retatrutide (LY3437943) / Eli Lilly - LARVOL DELTA

Comparative Metabolic Effects of Semaglutide, Tirzepatide, and Retatrutide in a Monogenic (db/db) Mouse Model of Obesity (ADA 2025) - "Overall, Tirzepatide demonstrated the most pronounced metabolic benefits in the monogenic model of obesity coupled with type-2 diabetes."

Late-breaking abstract • Preclinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

MWN109—A Novel Fatty Acid–Modified GLP-1/GIP/GCG Triagonist for Dual-Format Weight Management Demonstrates Superior Efficacy in Nonhuman Primates (ADA 2025) - "This study evaluates its weight loss efficacy, pharmacokinetics, and safety in NHP. In diet-induced obesity (DIO) monkey studies, SC MWN109 was compared with tirzepatide and retatrutide. MWN109 exhibits greater weight loss efficacy, favorable pharmacokinetics, and a promising safety profile, supporting its potential as a next-generation obesity treatment. The SC formulation has received IND clearance from both the NMPA and FDA and is currently in Phase 1 trials."

Clinical • Late-breaking abstract • Metabolic Disorders • Obesity • GCG

Cellular Characterisation of Signalling and Receptor Trafficking Induced by MET-097, a G Protein-Biased GLP-1R Agonist (ADA 2025) - "We aimed to further elucidate the signalling and trafficking profile of MET-097. In vitro BRET-based biosensors were used to compare clinically relevant GLP-1R agonists. Compared to reference agonists (GLP-1/exendin-4/semaglutide), MET-097 acted as a partial agonist for Gαs and Gαq recruitment at both the plasma membrane (36% and 22% of exendin-4) and endosomal compartments (34% and 37% of exendin-4), yet still showed full cAMP response (115% of exendin-4). We speculate the pharmacological attributes of MET-097 may contribute to a unique pharmacodynamic profile. Of particular interest will be to align these attributes with the efficacy and tolerability observed in clinical trials."

Metabolic Disorders • Obesity • ARRB1

Therapeutic NuSH Cocktails—Coadministration of Ultra-Long-Acting GLP-1, GIP, Glucagon, and Amylin Peptide Analogs Induce Profound Weight Loss in DIO Mice (ADA 2025) - "We sought preclinical proof of concept of their mixability and concerted efficacy. ULA analogs of human GLP-1, GIP, glucagon, and amylin afforded MET-097, MET-034, MET-067, and MET-233, respectively—a peptide combo we call M4...The M4 (25 nmol/kg total peptide) effects on body weight and food intake were compared to retatrutide (26 nmol/kg). In minipigs, M4 peptides had similar half-lives (range: 87-114 h)... M4 peptides may allow for infrequent coadministration in humans. Results from chronic M4 administration to rats confirm that engaging multiple mechanisms can achieve more weight loss. Further, a polymolecular approach allows adjusting of individual agent dose levels to enhance M4's efficacy to tolerability window, even in a semipersonalized way."

Preclinical • Metabolic Disorders

Robust Antiobesity Effect and Mechanistic Insights of HM15275, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist in Animal Model of Obesity (ADA 2025) - "Tirzepatide (TZP) and retatrutide (RETA, in-house synthesis) served as comparative controls. In DIO mice, HM15275 treatment for 3 weeks resulted in a greater weight loss (-39.9% vs. D0) than TZP (-25.3% vs. D0). In conclusion, HM15275 demonstrates potent weight loss with improved weight loss quality in DIO mice. Also, comprehensive elucidation of the underlying mechanism of action has been demonstrated. Clinical translation of such findings is under investigation in an ongoing phase 1, 4-week multiple ascending dose (MAD) study in obese patients."

Preclinical • Metabolic Disorders • Obesity

Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis. (PubMed, J Clin Endocrinol Metab) - "GLP-1RAs decreased liver fat deposition and improved histological steatosis, hepatocellular ballooning and lobular inflammation, without worsening of fibrosis in MASLD and MASH."

Journal • Retrospective data • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • KRT18

Comparative Analysis of Glucagon Receptor Agonists vs Resmetirom in MASLD and MASH:Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Resmetirom, a thyroid hormone receptor-β agonist, and glucagon receptor agonists (GRAs), such as Cotadutide, Retatrutide, and Survodutide, have demonstrated potential efficacy in recent clinical trials. SAE risk was not significantly elevated for Resmetirom (RR: 1.11, 95% CI: [0.77; 1.59], p = 0.58), but GRAs showed a trend toward higher SAE rates (RR: 2.38, 95% CI: [0.98; 5.82], p = 0.056).ConclusionsBoth Resmetirom and GRAs effectively reduce liver fat and ALT levels in MASLD/MASH patients, with Resmetirom offering a favorable safety profile and GRAs demonstrating superior ALT reductions but a potential increase in SAE risk. These findings underscore the promise of both therapeutic classes and highlight the need for further comparative trials to inform treatment decisions."

Retrospective data • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology • Solid Tumor

Comparative Efficacy and Safety of Glucagon Receptor Agonists in Metabolic Outcomes: A Network Meta-Analysis of Randomized Controlled Trials (ENDO 2025) - "Retatrutide and survodutide demonstrate superior efficacy in weight loss and glycemic control among glucagon receptor agonists, though at the cost of higher adverse event-related discontinuation."

Retrospective data • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Comparative Efficacy and Safety of Tirzepatide vs Retatrutide in Weight Loss: A Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Retatrutide demonstrates superior efficacy in both absolute and percentage weight reduction compared to tirzepatide, albeit with a higher frequency of adverse events. These findings underscore the potential of retatrutide in achieving substantial weight loss and highlight the need for further direct comparisons in head-to-head trials to assess long-term safety and efficacy."

Retrospective data • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • Type 2 Diabetes Mellitus

Comparative Analysis of Glucagon Receptor Agonists vs Resmetirom in MASLD and MASH:Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Resmetirom, a thyroid hormone receptor-β agonist, and glucagon receptor agonists (GRAs), such as Cotadutide, Retatrutide, and Survodutide, have demonstrated potential efficacy in recent clinical trials. SAE risk was not significantly elevated for Resmetirom (RR: 1.11, 95% CI: [0.77; 1.59], p = 0.58), but GRAs showed a trend toward higher SAE rates (RR: 2.38, 95% CI: [0.98; 5.82], p = 0.056).ConclusionsBoth Resmetirom and GRAs effectively reduce liver fat and ALT levels in MASLD/MASH patients, with Resmetirom offering a favorable safety profile and GRAs demonstrating superior ALT reductions but a potential increase in SAE risk. These findings underscore the promise of both therapeutic classes and highlight the need for further comparative trials to inform treatment decisions."

Retrospective data • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology • Solid Tumor

To Investigate the Effect of Retatrutide (LY3437943) on Metoprolol Pharmacokinetics in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care-a systematic review and network meta-analysis. (PubMed, Acta Diabetol) - "Receptor-specific targeting optimizes T2DM treatment, with Semaglutide supporting glycemic control, Tirzepatide enhancing weight loss and glucose regulation, and Retatrutide potentially offering broader metabolic benefits, advancing receptor-targeted, personalized therapy."

Journal • Retrospective data • Review • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Contractile effects of retatrutide in isolated mouse atrial preparations. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "In isolated mouse right atrial preparations (RA), retatrutide exerted PCE that were potentiated by 100 nM rolipram but that were antagonized by adomeglivant, a GCGR antagonist...The PCE of retatrutide were not weakened by the β-adrenoceptor antagonist propranolol (1 µM) but were blocked by 1 µM carbachol, an agonist at M2-cholinoceptor, and this effect was reversed by 1 µM atropine, a muscarinic receptor antagonist...We conclude that retatrutide excites the beating rate in RA via GCGR, signalling via cAMP and PKA. Isoprenaline and retatrutide might increase cAMP in different compartments of the mouse sinus node."

Journal • Preclinical

Spotlight on the Effects of Incretin-Based Therapies on Metabolic and Muscular Homeostasis: A Comparative Study of GLP-1, GIPR, and GCGR Multi-Target Agonists (ECO 2025) - "Our study shows that the GLP-1 agonist semaglutide, dual-target agonist tirzepatide, and triple-target agonist retatrutide significantly reduce body weight and fat mass in a humanized diet-induced obesity (DIO) mouse model. Retatrutide exhibited the most pronounced effects but with slightly higher muscle loss. Despite differences in weight and fat loss, glucose and insulin levels were similar across all treatment groups, indicating effective glycemic control."

Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Comparison of anti-obese effects on GLP-1 analogue peptides, Semaglutide, Tirzepatide and Retatrutide using MC4R deficient obesity model mice (ECO 2025) - "In this study, we confirmed all GLP-1 analogs showed an excellent anti-obesity effect in MC4R KO mice. According to the study on energy expenditure evaluation, the reduction of lean mass and muscle amounts might be derived from decrease of energy consumption. Similar with clinical study, the anti-obese effect of tirzepatide and retatrutide were stronger than those of semaglutide treatment."

Preclinical • Genetic Disorders • Obesity • Prader–Willi syndrome • LEP • MC4R • PCSK1

Lilly announces details of presentations at American Diabetes Association's (ADA) 85th Scientific Sessions (Eli Lilly Press Release) - "Eli Lilly and Company...announced that data from studies of...tirzepatide (Zepbound and Mounjaro), retatrutide, eloralintide and bimagrumab will be presented at the American Diabetes Association's (ADA) 85th Scientific Sessions taking place June 20-23 in Chicago."

Clinical data • Preclinical • Obesity

Retatrutide, to Agonist of Gip, GLP-1, and Glucagon Receptors, Impoved Markers of Pancreatic Beta Cell Function and Insulin Sensitivity (DDG 2025) - "In Conclusion, Reta Impovered Markers of Beta-Cell Function in T2D and Markers of Insulin Sensitivity in T2D and OB."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study to Evaluate the Effect of Retatrutide on Insulin Secretion and Insulin Sensitivity in Adult Participants With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P1 | N=95 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study to Investigate the Response of Participants With Type 2 Diabetes Mellitus on Once-Weekly Retatrutide to Hypoglycemia (clinicaltrials.gov) - P1 | N=78 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study of Retatrutide (LY3437943) on Renal Function in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes (clinicaltrials.gov) - P2 | N=146 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

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) (clinicaltrials.gov) - P3 | N=1250 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: Dec 2026 ➔ Aug 2026

Trial primary completion date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Retatrutide: Primary completion and completion of P3 TRIUMPH-6 trial (NCT06859268) for obesity in Apr 2028 (Eli Lilly) - Q1 2025 Results

Trial completion date • Trial primary completion date • Obesity

Retatrutide: Primary completion and completion of P3 TRIUMPH-4 trial (NCT05931367) for obesity in Dec 2025 (Eli Lilly) - Q1 2025 Results: Primary completion and completion of P3 trial (NCT06662383) for obesity in Dec 2026

Trial completion date • Trial primary completion date • Obesity

TRIUMPH-5: A Study of Retatrutide (LY3437943) Compared to Tirzepatide (LY3298176) in Adults Who Have Obesity (clinicaltrials.gov) - P3 | N=800 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Apr 2027 ➔ Dec 2026 | Trial primary completion date: Apr 2027 ➔ Dec 2026

Trial completion date • Trial primary completion date • Genetic Disorders • Obesity

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. (PubMed, Proc (Bayl Univ Med Cent)) - "Retatrutide demonstrated significant improvements in body weight and metabolic outcomes among adults with obesity and had an appropriate safety profile. However, additional large and long-term trials are required to establish these results."

Journal • Retrospective data • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity