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Review
. 2021 Apr:46:101090.
doi: 10.1016/j.molmet.2020.101090. Epub 2020 Sep 25.

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

Laurie L Baggio  1 , Daniel J Drucker  2
Affiliations
Review

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

Laurie L Baggio et al. Mol Metab. 2021 Apr.

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.

Keywords: Adipose tissue; Cardiovascular disease; Diabetes; Obesity; Peptide; Receptor.

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Figures

Image 1
Graphical abstract
Figure 1
Figure 1
Actions of GLP-1, amylin, fibroblast growth factors (FGFs), leptin, and glucagon on key target organs relevant to metabolism.
Figure 2
Figure 2
Metabolic actions of GLP-1 and GIP on key target tissues.
Figure 3
Figure 3
Possible mechanisms of the interaction of GIP and GLP-1 for treatment of metabolic disorders.
See this image and copyright information in PMC

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References

    1. Drucker D.J., Habener J.F., Holst J.J. Discovery, characterization, and clinical development of the glucagon-like peptides. Journal of Clinical Investigation. 2017;127(12):4217–4227. - PMC - PubMed
    1. Schauer P.R., Bhatt D.L., Kirwan J.P., Wolski K., Aminian A., Brethauer S.A. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. New England Journal of Medicine. 2017;376(7):641–651. - PMC - PubMed
    1. Friedman S.L., Neuschwander-Tetri B.A., Rinella M., Sanyal A.J. Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine. 2018;24(7):908–922. - PMC - PubMed
    1. Roberts G.P., Larraufie P., Richards P., Kay R.G., Galvin S.G., Miedzybrodzka E.L. Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. Diabetes. 2019;68(5):1062–1072. - PMC - PubMed
    1. Beumer J., Puschhof J., Bauza-Martinez J., Martinez-Silgado A., Elmentaite R., James K.R. High-resolution mRNA and secretome atlas of human enteroendocrine cells. Cell. 2020;181(6):1291–1306. e1219. - PubMed

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