GIPR/GLP-1R dual agonist therapies for diabetes and weight loss—chemistry, physiology, and clinical applications

Jonathan E. Campbell, Timo D. Müller, Brian Finan, Richard D. DiMarchi, Matthias H. Tschöp, David A. D'Alessio

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations

Abstract

The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.

Original languageEnglish
Pages (from-to)1519-1529
Number of pages11
JournalCell Metabolism
Volume35
Issue number9
DOIs
StatePublished - 5 Sep 2023

Keywords

  • GIP
  • GLP-1
  • diabetes
  • incretin
  • obesity
  • tirzepatide

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