Transforming obesity: The advancement of multi-receptor drugs

Abstract

For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.

Figure 1.. The signaling pathways and metabolic processes that endogenous GLP-1, GIP and glucagon hormones act upon in target tissues.

The tissue-specific metabolic effects of the endogenous gut-secreted incretin’s glucagon-like peptide-1 (GLP-1) (blue dashed arrows), glucose-dependent insulinotropic peptide (GIP) (orange dashed arrows), in addition to the pancreatic hormone glucagon (GCG) (red dashed arrows). The primary actions of GLP-1, GIP, and GCG are shown for adipose tissue, brain, vasculature, heart, bone, liver, and pancreas. The dashed squares highlight the brain and adipose tissue; two of the primary sites of GLP-1R agonist, GLP-1R/GIPR co-agonist and GLP-1R/GCGR co-agonist action in the regulation of body weight. The solid arrows represent the direct action of each hormone, whereas a dashed arrows highlight their indirect action. A red (−) circle highlights an inhibitory role for GLP-1, GIP and GCG, whereas a green (+) circle represents a stimulatory role for each hormone. Each primary metabolic process, signaling pathway and/or metabolic outcome that is impacted by GLP-1, GIP or GCG, whether direct or indirect, is highlighted for each tissue.

Figure 2.. The main sites and tissue-specific action of GLP-1R mono-agonists, GLP-1R/GCGR co-agonists, GLP-1R/GIPR co-agonists and GLP-1R/GIPR/GCGR triagonists determined in preclinical studies.

The primary sites of receptor expression and action, and the pharmacological effects mediating body weight loss and improvements in glycemic control of GLP-1R agonists (blue text and circle), GLP-1R/GCGR co-agonists (blue/red text and circle), GLP-1R/GIPR co-agonists (blue/yellow text and circle), and GLP-1R/GIPR/GCGR triagonists (blue/yellow/red text and circle). Preclinical studies have reported the metabolic effects, signaling pathways and potential key regulators that each mono- or multi-receptor agonists target in the brain, pancreatic islets, adipose tissue, the liver and kidney. Graphics were created with BioRender.com.

Figure 3.. The mono- and unimolecular multi-receptor agonists that have completed or are currently in ongoing clinical trials.

Peptide-based therapeutics based on 1) GLP-1R single-agonists compared to unimolecular 2) GLP-1R/GCGR co-agonists, 3) GLP-1R/GIPR co-agonists and, 4) GLP-1R/GIPR/GCGR triagonists that have completed clinical studies, or are currently being examined in clinical trials. The blue boxes and arrows highlight GLP-1, the orange boxes and arrows represent GIP, and the red boxes and arrows show glucagon (GCG), and the corresponding ratio of in each hormone receptor in each multi-receptor agonist peptide. All co-agonists and triagonists have displayed beneficial metabolic effects in lowering HbA_1c levels and reducing body weight (BW) for the treatment of T2D and obesity. Examples of each category and their relative contributions of the respective ligands are displayed, adjacent to the percent BW loss (red text) reported in their corresponding clinical trials. *FDA-approved peptides. Graphics were created with BioRender.com.