Antiobesity therapeutics with complementary dual‐agonist activities at glucagon and glucagon‐like peptide 1 receptors

Objective: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in T2DM patients. Research Design and Methods: T2DM patients received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), Keratin-18 (K-18), Procollagen III (Pro-C3), and adiponectin, were analyzed in a modified intent-to-treat population. Results: Significant (p<0.05) reductions from baseline in ALT (all groups), AST (all groups, except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg) and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg), and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10 and 15 mg). Conclusions: In post-hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in T2DM patients.

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Unraveling oxyntomodulin, GLP1's enigmatic brother

Journal of Endocrinology ◽

10.1530/joe-12-0368 ◽

2012 ◽

Vol 215 (3) ◽

pp. 335-346 ◽

Cited By ~ 77

Author(s):

Alessandro Pocai

Keyword(s):

Weight Loss ◽

Glycemic Control ◽

Glucose Tolerance ◽

Obese Mice ◽

Glucagon Receptor ◽

Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Diabetes And Obesity ◽

Dual Agonist

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

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667-P: IBI362 (LY3305677), a Weekly-Dose Glucagon-Like Peptide-1/Glucagon Receptor Dual Agonist, in Subjects with Overweight or Obesity

Diabetes ◽

10.2337/db21-667-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 667-P

Author(s):

HONGWEI JIANG ◽

PEI AN ◽

HELENA DENG ◽

LI LI ◽

LIQI FENG ◽

...

Keyword(s):

Weekly Dose ◽

Glucagon Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist ◽

Overweight Or Obesity

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A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.07.046 ◽

2017 ◽

Vol 138 ◽

pp. 1158-1169 ◽

Cited By ~ 23

Author(s):

Jie Zhou ◽

Xingguang Cai ◽

Xun Huang ◽

Yuxuan Dai ◽

Lidan Sun ◽

...

Keyword(s):

Protective Effects ◽

Glucagon Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist

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Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia

Science Advances ◽

10.1126/sciadv.aaz9890 ◽

2020 ◽

Vol 6 (35) ◽

pp. eaaz9890 ◽

Cited By ~ 2

Author(s):

C. A. Gilroy ◽

M. E. Capozzi ◽

A. K. Varanko ◽

J. Tong ◽

D. A. D'Alessio ◽

...

Keyword(s):

Sustained Release ◽

Zero Order ◽

Drug Candidate ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Superior Efficacy ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)–based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.

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A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats

Neuropharmacology ◽

10.1016/j.neuropharm.2021.108599 ◽

2021 ◽

Vol 192 ◽

pp. 108599

Author(s):

Yafang Zhang ◽

Suditi Rahematpura ◽

Kael H. Ragnini ◽

Amanda Moreno ◽

Kamryn S. Stecyk ◽

...

Keyword(s):

Male Rats ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dual Agonist

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Effects of Novel Dual GIP and GLP-1 Receptor Agonist, Tirzepatide, on Biomarkers of Non-Alcoholic Steatohepatitis in Patients with T2DM

10.2337/dc20-1234/suppl.12014322.v1 ◽

2020 ◽

Author(s):

Mark L. Hartman ◽

Arun J. Sanyal ◽

Rohit Loomba ◽

Jonathan M. Wilson ◽

Amir Nikooienejad ◽

...

Keyword(s):

Receptor Agonist ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Keratin 18 ◽

Intent To Treat ◽

Post Hoc ◽

Design And Methods ◽

Dual Agonist ◽

Treat Population ◽

Procollagen Iii

Objective: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in T2DM patients. Research Design and Methods: T2DM patients received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), Keratin-18 (K-18), Procollagen III (Pro-C3), and adiponectin, were analyzed in a modified intent-to-treat population. Results: Significant (p<0.05) reductions from baseline in ALT (all groups), AST (all groups, except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg) and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg), and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10 and 15 mg). Conclusions: In post-hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in T2DM patients.

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