versus dual agonists. Mechanistically plausible; the glucagon contribution has not been directly isolated in humans.
A ~20% reduction in LDL cholesterol in Phase 2 has been attributed to glucagon-mediated effects on PCSK9 — a proposed mechanism, not a demonstrated causal pathway.
04 Pharmacokinetics / pharmacodynamics
Approximately dose-proportional pharmacokinetics with a terminal half-life of about 6 days (reported range ~5–7 days), supporting once-weekly administration. In the first-in-human single-ascending-dose study (45 healthy participants), maximum concentration occurred roughly 1–3 days post-dose.
Early-phase pharmacodynamics included dose-dependent increases in heart rate and decreases in systolic blood pressure, both returning toward baseline by about day 29 after single dosing.
05 Evidence by endpoint
Grades below are assigned per use-case, following the charter rubric, with the (topline) qualifier applied wherever data are announced but not yet published.
5.1 — Body-weight reduction in obesity (no type 2 diabetes)
A randomised, double-blind, placebo-controlled Phase 2 trial n=338 in adults with obesity/overweight without diabetes tested weekly retatrutide (1–12 mg, with escalation) or placebo. At 12 mg, mean body-weight reduction was about 17.5% at 24 weeks and 24.2% at 48 weeks, curves not yet plateaued.
Topline Phase 3 results (TRIUMPH-1, May 2026; TRIUMPH-4, Dec 2025) report high-20s to ~30% reductions but are sponsor announcements pending peer review — not equivalent to the published Phase 2 dataset.
Limited human — grade set by the published Phase 25.2 — Hepatic steatosis / MASLD
A peer-reviewed Phase 2a substudy n=98 reported dose-dependent relative liver-fat reductions at 24 weeks (≈ −43% to −82% across 1–12 mg) versus +0.3% on placebo; normal liver fat reached by 27–86% versus 0% on placebo.
Limited human — single small RCT5.3 — Type 2 diabetes
Sponsor topline (TRANSCEND-T2D-1, March 2026) reports ~16.8% weight reduction at 40 weeks on 12 mg, with glycaemic endpoints met. Full data pending.
Limited human (topline)5.4 — Knee osteoarthritis pain
TRIUMPH-4 topline reports improved WOMAC pain scores alongside weight loss. Whether the effect is independent of weight loss cannot be established from topline data.
Limited human (topline)5.5 — Cardiovascular outcomes
Phase 2 reported favourable cardiometabolic markers (blood pressure, lipids) as exploratory endpoints. A dedicated outcomes trial is reported underway. No completed event-reduction data exist.
Mechanistic / no outcome data5.6 — Obstructive sleep apnoea
A Phase 3 trial in OSA with obesity is reported ongoing. No results available.
No human outcome data yet06 Safety and adverse events
The most consistent adverse events are gastrointestinal — nausea, vomiting, diarrhoea, constipation — dose-dependent and concentrated during escalation. In Phase 2, nausea ranged from ~14% (lowest dose) to ~60% (12 mg). Discontinuation due to adverse events occurred in about 6–16% on retatrutide (rising with dose) versus none on placebo; serious adverse events were comparable to placebo.
Heart rate rose dose-dependently, peaking around week 24 then declining — similar in magnitude to GLP-1 receptor agonists. Altered skin sensation (dysesthesia) was reported in a minority, mild-to-moderate, not leading to discontinuation.
07 Evidence summary
| Endpoint | Grade |
|---|---|
| Weight loss, obesity (no T2D) | Limited human |
| Liver fat / MASLD | Limited human |
| Type 2 diabetes | Limited human (topline) |
| Knee osteoarthritis pain | Limited human (topline) |
| Cardiovascular outcomes | Mechanistic / no outcome data |
| Long-term safety (>~80 wk) | No data |
08 References
- Jastreboff AM, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. NEJM, 2023.DOI 10.1056/NEJMoa2301972 · ClinicalTrials.gov NCT04881760
- Triple hormone receptor agonist retatrutide for MASLD: a randomized phase 2a trial. Nature Medicine, 2024.DOI 10.1038/s41591-024-03018-2
- Urva S, Coskun T, Loh MT, et al. LY3437943 … phase 1b multiple-ascending-dose trial. Lancet 2022;400:1869–1881.
- Coskun T, et al. LY3437943 … from discovery to clinical proof of concept. Cell Metabolism 2022;34:1234.DOI 10.1016/j.cmet.2022.07.013
- Eli Lilly — TRIUMPH-1 (May 2026), TRIUMPH-4 (Dec 2025), TRANSCEND-T2D-1 (Mar 2026) topline announcements (sponsor press releases; topline only).Registered TRIUMPH Phase 3 trials confirmed on ClinicalTrials.gov: TRIUMPH-2 NCT05929079 (type 2 diabetes), TRIUMPH-3 NCT05882045 (obesity + cardiovascular disease). Match each announced trial above to its own NCT before publication.