Jul 07, 2025

Glucagon-like peptide-1 (GLP-1) receptor agonists have reshaped the medical landscape, growing from a breakthrough diabetes treatment to a multi-indication therapeutic powerhouse. These therapies have demonstrated remarkable success due to their strong clinical efficacy, broad treatment indications, and vast potential patient base. In this article, we’ll explore the reasons behind the success of GLP-1 receptor agonists, new multi-target therapies, and possible future trends in this exciting field.

Why Are GLP-1 Receptor Agonists So Successful?

As part of the G protein-coupled receptor (GPCR) family, GLP-1 receptors are broadly expressed across various human cell types. When bound to their endogenous ligand, GLP-1, these receptors regulate blood sugar levels, suppress appetite, slow gastric emptying, and promote satiety. These mechanisms make GLP-1 receptor agonists a strong contender for treating diabetes, obesity, cardiovascular diseases, and even neurodegenerative conditions.

New Directions: Multi-Target GLP-1 Therapies

While the efficacy of GLP-1 receptor agonists alone may plateau with higher doses in diabetic patients, multi-target approaches are opening new opportunities. These strategies combine GLP-1 receptor agonists with other active peptides, such as glucagon (GCG) or glucose-dependent insulinotropic polypeptide (GIP), to achieve greater weight reduction and metabolic benefits. Candidates or drugs targeting the GLP-1R/GIPR, GLP-1R/GCGR, and GLP-1R/GIPR/GCGR pathways that are in Phase II/III trials or have been approved are listed below.

Table 2. GLP-1 related multi targets therapeutics in phase II/III ¹

General GLP-1 Modification Strategies

However, Native GLP-1 is a complex polypeptide with an extremely short plasma half-life (~ 1.5 min), rendering it unsuitable for clinical use. Consequently, extensive research has been conducted to prolong its half-life through various modifications. The following strategies have been employed to overcome this limitation²:

1). Prevention from DPP-4 degradation. Replacement of the second N-terminal amino acid (Ala8) is the most widely used approach, as applied in exenatide, lixisenatide, semaglutide, dulaglutide, and albiglutide.

2). Albumin binding. Albumin's long plasma half-life, mediated by engagement of the neonatal Fc receptor (FcRn) that prevents its intracellular degradation is leveraged in albiglutide.3 Albiglutide is a dipeptidyl peptidase-4-resistant GLP-1 dimer fused to human albumin, and this fusion extends its half-life, permitting once-weekly dosing.⁴

3). Acylation with fatty acids. Commercially available therapeutic lapidated GLP-1 analogues, semaglutide and liraglutide, have the significant advantage of prolonged in vivo half-lives (hours to days) compared to native GLP-1, which degrades within minutes.⁵

4). PEGylation. Covalently linking PEG to protein/peptide drugs increases their size and shields proteolytic sites and immunogenic sites. This effectively prolongs the half-life and enhances bioavailability. Studies show that the blood half-life of ExC39PEG20 kDa was approximately 10 times longer than that of ExC39. ExC39 is an exendin-4 analog.⁶

5). Fc fusion. GLP-1 fused to albumin can escape lysosomal degradation. Similarly, fusing of GLP-1 with other proteins or engineered proteins can also achieve comparable or superior effects.⁷

6). Oral formulation. SNAC (Sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) has been used in a series of clinical trials for oral formulations containing poorly permeable active compounds since the late 1990s⁸. Semaglutide, an oral drug for type 2 diabetes, is successfully co-formulated with SNAC.

Manufacture of GLP-1 Related Candidates.

The selection of appropriate synthetic methods is often based on molecular features such as the presence of noncoded amino acids, a nonpeptidic side chain, and peptide length. Although recombinant technologies typically require longer development timelines than synthetic methods, they have been used successfully for semisynthetic peptides. Michael O. Frederick (Eli Lilly) reported kilogram-scale manufacturing of Tirzepatide using a hybrid of solid and liquid phase peptide synthesis (SPPS/LPPS) approach. Four fragments were synthesized separately and conjugated stepwise. Nanofiltration and continuous manufacturing with online HPLC analysis were employed to prevent gelling precipitation and ensure high-quality intermediates. The process yielded crude Tirzepatide with a 46% overall yield and >70% crude purity. GenScript offers extensive experience in manufacturing GLP-1-related candidates and can provide associated impurities. ⁹

Table 3. Synthetic Manufacturing Methods for Various Peptide Drugs⁹

Trends to Expect in 2025

According to current trends, GLP-1 receptor agonists could gain FDA approval for new indications such as chronic kidney disease, heart failure, and specific liver diseases in 2025. Moreover, several promising injectable GLP-1 therapies are in development. For example, CagriSema (cagrilintide/semaglutide), expected to file for approval in late 2025, has shown greater weight loss than Wegovy^® (semaglutide). Oral GLP-1 receptor agonists also present advantages: The small-molecule candidate orforglipron will complete its Phase III trial in 2025 and, if successful, may offer a lower-cost oral alternative to injectable therapies.¹⁰

GenScript Catalog Product

GenScript's industry-leading expertise can accelerate your discovery and development of GLP-1 receptor agonists. We have extensive experience in their modification, such as cyclization, lipidation, PEGlyation and adding active conjugation sites (Br, DBCO, or TCO) or linkers (GGGS, poly Sar). And our synthesis success rate is near 99%. Furthermore, our GMP manufacturing facilities can also support the manufacture for IND application to phase II from mg to kg.

GenScript's industry-leading expertise accelerates discovery and development of GLP-1 receptor agonists, supporting everything from fundamental research to drug development. With extensive experience in peptide modification—such as cyclization, lipidation, PEGylation, and the addition of active conjugation sites (Br, DBCO, or TCO) or linkers (GGGS, poly Sar). We offer precise, tailored solutions with an order completion rate of nearly 99%. Our GMP manufacturing facilities further enable IND application to phase II production, scaling from milligrams to kilograms, ensuring seamless progress in diabetes, obesity, and beyond.

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Reference

1. U.S. National Library of Medicine. (n.d.). ClinicalTrials.gov. National Institutes of Health. https://www.clinicaltrials.gov

2. Evolution of GLP‐1 Receptor Agonists for Diabetes Treatment | Biopharma PEG

3. Nilsen, J., Aaen, K.H., Benjakul, S. et al. Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end. Commun Biol 8, 810 (2025).

4. IUPHAR/BPS Guide to Pharmacology. (n.d.). Ligand: ID 7386 - Recombinant human glucagon-like peptide (GLP)-1-albumin protein. Retrieved from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=refs&ligandId=7386

5. Brichtová, E. P., Edu, I. A., Li, X., Becher, F., Gomes dos Santos, A. L., & Jackson, S. E. (2025). Effect of lipidation on the structure, oligomerization, and aggregation of glucagon-like peptide 1. Bioconjugate Chemistry, 36(3), 401–414.

6. T. Zhang, S. Liu, S. He, L. Shi, R. Ma, Strategies to Enhance the Therapeutic Efficacy of GLP‐1 Receptor Agonists through Structural Modification and Carrier Delivery. ChemBioChem, 26, e202400962 (2025)

7. Jiang P, Sun N, Yang W, et al. Development of a novel Fc fusion protein dual glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists. Diabetes Obes Metab 25(11): 3356-3365 (2023)

8. Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden DJ. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics. 11(2):78 (2019)

9. Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing. Org. Process Res. Dev. 2021, 25, 1628-1636

10. GoodRx. (n.d.). GLP-1 receptor agonists: Uses, common brands, and safety info. Retrieved from https://www.goodrx.com/classes/glp-1-agonists/glp-1-trends