Gut hormone co-agonists for the treatment of obesity: from bench to bedside

The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The first such compound, reported in 2009, was based on balanced co-agonism at glucagon and glucagon-like peptide-1 (GLP-1) receptors. Today, several classes of gut hormone co-agonists are in development and advancing through clinical trials, including dual GLP-1–glucose-dependent insulinotropic polypeptide (GIP) co-agonists (first described in 2013), and triple GIP–GLP-1–glucagon co-agonists (initially designed in 2015). The GLP-1–GIP co-agonist tirzepatide was approved in 2022 by the US Food and Drug Administration for the treatment of type 2 diabetes, providing superior HbA1c reductions compared to basal insulin or selective GLP-1 receptor agonists. Tirzepatide also achieved unprecedented weight loss of up to 22.5%—similar to results achieved with some types of bariatric surgery—in non-diabetic individuals with obesity. In this Perspective, we summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.