BACKGROUND: Myelodysplastic Syndrome (MDS) is a devastating hematologic malignancy associated with advanced age. Diabetes Mellitus (DM) is one of the most common morbidities worldwide, with metformin serving as the first line therapy for several decades. However, the potential association between previous metformin use and the risk of developing MDS remains uncertain. METHODS: This cross-sectional study addressed the possible association between prior metformin use in DM patients and the subsequent development of MDS. RESULTS: Data from 54,869 DM patients was retrieved from their medical records from a tertiary medical center. Of these, 20,318 patients had been exposed at some point in time to metformin, with 133 (0.7%) subsequently developing MDS. In contrast, among 34,551 DM patients with no prior exposure to metformin, only 154 (0.4%) developed MDS later in life. The Odds Ratio (OR) for MDS development amongst metformin users compared to the entire study population was 1.48 (95% CI 1.17-1.86; p = 0.001). A multivariate analysis adjusting for gender, age, congestive heart failure and chronic kidney disease, past exposure to metformin remained an independent risk factor for MDS development (OR = 1.6, 95% CI 1.26-2.03; p < 0.001). CONCLUSION: Previous exposure to metformin amongst DM patients is associated with an increased risk for MDS development later in life. This is a preliminary, cross-sectional study that show that larger studies in variable MDS patient populations are warranted.

Adelson School of Medicine Ariel University Ariel 4070000 Israel

Dan Petah Tikvah District at Clalit Health Service Petah Tikvah Israel

Department of Pediatric Intensive Care The Edmond and Lily Safra Children's Hospital at Chaim Sheba Medical Center Tel Hashomer Ramat Gan Israel

Education Authority Chaim Sheba Medical Center Tel Hashomer Ramat Gan Israel

Faculty of Health Science and Medicine Tel Aviv University Tel Aviv Israel

Faculty of Medicine and Dentistry Palacký University in Olomouc Olomouc 77900 Czech Republic

Faculty of Medicine Kharkiv National Medical University Kharkiv Ukraine

Hematology Division Chaim Sheba Medical Center Ramat Gan Israel

Internal Medicine Division Sheba Medical Center Ramat Gan Israel

Silesia Medical University Katowice Poland

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Lee PG, Cigolle C, Blaum C. The Co-Occurrence of chronic diseases and geriatric syndromes: the health and retirement study. J Am Geriatr Soc. 2009;57:511–6. 10.1111/J.1532-5415.2008.02150.X. PubMed

Garcia-Manero G, Chien KS, Montalban-Bravo G, Myelodysplastic S. 2021 Update on diagnosis, risk stratification and management. Am J Hematol. 2020;95:1399–420. 10.1002/AJH.25950. PubMed

Ogawa S, Genetics of MDS. Blood. 2019;133:1049–59. 10.1182/BLOOD-2018-10-844621. PubMed PMC

Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and Non-Molecular aspects of the disease. Blood Res. 2014;49:216–27. 10.5045/BR.2014.49.4.216. PubMed PMC

Oliva EN, Platzbecker U, Fenaux P, Garcia-Manero G, LeBlanc TW, Patel BJ, Kubasch AS, Sekeres MA. Targeting Health-Related quality of life in patients with myelodysplastic Syndromes - Current knowledge and lessons to be learned. Blood Rev. 2021;50:100851–100851. 10.1016/J.BLRE.2021.100851. PubMed

Kubasch AS, Platzbecker U. Patient stratification in myelodysplastic syndromes: how a puzzle May become a map. Hematology: Am Soc Hematol Educ Program 2020;2020:418. 10.1182/HEMATOLOGY.2020000126. PubMed PMC

Samiev D, Bhatt VR, Armitage JD, Maness LJ, Akhtari MA. Primary care approach to myelodysplastic syndromes. Korean J Fam Med. 2014;35:111–8. 10.4082/KJFM.2014.35.3.111. PubMed PMC

Bryan J, Jabbour E, Prescott H, Kantarjian H. Thrombocytopenia in patients with myelodysplastic syndromes. Semin Hematol. 2010;47:274. 10.1053/J.SEMINHEMATOL.2010.02.006. PubMed PMC

Kota V, Ogbonnaya A, Farrelly E, Schroader BK, Raju A, Kristo F, Dalal M. Clinical impact of transformation to acute myeloid leukemia in patients with Higher-Risk myelodysplastic syndromes. Future Oncol. 2022;18:4017–29. 10.2217/FON-2022-0334/ASSET/IMAGES/LARGE/FIGURE3.JPEG. PubMed

Shafrin J, Green S, Murphy R, Everson K, Dennen S, Price K, Batt K. Quantifying the economic burden of myelodysplastic syndromes among elderly US patients. Blood. 2019;134:2151–2151. 10.1182/blood-2019-124216.

Kaplan H, Malmgren J, De Roos AJ. Risk of myelodysplastic syndrome and acute myeloid leukemia post radiation treatment for breast cancer: A Population-Based study. Breast Cancer Res Treat. 2013;137:863–7. 10.1007/S10549-012-2386-9. PubMed

Yarosh R, Roesler MA, Murray T, Cioc A, Hirsch B, Nguyen P, Warlick E, Poynter JN. Risk factors for de Novo and therapy related myelodysplastic syndromes (MDS). Cancer Causes Control. 2021;32:241. 10.1007/S10552-020-01378-X. PubMed PMC

Le Deley MC, Suzan F, Cutuli B, Delaloge S, Shamsaldin A, Linassier C, Clisant S, De Vathaire F, Fenaux P, Hill C, Anthracyclines. Mitoxantrone, radiotherapy, and granulocyte Colony-Stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast Cancer. J Clin Oncol. 2007;25:292–300. 10.1200/JCO.2006.05.9048. PubMed

Maung SW, Burke C, Hayde J, Walshe J, McDermott R, Desmond R, McHugh J, Enright H. A review of Therapy-Related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: A single centre experience. Hematology. 2017;22:341–6. 10.1080/10245332.2017.1286539. PubMed

Abou Zahr A, Kavi AM, Mukherjee S, Zeidan AM. Therapy-Related myelodysplastic syndromes, or are they?? Blood Rev. 2017;31:119–28. 10.1016/J.BLRE.2016.11.002. PubMed

Sun LM, Lin CL, Lin MC, Liang JA, Kao CH. Radiotherapy- and Chemotherapy-Induced myelodysplasia syndrome: A nationwide Population-Based nested Case–Control study. Medicine. 2015;94:e737. 10.1097/MD.0000000000000737. PubMed PMC

Sweeney MR, Applebaum KM, Arem H, Braffett BH, Poynter JN, Robien K. Medical conditions and modifiable risk factors for myelodysplastic syndrome: A systematic review. Cancer Epidemiol Biomarkers Prev. 2019;28:1502–17. 10.1158/1055-9965.EPI-19-0106/69651/AM/MEDICAL-CONDITIONS-AND-MODIFIABLE-RISK-FACTORS-FOR. PubMed

Nisse C, Haguenoer JM, Grandbastien B, Preudhomme C, Fontaine B, Brillet JM, Lejeune R, Fenaux P. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br J Haematol. 2001;112:927–35. 10.1046/J.1365-2141.2001.02645.X. PubMed

Bailey CJ, Metformin. Hist Overv Diabetologia. 2017;60:1566–76. PubMed

Bailey CJ, Day C, Metformin. Its botanical background. Practical Diabetes Int. 2004;21:115–7. 10.1002/pdi.606.

Feldman H, ElSayed NA, McCoy RG, Moverley J, Oser SM, Segal AR, Trujillo J, Jones CW, Pilla SJ, Aung NL, et al. Standards of care in Diabetes—2023 abridged for primary care providers. Clin Diabetes. 2023;41:4–31. 10.2337/CD23-AS01.

Kaneto H, Kimura T, Obata A, Shimoda M, Kaku K. Multifaceted mechanisms of action of Metformin which have been unraveled one after another in the long history. Int J Mol Sci. 2021;22:1–13. PubMed PMC

An H, He L. Current Understanding of Metformin effect on the control of hyperglycemia in diabetes. J Endocrinol. 2016;228:R97–106. PubMed PMC

Hundal HS, Ramlal T, Reyes R, Leiter LA, Klip A. Cellular mechanism of Metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology. 1992;131:1165–73. 10.1210/ENDO.131.3.1505458. PubMed

Wiernsperger N.F., Bailey C.J. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs. 1999;58(Suppl 1):31–9. 10.2165/00003495-199958001-00009. PubMed

Lalau JD, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N. Metformin-Associated lactic acidosis (MALA): moving towards a new paradigm. Diabetes Obes Metab. 2017;19:1502–12. 10.1111/DOM.12974. PubMed

Ahmed MA. Metformin and vitamin B12 deficiency: where do we stand?? J Pharm Pharm Sci. 2016;19:382–98. 10.18433/J3PK7P. PubMed

Dziubak A, Wójcicka G, Wojtak A, Bełtowski J. Metabolic effects of Metformin in the failing heart. Int J Mol Sci. 2018;19. 10.3390/IJMS19102869. PubMed PMC

Imfeld P, Bodmer M, Jick SS, Meier CR, Metformin. Other antidiabetic drugs, and risk of Alzheimer’s disease: A Population-Based Case-Control study. J Am Geriatr Soc. 2012;60:916–21. 10.1111/J.1532-5415.2012.03916.X. PubMed

Li K, Zhang TT, Wang F, Cui B, Zhao CX, Yu JJ, Lv XX, Zhang XW, Yang ZN, Huang B, et al. Metformin Suppresses Melanoma Progression by Inhibiting KAT5-Mediated SMAD3 Acetylation, Transcriptional Activity and TRIB3 Expression. Oncogene. 2018;37:2967–2981. 10.1038/s41388-018-0172-9 PubMed

McCreight LJ, Bailey CJ, Pearson ER. Metformin and the Gastrointestinal tract. Diabetologia. 2016;59:426–35. 10.1007/S00125-015-3844-9. PubMed PMC

Ko EM, Walter P, Jackson A, Clark L, Franasiak J, Bolac C, Havrilesky LJ, Secord AA, Moore DT, Gehrig PA, et al. Metformin is associated with improved survival in endometrial Cancer. Gynecol Oncol. 2014;132:438–42. 10.1016/J.YGYNO.2013.11.021. PubMed

Anwar N, Arshad A, Fatima N, Shaheen S, Bukhari S, Shamsi T. Environmental and occupational determinants of myelodysplastic syndrome: A Case–Control study from Pakistan. Cancer Rep. 2022;5:e1580. 10.1002/CNR2.1580. PubMed PMC

Feng Z, Liao M, Guo X, Li L, Zhang L. Effects of immune cells in mediating the relationship between gut microbiota and myelodysplastic syndrome: A bidirectional Two-Sample, Two-Step Mendelian randomization study. Discover Oncol. 2024;15:1–11. 10.1007/S12672-024-01061-6/TABLES/1. PubMed PMC

Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321:1926–7. 10.1001/JAMA.2019.3805. PubMed PMC

Kristensen DT, Øvlisen AK, Jakobsen LH, Severinsen MT, Hannig LH, Starklint J, Hilsøe MH, Vallentin AP, Brabrand M, Hasselbalch HC, et al. Metformin use and risk of myeloproliferative neoplasms: A Danish population-based case-control study. Blood Adv. 2024;8. 10.1182/BLOODADVANCES.2023012266. PubMed PMC

Bangdiwala SI, Basic Epidemiology Research Designs I. Cross-Sectional design. Int J Inj Contr Saf Promot. 2019;26:124–6. 10.1080/17457300.2018.1556415/ASSET//CMS/ASSET/49B60D9A-DBE3-422C-AE3F-D3B3CB228A8A/17457300.2018.1556415.FP.PNG. PubMed

Asiamah N, Mends-Brew E, Boison BKT. A spotlight on Cross-Sectional research: addressing the issues of confounding and adjustment. Int J Healthc Manag. 2021;14:183–96. 10.1080/20479700.2019.1621022.