BEYOND GLYCEMIC CONTROL: ORGAN-PROTECTIVE EFFECTS AND SAFETY PROFILE OF GLP-1 RECEPTOR AGONISTS – A COMPREHENSIVE REVIEW
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6563Keywords:
GLP-1 Receptor Agonists, Incretin-based Therapies, Obesity, Type 2 DiabetesAbstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have evolved from glucose-lowering agents for type 2 diabetes (T2D) into multifunctional therapies with effects extending across multiple metabolic and organ systems. This review summarizes current evidence regarding the pleiotropic effects, safety profile, and future therapeutic potential of GLP-1–based therapies beyond diabetes and obesity. Clinical evidence indicates that GLP-1RAs, particularly semaglutide, may reduce cardiovascular events and slow kidney disease progression, while also improving outcomes in heart failure with preserved ejection fraction. Beneficial effects have additionally been reported in metabolic dysfunction-associated steatohepatitis, osteoarthritis, obstructive sleep apnea, and peripheral artery disease. Emerging evidence suggests potential neuroprotective effects, although the role of GLP-1–based therapies in neurodegenerative diseases remains under investigation. Despite their generally favorable safety profile, gastrointestinal adverse events are common, while pancreatic, biliary, renal, ophthalmic, and other less frequent complications require appropriate clinical monitoring. The development of dual and triple receptor agonists, including tirzepatide, retatrutide, CagriSema, and amycretin, may further enhance weight loss and metabolic efficacy. Future treatment strategies may increasingly incorporate personalized selection of receptor profiles based on metabolic phenotype, comorbidities, therapeutic goals, and individual tolerability. Overall, GLP-1–based therapies represent an expanding therapeutic platform with potential applications extending well beyond glycemic control and weight management, although long-term clinical trials are required to establish their efficacy, safety, and organ-protective effects across broader patient populations.
References
Gonzalez-Rellan, M. J., & Drucker, D. J. (2025). The expanding benefits of GLP-1 medicines. Cell Rep Med, 6(7), 102214. https://doi.org/10.1016/j.xcrm.2025.102214
Mahalingam, S., Kharbanda, K. K., Casey, C. A., & Rasineni, K. (2026). Beyond diabetes and obesity: GLP-1 receptor agonists as multifunctional therapeutics across the steatotic liver disease spectrum. Front Pharmacol, 17, 1752204. https://doi.org/10.3389/fphar.2026.1752204
He, X., Zhao, Z., Sun, Y., & Jiang, X. (2025). Unraveling the safety profile of GLP-1 receptor agonists: mechanistic insights with a focus on semaglutide. Eur J Med Chem, 300, 118163.
Yale, J. F., Major-Pedersen, A., Catarig, A. M., Jain, R., Menzen, M., & Holmes, P. (2024). Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: analysis of pooled data from the Semaglutide Real-world Evidence (SURE) programme. Diabetes Obes Metab, 26, 4429–4440.
Li, L., Shui, D., Zhang, X., Tan, B., & Deng, Y. (2025). Investigation into the efficacy and safety profile of oral small-molecule GLP-1 receptor agonists in type 2 diabetes and obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne), 17, 1854779.
Filippatos, T. D., Panagiotopoulou, T. V., & Elisaf, M. S. (2014). Adverse effects of GLP-1 receptor agonists. Rev Diabet Stud, 11, 202–230.
Smits, M. M., & van Raalte, D. H. (2021). Safety of semaglutide. Front Endocrinol (Lausanne), 12, 645563.
Sodhi, M., Rezaeianzadeh, R., Kezouh, A., & Etminan, M. (2023). Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA, 330, 1795–1797.
Hathaway, J. T., Shah, M. P., Hathaway, D. B., Zekavat, S. M., Krasniqi, D., Gittinger, J. W., Jr., et al. (2024). Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol, 142, 732–739.
Kornelius, E., Huang, J. Y., Lo, S. C., Huang, C. N., & Yang, Y. S. (2024). The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon-like peptide-1 receptor agonist therapy. Sci Rep, 14, 24433.
Able, C., Liao, B., Saffati, G., Maremanda, A., Applewhite, J., Nasrallah, A. A., et al. (2025). Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction: a TriNetX database study. Int J Impot Res, 37, 315–319.
Nauck, M. A., Tuttle, K. R., Tschöp, M. H., & Blüher, M. (2026). Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits. Lancet, 407, 892–908.
Goldney, J., Hamza, M., Surti, F., Davies, M. J., & Papamargaritis, D. (2025). Triple agonism based therapies for obesity. Curr Cardiovasc Risk Rep, 19, 18.
Bassatne, A., & Rizo, I. (2026). Medical treatments for obesity: what does the future have in store. J Clin Endocrinol Metab, dgag274.
Nicholls, S. J., Pavo, I., Bhatt, D. L., Buse, J. B., Del Prato, S., Kahn, S. E., et al. (2025). Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med, 393, 2409–2420.
Athauda, D., Greig, N. H., Meissner, W. G., Foltynie, T., & Gandhi, S. (2026). The promise of GLP-1 receptor agonists for neurodegenerative diseases. J Clin Invest, 136, e194745.
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Copyright (c) 2026 Magdalena Bukowska, Katarzyna Otrębska, Dominika Lewandowska, Anna Jastrzębska
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