Más allá del GLP-1: Eficacia multiórgano de los agonistas duales y triples de incretinas en el síndrome cardiometabólico
DOI:
https://doi.org/10.66201/ss.v1.26Palabras clave:
tirzepatida, retatrutida, survodutida, agonistas de incretinas, síndrome cardiometabólico, obesidad, diabetes mellitus tipo 2, insuficiencia cardíaca, enfermedad renal crónica, MASLDResumen
Antecedentes: Los agonistas duales del receptor de GIP/GLP-1 (tirzepatida) y los agonistas triples (retatrutida, survodutida) han redefinido los umbrales de eficacia esperados en la farmacoterapia de la obesidad y la diabetes mellitus tipo 2 (DM2), con evidencia emergente sobre beneficios multiórgano en poblaciones de alto riesgo cardiometabólico.
Métodos: Revisión integrativa (Whittemore y Knafl, 2005) con búsqueda en PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase y Web of Science (enero 2020 – marzo 2026). Se incluyeron 35 estudios con más de 320 000 participantes que evaluaron agonistas duales o triples de incretinas en adultos con obesidad, DM2 o comorbilidades cardiometabólicas.
Resultados: Tirzepatida demostró pérdidas de peso de hasta el 20,9 % (SURMOUNT-1) y reducciones de HbA1c de 2,30 pp frente a 1,86 pp con semaglutida en SURPASS-2 (diferencia: −0,45 pp; IC 95 %: −0,57 a −0,32). En la insuficiencia cardíaca con fracción de eyección preservada (ICFEp), tirzepatida redujo el compuesto de muerte cardiovascular o deterioro cardíaco en un 38 % (HR 0,62; SUMMIT). En la enfermedad renal crónica (ERC), redujo el compuesto renal en un 42 % (HR 0,58; SURPASS-4). En esteatohepatitis asociada a disfunción metabólica (MASH), logró resolución histológica en el 62 % frente al 10 % con placebo (SYNERGY-NASH), con mejoría de fibrosis en el 51–55 %. Retatrutida alcanzó pérdidas de peso de hasta el 24,2 % en fase 2. El perfil de seguridad es favorable con predominio de efectos adversos gastrointestinales leves a moderados.
Conclusión: Los agonistas duales y triples de incretinas representan el avance farmacológico más significativo de la medicina cardiometabólica en la última década. La evidencia disponible respalda su incorporación prioritaria en las guías clínicas, con la equidad de acceso como desafío ético central.
Referencias
World Health Organization. Obesity and Overweight [Internet]. 2025 [cited 2026 Apr 4]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
Aroda VR. Comparing insulin degludec with insulin glargine in type 2 diabetes: A meta-analysis. Diabetes Care [Internet]. 2022;45(4):898–907. Available from: https://doi.org/10.2337/dc21-2458
Chew NWS, Mehta A, Goh RSJ, Zhang A, Chen Y, Chong B, et al. Cardiovascular-liver-metabolic health: Recommendations in screening, diagnosis, and management of metabolic dysfunction-associated steatotic liver disease in cardiovascular disease via modified Delphi approach. Circulation [Internet]. 2025 Jan 7;151(1):98–119. Available from: https://doi.org/10.1161/circulationaha.124.070535
Liu X, Lu CA, Shih YCT, Jiang C. Coverage and prior authorization policies for semaglutide and tirzepatide in medicare part D plans. JAMA Netw Open [Internet]. 2025 Aug 1;8(8):e2529842. Available from: https://doi.org/10.1001/jamanetworkopen.2025.29842
Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation [Internet]. 2022 Dec 13;146(24):1882–94. Available from: https://doi.org/10.1161/circulationaha.122.059595
Gonzalez-Rellan MJ, Drucker DJ. New molecules and indications for GLP-1 medicines. JAMA [Internet]. 2025 Oct 14;334(14):1231–4. Available from: https://doi.org/10.1001/jama.2025.14392
Targher G, Mantovani A, Byrne CD, Tilg H. Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists. Gut [Internet]. 2025 Feb 6;74(3):487–97. Available from: https://doi.org/10.1136/gutjnl-2024-334023
Jiang Y, Zhu H, Gong F. Why does GLP-1 agonist combined with GIP and/or GCG agonist have greater weight loss effect than GLP-1 agonist alone in obese adults without type 2 diabetes? Diabetes Obes Metab [Internet]. 2025 Mar;27(3):1079–95. Available from: https://doi.org/10.1111/dom.16106
Alfaris N, Waldrop S, Johnson V, Boaventura B, Kendrick K, Stanford FC. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review. EClinicalMedicine [Internet]. 2024 Sep;75(102782):102782. Available from: https://doi.org/10.1016/j.eclinm.2024.102782
Jakubowska A, Roux CW le, Viljoen A. The road towards triple agonists: Glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and glucagon receptor - an update. Endocrinol Metab (Seoul) [Internet]. 2024 Feb;39(1):12–22. Available from: https://doi.org/10.3803/enm.2024.1942
Gutgesell RM, Nogueiras R, Tschöp MH, Müller TD. Dual and triple incretin-based co-agonists: Novel therapeutics for obesity and diabetes. Diabetes Ther [Internet]. 2024 May;15(5):1069–84. Available from: https://doi.org/10.1007/s13300-024-01566-x
Whittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs [Internet]. 2005 Dec [cited 2025 Nov 27];52(5):546–53. Available from: http://dx.doi.org/10.1111/j.1365-2648.2005.03621.x
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29;372:n71. Available from: https://doi.org/10.1136/bmj.n71
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet]. 2019 Aug 28;366:l4898. Available from: https://doi.org/10.1136/bmj.l4898
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ [Internet]. 2016 Oct 12;355:i4919. Available from: https://doi.org/10.1136/bmj.i4919
Lam CSP, Rodriguez A, Aminian A, Ferrannini E, Heerspink HJL, Jastreboff AM, et al. Tirzepatide for reduction of morbidity and mortality in adults with obesity: rationale and design of the SURMOUNT-MMO trial. Obesity (Silver Spring) [Internet]. 2025 Sep;33(9):1645–56. Available from: https://doi.org/10.1002/oby.24332
Neff GW. Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, metabolic dysfunction-associated steatotic liver disease, and other cardio-kidney-metabolic conditions. Diabetes Obes Metab [Internet]. 2025 Dec;27(12):6869–83. Available from: https://doi.org/10.1111/dom.70148
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 [Internet]. 2022 Jul 21;387(3):205–16. Available from: https://doi.org/10.1056/nejmoa2206038
Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet [Internet]. 2023 Aug 19;402(10402):613–26. Available from: https://doi.org/10.1016/s0140-6736(23)01200-x
Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med [Internet]. 2021 Aug 5;385(6):503–15. Available from: https://doi.org/10.1056/nejmoa2107519
Barazzoni R, Monami M, Buscemi S, Busetto L, De Luca M, Navarra G, et al. Efficacy and safety of European Medicines Agency ( EMA )‐approved pharmacological, endoscopic, and surgical treatments in different classes of obesity: A network meta‐analysis of randomised controlled trials for the development of the SIO (Società Italiana Obesità) Italian guidelines for the diagnosis and treatment of overweight and obesity. Diabetes Obes Metab [Internet]. 2026 Jan;28(1):358–78. Available from: https://doi.org/10.1111/dom.70204
Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med [Internet]. 2025 Jan 30;392(5):427–37. Available from: https://doi.org/10.1056/nejmoa2410027
Krüger N, Schneeweiss S, Fuse K, Matseyko S, Sreedhara SK, Hahn G, et al. Semaglutide and tirzepatide in patients with heart failure with preserved ejection fraction. JAMA [Internet]. 2025 Oct 14;334(14):1255–66. Available from: https://doi.org/10.1001/jama.2025.14092
He YM, Zeng C, Zhang YF, Wu Q, Zhou XY, Yan PJ, et al. Effect of tirzepatide on heart failure in type 2 diabetes mellitus and obesity: A systematic review and meta-analysis. Diabetes Metab Res Rev [Internet]. 2025 Oct;41(7):e70097. Available from: https://doi.org/10.1002/dmrr.70097
Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol [Internet]. 2022 Nov;10(11):774–85. Available from: https://doi.org/10.1016/s2213-8587(22)00243-1
Kosaraju SA, Zhang RM. Tirzepatide prescribing practices and efficacy in patients with diabetes and chronic kidney disease at a large tertiary care center in the United States. Diabetes Metab Syndr Obes [Internet]. 2024 Oct 3;17:3621–8. Available from: https://doi.org/10.2147/dmso.s473319
Idris I. Real world data showed that the dual GLP gip agonist, Tirzepatide is associated with lower mortality, cardiovascular events and adverse kidney events compared with GLP‐1 analogue. Diabetes Obes Metab Now [Internet]. 2024 Sep;2(9). Available from: https://doi.org/10.1002/doi2.70003
Neuen BL, Fletcher RA, Heath L, Perkovic A, Vaduganathan M, Badve SV, et al. Cardiovascular, kidney, and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: A systematic review and meta-analysis. Circulation [Internet]. 2024 Nov 26;150(22):1781–90. Available from: https://doi.org/10.1161/circulationaha.124.071689
Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med [Internet]. 2024 Jul 25;391(4):299–310. Available from: https://doi.org/10.1056/nejmoa2401943
Petta S, Kim K, Targher G, Romeo S, Sookoian S, Zheng MH, et al. Focus on semaglutide 2.4 mg/week for the treatment of metabolic dysfunction-associated steatohepatitis. Liver Int [Internet]. 2025 Nov;45(11):e70407. Available from: https://doi.org/10.1111/liv.70407
Horn P, Tacke F. Key takeaways from the updated multidisciplinary European MASLD guidelines. eGastroenterology [Internet]. 2025 Jun 8;3(2):e100196. Available from: https://doi.org/10.1136/egastro-2025-100196
Sinha B, Ghosal S. Efficacy and safety of GLP-1 receptor agonists, dual agonists, and retatrutide for weight loss in adults with overweight or obesity: A Bayesian NMA. Obesity (Silver Spring) [Internet]. 2025 Nov;33(11):2046–54. Available from: https://doi.org/10.1002/oby.24360
Ryan DH. New drugs for the treatment of obesity: do we need approaches to preserve muscle mass? Rev Endocr Metab Disord [Internet]. 2025 Oct;26(5):805–13. Available from: https://doi.org/10.1007/s11154-025-09967-4
Trinh H, Donovan A, McAdam-Marx C. Real-world effectiveness of tirzepatide versus semaglutide for weight loss in overweight or obese patients in an ambulatory care setting. Diabetes Obes Metab [Internet]. 2025 Jun;27(6):3523–5. Available from: https://doi.org/10.1111/dom.16343
Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight [Internet]. 2020 Sep 3;5(17). Available from: http://dx.doi.org/10.1172/jci.insight.140532
Samms RJ, Christe ME, Collins KA, Pirro V, Droz BA, Holland AK, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest [Internet]. 2021 Jun 15;131(12). Available from: http://dx.doi.org/10.1172/jci146353
De Fano M, Malara M, Vermigli C, Murdolo G. Adipose tissue: A novel target of the incretin axis? A paradigm shift in obesity-linked insulin resistance. Int J Mol Sci [Internet]. 2024 Aug 8;25(16):8650. Available from: https://doi.org/10.3390/ijms25168650
Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab [Internet]. 2021 Sep;23 Suppl 3(S3):5–29. Available from: http://dx.doi.org/10.1111/dom.14496
Michos ED, Bakris GL, Rodbard HW, Tuttle KR. Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: A review of their kidney and heart protection. Am J Prev Cardiol [Internet]. 2023 Jun;14(100502):100502. Available from: https://doi.org/10.1016/j.ajpc.2023.100502
Zafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review article: GLP-1 receptor agonists and glucagon/GIP/GLP-1 receptor dual or triple agonists-mechanism of action and emerging therapeutic landscape in MASLD. Aliment Pharmacol Ther [Internet]. 2025 Jun;61(12):1872–88. Available from: https://doi.org/10.1111/apt.70196
Publicado
Número
Sección
Licencia
Derechos de autor 2026 Elizabeth Valinotti Delmás, Luz Diana Vázquez Vera, Helen López Ovelar, Fabiola Romero Gómez, Andrés Giménez Benítez, Federico Fariña Mendieta, Nadia Liz García Fernández (Autor/a)
Esta obra está bajo una licencia internacional Creative Commons Atribución 4.0.
