{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:34:03Z","timestamp":1787027643739,"version":"build-2736575974"},"reference-count":94,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIHR Brendon Stubbs is part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust"},{"name":"Maudsley Charity, King\u2019s College London"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Although glucagon-like peptide-1 (GLP-1) receptor agonists and sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors have gained attention for their broad therapeutic effects, their influence on hematologic malignancy remains underexplored. Given the high mortality associated with hematologic cancers, clarifying the impact of these agents on such malignancies is essential. Objectives: This pilot network meta-analysis (NMA) aimed to assess the comparative risk of hematologic malignancies\u2014including lymphoma, leukemia, and myeloma\u2014associated with various GLP-1 receptor agonists and SGLT2 inhibitors. Methods: Following Cochrane-recommended confirmatory methods, we systematically searched multiple databases for randomized controlled trials (RCTs) published through 4 December 2024. The primary outcome was the incidence of overall hematologic malignancies. A frequentist random-effects NMA via the netmeta package was conducted, with additional validation through Bayesian NMA for solely sensitivity analyses. Results: Fifty-five RCTs (n = 200,606) were analyzed. Dulaglutide showed a significantly higher risk of overall hematologic malignancy [odds ratio (OR) = 2.18, 95% confidence interval (95%CI) = 1.14\u20134.19). In contrast, tirzepatide was linked to a significantly reduced risk (OR = 0.14, 95%CI = 0.03\u20130.60), especially for lymphoma. No statistically significant associations were identified for SGLT2 inhibitors (i.e., 95%CI across 1.0). Conclusions: Our preliminary findings reveal distinct and agent-specific effects of GLP-1 receptor agonists on hematologic malignancy risk. While dulaglutide may elevate the risk, tirzepatide appears protective, particularly against lymphoma. These results call for further long-term mechanistic studies to clarify causality and underlying pathways.<\/jats:p>","DOI":"10.3390\/biom15111622","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T08:50:07Z","timestamp":1763542207000},"page":"1622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Divergent Risks of Hematologic Malignancies Associated with GLP-1 Receptor Agonists and SGLT2 Inhibitors: Preliminary Findings from a Pilot Network Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1394-4567","authenticated-orcid":false,"given":"Pao-Yen","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"},{"name":"Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Yan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8650-4060","authenticated-orcid":false,"given":"Chih-Wei","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-0322","authenticated-orcid":false,"given":"Mein-Woei","family":"Suen","sequence":"additional","affiliation":[{"name":"Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan"},{"name":"Gender Equality Education and Research Center, Asia University, Taichung 413, Taiwan"},{"name":"Department of Medical Research, Asia University Hospital, Asia University, Taichung 413, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Ming","family":"Hung","sequence":"additional","affiliation":[{"name":"Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan"},{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendon","family":"Stubbs","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Department of Sport, University of Vienna, Vienna 1030, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-1311","authenticated-orcid":false,"given":"Tien-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Tri-Service General Hospital, National Defense Medical University, Taipei 114, Taiwan"},{"name":"Department of Psychiatry, College of Medicine, National Defense Medical University, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Te","family":"Lei","sequence":"additional","affiliation":[{"name":"Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Munipical MacKay Children\u2019s Hospital, Hsinchu 300, Taiwan"},{"name":"Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiann-Jy","family":"Chen","sequence":"additional","affiliation":[{"name":"Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan"},{"name":"Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Syuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-2502","authenticated-orcid":false,"given":"Kuan-Pin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan"},{"name":"Mind-Body Interface Research Center (MBI Lab & Care), China Medical University Hospital, Taichung 404, Taiwan"},{"name":"College of Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"An-Nan Hospital, China Medical University, Tainan 709, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-5586","authenticated-orcid":false,"given":"Chih-Sung","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical University, Taipei 112, Taiwan"},{"name":"Department of Psychiatry, National Defense Medical University, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5761-7800","authenticated-orcid":false,"given":"Ping-Tao","family":"Tseng","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan"},{"name":"Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan"},{"name":"Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/S2213-8587(22)00247-9","article-title":"Glucose-lowering drugs with cardiovascular benefits as modifiers of critical elements of the human life history","volume":"10","author":"Avogaro","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hung, C.M., Zeng, B.Y., Hsu, C.W., Chen, P.H., Sun, C.K., Carvalho, A.F., Stubbs, B., Chen, Y.W., Chen, T.Y., and Lei, W.T. (2025). The different colorectal tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: A network meta-analysis of 68 randomized controlled trials. Int. J. Surg.","DOI":"10.1097\/JS9.0000000000003450"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1007\/s00125-020-05338-7","article-title":"Association between diabetes and haematological malignancies: A population-based study","volume":"64","author":"Gong","year":"2021","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2575108","DOI":"10.1080\/07853890.2025.2575108","article-title":"Impact of diabetes and glycemic control during cancer care on mortality in non-metastatic solid and hematologic malignancies","volume":"57","author":"Wuthikraikun","year":"2025","journal-title":"Ann. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yang, Z., Lv, Y., Yu, M., Mei, M., Xiang, L., Zhao, S., and Li, R. (2022). GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.925377"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1182\/blood-2023-190760","article-title":"Sodium Glucose Cotransporter-2 Inhibitor Is Associated with Lower Risk of Lymphoid Malignancy: Result from Large Real-World Cohorts","volume":"142","author":"Lee","year":"2023","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"216793","DOI":"10.1016\/j.canlet.2024.216793","article-title":"Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis","volume":"595","author":"Yang","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/S0140-6736(18)32261-X","article-title":"Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial","volume":"392","author":"Hernandez","year":"2018","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_12","first-page":"721","article-title":"Opportunities and challenges of clinical research in the big-data era: From RCT to BCT","volume":"5","author":"Wang","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"ref_13","first-page":"1659","article-title":"Big data and clinical research: Perspective from a clinician","volume":"6","author":"Zhang","year":"2014","journal-title":"J. Thorac. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/S0140-6736(15)61478-7","article-title":"Network meta-analysis: A norm for comparative effectiveness?","volume":"386","author":"Higgins","year":"2015","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tseng, P.T., Zeng, B.Y., Hsu, C.W., Hung, C.M., Carvalho, A.F., Stubbs, B., Chen, Y.W., Chen, T.Y., Lei, W.T., and Chen, J.J. (2025). The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: Evidence from a network meta-analysis. BMC Med., 23.","DOI":"10.1186\/s12916-025-04018-w"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hsu, C.W., Zeng, B.S., Liang, C.S., Zeng, B.Y., Hung, C.M., Stubbs, B., Chen, Y.W., Lei, W.T., Chen, J.J., and Chen, P.H. (2025). The Preventive Effects of GLP-1 Receptor Agonists and SGLT2 Inhibitors on Cancer Metastasis: A Network Meta-Analysis of 67 Randomized Controlled Trials. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178202"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, J.J., Hsu, C.W., Hung, C.M., Liang, C.S., Su, K.P., Carvalho, A.F., Stubbs, B., Chen, Y.W., Chen, T.Y., and Lei, W.T. (2025). Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors. Pharmaceuticals, 18.","DOI":"10.3390\/ph18050735"},{"key":"ref_18","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2023). Chapter 19: Adverse effects. Cochrane Handbook for Systematic Reviews of Interventions, Cochrane."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"777","DOI":"10.7326\/M14-2385","article-title":"The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations","volume":"162","author":"Hutton","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e024537","DOI":"10.1136\/bmjopen-2018-024537","article-title":"Analysis and reporting of adverse events in randomised controlled trials: A review","volume":"9","author":"Phillips","year":"2019","journal-title":"BMJ Open"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Higgins, J., and Green, S. (2009). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2, The Cochrane Collaboration.","DOI":"10.1002\/9780470712184"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40164-021-00198-2","article-title":"A global, regional, and national survey on burden and Quality of Care Index (QCI) of hematologic malignancies; global burden of disease systematic analysis 1990\u20132017","volume":"10","author":"Keykhaei","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chaimani, A., Caldwell, D.M., Li, T., Higgins, J.P.T., and Salanti, G. (2018). Chapter 11: Undertaking network meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions, Cochrane.","DOI":"10.1002\/9781119536604.ch11"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/jrsm.12","article-title":"A basic introduction to fixed-effect and random-effects models for meta-analysis","volume":"1","author":"Borenstein","year":"2010","journal-title":"Res. Synth. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/jrsm.1373","article-title":"MetaInsight: An interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta","volume":"10","author":"Owen","year":"2019","journal-title":"Res. Synth. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e010983","DOI":"10.1136\/bmjopen-2015-010983","article-title":"Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: A simulation study","volume":"6","author":"Cheng","year":"2016","journal-title":"BMJ Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1002\/sim.6301","article-title":"The Peto odds ratio viewed as a new effect measure","volume":"33","author":"Brockhaus","year":"2014","journal-title":"Stat. Med."},{"key":"ref_29","unstructured":"Borenstein, M. Converting Among Effect Sizes. Available online: https:\/\/www.meta-analysis.com\/downloads\/Meta-analysis%20Converting%20among%20effect%20sizes.pdf."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/sim.3767","article-title":"Checking consistency in mixed treatment comparison meta-analysis","volume":"29","author":"Dias","year":"2010","journal-title":"Stat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jclinepi.2023.02.016","article-title":"A multifaceted graphical display, including treatment ranking, was developed to aid interpretation of network meta-analysis","volume":"157","author":"Nevill","year":"2023","journal-title":"J. Clin. Epidemiol."},{"key":"ref_32","unstructured":"Scott, M., and Barnett, V. (2002). Chapter 3: Model fit, model comparison and outlier detection. Network Meta-Anlaysis for Decision-Making, John Wiley & Sons Ltd."},{"key":"ref_33","first-page":"m3907","article-title":"GRADE approach to drawing conclusions from a network meta-analysis using a partially contextualised framework","volume":"371","author":"Izcovich","year":"2020","journal-title":"BMJ"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in Heart Failure with a Preserved Ejection Fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jama.2023.24945","article-title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial","volume":"331","author":"Aronne","year":"2024","journal-title":"JAMA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/S0140-6736(10)60407-2","article-title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: A randomised, double-blind, placebo-controlled trial","volume":"375","author":"Bailey","year":"2010","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1056\/NEJMoa2030186","article-title":"Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease","volume":"384","author":"Bhatt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0140-6736(09)60659-0","article-title":"Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)","volume":"374","author":"Buse","year":"2009","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1056\/NEJMoa2004967","article-title":"Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes","volume":"383","author":"Cannon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1111\/dom.15019","article-title":"Efficacy and safety of sotagliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease","volume":"25","author":"Cherney","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.2337\/dc18-0342","article-title":"HbA(1c) and Hypoglycemia Reductions at 24 and 52 Weeks with Sotagliflozin in Combination with Insulin in Adults with Type 1 Diabetes: The European inTandem2 Study","volume":"41","author":"Danne","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(21)00213-0","article-title":"Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial","volume":"397","author":"Davies","year":"2021","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1016\/S0140-6736(21)02188-7","article-title":"Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial","volume":"398","author":"Kahn","year":"2021","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.2337\/dc13-0663","article-title":"Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes","volume":"36","author":"Ferrannini","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Frias","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/dom.13631","article-title":"Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial","volume":"21","author":"Gallo","year":"2019","journal-title":"Diabetes Obes. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(23)01200-X","article-title":"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","volume":"402","author":"Garvey","year":"2023","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0140-6736(19)31149-3","article-title":"Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial","volume":"394","author":"Gerstein","year":"2019","journal-title":"Lancet"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1056\/NEJMoa2108269","article-title":"Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes","volume":"385","author":"Gerstein","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2337\/dc14-1625","article-title":"Efficacy and Safety of Once-Weekly Dulaglutide Versus Insulin Glargine in Patients With Type 2 Diabetes on Metformin and Glimepiride (AWARD-2)","volume":"38","author":"Giorgino","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s13300-017-0337-5","article-title":"Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study","volume":"9","author":"Grunberger","year":"2018","journal-title":"Diabetes Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.2337\/dc16-0522","article-title":"Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes","volume":"39","author":"Hadjadj","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in Patients with Chronic Kidney Disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1056\/NEJMoa1612917","article-title":"Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes","volume":"377","author":"Holman","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.diabres.2017.06.013","article-title":"Three-year data from 5 HARMONY phase 3 clinical trials of albiglutide in type 2 diabetes mellitus: Long-term efficacy with or without rescue therapy","volume":"131","author":"Home","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1056\/NEJMoa1901118","article-title":"Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"381","author":"Husain","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1111\/dom.13218","article-title":"Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial","volume":"20","author":"Kaku","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_59","unstructured":"Lock, J.P. Bexagliflozin Efficacy and Safety Trial (BEST), Available online: https:\/\/clinicaltrials.gov\/study\/NCT02558296?cond=NCT02558296&rank=1."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","article-title":"Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"84","DOI":"10.2337\/dc08-1355","article-title":"Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study","volume":"32","author":"Nauck","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.2337\/dc15-2479","article-title":"Once-Daily Liraglutide Versus Lixisenatide as Add-on to Metformin in Type 2 Diabetes: A 26-Week Randomized Controlled Clinical Trial","volume":"39","author":"Nauck","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1007\/s00125-015-3795-1","article-title":"Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise","volume":"59","author":"Nauck","year":"2016","journal-title":"Diabetologia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1056\/NEJMoa1509225","article-title":"Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome","volume":"373","author":"Pfeffer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1411892","article-title":"A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management","volume":"373","author":"Astrup","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S2213-8587(14)70120-2","article-title":"Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: A 104-week randomised, active-controlled, double-blind, phase 3 trial","volume":"2","author":"Ridderstrale","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1001\/jama.2019.2942","article-title":"Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial","volume":"321","author":"Rosenstock","year":"2019","journal-title":"JAMA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.2337\/dc14-0001","article-title":"Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: A comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro","volume":"37","author":"Rosenstock","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1001\/jama.2021.3224","article-title":"Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial","volume":"325","author":"Rubino","year":"2021","journal-title":"JAMA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa2204233","article-title":"Empagliflozin in Patients with Chronic Kidney Disease","volume":"388","author":"Herrington","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.2337\/dc21-2034","article-title":"Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials","volume":"45","author":"Tuttle","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.2337\/dc13-2759","article-title":"Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3)","volume":"37","author":"Umpierrez","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1111\/jdi.13888","article-title":"Effect of canagliflozin on the decline of estimated glomerular filtration rate in chronic kidney disease patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III study in Japan","volume":"13","author":"Wada","year":"2022","journal-title":"J. Diabetes Investig."},{"key":"ref_79","unstructured":"Wason, S. Efficacy and Safety of Sotagliflozin Versus Placebo in Participants with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control While Taking Insulin Alone or with Other Oral Antidiabetic Agents (SOTA-INS), Available online: https:\/\/clinicaltrials.gov\/study\/NCT03285594?cond=NCT03285594&rank=1."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1007\/s00125-014-3360-3","article-title":"HARMONY 4: Randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea","volume":"57","author":"Weissman","year":"2014","journal-title":"Diabetologia"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"405","DOI":"10.7326\/0003-4819-156-6-201203200-00003","article-title":"Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: A randomized trial","volume":"156","author":"Wilding","year":"2012","journal-title":"Ann. Intern. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1007\/s11064-022-03853-0","article-title":"Dulaglutide Improves Gliosis and Suppresses Apoptosis\/Autophagy Through the PI3K\/Akt\/mTOR Signaling Pathway in Vascular Dementia Rats","volume":"48","author":"Guan","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"A893","DOI":"10.1210\/jendso\/bvab048.1823","article-title":"Medullary Carcinoma of Thyroid Due to GLP-1 Receptor Agonist","volume":"5","author":"Vemula","year":"2021","journal-title":"J. Endocr. Soc."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.2217\/epi-2023-0332","article-title":"Dulaglutide as a demethylating agent to improve the outcome of breast cancer","volume":"15","author":"Tatsch","year":"2023","journal-title":"Epigenomics"},{"key":"ref_87","first-page":"454","article-title":"The Gene Expression Profile and DNA Methylation Pattern of CDH1 and DNMT1 Genes in Acute Promyelocytic Leukemia (APL)","volume":"8","author":"Zebardast","year":"2020","journal-title":"Rep. Biochem. Mol. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5891532","DOI":"10.1155\/2023\/5891532","article-title":"Research Progress on the GIP\/GLP-1 Receptor Coagonist Tirzepatide, a Rising Star in Type 2 Diabetes","volume":"2023","author":"Ma","year":"2023","journal-title":"J. Diabetes Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e140532","DOI":"10.1172\/jci.insight.140532","article-title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","volume":"5","author":"Willard","year":"2020","journal-title":"JCI Insight"},{"key":"ref_90","first-page":"631","article-title":"The role and mechanism of beta-arrestins in cancer invasion and metastasis (Review)","volume":"41","author":"Song","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ygyno.2024.10.004","article-title":"Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer","volume":"191","author":"Kong","year":"2024","journal-title":"Gynecol. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1126\/science.1074611","article-title":"Structure of the extracellular region of HER3 reveals an interdomain tether","volume":"297","author":"Cho","year":"2002","journal-title":"Science"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ccr.2014.02.025","article-title":"ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics","volume":"25","author":"Arteaga","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.annepidem.2023.05.004","article-title":"The application of lag times in cancer pharmacoepidemiology: A narrative review","volume":"84","author":"Hicks","year":"2023","journal-title":"Ann. Epidemiol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T10:28:04Z","timestamp":1763548084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":94,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111622"],"URL":"https:\/\/doi.org\/10.3390\/biom15111622","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}