Dual gut hormone receptor agonists for diabetes and obesity

Bass, Joseph; Tschöp, Matthias H.; Beutler, Lisa R.

doi:10.1172/jci167952

Cited by 18 publications

(7 citation statements)

References 29 publications

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“…Agonism of each incretin receptor has different, often complementary effects on body weight and energy metabolism (Fig. 2 ) [ 5 , 23 , 104 – 107 ].…”

Section: Open Questions On Mechanism For Weight Loss: Insights From P...mentioning

confidence: 99%

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

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The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects.

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“…Agonism of each incretin receptor has different, often complementary effects on body weight and energy metabolism (Fig. 2 ) [ 5 , 23 , 104 – 107 ].…”

Section: Open Questions On Mechanism For Weight Loss: Insights From P...mentioning

confidence: 99%

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Gutgesell,

Nogueiras,

Tschöp

et al. 2024

Diabetes Ther

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“…Although the role of GIP in satiety suppression and weight reduction is under debate, the coadministration of GLP-1RA and GIPRA has produced promising results. Combining GIPRA with GLP-1RA significantly increases weight loss, glycemic control, and lipid profile management compared with mono GLP-1RA alone[ 21 , 78 ].…”

Section: Pathophysiological Mechanisms and Sites Of Action Of Increti...mentioning

confidence: 99%

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

Xie,

Alkhouri,

Elfeki

2024

World J Hepatol

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Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

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“…GLP-1 was first identified as a cleavage product of preproglucagon generated by L cells in the small intestine and functions to increase postprandial insulin production and lower blood glucose. 10 11 12 13 Since its discovery, efforts have focused on extending GLP-1 agonist activity through structural changes. 14 Liraglutide and semaglutide, two long-acting GLP-1 RAs, have been authorized for the treatment of T2DM and obesity.…”

Section: Glp-1 and Gipmentioning

confidence: 99%

“…GIP was initially isolated from intestinal extracts and shown to have a potent insulinotropic effect. 10 15 16 However, clinical studies demonstrated that, in hyperglycemic states, the insulinotropic action of GIP is inhibited, while GLP-1’s function remains intact. 17 18 Recent research indicates that GIP is largely responsible for postprandial insulin secretion in T2DM, rather than the opposite.…”

Section: Glp-1 and Gipmentioning

confidence: 99%

The Cardiovascular Effect of Tirzepatide: A Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Dual Agonist

Cho,

La Lee,

Jung

2023

J Lipid Atheroscler

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Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname “twincretin.” Tirzepatide’s dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data.

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Dual gut hormone receptor agonists for diabetes and obesity

Cited by 18 publications

References 29 publications

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

The Cardiovascular Effect of Tirzepatide: A Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Dual Agonist

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