Side-by-side comparison
| Property | Retatrutide (LY3437943) | Tirzepatide |
|---|---|---|
| Receptor targets | Triple: GIP + GLP-1 + glucagon | Dual: GIP + GLP-1 |
| Brand names | None — investigational | Mounjaro, Zepbound |
| Approval status (Jun 2026) | Phase 3 (TRIUMPH program); not approved | FDA-approved (T2D, obesity, OSA) |
| Approximate half-life | ~6 days | ~5 days |
| Dosing | Once weekly (subcutaneous) | Once weekly (subcutaneous) |
| Time to steady state | ~4–5 weeks | ~4–5 weeks |
| Near-complete clearance (5 half-lives) | ~30 days after last dose | ~25 days after last dose |
| Peak weight loss in trials | ~24.2% at 48 wks (Ph2); up to ~28% in Ph3 TRIUMPH-1 | ~20.9–22.5% at 72 wks (SURMOUNT-1) |
| Clearance mechanism | Proteolytic degradation; minor renal | Proteolytic degradation |
For the full source-level profiles, see the retatrutide pharmacokinetic page and the tirzepatide pharmacokinetic page, or plot both decay curves side by side with the free half-life calculator.
Mechanism: two receptors versus three
The clearest difference is what each molecule binds. Tirzepatide is a dual agonist: it activates the GIP and GLP-1 receptors, the two incretin pathways that drive insulin response and appetite suppression. Retatrutide is a triple agonist — it adds a third target, the glucagon receptor.
That third receptor is the strategic bet. Glucagon agonism is thought to increase energy expenditure and mobilize hepatic fat, which is why retatrutide's Phase 2 data showed reductions in liver fat larger than weight loss alone would predict. The trade-off is that glucagon activity must be balanced carefully against its effect on glucose, which is part of why the compound moved through trials methodically.
Half-life and pharmacokinetics
Both compounds are engineered for once-weekly dosing, and both achieve it the same way — a fatty-acid chain that binds albumin and slows clearance. The half-lives are close: ~6 days for retatrutide and ~5 days for tirzepatide.
Both reach steady state in roughly 4–5 weeks of consistent weekly dosing — concentrations climb dose over dose until weekly input and elimination settle into a repeating pattern. Tirzepatide accumulates to roughly 2.1× its first-dose exposure at steady state. This accumulation is why the early weeks of any GLP-1 protocol feel different from month three, and why titration schedules exist. You can model this build-up for your own schedule with the GLP-1 dose-escalation calculator.
Weight-loss results: read the footnotes
This is where headlines outrun the evidence. The honest framing: there has never been a head-to-head trial of retatrutide versus tirzepatide. Every comparison below is across separate studies with different doses, durations, and populations.
- Retatrutide — Phase 2 (NEJM, 2023): ~24.2% mean weight loss at 48 weeks on the 12 mg dose.
- Retatrutide — Phase 3 TRIUMPH-1 (2026): up to ~28% mean weight loss at the highest dose, the largest figure published in a Phase 3 obesity trial.
- Tirzepatide — SURMOUNT-1: ~20.9–22.5% mean weight loss at 72 weeks on the 15 mg dose.
On the surface retatrutide leads, and the glucagon mechanism gives a plausible reason. But the timepoints and doses differ, the populations differ, and cross-trial comparison overstates precision. Until a head-to-head study reports, "retatrutide produced higher average weight loss in its own trials" is the most defensible statement.
Side effects
The profiles look broadly similar: both are dominated by gastrointestinal effects — nausea, vomiting, diarrhea, constipation — concentrated during dose escalation and easing as the body adapts. The notable signal is that nausea and GI events appear somewhat more frequent at retatrutide's highest doses, and retatrutide's added glucagon activity can produce a modest, dose-dependent rise in heart rate that trials monitored closely. Tirzepatide's safety profile is backed by large completed trials and years of real-world use; retatrutide's is still being characterized in Phase 3.
Approval and availability
For anyone choosing today, this is the deciding factor: one is an approved medicine you can be prescribed; the other is a promising trial drug you cannot legally obtain as an approved product.
Switching and washout
Because retatrutide is not approved, there is no validated dose-conversion table between the two compounds — they hit different receptors and behave differently per milligram, so equivalence cannot be assumed. The pharmacokinetics do, however, explain the timing questions people ask. After a final tirzepatide dose, the drug is ~97% cleared in about 25 days (five half-lives); retatrutide takes about 30 days. That clearance window is exactly what a washout describes. Any actual switch should be directed by a clinician — see our explainer on the tirzepatide 4-day missed-dose rule for how dosing-interval decisions follow from pharmacokinetics rather than guesswork.
How they compare to semaglutide
Both sit a step beyond first-generation GLP-1 therapy. Semaglutide is a single GLP-1 agonist with a ~7-day half-life; tirzepatide added GIP; retatrutide adds glucagon on top. If you are weighing the earlier generation too, read semaglutide vs tirzepatide half-life and the semaglutide profile. The full half-life reference for all 44 tracked compounds lives in the compound database.
Frequently asked questions
What is the difference between retatrutide and tirzepatide?
Tirzepatide is a dual agonist (GIP + GLP-1) and is FDA-approved. Retatrutide is a triple agonist (GIP + GLP-1 + glucagon) and is investigational, in Phase 3 trials as of June 2026.
Which has a longer half-life, retatrutide or tirzepatide?
Retatrutide, at approximately 6 days, versus approximately 5 days for tirzepatide. Both are dosed once weekly.
Is retatrutide more effective than tirzepatide for weight loss?
Early data show higher average weight loss for retatrutide in its own trials, but the two have never been compared head-to-head, and the studies differ in dose, duration, and population — so a direct claim is not yet supportable.
Is retatrutide FDA approved?
No. As of June 2026 it is investigational and in Phase 3 trials. Tirzepatide is approved. Retatrutide approval is not expected before 2027.
How long do retatrutide and tirzepatide stay in the body after stopping?
Roughly 30 days for retatrutide and 25 days for tirzepatide, using the ~5-half-lives rule of thumb. Individual clearance varies.