Incidence of hematologic malignancies and mortality associated with GLP-1 receptor agonist and SGLT2 inhibitor use in type 2 diabetes mellitus: results of a retrospective cohort study of electronic health records

Background: Individuals with type 2 diabetes mellitus are treated with a growing variety of medications targeting multiple metabolic pathways. In recent years, incretins such as the GLP-1 receptor agonists have proven effective in the control of hyperglycemia but also in weight loss, where they are now separately approved as a treatment for obesity. Given the importance of obesity and metabolic syndrome as risk factors for malignancy, the impact of GLP-1 receptor agonists on cancer risk is of increasing interest. Here, we performed an analysis of the impact of GLP-1 receptor agonists and SGLT2 inhibitors on cancer risk and mortality. Methods: We performed a multicenter retrospective cohort study using the TriNetX database of electronic health records between 2019 and 2024, including patients with a diagnosis of type 2 diabetes mellitus. Individuals prescribed GLP-1 receptor agonists, SGLT2 inhibitors, or neither were compared for the incidence of four obesity-related hematologic malignancies using a Cox proportional hazards model. Similar analysis was applied to mortality associated with these medication classes in individuals with type 2 diabetes mellitus and the hematologic malignancies under study. Findings: GLP-1 receptor agonist use is associated with a significantly decreased risk of multiple myeloma (HR 0.64, p = 0.01), but not chronic myeloid leukemia (HR 1.06, p = 0.857), acute myeloid leukemia (HR 0.81, p = 0.354), or myelodysplastic syndrome (HR 0.98, p = 0.996). This effect was preserved in subgroups with BMI >30 and HbA1c >8%. Further, we find that in patients with multiple myeloma and acute myeloid leukemia, SGLT2 inhibitor use is associated with a significantly increased risk of mortality, independent of heart or kidney failure (MM HR 2.27, p < 0.001, AML HR 2.00, p = 0.006). Interpretation: Our results strengthen the association between metabolic disease and multiple myeloma yet call for prospective investigation into the use of SGTL2 inhibitors in patients with specific hematologic neoplasms. Funding: National Institutes of Health.