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Retatrutide

GLP-1, GIP and glucagon receptor triple agonist

Also known as LY3437943, Triple agonist, GGG agonist

A triple incretin agonist with phase 2 obesity results larger than anything before it, and no completed phase 3. The most interesting unfinished story in the class.

Guide updated Sep 2, 2026Literature checked Sep 2, 20261 curated study46 literature recordsBaseline editorial

Overview

In shortIt hits three receptors at once. The third is the surprising part, because glucagon normally raises blood sugar; the bet is that what it does to energy burn and liver fat outweighs that. Mid-stage weight results were the largest reported for any drug so far, but late-stage trials are still running, and that gap is where most candidates die.

Retatrutide activates three receptors at once: GLP-1, GIP, and glucagon. The glucagon arm is the novel and counterintuitive part, since glucagon raises blood glucose, and the rationale is that its effect on energy expenditure and hepatic fat outweighs that in the presence of the other two.

Phase 2 results in obesity were the largest reported for any pharmacological agent to date. Phase 3 is running. Until it reports, this entry is a promising phase 2 compound, and the gap between those two things is where most drug candidates die.

Mechanism

In shortTwo of the three receptors do the familiar things: insulin when blood sugar is high, slower stomach emptying, less appetite. The third is proposed to raise how much energy you burn and cut liver fat, with its blood sugar downside offset by the other two. Whether that balance holds across a wide population, and over years, is what late-stage trials exist to find out.

GLP-1 and GIP receptor agonism supply the familiar incretin effects: glucose-dependent insulin secretion, slowed gastric emptying, appetite suppression.

Glucagon receptor agonism is the addition. In this combination it is proposed to increase energy expenditure and reduce hepatic fat, with the glycaemic downside offset by the incretin arms. Whether the balance holds across a broad population, and over years rather than months, is precisely what phase 3 exists to find out.

Evidence

In shortEarly human work. A mid-stage trial in obesity reported about 24% average weight loss at the highest dose over 48 weeks, with encouraging liver fat results too. No late-stage trial has reported for anything yet. Results in this class have held up better than average historically, but effects usually shrink in larger groups.

Early clinical. A phase 2 randomised placebo-controlled trial in adults with obesity reported mean weight reduction around 24% at the highest dose over 48 weeks, with a separate phase 2 in type 2 diabetes and encouraging hepatic fat results.

There is no completed phase 3 reporting results for any indication. Phase 2 results in this class have historically held up better than average, but "better than average" is not the same as reliable, and effect sizes typically shrink in larger, more heterogeneous populations.

Safety

In shortThe mid-stage profile is dominated by stomach effects, similar to the other drugs in this family but at higher rates at the top doses. The third receptor brings its own questions: heart rate went up, and nobody has characterised what switching it on for years does. Trials so far are too short to say anything about slow effects. Not approved anywhere.

The phase 2 profile is dominated by gastrointestinal events, dose-related, similar in character to other incretin agents but at higher rates at the top doses.

The glucagon arm brings its own questions: heart rate increases were observed, and the long-term consequences of chronic glucagon receptor agonism are not characterised. Trial durations to date are too short to speak to anything slow.

Not approved anywhere. Material sold under this name outside a trial is unverified.

Regulatory status

In shortInvestigational, in late-stage development for obesity and related uses. Not approved in any country, and not legally available outside a clinical trial.

Investigational. In phase 3 development for obesity and related indications. Not approved in any jurisdiction, and not legally available outside a clinical trial.

The literature

1 study indexed. Findings and limitations get equal weight, on purpose.

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Everything above is free to read. What an account opens is the evidence underneath it: 1 study with their limitations, and the regimen each trial actually reported.

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The wider literature

20 indexed papers and 26 registered trials mentioning Retatrutide, straight from PubMed and ClinicalTrials.gov. 26 of 26 administer it; the rest measure it. These have not been read by us. Unlike the studies above, they carry no findings and no limitations written by anyone here, because writing either would mean claiming a reading nobody has done. They are a starting point for yours.

Registered trials (26)

  1. A Study of Retatrutide (LY3437943) in Participants Without Type 2 Diabetes Who Have Obesity or Overweight

    Eli Lilly and Company2026NCT07357415

    interventionalphase3active not recruitingn=600

  2. Effect of LY3437943 Versus Placebo in Participants Who Have Obesity or Are Overweight

    Hudson Biotech2026NCT07467447

    interventionalphase2recruitingn=300

  3. A Study of Retatrutide (LY3437943) in the Maintenance of Weight Reduction in Individuals With Obesity

    Eli Lilly and Company2025NCT06859268

    interventionalphase3active not recruitingn=643

  4. A Study to Evaluate the Effect of Retatrutide on Insulin Secretion and Insulin Sensitivity in Adult Participants With Type 2 Diabetes Mellitus

    Eli Lilly and Company2025NCT06982859

    interventionalphase1active not recruitingn=95

  5. A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight and Chronic Low Back Pain

    Eli Lilly and Company2025NCT07035093

    interventionalphase3active not recruitingn=586

  6. Effect of Retatrutide Compared With Placebo in Participants With Type 2 Diabetes and Moderate or Severe Renal Impairment, With Inadequate Glycemic Control on Basal Insulin, With or Without Metformin and/or SGLT2 Inhibitor (TRANSCEND-T2D-3)

    Eli Lilly and Company2024NCT06297603

    interventionalphase3active not recruitingn=320

  7. Effect of Retatrutide Compared With Semaglutide in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Metformin With or Without SGLT2 Inhibitor (TRANSCEND-T2D-2)

    Eli Lilly and Company2024NCT06260722

    interventionalphase3active not recruitingn=1250

  8. The Effect of Retatrutide Once Weekly on Cardiovascular Outcomes and Kidney Outcomes in Adults Living With Obesity (TRIUMPH-Outcomes)

    Eli Lilly and Company2024NCT06383390

    interventionalphase3active not recruitingn=10000

  9. A Study to Measure Calorie Consumption and Usage in Participants With Obesity Using LY3437943

    Eli Lilly and Company2024NCT06313528

    interventionalphase1completedn=85

  10. A Study of Retatrutide (LY3437943) Compared to Tirzepatide (LY3298176) in Adults Who Have Obesity

    Eli Lilly and Company2024NCT06662383

    interventionalphase3active not recruitingn=800

  11. A Study of LY3437943 in Postmenopausal Female Participants Who Are Overweight or Obese

    Eli Lilly and Company2023NCT06039826

    interventionalphase1completedn=46

  12. A Study of Retatrutide (LY3437943) in Participants With Type 2 Diabetes Mellitus Who Have Obesity or Overweight

    Eli Lilly and Company2023NCT05929079

    interventionalphase3completedn=1152

  13. A Study of LY3437943 in Participants With Impaired and Normal Liver Function

    Eli Lilly and Company2023NCT05916560

    interventionalphase1completedn=43

  14. A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee

    Eli Lilly and Company2023NCT05931367

    interventionalphase3completedn=445

  15. A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease

    Eli Lilly and Company2023NCT05882045

    interventionalphase3completedn=1946

  16. A Study of Retatrutide (LY3437943) on Renal Function in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes

    Eli Lilly and Company2023NCT05936151

    interventionalphase2completedn=146

  17. A Research Study Looking at Similarity Between LY3437943 Versions for Different Injection Devices

    Eli Lilly and Company2023NCT06003465

    interventionalphase1completedn=57

  18. A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight

    Eli Lilly and Company2023NCT05929066

    interventionalphase3completedn=2335

  19. A Drug-Drug Interaction (DDI) Study of LY3437943 in Obese Participants

    Eli Lilly and Company2022NCT05445232

    interventionalphase1completedn=32

  20. A Study of LY3437943 in Healthy Participants and Participants With Impaired Renal Function

    Eli Lilly and Company2022NCT05611957

    interventionalphase1completedn=29

  21. A Study of LY3437943 in Chinese Participants With Obesity Or Overweight

    Eli Lilly and Company2022NCT05548231

    interventionalphase1completedn=32

  22. A Study of LY3437943 in Japanese Participants With Type 2 Diabetes Mellitus (T2DM)

    Eli Lilly and Company2021NCT04823208

    interventionalphase1completedn=64

  23. A Study of LY3437943 in Participants Who Have Obesity or Are Overweight

    Eli Lilly and Company2021NCT04881760

    interventionalphase2completedn=338

  24. A Study of LY3437943 in Participants With Type 2 Diabetes

    Eli Lilly and Company2021NCT04867785

    interventionalphase2completedn=281

  25. A Study of LY3437943 in Participants With Type 2 Diabetes Mellitus (T2DM)

    Eli Lilly and Company2019NCT04143802

    interventionalphase1completedn=72

  26. A Safety Study of LY3437943 Given as a Single Injection in Healthy Participants

    Eli Lilly and Company2019NCT03841630

    interventionalphase1completedn=45

Papers (20)

  1. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials.

    Giblin K, et al.Diabetes, obesity & metabolism2026PMID 41090431

    journal article

  2. 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.

    Bajaj HS, et al.Lancet (London, England)2026PMID 42250575

    journal articlerandomized controlled trialclinical trial, phase iiimulticenter study

  3. Kynurenic acid mediates epicardial fat-induced lymphatic metabolic dysfunction in atrial fibrillation.

    Takahashi M, et al.Nature communications2026PMID 42156758

    journal article

  4. What is the pipeline for future medications for obesity?

    Melson E, et al.International journal of obesity (2005)2025PMID 38302593

    journal articlereviewresearch support, non-u.s. gov't

  5. Emerging pharmacotherapies for obesity: A systematic review.

    Kokkorakis M, et al.Pharmacological reviews2025PMID 39952695

    journal articlesystematic review

  6. The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.

    Madsbad S, et al.Expert opinion on investigational drugs2025PMID 40022548

    journal articlereview

  7. Retatrutide-A Game Changer in Obesity Pharmacotherapy.

    Katsi V, et al.Biomolecules2025PMID 40563436

    journal articlereview

  8. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials.

    Moiz A, et al.Annals of internal medicine2025PMID 39761578

    journal articlesystematic review

  9. Weight management treatment in obesity.

    Rubio-Herrera MA, et al.Medicina clinica2025PMID 40865172

    journal articlereview

  10. Why does GLP-1 agonist combined with GIP and/or GCG agonist have greater weight loss effect than GLP-1 agonist alone in obese adults without type 2 diabetes?

    Jiang Y, et al.Diabetes, obesity & metabolism2025PMID 39592891

    journal articlereview

  11. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.

    Marathe SJ, et al.npj metabolic health and disease2025PMID 40094000

    journal article

  12. 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.

    Coskun T, et al.The lancet. Diabetes & endocrinology2025PMID 40609566

    journal articlerandomized controlled trialclinical trial, phase iimulticenter study

  13. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.

    Drucker DJDiabetes care2024PMID 38843460

    journal articlereviewresearch support, non-u.s. gov't

  14. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

    Sanyal AJ, et al.Nature medicine2024PMID 38858523

    journal articlerandomized controlled trialclinical trial, phase ii

  15. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?

    Locatelli JC, et al.Diabetes care2024PMID 38687506

    journal articlereviewresearch support, non-u.s. gov't

  16. Gut hormones and appetite regulation.

    Hong SH, et al.Current opinion in endocrinology, diabetes, and obesity2024PMID 38511400

    journal articlereviewresearch support, non-u.s. gov't

  17. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. Reply.

    Jastreboff AM, et al.The New England journal of medicine2023PMID 37888927

    lettercomment

  18. 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.

    Rosenstock J, et al.Lancet (London, England)2023PMID 37385280

    randomized controlled trialclinical trial, phase iijournal articleresearch support, non-u.s. gov't

  19. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.

    Jastreboff AM, et al.The New England journal of medicine2023PMID 37366315

    randomized controlled trialclinical trial, phase iijournal article

  20. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.

    Coskun T, et al.Cell metabolism2022PMID 35985340

    journal article

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For Research & Educational Discussion Only. Not Medical Advice

This guide is educational reference material compiled from published literature. It is not medical advice, not a recommendation, and not a substitute for a clinician who knows your history. Nothing here should be used to make a decision about your own health without one.

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