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

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. 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. 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. SGLT2i is associated with a lower risk of MM in patients with diabetes.