A Scoping Review on Recent Advances in Antidiabetic Medications: From GLP-1 Receptor Agonists to Dual and Triple Agonists
DOI:
https://doi.org/10.63623/8cv4gh26Keywords:
GLP-1 receptor agonists, Dual GLP-1/GIP receptor agonists, Triple GLP-1/GIP and glucagon agonists, Type 2 diabetes mellitus, Management, Cardiometabolic protectionAbstract
The management of type 2 diabetes mellitus (T2DM) has evolved substantially with the development of incretin-based therapies targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide (GIP) receptor, and glucagon receptor. This review provides a comprehensive overview of the mechanisms, clinical efficacy, and therapeutic relevance of GLP-1 receptor agonists (GLP-1 RAs), dual GLP-1/GIP receptor agonists, and emerging triple agonists targeting GLP-1, GIP, and glucagon receptors. GLP-1 RAs, now well-established in clinical practice, offer robust glycemic control, weight reduction, and proven cardiovascular and renal benefits through glucose-dependent insulinotropic effects, appetite suppression, and cardiometabolic protection. Dual agonists, such as tirzepatide, expand upon these benefits by simultaneously activating the GIP receptor, yielding superior glycemic efficacy and unprecedented weight loss, alongside potential insulin-sensitizing effects. The latest innovation, triple agonists like retatrutide, incorporate glucagon receptor activation to further enhance energy expenditure, fat loss, and metabolic flexibility, with promising early results in obesity, diabetes, and nonalcoholic fatty liver disease. Together, these agents represent a significant therapeutic advancement in T2DM, with increasing potential for comprehensive cardiometabolic disease management. This review summarizes current evidence from clinical trials and mechanistic studies, discusses comparative benefits, and highlights future directions for optimizing their clinical use.
References
[1]Ogurtsova K, Guariguata L, Barengo NC, Ruiz PL, Sacre JW, Karuranga S, et al. IDF diabetes atlas: Global estimates of undiagnosed diabetes in adults for 2021. Diabetes Research and Clinical Practice, 2022, 183, 109118. DOI: 10.1016/j.diabres.2021.109118
[2]Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes, Obesity and Metabolism, 2018, 20 Suppl 1, 5-21. DOI: 10.1111/dom.13129
[3]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. New England Journal of Medicine, 2021, 385(6), 503-515. DOI: 10.1056/NEJMoa2107519
[4]Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, et al. LY3437943, A novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet, 2022, 400(10366), 1869-1881. DOI: 10.1016/s0140-6736(22)02033-5
[5]Lee HY, Ko SH, Park S, Kim K, Kim SY, Cho IJ, et al. The role of glucagon-like peptide-1 receptor agonists (GLP1-RAS) in the management of the hypertensive patient with metabolic syndrome: A position paper from the Korean society of hypertension. Clinical Hypertension, 2024, 30(1), 24. DOI: 10.1186/s40885-024-00279-4
[6]Zhang X, Cao C, Zheng F, Liu C, Tian X. Therapeutic potential of GLP-1 receptor agonists in diabetes and cardiovascular disease: Mechanisms and clinical implications. Cardiovascular Drugs and Therapy, 2025. DOI: 10.1007/s10557-025-07670-9
[7]Tariq S, Ali MA, Hassan Iftikhar HM, Fareh Ali M, Shah SQA, Perveen F, et al. Long-term cardiovascular outcomes of glucagon-like peptide-1 (GLP-1) receptor agonists in type 2 diabetes: A systematic review. Cureus, 2024, 16(11), e73705. DOI: 10.7759/cureus.73705
[8]Turkistani Y. Glucagon-like peptide-1 receptor agonists: A review from a cardiovascular perspective. Frontiers in Cardiovascular Medicine, 2025, 12, 1535134. DOI: 10.3389/fcvm.2025.1535134
[9]Joshi N, Qasim MZ, Kanumilli S, Shaukat F, Kumar A, Mahek F, et al. Exploring the clinical effectiveness of glucagon-like peptide-1 receptor agonists in managing cardiovascular complications: An updated comprehensive review and future directives. Annals of Medicine and Surgery, 2024, 86(10), 5947-5956. DOI: 10.1097/ms9.0000000000002494
[10]Hullon D, Subeh GK, Volkova Y, Janiec K, Trach A, Mnevets R. The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: A potential avenue for improving heart failure with preserved ejection fraction (HFpEF). Cardiovascular Diabetology, 2025, 24(1), 70. DOI: 10.1186/s12933-025-02607-w
[11]Caruso I, Cignarelli A, Sorice GP, Natalicchio A, Perrini S, Laviola L, et al. Cardiovascular and renal effectiveness of GLP-1 receptor agonists vs. Other glucose-lowering drugs in type 2 diabetes: A systematic review and meta-analysis of real-world studies. Metabolites, 2022, 12(2), 183. DOI: 10.3390/metabo12020183
[12]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, 2022, 146(24), 1882-1894. DOI: 10.1161/circulationaha.122.059595
[13]Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 2016, 375(4), 311-322. DOI: 10.1056/NEJMoa1603827
[14]Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine, 2016, 375(19), 1834-1844. DOI: 10.1056/NEJMoa1607141
[15]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. DOI: 10.1016/s0140-6736(19)31149-3
[16]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. DOI: 10.1016/s0140-6736(18)32261-x
[17]Mullur N, Morissette A, Morrow NM, Mulvihill EE. GLP-1 receptor agonist-based therapies and cardiovascular risk: A review of mechanisms. Journal of Endocrinology, 2024, 263(1). DOI: 10.1530/joe-24-0046
[18]Mahapatro A, Bozorgi A, Obulareddy SUJ, Jain SM, Reddy Korsapati R, Kumar A, et al. Glucagon-like peptide-1 agonists in cardiovascular diseases: A bibliometric analysis from inception to 2023. Annals of Medicine and Surgery, 2024, 86(11), 6602-6618. DOI: 10.1097/ms9.0000000000002592
[19]Rolek B, Haber M, Gajewska M, Rogula S, Pietrasik A, Gąsecka A. SGLT2 inhibitors vs. GLP-1 agonists to treat the heart, the kidneys and the brain. Journal of Cardiovascular Development and Disease, 2023, 10(8), 322. DOI: 10.3390/jcdd10080322
[20]Felix N, Gauza MM, Bittar V, Nogueira A, Costa TA, Godoi A, et al. Cardiovascular and kidney outcomes of glucagon-like peptide 1 receptor agonist therapy in type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Cardiorenal Medicine, 2025, 15(1), 98-107. DOI: 10.1159/000543149
[21]Das SR, Everett BM, Birtcher KK, Brown JM, Januzzi JL, Jr., Kalyani RR, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: A report of the American college of cardiology solution set oversight committee. Journal of the American College of Cardiology, 2020, 76(9), 1117-1145. DOI: 10.1016/j.jacc.2020.05.037
[22]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 & Endocrinology, 2021, 9(10), 653-662. DOI: 10.1016/s2213-8587(21)00203-5
[23]Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, 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 cardiovascular outcome trials. Lancet Diabetes Endocrinol, 2019, 7(10), 776-785. DOI: 10.1016/s2213-8587(19)30249-9
[24]Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Christensen L, Davies M, et al. Design and baseline characteristics of STEP-HFpEF program evaluating semaglutide in patients with obesity HFpEF phenotype. JACC Heart Failure, 2023, 11(8 Pt 1), 1000-1010. DOI: 10.1016/j.jchf.2023.05.010
[25]Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. New England Journal of Medicine, 2023, 389(12), 1069-1084. DOI: 10.1056/NEJMoa2306963
[26]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 to Translational Science, 2018, 3(6), 844-857. DOI: 10.1016/j.jacbts.2018.09.004
[27]Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes, 2010, 59(4), 1030-1037. DOI: 10.2337/db09-1694
[28]Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: A systematic review and network meta-analysis. Clinical Therapeutics, 2015, 37(1), 225-241.e228. DOI: 10.1016/j.clinthera.2014.11.008
[29]Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. International Journal of Obesity, 2012, 36(6), 843-854. DOI: 10.1038/ijo.2011.158
[30]Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine, 2019, 381(9), 841-851. DOI: 10.1056/NEJMoa1901118
[31]Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 2017, 377(13), 1228-1239. DOI: 10.1056/NEJMoa1612917
[32]Skrobucha A, Pindlowski P, Krajewska N, Grabowski M, Jonik S. Anti-inflammatory effects of glucagon-like peptide-1 (GLP-1) in coronary artery disease: A comprehensive review. Frontiers in Cardiovascular Medicine, 2024, 11, 1446468. DOI: 10.3389/fcvm.2024.1446468
[33]Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators of Inflammation, 2016, 2016, 3094642. DOI: 10.1155/2016/3094642
[34]ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 10. Cardiovascular disease and risk management: Standards of care in diabetes-2023. Diabetes Care, 2023, 46(Suppl 1), S158-s190. DOI: 10.2337/dc23-S010
[35]Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC guidelines for the management of chronic coronary syndromes. European Heart Journal, 2024, 45(36), 3415-3537. DOI: 10.1093/eurheartj/ehae177
[36]Kelly M, Lewis J, Rao H, Carter J, Portillo I, Beuttler R. Effects of GLP-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and meta-analysis. Pharmacotherapy, 2022, 42(12), 921-928. DOI: 10.1002/phar.2737
[37]Gerstein HC, Mian R, Ramasundarahettige C, Branch KRH, Del Prato S, Lam CSP, et al. Cardiovascular and renal outcomes with varying degrees of kidney disease in high-risk people with type 2 diabetes: An epidemiological analysis of data from the AMPLITUDE-O trial. Diabetes, Obesity and Metabolism, 2024, 26(4), 1216-1223. DOI: 10.1111/dom.15417
[38]Pratley RE, Tuttle KR, Rossing P, Rasmussen S, Perkovic V, Nielsen OW, et al. Effects of semaglutide on heart failure outcomes in diabetes and chronic kidney disease in the flow trial. Journal of the American College of Cardiology, 2024, 84(17), 1615-1628. DOI: 10.1016/j.jacc.2024.08.004
[39]Klein KR, Clemmensen KKB, Fong E, Olsen S, Abrahamsen T, Lingvay I. Occurrence of gastrointestinal adverse events upon GLP-1 receptor agonist initiation with concomitant metformin use: A post hoc analysis of LEADER, STEP 2, SUSTAIN-6, and PIONEER 6. Diabetes Care, 2024, 47(2), 280-284. DOI: 10.2337/dc23-1791
[40]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. African Health Sciences, 2022, 22(3), 267-274. DOI: 10.4314/ahs.v22i3.28
[41]Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Research and Clinical Practice, 2015, 110(1), 26-37. DOI: 10.1016/j.diabres.2015.07.015
[42]Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: Combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovascular Diabetology, 2020, 19(1), 156. DOI: 10.1186/s12933-020-01106-4
[43]Baggio LL, Yusta B, Mulvihill EE, Cao X, Streutker CJ, Butany J, et al. GLP-1 receptor expression within the human heart. Endocrinology, 2018, 159(4), 1570-1584. DOI: 10.1210/en.2018-00004
[44]Mann JFE, Ørsted DD, Buse JB. Liraglutide and renal outcomes in type 2 diabetes. New England Journal of Medicine, 2017, 377(22), 2197-2198. DOI: 10.1056/NEJMc1713042
[45]Lingvay I, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics. Obesity (Silver Spring), 2023, 31(1), 111-122. DOI: 10.1002/oby.23621
[46]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. New England Journal of Medicine, 2024, 391(2), 109-121. DOI: 10.1056/NEJMoa2403347
[47]Mathiesen DS, Bagger JI, Bergmann NC, Lund A, Christensen MB, Vilsbøll T, et al. The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-a review. International Journal of Molecular Sciences, 2019, 20(17). DOI: 10.3390/ijms20174092
[48]Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 2024, 9(1), 234. DOI: 10.1038/s41392-024-01931-z
[49]Ma X, Liu Z, Ilyas I, Little PJ, Kamato D, Sahebka A, et al. GLP-1 receptor agonists (GLP-1RAs): Cardiovascular actions and therapeutic potential. International Journal of Biological Sciences, 2021, 17(8), 2050-2068. DOI: 10.7150/ijbs.59965
[50]Menghini R, Casagrande V, Rizza S, Federici M. GLP-1RAs and cardiovascular disease: Is the endothelium a relevant platform? Acta Diabetologica, 2023, 60(11), 1441-1448. DOI: 10.1007/s00592-023-02124-w
[51]Oh YS, Jun HS. Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. International Journal of Molecular Sciences, 2017, 19(1). DOI: 10.3390/ijms19010026
[52]Vergès B, Aboyans V, Angoulvant D, Boutouyrie P, Cariou B, Hyafil F, et al. Protection against stroke with glucagon-like peptide-1 receptor agonists: A comprehensive review of potential mechanisms. Cardiovascular Diabetology, 2022, 21(1), 242. DOI: 10.1186/s12933-022-01686-3
[53]Alharbi SH. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Therapeutic Advances in Endocrinology and Metabolism, 2024, 15, 20420188231222367. DOI: 10.1177/20420188231222367
[54]Park B, Bakbak E, Teoh H, Krishnaraj A, Dennis F, Quan A, et al. GLP-1 receptor agonists and atherosclerosis protection: The vascular endothelium takes center stage. American Journal of Physiology-Heart and Circulatory Physiology, 2024, 326(5), H1159-H1176. DOI: 10.1152/ajpheart.00574.2023
[55]Hinrichs GR, Hovind P, Asmar A. The GLP-1-mediated gut-kidney cross talk in humans: Mechanistic insight. American Journal of Physiology-Cell Physiology, 2024, 326(2), C567-C572. DOI: 10.1152/ajpcell.00476.2023
[56]Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nature Medicine, 2013, 19(5), 567-575. DOI: 10.1038/nm.3128
[57]Song W, Wang H, Wu Q. Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene, 2015, 569(1), 1-6. DOI: 10.1016/j.gene.2015.06.029
[58]Karakasis P, Patoulias D, Theofilis P, Pamporis K, Sagris M, Vlachakis PK, et al. GLP-1 receptor agonists and myocardial perfusion: Bridging mechanisms to clinical outcomes. International Journal of Molecular Sciences, 2025, 26(7), 3050. DOI: 10.3390/ijms26073050
[59]Buse JB, Bain SC, Mann JFE, Nauck MA, Nissen SE, Pocock S, et al. Cardiovascular risk reduction with liraglutide: An exploratory mediation analysis of the LEADER trial. Diabetes Care, 2020, 43(7), 1546-1552. DOI: 10.2337/dc19-2251
[60]Lin Y, Wang TH, Tsai ML, Wu VC, Tseng CJ, Lin MS, et al. The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease. Cardiovascular Diabetology, 2023, 22(1), 60. DOI: 10.1186/s12933-023-01793-9
[61]Liarakos AL, Koliaki C. Novel dual incretin receptor agonists in the spectrum of metabolic diseases with a focus on tirzepatide: Real game-changers or great expectations? A narrative review. Biomedicines, 2023, 11(7), 1875. DOI: 10.3390/biomedicines11071875
[62]Yang J, Gu Y, Chen H, Wang H, Hong L, Li B, et al. Tirzepatide's innovative applications in the management of type 2 diabetes and its future prospects in cardiovascular health. Frontiers in Pharmacology, 2024, 15, 1453825. DOI: 10.3389/fphar.2024.1453825
[63]Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity. Frontiers in Endocrinology, 2022, 13, 1004044. DOI: 10.3389/fendo.2022.1004044
[64]Yan K, Yu H, Blaise B. Beyond GLP-1: Efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care-a systematic review and network meta-analysis. Acta Diabetologica, 2025. DOI: 10.1007/s00592-025-02534-y
[65]Rizvi AA, Rizzo M. The emerging role of dual GLP-1 and GIP receptor agonists in glycemic management and cardiovascular risk reduction. Diabetes, Metabolic Syndrome and Obesity, 2022, 15, 1023-1030. DOI: 10.2147/dmso.s351982
[66]De Block C, Bailey C, Wysham C, Hemmingway A, Allen SE, Peleshok J. Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective. Diabetes, Obesity and Metabolism, 2023, 25(1), 3-17. DOI: 10.1111/dom.14831
[67]Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Correction: Chavda Et Al. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: A mini-review. Molecules, 2025(6), 1190. DOI: 10.3390/molecules30061190
[68]Cho YK, La Lee Y, Jung CH. The cardiovascular effect of tirzepatide: A glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide dual agonist. Journal of Lipid and Atherosclerosis, 2023, 12(3), 213-222. DOI: 10.12997/jla.2023.12.3.213
[69]Ma Z, Jin K, Yue M, Chen X, Chen J. Research progress on the GIP/GLP-1 receptor coagonist tirzepatide, a rising star in type 2 diabetes. Journal of Diabetes Research, 2023, 2023, 5891532. DOI: 10.1155/2023/5891532
[70]Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet, 2018, 392(10160), 2180-2193. DOI: 10.1016/s0140-6736(18)32260-8
[71]Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes & Endocrinology, 2022, 10(6), 393-406. DOI: 10.1016/s2213-8587(22)00070-5
[72]Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 randomized clinical trial. Journal of the American Medical Association, 2022, 327(6), 534-545. DOI: 10.1001/jama.2022.0078
[73]Battelino T, Bergenstal RM, Rodríguez A, Fernández Landó L, Bray R, Tong Z, et al. Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes & Endocrinology, 2022, 10(6), 407-417. DOI: 10.1016/s2213-8587(22)00077-8
[74]Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial. Lancet, 2021, 398(10300), 583-598. DOI: 10.1016/s0140-6736(21)01443-4
[75]Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet, 2021, 398(10295), 143-155. DOI: 10.1016/s0140-6736(21)01324-6
[76]Zhou Q, Lei X, Fu S, Liu P, Long C, Wang Y, et al. Efficacy and safety of tirzepatide, dual GLP-1/GIP receptor agonists, in the management of type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetology & Metabolic Syndrome, 2023, 15(1), 222. DOI: 10.1186/s13098-023-01198-4
[77]Dutta D, Surana V, Singla R, Aggarwal S, Sharma M. Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A cochrane meta-analysis. Indian Journal of Endocrinology and Metabolism, 2021, 25(6), 475-489. DOI: 10.4103/ijem.ijem_423_21
[78]Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas A, et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: A systematic review and meta-analysis. Diabetologia, 2022, 65(8), 1251-1261. DOI: 10.1007/s00125-022-05715-4
[79]Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Science Translational Medicine, 2013, 5(209), 209ra151. DOI: 10.1126/scitranslmed.3007218
[80]Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet, 2021, 398(10313), 1811-1824. DOI: 10.1016/s0140-6736(21)02188-7
[81]Syed YY. Tirzepatide: First approval. Drugs, 2022, 82(11), 1213-1220. DOI: 10.1007/s40265-022-01746-8
[82]Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, et al. Tirzepatide cardiovascular event risk assessment: A pre-specified meta-analysis. Nature Medicine, 2022, 28(3), 591-598. DOI: 10.1038/s41591-022-01707-4
[83]Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Molecular Metabolism, 2022, 63, 101533. DOI: 10.1016/j.molmet.2022.101533
[84]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. Alimentary Pharmacology & Therapeutics, 2025, 61(12), 1872-1888. DOI: 10.1111/apt.70196
[85]Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity-a phase 2 trial. New England Journal of Medicine, 2023, 389(6), 514-526. DOI: 10.1056/NEJMoa2301972
[86]Abdrabou Abouelmagd A, Abdelrehim AM, Bashir MN, Abdelsalam F, Marey A, Tanas Y, et al. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: A systematic review and meta-analysis of randomized controlled trials. Baylor University Medical Center Proceedings, 2025, 38(3), 291-303. DOI: 10.1080/08998280.2025.2456441
[87]Enyew Belay K, Jemal RH, Tuyizere A. Innovative glucagon-based therapies for obesity. Journal of the Endocrine Society, 2024, 8(12), bvae197. DOI: 10.1210/jendso/bvae197
[88]Jakubowska A, Roux CWL, Viljoen A. The road towards triple agonists: Glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and glucagon receptor-an update. Endocrinology and Metabolism, 2024, 39(1), 12-22. DOI: 10.3803/EnM.2024.1942
[89]Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: A randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet, 2023, 402(10401), 529-544. DOI: 10.1016/s0140-6736(23)01053-x
[90]Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism, 2022, 34(9), 1234-1247.e1239. DOI: 10.1016/j.cmet.2022.07.013
[91]Doggrell SA. Retatrutide showing promise in obesity (and type 2 diabetes). Expert Opinion on Investigational Drugs, 2023, 32(11), 997-1001. DOI: 10.1080/13543784.2023.2283020
[92]Abdelmalek MF, Suzuki A, Sanchez W, Lawitz E, Filozof C, Cho H, et al. A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis-study design and rationale of HM-TRIA-201 study. Contemporary Clinical Trials, 2023, 130, 107176. DOI: 10.1016/j.cct.2023.107176
[93]Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, et al. Effects on Weight Loss and Glycemic Control with SAR441255, a Potent Unimolecular Peptide GLP-1/GIP/GCG Receptor Triagonist. Cell Metabolism, 2022, 34(1), 59-74.e10. DOI: 10.1016/j.cmet.2021.12.005
[94]Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: A randomized phase 2a trial. Nature Medicine, 2024, 30(7), 2037-2048. DOI: 10.1038/s41591-024-03018-2
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