Oral Treatment of Obesity by GLP-1 and Its Analogs

Obesity is a multifaceted disease that significantly increases the risk of various chronic conditions. GLP-1R (co)-agonists first emerged as therapeutics for treatment of type 2 diabetes mellitus and have since become an established drug class for improving glycemic control. The interest in GLP-1 for obesity treatment has surged in 2015 after the approval of Saxenda^® (liraglutide). To date, GLP-1 analogs are primarily administered by s.c. injection, which poses a significant burden on patient compliance. To address this challenge, research has focused on oral delivery. This review (1) provides a concise overview of the techniques explored to enhance the oral delivery of GLP-1 analogs for the treatment of obesity. Relevant strategies include the following: (1) the use of permeation enhancers to increase gastrointestinal absorption of peptides; (2) micro- and nanocarriers loaded with GLP-1, including targeted delivery systems and general techniques for active drug targeting; (3) GLP-1 gene delivery; and (4) advanced microbiome systems for GLP-1 delivery. The potential for misuse and side-effects of GLP-1 analogs are also discussed.

The work of Presas et al. is ,entioned as an example of cyclodextrin-enabled formulation. They have used amphiphilic cyclodextrins, functionalized with cationic groups and PEGylated-phospholipid chains (mPEG-DSPE 2000), to form electrostatic complexes with liraglutide and further self-assemble to NPs, which protect the drug from enzymatic degradation (2). Finally, a dextran sulphate coating was added to the nanocomplexes. Liraglutide was encapsulated to a striking 100%. After intra-jejunal application of the NPs (200 µg liraglutide/kg), they reduced the glycemic response in rats significantly and to a similar extent as s.c. injection of 200 µg liraglutide/kg. The oral administration of the invented nanocomplexes has not been tested so far.

1. Holler N, Ruseska I, Schachner-Nedherer AL, Zimmer A, Petschacher C. Oral Treatment of Obesity by GLP-1 and Its Analogs. Pharmaceutics. 2025 Dec 10;17(12):1596. doi: https://doi.org/10.3390/pharmaceutics17121596.
2. Presas E., Tovar S., Cuñarro J., O’Shea J.P., O’Driscoll C.M. Pre-Clinical Evaluation of a Modified Cyclodextrin-Based Nanoparticle for Intestinal Delivery of Liraglutide. J. Pharm. Sci. 2021;110:292–300. https://doi.org/10.1016/j.xphs.2020.10.058. See also: https://cyclodextrinnews.com/2021/07/07/pre-clinical-evaluation-of-a-modified-cyclodextrin-based-nanoparticle-for-intestinal-delivery-of-liraglutide/