Designer GLP1 poly-agonist peptides in the management of diabesity

ABSTRACT

Introduction

To date, the 21^st Century has witnessed key developments in the management of diabesity (a conflation of obesity and Type 2 Diabetes Mellitus [T2D]), including Glucagon Like Peptide 1 (GLP1) receptor agonist therapies, and recently the ‘designer’ GLP1 Poly-agonist Peptides (GLP1PPs).

Areas covered

A PubMed search of published data on the GLP1PP class of therapies was conducted. The gut-brain axis forms complex multi-directional interlinks that include autonomic nervous signaling, components of the gut microbiota (including metabolic by-products and gram-negative cell wall components [e.g. endotoxinaemia]), and incretin hormones that are secreted from the gut in response to the ingestion of nutrients. The development of dual-incretin agonist therapies includes combinations of the GLP1 peptide with Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon (Gcg), Cholecystokinin (CCK), Peptide YY (PYY), and Glucagon-Like Peptide 2 (GLP2). Triple incretin agonist therapies are also under development.

Expert opinion

At the dawn of a new era in the therapeutic management of diabesity, the designer GLP1PP class holds great promise, with each novel combination building on a preexisting palimpsest of clinical data and insights. Future innovations of the GLP1PP class will likely enable medically induced weight loss and glycemic control in diabesity to rival or even out-perform those resulting from bariatric surgery.

KEYWORDS:

• Incretin
• Diabesity
• Glucagon Like Peptide 1
• obesity
• diabetes

Article highlights

• The first two decades of the 21st Century have borne witness to the generation of a multitude of pharmaco-therapeutic choices for T2D.

• The recent rise of ‘designer’ GLP1 Poly-agonist Peptides (GLP1PPs) has emerged as a novel therapeutic strategy for the effective management of diabesity.

• Incretin hormones act via G-coupled protein receptors (GCPR) to increase intracellular cyclic adenosine monophosphate (cAMP), thereby stimulating glucose-dependent insulin secretion from islet β-cells.

• Beyond GIP and GLP1, there are numerous other gut-derived intestinal hormones that have a variety of physiological effects that include the mediation of hypothalamic control of appetite and metabolism. Amongst these are Glucagon (Gcg), Cholecystokinin (CCK), Peptide YY (PYY), and Glucagon-Like Peptide 2 (GLP2).

• Phase 3 trials demonstrate the superior glycemic and weight-loss efficacy of Tirzepatide compared with placebo, with >20% body weight loss in the majority (57%) of participants in a 72-week trial (on highest dose) with minimal adverse effects.

• Beyond body weight loss and improved glycemic control, the GLP1:Gcg dual agonists have also been assessed for their efficacy in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).

• The administration of a novel GLP1:CCK dual agonist in a mouse model resulted in reduced feeding behavior and body weight.

• In a preliminary human-based study, participants tolerated single doses of SAR441255 (a GLP1:GIP:Gcg triple agonist) with mild adverse effects. In diabetic cynomolgus monkeys, SAR441255 associated with a 12.6% reduction in body weight, although the glycemic benefit of SAR441255 was inferior to that of a GLP1:GIP dual agonist therapy (HbA1c reduction of 1.37% vs 1.85%, respectively).

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.