The glucagon-like peptide-1 (GLP-1) drugs poised to conquer obesity

Abstract

Obesity has become a global public health issue, with the number of overweight/obese individuals increasing annually. However, weight loss faces various difficulties and challenges. Incretin medications, represented by glucagon-like peptide-1 (GLP-1), have brought new hope in the battle against obesity. As a result, GLP-1 was recognized as the top scientific breakthrough of 2023. Since its isolation and identification in 1983, GLP-1 has been increasingly gaining attention for its clinical applications. Exendin-4 is the first GLP-1 receptor agonist (GLP-1RA) approved for market by the U.S. Food and Drug Administration (FDA). Subsequently, the development of GLP-1RAs has entered the fast track. Liraglutide, dulaglutide, semaglutide, and other GLP-1 receptor agonists (GLP-1RAs) have been successively developed and approved for market. Initially introduced as antidiabetic agents, further research revealed the positive impact of GLP-1RAs on conditions such as obesity, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). As scientific exploration into GLP-1 deepens, researchers have begun to investigate broader therapeutic pathways, with a particular focus on the development of multi-receptor agonists. The 2023 Banting Scientific Achievement Award was conferred upon Dr. Matthias H. Tschöp, dedicated to multi-receptor agonist research. Dr. Tschöp’s team proposed an efficient weight-loss strategy by simultaneously targeting multiple gut hormone receptors, such as GLP-1R, GIPR, and GCGR, to harness synergistic effects. GLP-1RA-based single-target and multi-target combination drugs are a new generation of treatment for obesity and diabetes, and their weight loss is close to that of bariatric surgery, and may be effective in preventing type 2 diabetes mellitus, and a variety of dual- and triple-receptor agonists are currently under development. However, the long-term practice and application of such drugs for obesity control still need to be further considered. In summary, the results of GLP-1 studies in the fields of type 2 diabetes mellitus, obesity, and cardiovascular diseases demonstrate excellent therapeutic potential. With the in-depth study of its mechanism and the continuous upgrading of technical methods, GLP-1 is expected to make new breakthroughs in many aspects. Firstly, future studies may explore the application of GLP-1 in neurodegenerative diseases, oncology, nonalcoholic fatty liver disease, and other fields. Secondly, GLP-1RA has greatly improved the convenience of patient treatment from daily to weekly preparations, from injection preparations to oral peptide preparations, and then to small molecule oral preparations, and GLP-1 preparations will become more diversified in the future to meet the individualized needs of patients. In addition, the in-depth exploration of multi-receptor agonists will lead to more efficient and comprehensive treatment options, providing more benefits to patients.