retatrutide (LY3437943) / Eli Lilly - LARVOL DELTA

Triple Agonism Based Therapies for Obesity. (PubMed, Curr Cardiovasc Risk Rep) - "Other unimolecular triple agonists and combination regimens involving tirzepatide with additional mono agonists are also in development. Retatrutide, a triple agonist now in phase 3 trials, has the potential to become the most effective pharmacological treatment for obesity while also offering substantial benefits in T2D management and other cardiometabolic risk factors."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Association between patient-reported eating behaviours and weight change: Secondary analyses of a randomized, double-blind trial comparing retatrutide and placebo in people with obesity or overweight. (PubMed, Diabetes Obes Metab) - No abstract available

Clinical • Journal • Genetic Disorders • Obesity

Review: Special Issue: Real-world evidence on the use of GLP1 receptor agonists: Emerging concepts in obesity management: focus on glucagon receptor agonist combinations. (PubMed, Drugs Context) - "Agents like mazdutide, pemvidutide, survodutide and retatrutide have demonstrated the ability to trigger significant weight loss in earlier phase trials, often surpassing the amount of weight loss obtained with existing therapies...Key considerations as these drugs move forward in development to eventual approval include cost, access and long-term safety. This article is part of the Real-world evidence on the use of GLP1 receptor agonists Special Issue: https://www.drugsincontext.com/special_issues/real-world-evidence-on-the-use-of-glp1-receptor-agonists."

HEOR • Journal • Real-world evidence • Review • Cardiovascular • Diabetes • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials. (PubMed, J Basic Clin Physiol Pharmacol) - "Weekly subcutaneous injections of retatrutide in obese patients resulted in significant weight loss and metabolic improvements compared to a placebo."

Journal • Review • Genetic Disorders • Obesity

Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids. (PubMed, Diabetes Obes Metab) - "Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels."

Journal • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • ANGPTL3 • GCG

Glucagon-like peptide-1 receptor analogues and beyond: emerging obesity pharmacotherapies. (PubMed, Panminerva Med) - "Notably, the combinations of GLP-1 RA, GIP and glucagon RA (retatrutide) have shown WL efficacy closing on to that observed in bariatric surgery. While entero-pancreatic hormone-based therapies have been the centre of attention for obesity pharmacotherapies, non- entero-pancreatic hormone treatments also hold promise. In this review, we present the future pharmacotherapies for weight management in people with obesity, focusing on entero-pancreatic hormone-based molecules."

Journal • Genetic Disorders • Obesity

Semaglutide, tirzepatide, and retatrutide attenuate the interoceptive effects of alcohol in male and female rats. (PubMed, Psychopharmacology (Berl)) - "Building on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Comparative Efficacy and Safety of Tirzepatide vs Retatrutide in Weight Loss: A Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Background:The global rise in obesity poses a significant public health challenge, contributing to an increased burden of comorbidities such as cardiovascular disease, type 2 diabetes, and certain cancers...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

Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A Bayesian NMA. (PubMed, Obesity (Silver Spring)) - "Retatrutide offers superior weight loss efficacy but with a higher AE risk. Dual agonists provide a favorable efficacy-safety balance. Personalized treatment selection based on patient characteristics is recommended."

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

TRIUMPH-7: A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight and Chronic Low Back Pain (clinicaltrials.gov) - P3 | N=586 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Back Pain • Genetic Disorders • Lumbar Back Pain • Musculoskeletal Pain • Obesity • Pain

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

TRIUMPH-3: A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease (clinicaltrials.gov) - P3 | N=1800 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: Jan 2026 ➔ Apr 2026

Trial primary completion date • Cardiovascular • Genetic Disorders • Obesity

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 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • 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 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity. (PubMed, Kidney Int Rep) - "Both studies were placebo-controlled; the T2D study included dulaglutide 1.5 mg as an active comparator. Because most patients had normal albuminuria, the absolute reduction in UACR was modest. Higher doses of retatrutide were associated with reduced UACR in participants with T2D and obesity, and with increased eGFR in participants with obesity but not in those with T2D."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • CST3

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

Incretin-based therapies for the treatment of obesity-related diseases. (PubMed) - "Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4 mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development...Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the underlying mechanism, whether involving direct effects on target tissues or mediated by improvement in BW, glucose levels and other CV risk factors."

Journal • Review • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Obstructive Sleep Apnea • Osteoarthritis • Pain • Respiratory Diseases • Rheumatology • Sleep Disorder • Type 2 Diabetes Mellitus

Synergy in Action: Novel Combination Strategies for DKD: New Horizons in DKD: Emerging Diagnostic and Therapeutic Approaches (KSN 2025) - "The lecture will then explore the revolutionary potential of multi-receptor agonists—including dual GLP-1/GIP agonists (tirzepatide), triple GLP-1/GIP/glucagon agonists (retatrutide, mazdutide), and novel combinations like amycretin and cagrisema—which may fundamentally "remodel" the metabolic phenotype of DKD...Special consideration will be given to Asian populations, where lower BMI but high metabolic risk may offer unique opportunities for these novel combinations. The lecture will conclude with a vision for precision medicine in DKD."

Chronic Kidney Disease • Diabetic Nephropathy • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease

Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes. (PubMed, Acad Emerg Med) - No abstract available

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

Mechanistic insights into the potent anti-obesity effects of HM15275, a novel long-acting GLP-1/GIP/glucagon triple agonist (EASD 2025) - "This study aimed to further evaluate the anti-obesity effects of HM15275 in comparison with other incretin drugs and to explore its mechanisms of action (MoA) in mouse models of obesity.Materials and The effects of HM15275 on BWL and body composition were evaluated in DIO mice, including a switching study from Semaglutide (SEMA) or tirzepatide(TZP) to HM15275...SEMA, TZP, and/or in-house synthesized retatrutide (RETA) served as comparative controls. In DIO mice, a 3-week treatment with HM15275 resulted in greater BWL (-39.9% vs. baseline) compared to SEMA (-14.9%) and TZP (-25.3%)... In DIO mice, HM15275 demonstrated BWL primarily driven by fat mass reduction, with greater effects than other incretin drugs. In addition, comprehensive MoA studies elucidated the underlying mechanism for its potent BWL. These findings highlight the potential of HM15275 to enable both quantitatively and qualitatively improved obesity management."

Metabolic Disorders • Obesity • GCG

Inotropic effects of retatrutide in isolated human atrial preparations. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "These positive inotropic effects of glucagon were diminished by a GLP1-R antagonist, by a GIPR antagonist, and by a CGCR antagonist but not by propranolol, an antagonist at β-adrenoceptors. The effects of retatrutide on FOC were also reduced by 100 nM ryanodine, an inhibitor of the ryanodine receptor in the sarcoplasmic reticulum, by 1 µM carbachol, a M-cholinoceptor agonist, and by 1 µM (-)-N6-phenylisopropyladenosine, an A1-adenosine receptor agonist. Summarily, we suggest that retatrutide enlarged FOC in HAP via the cAMP system through its cognate receptors."

Journal • Cardiovascular • Coronary Artery Disease • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

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. (PubMed, Lancet Diabetes Endocrinol) - P2 | "In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared with placebo and dulaglutide. The proportion of lean mass loss to weight loss was similar to other obesity treatments. These findings could provide reassurance that a greater proportion of lean mass is not lost with retatrutide despite the overall increased weight loss."

Journal • P2 data • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

The GLP-1/GIP/glucagon triple receptor agonist retatrutide demonstrates multiple metabolic benefits and strong improvement in liver steatosis in a diet-induced obese MASH mouse model (EASD 2025) - "In the AMLN-diet induced obese MASH mouse model, a 5-week treatment with retatrutide demonstrates multiple metabolic benefits and a strong reduction in liver steatosis. This preclinical data set will help to further assess the efficacy of novel therapies targeting obesity and MASH versus retatrutide as reference."

Preclinical • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity