Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(6), P. 514 - 526

Published: June 26, 2023

Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, efficacy for treatment obesity are not known.We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had body-mass index (BMI, weight in kilograms divided by square height meters) 30 or higher BMI 27 less than plus at least one weight-related condition. Participants were randomly assigned 2:1:1:1:1:2:2 ratio receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 8 12 mg]) placebo once weekly 48 weeks. The primary end point was percentage change body from baseline 24 Secondary points included weeks reduction 5% more, 10% 15% more. Safety also assessed.We enrolled 338 adults, 51.8% whom men. least-squares mean groups -7.2% 1-mg group, -12.9% combined 4-mg -17.3% 8-mg -17.5% 12-mg as compared -1.6% group. At weeks, -8.7% -17.1% -22.8% -24.2% -2.1% more occurred 92%, 75%, 60%, respectively, participants received retatrutide; 100%, 91%, 75% those mg; 93%, 83% 27%, 9%, 2% placebo. most common adverse events gastrointestinal; these dose-related, mostly mild moderate severity, partially mitigated lower starting dose (2 vs. mg). Dose-dependent increases heart rate peaked declined thereafter.In obesity, resulted substantial reductions weight. (Funded Eli Lilly; ClinicalTrials.gov number, NCT04881760.).

Language: Английский

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Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

The Lancet, Journal Year: 2023, Volume and Issue: 402(10401), P. 529 - 544

Published: June 26, 2023

Language: Английский

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LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial

The Lancet, Journal Year: 2022, Volume and Issue: 400(10366), P. 1869 - 1881

Published: Oct. 27, 2022

Language: Английский

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What is the pipeline for future medications for obesity?

International Journal of Obesity, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Abstract Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding the weight regulation mechanisms role gut-brain axis on appetite has led to development safe effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, subcutaneously administered GLP-1 RA approved treatment in 2021, results 15–17% mean loss (WL) evidence cardioprotection. Oral are also under early data shows similar WL efficacy semaglutide mg. Looking next generation treatments, combinations other hormones complementary actions and/or synergistic potential (such glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin) investigation enhance cardiometabolic benefits RA. Tirzepatide, dual GLP-1/GIP agonist been glycaemic control type 2 diabetes well management leading up 22.5% phase 3 trials. Other including cagrisema (GLP-1/amylin RA) triple retatrutide (GLP-1/GIP/glucagon have progressed trials suggests that may lead even greater than tirzepatide. Additionally, agents different action (e.g. bimagrumab) improve body composition during clinical We new era pharmacotherapy where approach achieved bariatric surgery. In this review, we present safety pipeline pharmacotherapies focus consider implications challenges bring.

Language: Английский

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Excess body weight: Novel insights into its roles in obesity comorbidities

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 92, P. 16 - 27

Published: March 24, 2023

Excess body weight is a global health problem due to sedentary lifestyle and unhealthy diet, affecting 2 billion population worldwide. Obesity major risk factor for metabolic diseases. Notably, the of obesity largely depends on distribution, which visceral adipose tissues but not subcutaneous fats are closely associated with comorbidities, including type diabetes, non-alcoholic fatty liver disease, cardiovascular disease certain types cancer. Latest multi-omics mechanistical studies reported crucial involvement genetic epigenetic alterations, adipokines dysregulation, immunity changes, imbalance white brown tissues, gut microbial dysbiosis in mediating pathogenic association between comorbidities. In this review, we explore epidemiology excess up-to-date mechanism how lead chronic complications. We also examine utilization fat measurement as an accurate clinical parameter assessment healthy individuals outcome prediction obese subjects. addition, current approaches prevention treatment its related comorbidities further discussed.

Language: Английский

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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 18, 2024

The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and found primarily on surfaces various cell types within human body. This specifically interacts with GLP-1, key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, several other crucial biological functions. In recent years, GLP-1 medications have become focal point medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, broad development prospects. article thoroughly traces developmental milestones drugs, from initial discovery clinical application, detailing evolution diverse along distinct pharmacological properties. Additionally, this paper explores potential applications agonists (GLP-1RAs) fields such neuroprotection, anti-infection measures, reduction inflammation, enhancement cardiovascular function. It provides in-depth assessment effectiveness GLP-1RAs across multiple body systems-including nervous, cardiovascular, musculoskeletal, digestive systems. includes integrating latest trial data delving into signaling pathways mechanisms. primary goal emphasize extensive benefits using treating spectrum diseases, obesity, non-alcoholic fatty liver disease (NAFLD), neurodegenerative musculoskeletal forms cancer. ongoing new indications for drugs offers promising prospects further expanding interventions, showcasing field.

Language: Английский

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New insights into the treatment of obesity

Diabetes Obesity and Metabolism, Journal Year: 2023, Volume and Issue: 25(8), P. 2058 - 2072

Published: April 14, 2023

Obesity is a chronic, progressive and relapsing disease with rising global prevalence associated increased morbidity mortality reduced quality of life. Treatment obesity requires comprehensive medical approach that includes behavioural interventions, pharmacotherapy bariatric surgery. The degree weight loss all approaches highly heterogeneous, long-term maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy raising numerous safety concerns. Therefore, there need for the development efficacious safe new agents. Recent insights into complex pathophysiology our understanding intervenable targets pharmacotherapies to treat improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia hypertension. As result, novel potent therapies emerged, such as semaglutide, glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved treatment obesity. Semaglutide 2.4 mg once weekly significantly reduces body by approximately 15%, simultaneous improvement risk factors physical functioning people Tirzepatide, first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has demonstrated reduction exceeding 20% coupled improved measures feasible. Thus, these agents promise narrow gap between weight-loss effects behaviour previous pharmacotherapies, In this narrative review, we highlight established emerging therapeutic treatments management position them framework according their effects.

Language: Английский

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New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics

Annual Review of Medicine, Journal Year: 2023, Volume and Issue: 74(1), P. 125 - 139

Published: Jan. 27, 2023

Nearly half of Americans are projected to have obesity by 2030, underscoring the pressing need for effective treatments. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent first agents in a rapidly evolving, highly promising landscape nascent hormone-based therapeutics. With understanding neurobiology expanding, these emerging entero-endocrine and endo-pancreatic combined or coformulated with GLP-1 RAs herald new era targeted, mechanism-based treatment obesity. This article reviews previews imminent future nutrient-stimulated anti-obesity

Language: Английский

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Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(6), P. 1557 - 1565

Published: Aug. 9, 2023

The principle pathological drivers of metabolic dysfunction associated steatohepatitis (MASH) are obesity and insulin resistance, rendering them key therapeutic targets. As Glucagon-like Peptide 1 receptor agonists (GLP-1RA) have been licensed for the treatment diabetes they were one first such drugs to be evaluated in patients with MASH. Successful phase 2a 2b studies resulted progression Phase 3 clinical trials. Alongside GLP-1RA, newer combinations Glucagon agonism and/or Glucose-dependent Insulinotropic (GIP) explored related patient groups evidence improvements weight loss, resistance non-invasive liver parameters. There remains debate as whether GLP-1 direct, independent effects improve MASH or impact on pathophysiology through weight, glycaemic control. Combinations being although this needs weighed against cumulative side-effect burden, potential drug-drug interactions cost goods. is also uncertainty regarding optimal ratio glucagon GIP combination agents, antagonism indeed approach. Finally, there multiple hypothetical permutations combining gut hormone emerging assets field. Given that likely dominant mode action upstream initial might focus agents which shown a more direct effect fibrosis would include FGF21 pan-PPAR

Language: Английский

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An update on peptide-based therapies for type 2 diabetes and obesity

Peptides, Journal Year: 2023, Volume and Issue: 161, P. 170939 - 170939

Published: Jan. 3, 2023

Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering weight-lowering efficacy when administered by once-weekly subcutaneous injection. These herald an exciting new era in peptide-based therapy type 2 diabetes (T2D) obesity. Of note is GLP-1R agonist semaglutide, available oral injectable formulations clinical trials combined long-acting amylin analogue, cagrilintide. Particularly both glucose- weight lowering capacities has been observed GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number GLP-1R/GCGR peptides GLP-1R/GCGR/GIPR triagonist entered trials. Other pharmacological approaches chronic management include human monoclonal antibody, bimagrumab which blocks activin II associated growth skeletal muscle, antibody blocking activation GIPR are conjugated peptide agonists (AMG-133), melanocortin-4 receptor setmelanotide use certain inherited obesity conditions. The global demand liraglutide semaglutide as anti-obesity agents led shortage so that their T2D currently being prioritized.

Language: Английский

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