Investigational · not FDA approved

Editorially reviewed · Last updated August 11, 2026 · How we review

Retatrutide vs Tirzepatide (Zepbound): Triple Agonist vs Dual Agonist

Key findings

Retatrutide activates three receptors (GLP-1 + GIP + glucagon); tirzepatide activates two (GLP-1 + GIP). Retatrutide's additional glucagon activation is what drives its higher weight loss ceiling.
Peak weight loss in published trials: retatrutide 28.7% at 68 weeks (TRIUMPH-4); tirzepatide 22.5% at 72 weeks (SURMOUNT-1).
Tirzepatide is FDA-approved (as Zepbound for weight loss and Mounjaro for type 2 diabetes). Retatrutide is still investigational (Phase 3, no approval yet).
Side-effect profiles are similar (predominantly GI); retatrutide's Phase 3 TRIUMPH-4 trial also reported a dose-dependent dysesthesia signal (8.8% at 9 mg, 20.9% at 12 mg).
TRIUMPH-5 is the first direct head-to-head trial. Results are not yet published.

Retatrutide vs Tirzepatide (Zepbound): Triple Agonist vs Dual Agonist

Q: 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.

Q: 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.

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 comparing retatrutide against tirzepatide in approximately 800 participants (status: active, not recruiting) — primary completion December 2026, with results expected to follow in 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 (active not recruiting, results ~2027)	TRIUMPH-5 (active not recruiting, results ~2027)
U.S. approval filing	Already approved	Lilly plans Q1 2027
Earliest possible approval	Already approved	2027-2028

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?

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 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) will be the first randomized head-to-head trial comparing retatrutide directly to tirzepatide in approximately 800 participants. Primary completion is December 2026, with results expected to follow in 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.
U.S. Food and Drug Administration. (2026). Zepbound (tirzepatide) prescribing information. FDA label.
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 and similar peptides are investigational — not approved by the FDA or any regulator. Semaglutide and tirzepatide are prescription-only medicines, available only through a licensed prescriber.
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