GLP-1: A Multifunctional Target

As an important class of hypoglycemic and weight loss drugs, GLP-1 drugs have attracted much attention and made significant development in recent years. Since GLP-1 drugs were found to have hypoglycemic effects, GLP-1 targets have been firmly in the hot track, especially after the approval of semaglutide for weight loss indications, the research and development of GLP-1 drugs has reached the peak. In 2023, the market value of Novo Nordisk and Eli Lilly skyrocketed, and the core factor driving the market value skyrocketed was the popular GLP-1 drugs. With the increasing number of diabetes and obesity patients worldwide, the demand for GLP-1 drugs has great potential, and the research and development momentum at home and abroad is strong. In the future, GLP-1 drugs are expected to play a therapeutic role in fields such as cardiovascular disease and fatty liver.

In 1985, a peptide chain composed of 31 amino acids, natural GLP-1 was first discovered, but its half-life is very short, about 2 minutes, and it is easy to be degraded by DPP-4 enzyme after secretion into the blood. The development of GLP-1 receptor agonists needs to solve the problem of short half-life.

The first short-acting GLP-1RA, exenatide (Astrazeneca), was approved by the FDA in 2005. It has a half-life of about 3 hours and requires twice daily subcutaneous injections. In 2009, the first long-acting GLP-1 RA, liraglutide (Novo Nordisk), was launched as a once-daily subcutaneous injection. Once-weekly injections of dulaglutide (Eli Lilly) and semaglutide (Novo Nordisk) were approved in 2014 and 2017, respectively. In 2022, the dual-target GLP-1/GIP telpotide (Eli Lilly) was approved for marketing, which kicked off the prologue of dual targets.

GIP-1 receptors are widely distributed, and multiple mechanisms of GLP-1RA act together. Glucagon like peptide-1 (GLP-1) : A hormone secreted by intestinal L-cells that promotes insulin secretion by pancreatic β cells in a glucose concentration-dependent manner, and its receptor (GLP-1R) is widely distributed in many organs and tissues such as the central nervous system, cardiovascular system, muscle, and gastrointestinal tract.

The receptor agonist of GLP-1 (GLP-1RA) stabilizes blood glucose and reduces body weight through various glucose-lowering mechanisms. If it acts on the stomach, it can delay gastric emptying by inhibiting gastrointestinal peristalsis; It acts on the central nervous system (especially the hypothalamus) to increase satiety and inhibit appetite; It acts on the liver and inhibits hepatic glucose output. Promoting insulin to stimulate glucose uptake in peripheral tissues (increasing insulin sensitivity).