Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice

Knerr, Patrick J.; Mowery, Stephanie A.; Douros, Jonathan D.; Premdjee, Bhavesh; Hjøllund, Karina Rahr; He, Yantao; Hansen, Ann Maria Kruse; Olsen, Anette Kristensen; Pérez-Tilve, Diego; DiMarchi, Richard D.; Finan, Brian

doi:10.1016/j.molmet.2022.101533

Cited by 74 publications

(39 citation statements)

References 71 publications

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“…The encouraging results of the SURMOUNT-1 trial and the ongoing trials on Tirzepatide are promising for its future application as a medication for obesity, heart failure, and NAFLD. In addition to drugs that act as dual agonists, such as Tirzepatide, preclinical studies have demonstrated that triagonists, achieving a concurrent activation of GLP-1, GIP, and glucagon receptors, normalize body weight in obese mice and enhance energy expenditure in a manner superior to that of monoagonists of the GLP-1 receptor and dual agonists acting on GLP-1 and GIP receptors [ 97 ]. Therefore, the unimolecular triple agonism [ 98 , 99 , 100 ] could soon represent a new standard for pharmaceutical interventions.…”

Section: Discussionmentioning

confidence: 99%

Tirzepatide: A Systematic Update

Forzano

Varzideh

Avvisato

et al. 2022

IJMS

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Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1–5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.

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Section: Discussionmentioning

confidence: 99%

Tirzepatide: A Systematic Update

Forzano

Varzideh

Avvisato

et al. 2022

IJMS

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“…Cyclic AMP (cAMP) production was assessed as a proxy for receptor activation or antagonism using a standardized Cre-luciferase assay that has been reported previously [ 24 , 25 ]. In brief, stably transfected baby hamster kidney (BHK) cell lines expressing either GLP-1R, GIPR, or glucagon receptor (GcgR) and firefly luciferase reporter gene linked to the cAMP response element (CRE) were seeded in poly- d -lysine-coated 96 well opaque well tissue culture plates at 5,000 cells per well in growth media.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

Yang¹,

Gelfanov²,

El³

et al. 2022

Molecular Metabolism

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“…Research on obese mice suggests that unimolecular poly-pharmacology is an effective means to deal with various mechanisms leading to obesity and further indicates that GCGR activation is the distinguishing factor between single or double agonists and triple agonists of incretin receptors ( 127 ). Studies in knock-out mice confirms the significant potential for novel triple-acting hybrid peptides as therapeutic options for obesity ( 128 ).…”

Section: Others: Gipr/glp-1r Dual Agonists and Gipr/glp-1r/gcgr Triag...mentioning

confidence: 99%

GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach

Wang

Wang²,

Yang³

et al. 2023

Front. Endocrinol.

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Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people’s health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

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Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice

Cited by 74 publications

References 71 publications

Tirzepatide: A Systematic Update

Tirzepatide: A Systematic Update

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach

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