Metabolic/Weight

Retatrutide

Research Reagent · Laboratory Use Only

Quick Answer

What do clinical trials show about retatrutide's mechanism and weight loss efficacy?

Retatrutide is an investigational triple agonist targeting GIP, GLP-1, and glucagon receptors. Phase 2 trials published in the New England Journal of Medicine (Jastreboff et al., 2023) reported mean body weight reductions of up to 24.2% over 48 weeks in adults with obesity, with ongoing Phase 3 evaluation for safety and efficacy.

PMID41997446↗DOI10.1056/NEJMoa2301972↗⟳ Reconstitution Calculator
Scientific AbstractPMID 41997446 · 2026

Objectives

Functional co- and tri-agonists at the receptors for GLP-1, GIP and glucagon effectively decrease body weight and hyperglycemia but are associated with adverse gastrointestinal effects related to GLP-1R agonism. Here we report the discovery that obesity can be reversed in the absence of a functional GLP-1R. It propelled the identification of a unimolecular GIPR:GCGR co-agonist lacking GLP-1 activity that corrects obesity in obese mice and rats.

Methods

Selective, dual, and triple sustained-action agonists at GIPR, GCGR and GLP-1R were used to assess body weight and glucose management in diet-induced obese (DIO) wildtype (WT) and GLP-1R knock-out (KO) mice. Indirect calorimetry and pair-feeding studies were used to characterize the magnitude of weight lowering specifically to suppression of food intake relative to energy expenditure.

Results

When used in physical co-mixture, selective GIPR agonism interacts with selective GCGR agonism to correct obesity and enhance glycemia in DIO mice. Retatrutide a balanced GLP-1R:GIPR:GCGR triagonist normalized body weight in obese GLP-1R KO mice. BWB3054, a fatty acylated GIPR:GCGR co-agonist, was identified as comparably potent as retatrutide to induce cAMP production at the mGIPR, and 4-fold reduced at mGCGR, but notably more than 100-fold diminished at mGLP-1R. Despite minimal relative GLP-1R potency, BWB3054 reduces excess body weight in obese DIO-mice to a similar degree as that observed for retatrutide in obese GLP-1R KO mice.

Conclusions

Correction of obesity and glycemia in mice without employing GLP-1 agonism was demonstrated by three independent methods (GLP-1R KO with retatrutide, GIPR:GCGR physical co-agonism mixture, and GIPR:GCGR covalent co-agonist) which advocate for the prospect that the adverse GI effects commonly associated with its use might be avoided.

Source:10.1056/NEJMoa2301972
Mechanistic Research SummaryCurated from PubMed

This data is for laboratory research purposes only. Not for human or animal consumption.

What is Retatrutide?

Retatrutide is a balanced unimolecular GLP-1R:GIPR:GCGR tri-agonist designed to simultaneously activate three metabolic receptors for enhanced glycemic and weight management. Laboratory research demonstrates that obesity correction can occur through GIP receptor and glucagon receptor agonism independent of GLP-1 receptor activation.

Mechanism of Action

Retatrutide functions as a multi-targeted agonist binding to three distinct G-protein coupled receptors: the GLP-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GCGR). The research reveals that synergistic activation of GIPR and GCGR pathways independently correct metabolic dysfunction through enhanced insulin secretion and increased hepatic glucose output regulation. Notably, laboratory data indicates that GLP-1R agonism may be dispensable for weight reduction, suggesting the therapeutic benefit derives primarily from coordinated GIP:glucagon signaling in appetite suppression and energy expenditure modulation.

Observed Laboratory Results

  • Obesity reversal in GLP-1R knock-out mice: Retatrutide normalized body weight in GLP-1R-deficient diet-induced obese mice, demonstrating weight loss independent of functional GLP-1 receptor activity
  • Dual GIPR:GCGR co-agonism efficacy: Physical co-mixture of selective GIPR agonists and GCGR agonists corrected obesity and enhanced glycemic control in diet-induced obese wildtype mice
  • BWB3054 potency profile: The selective GIPR:GCGR co-agonist demonstrated >100-fold reduced activity at mGLP-1R while maintaining efficacy equivalent to retatrutide in reducing excess body weight in obese mice
Clinical Research Parameters
10 trials4 human studies

The following data represents formally registered clinical research studies and peer-reviewed human subject research indexed in public registries. All dose ranges, endpoints, and observations below reflect published study parameters — not recommendations. For research reference only.

Registered Clinical Trials
ClinicalTrials.gov ↗
NCT06859268 ↗
ACTIVE NOT RECRUITINGPhase IIIn=643

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

This is a study of retatrutide in participants with obesity. The main purpose is to learn more about how retatrutide maintains body weight loss. The study will have two treatment phases: an 80 week lead-in phase in which all participants will take retatrutide dose 1 and a 36 week randomized, double-blinded phase in which participants will either take retatrutide dose 1, retatrutide dose 2, or swit

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Percent Change from Baseline in Body Weight
Study Period
2025-03-05 → 2028-04
NCT06808802 ↗
COMPLETEDPhase In=30

To Investigate the Effect of Retatrutide (LY3437943) on Metoprolol Pharmacokinetics in Healthy Participants

The purpose of this study J1I-MC-GZQE is to measure the effect of retatrutide on the pharmacokinetics (PK) of metoprolol in healthy participants.

Study Interventions
Retatrutide, Metoprolol
Primary Endpoints
Pharmacokinetics (PK): Area Under Concentration From Time Zero to Infinity (AUC[0-∞]) of Metoprolol; Pharmacokinetics (PK): AUC (0-∞) of Metoprolol with Retatrutide
Study Period
2025-02-03 → 2025-04-15
NCT07357415 ↗
RECRUITINGPhase IIIn=600

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

The purpose of this study is to investigate the efficacy and safety of different retatrutide dose escalation schemes in participants without type 2 diabetes who have obesity or overweight. Participation in the study will last about 113 weeks.

Study Interventions
Retatrutide
Primary Endpoints
Percent Change from Baseline in Body Weight
Study Period
2026-01-24 → 2028-11
NCT05936151 ↗
COMPLETEDPhase IIn=146

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

The main purpose of this study is to investigate the effect of retatrutide on renal function in participants with overweight or obesity and chronic kidney disease (CKD), with or without Type 2 Diabetes (T2D). The study will last around 31 weeks.

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Change from Baseline in Glomerular Filtration Rate (mGFR)
Study Period
2023-07-20 → 2025-10-21
NCT07232719 ↗
ACTIVE NOT RECRUITINGPhase IIIn=250

A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight

The purpose of this study is to evaluate the efficacy and safety of retatrutide compared with placebo for body weight reduction. Participation in the study will last about 65 weeks and may include about 18 visits.

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Percent Change from Baseline in Body Weight
Study Period
2025-11-17 → 2027-07
NCT05882045 ↗
ACTIVE NOT RECRUITINGPhase IIIn=1,800

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

The main purpose of this study is to evaluate the efficacy and safety of retatrutide once weekly in participants with obesity and established cardiovascular disease (CVD). The study will last about 113 weeks.

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Percent Change from Baseline in Body Weight
Study Period
2023-05-30 → 2026-05
NCT05929066 ↗
ACTIVE NOT RECRUITINGPhase IIIn=2,300

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

The purpose of this study is to evaluate the efficacy and safety of retatrutide in participants who have obesity or overweight (J1I-MC-GZBJ master protocol) including subsets of participants who have knee osteoarthritis (OA) (J1I-MC-GOA1) or who have obstructive sleep apnea (OSA) (J1I-MC-GSA1). This study will last about 89 weeks and will include up to 24 visits. Addendum (2) is optional and avail

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Percent Change From Baseline in Body Weight; Change from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score for GOA1 Subset
Study Period
2023-07-10 → 2026-05
NCT06297603 ↗
ACTIVE NOT RECRUITINGPhase IIIn=320

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)

The purpose of this study is to investigate the efficacy and safety of retatrutide compared with placebo in participants with Type 2 Diabetes and renal impairment, with inadequate glycemic control on basal insulin alone or a combination of basal insulin with or without metformin and/or sodium-glucose cotransporter-2 (SGLT2) inhibitor. The study will last about 14 months and may include up to 22 vi

Study Interventions
Retatrutide, Placebo
Primary Endpoints
Change from Baseline in Hemoglobin A1c (HbA1c) (%)
Study Period
2024-03-15 → 2026-11
NCT06662383 ↗
ACTIVE NOT RECRUITINGPhase IIIn=800

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

The main purpose of this study is to evaluate the efficacy and safety of retatrutide compared to tirzepatide in adults who have obesity. The study will last about 89 weeks.

Study Interventions
Retatrutide, Tirzepatide
Primary Endpoints
Percent Change from Baseline in Body Weight
Study Period
2024-11-01 → 2026-12
NCT04143802 ↗
COMPLETEDPhase In=72

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

The main purpose of this study is to learn about the side effects of LY3437943 when given to participants with type 2 diabetes. Blood tests will be performed to investigate how the body processes the study drug and how the study drug affects the body. Each enrolled participant will receive injections of LY3437943, dulaglutide, or placebo given just under the skin. For each participant, the study w

Study Interventions
LY3437943, Dulaglutide, Placebo
Primary Endpoints
Number of Participants with One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration
Study Period
2019-12-18 → 2020-12-28
Research Compliance Notice

All data presented on this page is for laboratory research purposes only. Retatrutide is referenced here as a research reagent. This page does not constitute medical advice, clinical guidance, or endorsement of any compound for human or animal use. All referenced studies are available via PubMed (PMID: 41997446) and the DOI-linked journal publication. Researchers must consult applicable institutional and regulatory frameworks before conducting any protocols.

Related Compounds

Other Metabolic/Weight Research Compounds

Semaglutide
Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the management of ob…
→
Tirzepatide
INTRODUCTION: Tirzepatide has been associated with significant reductions in body weight i…
→
Liraglutide
PURPOSE: To evaluate the association of glucagon-like peptide-1 receptor agonists (GLP-1 R…
→
MOTS-c
OBJECTIVE: MOTS-c is a mitochondria-derived peptide associated with reduced insulin resist…
→
View all Metabolic/Weight compounds →