Retatrutide: The Triple Agonist Weight Loss Peptide

Key takeaways

• Retatrutide targets three hormone receptors (GLP-1, GIP, and glucagon) instead of the one or two targeted by existing weight loss medications
• In phase 2 trials, the 12 mg dose produced 24.2% average body weight loss over 48 weeks (Jastreboff et al., 2023)
• Phase 3 TRIUMPH-4 data showed 28.7% weight loss at 68 weeks with improvements in knee osteoarthritis pain
• Eli Lilly is developing it with potential FDA approval projected for late 2027 to early 2028
• It is not yet commercially available and has no FDA approval for any indication

Semaglutide targets one receptor. Tirzepatide targets two. Retatrutide targets three. That alone doesn’t make it better, but the clinical data so far is hard to ignore.

In a phase 2 trial published in the New England Journal of Medicine, participants on the highest dose of retatrutide lost an average of 24.2% of their body weight over 48 weeks. That translates to roughly 58 pounds. No previously tested weight loss medication had produced numbers that high at the time of publication. For context, semaglutide typically produces around 15% weight loss, and tirzepatide around 20-22%.

Retatrutide is still in phase 3 clinical trials. It is not FDA-approved. But it’s the furthest-along triple agonist in development, and the data from Eli Lilly’s TRIUMPH program has attracted serious attention from endocrinologists and obesity researchers.

What is retatrutide?

Retatrutide (also known as LY3437943) is a 39-amino acid peptide linked to a C20 fatty diacid moiety. That fatty acid attachment extends its half-life enough for once-weekly dosing, similar to how tirzepatide and semaglutide are engineered [1].

What makes retatrutide different from every FDA-approved weight loss medication is its receptor profile. It activates three receptors simultaneously:

• GLP-1 receptor (glucagon-like peptide-1): reduces appetite, slows gastric emptying, improves insulin sensitivity
• GIP receptor (glucose-dependent insulinotropic polypeptide): enhances insulin secretion and may influence fat metabolism
• Glucagon receptor: increases energy expenditure, promotes lipolysis, and drives fatty acid oxidation in the liver

This triple-receptor approach is why researchers call it a “triagonist.” The theory is straightforward: each receptor contributes something different to weight loss. GLP-1 cuts appetite. GIP improves metabolic signaling. Glucagon ramps up calorie burning. Together, the effects compound [2].

Eli Lilly is developing retatrutide under the TRIUMPH clinical trial program. Six phase 3 trials are underway or completed, enrolling more than 5,800 participants across obesity, type 2 diabetes, knee osteoarthritis, and obstructive sleep apnea indications [3].

How retatrutide works

The three-receptor mechanism of retatrutide reflects what the body already does. GLP-1, GIP, and glucagon are hormones your gut and pancreas release naturally in response to food. Retatrutide mimics all three, but at levels that produce a stronger metabolic effect than the body generates on its own.

GLP-1 receptor activation

GLP-1 is the receptor that semaglutide and liraglutide target. When activated, it slows gastric emptying (food moves through your stomach more slowly, keeping you full longer), reduces appetite through hypothalamic signaling, and stimulates insulin secretion when blood sugar is elevated [1].

This is the mechanism responsible for most of the appetite suppression patients experience on GLP-1 medications. Retatrutide includes GLP-1 agonism, so it produces the same satiety effects that drugs like Ozempic and Wegovy are known for.

GIP receptor activation

GIP is the second receptor that tirzepatide (Mounjaro/Zepbound) added to the picture. GIP amplifies insulin secretion in response to meals and appears to play a role in fat metabolism, though its exact contribution to weight loss is still debated [2].

The combination of GLP-1 and GIP is what gives tirzepatide its edge over semaglutide alone. Retatrutide includes both of these, plus one more.

Glucagon receptor activation

This is what separates retatrutide from everything else in development. Glucagon has traditionally been viewed as a blood sugar raiser, the hormone your pancreas releases to prevent hypoglycemia. Stimulating it on purpose seems counterintuitive.

But glucagon does more than raise blood sugar. It increases hepatic lipid oxidation (the liver burns more fat), boosts resting energy expenditure, and reduces food intake through its own signaling pathways [2]. In isolation, activating glucagon would raise blood glucose. But when combined with GLP-1 and GIP agonism, the insulin-stimulating effects counterbalance the glycemic impact while preserving the increased calorie burn [4].

This is the theoretical advantage of triple agonism: you get the appetite suppression of GLP-1, the metabolic syncing of GIP, and the thermogenic and lipolytic effects of glucagon, without the blood sugar spikes that glucagon alone would cause.

Clinical trial results

Phase 2 obesity trial (Jastreboff et al., 2023)

The landmark study was published in the New England Journal of Medicine in August 2023 [1]. Here are the specifics:

• Participants: 338 adults with obesity (BMI ≥30) or overweight with a weight-related condition (BMI 27-30)
• Design: Randomized, double-blind, placebo-controlled
• Duration: 48 weeks
• Doses tested: 1 mg, 4 mg, 8 mg, and 12 mg weekly

Weight loss at 24 weeks (primary endpoint):

Dose	Weight change
1 mg	-7.2%
4 mg (combined)	-12.9%
8 mg (combined)	-17.3%
12 mg	-17.5%
Placebo	-1.6%

Weight loss at 48 weeks:

Dose	Weight change
1 mg	-8.7%
4 mg (combined)	-17.1%
8 mg (combined)	-22.8%
12 mg	-24.2%
Placebo	-2.1%

At the 12 mg dose, 100% of participants lost at least 5% of their body weight. 93% lost at least 10%. And 83% lost 15% or more. Those response rates are higher than any previously published weight loss medication trial [1].

The weight loss curves at 48 weeks hadn’t fully plateaued, suggesting that longer treatment could produce even greater reductions.

Phase 3 TRIUMPH-4 (December 2025)

The first phase 3 results confirmed and extended the phase 2 findings [3]:

• Population: Adults with obesity or overweight plus knee osteoarthritis
• Duration: 68 weeks (longer than phase 2)
• 12 mg dose: 28.7% body weight loss (26.6% placebo-adjusted)
• Average absolute weight loss: approximately 71.2 pounds
• Knee OA pain improvement: 75% reduction

The weight loss at 68 weeks exceeded phase 2 numbers, consistent with the observation that the weight loss curve hadn’t plateaued at 48 weeks. Discontinuation rates were 12.2% at 9 mg and 18.2% at 12 mg, compared to 4% with placebo. Some discontinuations were attributed to “perceived excessive weight loss” [3].

MASLD/fatty liver trial (Sanyal et al., 2024)

A phase 2a trial published in Nature Medicine tested retatrutide in patients with metabolic dysfunction-associated steatotic liver disease (MASLD, formerly called NAFLD) [5]:

• At 24 weeks, participants on 8 mg and 12 mg doses saw liver fat reductions of up to 82%
• 86% of those on 12 mg achieved normal liver fat levels (below 5%)
• More than 85% had complete resolution of steatosis

This is a meaningful finding. Fatty liver disease affects roughly 30% of the U.S. population, and no drug is currently FDA-approved specifically for it. The glucagon component of retatrutide likely drives the liver fat reduction, since glucagon directly promotes hepatic fat oxidation [5].

Additional phase 2 data in type 2 diabetes

A separate phase 2 trial in adults with type 2 diabetes showed dose-dependent reductions in HbA1c and body weight. The 72% prediabetes-to-normoglycemia reversion rate in the obesity trial also suggests metabolic benefits beyond weight loss alone [1].

Side effects

The side effect profile of retatrutide follows the same general pattern as other GLP-1 medications, with gastrointestinal symptoms being most common. But there are some differences worth noting.

Gastrointestinal effects

In the phase 2 trial, GI side effects were dose-dependent and occurred primarily during dose escalation [1]:

• Nausea: 14-60% depending on dose (vs. ~10% placebo)
• Diarrhea: 9-20%
• Vomiting: 3-26%
• Constipation: reported across dose groups

Most GI events were mild to moderate. Starting at a lower dose (2 mg rather than 4 mg) reduced their frequency. They typically improved once participants reached a stable maintenance dose [1].

In the phase 3 TRIUMPH-4 trial, nausea occurred in 43% of participants, diarrhea in 33%, and vomiting in 21% [3].

Heart rate changes

Dose-dependent increases in heart rate were observed, peaking at 24 weeks and declining afterward. This pattern is similar to what’s seen with other GLP-1 receptor agonists [1].

Dysesthesia (new phase 3 signal)

The TRIUMPH-4 trial identified a new safety signal not seen in phase 2: dysesthesia, an abnormal sensation of touch where normal sensations feel unusual or uncomfortable. It occurred in 8.8% of participants on 9 mg and 20.9% on 12 mg, compared to 0.7% with placebo [3].

The events did not appear to cause treatment discontinuation, but this signal will be closely watched in the remaining TRIUMPH trials.

Discontinuation rates

In TRIUMPH-4, 12.2% of those on 9 mg and 18.2% on 12 mg discontinued treatment, compared to 4% on placebo. For context, discontinuation rates across other GLP-1 trials typically range from 5-15% [3].

Dosage

The retatrutide dosing schedule used in clinical trials follows a gradual escalation to minimize GI side effects [1]:

Period	Weekly dose
Weeks 1-4	2 mg
Weeks 5-8	4 mg
Weeks 9-12	8 mg
Week 13+ (maintenance)	12 mg

Each dose is administered once weekly via subcutaneous injection. The 4-week intervals between escalations give the body time to adjust to each dose level. The phase 2 trial demonstrated that starting at 2 mg (rather than 4 mg) reduced gastrointestinal side effects during the titration period [1].

Since retatrutide is not yet FDA-approved, there is no official prescribing information. The dosing above reflects the protocol used in clinical trials, not a clinical recommendation.

Cost

Retatrutide has no commercial pricing because it hasn’t received FDA approval. However, some compounding pharmacies and telehealth platforms offer access. Current estimated costs [based on 2026 market data]:

Access route	Estimated monthly cost
Compounding pharmacy	$250-$500
Telehealth platform	$200-$400
Projected brand-name (post-approval)	$1,000-$1,500

For a detailed pricing breakdown, see the retatrutide cost guide.

Insurance coverage is not available since the drug lacks FDA approval. When it does reach the market, pricing will likely follow patterns set by Mounjaro and Zepbound. For current weight loss medication pricing, see our guide on peptide therapy cost.

How to get retatrutide

Since retatrutide is not FDA-approved, access is limited:

1. Clinical trials: Eli Lilly’s TRIUMPH program is still enrolling participants in some studies. Check ClinicalTrials.gov for active enrollment.

2. Compounding pharmacies: Some compounding pharmacies may offer retatrutide, though availability varies and the legal status of peptides is shifting.

3. Telehealth providers: Certain online peptide clinics have begun offering retatrutide through telehealth consultations.

Any access outside of a clinical trial should involve a licensed medical provider who can monitor your health during treatment.

Retatrutide vs. other weight loss medications

Feature	Retatrutide	Tirzepatide	Semaglutide
Receptors	GLP-1, GIP, glucagon	GLP-1, GIP	GLP-1
Max weight loss (trials)	24-29%	20-22%	15-17%
Dosing frequency	Once weekly	Once weekly	Once weekly
FDA approved	No	Yes	Yes
Brand names	N/A	Mounjaro, Zepbound	Ozempic, Wegovy
Administration	Subcutaneous	Subcutaneous	Subcutaneous

The additional glucagon receptor activity in retatrutide produces two effects not seen with tirzepatide or semaglutide: increased energy expenditure and enhanced liver fat oxidation. This may explain both the higher weight loss percentages and the dramatic liver fat reduction seen in the MASLD trial [5].

For detailed comparisons, see semaglutide vs tirzepatide.

Frequently asked questions

Is retatrutide FDA-approved?▼

No. Retatrutide is in phase 3 clinical trials under Eli Lilly’s TRIUMPH program. Based on current timelines, FDA approval is projected for late 2027 to early 2028, assuming positive trial results and standard review periods [3].

How much weight can you lose on retatrutide?▼

In the phase 2 trial, participants on 12 mg lost an average of 24.2% of their body weight (about 58 pounds) over 48 weeks. Phase 3 data showed 28.7% loss at 68 weeks. Individual results varied widely based on dose, starting weight, diet, and exercise [1, 3].

What are the most common side effects?▼

Gastrointestinal symptoms are the most frequently reported: nausea (14-60%), diarrhea (9-33%), and vomiting (3-26%). These typically occur during dose escalation and improve at stable doses. A newer phase 3 signal, dysesthesia (abnormal touch sensation), occurred in up to 20.9% of participants on the highest dose [1, 3].

How is retatrutide different from Mounjaro?▼

Both are made by Eli Lilly. Mounjaro (tirzepatide) targets two receptors (GLP-1 and GIP), while retatrutide adds a third (glucagon). The glucagon component increases energy expenditure and liver fat oxidation, which appears to drive the higher weight loss seen in retatrutide trials [2].

Can I get retatrutide now?▼

Not through a standard pharmacy. Some compounding pharmacies and telehealth platforms offer access, and Eli Lilly’s TRIUMPH clinical trials are still enrolling. Any use should be supervised by a licensed healthcare provider.

How does retatrutide compare to semaglutide?▼

Semaglutide targets one receptor (GLP-1) and produces about 15-17% weight loss. Retatrutide targets three receptors and has shown 24-29% weight loss in trials. The trade-off is that retatrutide is not yet approved, has a shorter safety track record, and is only available through limited channels. For current weight loss options, semaglutide and tirzepatide remain the FDA-approved standards.

What is the TRIUMPH trial program?▼

TRIUMPH is Eli Lilly’s phase 3 clinical development program for retatrutide. It includes at least six trials testing the drug in obesity, type 2 diabetes, knee osteoarthritis, obstructive sleep apnea, and MASLD. Results from TRIUMPH-4 were reported in December 2025, with additional readouts expected through 2026 [3].

Does retatrutide help with fatty liver disease?▼

Phase 2a data published in Nature Medicine showed retatrutide reduced liver fat by up to 82%, with more than 85% of participants on higher doses achieving complete resolution of steatosis. The glucagon receptor component appears to drive this effect by increasing hepatic fat oxidation [5].

References

1. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
2. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247. doi:10.1016/j.cmet.2022.07.013
3. Eli Lilly. Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs in first successful Phase 3 trial. Press release. December 11, 2025.
4. Finan B, Yang B, Ottaway N, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27-36.
5. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30:2037-2048. doi:10.1038/s41591-024-03018-2
6. Rosenstock J, Frias JP, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes. Lancet. 2023;402(10401):529-544.
7. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials. Proc (Bayl Univ Med Cent). 2025.
8. American Association for the Study of Liver Diseases (AASLD). Triple hormone receptor agonist retatrutide resolves steatosis in >85% of subjects with MASLD. Abstract, The Liver Meeting 2024.