Retatrutide (LY3437943) is an investigational peptide from Eli Lilly that activates three receptors at once: the GIP receptor, the GLP-1 receptor and the glucagon receptor. It is a 39-amino-acid peptide built on a GIP backbone and carries a C20 fatty diacid side chain that binds albumin, which gives it a half-life of about six days in humans (Urva 2022). It is in phase 3 trials and, as of September 2026, has no FDA approval for any use.
Lilly scientists described LY3437943 in 2022 as a triple agonist at the glucagon receptor (GCGR), the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R). In cell assays it showed balanced GCGR and GLP-1R activity and stronger GIPR activity (Coskun 2022). The compound later received the name retatrutide.
A 2026 mass spectrometry paper gives a detailed structural description. The peptide chain has 39 residues. It includes two non-standard amino acids, α-aminoisobutyric acid (Aib) at positions 2 and 20 and α-methyl-leucine at position 13, and the C-terminus is amidated. Lysine 17 carries a side chain made of an AEEA spacer, a γ-glutamate linker and a C20 fatty diacid, which lets the molecule bind serum albumin reversibly (Carneiro 2026).
The phase 1b study in people with type 2 diabetes reported dose-proportional pharmacokinetics and a half-life of about 6 days, consistent with the once-weekly schedule used in later trials (Urva 2022).
GLP-1 receptor agonism is the shared base of semaglutide, tirzepatide and retatrutide. In the discovery paper, reduced calorie intake in obese mice was attributed to GIPR and GLP-1R activity (Coskun 2022). A separate clinical pharmacology study found that retatrutide delays gastric emptying, without separating the contribution of each receptor (Urva 2023).
GIP receptor agonism is what tirzepatide added to GLP-1 agonism. Retatrutide was engineered from a GIP backbone and, in vitro, showed more GIPR activity than GCGR or GLP-1R activity (Coskun 2022).
The glucagon receptor is the part that separates retatrutide from the dual agonists. In obese mice, body weight loss was larger when GCGR-mediated increases in energy expenditure were added to the intake reduction from GIPR and GLP-1R (Coskun 2022). That finding is from rodents; human data come mainly from the liver-fat and body-composition substudies below.
This double-blind, placebo-controlled trial enrolled 338 adults with a BMI of 30 or higher, or 27 to under 30 with at least one weight-related condition. Participants were randomized to once-weekly retatrutide at 1 mg, 4 mg, 8 mg or 12 mg (some arms with a 2 mg or 4 mg starting dose) or placebo for 48 weeks. The primary endpoint was percentage change in body weight at 24 weeks (Jastreboff 2023).
| Group | Weight change at 24 weeks | Weight change at 48 weeks | Share with 15% or more loss at 48 weeks |
|---|---|---|---|
| Placebo | -1.6% | -2.1% | 2% |
| Retatrutide 1 mg | -7.2% | -8.7% | Not reported in abstract |
| Retatrutide 4 mg (combined) | -12.9% | -17.1% | 60% |
| Retatrutide 8 mg (combined) | -17.3% | -22.8% | 75% |
| Retatrutide 12 mg | -17.5% | -24.2% | 83% |
Figures are least-squares means from the published abstract (Jastreboff 2023).
The most common adverse events were gastrointestinal. They were dose-related, mostly mild to moderate, and partly reduced with a lower starting dose (2 mg versus 4 mg). The authors also reported dose-dependent increases in heart rate that peaked at 24 weeks and declined afterwards (Jastreboff 2023).
A subgroup of 98 participants from the same trial had metabolic dysfunction-associated steatotic liver disease with at least 10% liver fat. At 24 weeks, mean relative change in liver fat was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg) and -82.4% (12 mg), against +0.3% with placebo. Liver fat fell below 5% in 86% of the 12 mg group and in none of the placebo group (Sanyal 2024). The authors linked the reductions to changes in body weight, abdominal fat and markers of insulin sensitivity and lipid metabolism.
This trial randomized 281 adults with type 2 diabetes (HbA1c 7.0-10.5%, BMI 25-50) at 42 US sites to placebo, dulaglutide 1.5 mg, or retatrutide at maintenance doses from 0.5 mg to 12 mg. The primary endpoint was HbA1c change at 24 weeks (Rosenstock 2023).
The authors stated that these data informed dose selection for phase 3 (Rosenstock 2023). A body-composition substudy of the same trial used DXA scans and found total fat mass reductions of 23.2% with 12 mg and 26.1% with the pooled 8 mg groups at 36 weeks, versus 4.5% with placebo. The authors reported that the proportion of lean mass lost relative to total weight lost was similar to other obesity treatments (Coskun 2025).
TRIUMPH is the phase 3 obesity program. Its published design paper describes four multicenter, randomized, double-blind, placebo-controlled trials with more than 5,800 participants in total. TRIUMPH-1 and TRIUMPH-2 are weight management trials with nested obstructive sleep apnea and knee osteoarthritis sub-studies, TRIUMPH-3 enrolls people with cardiovascular disease, and TRIUMPH-4 is a stand-alone knee osteoarthritis trial (Giblin 2026).
| Trial | Population (per registry) | Primary outcome | Registry status (Sept 2026) |
|---|---|---|---|
| TRIUMPH-1 | Obesity or overweight without type 2 diabetes; 2,335 enrolled | Percent change in body weight at week 80 | Completed; no results posted |
| TRIUMPH-2 | Type 2 diabetes with obesity or overweight; 1,152 enrolled | Percent change in body weight at week 80 | Completed; no results posted |
| TRIUMPH-3 | Severe obesity with established cardiovascular disease; 1,946 enrolled | Percent change in body weight at week 80 | Completed; no results posted |
| TRIUMPH-4 | Obesity or overweight with knee osteoarthritis; 445 enrolled | WOMAC pain score and percent body weight change at week 68 | Completed; no results posted |
| TRIUMPH-5 | Obesity; retatrutide compared with tirzepatide; about 800 planned | Percent change in body weight at week 80 | Active, not recruiting |
At the time of writing, ClinicalTrials.gov showed no posted results for any TRIUMPH trial, and we found no peer-reviewed TRIUMPH efficacy paper in PubMed. Weight-loss figures for TRIUMPH that circulate online come from company announcements, so they are not reported here.
A peer-reviewed phase 3 result is available from the separate type 2 diabetes program. TRANSCEND-T2D-1 randomized 537 adults with type 2 diabetes managed by diet and exercise alone to retatrutide 4 mg, 9 mg or 12 mg or placebo for 40 weeks. HbA1c fell by 1.69, 1.86 and 1.94 percentage points with retatrutide versus 0.81 with placebo, and body weight fell by 11.5%, 13.9% and 15.3% versus 2.6%. Discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo (Bajaj 2026).
Retatrutide is not approved by the FDA for any indication. FDA’s Drugs@FDA database lists no approved application for it, and Lilly’s own ClinicalTrials.gov record for the compound is titled “Pre-approval Expanded Access of Retatrutide“. Lilly’s phase 3 cardiovascular and kidney outcomes trial is still running (NCT06383390). Any product sold outside those trials is not an approved drug.
The three compounds share the GLP-1 receptor and differ in what else they activate. The weight figures below come from separate trials with different lengths and populations. They are not head-to-head results, and TRIUMPH-5 is the trial designed to compare retatrutide and tirzepatide directly.
| Compound | Receptor targets | Key published obesity trial | Mean weight change (highest dose vs placebo) | FDA status |
|---|---|---|---|---|
| Semaglutide | GLP-1 | STEP 1, phase 3, 68 weeks, 1,961 adults (Wilding 2021) | -14.9% vs -2.4% | Approved for chronic weight management as Wegovy (FDA label) |
| Tirzepatide | GLP-1 and GIP | SURMOUNT-1, phase 3, 72 weeks, 2,539 adults (Jastreboff 2022) | -20.9% vs -3.1% | Approved for chronic weight management as Zepbound, November 2023 (FDA) |
| Retatrutide | GLP-1, GIP and glucagon | Phase 2, 48 weeks, 338 adults (Jastreboff 2023) | -24.2% vs -2.1% | Not approved; phase 3 ongoing |
For lab work comparing receptor profiles, reference material is available for tirzepatide and semaglutide. Amylin-pathway compounds are a separate research line. A 2026 study in diet-induced obese male rats found that combining retatrutide with cagrilintide, an amylin and calcitonin receptor co-agonist, reduced body weight and food intake more than either compound alone at equimolar doses (Petersen 2026). That result is preclinical only.
Adverse events reported in the published trials were:
Longer-term safety, including cardiovascular and kidney outcomes, depends on the event-driven outcomes trial, which is not expected to finish until 2029 according to its registry entry (NCT06383390).
No. It has no FDA approval for any indication, and phase 3 trials are still being completed and analyzed. Lilly runs a pre-approval expanded access program listed on ClinicalTrials.gov.
Tirzepatide activates the GLP-1 and GIP receptors. Retatrutide activates those two plus the glucagon receptor, which mouse studies linked to higher energy expenditure (Coskun 2022). A head-to-head phase 3 trial, TRIUMPH-5, is under way.
It is a lipidated peptide with 39 amino acids. That sets it apart from oral small-molecule compounds studied for weight research, such as the monoamine reuptake inhibitor covered in our tesofensine research overview.
For in vitro receptor assays or analytical method work, check that each lot comes with a certificate of analysis showing HPLC purity and mass spectrometry identity confirmation. The published LC-HRMS fragment data for retatrutide can serve as an identity reference (Carneiro 2026). Peptides For Sale lists retatrutide 12 mg research peptide with batch documentation, labeled for research use only.
Research use only disclaimer: Retatrutide is an investigational compound that is not approved by the FDA for any indication. This article summarizes published research for educational purposes and is not medical advice. Products sold by this store are intended strictly for in vitro and laboratory research by qualified professionals. They are not for human or veterinary use, and not for use as food, drugs, cosmetics or household chemicals.
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