GLP-1 Reseptör Agonistlerinin Kardiyorenal-Metabolik Etkileri: Kardiyovasküler ve Renal Sonuçlara İlişkin Güncel Kanıtlar

Fatma Zehra Ağan

doi:10.5281/zenodo.21033933

Authors

Fatma Zehra Ağan Harran University https://orcid.org/0000-0002-3784-8553

DOI:

https://doi.org/10.5281/zenodo.21033933

Keywords:

GLP-1 receptor agonists, cardiorenal-metabolic disease, cardiovascular outcomes, chronic kidney disease, type 2 diabetes

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially developed as glucose-lowering agents for the treatment of type 2 diabetes mellitus (T2DM). However, accumulating evidence has demonstrated that their clinical benefits extend beyond glycemic control and include cardiovascular and renal protection. Obesity, T2DM, cardiovascular disease, and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions within the cardiorenal-metabolic disease continuum and share common pathophysiological mechanisms including insulin resistance, chronic inflammation, endothelial dysfunction, oxidative stress, and neurohormonal activation. Recent cardiovascular and renal outcome studies have shown that GLP-1 receptor agonists reduce major adverse cardiovascular events and may delay the progression of kidney dysfunction. Proposed mechanisms include weight reduction, improvement in blood pressure and metabolic control, suppression of inflammatory and oxidative pathways, preservation of endothelial function, and favorable effects on renal hemodynamics and albuminuria. Landmark trials including LEADER, SUSTAIN-6, REWIND, HARMONY Outcomes, AMPLITUDE-O, and more recently FLOW have strengthened the evidence supporting the organ-protective effects of this drug class. In this review, current evidence regarding the cardiovascular and renal effects of GLP-1 RA, is summarized within the framework of cardiorenal-metabolic disease, and their evolving role in internal medicine practice is discussed.

References

1. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023;148(20):1606-1635.

2. Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022;28(10):923-1049.

3. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130.

4. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121.

5. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.

6. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.

7. Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-based chronic disease, addressing knowledge and clinical practice gaps: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(5):539-555.

8. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of hyperglycaemia in type 2 diabetes, 2022: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;65(12):1925-1966.

9. American Diabetes Association Professional Practice Committee. Diabetes care in the hospital: Standards of Care in Diabetes-2026. Diabetes Care. 2026;49(Suppl 1):S339-S355.

10. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021;398(10296):262-276.

11. Luo C, He D, Yang H, Zhu C, Zhu J, Hu Z. The effect of liraglutide on renal function in type 2 diabetes: a meta-analysis of randomized controlled studies. Afr Health Sci. 2022;22(3):267-274.

12. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756.

13. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130.

14. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.

15. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes-state-of-the-art. Mol Metab. 2021;46:101102.

16. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15-30.

17. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114(11):1788-1803.

18. Neeland IJ, Marso SP, Ayers CR, Lewis B, Oslica R, Francis W, et al. Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled clinical trial. Lancet Diabetes Endocrinol. 2021;9(9):595-605.

19. Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138-150.

20. Sposito AC, Berwanger O, de Carvalho LSF, Saraiva JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol. 2018;17(1):157.

21. Rakipovski G, Rolin B, Nøhr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE−/− and LDLr−/− mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3(6):844-857.

22. Badve SV, Bilal A, Lee MMY, et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2025;13(1):15-28.

23. Skov J. Effects of GLP-1 in the kidney. Rev Endocr Metab Disord. 2014;15(3):197-207. doi:10.1007/s11154-014-9287-7.

24. Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017;13(10):605-628.

25. Yuan D, Sharma H, Krishnan A, Vangaveti VN, Malabu UH. Effect of glucagon-like peptide 1 receptor agonists on albuminuria in adult patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2022;24(9):1869-1881.

26. Kawanami D, Takashi Y. GLP-1 receptor agonists in diabetic kidney disease: from clinical outcomes to mechanisms. Front Pharmacol. 2020;11:967.

27. Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia. 2011;54(4):965-978.

28. Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-848.

29. Sue YM, Lu DE, Chang TI, Chen CY, Chen CH, Hsu SC, et al. Comparative effects of dulaglutide and semaglutide on kidney function decline and proteinuria reduction in patients with diabetes: a retrospective cohort study. J Clin Med. 2025;14(12):4287. doi:10.3390/jcm14124287.

30. Tuttle KR, Lakshmanan MC, Rayner B, Zimmermann AG, Woodward B, Botros FT. Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7). Diabetes Obes Metab. 2019;21(6):1493-1497.

31. McGuire DK, Marx N, Johansen OE, Inzucchi SE, Rosenstock J, George JT. FDA guidance on antihyperglyacemic therapies for type 2 diabetes: one decade later. Diabetes Obes Metab. 2019;21(5):1073-1078. doi:10.1111/dom.13645.

32. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.

33. Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-1529.

34. Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385(10):896-907.

35. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(Suppl 1):S181-S206. doi:10.2337/dc25-S009.

36. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662.

37. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105(4 Suppl):S117-S314.

38. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023;44(39):4043-4140.

39. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.