retatrutide (LY3437943) / Eli Lilly - LARVOL DELTA

Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial (The Malaysian Reserve) - "In TRIUMPH-4, participants with obesity and knee osteoarthritis taking retatrutide 12 mg lost an average of 28.7% of their body weight at 68 weeks; Retatrutide reduced WOMAC pain scores by up to an average of 4.5 points (75.8%) and significantly improved measures of physical function, with more than 1 out of 8 retatrutide-treated patients completely free from knee pain at the end of the trial; Seven additional Phase 3 trials evaluating the investigational once-weekly treatment in obesity and type 2 diabetes are expected to complete in 2026"

P3 data • Trial completion date • Obesity • Type 2 Diabetes Mellitus

Diabetes Mellitus and Chronic Kidney Disease: The Future Is Being Surpassed. (PubMed, J Clin Med) - "(5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent...Many novel agents-many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)-are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Genetic Disorders • Heart Failure • Metabolic Disorders • Nephrology • Obesity • Renal Disease

Engineered nutrient-stimulated hormonal multi-agonist for precision targeting of obesity and metabolic disorders. (PubMed, Clin Mol Hepatol) - "Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1RAs, such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence...These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists."

Journal • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Harnessing GLP-1 Receptor Agonists for Obesity Treatment: Prospects and Obstacles on the Horizon. (PubMed, J Obes) - "Currently, liraglutide, semaglutide, and tirzepatide are FDA-approved for obesity treatment, while other agents are used off-label...Novel agents including CagriSema and higher dose oral semaglutide are advancing through clinical trials, while pivotal trial results for orforglipron, mazdutide, retatrutide, and survodutide are anticipated to further expand the therapeutic landscape...The convergence of pharmacological innovation, digital health strategies, and equitable care initiatives is expected to revolutionize obesity therapeutics in the coming decade. Priorities for future research include sustaining long-term weight loss, establishing disease-modifying potential in nonmetabolic disorders, and addressing health equity concerns to ensure broader global benefit."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Congestive Heart Failure • Diabetes • Dyslipidemia • Genetic Disorders • Heart Failure • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Retatrutide warning as people risking lives with fake weight-loss drug (Cambridge News) - "Retatrutide - nicknamed the 'Godzilla' or 'Triple-G' jab due to early trial results showing significant weight loss - is still strictly experimental. Yet counterfeit versions are being sold through online and social media shops, Telegram groups and private accounts, often with no medical assessment, no batch control and no legal oversight."

Commercial • Obesity

Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review. (PubMed, Medicina (Kaunas)) - "Orlistat commonly linked to steatorrhea and flatulence, while phentermine was associated with reduced GI motility. Newer agents, including retatrutide and orforglipron, also demonstrated notable GI side effect profiles...Tailored titration schedules, proactive patient counseling, and standardized adverse event reporting may improve tolerability. Further research is warranted to evaluate long-term GI outcomes and compare safety across emerging pharmacologic agents."

Adverse events • Journal • Review • Constipation • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity

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 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Obesity Drugs Over the Past 20 Years: A Meta-Analysis of Clinical Trials using ML and AI (OBESITY WEEK 2025) - "GLP-1 receptor agonists such as liraglutide, semaglutide, and tirzepatide have emerged as the most effective treatments to date, achieving 10–22% weight loss in clinical trials. Novel multi-receptor agonists—including retatrutide (GLP-1/GIP/glucagon) and the investigational NA-931 (IGF-1/GLP-1/GIP/glucagon)—demonstrate even greater promise, with weight loss exceeding 24% and favorable safety profiles. In contrast, older agents such as sympathomimetics (phentermine), lipase inhibitors (orlistat), and withdrawn serotonergic drugs (lorcaserin) have shown moderate efficacy (5–15% weight loss) but are limited by tolerability and safety concerns... GLP-1 agonists outperform traditional agents in promoting sustained weight loss and metabolic improvements; however, they are associated with gastrointestinal side effects, high costs, and rare but serious risks (e.g., pancreatitis, thyroid tumors). Sympathomimetics raise cardiovascular concerns, while orlistat often results in poor..."

Retrospective data • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Pancreatic Cancer • Pancreatitis • Solid Tumor • Thyroid Gland Carcinoma • IGF1

TRIUMPH-8: A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight (clinicaltrials.gov) - P3 | N=250 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Within this year, the first Phase 3 results for retatrutide are expected to be announced, along with the results of MSD's MASH Phase 2b trial, which Hanmi Pharmaceutical has licensed out. (The Asia Business Daily)

Clinical data • Metabolic Dysfunction-Associated Steatohepatitis

Perceived benefits of treatment for obesity with retatrutide: A qualitative study of patients in a phase 2 clinical trial. (PubMed, Obes Pillars) - P2 | "In this exit interview analysis of adult study participants, those treated with retatrutide reported early changes in eating behavior, improved physical and emotional well-being, and weight reduction goal achievement. Some participants experienced social limitations or frustration due to adverse events or unmet expectations."

Journal • P2 data • Genetic Disorders • Obesity

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) (clinicaltrials.gov) - P3 | N=320 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Renal Disease • Type 2 Diabetes Mellitus

Retatrutide Alters Circulating Proteomic Markers Related to Lipid Metabolism (OBESITY WEEK 2025) - " Serum samples were collected under fasting conditions from two Phase 2 double-blind, randomized, placebo-controlled trials at baseline, 24 weeks and either 36 weeks (T2D: placebo, dulaglutide 1.5 mg, and RETA 0.5, 4, 8, and 12 mg) or 48 weeks (OB: placebo, and RETA 1, 4, 8, and 12 mg). In these post hoc analyses of two phase 2 studies, treatment with GIP, GLP-1 and glucagon receptor agonist, retatrutide, was associated with modulation of circulating protein biomarkers involved in the regulation of adipose stores, insulin sensitivity, and lipid metabolism, which are suggestive of improved metabolic health."

Atherosclerosis • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Myocardial Infarction • Obesity • Type 2 Diabetes Mellitus • IGFBP2 • LEP

GIPR-Dependent Action of Anti-Obesity Medication in Human White and Brown Adipocytes (OBESITY WEEK 2025) - "Tirzepatide and retatrutide increased signaling via PKA but not semaglutide or bupropion. Clinical studies have shown an enhanced efficacy of GIP/GLP1 dual agonism over GLP1 agonism alone. Our results provide a mechanistic basis for this difference by demonstrating that incretin mimetic peptide AOMs directly influence human adipocyte metabolism in a GIPR-dependent manner. This work provides additional understanding of incretin mimetic drug physiology."

Genetic Disorders • Metabolic Disorders • Obesity • GCG

Anti-Obese Effects of GLP-1 Related Peptides on MC4R Deficient Mice and Nauseous Experiment Systems (OBESITY WEEK 2025) - "Therefore, we evaluated anti-obese effects of clinical stage GLP-1 related peptides, semaglutide, tirzepatide, and retatrutide using MC4R KO mice... This is the first report evaluating the anti-obese effects of three GLP-1 related peptides on MC4R KO mice, suggesting that GLP-1 related peptides may also be effective in the obesity pathway caused by POMC-MC4R pathway deficiency. It has been reported that treatment with GLP-1 related peptides reduce muscle mass, and there is concern that this may lead to sarcopenia, and our results showed that treatment with GLP-1 related peptides also reduced lean mass. In this regard, the MC4R KO mice might be a clinically reflective model for obesity."

Preclinical • Constipation • Diabetes • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity • Sarcopenia • MC4R

Retatrutide Shows Multiple Metabolic Benefits in Diet-induced Obese MASH Mouse and Hamster Models (OBESITY WEEK 2025) - "Retatrutide demonstrates multiple metabolic benefits in both mice and hamster models. Our preclinical setting will help to assess the efficacy of novel therapies targeting obesity and MASH versus retatrutide as reference."

Preclinical • Dyslipidemia • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity

The Evolution of Oral Incretin-based Therapies for Obesity (OBESITY WEEK 2025) - "The prevalence of obesity across the world continues to rise, and this is now recognised as one of the most important public health problems, which needs to be addressed.The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the gut after nutrient intake and play an important role in glucose homoeostasis and in the control of food intake, nutrient assimilation, and whole-body metabolism.Recently developed GLP-1-based therapies for weight management represent highly effective treatment options for people living with obesity.The field of GLP-1-based medicines has evolved from selective GLP-1 RAs, liraglutide and semaglutide, which were the first incretin-based therapies approved for weight management. The more recently approved tirzepatide, which activates both GLP-1 and GIP receptors has demonstrated higher efficacy in terms of body weight reduction, while retatrutide, a triple receptor agonist..."

Genetic Disorders • Obesity

Development and Content Evaluation of the Eating Behavior and Appetite Questionnaire (EBAQ) for Individuals with Obesity. (PubMed, Adv Ther) - P2 | "The EBAQ may be used in clinical trials, clinical practice, or observational research to evaluate the impact of obesity and the effect of obesity treatment on appetite and eating behaviors."

Journal • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension • Metabolic Disorders • Obesity

A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes) (clinicaltrials.gov) - P3 | N=4500 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Adverse events • Enrollment open • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Comparative Efficacy of Glucagon-Like Peptide-1 Receptor Agonists and Co-Agonists for Weight Loss Among Patients Without Diabetes: A Network Meta-Analysis (AHA 2025) - "BACKGROUND: Multiple glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and newer dual/triple co-agonists promote weight loss in adults without diabetes, yet comparative efficacy across agents remains uncertain.AIM: To compare and rank the efficacy of GLP-1 RAs and co-agonists for weight loss using network meta-analysis (NMA). We searched MEDLINE, EMBASE and Cochrane CENTRAL from inception to May 2025 for randomized controlled trials (RCTs) enrolling adults with overweight/obesity without diabetes...At 6 months, all agents significantly reduced weight versus placebo; retatrutide ranked highest (mean difference [MD]: -15.8%, 95% confidence interval [CI] -17.6 to -14.1; SUCRA 1.00), followed by mazdutide (MD: -12.3%, 95% CI -14.1 to -10.5; SUCRA 0.89) and orforglipron (MD: -10.6%, 95% CI -12.8 to -8.4; SUCRA 0.75)... Among adults without diabetes, dual- and triple-agonists, particularly tirzepatide and retatrutide, achieve the greatest weight reductions, while..."

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

Incretin-Based Therapies in MASH: A Meta-Analysis of Hepatic and Metabolic Outcomes (ACG 2025) - "Incretin-based therapies significantly reduced liver fat in MASH patients. Triple agonist retatrutide achieved the greatest reduction (up to 83%), followed by dual GLP-1/glucagon agonists (pemvidutide: 64%, survodutide: 60%) and GLP-1/GIP agonist tirzepatide (47%). GLP-1 monotherapy (semaglutide) also reduced liver fat (39%) and improved liver enzymes."

Retrospective data • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

The Effects of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists on Polycystic Ovarian Syndrome: A Scoping Review. (PubMed, Cureus) - "The aim of this review was to explore the classes of incretin mimetics, such as glucagon-like peptide-1 (GLP-1) receptor agonists or semaglutide, dual agonists of the GLP-1 receptor and gastric inhibitory peptide (GIP) or tirzepatide, and a new triple agonist, or retatrutide (which is currently seeking Food and Drug Administration (FDA) approval), and their suggested benefits as a treatment for PCOS...All three classes of incretin mimetics showed significant improvement in weight loss and insulin sensitivity when compared to traditional pharmacological management with metformin and estradiol-progesterone combination pills in patients with PCOS...Some research demonstrated symptom improvements specific to PCOS presentation, such as dysmenorrhea and the classic dysmorphic ovarian morphology. Further research is warranted to determine the exact mechanism behind how incretin mimetics may improve the hormonal dysregulation in patients with PCOS, as well as how to best use..."

Journal • Review • Diabetes • Endocrine Disorders • Genetic Disorders • Infertility • Metabolic Disorders • Polycystic Ovary Syndrome • Sexual Disorders • Women's Health

Retatrutide: Primary completion and completion of P3 TRIUMPH-6 trial (NCT06859268) for obesity in Apr 2028 (Eli Lilly) - Q3 2025 Results: Primary completion and completion of P3 TRIUMPH-5 trial (NCT06662383) for obesity in Dec 2026

Trial completion date • Trial primary completion date • Obesity

Retatrutide: Data from P3 TRIUMPH-4 trial (NCT05931367) for osteoarthritis pain of the knee and obesity in 2025 (Eli Lilly) - Q3 2025 Results

P3 data • Obesity

Rationale, Design, and Baseline Characteristics of the TRANSCEND-CKD trial of Retatrutide in Patients with Chronic Kidney Disease. (PubMed, Nephrol Dial Transplant) - P3 | "TRANSCEND-CKD is designed to provide mechanistic insights on the effects of retatrutide on kidney function and structure, and to inform clinical findings in the ongoing cardio-kidney outcome trial TRIUMPH-Outcomes (NCT06383390)."

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