The risk of myelodysplastic syndrome and acute myeloid leukemia by metformin use and type 2 diabetes status - a Danish nation-wide cohort study

BACKGROUND AND PURPOSE: The treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have increased recently. However, drug resistance persists and patients who are ineligible for curative treatments still have a very poor prognosis. Previous studies support a general anti-neoplastic effect of metformin, and a recent preclinical investigation has shown that metformin may control the expansion of Dnmt3a clonal hematopoiesis, which is known to precede MDS and AML.

PATIENTS/MATERIAL AND METHODS: In this study we investigated the effect of metformin and type 2 diabetes (T2D) on the risk of developing MDS or AML. T2D was defined based on hospital diagnosis codes and glucose-lowering drug prescriptions. The study was performed as a cohort study with follow-up from 1 January 2000 to 31 December 2017 using Danish national, population-based register data.

RESULTS AND INTERPRETATION: In all, 6,031,132 persons contributed to the study of whom 302,403 had T2D, and 295,365 received metformin. Median follow-up time among individuals with T2D was more than 5 years, and among individuals without T2D more than 15 years. Our analyses revealed no association between T2D (hazard ratio [HR] 1.02 [95% confidence intervals (CI) 0.92-1.13]) or metformin use (HR 1.21 [95% CI 0.91-1.60]) and the risk of MDS or AML. However, when outcomes were studied separately, T2D was associated with an increased risk of MDS (HR 1.24 [95% CI 1.08-1.32]) but not with AML. Metformin use was not associated with MDS nor AML. Future studies should determine which patient groups may benefit from metformin to prevent MDS or AML development.