Retatrutide in Human Clinical Trials: Populations, Endpoints and Findings
A trial-by-trial account of the published human clinical literature on retatrutide: who was enrolled, how each study was designed, how long it ran, what the primary endpoint was, what the papers report, and what the record does not establish.
Retatrutide, developed under the code LY3437943, is a single synthetic peptide with agonist activity at three receptors: the glucose-dependent insulinotropic polypeptide receptor, the glucagon-like peptide-1 receptor and the glucagon receptor [1]. It has been studied in a sequence of registered, sponsor-run clinical trials since December 2019, and enough of those trials have now been published in full that the shape of the human record can be described rather than guessed at.
This article sets out that record trial by trial. For each study it states the population enrolled, the design, the duration, the primary endpoint as the protocol defined it, the results as the publication reports them, the adverse events described, and the limitations the publication itself acknowledges. It closes with what the evidence base does not contain.
Two boundaries apply throughout. The first is that every study described here tested a pharmaceutical investigational product: material manufactured to a regulatory standard, administered under clinical supervision, to defined and screened populations, under a protocol registered before enrolment began. The second is that this article contains no guidance of any kind on handling any material, no comparison of products, and no recommendation. It describes published research and nothing else.
The molecule these trials tested
In vitro research
The compound entered clinical study on the strength of a characterisation published in 2022. In cell-based assays retatrutide was reported as balanced between the glucagon and GLP-1 receptors with relatively greater activity at the GIP receptor, and its structure was described as a backbone stabilised against dipeptidyl peptidase-4 cleavage with a fatty diacid attached to a lysine side chain through a hydrophilic linker [1]. That acylation is what binds the peptide reversibly to serum albumin and gives it a plasma half-life measured in days rather than minutes.
Two things follow for reading the clinical papers. First, "triple agonist" is a statement about behaviour at three cloned receptors in transfected cells, not a statement about what happens in a human body — receptor densities and tissue distributions differ, and the albumin binding that dominates the pharmacokinetics is absent from the assay entirely. Second, the published single-letter sequence describes the backbone, not the complete covalent structure, so a mass calculated from the letters does not match the finished molecule.
Phase 1b in adults with type 2 diabetes
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
Population. Adults aged 20 to 70 years with type 2 diabetes of at least three months' standing, glycated haemoglobin between 7.0% and 10.5%, body-mass index between 23 and 50 kg/m², and stable body weight — less than 5% change over the preceding three months. Recruitment ran at four centres in the United States between 18 December 2019 and 28 December 2020. Of 210 people screened, 72 were enrolled and received at least one administration [2, 10].
Design and duration. A phase 1b, double-blind, placebo-controlled, randomised, multiple-ascending trial over 12 weeks. Five ascending cohorts were studied; within each, a minimum of nine participants received retatrutide, three received placebo and one received dulaglutide 1.5 mg. The two highest cohorts reached their maintenance amounts by stepwise escalation. Administration was once-weekly and subcutaneous [2].
Primary endpoint. Safety and tolerability. Pharmacokinetics and pharmacodynamics were secondary. No efficacy measure was primary in this study, which is the ordinary shape of a phase 1b and is worth stating plainly, because the glycaemic and body-weight figures it produced are frequently quoted as though they had been the point of the trial.
Results as reported. Pharmacokinetics were proportional to the amount administered and the half-life was approximately six days. At week 12, placebo-adjusted mean daily plasma glucose decreased significantly in the three highest groups, by 2.8 to 3.1 mmol/L. Placebo-adjusted glycated haemoglobin decreased by 1.2% to 1.6% in those same three groups. Placebo-adjusted body-weight reduction appeared graded with the amount administered, reaching 8.96 kg in the highest group [2].
Adverse events. Treatment-emergent adverse events were reported by 33 of 52 participants receiving retatrutide (63%), three of five receiving dulaglutide (60%) and eight of 15 receiving placebo (54%). Gastrointestinal disorders were the most frequent category [2].
Limitations. 29 of the 72 participants discontinued prematurely — a rate above 40%, in a 12-week study, that constrains how much any of the 12-week figures can carry. The trial was small, unpowered for efficacy, conducted at four sites in one country, and placebo-adjusted comparisons in cohorts of nine to twelve carry wide intervals. The dulaglutide arm, at one participant per cohort, was not a comparison in any statistical sense.
Phase 2 in adults with obesity or overweight
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
Population. 338 adults with a body-mass index of 30 or higher, or 27 to below 30 with at least one weight-related condition. 51.8% were men [3, 11].
Design and duration. Phase 2, double-blind, randomised, placebo-controlled, with random assignment in a 2:1:1:1:1:2:2 ratio across seven arms: retatrutide 1 mg, 4 mg from a 2 mg start, 4 mg from a 4 mg start, 8 mg from a 2 mg start, 8 mg from a 4 mg start, 12 mg from a 2 mg start, or placebo. Administration was subcutaneous and once weekly for 48 weeks [3].
Primary endpoint. Percentage change in body weight from baseline to 24 weeks. Secondary endpoints included percentage change at 48 weeks and the proportions reaching reductions of 5%, 10% and 15% or more.
Results as reported. At 24 weeks, the least-squares mean percentage change in body weight was −7.2% in the 1 mg group, −12.9% in the combined 4 mg groups, −17.3% in the combined 8 mg groups and −17.5% in the 12 mg group, against −1.6% for placebo. At 48 weeks the corresponding figures were −8.7%, −17.1%, −22.8% and −24.2%, against −2.1% for placebo. Reductions of 5%, 10% and 15% or more had occurred by 48 weeks in 92%, 75% and 60% of the 4 mg participants; 100%, 91% and 75% of the 8 mg participants; 100%, 93% and 83% of the 12 mg participants; and 27%, 9% and 2% of the placebo participants [3].
Adverse events. The most common adverse events in the retatrutide groups were gastrointestinal. They were graded with the amount administered, mostly mild to moderate in severity, and partially mitigated by a lower starting amount — 2 mg rather than 4 mg. Increases in heart rate that were graded with the amount administered peaked at 24 weeks and declined thereafter [3].
Limitations. This is a phase 2 trial of 338 people over 48 weeks. Its endpoint is anthropometric, not clinical: nothing in it counts a cardiovascular event, a hospitalisation or a death. The heart-rate finding is described but not explained, and 48 weeks is too short to say what happens to it afterwards. There is no active comparator, so the trial locates retatrutide against placebo and against nothing else.
Phase 2 in adults with type 2 diabetes
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
Population. 281 adults aged 18 to 75 with type 2 diabetes, glycated haemoglobin of 7.0% to 10.5% and body-mass index of 25 to 50 kg/m², managed by diet and exercise alone or with stable metformin of at least 1000 mg daily for three months before screening. Recruitment ran at 42 centres in the United States between 13 May 2021 and 13 June 2022. Mean age was 56.2 years, mean diabetes duration 8.1 years; 56% were female and 84% were White [4, 12].
Design and duration. Randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2, with assignment in a 2:2:2:1:1:1:1:2 ratio to placebo, dulaglutide 1.5 mg, or one of six retatrutide regimens from 0.5 mg to 12 mg. Reporting was at 24 and 36 weeks [4].
Primary endpoint. Change in glycated haemoglobin from baseline to 24 weeks. Change in glycated haemoglobin and body weight at 36 weeks were secondary.
Results as reported. At 24 weeks, least-squares mean changes in glycated haemoglobin were −0.43% (0.5 mg), −1.39% and −1.30% (the two 4 mg groups), −1.99% and −1.88% (the two 8 mg groups) and −2.02% (12 mg), against −0.01% for placebo and −1.41% for dulaglutide 1.5 mg. All retatrutide groups except 0.5 mg differed significantly from placebo; the 8 mg slow-escalation and 12 mg groups also differed significantly from dulaglutide. Body weight decreased at 36 weeks by 3.19% to 16.94% across the retatrutide groups, against 3.00% for placebo and 2.02% for dulaglutide [4].
Adverse events. Mild-to-moderate gastrointestinal events — nausea, diarrhoea, vomiting, constipation — were reported in 67 of 190 retatrutide participants (35%), ranging from 13% in the 0.5 mg group to 50% in the 8 mg fast-escalation group; in six of 45 placebo participants (13%); and in 16 of 46 dulaglutide participants (35%). There were no reports of severe hypoglycaemia and no deaths [4].
Limitations. 84% of participants completed the study and 79% completed study treatment, so roughly a fifth of the randomised population did not finish on treatment. The cohort was 84% White and recruited entirely within the United States. The active comparator was dulaglutide 1.5 mg — a reasonable choice in 2021 and not the most potent comparator available by the time the results appeared.
The body-composition substudy
A prespecified substudy of the same trial enrolled 189 of its participants for dual-energy X-ray absorptiometry. Of those, 155 had a baseline scan and 103 completed treatment with both a baseline and a week-36 scan. The primary substudy endpoint was percentage change in total fat mass at 36 weeks. Reported reductions were 4.9% (0.5 mg), 15.2% (4 mg pooled), 26.1% (8 mg pooled) and 23.2% (12 mg), against 2.6% for dulaglutide and 4.5% for placebo. The authors report that the proportion of lean mass reduction to total body-weight reduction was similar to that described for other obesity treatments [6].
The substudy's own constraint is the completion figure: 103 of 189 enrolled participants contributed both scans, so the body-composition result rests on roughly half the substudy population and an eighth of the parent trial.
Phase 2a substudy in steatotic liver disease
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
Population. 98 participants drawn from the phase 2 obesity trial who had metabolic dysfunction-associated steatotic liver disease and at least 10% liver fat at baseline [5].
Design and duration. Randomised, double-blind, placebo-controlled substudy within the 48-week parent trial, with assignment to retatrutide 1, 4, 8 or 12 mg or placebo. The primary substudy objective was assessed at 24 weeks [5].
Primary endpoint. Mean relative change from baseline in liver fat at 24 weeks, measured by imaging.
Results as reported. Mean relative change in liver fat at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg) and −82.4% (12 mg), against +0.3% for placebo, all significant against placebo. Liver fat below 5% was reached by 27%, 52%, 79% and 86% of those groups respectively, and by none of the placebo group. Reductions in liver fat were reported as significantly related to changes in body weight, abdominal fat and measures associated with insulin sensitivity and lipid metabolism [5].
Limitations. The endpoint is an imaging measure of hepatic fat fraction. No histology was performed, so nothing in this substudy speaks to inflammation, ballooning or fibrosis — the features that define steatohepatitis and that determine hepatic prognosis. With 98 participants across five groups, individual groups are small. And because the substudy sits inside the obesity trial, its participants were selected for the parent trial's criteria rather than for a hepatic population.
Phase 3: TRANSCEND-T2D-1, and the TRIUMPH programme
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
Population. 537 adults aged 18 or over with type 2 diabetes inadequately controlled by diet and exercise alone, glycated haemoglobin between 7.0% and 9.5%, and body-mass index of at least 23 kg/m². Recruitment ran at 48 sites in the United States, Mexico and India between 10 April 2024 and 21 April 2025, from 930 screened. Baseline mean age was 48.8 years, mean glycated haemoglobin 7.9%, mean diabetes duration 2.5 years and mean body-mass index 35.8 kg/m²; 55% were female [8, 13].
Design and duration. A 40-week, phase 3, randomised, double-blind, placebo-controlled monotherapy trial, with assignment 1:1:1:1 to retatrutide 4 mg, 9 mg or 12 mg or placebo, administered once weekly by subcutaneous injection [8].
Primary endpoint. Change in glycated haemoglobin from baseline to week 40. Percentage change in body weight at week 40 was a key secondary endpoint.
Results as reported. For the treatment-regimen estimand, mean change in glycated haemoglobin was −1.69% (4 mg), −1.86% (9 mg) and −1.94% (12 mg) against −0.81% for placebo, giving estimated treatment differences of −0.88%, −1.04% and −1.12% respectively, all with p<0.0001. Mean percentage change in body weight was −11.5%, −13.9% and −15.3% against −2.6% for placebo. 91% of participants completed the treatment period on study drug and 94% completed the study [8].
Adverse events. The most frequent adverse events were described as generally mild to moderate gastrointestinal events that subsided over time. Discontinuations of study intervention attributed to adverse events were 2–5% with retatrutide against 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the 4 mg group, both reported as unrelated to the study drug [8].
Limitations. The trial ran 40 weeks in a population with a mean diabetes duration of 2.5 years — early disease, on no background glucose-lowering agent. That is the cleanest possible setting for a monotherapy signal and the least representative of established type 2 diabetes. The placebo comparison says nothing about how retatrutide compares with any active agent. And the placebo change in glycated haemoglobin of −0.81% is itself substantial, which is the usual consequence of trial participation and diet-and-exercise counselling in an untreated population.
The registrational programme. TRIUMPH comprises four phase 3, multicentre, randomised, double-blind studies against placebo in more than 5,800 participants, using a basket design: two weight-management trials with obstructive sleep apnoea and knee osteoarthritis protocols nested inside them (TRIUMPH-1 and TRIUMPH-2), one weight-management trial in a population with cardiovascular disease (TRIUMPH-3), and one stand-alone osteoarthritis trial (TRIUMPH-4). Primary endpoints are percentage change in body weight for weight management, change in the Apnea-Hypopnea Index for obstructive sleep apnoea, and change in the WOMAC pain subscale for knee osteoarthritis [9, 14, 15, 16]. No TRIUMPH primary results have been published. The design paper describes what the programme will measure; it reports no findings, and a design publication is not evidence of an outcome.
Pooled analysis across the randomised trials
Human clinical research
Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.
A systematic review and meta-analysis searched four databases to May 2024 and found three randomised controlled trials comparing retatrutide with placebo in adults with obesity, encompassing 878 participants. Pooled mean differences against placebo were −14.33% for body weight, −5.38 for body-mass index, −10.51 cm for waist circumference, −23.51 mg/dL for fasting plasma glucose, −0.91% for glycated haemoglobin, and −9.88 and −3.88 mm Hg for systolic and diastolic blood pressure, all at p<0.00001. No significant difference in adverse events between groups was observed, at a relative risk of 1.11 (p=0.24). The authors conclude that larger and longer trials are required [7].
A pooled estimate across three trials of 878 participants inherits every constraint of those three trials and adds heterogeneity of its own: different populations, different durations, different comparator arms and amounts pooled across groups. It is a summary of the same short-duration surrogate-endpoint evidence, not a stronger form of it.
What the evidence base does not establish
Six gaps are worth naming precisely, because each of them is routinely filled in by inference.
No outcome trial has reported. Every published retatrutide endpoint is a laboratory value, an imaging measure or an anthropometric measure. No trial has counted deaths, myocardial infarctions, strokes, kidney failure or hospitalisations as a primary endpoint. TRIUMPH-3 enrols a population with cardiovascular disease but is a weight-management trial with a body-weight primary endpoint, not a cardiovascular outcome trial [9].
No trial has exceeded 48 weeks. The longest published treatment period is the 48 weeks of the phase 2 obesity trial [3]. Nothing in the published literature describes what happens over two years, five years, or after discontinuation.
No head-to-head comparison with a modern comparator exists. The only active comparator in the published record is dulaglutide 1.5 mg [2, 4]. There is no published trial of retatrutide against tirzepatide, against semaglutide, or against any other multi-receptor agonist.
The populations are narrow. The phase 2 type 2 diabetes trial was 84% White and recruited entirely within the United States [4]; the phase 3 trial added Mexico and India but enrolled a population with a mean diabetes duration of 2.5 years and no background therapy [8]. Adolescents, older adults with multiple morbidities, and people with significant renal or hepatic impairment are not represented in the published trials.
The mechanism has not been separated in humans. The premise of adding a glucagon receptor arm — that it contributes through a route distinct from the two incretin arms — was demonstrated in mice [1]. No human study has decomposed the observed effects into contributions from the three receptors, and no trial design in the published programme would allow it.
Discontinuation and attrition are material. 29 of 72 participants discontinued the 12-week phase 1b study [2]; a fifth of the phase 2 type 2 diabetes population did not complete treatment [4]; the body-composition substudy produced paired scans for 103 of 189 enrolled participants [6]. Completion was markedly better in the phase 3 trial at 91% on study drug [8], but the earlier figures are part of the record and are rarely quoted alongside the efficacy numbers they qualify.
Regulatory position. Retatrutide is not approved for any indication, in the United States or anywhere else. It is an investigational compound, and every trial above was conducted under an investigational protocol.
All of the research described in this article is research into a pharmaceutical product candidate, conducted by its sponsor under registered protocols, using investigational material manufactured to a regulatory standard and administered under clinical supervision in defined populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.
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References
- 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. PMID 35985340 doi:10.1016/j.cmet.2022.07.013
- 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 Lancet; 2022. PMID 36354040 doi:10.1016/S0140-6736(22)02033-5
- Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial The New England Journal of Medicine; 2023. PMID 37366315 doi:10.1056/NEJMoa2301972
- 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 Lancet; 2023. PMID 37385280 doi:10.1016/S0140-6736(23)01053-X
- Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial Nature Medicine; 2024. PMID 38858523 doi:10.1038/s41591-024-03018-2
- Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial The Lancet Diabetes & Endocrinology; 2025. PMID 40609566 doi:10.1016/S2213-8587(25)00092-0
- 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 Proceedings (Baylor University Medical Center); 2025. PMID 40291085 doi:10.1080/08998280.2025.2456441
- Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes inadequately controlled by diet and exercise (TRANSCEND-T2D-1): a 40-week, randomised, double-blind, placebo-controlled, phase 3 trial Lancet; 2026. PMID 42250575 doi:10.1016/S0140-6736(26)00967-0
- Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials Diabetes, Obesity & Metabolism; 2026. PMID 41090431 doi:10.1111/dom.70209
- A Study of LY3437943 in Participants With Type 2 Diabetes Mellitus (T2DM). NCT04143802
- A Study of LY3437943 in Participants Who Have Obesity or Are Overweight. NCT04881760
- A Study of LY3437943 in Participants With Type 2 Diabetes. NCT04867785
- Effect of Retatrutide Compared With Placebo in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise. NCT06354660
- A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight. NCT05929066
- A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease. NCT05882045
- A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee. NCT05931367
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