Investigational and emerging gastric inhibitory polypeptide (GIP) receptor-based therapies for the treatment of obesity

ABSTRACT

Introduction

One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified.

Areas covered

This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of ‘biased agonism’ wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction.

Expert opinion

Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.

KEYWORDS:

• Incretin
• GIP
• obesity
• dual-agonist
• triple agonist
• tirzepatide
• retatrutide

Article highlights

• Glucose-dependent insulinotropic peptide (GIP) is an insulinotropic hormone secreted in response to food with evidence for weight loss.

• GIP receptors knock out mice also are resistant to weight gain.

• GIP receptors are expressed throughout the body but notably pancreatic islet cells, adipose tissue, the hypothalamus, and the brainstem, playing a key role in mediating metabolism and satiety.

• A GIP/glucagon-like peptide-1 (GLP-1) receptor co-agonist is approved as a treatment for obesity.

• Numerous compounds both agonizing and antagonizing the GIP receptors are being studied for weight loss potential.

Declaration of interest

AP Shukla reports receiving research grants from Eli Lilly and Company, and Novo Nordisk, and personal fees for serving on the Scientific Advisory Board for Sun Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed they were a previous employee of Novo Nordisk and employee stockholder. A second reviewer has disclosed they are a shareholder and consultant for Zihipp Ltd., a company that is developing gut hormone analogues for treatment of diabetes. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.