BEYOND WEIGHT LOSS: EMERGING EXTRA-METABOLIC APPLICATIONS OF GLP-1 RECEPTOR AGONISTS IN CARDIOVASCULAR, RENAL, NEUROLOGICAL AND INFLAMMATORY DISORDERS: A NARRATIVE REVIEW
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6153Keywords:
GLP-1 Receptor Agonists, Cardiovascular Outcome Trials, Diabetic Kidney Disease, Neurodegeneration, Alzheimer's Disease, Parkinson's Disease, Anti-inflammatory, MASLD, Semaglutide, Liraglutide, TirzepatideAbstract
Introduction. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed as antidiabetic agents exploiting the incretin effect to achieve glucose-dependent insulin secretion. Over the past decade, evidence from large-scale cardiovascular outcome trials (CVOTs), mechanistic studies, and emerging clinical investigations has demonstrated that the therapeutic potential of this drug class extends well beyond glycaemic control. GLP-1 receptors are expressed in the heart, vasculature, kidneys, brain, liver, lungs, and immune cells, providing the biological substrate for diverse extra-metabolic effects observed in both preclinical models and clinical cohorts.
Methodology. This narrative review was conducted through a systematic search of PubMed, MEDLINE, and the Cochrane Library using MeSH terms and free-text keywords related to GLP-1 RAs and their extra-metabolic effects. Publications up to early 2026 were considered, including randomised controlled trials, CVOTs, systematic reviews, meta-analyses, and mechanistic preclinical studies. Eligibility was based on methodological rigour, sample size, and clinical relevance to four main domains: cardiovascular, renal, neurological, and anti-inflammatory effects.
Results. GLP-1 RAs demonstrated a 13–14% reduction in major adverse cardiovascular events (MACE) across CVOTs, with semaglutide reducing MACE by 20% in patients with obesity but without diabetes (SELECT trial). In the renal domain, the FLOW trial showed a 24% reduction in the composite renal endpoint (HR 0.76; 95% CI: 0.66–0.88; p < 0.001) with semaglutide in patients with diabetic kidney disease. In the neurological domain, preclinical evidence strongly supports neuroprotection in Alzheimer's and Parkinson's disease, with initial clinical trials showing improvement in motor function in Parkinson's patients treated with exenatide or lixisenatide and prevention of cerebral metabolic decline in Alzheimer's disease with liraglutide. Anti-inflammatory properties — demonstrated across hepatic (NASH resolution in up to 59% with semaglutide), pulmonary, dermatological, and systemic contexts — further broaden the therapeutic scope. Emerging data also suggest potential roles in obstructive sleep apnoea, substance use disorders, and knee osteoarthritis.
Conclusions. GLP-1 RAs constitute a versatile class of pleiotropic, disease-modifying agents with organ-protective properties extending far beyond glycaemic management. The advent of dual GIP/GLP-1 agonists (tirzepatide) and investigational triple agonists further expands this landscape. Significant gaps remain regarding long-term neurological outcomes, optimal patient selection, and the relative contributions of direct receptor-mediated versus weight-loss-dependent effects, necessitating dedicated mechanism-focused trials and biomarker-guided patient stratification.
References
Drucker, D. J. (2006). The biology of incretin hormones. Cell Metabolism, 3(3), 153–165. https://doi.org/10.1016/j.cmet.2006.01.004
Drucker, D. J. (2018). Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001
Du, H., Meng, X., Yao, Y., & Xu, J. (2022). The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease. Frontiers in Endocrinology, 13, 1033479. https://doi.org/10.3389/fendo.2022.1033479
Ferhatbegović, L., Mršić, D., & Macić-Džanković, A. (2023). The benefits of GLP1 receptors in cardiovascular diseases. Frontiers in Clinical Diabetes and Healthcare, 4, 1293926. https://doi.org/10.3389/fcdhc.2023.1293926
Gallwitz, B. (2009). Preclinical and clinical data on extraglycemic effects of GLP-1 receptor agonists. Review of Diabetic Studies, 6(4), 247–259. https://doi.org/10.1900/RDS.2009.6.247
Granata, A., Pellegrino, S., Fatuzzo, P., & Morale, W. (2022). GLP-1 receptor agonists and renal disease: a state-of-the-art review. Clinical Kidney Journal, 15(9), 1657–1665. https://doi.org/10.1093/ckj/sfac084
Heerspink, H. J. L., Sattar, N., Pavo, I., Haupt, A., Duffin, K. L., Yang, Z., Wiese, R. J., Tuttle, K. R., & Cherney, D. Z. I. (2023). Effects of semaglutide versus placebo on measures of kidney function in people with overweight or obesity with or without type 2 diabetes. Diabetes Care, 46(4), 801–810. https://doi.org/10.2337/dc22-1939
Helmstädter, J., Frenis, K., Filippou, K., Grill, A., Dib, M., Kalinovic, S., Pawelke, R., Lagrange, J., Kus, K., Oelze, M., Wenzel, P., Munzel, T., Daiber, A., & Steven, S. (2022). Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits. British Journal of Pharmacology, 179(4), 659–676. https://doi.org/10.1111/bph.15462
Holst, J. J. (2007). The physiology of glucagon-like peptide 1. Physiological Reviews, 87(4), 1409–1439. https://doi.org/10.1152/physrev.00034.2006
Kalinderi, K., Papaliagkas, V., & Fidani, L. (2024). GLP-1 receptor agonists: a new treatment in Parkinson's disease. International Journal of Molecular Sciences, 25(7), 3812. https://doi.org/10.3390/ijms25073812
Klausen, M. K., Thomsen, M., Wortwein, G., & Fink-Jensen, A. (2022). The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. British Journal of Pharmacology, 179(4), 625–641. https://doi.org/10.1111/bph.15677
Lee, Y. S., & Jun, H. S. (2016). Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators of Inflammation, 2016, Article 3094642. https://doi.org/10.1155/2016/3094642
Liang, Y., Chen, H., Liu, Y., Hou, X., Wei, L., Hua, X., Tian, H., & Pan, Z. (2024). Association of GLP-1 RAs with cognitive function in patients with Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis. Journal of Alzheimer's Disease Reports, 8(1), 777–789. https://doi.org/10.3233/ADR-230066
Liu, M. (2024). Mechanisms and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists in diabetes mellitus, cardiovascular disease, obesity, and beyond. Frontiers in Endocrinology, 15, 1431292. https://doi.org/10.3389/fendo.2024.1431292
Ma, X., Liu, Z., Ilyas, I., Little, P. J., Kamato, D., Sahebkar, A., Chen, Z., Luo, S., Zheng, X., & Weng, J. (2021). GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. International Journal of Biological Sciences, 17(8), 2050–2068. https://doi.org/10.7150/ijbs.59965
Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L. S., Steinberg, W. M., Stockner, M., Zinman, B., Bergenstal, R. M., & Buse, J. B. (2016). Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 375(4), 311–322. https://doi.org/10.1056/NEJMoa1603827
Mehdi, S. F., Pusapati, S., Anwar, M. S., Lohana, D., Kumar, P., Nandula, S. A., Nawaz, F. K., Tracey, K., Yang, H., LeRoith, D., Brownstein, M. J., & Roth, J. (2023). Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent. Frontiers in Immunology, 14, 1148209. https://doi.org/10.3389/fimmu.2023.1148209
Michos, E. D., Bakris, G. L., Bhatt, D. L., & Lam, C. S. P. (2023). Similarities and differences between GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal protection. American Journal of Preventive Cardiology, 14, 100502. https://doi.org/10.1016/j.ajpc.2023.100502
Mosterd, C. M., Bjornstad, P., van Raalte, D. H., & Heerspink, H. J. L. (2020). Nephroprotective effects of GLP-1 receptor agonists. Journal of Nephrology, 33(5), 965–975. https://doi.org/10.1007/s40620-020-00716-x
Mullur, R. S., Liu, Y. Y., & Brent, G. A. (2024). GLP-1 receptor agonist-based therapies and cardiovascular risk: mechanisms of action. Journal of Endocrinology, 263(1), e240046. https://doi.org/10.1530/JOE-24-0046
Nauck, M. A., Quast, D. R., & Wefers, J. (2026). GLP-1 receptor agonists: expanding horizons beyond type 2 diabetes. The Lancet, 407(10557), 892–908. https://doi.org/10.1016/S0140-6736(25)02143-5
Nevola, R., Epifani, R., Imbriani, S., Tortorella, G., Aprea, C., Galiero, R., Rinaldi, L., Marfella, R., & Sasso, F. C. (2023). GLP-1 receptor agonists in non-alcoholic fatty liver disease: current evidence and future perspectives. International Journal of Molecular Sciences, 24(2), 1703. https://doi.org/10.3390/ijms24021703
West, T., Bhatt, D. L., & Bhatt, S. (2025). Blood-brain barrier penetrance of GLP-1 receptor agonists: a narrative review. Neurological Therapy, 14(3), 1157–1166. https://doi.org/10.1007/s40120-025-00697-5
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Paulina Bigda, Zuzanna Rafałowska, Stanisław Rutz, Anna Wojtala, Julia Kret, Aleksandra Wyrostkiewicz, Aleksander Sadkowski, Jan Gdula, Lilianna Zielińska, Michał Szpunar, Adrianna Zabiegałowska, Magda Buśko, Jagoda Pałubska, Oliwer Muller
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
