Metabolik Hastalıkların Yönetiminde Glp-1 Reseptör Agonistlerinin Yeri
Özet
Metabolik hastalıklar, günümüzde küresel ölçekte önemli bir halk sağlığı yükü oluşturmaktadır. Özellikle tip 2 diyabet ve obezite, insülin direnci, glikoz homeostazındaki bozulmalar ve inflamatuvar süreçlerle ilişkili çok faktörlü patofizyolojiye sahiptir. Bu hastalıkların tedavisinde kullanılan geleneksel ajanların sınırlı etkinliği ve güvenlik endişeleri, yeni farmakoterapötik yaklaşımların geliştirilmesini zorunlu kılmıştır. Bu bağlamda inkretin temelli tedavilerin önemli bileşeni olan glukagon benzeri peptid-1 (GLP-1) reseptör agonistleri klinik uygulamada giderek daha fazla yer bulmaktadır. GLP-1 reseptör agonistleri, glisemik kontrolü iyileştirmenin yanı sıra glukagon sekresyonunu baskılamakta, gastrik boşalmayı yavaşlatmakta ve iştahı azaltarak kilo kaybına katkı sağlamaktadır. Kardiyovasküler ve renal koruyucu etkileri de kanıtlanmış olup, majör advers kardiyovasküler olayların sıklığını azaltmaktadır. Klinik kullanıma sunulan eksenatid, liraglutid, semaglutid, dulaglutid ve tirzepatid gibi ajanlar farklı farmakokinetik özellikler sergilemektedir. Ayrıca obezite, ateroskleroz ve hipertansiyon yönetiminde de etkinlik göstermeleri kullanım alanlarını genişletmiştir. Bununla birlikte gastrointestinal yan etkiler ve maliyet gibi sınırlayıcı faktörler tedaviye uyumu etkileyebilmektedir. Gelecekte yapılacak araştırmalar, oral formülasyonlar ve çoklu agonist kombinasyonlarıyla etkinlik ve güvenliği artırmaya odaklanmalıdır.
Referanslar
Chew NWS, Ng CH, Tan DJH, et al. The global burden of metabolic disease: Data from 2000 to 2019. Cell Metab. 2023;35(3): 414-428. doi: 10.1016/j.cmet.2023.02.003
Zhang H, Zhou XD, Shapiro MD, et al. Global burden of metabolic diseases, 1990–2021. Metabolism. 2024;160:155999. doi: 10.1016/j.metabol.2024.155999
Sarma S, Sockalingam S, Dash S. Obesity as a multisystem disease: trends in obesity rates and obesity-related complications. Diabetes, Obesity and Metabolism. Blackwell Publishing Ltd; 2021;1: 3–16. doi: 10.1111/dom.14290
Abel ED, Gloyn AL, Evans-Molina C, et al. Diabetes mellitus—Progress and opportunities in the evolving epidemic. Cell. Elsevier B.V.; 2024;187(15): 3789–3820. doi: 10.1016/j.cell.2024.06.029
Qiu T, Yan D. Editorial: Benefits and risks of drug combination therapy for chronic metabolic diseases. Frontiers in Endocrinology. Frontiers Media SA; 2024;15:1390248. doi: 10.3389/fendo.2024.1390248
Blüher M, Aras M, Aronne LJ, et al. New insights into the treatment of obesity. Diabetes, Obesity and Metabolism. John Wiley and Sons Inc; 2023;25(8): 2058–2072. doi: 10.1111/dom.15077
Tan Q, Akindehin SE, Orsso CE, et al. Recent advances in incretin-based pharmacotherapies for the treatment of obesity and diabetes. Frontiers in Endocrinology. Frontiers Media S.A.; 2022;13:838410. doi: 10.3389/fendo.2022.838410
Psaltis JP, Marathe JA, Nguyen MT, et al. Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future. Medicinal Research Reviews. John Wiley and Sons Inc; 2025;45(1): 29-65. doi: 10.1002/med.22070
Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetologia. Springer Science and Business Media Deutschland GmbH; 2023;66(10): 1765–1779. doi: 10.1007/s00125-023-05906-7
Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Molecular Metabolism. Elsevier GmbH; 2021;46:101102. doi: 10.1016/j.molmet.2020.101102
Liu QK. Mechanisms of action and therapeutic applications of glp-1 and dual GIP/GLP-1 receptor agonists. Frontiers in Endocrinology. Frontiers Media SA; 2024;15:1431292. doi: 10.3389/fendo.2024.1431292
Sfairopoulos D, Liatis S, Tigas S, et al. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones. Springer; 2018;17(3): 333–350. doi: 10.1007/s42000-018-0038-0
Jalleh RJ, Plummer MP, Marathe CS, et al. Clinical consequences of delayed gastric emptying with glp-1 receptor agonists and tirzepatide. Journal of Clinical Endocrinology and Metabolism. Endocrine Society; 2024;110(1): 1–15. doi: 10.1210/clinem/dgae719
Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of glp-1 receptor agonists. Nat Med. 2025;31(3):951–962. doi: 10.1038/s41591-024-03412-w
Yao H, Zhang A, Li D, et al. Comparative effectiveness of glp-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410 doi: 10.1136/bmj-2023-076410
Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy. Springer Nature; 2024;9(1):234. doi: 10.1038/s41392-024-01931-z
Lu C, Xu C, Yang J. The beneficial effects of glp-1 receptor agonists other than their anti-diabetic and anti-obesity properties. Medicina. Multidisciplinary Digital Publishing Institute (MDPI); 2024;61(1):17. doi: 10.3390/medicina61010017
Wang JY, Wang QW, Yang XY, et al. GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach. Frontiers in Endocrinology. Frontiers Media S.A.; 2023;14:1085799. doi: 10.3389/fendo.2023.1085799
Kalinderi K, Papaliagkas V, Fidani L. GLP-1 receptor agonists: a new treatment in parkinson’s disease. International Journal of Molecular Sciences. Multidisciplinary Digital Publishing Institute (MDPI); 2024;25(7):3812. doi: 10.3390/ijms25073812
Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nature Reviews Cardiology. Nature Research; 2023;20(7): 463–474. doi: 10.1038/s41569-023-00849-3
Brunton SA, Wysham CH. GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date. Postgraduate Medicine. Bellwether Publishing, Ltd.; 2020;132(2): 3-14. doi: 10.1080/00325481.2020.1798099
Nachawi N, Rao PP, Makin V. The role of glp-1 receptor agonists in managing type 2 diabetes. Cleve Clin J Med. 2022;89(8):457-464. doi: 10.3949/ccjm.89a.21110
Raza FA, Altaf R, Bashir T, et al. Effect of glp-1 receptor agonists on weight and cardiovascular outcomes: a review. Medicine. Lippincott Williams and Wilkins; 2024;103(44): e40364. doi: 10.1097/MD.0000000000040364
Zhao X, Wang M, Wen Z, et al. GLP-1 receptor agonists: beyond their pancreatic effects. Frontiers in Endocrinology. Frontiers Media S.A.; 2021;12:721135. doi: 10.3389/fendo.2021.721135
Ard J, Fitch A, Fruh S, Herman L. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Advances in Therapy. Adis; 2021;38(6): 2821–2839. doi: 10.1007/s12325-021-01710-0
Melson E, Ashraf U, Papamargaritis D, et al. What is the pipeline for future medications for obesity?: clinical research. International Journal of Obesity. Springer Nature; 2025;49(3): 433–451. doi: 10.1038/s41366-024-01473-y
Madsbad S, Holst JJ. The promise of glucagon-like peptide 1 receptor agonists (glp-1ra) for the treatment of obesity: a look at phase 2 and 3 pipelines. Expert Opinion on Investigational Drugs. Taylor and Francis Ltd.; 2025;34(3): 197–215. doi: 10.1080/13543784.2025.2472408
Beauregard N, McInnis K, Goldfield GS, et al. Energy balance and obesity: the emerging role of glucagon like peptide-1 receptor agonists. Current Opinion in Clinical Nutrition and Metabolic Care. Lippincott Williams and Wilkins; 2024;27(6): 472–478. doi: 10.1097/MCO.0000000000001064
Ibrahim E, Burken M, Lastra G, et al. Prevention of cardiovascular disease in women with type 2 diabetes: the role of incretin mimetics and sodium-glucose cotransporter-2 inhibitors. American Journal of Physiology - Cell Physiology. American Physiological Society; 2025;328(1): C315–C322. doi: 10.1152/ajpcell.00765.2024
Tang ASP, Hsu JTY, Chong SKS, et al. Glucagon-like peptide-1 receptor agonist in myocardial infarction and atherosclerotic cardiovascular disease risk reduction: a comprehensive meta-analysis of number needed to treat, efficacy and safety. Cardiovascular Diabetology. BioMed Central Ltd; 2025;24(1):285. doi: 10.1186/s12933-025-02840-3
Lin LC, Chen JY, Huang TTM, et al. Association of glucagon-like peptide-1 receptor agonists with cardiovascular and kidney outcomes in type 2 diabetic kidney transplant recipients. Cardiovasc Diabetol. 2025;24(1):87. doi: 10.1186/s12933-025-02649-0
Wang X, Yang X, Qi X, et al. Anti-atherosclerotic effect of incretin receptor agonists. Frontiers in Endocrinology. Frontiers Media SA; 2024;15:1463547. doi: 10.3389/fendo.2024.1463547
33. 34. Xu D, Nair A, Sigston C, et al. Potential roles of glucagon-like peptide 1 receptor agonists (glp-1 ras) in nondiabetic populations. Cardiovascular Therapeutics. Hindawi Limited; 2022;2022:6820377. doi: 10.1155/2022/6820377
Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of glp-1 receptor agonists in obesity: recommendations for clinical practice. Postgraduate Medicine. Taylor and Francis Ltd.; 2022;134(1):14–19. doi: 10.1080/00325481.2021.2002616
Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes, Obesity and Metabolism. Blackwell Publishing Ltd; 2016;18(4):317-332. doi: 10.1111/dom.12596
Patel S, Niazi SK. Emerging frontiers in glp-1 therapeutics: a comprehensive evidence base (2025). Pharmaceutics. Multidisciplinary Digital Publishing Institute (MDPI); 2025;17(8):1036. doi: 10.3390/pharmaceutics17081036
Moiz A, Filion KB, Tsoukas MA, et al. The expanding role of glp-1 receptor agonists: a narrative review of current evidence and future directions. eClinicalMedicine. Elsevier Ltd; 2025;86:103363. doi: 10.1016/j.eclinm.2025.103363
