{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:08:53Z","timestamp":1779340133791,"version":"3.51.4"},"reference-count":123,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The current literature indicates that type 2 diabetes (T2DM) significantly increases the risk of cancer, including pancreatic cancer (PC). While metformin\u2019s primary role is the management of T2DM, its utility extends to systemic anti-cancer effects against various cancers. Nevertheless, its impact appears limited to risk reduction, as its efficacy as a primary or adjuvant treatment for established cancer remains unproven in clinical settings. This meta-analysis aimed to evaluate the association between metformin use\u2014both as monotherapy and in combination with other antidiabetic drugs (ADs)\u2014and the risk of PC. We synthesized data from 16 observational studies identified through PubMed, Cochrane Library, and Clinical Trials using the Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) framework. The data were analyzed using Cochrane Review Manager software 5.4, with results reported as the relative risk (RR) and 95% confidence interval (95% CI) for each comparative group; statistical significance was defined as p-value &lt; 0.05. Our findings indicate that metformin demonstrated a significant reduction in overall PC risk when compared to the pooled group of alternative ADs. Furthermore, metformin significantly lowers PC risk compared to sulfonylureas (SUs), alpha-glucosidase inhibitors (AGIs), and insulin. Conversely, metformin use was associated with a markedly elevated PC risk relative to thiazolidinediones (TZDs) and DPP-4 inhibitors (DPP4i). Considering metformin monotherapy vs. its combination with other ADs, we found that metformin lowered the risk of PC compared to its combination with SUs and AGIs but elevated the PC risk relative to its combination with TZDs and DPP4i. To conclude, these results suggest that metformin may protect patients with T2DM from PC development. However, individual PC risk and diabetes compliance should be taken into account when deciding whether to add an additional AD(s) to metformin therapy.<\/jats:p>","DOI":"10.3390\/ijms27104195","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T19:10:52Z","timestamp":1778267452000},"page":"4195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6545-579X","authenticated-orcid":false,"given":"Izabela","family":"Szymczak-Pajor","sequence":"first","affiliation":[{"name":"Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-9476","authenticated-orcid":false,"given":"J\u00f3zef","family":"Drzewoski","sequence":"additional","affiliation":[{"name":"Central Teaching Hospital of the Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylwia","family":"Wenclewska","sequence":"additional","affiliation":[{"name":"Department of Internal Diseases and Diabetology, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-1693","authenticated-orcid":false,"given":"Aneta","family":"Rogalska","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141\/143 Pomorska Str., 90-236 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6864-0704","authenticated-orcid":false,"given":"Agnieszka","family":"\u015aliwi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zottl, J., Sebesta, C.G., Tomosel, E., Sebesta, M.-C., and Sebesta, C. (2025). Unraveling the Burden of Pancreatic Cancer in the 21st Century: Trends in Incidence, Mortality, Survival, and Key Contributing Factors. Cancers, 17.","DOI":"10.3390\/cancers17101607"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e001544","DOI":"10.1136\/bmjgast-2024-001544","article-title":"Current and Projected Incidence Rates of Pancreatic Cancer in 43 Countries: An Analysis of the Cancer Incidence in Five Continents Database","volume":"12","author":"Shou","year":"2025","journal-title":"BMJ Open Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12029-025-01183-2","article-title":"Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of Its Histologic and Molecular Subtypes","volume":"56","author":"Leiphrakpam","year":"2025","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Antony, V., Sun, T., Dolezal, D., and Cai, G. (2025). Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas. Cancers, 17.","DOI":"10.3390\/cancers17030335"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"goaf030","DOI":"10.1093\/gastro\/goaf030","article-title":"Trends in Pancreatic Cancer Incidence, Prevalence, and Survival Outcomes by Histological Subtypes: A Retrospective Cohort Study","volume":"13","author":"Lei","year":"2025","journal-title":"Gastroenterol. Rep."},{"key":"ref_6","unstructured":"(2025, November 03). Cancer of the Pancreas\u2014Cancer Stat Facts, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/pancreas.html."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2021.06.027","article-title":"Advances in the Epidemiology of Pancreatic Cancer: Trends, Risk Factors, Screening, and Prognosis","volume":"520","author":"Cai","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1053\/j.gastro.2022.03.056","article-title":"Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment","volume":"163","author":"Wood","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mustafa, M., Abbas, K., Alam, M., Habib, S., Zulfareen, Z., Hasan, G.M., Islam, S., Shamsi, A., and Hassan, I. (2024). Investigating Underlying Molecular Mechanisms, Signaling Pathways, Emerging Therapeutic Approaches in Pancreatic Cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1427802"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Olakowski, M., and Bu\u0142dak, \u0141. (2022). Modifiable and Non-Modifiable Risk Factors for the Development of Non-Hereditary Pancreatic Cancer. Medicina, 58.","DOI":"10.3390\/medicina58080978"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"He, K.-J., Wang, H., Xu, J., Gong, G., Liu, X., and Guan, H. (2024). Global Burden of Type 2 Diabetes Mellitus from 1990 to 2021, with Projections of Prevalence to 2044: A Systematic Analysis across SDI Levels for the Global Burden of Disease Study 2021. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1501690"},{"key":"ref_12","unstructured":"International Diabetes Federation (2021). Over 250 Million People Worldwide Unaware They Have Diabetes, According to New IDF Research, International Diabetes Federation."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1200\/JCO.2016.67.4044","article-title":"Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy","volume":"34","author":"Shlomai","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Asiri, A., Al Qarni, A., and Bakillah, A. (2024). The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights. Diagnostics, 14.","DOI":"10.20944\/preprints202408.1919.v2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1158\/1055-9965.EPI-20-1245","article-title":"Type 2 Diabetes and Cancer: An Umbrella Review of Observational and Mendelian Randomization Studies","volume":"30","author":"Papadimitriou","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cosmin Stan, M., and Paul, D. (2024). Diabetes and Cancer: A Twisted Bond. Oncol. Rev., 18.","DOI":"10.3389\/or.2024.1354549"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"372","DOI":"10.4239\/wjd.v5.i3.372","article-title":"Diabetes and Cancer: Associations, Mechanisms, and Implications for Medical Practice","volume":"5","author":"Xu","year":"2014","journal-title":"World J. Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Scully, T., Ettela, A., LeRoith, D., and Gallagher, E.J. (2020). Obesity, Type 2 Diabetes, and Cancer Risk. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.615375"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Liu, H., Zhang, T.-Y., Wang, Y.-W., and Gao, J.-J. (2025). Risk Factors for Cancer among Patients with Type 2 Diabetes: A Retrospective Cohort Study. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14483-4"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rey-Re\u00f1ones, C., Baena-D\u00edez, J.M., Aguilar-Palacio, I., Miquel, C., and Grau, M. (2021). Type 2 Diabetes Mellitus and Cancer: Epidemiology, Physiopathology and Prevention. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101429"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1159\/000264676","article-title":"Diabetes Mellitus in Pancreatic Cancer and the Need for Diagnosis of Asymptomatic Disease","volume":"10","author":"Andersson","year":"2010","journal-title":"Pancreatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1470-2045(08)70337-1","article-title":"New-Onset Diabetes: A Potential Clue to the Early Diagnosis of Pancreatic Cancer","volume":"10","author":"Pannala","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_23","first-page":"189","article-title":"Diabetes and Risk of Pancreatic Cancer: A Pooled Analysis of Three Large Case-Control Studies","volume":"22","author":"Li","year":"2011","journal-title":"Cancer Causes Control CCC"},{"key":"ref_24","first-page":"13","article-title":"Diabetes and Risk of Pancreatic Cancer: A Pooled Analysis from the Pancreatic Cancer Cohort Consortium","volume":"24","author":"Elena","year":"2013","journal-title":"Cancer Causes Control CCC"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1093\/annonc\/mdu276","article-title":"Diabetes, Antidiabetic Medications, and Pancreatic Cancer Risk: An Analysis from the International Pancreatic Cancer Case-Control Consortium","volume":"25","author":"Bosetti","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee for Diabetes (2025). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S183\u2013S215.","DOI":"10.2337\/dc26-S009"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.2174\/0929867324666170412145232","article-title":"Effect of Metformin and Statin Use on Survival in Pancreatic Cancer Patients: A Systematic Literature Review and Meta-Analysis","volume":"25","author":"Graber","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1159\/000493214","article-title":"Survival Benefit of Metformin Adjuvant Treatment for Pancreatic Cancer Patients: A Systematic Review and Meta-Analysis","volume":"49","author":"Wan","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1158\/1535-7163.MCT-09-1186","article-title":"Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?","volume":"9","author":"Tanti","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1158\/1078-0432.CCR-12-0694","article-title":"Metformin and Pancreatic Cancer: A Clue Requiring Investigation","volume":"18","author":"Pollak","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1158\/1940-6207.CAPR-12-0026","article-title":"Metformin and Cancer Stem Cells: Old Drug, New Targets","volume":"5","author":"Bednar","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1158\/1940-6207.CAPR-11-0299","article-title":"Metformin Inhibits Cell Proliferation, Migration and Invasion by Attenuating CSC Function Mediated by Deregulating miRNAs in Pancreatic Cancer Cells","volume":"5","author":"Bao","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1097\/MPA.0b013e31827aec40","article-title":"Metformin Inhibits the Growth of Human Pancreatic Cancer Xenografts","volume":"42","author":"Kisfalvi","year":"2013","journal-title":"Pancreas"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Noto, H., Goto, A., Tsujimoto, T., and Noda, M. (2012). Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-Analysis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033411"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1158\/1940-6207.CAPR-10-0157","article-title":"Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-Analysis","volume":"3","author":"Decensi","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00423-020-01874-3","article-title":"Oncological Benefit of Metformin in Patients with Pancreatic Ductal Adenocarcinoma and Comorbid Diabetes Mellitus","volume":"405","author":"Terasaki","year":"2020","journal-title":"Langenbecks Arch. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/ajg.2016.288","article-title":"Metformin Improves Survival in Patients with Pancreatic Ductal Adenocarcinoma and Pre-Existing Diabetes: A Propensity Score Analysis","volume":"111","author":"Amin","year":"2016","journal-title":"Am. J. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/ajg.2011.483","article-title":"Use of Antidiabetic Agents and the Risk of Pancreatic Cancer: A Case-Control Analysis","volume":"107","author":"Bodmer","year":"2012","journal-title":"Am. J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"413782","DOI":"10.1155\/2012\/413782","article-title":"The Influence of Type 2 Diabetes and Glucose-Lowering Therapies on Cancer Risk in the Taiwanese","volume":"2012","author":"Hsieh","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9719","DOI":"10.1038\/s41598-018-27965-2","article-title":"The Influence of Diabetes and Antidiabetic Medications on the Risk of Pancreatic Cancer: A Nationwide Population-Based Study in Korea","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1440-1746.2011.06938.x","article-title":"Diabetes Mellitus Correlates with Increased Risk of Pancreatic Cancer: A Population-Based Cohort Study in Taiwan","volume":"27","author":"Liao","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_42","first-page":"823","article-title":"Metformin Use and Incidence Cancer Risk: Evidence for a Selective Protective Effect against Liver Cancer","volume":"29","author":"Murff","year":"2018","journal-title":"Cancer Causes Control CCC"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.dsx.2007.11.002","article-title":"Cancer Incidence among Patients Treated with Antidiabetic Pharmacotherapy","volume":"2","author":"Oliveria","year":"2008","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2337\/dc11-0857","article-title":"Lower Risk of Cancer in Patients on Metformin in Comparison with Those on Sulfonylurea Derivatives: Results from a Large Population-Based Follow-up Study","volume":"35","author":"Ruiter","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.2337\/dc14-0584","article-title":"Metformin Does Not Affect Cancer Risk: A Cohort Study in the U.K. Clinical Practice Research Datalink Analyzed like an Intention-to-Treat Trial","volume":"37","author":"Tsilidis","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1007\/s00125-011-2390-3","article-title":"Glucose-Lowering Agents and the Patterns of Risk for Cancer: A Study with the General Practice Research Database and Secondary Care Data","volume":"55","author":"Patel","year":"2012","journal-title":"Diabetologia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e00254","DOI":"10.14309\/ctg.0000000000000254","article-title":"Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea","volume":"11","author":"You","year":"2020","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhao, H., Liu, Z., Zhuo, L., Shen, P., Lin, H., Sun, Y., and Zhan, S. (2022). Sulfonylurea and Cancer Risk Among Patients with Type 2 Diabetes: A Population-Based Cohort Study. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.874344"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1053\/j.gastro.2009.04.013","article-title":"Antidiabetic Therapies Affect Risk of Pancreatic Cancer","volume":"137","author":"Li","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1038\/bjc.2015.353","article-title":"New-Onset Type 2 Diabetes, Elevated HbA1c, Anti-Diabetic Medications, and Risk of Pancreatic Cancer","volume":"113","author":"Lu","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1530\/ERC-17-0040","article-title":"Risk and Protective Factors for the Occurrence of Sporadic Pancreatic Endocrine Neoplasms","volume":"24","author":"Valente","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"E646-653","DOI":"10.1002\/ijc.29120","article-title":"Metformin Use among Type 2 Diabetics and Risk of Pancreatic Cancer in a Clinic-Based Case-Control Study","volume":"136","author":"Walker","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1158\/1940-6207.CAPR-16-0277","article-title":"No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure","volume":"10","author":"Burden","year":"2017","journal-title":"Cancer Prev. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1271189","DOI":"10.1155\/jdr\/1271189","article-title":"Association Between Diabetes and Site-Specific Cancer Risk: A Population-Based Cohort Study on the Differential Role of Metabolic Profiles","volume":"2025","author":"Yau","year":"2025","journal-title":"J. Diabetes Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Fuentes, A., Montserrat-Capdevila, J., Florensa, D., Godoy, S., Serrano, J., and Godoy, P. (2025). The Diabetes-Pancreatic Cancer Risk Relationship over Time: A Systematic Review and Meta-Analysis. Diabetology, 6.","DOI":"10.3390\/diabetology6110131"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zhang, Y.-Y., Li, Y.-J., Xue, C.-D., Li, S., Gao, Z.-N., and Qin, K.-R. (2024). Effects of T2DM on Cancer Progression: Pivotal Precipitating Factors and Underlying Mechanisms. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1396022"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.biochi.2025.03.002","article-title":"Metformin\u2019s Anticancer Odyssey: Revealing Multifaceted Mechanisms across Diverse Neoplastic Terrains\u2014A Critical Review","volume":"233","author":"Pal","year":"2025","journal-title":"Biochimie"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"101945","DOI":"10.1016\/j.tranon.2024.101945","article-title":"Metformin as Anticancer Agent and Adjuvant in Cancer Combination Therapy: Current Progress and Future Prospect","volume":"44","author":"Zhu","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3132\/dvdr.2008.027","article-title":"Metformin Therapy and Clinical Uses","volume":"5","author":"Scarpello","year":"2008","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.2337\/diabetes.51.7.2074","article-title":"Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects with Type 2 Diabetes","volume":"51","author":"Musi","year":"2002","journal-title":"Diabetes"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"354","DOI":"10.2337\/diab.41.3.354","article-title":"Metformin Normalizes Nonoxidative Glucose Metabolism in Insulin-Resistant Normoglycemic First-Degree Relatives of Patients with NIDDM","volume":"41","author":"Eriksson","year":"1992","journal-title":"Diabetes"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s00259-007-0563-6","article-title":"High and Typical 18F-FDG Bowel Uptake in Patients Treated with Metformin","volume":"35","author":"Gontier","year":"2008","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin Alters the Gut Microbiome of Individuals with Treatment-Naive Type 2 Diabetes, Contributing to the Therapeutic Effects of the Drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1073\/pnas.1221055110","article-title":"Metformin Inhibits the Inflammatory Response Associated with Cellular Transformation and Cancer Stem Cell Growth","volume":"110","author":"Hirsch","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19","DOI":"10.21037\/cco.2019.04.02","article-title":"Inflammation and Development of Pancreatic Ductal Adenocarcinoma","volume":"8","author":"Shi","year":"2019","journal-title":"Chin. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"512","DOI":"10.5483\/BMBRep.2020.53.10.149","article-title":"A New Aspect of an Old Friend: The Beneficial Effect of Metformin on Anti-Tumor Immunity","volume":"53","author":"Kim","year":"2020","journal-title":"BMB Rep."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Stanciu, S., Ionita-Radu, F., Stefani, C., Miricescu, D., Stanescu-Spinu, I.-I., Greabu, M., Ripszky Totan, A., and Jinga, M. (2022). Targeting PI3K\/AKT\/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231710132"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"338","DOI":"10.7150\/ijbs.15020","article-title":"The Significance of Ras Activity in Pancreatic Cancer Initiation","volume":"12","author":"Logsdon","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1203\/00006450-198509000-00001","article-title":"Insulin as a Growth Factor","volume":"19","author":"Hill","year":"1985","journal-title":"Pediatr. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"25242","DOI":"10.18632\/oncotarget.15692","article-title":"Metformin Is Associated with Survival Benefit in Pancreatic Cancer Patients with Diabetes: A Systematic Review and Meta-Analysis","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e21687","DOI":"10.1097\/MD.0000000000021687","article-title":"Relationships Are between Metformin Use and Survival in Pancreatic Cancer Patients Concurrent with Diabetes: A Systematic Review and Meta-Analysis","volume":"99","author":"Shi","year":"2020","journal-title":"Medicine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1634\/theoncologist.2013-0111","article-title":"Metformin Is Associated with Survival Benefit in Cancer Patients with Concurrent Type 2 Diabetes: A Systematic Review and Meta-Analysis","volume":"18","author":"Yin","year":"2013","journal-title":"Oncologist"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1158\/1078-0432.CCR-11-2994","article-title":"Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer","volume":"18","author":"Sadeghi","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.bbrc.2012.11.010","article-title":"Metformin Inhibition of mTORC1 Activation, DNA Synthesis and Proliferation in Pancreatic Cancer Cells: Dependence on Glucose Concentration and Role of AMPK","volume":"430","author":"Kisfalvi","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Karnevi, E., Said, K., Andersson, R., and Rosendahl, A.H. (2013). Metformin-Mediated Growth Inhibition Involves Suppression of the IGF-I Receptor Signalling Pathway in Human Pancreatic Cancer Cells. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-235"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7192","DOI":"10.3748\/wjg.14.7192","article-title":"Metformin Induces Apoptosis of Pancreatic Cancer Cells","volume":"14","author":"Wang","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1007\/s12032-011-9846-7","article-title":"Metformin and Cancer: New Applications for an Old Drug","volume":"29","author":"Kourelis","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.diabres.2011.12.028","article-title":"Metformin Alters the Expression Profiles of microRNAs in Human Pancreatic Cancer Cells","volume":"96","author":"Li","year":"2012","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Gou, S., Cui, P., Li, X., Shi, P., Liu, T., and Wang, C. (2013). Low Concentrations of Metformin Selectively Inhibit CD133+ Cell Proliferation in Pancreatic Cancer and Have Anticancer Action. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063969"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1038\/bjc.2013.187","article-title":"Metformin Inhibits Growth and Enhances Radiation Response of Non-Small Cell Lung Cancer (NSCLC) through ATM and AMPK","volume":"108","author":"Storozhuk","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/srep00362","article-title":"Metformin Kills and Radiosensitizes Cancer Cells and Preferentially Kills Cancer Stem Cells","volume":"2","author":"Song","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_83","first-page":"867","article-title":"A Humanized Anti-IGF-1R Monoclonal Antibody (R1507) and\/or Metformin Enhance Gemcitabine-Induced Apoptosis in Pancreatic Cancer Cells","volume":"27","author":"Kawanami","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1111\/j.1447-0756.2011.01839.x","article-title":"Metformin Sensitizes Endometrial Cancer Cells to Chemotherapy by Repressing Glyoxalase I Expression","volume":"38","author":"Dong","year":"2012","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1053\/gast.2001.23258","article-title":"Prevention of Pancreatic Cancer Induction in Hamsters by Metformin","volume":"120","author":"Schneider","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.2337\/db14-1132","article-title":"Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms","volume":"64","author":"Cifarelli","year":"2015","journal-title":"Diabetes"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5899","DOI":"10.1038\/s41598-018-24337-8","article-title":"Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-Induced Obesity in the Conditional KrasG12D Mouse Model","volume":"8","author":"Chang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"G763","DOI":"10.1152\/ajpgi.00170.2019","article-title":"Metformin Alters the Duodenal Microbiome and Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-Induced Obesity","volume":"317","author":"Dong","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12943-017-0701-0","article-title":"Metformin Suppresses Cancer Initiation and Progression in Genetic Mouse Models of Pancreatic Cancer","volume":"16","author":"Chen","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.diabres.2014.04.007","article-title":"Metformin Is Associated with Reduced Risk of Pancreatic Cancer in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"106","author":"Wang","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Hu, J., Fan, H.-D., Gong, J.-P., and Mao, Q.-S. (2023). The Relationship between the Use of Metformin and the Risk of Pancreatic Cancer in Patients with Diabetes: A Systematic Review and Meta-Analysis. BMC Gastroenterol., 23.","DOI":"10.1186\/s12876-023-02671-0"},{"key":"ref_92","first-page":"195","article-title":"Relation between metformin and the risk of pancreatic cancer in type 2 diabetes patients: A meta-analysis","volume":"2","author":"Yu","year":"2016","journal-title":"Chin. Gen. Pract."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.canep.2012.12.009","article-title":"Association of Metformin Use with Cancer Incidence and Mortality: A Meta-Analysis","volume":"37","author":"Zhang","year":"2013","journal-title":"Cancer Epidemiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/ajg.2013.7","article-title":"Anti-Diabetic Medications and Risk of Pancreatic Cancer in Patients with Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"108","author":"Singh","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.pcd.2020.06.001","article-title":"Metformin and Risk of Cancer among Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"15","author":"Zhang","year":"2021","journal-title":"Prim. Care Diabetes"},{"key":"ref_96","first-page":"4885","article-title":"Mechanisms of Metformin Inhibiting Cancer Invasion and Migration","volume":"12","author":"Chen","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e2122217119","DOI":"10.1073\/pnas.2122217119","article-title":"Let-7 Underlies Metformin-Induced Inhibition of Hepatic Glucose Production","volume":"119","author":"Xie","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.3892\/ol.2014.2466","article-title":"Regulation of Insulin-like Growth Factor Signaling by Metformin in Endometrial Cancer Cells","volume":"8","author":"Xie","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e02242","DOI":"10.7554\/eLife.02242","article-title":"Metformin Inhibits Mitochondrial Complex I of Cancer Cells to Reduce Tumorigenesis","volume":"3","author":"Wheaton","year":"2014","journal-title":"eLife"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1053\/meta.2000.17822","article-title":"Sulfonylurea Sensitivity of Adenosine Triphosphate-Sensitive Potassium Channels from Beta Cells and Extrapancreatic Tissues","volume":"49","author":"Gribble","year":"2000","journal-title":"Metabolism"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"108047","DOI":"10.1016\/j.jbc.2024.108047","article-title":"The Signaling Landscape of Insulin-like Growth Factor 1","volume":"301","author":"Khan","year":"2025","journal-title":"J. Biol. Chem."},{"key":"ref_102","unstructured":"Akmal, M., Patel, P., and Wadhwa, R. (2025). Alpha Glucosidase Inhibitors. StatPearls, StatPearls Publishing."},{"key":"ref_103","first-page":"25","article-title":"Thiazolidinediones as Anti-Cancer Agents","volume":"6","author":"Blanquicett","year":"2008","journal-title":"Cancer Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.tips.2018.07.006","article-title":"Metformin as an Anticancer Agent","volume":"39","author":"Vancura","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Giglio, R.V., Papanas, N., Rizvi, A.A., Ciaccio, M., Patti, A.M., Ilias, I., Pantea Stoian, A., Sahebkar, A., Janez, A., and Rizzo, M. (2022). An Update on the Current and Emerging Use of Thiazolidinediones for Type 2 Diabetes. Medicina, 58.","DOI":"10.3390\/medicina58101475"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1191\/0961203305lu2223oa","article-title":"Thiazolidinediones and Inflammation","volume":"14","author":"Consoli","year":"2005","journal-title":"Lupus"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Zheng, X., Wang, Y., Chen, Y., Liu, C., Tong, L., Lin, S., Wang, Z., Xie, H., Liu, X., and Shi, J. (2025). Temporal Relationship between Chronic Inflammation and Insulin Resistance and Their Combined Cumulative Effect on Cancer Risk: A Longitudinal Cohort Study. BMC Public Health, 25.","DOI":"10.1186\/s12889-025-22632-4"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1210\/jc.2012-2396","article-title":"Mechanism of Action of DPP-4 Inhibitors\u2014New Insights","volume":"97","author":"Vella","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Ailawadi, S., Murphy, J.E., Storandt, M.H., and Mahipal, A. (2026). Glucagon-like Peptide-1 Receptor Agonist Use and Pancreatic Cancer Risk in Patients with Chronic Pancreatitis. Cancers, 18.","DOI":"10.3390\/cancers18020179"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Gaggini, M., Sabatino, L., Suman, A.F., Chatzianagnostou, K., and Vassalle, C. (2025). Insights into the Roles of GLP-1, DPP-4, and SGLT2 at the Crossroads of Cardiovascular, Renal, and Metabolic Pathophysiology. Cells, 14.","DOI":"10.3390\/cells14050387"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Zhao, X., Wang, M., Wen, Z., Lu, Z., Cui, L., Fu, C., Xue, H., Liu, Y., and Zhang, Y. (2021). GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.721135"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Rea, N., and Ramdass, P.V.A.K. (2025). GLP-1 Receptor Agonists and Pancreatic Beta Cell Apoptosis in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Preclinical Studies. Front. Clin. Diabetes Healthc., 6.","DOI":"10.3389\/fcdhc.2025.1579961"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.2147\/JIR.S442106","article-title":"Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors","volume":"17","author":"Rahim","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/sjg.SJG_390_18","article-title":"Inflammation and Pancreatic Cancer: An Updated Review","volume":"25","author":"Shadhu","year":"2019","journal-title":"Saudi J. Gastroenterol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"E410","DOI":"10.1152\/ajpendo.00463.2010","article-title":"Dipeptidyl Peptidase IV Inhibitor Sitagliptin Reduces Local Inflammation in Adipose Tissue and in Pancreatic Islets of Obese Mice","volume":"300","author":"Dobrian","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbagen.2016.10.006","article-title":"Paracrine IL-6 Signaling Mediates the Effects of Pancreatic Stellate Cells on Epithelial-Mesenchymal Transition via Stat3\/Nrf2 Pathway in Pancreatic Cancer Cells","volume":"1861","author":"Wu","year":"2017","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1074\/jbc.M107582200","article-title":"Ligands of Peroxisome Proliferator-Activated Receptor-Gamma Block Activation of Pancreatic Stellate Cells","volume":"277","author":"Masamune","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"41487","DOI":"10.1038\/srep41487","article-title":"Identification of a Novel Selective PPAR\u03b3 Ligand with a Unique Binding Mode and Improved Therapeutic Profile in Vitro","volume":"7","author":"Yi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1053\/j.gastro.2005.03.025","article-title":"Cytokines and Peroxisome Proliferator-Activated Receptor Gamma Ligand Regulate Phagocytosis by Pancreatic Stellate Cells","volume":"128","author":"Shimizu","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1089\/met.2015.0095","article-title":"Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies","volume":"13","author":"Manna","year":"2015","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Souto, M., C\u00fardia Gon\u00e7alves, T., and Cotter, J. (2025). Obesity and Pancreatic Diseases: From Inflammation to Oncogenesis and the Impact of Weight Loss Interventions. Nutrients, 17.","DOI":"10.3390\/nu17142310"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"984245","DOI":"10.1155\/2011\/984245","article-title":"Weight Considerations in Pharmacotherapy for Type 2 Diabetes","volume":"2011","author":"Cheng","year":"2011","journal-title":"J. Obes."},{"key":"ref_123","unstructured":"Feingold, K.R., Adler, R.A., Ahmed, S.F., Anawalt, B., Blackman, M.R., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., and Dungan, K. (2000). Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes. Endotext, MDText.com, Inc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:21:41Z","timestamp":1779337301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":123,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104195"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104195","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}