Rapid increase in obesity rate is becoming a global public health crisis^[1]. GLP-1RAs (Glucagon-like peptide 1 receptor agonists) benefit not only blood sugar but obese and related metabolic disorders. GLP-1RAs, which achieved great success in 2023 and draws people’s attention back to obesity treatments and GLP-1 therapies worldwide, was chosen as the breakthrough of year 2023 by Science^[2].

Nutrients intake can stimulate the secretion of GLP-1, which functions through binging to GLP-1R. This binding activates adenylate cyclase, leading to elevation of cAMP and PKA, which finally enhances insulin biosynthesis and secretion, and suppressed glucagon secretion^[4]. Besides pancreas, GLP-1R also presents in kidney, heart, liver, etc. So GLP-1 exerts broad benefits like suppressing appetite, delaying gastric emptying, decreasing glucose production as well as lowering the risk of cardiovascular diseases^[3][5].

An agonist is a natural ligand or a substance mimics the action of natural ligands that initiates responses when it binds to a specific receptor. GLP-1R agonists (GLP-1RAs) function through activating GLP-1R and are primarily used in the treatment of type 2 diabetes (T2D) and obesity.

Exenatide

After the discovery of GLP-1 and its physiological functions in the 1980s, scientists tried to design drugs based on the active forms of GLP-1—— GLP-1(7-37) and GLP-1(7-36) amide. However, these two natural GLP-1R agonists are rapidly digested by the enzyme DPP-4 and cleared by the kidneys within 1-2 minutes, making them unsuitable for direct therapeutic use.

This issue troubled scientists for years. Until 1992, exenatide, which shares 53% homology with GLP-1(7-37), was discovered from venom of Gila monster. Similar to GLP-1(7-37), exenatide also acts as an agonist for GLP-1(7-37), but shows resistance to DPP-4 degradation and has a lower renal clearance rate in human, making exenatide the first successfully developed GLP-1 drug^[6].

Semaglutide

GLP-1 drugs facing the challenges in oral administration, injection administration can result in decreased patient compliance and therapeutic efficiency. Therefore, following the approval of Exenatide, development of GLP-1 drugs mainly focused on two directions: developing long-acting GLP-1RAs and oral GLP-1RAs (Figure 3).

Semaglutide’s sales reached $21.2 billion in 2023 with an 88% increase, becoming top 3 best-selling drugs worldwide. Great success achieved by Semaglutide has sparked immense interest among both the market and researchers in developing GLP-1 drugs.

Semaglutide was developed based on GLP-1(7-37) backbone, its Lys side chain was modified with a long chain fatty acid, enabling it to bind to plasma albumin for slower drug release. More, amino acids at positions 8 and 34 were substituted with Aib and Arg to prevent DPP-4 enzyme degradation and erroneous binding, resulting in a significantly extended half-life (7 days). Subsequently, Novo Nordisk developed an oral formulation Rybelsus, the first launched oral GLP-1RA, by combining semaglutide with intestinal permeation enhancer SNAC^[7][8].

In 2021, semaglutide was approved by FDA for weight loss and quickly achieved commercial success. Continual administration of semaglutide led to 15% reduction in body weight at 68 weeks, along with improvements in cardiovascular risk and overall physiological condition^[9]. Beyond T2D and obesity, semaglutide was also applied for other indications such as cardiovascular disease, fatty liver, chronic kidney disease, all of which have progressed to Phase 3, expanding the influence of GLP-1RAs into more medical fields.

Multi-functional peptides and Small-molecule oral GLP-RAs

In addition to expanding the indications for GLP-1RAs, cutting-edge research on GLP-1RAs is focused more on developing multi-target GLP-1RAs and small-molecule oral GLP-1RAs.

In 2009, Richard DiMarchi and Matthias H Tschöp's team reported that dual agonists targeting GLP-1R/GCGR did better in weight loss compared to GLP-1RA^[10]. In 2014, they reported a tri-agonist targeting GLP-1R/GIPR/GCGR, demonstrating superior efficacy in mouse experiments^[11]. Building on these research findings, Eli Lilly developed a dual agonist targeting GLP-1R/GIPR, called tirzepatide, which was approved by the FDA in 2022 and showed promising therapeutic effects for T2D and obesity. A tri-agonist developed by the same company targeting GIP-1R/GIPR/GCGR, retatrutide, demonstrated better weight loss effects in Phase 3 compared to tirzepatide.

Multi-functional GLP-1RA peptides demonstrate superior efficacy, but their administration is still limited now. Some researchers have moved their eyes to small-molecule GLP-1RA - with high oral bioavailability, and high patient compliance. This new avenue has yet to see a standout success, with Orforglipron emerging as a leading contender, showing promising results in blood sugar control and weight management according to clinical trials^[14][15]. The development of small molecule GLP-1RAs provides a new option for obese and T2D individuals who have been undergoing long-term injection therapy.

GLP-1RAs have achieved remarkable success in clinical practice for blood sugar control and body weight management. While the long-term safety and effectiveness of GLP-1RA for other indications like kidney disease and fatty liver still need verification, attention and research investment in GLP-1RAs for obesity and related conditions are keeping increasing, driving further scientific and medical advancements in metabolic diseases.