Retatrutide
Eli Lilly's triple GIP/GLP-1/glucagon receptor agonist — the most impressive Phase 2 weight-loss numbers published so far, in a drug that remains strictly investigational
🧑🐀 Both
- Also known as
- LY3437943
- Manufacturer
- Eli Lilly and Company
- Class
- Synthetic long-acting triple agonist peptide
- Receptors
- GIP receptor (GIPR), GLP-1 receptor (GLP-1R), glucagon receptor (GCGR)
- Molecular weight
- ~4731.4 g/mol
- CAS number
- 2381089-83-2
- Development stage
- Phase 3 clinical trials (TRIUMPH programme). Phase 2 data published 2023.
- Regulatory status
- Investigational. Not approved for clinical use anywhere as of early 2026.
What it is
Retatrutide — code name LY3437943 — is a long-acting synthetic peptide developed by Eli Lilly that simultaneously activates three receptors involved in glucose metabolism and energy balance: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). That triple mechanism distinguishes it from the current generation of approved weight-loss drugs. Semaglutide (Ozempic/Wegovy) is a GLP-1-only agonist; tirzepatide (Mounjaro/Zepbound) is a dual GIP/GLP-1 agonist. Retatrutide adds glucagon receptor activity on top of both, with the goal of further increasing energy expenditure and driving larger fat loss.
The drug is administered by subcutaneous injection once weekly, with a half-life of approximately six days supporting that dosing interval. Phase 2 results published in 2023 generated significant scientific attention: in the obesity trial, participants in the highest-dose arm lost a mean of 24.2% of body weight at 48 weeks — a number that, if confirmed in Phase 3, would exceed tirzepatide's Phase 3 benchmark. Phase 3 trials (the TRIUMPH programme) are now enrolling. Retatrutide is not approved anywhere, it cannot be prescribed, and versions sold online as "research chemicals" are not pharmaceutical-grade.
How it works
The three-receptor design targets complementary metabolic pathways. GLP-1 receptor agonism slows gastric emptying, reduces appetite via central hypothalamic signalling, and stimulates glucose-dependent insulin secretion — these are the well-established effects responsible for the weight loss seen with semaglutide. GIP receptor agonism augments the incretin effect and, at the level of adipose tissue, appears to enhance GLP-1-driven fat reduction rather than oppose it — the mechanism that gives tirzepatide its edge over GLP-1-only agents. The addition of glucagon receptor agonism introduces a third lever: glucagon raises hepatic glucose output and, critically, increases energy expenditure by stimulating fatty acid oxidation and thermogenesis in brown adipose tissue. In isolation, glucagon agonism would be problematic because it raises blood glucose; paired with robust GLP-1 and GIP activity, that hyperglycaemic risk is blunted while the calorie-burning effect is retained.
Retatrutide was engineered with balanced GCGR and GLP-1R activity but somewhat greater GIPR potency. Preclinical studies confirmed that the GCGR component makes a meaningful independent contribution to energy expenditure beyond GIP/GLP-1 agonism alone. Its long half-life comes from fatty acid conjugation and albumin binding, the same structural strategy used in semaglutide and tirzepatide.
What the research shows
Retatrutide has been studied in one published Phase 2 obesity trial, one Phase 2 type 2 diabetes trial, a Phase 2a MASH liver trial, a Phase 1b multiple-ascending-dose study, and the preclinical Cell Metabolism discovery paper. All five are summarised below.
Jastreboff et al. (2023) — Phase 2 obesity trial (NEJM)
Jastreboff A.M. et al., 2023, New England Journal of Medicine, 389(6):514–526 🧑 Human (Phase 2 RCT)
A 48-week, double-blind, placebo-controlled Phase 2 trial in 338 adults with a BMI of 30 or higher (or ≥27 with a weight-related comorbidity). Participants were randomised to once-weekly subcutaneous retatrutide at doses of 1 mg, 4 mg, 8 mg, or 12 mg, or placebo.
At 48 weeks, mean body weight change was −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg), and −24.2% (12 mg), versus −2.1% with placebo. In the 12 mg arm, 92% of participants achieved ≥10% weight loss and 75% achieved ≥20%. Waist circumference, fasting insulin, triglycerides, and blood pressure all improved dose-dependently. The most common adverse events were gastrointestinal — nausea, vomiting, diarrhoea — and were mostly mild to moderate in severity.
Limitations: Single Phase 2 trial; 48 weeks does not capture long-term durability or regain after discontinuation. Head-to-head comparisons with tirzepatide or semaglutide have not been completed. Phase 3 data are needed before efficacy can be considered established.
Rosenstock et al. (2023) — Phase 2 type 2 diabetes trial (Lancet)
Rosenstock J. et al., 2023, The Lancet, 402(10401):529–544 🧑 Human (Phase 2 RCT)
A 36-week Phase 2 dose-ranging trial in adults with type 2 diabetes and BMI 25–50 kg/m². Retatrutide was compared with placebo and with dulaglutide 1.5 mg across seven dose arms. The primary endpoint was HbA1c reduction at 36 weeks.
HbA1c fell dose-dependently, with the 12 mg arm achieving mean reductions of approximately 2.2 percentage points from baseline. Body weight decreased 3.2% to 16.9% across dose arms, versus 3.0% with placebo. Retatrutide outperformed dulaglutide on both endpoints. Gastrointestinal adverse events occurred in 13–50% of treated participants depending on dose and escalation speed; hypoglycaemia rates were low without background insulin.
Limitations: 36-week duration; no insulin background in most participants, which may underestimate hypoglycaemia risk in real-world type 2 diabetes management. Longer Phase 3 data are needed for cardiovascular outcome assessment.
Coskun et al. (2022) — Discovery and preclinical pharmacology (Cell Metabolism)
Coskun T. et al., 2022, Cell Metabolism, 34(9):1234–1247 🧑🐀 Both (preclinical + Phase 1 human data)
The foundational paper describing LY3437943's design, in vitro receptor pharmacology, and preclinical-to-human proof of concept. In rodent and non-human primate models, LY3437943 produced greater body weight reduction and improved glycaemia compared with matched GLP-1-only or dual GIP/GLP-1 controls, demonstrating that the added GCGR component made an independent contribution to energy expenditure. Phase 1 single ascending dose human data showed acceptable tolerability and confirmed a pharmacokinetic half-life of approximately six days, supporting once-weekly dosing.
Limitations: Preclinical findings require Phase 3 confirmation. Phase 1 human data are limited to pharmacokinetics and early safety; no efficacy endpoints reported at this stage.
Sanyal et al. (2024) — Retatrutide in MASH (Phase 2a)
Sanyal A.J. et al., 2024, Nature Medicine 🧑 Human (Phase 2a RCT)
A randomised Phase 2a trial examining retatrutide's effect on liver fat in patients with metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), using MRI-PDFF to quantify hepatic steatosis at baseline and follow-up. Retatrutide produced substantial, dose-dependent reductions in liver fat content, with high proportions of treated patients achieving MRI-defined resolution of steatosis. Effects on liver enzymes (ALT, AST) and metabolic markers were consistent with the obesity trial findings.
Limitations: Phase 2a trial with limited sample size; histological endpoints (fibrosis resolution) rather than imaging-only outcomes were not the primary focus. Longer-duration trials with biopsy endpoints are needed to assess fibrosis regression.
Urva et al. (2022) — Phase 1b multiple-ascending-dose trial (Lancet)
Urva S. et al., 2022, The Lancet, 400(10366):1869–1881 🧑 Human (Phase 1b RCT)
A multicentre, double-blind, placebo-controlled, randomised Phase 1b multiple-ascending-dose trial in adults with type 2 diabetes. Retatrutide was administered once weekly for twelve weeks at doses from 0.5 mg to 10 mg. The study characterised steady-state pharmacokinetics, dose proportionality, and early safety signals.
Pharmacokinetics were dose-proportional and consistent with once-weekly dosing. Meaningful reductions in HbA1c and body weight were observed even in this short-duration PK trial. Gastrointestinal events were the primary tolerability concern, dose-related and mostly mild.
Limitations: Short duration (12 weeks); type 2 diabetes population only. Not powered for efficacy endpoints — designed to confirm PK and inform dose selection for Phase 2.
Reported benefits (from research)
- In the Phase 2 obesity trial (Jastreboff 2023, NEJM), participants receiving 12 mg retatrutide weekly lost a mean of 17.5% body weight at 24 weeks and 24.2% at 48 weeks — among the largest weight-loss effects observed in a pharmacological trial to that date.
- Significant improvements in waist circumference, fasting glucose, triglycerides, and blood pressure were observed alongside weight loss in the Jastreboff 2023 trial, consistent with broad cardiometabolic benefit.
- In the Rosenstock 2023 Phase 2 type 2 diabetes trial, retatrutide produced substantial reductions in HbA1c (up to ~2.2 percentage points) and body weight across all active dose arms compared with placebo.
- Preclinical data indicate retatrutide's glucagon receptor agonism increases hepatic fat oxidation and reduces liver triglyceride content, suggesting potential benefit in non-alcoholic fatty liver disease (NAFLD/NASH).
- The triple-receptor mechanism (GLP-1/GIP/GCGR) produced greater weight loss than comparable GLP-1 or dual GLP-1/GIP agonists in indirect cross-trial comparisons, suggesting additive or synergistic receptor effects.
Drawbacks and concerns
- Gastrointestinal adverse events — nausea, vomiting, diarrhoea, constipation — were reported in a substantial proportion of participants at higher doses in all trials; these drove discontinuation in some participants.
- As of 2024, retatrutide has not been approved by the FDA or any other regulator; all data are from Phase 1 and Phase 2 trials — Phase 3 outcomes, long-term safety data, and cardiovascular event trials are pending or incomplete.
- Lean mass loss accompanied fat mass loss in the obesity trial; the proportion attributable to muscle versus fat is not fully characterised, which matters for long-term metabolic and functional health.
- The glucagon receptor agonism introduces a potential hyperglycaemia risk in non-diabetic patients that requires ongoing monitoring; the balance of glycaemic effects across the three receptors is context-dependent.
- Gallbladder adverse events (cholelithiasis, cholecystitis) — a recognised class effect of rapid weight loss and incretin therapies — were observed in longer-duration arms and require monitoring.
- Long-term durability of weight loss, effects of discontinuation, and risk of weight regain (as seen with other GLP-1 agents) have not been characterised for retatrutide specifically.
Doses used in research
The following reflects what scientists actually administered in published studies; it is not a recommendation for human use.
- Jastreboff 2023 Phase 2 obesity trial (NEJM, PubMed 37366315): Retatrutide 1 mg, 4 mg, 8 mg, or 12 mg subcutaneous once weekly for 48 weeks, with a dose-escalation run-in period for higher dose arms.
- Rosenstock 2023 Phase 2 type 2 diabetes trial (Lancet, PubMed 37356429): Retatrutide 0.5 mg, 4 mg, 8 mg, or 12 mg subcutaneous once weekly for 24 weeks, compared with placebo and dulaglutide 1.5 mg.
- Urva Phase 1 single-ascending-dose study (Urva 2020, Br J Clin Pharmacol): Single subcutaneous doses of 0.1, 0.3, 1, 3, or 8 mg in healthy volunteers to characterise pharmacokinetics and tolerability.
These doses are from published research only. No safe or effective dose has been established outside a controlled clinical trial for human use of retatrutide, and retatrutide is not approved for human use by any regulatory authority.
Safety and limitations
Across all Phase 2 trials, gastrointestinal adverse events — nausea, vomiting, diarrhoea, constipation — were the predominant side effect of retatrutide, occurring in a large proportion of participants at higher doses. These are consistent with the class effects seen across all GLP-1-based agents. Slower dose-escalation schedules reduced, but did not eliminate, GI burden. No unexpected safety signals specific to glucagon receptor agonism (such as clinically significant hyperglycaemia or hepatotoxicity) emerged at the doses tested, though the dual insulin-stimulating mechanism of GLP-1/GIP agonism effectively offsets the GCGR hyperglycaemic effect.
The Phase 2 weight-loss results are striking — 24% mean weight loss at 48 weeks is the highest figure published for any agent in a randomised trial to date. However, these numbers come from a single 338-person trial. They have not been replicated in Phase 3, they do not include long-term safety follow-up, and no head-to-head comparison with tirzepatide or semaglutide has been published. Phase 2 results frequently exceed Phase 3.
Weight regain after stopping GLP-1 class agents is well documented with semaglutide and tirzepatide; whether retatrutide differs is unknown. Long-term cardiovascular outcome data — a prerequisite for broad clinical adoption — will not be available until the TRIUMPH Phase 3 programme reports. There are also open questions about bone density (glucagon receptor activation may affect bone metabolism) and about thyroid C-cell effects that apply to the whole GLP-1 class.
Research chemical versions sold online are not the same as trial-grade drug. Retatrutide is a large, complex peptide (~4731 Da); purity, folding, and sterility cannot be guaranteed by grey-market suppliers, and the correct dose-escalation schedule has only been established under clinical trial conditions. Self-administration carries real risks.
Sources
- Jastreboff A.M. et al. "Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial." New England Journal of Medicine, 2023;389(6):514–526. PubMed 37366315
- Rosenstock J. et al. "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." The Lancet, 2023;402(10401):529–544. PubMed 37385280
- Coskun T. 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 Metabolism, 2022;34(9):1234–1247. PubMed 35985340
- Sanyal A.J. et al. "Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial." Nature Medicine, 2024. PubMed 38858523
- Urva S. et al. "LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial." The Lancet, 2022;400(10366):1869–1881. PubMed 36354040
Related products & further reading
Curated books, research supplies and related products from trusted retailers. Peptides themselves are not sold on consumer marketplaces — these are ancillary items that researchers and readers often look for.
Peptide Protocols Vol. 1 — Dr. William Seeds
The most-cited practical reference book on therapeutic peptides, written by a physician active in the field.
Bacteriostatic & sterile water
0.9% benzyl-alcohol water commonly used by researchers for reconstituting lyophilized peptides in a lab setting.
Insulin syringes (0.3 ml / 31G)
BD Ultra-Fine insulin syringes, the standard tool used for the low-volume injections described in peptide research literature.
Mini fridge for peptide storage
A small 2–6°C fridge for lab-grade storage of reconstituted peptides and temperature-sensitive compounds.
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