Retatrutide vs Tirzepatide (Zepbound): Triple Agonist vs Dual Agonist
Approval status varies by treatment
Editorially reviewed · Last updated September 8, 2026 · How we review
Key findings
- Retatrutide targets GLP-1, GIP, and glucagon; tirzepatide targets GLP-1 and GIP. Receptor count does not establish a treatment advantage.
- Selected efficacy-estimand results are 28.7% at 68 weeks with retatrutide 12 mg in TRIUMPH-4 and 22.5% at 72 weeks with tirzepatide 15 mg in SURMOUNT-1. They come from different populations.
- Tirzepatide is approved as Mounjaro for diabetes and Zepbound for weight management; retatrutide remains investigational.
- Both have gastrointestinal adverse events. Dysesthesia is reported with retatrutide and in current tirzepatide and semaglutide labels.
- TRIUMPH-5 is studying retatrutide versus tirzepatide; no results were available at this review.
Retatrutide and tirzepatide are different drugs from Eli Lilly. Retatrutide activates three receptors (GLP-1, GIP, and glucagon); tirzepatide activates two (GLP-1 and GIP). Retatrutide has produced larger average weight-loss results in some separate trials, but that does not establish that it works better or is less tolerable than tirzepatide. The direct comparison, TRIUMPH-5, has not reported results.
Tirzepatide is already FDA-approved as Zepbound (for obesity) and Mounjaro (for type 2 diabetes). Retatrutide is still in Phase 3 clinical trials and has not been approved.
This is the molecule-level comparison. For the weight-management brand, read retatrutide vs Zepbound; for diabetes-brand context, read retatrutide vs Mounjaro and Ozempic. These comparisons do not establish a switching or combined-use protocol.
Side-by-Side Comparison
| Retatrutide | Tirzepatide (Zepbound / Mounjaro) | |
|---|---|---|
| Mechanism | Triple agonist: GLP-1 + GIP + Glucagon | Dual agonist: GLP-1 + GIP |
| Selected Phase 3 weight-loss results | -28.7% at 68 weeks (TRIUMPH-4, 12 mg; efficacy estimand) | -22.5% at 72 weeks (SURMOUNT-1, 15 mg; efficacy estimand) |
| ≥25% weight loss rate | 58.6% (12 mg) | Not reported in the cited topline release |
| Administration | Once-weekly injection | Once-weekly injection |
| Doses in the results above | 12 mg weekly (investigational) | 15 mg weekly |
| FDA status | Not approved (Phase 3) | Approved — Zepbound (obesity), Mounjaro (T2D) |
| Brand name | None yet | Zepbound / Mounjaro |
| Discontinuation rate (AEs) | 18.2% (TRIUMPH-4, 12 mg) | 6.2% (SURMOUNT-1, 15 mg) |
| Safety considerations | GI events and dysesthesia in trials | GI events; label also includes gallbladder disease and dysesthesia |
| Monthly cost | No approved product or announced price | Depends on coverage, device and eligibility; check Lilly's current savings terms |
How the Mechanisms Differ
Tirzepatide: Two Receptors (GLP-1 + GIP)
Tirzepatide activates GLP-1 and GIP receptors. GLP-1 reduces appetite, slows gastric emptying, and enhances glucose-dependent insulin secretion. GIP amplifies GLP-1's satiety effects, improves insulin sensitivity, and may influence fat cell metabolism directly. The combination works primarily by reducing calorie intake through powerful appetite suppression.
Retatrutide: Three Receptors (GLP-1 + GIP + Glucagon)
Retatrutide also activates the glucagon receptor, which tirzepatide does not. Preclinical research supports effects on energy expenditure and liver fat metabolism. Human studies have measured substantial weight and liver-fat reductions, but they do not isolate how much of the effect comes from each receptor. Retatrutide is a distinct molecule, not tirzepatide with an extra ingredient. Retatrutide liver-fat trial.
Receptor count alone cannot predict an individual's response or establish a treatment advantage. For details on each receptor, see What Is Retatrutide?.
Weight Loss Comparison
Phase 3 Results
These are selected historical results, not a ranking of the drugs. Both columns below use each trial's efficacy estimand, which estimates effects while treatment is taken as specified. TRIUMPH-4 studied obesity with knee osteoarthritis; SURMOUNT-1 studied obesity or overweight without diabetes. Total trial enrollment is shown, not enrollment in each dose arm. TRIUMPH-4, SURMOUNT-1.
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| Drug | Trial | Duration | Weight Loss | Participants |
|---|---|---|---|---|
| Retatrutide 12 mg | TRIUMPH-4 | 68 weeks | -28.7% | 445 |
| Retatrutide 9 mg | TRIUMPH-4 | 68 weeks | -26.4% | 445 |
| Tirzepatide 15 mg | SURMOUNT-1 | 72 weeks | -22.5% | 2,539 |
| Tirzepatide 10 mg | SURMOUNT-1 | 72 weeks | -21.4% | 2,539 |
Weight Loss Thresholds
| Threshold | Retatrutide 12 mg | Tirzepatide 15 mg |
|---|---|---|
| Lost at least 15% | Not stated in the cited TRIUMPH-4 topline release | 78% (efficacy estimand) |
| Lost at least 20% | Not stated in the cited TRIUMPH-4 topline release | 63% (efficacy estimand) |
| Lost at least 25% | 58.6% | Not reported in the cited topline release |
In TRIUMPH-4, 58.6% of participants assigned to retatrutide 12 mg achieved at least 25% weight loss under the efficacy estimand. This does not compare the drug with bariatric surgery.
What This Means in Practice
Trial averages are not personal forecasts. Applying these separate-trial percentages to a starting weight cannot tell you how many extra pounds one drug would help you lose. For treatment decisions, the relevant questions are eligibility, health conditions, tolerability and access to an approved medicine.
Network Meta-Analysis
A 2025 network meta-analysis in the Journal of the Endocrine Society reported estimated weight reductions versus placebo of -16.34 kg for retatrutide and -11.82 kg for tirzepatide. This is an indirect comparison that depends on the included studies; it does not confirm head-to-head superiority.
Important Caveat
These results come from different trials with different patient populations. TRIUMPH-4 enrolled patients with obesity and knee osteoarthritis (445 participants). SURMOUNT-1 enrolled a broader obesity population (2,539 participants). Eli Lilly's TRIUMPH-5 trial (NCT06662383) is comparing retatrutide against tirzepatide in approximately 800 participants (status: active, not recruiting) — estimated primary completion in November 2026 and study completion in December 2026; those dates are not a results-publication schedule. Current trial record.
Side Effects and Tolerability
| Retatrutide 12 mg (TRIUMPH-4) | Tirzepatide 15 mg (SURMOUNT-1) | |
|---|---|---|
| Nausea | 43% | 33% |
| Diarrhea | 33% | 21% |
| Vomiting | 21% | 10% |
| Severity | Mostly mild-moderate | Mostly mild-moderate |
| Discontinuation (AEs) | 18.2% | 6.2% |
| Dysesthesia | 20.9% | Reported in the current Zepbound label; see below |
The Dysesthesia Signal
Dysesthesia means altered skin sensations such as tingling or burning. Lilly reported it in 20.9% of the 12 mg arm and 8.8% of the 9 mg arm in TRIUMPH-4; events were generally mild and rarely caused discontinuation. It is not unique to retatrutide: the current Zepbound label reports dysesthesia in its pooled studies, and Wegovy's label also includes it. These reports do not establish that glucagon activation is the cause. Zepbound label, section 6.1, Wegovy label, section 6.1.
The Trade-Off
The adverse-event discontinuation figures above are 18.2% in TRIUMPH-4's 12 mg arm and 6.2% in SURMOUNT-1's 15 mg arm. Trial populations and treatment protocols differed, so these are not individual risk estimates or a direct safety comparison. Lilly also noted that TRIUMPH-4 discontinuations included perceived excessive weight loss. TRIUMPH-4 release, SURMOUNT-1 publication.
Cardiovascular and Metabolic Effects
Both drugs have improved cardiovascular risk markers in trials. Changes in these markers do not establish that one prevents more heart attacks or strokes:
Tirzepatide's SURPASS-CVOT has reported: in adults with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide for cardiovascular death, heart attack or stroke; superiority was not established. That is a different population and question from obesity without diabetes. Retatrutide's dedicated TRIUMPH-Outcomes study is ongoing. Its TRIUMPH-3 cardiovascular-event estimates did not establish a reduction in events. SURPASS-CVOT, TRIUMPH-3 results.
The August 2026 Mounjaro label includes reducing major cardiovascular event risk in adults with type 2 diabetes at high risk. This is a Mounjaro indication; it should not be generalized to retatrutide or every tirzepatide brand.
Regulatory Status and Timeline
| Milestone | Tirzepatide | Retatrutide |
|---|---|---|
| FDA approved for obesity | Yes — Zepbound (November 2023) | No |
| FDA approved for T2D | Yes — Mounjaro (May 2022) | No |
| Phase 3 program | SURMOUNT (multiple reported and ongoing trials) | TRIUMPH (multiple reported and ongoing trials) |
| Head-to-head trial | TRIUMPH-5 (active, not recruiting; no results yet) | TRIUMPH-5 (active, not recruiting; no results yet) |
| U.S. approval filing | Already approved | Lilly plans Q1 2027 |
| Approval date | Already approved | Not established; a planned filing is not approval |
Frequently Asked Questions
GLP-3 vs tirzepatide: what is the difference?
"GLP-3" is an informal name for retatrutide, an investigational agonist of GIP, GLP-1, and glucagon receptors. Tirzepatide activates GIP and GLP-1 receptors and is FDA-approved as Zepbound and Mounjaro. They are different molecules: retatrutide adds glucagon-receptor activity but is not currently available by prescription. Sources: Lilly's retatrutide status and the FDA tirzepatide label.
Is retatrutide better than tirzepatide?
We do not yet have a reported head-to-head answer. TRIUMPH-4 and SURMOUNT-1 reported -28.7% and -22.5% under their efficacy estimands, but they enrolled different populations and ran for different durations. Tirzepatide is approved; retatrutide remains investigational. TRIUMPH-5 is the direct comparison to watch.
Is retatrutide the same as Zepbound?
No. Zepbound is the brand name for tirzepatide (approved for obesity). Retatrutide is a different molecule that does not yet have a brand name. Both are made by Eli Lilly and given as weekly injections, but they target different receptors.
Can I switch from Zepbound to retatrutide?
Not currently. Retatrutide is only available through clinical trials. If it is approved after Lilly's planned Q1 2027 U.S. submission, switching would be a decision for your doctor. No studies have examined switching directly from tirzepatide to retatrutide.
Will TRIUMPH-5 settle the comparison?
TRIUMPH-5 (NCT06662383) is designed to compare retatrutide directly with tirzepatide. Its results should be more informative than comparisons across separate trials, but they will still apply to the population, doses and follow-up studied; they cannot settle every question about long-term safety or individual response.
Why does Lilly make both drugs?
Lilly is studying whether retatrutide's different receptor profile can help people with obesity and related conditions. That research does not yet establish which patients should receive it instead of tirzepatide. Tirzepatide's approved uses and retatrutide's investigational program should be considered separately.
Sources
-
Nicholls, S.J., et al. (2025). Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. PubMed.
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Eli Lilly. (2022). SURMOUNT-1 efficacy estimands and safety results. Release.
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Sanyal, A.J., et al. (2024). Retatrutide for metabolic dysfunction-associated steatotic liver disease. Nature Medicine.
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Eli Lilly. (2025). TRIUMPH-4 results. Press release.
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Jastreboff, A.M., et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity. New England Journal of Medicine. DOI: 10.1056/NEJMoa2301972.
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Jastreboff, A.M., et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine (SURMOUNT-1). DOI: 10.1056/NEJMoa2206038.
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Salhab, S., et al. (2025). Comparative Efficacy and Safety of Tirzepatide vs Retatrutide. Journal of the Endocrine Society. PMC12544991.
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ClinicalTrials.gov. TRIUMPH-5 (NCT06662383). Lilly Trial Guide.
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U.S. Food and Drug Administration. (2026). Zepbound (tirzepatide) prescribing information. FDA label.
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Eli Lilly and Company. (2026). Retatrutide Phase 3 status and planned U.S. submission. Press release.
How we keep this honest
- What this is
- Educational information, not medical advice. It reports published research — it doesn’t recommend that you use, obtain, or supply anything.
- Regulatory status
- Retatrutide is not FDA-approved. Tirzepatide has approved prescription products, including Mounjaro and Zepbound, with different indications.
- Our standard
- Every claim traces to a primary source. We label the strength of evidence and flag estimates as estimates — never as clinical fact.
- No commercial ties
- We don’t sell, supply, or link to suppliers of any medicine, and aren’t affiliated with any manufacturer.
Do not make decisions about your health without consulting a qualified healthcare provider. For trial enrolment, see ClinicalTrials.gov. More on how we review.
Sources
- SURMOUNT-1 trial (tirzepatide)
NEJM
- TRIUMPH-4 results
Eli Lilly
- TRIUMPH-5 head-to-head trial
Lilly Trial Guide
Grounded in primary sources
NEJM
The Lancet
JAMA
FDA
ClinicalTrials.govRelated reading
Comparison
Tirzepatide vs Semaglutide: Complete Comparison (2026 Data)
Tirzepatide vs semaglutide with SURMOUNT-5 head-to-head data: -20.2% vs -13.7% weight loss. Full comparison of efficacy, side effects, and access.
Comparison
Retatrutide vs Mounjaro vs Ozempic
Mounjaro and Ozempic are diabetes brands; Zepbound and Wegovy have weight-management indications. Compare their evidence with investigational retatrutide.
Explainer
What Is Retatrutide (GLP-3)?
Eli Lilly’s investigational triple receptor agonist: how it works, what trials show, and why GLP-3 is an informal nickname.
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