Retatrutide vs Tirzepatide (Zepbound): Triple Agonist vs Dual Agonist
Retatrutide and tirzepatide are both made by Eli Lilly, both given as once-weekly injections, and both target overlapping receptors. The key difference: retatrutide activates three receptors (GLP-1, GIP, and glucagon) while tirzepatide activates two (GLP-1 and GIP). That additional glucagon receptor drives substantially more weight loss — but also comes with a higher side effect burden.
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.
Side-by-Side Comparison
| Retatrutide | Tirzepatide (Zepbound / Mounjaro) | |
|---|---|---|
| Mechanism | Triple agonist: GLP-1 + GIP + Glucagon | Dual agonist: GLP-1 + GIP |
| Max weight loss (Phase 3) | -28.7% at 68 weeks (TRIUMPH-4, 12 mg) | -22.5% at 72 weeks (SURMOUNT-1, 15 mg) |
| ≥20% weight loss rate | 72.5% (12 mg) | 63% (15 mg) |
| ≥25% weight loss rate | 58.6% (12 mg) | 39.7% (15 mg) |
| Administration | Once-weekly injection | Once-weekly injection |
| Max dose | 12 mg weekly | 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% (12 mg) | 10.5% (15 mg) |
| Unique safety signal | Dysesthesia (20.9% at 12 mg) | Gallbladder/biliary risk |
| Monthly cost | Not yet available | ~$1,060 (Zepbound) |
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 has everything tirzepatide does, plus glucagon receptor activation. The glucagon component increases energy expenditure through thermogenesis — your body burns more calories at rest — and promotes breakdown of stored fat, particularly liver fat. This means retatrutide attacks obesity from both sides of the energy equation: reduced intake (GLP-1 + GIP) and increased expenditure (glucagon).
This likely explains the ~6 percentage point weight loss advantage. For details on each receptor, see What Is Retatrutide?.
Weight Loss Comparison
Phase 3 Results
| 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% | 83.2% | 73% |
| Lost at least 20% | 72.5% | 63% |
| Lost at least 25% | 58.6% | 39.7% |
Retatrutide is the first obesity medication where over 50% of participants achieved ≥25% weight loss — a threshold previously only reached with bariatric surgery.
What This Means in Practice
For a 250-pound person:
- Retatrutide 12 mg: ~72 lbs lost (final weight ~178 lbs)
- Tirzepatide 15 mg: ~56 lbs lost (final weight ~194 lbs)
That is approximately 16 extra pounds of weight loss with retatrutide.
Network Meta-Analysis
A 2025 network meta-analysis in the Journal of the Endocrine Society confirmed the difference across trials, finding retatrutide produced -16.34 kg absolute weight reduction vs tirzepatide's -11.82 kg compared to placebo.
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 currently enrolling approximately 800 participants to directly compare retatrutide against tirzepatide — results are expected around April 2027.
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% | 10.5% |
| Dysesthesia | 20.9% | Not reported |
| Systolic BP reduction | -14.0 mmHg | -7.4 mmHg |
The Dysesthesia Signal
Retatrutide's most distinctive side effect is dysesthesia — tingling, burning, or prickling sensations on the skin. This occurred in 20.9% of participants on the 12 mg dose and 8.8% on the 9 mg dose. It is generally described as mild and rarely led to discontinuation, but it is not seen with tirzepatide or other GLP-1 drugs. The glucagon receptor component is the likely cause.
The Trade-Off
Higher efficacy comes with a higher side effect burden. Retatrutide had roughly double the vomiting rate and nearly double the discontinuation rate compared to tirzepatide. A network meta-analysis found retatrutide's overall adverse event rate was 4.10 times placebo, compared to 2.78 times placebo for tirzepatide.
Cardiovascular and Metabolic Effects
Both drugs improve cardiovascular risk markers, but retatrutide shows larger blood pressure reductions:
| Marker | Retatrutide 12 mg | Tirzepatide 15 mg |
|---|---|---|
| Systolic blood pressure | -14.0 mmHg | -7.4 mmHg |
| Waist circumference | Significant reduction | Significant reduction |
| HbA1c (in T2D) | -2.02% (Phase 2, 12 mg) | -2.24% (SURPASS-1, 15 mg) |
Neither drug has completed cardiovascular outcomes trials. Tirzepatide's SURMOUNT-MMO trial and retatrutide's TRIUMPH cardiovascular outcomes study are both ongoing, with results expected in 2027-2028.
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 (completed) | TRIUMPH (ongoing) |
| Head-to-head trial | TRIUMPH-5 (enrolling, results ~2027) | TRIUMPH-5 (enrolling, results ~2027) |
| Expected NDA filing | Already filed | TBD — depends on TRIUMPH readouts |
| Earliest possible approval | Already approved | 2027-2028 |
Frequently Asked Questions
Is retatrutide better than tirzepatide?
Retatrutide produces more weight loss (-28.7% vs -22.5%) but has higher side effect rates. Whether it is "better" depends on individual goals and tolerance. Tirzepatide is available now; retatrutide is not. The TRIUMPH-5 head-to-head trial will provide a direct comparison.
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 approved (~2027-2028), 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) will be the first randomized head-to-head trial comparing retatrutide directly to tirzepatide in approximately 800 participants. Results are expected around April 2027. This will provide definitive efficacy and safety comparisons.
Why does Lilly make both drugs?
Both target different patient needs. Tirzepatide (Zepbound) is available now with strong efficacy and a well-established safety profile. Retatrutide may become the option for patients seeking maximum weight loss or those with conditions where the glucagon mechanism adds specific benefit (e.g., fatty liver disease, metabolic health). They are complementary, not competing — Lilly projects combined 2031 sales exceeding $30 billion.
Sources
- Eli Lilly. (2025). TRIUMPH-4 results. Press release.
- Jastreboff, A.M., et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity. New England Journal of Medicine. DOI: 10.1056/NEJMoa2301972.
- 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.
- Salhab, S., et al. (2025). Comparative Efficacy and Safety of Tirzepatide vs Retatrutide. Journal of the Endocrine Society. PMC12544991.
- ClinicalTrials.gov. TRIUMPH-5 (NCT06662383). Lilly Trial Guide.
Medical Disclaimer
The content on glp3.wiki is for informational purposes only and does not constitute medical advice, diagnosis, or treatment. Retatrutide is an investigational drug that has not been approved by the FDA. Tirzepatide (Zepbound/Mounjaro) is FDA-approved for specific indications.
Do not use this information to make decisions about your health without consulting a qualified healthcare provider. If you are considering weight loss medication, talk to your doctor about currently approved options.
This site is not affiliated with Eli Lilly and Company or any pharmaceutical manufacturer.
Sources
- SURMOUNT-1 trial (tirzepatide)
NEJM
- TRIUMPH-4 results
Eli Lilly
- TRIUMPH-5 head-to-head trial
Lilly Trial Guide
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