SGLT ‐2 Inhibitors are Associated With a Lower Risk of Multiple Myeloma

Aims We aimed to investigate drug response of sodium‐glucose transport protein‐2 inhibitors (SGLT2i) in multiple myeloma (MM), as SGLT2i have potential favorable effects on conditions related to MM. Methods We conducted a pharmacoepidemiologic study with a US nationwide health insurance claim data using Cox models to investigate the comparative risk of MM between SGLT2i exposure and dipeptidyl peptidase‐4 inhibitors (DPP4i) exposure. Additionally, we conducted differential gene expression analysis with drug responses in cell lines. Results We observed SGLT2i compared with DDP4i exposure was associated with a reduced risk of MM in the general population (hazard ratios [HRs] ≤ 0.37, p < 0.001); and subpopulations defined by age, gender, race, deficiency anemia, renal failure, obesity, normal weight, and patients with monoclonal gammopathy of undetermined significance (HRs ≤ 0.49, p ≤ 0.032). Moreover, we revealed 450 and 660 unique differentially expressed genes (DEGs) associated with SGLT2i and DPP4i, respectively. We identified that MM‐associated DEGs were significantly enriched in unique DEGs of SGLT2i compared with DPP4i (odds ratio = 2.0, p = 0.03). We found consistent DEGs between SGLT2i vs. control and normal vs. MM patients (e.g., AKT1, PHLPP2, CFD, FBLN2 proteasome genes, etc.) that regulate cell cycle, ubiquitination‐proteasome system (UPS), and cell adhesion activities. SGLT2i showed potential beneficial effects in preventing MM, which could be due to SGLT2‐mediated tumor‐suppressing activities for MM from various aspects. Conclusion SGLT2i is associated with a lower risk of MM in patients with diabetes.