PL8 - GLP-1 and beyond: next-gen therapies for obesity and metabolic disease
TL;DR
The application of omics in clinical trials has elucidated diverse mechanisms underlying GLP-1RA efficacy across diseases, highlighting their broad therapeutic potential and informing drug repurposing approaches.
Abstract
Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), such as liraglutide and semaglutide, are long-acting pharmacological agents approved for diabetes and obesity management, with additional benefits on cardiovascular, renal, and hepatic systems, and emerging potential in brain-related disorders with significant unmet needs. These fatty acid-acylated molecules bind non-covalently to serum albumin, enhancing pharmacokinetic stability, and signal through a specific GLP-1 receptor expressed on select cell types across various organs. GLP-1RAs mimic the multifaceted physiological roles of GLP-1, a key regulator of post-prandial responses, including glucose homeostasis, appetite regulation, and other biological processes. Peripherally administered GLP-1RAs access specific brain regions via circumventricular organs expressing GLP-1 receptors, as shown in rodent whole-brain imaging. The weight loss mechanism is primarily driven by brain GLP-1R activation, reducing energy intake through neuromodulation and potentially altering reward signaling to influence food choice. GLP-1RAs also reduce systemic inflammation by approximately 50%, as measured by C-reactive protein, which, alongside reductions in blood pressure, triglycerides, blood glucose, and body weight, is hypothesized to decrease atherosclerotic burden. Furthermore, the application of omics in clinical trials has elucidated diverse mechanisms underlying GLP-1RA efficacy across diseases, highlighting their broad therapeutic potential and informing drug repurposing approaches. Beyond GLP-1, additional mechanisms come from amylin, GIP and glucagon agonism.