The triple agonist (GLP-1 + GIP + glucagon) in Phase 3 trials — Phase 2 showed ~24% body-weight reduction at 48 weeks, and TRIUMPH-4 (knee-OA cohort) reported 28.7% at 68 weeks.
Retatrutide (LY3437943) is a triple agonist (GLP-1 + GIP + glucagon) developed by Eli Lilly (Coskun 2022 Cell Metab, PMID 35985340). The TRIUMPH Phase 3 program covers obesity, obesity with type 2 diabetes, obesity with cardiovascular disease, obesity with knee osteoarthritis (TRIUMPH-4 read out December 2025), and MASH, with nested OSA subsets (Giblin 2026, PMID 41090431).
The addition of glucagon receptor agonism is what differentiates it from tirzepatide. Glucagon increases energy expenditure and fat oxidation; Phase 2 showed ~24% body-weight loss at 48 weeks at 12 mg (Jastreboff 2023 NEJM, PMID 37366315) — the largest weight-loss number reported in a Phase 2 trial to date. TRIUMPH-4 (Phase 3, obesity + knee OA) subsequently reported 28.7% at 68 weeks at 12 mg (Lilly investor release, Dec 11 2025).
Not commercially available. Retatrutide is not FDA approved and the FDA has explicitly stated it cannot be lawfully compounded under U.S. federal law (warning letters issued September 9, 2025; not on USP/NF, not a component of an approved drug, not on the 503A or 503B bulks lists). Vials sold by online research-chemical suppliers operate outside FDA oversight; documented quality issues include wrong peptide content, off-spec dosing, and contamination. The only legitimate access pathway is enrollment in a TRIUMPH Phase 3 trial. Not WADA prohibited as of the 2026 list.
Same as semaglutide: appetite suppression, delayed gastric emptying, glucose-dependent insulin release.
Same class as tirzepatide: enhances fat metabolism in adipose tissue and may attenuate GLP-1-driven GI side effects (mechanism debated).
Glucagon increases resting energy expenditure (metabolic rate) and promotes hepatic fat oxidation. It’s what lets retatrutide push weight loss beyond the GLP-1/GIP ceiling — the body is burning more energy even at rest.
GLP-1 suppresses intake, GIP redirects fat metabolism, glucagon increases expenditure. Combined, retatrutide produces the largest weight-loss numbers reported in Phase 2/3 trials of any incretin-based agent to date, though no head-to-head comparator trials have been conducted.
| Benefit | Evidence |
|---|---|
| Weight loss | Phase 2 (Jastreboff 2023, PMID 37366315): −24.2% body-weight loss at 48 weeks on 12 mg; weight still declining at trial end (no plateau) |
| HbA1c reduction | Phase 2 T2DM (Rosenstock 2023 Lancet, PMID 37385280): HbA1c reduction ~2.0–2.2 percentage points at 12 mg |
| Liver fat (MASLD/MASH) | Phase 2a (Sanyal 2024 Nat Med, PMID 38858523): ~80–82% reduction in liver fat content at 8–12 mg |
| Resting energy expenditure | Increased vs baseline — a mechanism GLP-1 mono-agonists and the GLP-1/GIP dual (tirzepatide) lack. GLP-1/glucagon duals (mazdutide, survodutide) share this arm |
| Lipid profile | Favorable changes in triglycerides at all doses; LDL reductions dose-dependent |
TRIUMPH Phase 3 program is in progress. TRIUMPH-4 (obesity + knee OA) read out 11 December 2025 with 28.7% weight loss at 12 mg — the first successful retatrutide Phase 3. TRIUMPH-1 (obesity pivotal) and TRIUMPH-2 (T2DM pivotal) read out in 2026; FDA submission expected after pivotals complete. New safety signal: dysesthesia (painful or abnormal skin sensation) was reported in 8.8% at 9 mg and 20.9% at 12 mg vs 0.7% placebo in TRIUMPH-4 — this is a distinguishing AE not seen at material rates in semaglutide or tirzepatide.
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Start Tracking FreeSlow titration is critical — retatrutide’s GI side effects can be intense at dose jumps.
| Weeks | Weekly Dose |
|---|---|
| 1–4 | 2 mg |
| 5–8 | 4 mg |
| 9–12 | 6 mg |
| 13–16 | 8 mg |
| 17–20 | 10 mg |
| 21+ | 12 mg (max studied) |
Note on the studied schedule: PMID 37366315 (Phase 2) actually used starting doses of 2 mg or 4 mg titrating to target maintenance doses of 4 mg, 8 mg, or 12 mg — 6 mg and 10 mg were not studied as maintenance arms. The uniform 2 mg step-up table above is a community interpolation for smoother tolerability; the trial-validated targets are 4, 8, and 12 mg. Many users settle at 4–8 mg once appetite and weight trajectory are where they want — max dose isn’t required.
10 mg vial + 2 mL BAC water = 5 mg/mL
| Dose | Volume | Syringe Units |
|---|---|---|
| 2 mg | 0.40 mL | 40 units |
| 4 mg | 0.80 mL | 80 units |
| 6 mg | 1.20 mL | 120 units (split if needed) |
| 8 mg | 1.60 mL | 160 units |
For higher doses (10–12 mg) reconstitute with less water (1 mL → 10 mg/mL) to keep injection volumes practical.
Pre-filled with a typical Retatrutide setup. Edit any field — the draw updates live.
Insulin syringe — 100 units = 1 mL
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Retatrutide’s side effect profile is similar to other GLP-1/GIPs but with additional glucagon-related considerations and a notable cardiovascular signal.
Heart rate increase of ~5–7 bpm at 8–12 mg in Phase 2, peaking ~week 24 (Jastreboff 2023, PMID 37366315). Mechanism is glucagon-driven (glucagon is chronotropic) and the magnitude is larger than reported in the pivotal trials of tirzepatide or semaglutide. Phase 2 was underpowered for hard cardiovascular endpoints; the TRIUMPH-Outcomes CVOT (NCT06383390) is the trial that will resolve long-term CV safety, with readout expected 2028–2029 (Giblin 2026, PMID 41090431).
No FDA label exists. The list below is class-effect-extrapolated and trial-exclusion-derived.
Human long-term safety data are limited. Not recommended for use outside of trial settings without medical supervision.
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Start Tracking FreeNo. As of May 2026, retatrutide is investigational and is not approved by the FDA, EMA, MHRA, PMDA, Health Canada, or TGA. Lilly’s NDA filing for obesity is anticipated Q4 2026 at the earliest, with an FDA decision realistically in 2027 or later. The FDA issued warning letters in September 2025 explicitly stating retatrutide cannot be lawfully compounded in the US. There is no legitimate access pathway outside an active clinical trial.
TRIUMPH-4 (announced December 11, 2025) — the first Phase 3 readout — showed adults with obesity and knee osteoarthritis on retatrutide 12 mg achieved 28.7% mean body-weight reduction at 68 weeks vs. placebo, with WOMAC pain score reductions of approximately 75.8% on the 12 mg arm. Both the 9 mg and 12 mg arms hit primary and key secondary endpoints. The pure-obesity pivotal (TRIUMPH-1) and T2DM trial (TRIUMPH-2) have not yet read out.
Trial-validated maintenance doses are 4 mg, 8 mg, and 12 mg once weekly subcutaneously. Phase 2/3 used a 2 mg or 4 mg starting dose, titrating to the maintenance target over the first weeks — the 2 mg start was specifically observed to reduce GI side effects vs. starting at 4 mg, with similar 48-week efficacy. Doses of 6 mg and 10 mg were NOT studied as maintenance arms; community schedules listing these are interpolation, not trial data.
TRIUMPH-4 surfaced a new safety signal: dysesthesia (abnormal sense of touch — normal sensations feel unusual or painful). Reported in 8.8% of participants on 9 mg and 20.9% on 12 mg vs. 0.7% on placebo. This was not flagged at this magnitude in the Phase 2 dataset and is one of the things to watch as the remaining TRIUMPH trials read out.
A typical reconstitution is 10 mg + 2 mL of bacteriostatic water, yielding a concentration of 5 mg/mL. A 4 mg weekly dose draws to 0.80 mL (80 units on a 100-unit insulin syringe). At the 12 mg maximum trial dose, the draw is 2.40 mL — switch to a 3 mL syringe above 5 mg per dose.
Direct head-to-head trials have not been completed. Indirectly: tirzepatide in SURMOUNT-1 produced approximately 22.5% mean weight loss at 72 weeks on 15 mg/week; retatrutide in TRIUMPH-4 produced 28.7% at 68 weeks on 12 mg/week — but in a different population (obesity + knee OA). Trial-to-trial comparisons across different cohorts have known limitations; a true head-to-head trial would be needed to make a defensible direct comparison.
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