Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease.

Abstract

BACKGROUND:

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy.

SCOPE OF REVIEW:

In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity.

MAJOR CONCLUSIONS:

Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.

• Authors: Laurie L Baggio, Daniel J Drucker
• Journal: Molecular metabolism (Mol Metab) Vol. 46 Pg. 101090 (04 2021) ISSN: 2212-8778 [Electronic] Germany
• PMID: 32987188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Receptors, Gastrointestinal Hormone
• semaglutide
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptides
• gastric inhibitory polypeptide receptor
• tirzepatide

Topics

• Adipose Tissue
• Animals
• Cardiovascular Diseases
• Diabetes Mellitus, Type 2 (metabolism)
• Fatty Liver
• Gastric Inhibitory Polypeptide (pharmacology, therapeutic use)
• Glucagon-Like Peptide-1 Receptor (agonists, genetics, metabolism)
• Glucagon-Like Peptides (pharmacology, therapeutic use)
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Metabolic Diseases (drug therapy)
• Obesity (metabolism)
• Receptors, Gastrointestinal Hormone (drug effects)
• Weight Loss