Update Date: September 2026

GLP-1 receptor agonists (GLP-1 RAs) are an important class of glucose-lowering medicines used primarily to treat type 2 diabetes. They mimic the actions of endogenous glucagon-like peptide-1 (GLP-1), enhancing glucose-dependent insulin secretion, suppressing glucagon release, and slowing gastric emptying. Many GLP-1-based therapies also promote weight loss, while some have demonstrated cardiovascular and kidney benefits.

The development of GLP-1 RAs has focused on extending the short half-life of native GLP-1 and reducing dosing frequency. Drug developers have used several approaches, including DPP-4-resistant peptide modification, albumin binding, fatty-acid acylation, PEGylation, Fc fusion, sustained-release formulations, and oral delivery technologies. This article reviews the evolution of GLP-1 receptor agonists for diabetes and compares the major strategies used to improve their stability, pharmacokinetics, and dosing convenience.

Discovery of GLP-1

In the mid to late 20th century, intestinal extracts were found to have blood glucose lowering effect. In addition, injecting glucose into the intestine was able to stimulate the production of more insulin than injecting it into the vein. These findings initiated the study of the incretin hormone. In the 1970s, the first incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), was discovered, and glucagon-like peptide-1 (GLP-1), was subsequently discovered.

By the 1980s, the amino acid and gene sequences of proglucagon (Figure 1) were unraveled. It can be observed that proglucagon is not expressed by a single gene, but is embedded in a larger gene, and when this large gene expresses a large peptide chain (called preprohormones), it is then cleaved by specific enzymes and post-translationally modified to finally obtain fragments with different biological activities. Proglucagon is mainly expressed in the intestine, pancreas and hindbrain. Intestinal and brain cells contain prohormone convertase 1 (PC1), which is able to cleave proglucagon into Glicentin, Oxyntomodulin, GLP-1, GLP-2 and IP-2, while pancreatic islet cells contain prohormone convertase 2 (PC2), which capable of cleaving proglucagon into Glucagon and MPGF. Therefore, GLP-1 in human blood is mainly secreted through the intestine.

GLP-1RA Mechanism of Action

GLP-1 (glucagon-like peptide-1) is a hormone secreted by the intestinal tract during feeding, which enhances insulin secretion and inhibits glucagon secretion in a glucose concentration-dependent manner, and delays gastric emptying to reduce the amount of food eaten through central appetite suppression. GLP-1RA exerts its glucose lowering effect by stimulating GLP-1 receptors, which not only has significant glucose-lowering efficacy, but also has the advantage of low incidence of hypoglycemia.

In addition, because the tissues in which the GLP-1 receptor is expressed are not limited to the gastrointestinal and pancreatic glands, GLP-1RA can reduce cardiovascular risk in addition to lowering glucose and reducing body weight. These are benefits that insulin and the vast majority of oral hypoglycemic agents do not have.

Figure 1. Biological actions of  GLP-1, source: reference [1]

Evolution of GLP-1RAs

Currently, there are several GLP-1RAs approved for marketing worldwide (Table 1), mainly for the treatment of diabetes and obesity, of which tirzepatide is a novel dual GLP-1RA/GIPR agonist.

In 2005, Exendin-4 (Exenatide/ BYETTA), the world's first GLP-1RA, was approved by the FDA for the adjuvant treatment of type 2 diabetes with two injections per day (BID).

In 2009, Novo Nordisk's Liraglutide (Victoza) was approved by the EMA and in January 2010 by the FDA for the treatment of type 2 diabetes. Liraglutide subsequently demonstrated cardiovascular benefit in patients with type 2 diabetes and high cardiovascular risk. Also, Liraglutide was the world's first once-daily GLP-1RA drug.

To address the problem of once-a-day injections of Liraglutide, Lilly launched Dulaglutide, which is administered once a week and was approved by the FDA in 2014 for the treatment of type 2 diabetes. Dulaglutide sales surged starting in 2019 and became the top seller in GLP-1RA in 2020.

In 2017, Novo Nordisk launched its blockbuster product, Semaglutide (Ozempic), with an extended half-life of 7 days, enabling once-a-week dosing. In 2019, the FDA approved oral semaglutide (Rybelsus), the first orally administered GLP-1 receptor agonist for adults with type 2 diabetes.

In 2022, Eli Lilly launched Tirzepatide, a novel dual GLP-1RA/GIPR agonist administered once weekly by subcutaneous injection that activates both GLP-1 and GIP receptors. GIP (glucose-dependent insulinotropic polypeptide) is a hormone that may complement the effects of GLP-1 receptor agonists. Preclinical studies have shown that GIP may reduce body weight by reducing food intake and increasing energy consumption, and in combination with GLP-1 receptor agonists, may have a greater effect on patients' blood glucose and body weight.

In 2026, the FDA approved Lilly's Foundayo (orforglipron), the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions. It is an oral small-molecule GLP-1 receptor agonist.

Retatrutide is an investigational triple agonist targeting the GIP, GLP-1, and glucagon receptors. In clinical development, it has demonstrated substantial body-weight reductions, highlighting the potential of multi-receptor agonism as a next-generation approach to metabolic disease. [7]

GLP-1RAs: Challenges and Solutions

The short action profile of native GLP-1 imposes a major challenge towards its successful clinical utilization. To overcome this limitation, various strategies have been applied to extend the half-life of GLP-1 and to accelerate its in vivo action and potency.

(1) Resistance to DPP-4 degradation. Native GLP-1 is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4). One important strategy for developing longer-acting GLP-1 receptor agonists is to introduce structural modifications that reduce susceptibility to DPP-4 cleavage. For example, semaglutide incorporates an Aib substitution at position 8, while exenatide is derived from exendin-4, a peptide with intrinsic resistance to DPP-4 degradation.

(2) Albumin-Based Half-Life Extension. Albumin-based strategies can extend the circulation time of GLP-1 analogs through either direct fusion with albumin or reversible albumin binding. Albiglutide (GlaxoSmithKline) is a fusion of two GLP-1 molecules with human albumin, which increases the proteolytic stability of GLP-1 and slows renal clearance, extending the half-life to 120 h. Albumin binds to the neonatal Fc receptor (FcRn) in a pH-dependent manner, thus avoiding degradation. Upon endocytosis by the endothelial cells, albumin binds to the Fc receptor (FcRn) during endosomal acidification, which sorts the intracellular trafficking of the albumin away from degradative lysosomes and back to the plasma membrane where it can once again reenter the general circulation.

(3) Acylation with fatty acids. Fatty-acid acylation is an important strategy for extending the half-life of GLP-1 receptor agonists. The attached fatty-acid moiety promotes reversible, non-covalent binding to human serum albumin, which reduces renal clearance and prolongs systemic exposure. This strategy is used in liraglutide and semaglutide, with half-lives of approximately 13 hours and 1 week, respectively. 

(4) PEGylation. Polyethylene glycol (PEG) conjugation is another strategy for modifying the pharmacokinetic properties of peptide and protein therapeutics. Depending on the PEG molecular weight, architecture, conjugation site, and linker chemistry, PEGylation can increase apparent molecular size, reduce renal clearance, improve aqueous solubility, and potentially prolong systemic exposure. PEGylation has also been investigated for long-acting GLP-1 receptor agonists, including PEG-loxenatide.

Biopharma PEG, a leading PEG linker supplier, offers PEGylation as a cost-effective modification of peptides which has the potential to improve bioavailability compared to the nmodified molecule.

(5) Fc fusion. As already mentioned, GLP-1 fused to albumin is able to escape lysosomal degradation. In a similar way, fusion of GLP-1 with IgG can achieve the same effect (Figure 4). This strategy has been applied to dulaglutide, where two GLP-1 molecules are fused to the Fc fragment of IgG4, increasing the half-life while reducing the renal elimination due to the increased molecular weight.

(6) Sustained-release formulations. Bydureon® (AstraZeneca) is an extended release (ER) formulation of Exenatide that requires only once a week dosing. Sustained release is achieved by incorporating exendin-4 into 0.06 mm diameter biodegradable microspheres containing 50:50 poly (D,L-lactide-co-glycolide) (PLG) polymer and sucrose. In the human body, the PLG polymers slowly degrade through the non-catalyzed hydrolysis of the ester linkages into lactic acid and glycolic acid, which are finally eliminated as carbon dioxide and water.

(7) Oral formulation. Peptide drugs generally have poor oral bioavailability because of enzymatic degradation in the gastrointestinal tract and limited absorption across the gastrointestinal epithelium. Oral semaglutide demonstrated that these barriers can be addressed through an absorption-enhancing formulation.
In Rybelsus® (Novo Nordisk), semaglutide is co-formulated with N-[8-(2-hydroxybenzoyl)aminocaprylate] (SNAC), an absorption enhancer. SNAC helps facilitate semaglutide absorption in the stomach by locally increasing pH and enhancing transcellular permeability of the gastric epithelium. 

Orforglipron represents a fundamentally different approach to oral GLP-1 therapy. Unlike semaglutide, which is a peptide and requires an absorption-enhancing formulation to achieve oral delivery, orforglipron is a non-peptide, small-molecule GLP-1 receptor agonist. Orforglipron does not face the same gastrointestinal degradation and absorption barriers associated with orally administered peptide therapeutics. This small-molecule approach may simplify oral administration and does not require the peptide-specific absorption-enhancement approach used for oral semaglutide.

Summary

Half a century has passed since the discovery of GLP-1, which has provided a new way for humans to fight diabetes. Today, there is still a large number of GLP-1R agonists entering clinical trials, which will lead to a big explosion in the future, so let's wait and see together.

PEG Building Blocks for GLP-1 and Peptide Drug Development

Biopharma PEG supplies polyethylene glycol (PEG) derivatives, monodisperse PEGs, custom PEG derivative synthesis and PEGylation services worldwide, from R&D through GMP commercial quantities, for preclinical, clinical trials, and commercial products for pharma, biotech, medical devices, and diagnostics. And, Biopharma PEG now provides semaglutide side chain with the best price and high quality. 
CAS No. 166108-71-0, Fmoc-NH-PEG2-CH2COOH
CAS No. 134978-97-5, NH2-PEG2-CH2COOH
CAS No. 108466-89-3, Boc-NH-PEG2-CH2COOH
CAS No. 134979-01-4, CH2COOH-PEG2-NH2.HCl

References:
[1] Tan, Q., Akindehin, S. E.,Orsso, C. E., Waldner, R. C., DiMarchi, R. D., Müller, T. D., & Haqq, A. M.(2022). Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes. Frontiers inendocrinology, 13, 838410. https://doi.org/10.3389/fendo.2022.838410
[2] Drucker, D. J., Habener, J. F.,& Holst, J. J. (2017). Discovery, characterization,and clinical development of the glucagon-like peptides. The Journal ofclinical investigation, 127(12), 4217–4227. https://doi.org/10.1172/JCI97233
[3] Reed, J., Bain, S., &Kanamarlapudi, V. (2020). Recent advances in understanding the role ofglucagon-like peptide 1. F1000Research, 9, F1000 Faculty Rev-239. https://doi.org/10.12688/f1000research.20602.1
[4] Baldwin, W. M., 3rd, Valujskikh,A., & Fairchild, R. L. (2019). The neonatal Fc receptor: Key to homeostasiccontrol of IgG and IgG-related biopharmaceuticals. American journal oftransplantation : official journal of the American Society of Transplantationand the American Society of Transplant Surgeons, 19(7), 1881–1887. https://doi.org/10.1111/ajt.15366
[5] Twarog, C., Fattah, S., Heade,J., Maher, S., Fattal, E., & Brayden, D. J. (2019). Intestinal PermeationEnhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics, 11(2), 78. https://doi.org/10.3390/pharmaceutics11020078
[6] https://news.vanderbilt.edu/2013/08/01/golden-goose/
[7] https://learn.hms.harvard.edu/insights/all-insights/investigational-glp-1-based-medicine-uses-triple-targeting-accelerate-weight-loss

Related Articles
Peptide Therapeutics: Current Status And Future Directions
​​Anti-Cancer Peptide Drug Conjugates (PDCs): An Overview
​9 Potential Blockbuster Drugs to be Approved in 2022