7571 Background: Incretin-based therapies, including dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), are widely used in the management of type 2 diabetes mellitus (T2DM). Experimental and clinical data suggest that metabolic and immune pathways may influence plasma cell dyscrasia development, yet the relationship between incretin-based therapies and monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) remains unclear. In this study, we aimed to evaluate the association between incretin-based therapy exposure and the risk of MGUS and MM. Methods: A multicenter, retrospective cohort study was conducted using the TriNetX Global Collaborative Network, a federated electronic health record database, between January 1, 2015, and December 31, 2025. Adult patients with T2DM were categorized into six exposure cohorts. Individuals treated with GLP-1RAs with a minimum of one year of therapy were compared with patients initiating sodium–glucose cotransporter-2 inhibitors (SGLT2i), sulfonylureas (SU), and thiazolidinediones (TZDs). The same cohort design was applied to DPP-4i users. A 1:1 propensity score matching (PSM) model was applied to minimize confounding by balancing baseline demographics, clinical comorbidities, laboratory parameters, and concurrent medication use. Individuals with a prior cancer diagnosis were excluded. The primary endpoint was progression to MM, and the secondary endpoint was the development of MGUS. Statistical analyses were performed within the TriNetX platform. Results: After 1:1 PSM, GLP-1RA therapy was associated with a significantly lower risk of both MGUS and MM compared with SU (n = 141,225 per group; MGUS RR 0.59, 95% CI 0.50–0.69; MM RR 0.84, 95% CI 0.77–0.92) and SGLT2i (n = 57,919 per group; MGUS RR 0.75, 95% CI 0.65–0.86; MM RR 0.62, 95% CI 0.49–0.79). No significant differences in MGUS or MM risk were observed when GLP-1RAs were compared with TZDs. In contrast, DPP-4i use was associated with aincreased risk of MM compared with TZDs (n = 29,462 per group; RR 1.93, 95% CI 1.40–2.66) and SGLT2i (n = 68,481 per group; RR 1.44, 95% CI 1.19–1.74).No significant associations were observed for MGUS across comparators, and no significant differences in MGUS or MM risk were seen between DPP-4i and SU (Table 1). Conclusions: In patients with T2DM, GLP-1RA exposure were associated with differential rates of MGUS and MM diagnosis across antihyperglycemic drug classes. GLP-1RA was associated with a lower rates of MGUS and MM compared with SU and SGLT2i, whereas DPP-4i use was associated with higher MM rates when compared with SGLT2i and TZDs. While these findings are clinically promising, prospective studies are needed to confirm causality and clarify underlying mechanisms.
Ateiwi et al. (Thu,) studied this question.