Exploratory associations between incretin-based therapies and plasma cell disorders in patients with type 2 diabetes: A real-world study.

Abstract

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.