Retatrutide

Retatrutide is an experimental weight-loss drug from Eli Lilly. It is a single peptide of 39 amino acids that activates the receptors of three gut and pancreatic hormones: GIP, GLP-1 and glucagon[1]. In the largest trial so far, people treated with the highest dose lost on average a quarter of their body weight over 80 weeks[2].

As of October 2026 it is still an investigational drug, not approved for any use[3][4]. Even so, it is already sold online as a "research peptide" under the nickname "reta", and the FDA has issued warning letters to sellers[5][6]. This page explains how the peptide is designed, what the trials showed, and why a vial bought online is not the drug that was tested.

One peptide, three hormones

After a meal the gut releases two hormones that boost insulin secretion, GIP and GLP-1. GLP-1 also slows the emptying of the stomach and reduces appetite. Glucagon, made in the pancreas, does the opposite of insulin in many ways: it raises blood sugar, but it also increases energy expenditure and the burning of fat[4][1]. Drugs that copy GLP-1, such as semaglutide, and the dual GIP and GLP-1 agonist tirzepatide are already in use[4]. Retatrutide adds glucagon receptor activity to the other two[1].

Adding glucagon sounds odd for a diabetes drug, since glucagon raises blood glucose. The idea is that GLP-1 and GIP keep glucose under control while the glucagon component adds energy expenditure[1][4]. In obese mice, blocking the glucagon receptor with an antibody reduced the weight loss caused by retatrutide, which shows that this component contributes[1].

The peptide is not equally strong at the three receptors. In cell assays it was about nine times more potent than natural GIP at the GIP receptor, but about 2.5 times weaker than GLP-1 at the GLP-1 receptor and about 3 times weaker than glucagon at the glucagon receptor[1]. This balance between the three activities was set deliberately when the molecule was designed[1].

How the molecule is built

Retatrutide was engineered from the sequence of GIP[1]. In the body, the enzyme DPP-4 inactivates GIP and GLP-1 by cutting off their first two amino acids. A drug injected once a week needs protection against this and against rapid clearance. Retatrutide gets it from three modifications[1][7]:

• Noncanonical amino acids. α-Aminoisobutyric acid (Aib) at position 2 makes the peptide resistant to cleavage by DPP-4. A second Aib at position 20 and an α-methyl-leucine at position 13 were chosen to tune the activity at the GIP and glucagon receptors.
• A fatty acid chain. The lysine at position 17 carries a C20 fatty diacid, attached through a short linker. The fatty acid binds albumin, the most abundant protein in blood, which slows clearance.
• An amidated C-terminus, ending in serine amide.

The result is a half-life of about six days in people, which allows weekly injection[1]. Lilly makes the peptide by Fmoc solid-phase synthesis[1], the same method used for most synthetic peptides. With three noncanonical amino acids and a lipidated lysine, it is a demanding molecule to make and purify, which matters for the products sold outside clinical trials.

Early trials

The first study in people, in Singapore, gave 45 healthy volunteers a single injection. At 4.5 and 6 mg, body weight fell by up to about 3.5 kg, and the loss was still visible six weeks later. Most side effects were gastrointestinal, and their frequency rose with dose[1].

Phase 2 studies then examined obesity and type 2 diabetes, with a liver-fat substudy conducted within the obesity trial:

• Obesity: 338 adults treated for 48 weeks. With 12 mg, weight fell by 24.2%, against 2.1% with placebo. All participants on 12 mg lost at least 5% of their weight, and 83% lost at least 15%[8].
• Liver fat (substudy of the obesity trial): in 98 participants with at least 10% liver fat, the 12 mg dose reduced liver fat by 82% at 24 weeks, and 86% of them reached normal levels (below 5%)[9].
• Type 2 diabetes: a separate trial in 281 adults, which also included the GLP-1 drug dulaglutide as a comparator. HbA1c, a measure of long-term blood sugar, fell by up to 2.0 percentage points at 24 weeks, against 1.4 points with dulaglutide. At 36 weeks, weight had fallen by up to 16.9%, against 2.0% with dulaglutide and 3.0% with placebo[10].

Phase 3 results

The phase 3 programme began reporting in December 2025[11]. By October 2026, three trials had been published in full. All three were funded by Lilly[2][12][4].

Mean change in body weight, counting all randomised participants whether or not they stayed on treatment (treatment-regimen estimand). TRIUMPH-1: 2,339 adults with obesity, without diabetes, 80 weeks[2]. TRIUMPH-2: 1,152 adults with obesity or overweight and type 2 diabetes, most of them on oral diabetes drugs, 80 weeks[12]. TRANSCEND-T2D-1: 537 adults with early type 2 diabetes treated with diet and exercise alone, 40 weeks[4].

People with type 2 diabetes lost less weight than people without it, a pattern also seen with earlier drugs of this class[4][12]. In TRANSCEND-T2D-1, HbA1c fell by 1.7–1.9 percentage points with retatrutide alone, compared with 0.8 points with placebo, and no participant had severe hypoglycaemia[4].

TRIUMPH-1 also looked at knee osteoarthritis. In 574 participants with this condition, counting everyone randomised (intention-to-treat analysis), knee pain on the 10-point WOMAC scale fell by 4.1 points with 12 mg, against 2.5 points with placebo[2]. A separate report combined the sleep apnoea substudies of TRIUMPH-1 (243 participants without diabetes) and TRIUMPH-2 (448 participants with type 2 diabetes). At the start they had on average 56 to 59 breathing interruptions per hour of sleep. After 80 weeks, with 9 or 12 mg the number fell by about 22 to 24 per hour more than with placebo in people without diabetes, and by about 14 to 15 per hour more in people with diabetes[13]. Further phase 3 trials, including a comparison with semaglutide, are still running[4].

Reading the numbers

The headline of Lilly's TRIUMPH-1 announcement was a weight loss of 28.3% with 12 mg[3]. The published trial and the table above give 25.0% for the same dose[2]. Both numbers are correct, because they answer different questions[3]:

• The efficacy estimand estimates what would have happened if every participant had stayed on the drug. It gave 28.3% for 12 mg and 2.2% for placebo.
• The treatment-regimen estimand counts everyone who was randomised, including those who stopped injecting. It gave 25.0% and 3.9%.

The second estimate also accounts for participants who discontinued treatment, making it less dependent on the assumption that everyone remained on the drug. Company announcements tend to lead with the first. Neither number is a promise for an individual, whose response may be much larger or smaller than the average.

Side effects

The most common side effects are nausea, diarrhoea, vomiting and constipation, as with other drugs that act on the GLP-1 receptor. They are usually mild to moderate and become more frequent at higher doses[2][4]. In TRIUMPH-1, nausea was reported by 42% of participants on 12 mg and 15% on placebo, and 11.1% of participants on 12 mg stopped treatment because of adverse events, against 4.6% on placebo[2].

Two other adverse events were reported clearly more often than with placebo. Dysaesthesia, an unpleasant skin sensation such as sensitivity or burning, affected 12.5% of participants on 12 mg in TRIUMPH-1, against 0.9% on placebo. Low blood pressure affected 8.8%, against 0.9%, and was more common in people taking drugs for high blood pressure. Both were mostly mild or moderate[2]. TRIUMPH-2 showed the same pattern at lower rates[12].

The pulse rate rose with retatrutide, peaking at about 20 weeks and declining afterwards, as it had in the phase 2 obesity trial[2][8]. In TRIUMPH-1, serious heart rhythm or conduction disorders were as frequent with 12 mg as with placebo, 0.9% in each group[2]. The trials so far ran for 40 to 104 weeks[4][2]. The effects of use over many years are not yet known[4].

Legal status and the black market

Retatrutide remains investigational and is not approved for routine medical use[3][4]. In the United States, the FDA has told state medical, pharmacy and nursing boards that compounding pharmacies cannot legally make it, because it is not part of an approved drug and is not on the lists of substances allowed for compounding[14]. Websites nevertheless sell vials labelled "research use only" or "not for human consumption". The FDA does not accept this label when the marketing shows that the product is meant for people. In a December 2024 warning letter to one seller of retatrutide, semaglutide and tirzepatide, it described such products as unapproved new drugs[5]. It advises consumers not to buy them, because they "are of unknown quality and may be harmful to their health"[14].

The market is not limited to the United States. In August 2026 Lilly reported more than 14,000 websites, advertisements, social media posts and listings offering retatrutide in over 100 countries, and filed lawsuits against six US sellers[6]. The trial results on this page apply to Lilly's drug, made to pharmaceutical standards and given under medical supervision. A powder sold under the same name may contain less of the peptide, a different peptide or by-products of synthesis. Even a laboratory test of a single vial cannot provide the control of purity, sterility and consistency that an injectable medicine requires.

For the wider group of weight-loss drugs, see peptides for weight loss.

References

1. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK, Pirro V, Wainscott DB, Willard FS, Abernathy M, Morford L, Du Y, Benson C, Gimeno RE, Haupt A, Milicevic Z (2022). 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 Metabolism 34:1234–1247. DOI: 10.1016/j.cmet.2022.07.013
2. Jastreboff AM, Kaplan LM, Davies MJ, Wilding JPH, Ahmad NN, Murray M, Du Y, Makarova N, Giblin K, Schloot NC, Wang Y, for the TRIUMPH-1 Investigators (2026). Retatrutide, a triple hormone receptor agonist, for treatment of obesity. New England Journal of Medicine, published online 29 September 2026. DOI: 10.1056/NEJMoa2604169
3. Eli Lilly and Company (21 May 2026). Lilly's triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial. Press release. investor.lilly.com
4. Bajaj HS, Welch M, Shah P, Luna E, Jaouimaa F-Z, Liu B, Liu R, Chen Y, Patel H, Bartee A (2026). Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. The Lancet 407:2402–2413. DOI: 10.1016/S0140-6736(26)00967-0
5. U.S. Food and Drug Administration (10 December 2024). Warning letter to Summit Research Peptides. fda.gov
6. Eli Lilly and Company (12 August 2026). Lilly calls on online platforms, payment companies and regulators to shut down the illegal retatrutide black market. Press release. investor.lilly.com
7. National Center for Advancing Translational Sciences (NCATS). Inxight Drugs: retatrutide sodium, UNII LQ42M82ZU6. drugs.ncats.io
8. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML, for the Retatrutide Phase 2 Obesity Trial Investigators (2023). Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine 389:514–526. DOI: 10.1056/NEJMoa2301972
9. Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML (2024). Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine 30:2037–2048. DOI: 10.1038/s41591-024-03018-2
10. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet 402:529–544. DOI: 10.1016/S0140-6736(23)01053-X
11. Eli Lilly and Company (11 December 2025). Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. Press release. investor.lilly.com
12. Bellido V, le Roux CW, Ekinci EI, Bjornstad P, Frias JP, Giblin K, Eyde S, Park SY, Ferro J, Johnson C, Taylor A (2026). Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. The Lancet 408:1455–1472. DOI: 10.1016/S0140-6736(26)01861-1
13. Grunstein RR et al., for the TRIUMPH-1 and TRIUMPH-2 Investigators (2026). Retatrutide once weekly for treatment of obstructive sleep apnea. New England Journal of Medicine, published online October 2026. DOI: 10.1056/NEJMoa2611477
14. U.S. Food and Drug Administration, Office of Compounding Quality and Compliance (31 March 2025). Letter to the Federation of State Medical Boards on the regulatory status of compounded retatrutide. PDF