retatrutide (LY3437943) / Eli Lilly - LARVOL DELTA

ACCURATE PREDICTION OF LIVER FAT REDUCTIONS ACROSS RANGE OF WEIGHT LOSS BY QUANTITATIVE SYSTEMS PHARMACOLOGY MODELING (AASLD 2024) - "The overall effects of WL on steatosis reductions in NAFLDsym were calibrated with data from clinical studies with liraglutide (1), canagliflozin (2), and retatrutide (3). WL in excess of 10% has substantial, positive effects on reducing hepatic lipid burden and steatosis."

Metabolic Dysfunction-Associated Steatohepatitis

Retatrutide. (PubMed, Clin Diabetes) - No abstract available

Journal

RETATRUTIDE IMPROVES STEATOHEPATITIS IN A NEW ACCELERATED MOUSE MODEL OF DIET-INDUCED STEATOHEPATITIS WITH A FRUCTOSE BINGE (AASLD 2024) - "Female mice are more prone to acute fructose-induced liver injury than males, whereas both female and male mice develop robust steatohepatitis in a novel chronic diet-induced steatohepatitis model over 31 days with a final fructose binge. Retatrutide improves diet-induced steatohepatitis in mice."

Preclinical • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

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 | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Genetic Disorders • Obesity

Modern Challenges in Type 2 Diabetes: Balancing New Medications with Multifactorial Care. (PubMed, Biomedicines) - "A key focus of this review is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors...We also address future perspectives in diabetes management, including the potential of retatrutide as a triple receptor agonist and evolving guidelines advocating for a comprehensive, multifactorial approach to care...By focusing on the physiological mechanisms of these new therapies, this review underscores their role in enhancing T2DM management and highlights the importance of personalized care plans to address the complexities of the disease. This holistic perspective aims to improve patient quality of life and long-term health outcomes."

Journal • Review • Diabetes • Metabolic Disorders • Tobacco Cessation • Type 2 Diabetes Mellitus

A Study of LY3437943 in Healthy Participants With a High Body Mass Index (clinicaltrials.gov) - P1 | N=85 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Obesity

TRIUMPH-1: A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight (clinicaltrials.gov) - P3 | N=2100 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Musculoskeletal Pain • Obesity • Obstructive Sleep Apnea • Osteoarthritis • Pain • Respiratory Diseases • Rheumatology • Sleep Disorder • Type 2 Diabetes Mellitus

Perceived Benefits of Retatrutide for Obesity: A Qualitative Study of Phase 2 Trial Participants (OBESITY WEEK 2024) - No abstract available

P2 data • Genetic Disorders • Obesity

Improved HRQoL and Eating Behaviors in Adults With Obesity Treated With Retatrutide: A Phase 2 Study (OBESITY WEEK 2024) - "In adults with obesity or overweight, RETA treatment significantly improved multiple domains of HRQoL, reduced disinhibition, and reduced hunger more than PBO in this Phase 2 study."

Clinical • P2 data • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Pain • Type 2 Diabetes Mellitus

Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials. (PubMed, Metabol Open) - "In this meta-analysis, the use of once-weekly subcutaneous retatrutide was associated with a significant reduction in body weight and improvement of metabolic markers in patients with overweight, obesity and/or T2D, compared with placebo, with an increase in non-severe gastrointestinal and hypersensitivity adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-weekly subcutaneous retatrutide over the long term."

Clinical • Journal • Retrospective data • Review • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Immunology • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists."

Journal • Retrospective data • Review • Diabetes • Genetic Disorders • Hypoglycemia • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Emerging Pharmacotherapies for Obesity: A Systematic Review. (PubMed, Pharmacol Rev) - "Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate...This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives."

Journal • Review • Developmental Disorders • Genetic Disorders • Obesity

Effects of triple-hormone receptor agonist retatrutide on lipid profiling in participants with obesity (EASD 2024) - P2 | "The increase in ketone body and C2/C0 observed after 24 wk is consistent with adipose tissue lipolysis and reliance on fat oxidation. Inverse changes in TGs and DhCers were associated with improved insulin sensitivity, reduced hepatic steatosis and systemic inflammation. Evaluation of potential benefits on cardiovascular events and MASLD may merit further investigation."

Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

Effect of retatrutide on kidney parameters in people with type 2 diabetes and/or obesity: a post-hoc analysis of two phase 2 trials (EASD 2024) - P2 | "Materials and Data from randomized participants in 2 phase 2 studies were included: T2D (N=281): RETA (0.5, 4, 8, 12 mg) vs dulaglutide 1.5 mg vs PBO (N=45-50/arm); OB (non-T2D; N=338): RETA (1, 4, 8, 12 mg) vs PBO (N=62-70/arm). RETA 8 and 12 mg increased eGFR in people with OB but not in those with T2D. UACR and BP were reduced vs PBO with higher doses of RETA in both trials. These data suggest possible benefits on kidney function that warrant further investigation in larger populations."

P2 data • Retrospective data • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CST3

Retatrutide, an agonist of GIP, GLP-1 and glucagon receptors, improves lipoprotein biomarkers associated with cardiovascular risk in participants with obesity or overweight (EASD 2024) - P2 | "RETA treatment for 48 weeks dose-dependently reduced levels of non-HDL-C and apoB and the number of total and small LDL particles, suggesting an improvement in atherogenic lipoprotein profile and cardiovascular risk in subjects who have obesity or overweight but not T2D."

Biomarker • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • APOB

A triple GIP, GLP-1 and glucagon receptor agonist, retatrutide, decreases inflammatory CV risk biomarkers in people with overweight or obesity, with or without type 2 diabetes (EASD 2024) - P2 | "Materials and Data from adult participants in two phase 2 studies of RETA were included: Study 1(OB) -participants with overweight or obesity, without T2D treated with RETA (1, 4, 8 and 12 mg) vs placebo (PBO); Study 2 (T2D)-participants with T2D and BMI 25-50 kg/m 2 with RETA (0.5, 4, 8 and 12 mg) vs PBO and dulaglutide 1.5 mg. RETA robustly reduced hsCRP and IL-6 levels in participants with overweight or obesity, without T2D in a dose-dependent manner. Similarly, RETA reduced hsCRP and IL-6 levels in patients with T2D, even though not significantly vs placebo. These data suggest that RETA may reduce cardiovascular risk in people with overweight or obesity, with or without type 2 diabetes, through inflammation reduction as evidenced by reduced circulating inflammatory biomarkers."

Biomarker • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CRP • IL6 • LEP • TNFA

Retatrutide, an agonist of GIP, GLP-1, and glucagon receptors, improves markers of pancreatic beta cell function and insulin sensitivity (EASD 2024) - P2 | "Materials and Mixed models for repeated measures evaluated fasting biomarkers from these two Phase 2 double-blind randomized placebo-controlled trials: T2D (281 subjects, 36 weeks, RETA 0.5, 4, 8, and 12 mg vs placebo and 1.5 mg dulaglutide) and in OB (338 subjects, 48 weeks, RETA 1, 4, 8, 12 mg vs placebo). Enhanced glycemic control with RETA was associated with improvements in markers of both beta-cell function and insulin sensitivity in T2D and OB."

Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Weight Loss Blockbuster Development: A Role for Unimolecular Polypharmacology. (PubMed, Annu Rev Pharmacol Toxicol) - "Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine."

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

Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice. (PubMed, Endocrine) - "Retatrutide and Tirzepatide were significantly effective in improving DKD, controlling blood glucose and body weight. Retatrutide was the most effective in improving DKD and body weight, while Tirzepatide was the most effective in controlling blood glucose. Inhibiting the expression of inflammatory factors and fibrosis mediators and regulating intestinal microbiota may be the potential mechanisms of these two drugs to delay the progression of DKD."

Journal • Preclinical • Diabetic Nephropathy • Dyslipidemia • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • CASP1 • NLRP3 • TNFA

Multiomic comparison of GLP1R analogues interaction networks (ESC 2024) - " Specific processes for tirzepatide included behavior-related terms and hydrochloric acid secretion, while retatrutide exhibited associations with fibrosarcoma, thinking and speaking disturbances, and adipogenesis signaling. Integration of interaction networks with metabolomic and lipidomic data revealed top interactors and impacted metabolites, shedding light on the intricate molecular landscape of GLP1Ri. These findings contribute valuable insights into the potential therapeutic implications and broader health considerations of GLP1R drugs"

Cardiovascular • Hypertension

Reduction of triglyceride-rich lipoproteins with retatrutide in type 2 diabetes may be explained by concurrent reduction in ANGPTL3/8 levels (ESC 2024) - P2 | "In patients with T2D, retatrutide dose-dependently decreased serum concentrations of ANGPTL3/8, the most potent circulating LPL inhibitor. These data suggest that retatrutide may reduce TG-rich lipoproteins by decreasing ANGPTL3/8 levels."

Cardiovascular • Dyslipidemia • ANGPTL3 • LPL

Triple-hormone receptor agonist retatrutide significantly improves lipoprotein and apolipoprotein profiles in participants with obesity or overweight (ESC 2024) - "RETA treatment for 48 weeks dose-dependently reduced levels of non-HDL-C and apoB and the number of total and small LDL particles, suggesting an improvement in atherogenic lipoprotein profile and cardiovascular risk in subjects who have obesity or overweight but not T2D."

Acute Coronary Syndrome • Cardiovascular • APOB

Pharmacological Treatment of Binge Eating Disorder and Frequent Comorbid Diseases. (PubMed, CNS Drugs) - "We recommend the ADHD medication lisdexamfetamine (LDX) and the antiepileptic and antimigraine drug topiramate for the pharmacological treatment of BED...Medications to treat diseases frequently comorbid with BED include atomoxetine and LDX for ADHD; citalopram, fluoxetine, sertraline, duloxetine, and venlafaxine for anxiety disorders and depression; aripiprazole for manic episodes of BD; lamotrigine, lirasidone and lumateperone for depressive episodes of BD; naltrexone for alcohol use disorder; bupropion for nicotine use disorder; and liraglutide, semaglutide, and the combination of bupropion and naltrexone for obesity. As obesity is a frequent health consequence of BED, weight gain-inducing medications, such as the atypical antipsychotics olanzapine or clozapine, the novel antidepressant mirtazapine and tricyclic antidepressants, and the mood stabilizer valproate should be avoided where possible. It is currently unclear whether the novel and promising glucagon,..."

Journal • Review • Addiction (Opioid and Alcohol) • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Binge Eating Disorder • Bipolar Disorder • CNS Disorders • Depression • Genetic Disorders • Migraine • Mood Disorders • Nicotine Addiction • Obesity • Pain • Psychiatry

Molecular Mechanisms behind Obesity and Their Potential Exploitation in Current and Future Therapy. (PubMed, Int J Mol Sci) - "A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials."

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

A Study of LY3437943 in Postmenopausal Female Participants Who Are Overweight or Obese (clinicaltrials.gov) - P1 | N=46 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Obesity