Glucagon-like peptide-1 (GLP-1) is a type of incretin hormone that is secreted by intestinal L-cells in response to a meal. Within minutes after a meal, GLP-1 is released from L cells in the ileum and colon, and it regulates insulin secretion in a glucose-dependent manner. When GLP-1 reaches the pancreas, it binds to GLP-1 receptors (GLP-1R) expressed on the pancreatic β cells, stimulating insulin release. Because this effect is directly related to blood glucose levels, it lowers the risk of hypoglycemia. Additionally, GLP-1 promotes the growth and proliferation of pancreatic β cells, inhibits glucagon secretion, and enhances glucose uptake in peripheral tissues, making it a crucial factor in maintaining blood glucose stability.

However, the natural GLP-1 has a very short half-life, lasting only 1-2 minutes in the bloodstream. Extending its duration of action has become a key focus in drug development. As a result, GLP-1 receptor agonists (GLP-1RA) were developed. These are analogs of GLP-1 that have a longer half-life and sustained effects, effectively enhancing insulin secretion and inhibiting glucagon release. GLP-1RAs are widely used in the treatment of type 2 diabetes (T2DM).

Research shows that GLP-1 receptors are found in several organs, including the pancreas, heart, and kidneys, which means GLP-1RAs have broad pharmacological effects. In addition to lowering blood glucose, GLP-1RAs can increase feelings of fullness, promote weight loss, and have potential benefits in cardiovascular protection. Moreover, GLP-1 and its analogs have shown positive effects in kidney protection, neuroprotection, and lipid metabolism regulation, and they hold promise in treating conditions like non-alcoholic steatohepatitis (NASH) and Alzheimer's disease. Currently, there are 9 GLP-1RAs approved by the FDA, widely used for the treatment of type 2 diabetes.

Table 1. Approved GLP-1RAs Worldwide

Future Trends in GLP-1RAs Development

Looking back at the development of GLP-1 RAs, two main goals have consistently guided their development: improving patient adherence and enhancing product efficacy. However, as competition in the GLP-1 RAs market becomes more intense, relying solely on effectiveness is no longer enough for products to stand out. In the future, innovation will likely focus on five key areas: long-acting formulations, oral delivery methods, multi-target approaches, combination therapies, and expanding the range of indications.

Long-Acting Formulations

GLP-1 RAs can be classified into two main categories: short-acting and long-acting. Short-acting agents primarily work by slowing gastric emptying to reduce postprandial blood glucose levels, while long-acting GLP-1 RAs are more effective at lowering fasting blood glucose levels, mainly by promoting insulin secretion and inhibiting glucagon release. Both types of drugs are effective in lowering blood glucose, but long-acting agents are likely to dominate the market due to their higher patient adherence.

Common strategies for extending the duration of GLP-1 RAs include:

• • Amino Acid Sequence Optimization: Reducing rapid degradation by DPP-4 enzymes to extend the drug's half-life.
• • Fusion Proteins: Utilizing fusion partners like albumin or Fc fragments to increase the drug's molecular weight, reduce rapid renal filtration, and coordinate with other mechanisms to prolong circulation time in the body.
• • Fatty Acid Modification: Leveraging interactions between fatty acids and albumin for metabolic stability and circulation, and using the self-association and ionic properties of fatty acids to extend the drug's half-life.
• • PEGylation: Increasing the drug's molecular size to slow down enzymatic degradation. (Biopharma PEG, a leading worldwide PEG derivatives supplier,  provides PEG derivatives for PEGylated peptide and protein drugs and a variety of supporting technical services. We will support you in all aspects of PEGylation from the laboratory R&D level to the scale-up level.)
• •​ Polymer-Based Sustained-Release Formulations: Developing sustained-release formulations to extend the drug's release time in the body.

Figure 1. Long-Acting strategies for GLP-1 RAs, source: Designing a Dual GLP-1R/GIPR Agonist from Tirzepatide: Comparing Residues Between Tirzepatide, GLP-1, and GIP, Drug Design, Development and Therapy,

Oral Formulation

The only available oral GLP-1RA is semaglutide (Rybelsus, Novo Nordisk). Its oral bioavailability is achieved by incorporating the absorption enhancer SNAC (Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate), which works through two mechanisms: (1) temporarily raising the local pH in the stomach to reduce pepsin-induced degradation of the peptide drug, and (2) forming hydrophobic ion pairs (HIP) with the peptide drug, improving its membrane permeability. This approach significantly increases the bioavailability of the drug when taken orally. 

Figure 2. SNAC in semaglutide, source: Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10), Pharmaceutics，

The advantages of oral peptide-based GLP-1 RAs include high potency, low dosage requirements, and low toxicity. The molecular size of peptides is between that of small-molecule drugs and large protein drugs, offering higher activity and better selectivity than small molecules.

However, these drugs have drawbacks, including low stability in the body, short half-lives, poor membrane permeability, complex manufacturing processes, and high costs. Additionally, the administration of oral GLP-1 drugs requires strict guidelines: for example, semaglutide must be taken on an empty stomach in the morning, with no more than 120 mL of water, and followed by at least 30 minutes of waiting before breakfast.

Multi-Target Synergy

The GLP-1R plays a critical role in regulating blood glucose balance, fat metabolism, and food intake. Additionally, the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and fibroblast growth factor 21 receptor (FG21R) also significantly influence these metabolic processes.

GLP-1R, GIPR, and GCGR are all found in pancreatic β-cells. During glucose regulation, activation of these receptors helps improve the function of β-cells and protect the pancreas, enhancing insulin secretion and better controlling blood sugar levels. Tirzepatide, the world's first dual GLP-1R/GIPR agonist, developed by Eli Lilly, has demonstrated superior weight loss effects compared to semaglutide.

In addition to GLP-1R/GIPR dual-target drugs, GLP-1R/GCGR dual-target and GLP-1R/GIPR/GCGR triple-target drugs are the focus of ongoing multi-target GLP-1 drug development. Several drugs are in advanced clinical trials:

• • In Phase III trials: IBI362 (Innovent/Eli Lilly), CagriSema (Novo Nordisk), Retatrutide (Eli Lilly), and Survodutide (Boehringer Ingelheim).
• •​ In Phase II trials: Efinopegdutide (Merck/Johnson & Johnson/Hanmi Harma), VK2735 (Viking Therapeutics), BGM0504 (BrightGene), Pemvidutide (Altimmune/Spitfire Pharma), AMG133 (Amgen), Dapiglutide (Zealand Pharma), etc.

Combination Therapies and Expanded Indications

Combining medications often produces a synergistic effect, where the benefits are greater than the sum of the individual treatments. Using GLP-1 RAs alongside other glucose-lowering or cardiovascular medications can significantly enhance therapeutic outcomes, reduce side effects, and better address the diverse needs of different patients. For example, Novo Nordisk's CagriSema, a combination of semaglutide and cagrilintide, has shown superior results in lowering blood sugar and promoting weight loss compared to semaglutide alone.

Additionally, expanding indications aims to tap into new markets. GLP-1 RAs are currently being explored for use in various new areas, such as cardiovascular disease, non-alcoholic steatohepatitis (NASH), Alzheimer's disease, and chronic kidney disease. These new indications could open up growth opportunities for GLP-1 medications and provide more treatment options for a broader range of patients.

Summary

The GLP-1 drug market is rapidly expanding, driving strong enthusiasm among companies for GLP-1 drug development. In recent years, the number of drug pipelines has steadily increased. Looking ahead, the market is expected to continue growing as breakthroughs in novel molecular designs, oral formulations, and dual-target drugs push the boundaries of GLP-1 drug innovation.

Related Articles:
What is SNAC in oral semaglutide?
​Long Acting GLP-1 Receptor Agonist Drugs Lists and Overview