The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
In recent years, GLP-1R and its agonists have garnered widespread attention in the medical community. GLP-1R, a core member of the GPCR family, is widely present on the surfaces of various cells in the human body. By specifically binding to the key hormone GLP-1, it regulates blood glucose levels and lipid metabolism. This receptor and its agonists hold significant therapeutic potential, reshaping the treatment approaches for multiple diseases, including diabetes, cardiovascular disorders, and neurodegenerative diseases. GLP-1 is a peptide produced by the cleavage of proglucagon, mainly synthesized in the intestinal mucosal L-cells, pancreatic islet α-cells, and neurons in the nucleus of the solitary tract. GLP-1RAs mimic the action of endogenous GLP-1, activating GLP-1R, thereby enhancing insulin secretion, inhibiting glucagon release, delaying gastric emptying, and reducing food intake through central appetite suppression. These mechanisms make GLP-1RAs powerful tools for controlling blood glucose and improving metabolic syndrome. Furthermore, their multifaceted mechanisms of action suggest potential applications beyond traditional metabolic disorders. From the discovery of the GLP-1 fragment GLP-1(7-37) to the development of more stable and long-acting GLP-1 analogs, these milestones represent significant breakthroughs in the medical field. For instance, the success of exenatide has not only spurred the development of potent GLP-1 analogs such as liraglutide and semaglutide but also unveiled the vast potential of GLP-1RAs in treating various systemic diseases. These developments underscore the importance of GLP-1RAs in modern therapeutics. The applications of GLP-1RAs extend far beyond diabetes management.
Here we summarized the complex mechanisms of GLP-1RAs and their latest advancements in treating various diseases, such as musculoskeletal inflammation, obesity, cardiovascular diseases, NAFLD, neurodegenerative diseases, and various cancers. We introduce recent studies that demonstrate the remarkable performance of GLP-1RAs in slowing the progression of neurodegenerative diseases, reducing inflammation, and enhancing cardiovascular health. For example, in the treatment of Alzheimer’s diseases (AD) and Parkinson’s diseases (PD), GLP-1RAs have shown potential in slowing disease progression, while their anti-inflammatory properties offer new hope for conditions such as osteoarthritis (OA), rheumatoid arthritis (RA) and cardiovascular diseases. By integrating the latest clinical trial data, we explore the efficacy of GLP-1RAs in treating diseases of the nervous, cardiovascular, endocrine, and digestive systems. We show readers that GLP-1RAs have also been found to significantly reduce the risks of heart failure, atherosclerosis (AS), and hypertension, highlighting their broad therapeutic potential. As new indications continue to be developed, GLP-1 drugs demonstrate immense potential in the medical field, with future research expected to expand their therapeutic applications. The comprehensive exploration of their benefits underscores their transformative potential in medicine, positioning them as a promising approach for addressing a wide array of health issues and paving the way for new research and clinical applications.
The future of GLP-1RA therapy is promising. Researchers are developing more efficient formulations, such as long-acting and oral versions, to improve patient compliance and outcomes. With increasing clinical evidence, GLP-1RAs are set to become essential in treating complex and chronic diseases, offering significant health benefits and addressing unmet medical needs, thus enhancing patient quality of life and solidifying their role in future medical advancements.
In 1979, Richard Goodman found that anglerfish are an ideal source for pancreatic mRNA due to their concentrated cells. He extracted mRNA, spliced anglerfish DNA into bacteria, and used radioactive probes to find the somatostatin gene. In 1982, they published a paper in the Proceedings of the National Academy of Sciences (PNAS), revealing that the glucagon precursor gene actually encodes three peptides-glucagon and two new hormones expressed in the intestine. A year later, a research team led by Graeme Bell from Chiron Corporation published two papers in the journal Nature. They cloned and sequenced the preproglucagon gene, discovering GLP-1 and GLP-2 hormones. The focus shifted to GLP-1, with Svetlana Mojsov identifying its insulin-stimulating fragment, GLP-1(7-37), in 1983. This was inspired by prior GIP (glucose-dependent insulinotropic polypeptide) research, highlighting that besides GIP, other substances in the intestine also stimulate insulin secretion. This finding was later combined with research by Joel Habener and jointly published in JCI. The team of Jens Juul Holst at the University of Copenhagen in Denmark published a report in FEBS Letters, reaching the same conclusion in January 1987. In December 1987, Stephen Bloom’s team confirmed in a Lancet paper that GLP-1(7-36) is a human intestinal hormone that stimulates insulin production in the pancreas and lowers blood sugar. GLP-1, used for treating diabetes, is quickly broken down in the body, requiring high doses that can cause side effects like nausea. This led to the development of new drugs similar to GLP-1 but with a longer-lasting effect. John Eng marked a significant breakthrough; he isolated exendin-4, a peptide from the Gila monster’s venom, which is structurally similar to human GLP-1 but more stable. GLP-1 is degraded in the bloodstream in less than a minute, whereas this peptide, consisting of 39 amino acids, exendin-4, could last for more than two hours. This work was eventually published in the JBC journal in August 1991. In the early 1990s, despite John Eng’s team identifying a potential diabetes treatment in exendin-4, it initially lacked attention and funding for development. Eng personally secured a patent and partnered with Amylin, leading to the FDA-approved diabetes drug exenatide in 2005, the first GLP-1 analog. This sparked further advancements, including Novo Nordisk’s development of more potent analogs like liraglutide and semaglutide, with the latter achieving over $12 billion in sales by 2022. The journey began in the 1980s with research on Gila monster venom, culminating in the discovery of exendin-4, a stable, effective peptide for treating diabetes, demonstrating the progression from initial discovery to blockbuster diabetes medications. In July 2009, they published a paper in Nature Chemical Biology, reporting for the first time that dual agonists targeting GLP-1R and glucagon receptor (GCGR) had a better weight loss effect. This marked a significant advancement in obesity treatment research, especially in combining multiple drug targets. Matthias Tschöp and Richard DiMarchi developed the first dual and triple agonist weight loss drugs. Eli Lilly and Company is currently researching a dual agonist called tirzepatide, which has outperformed semaglutide in phase 3 clinical trials. Additionally, their under-development triple agonist, Retatrutide, has shown unprecedented weight loss effects in phase 2 clinical trials. Matthias Tschöp and his team discovered that dual agonists targeting both GLP-1 and GIP receptors (GIPR) are more effective in treating diabetes than those targeting only GLP-1R. These dual agonists were found to reduce blood sugar and increase insulin secretion in mice, monkeys, and humans. Subsequently, they investigated a triple agonist capable of simultaneously targeting the GLP-1R, the GCGR, and the GIPR. In December 2014, they published a paper in Nature Medicine, showing that the triple agonist’s weight loss effects in mice exceeded those of the dual agonists.
GLP-1 is a peptide hormone generated through the enzymatic breakdown of proglucagon. It is synthesized in L-cells located in the intestinal mucosa, α-cells found in the pancreatic islet, and neurons residing in the nucleus of the solitary tract. GLP-1, an endocrine hormone, is secreted by enteroendocrine L-cells located in the distal jejunum, ileum, and colon in response to nutrient ingestion and neuroendocrine stimulation. It originates from the preproglucagon precursor, which undergoes enzymatic processing within intestinal L-cells, ultimately giving rise to GLP-1(1-37) and GLP-1(7-36) amide or GLP-1(7-37) peptide variants. GLP-1 is an incretin hormone that plays a pivotal role in the meticulous control of human blood glucose levels. Nevertheless, its duration of action is rather ephemeral, lasting a mere 1–2 min within the circulatory system under typical physiological conditions. Subsequently, GLP-1 undergoes enzymatic degradation facilitated by dipeptidyl peptidase IV (DPP-4), leading to the loss of its biological efficacy.
GLP-1R, a member of the GPCR family, exhibits specific affinity for GLP-1. It predominantly localizes to the cellular membrane of diverse cell types throughout the human body. Indeed, GLP-1R is present beyond the confines of the pancreas and extends to
