SGLT2 Inhibitor Use and Incident Multiple Sclerosis in Type 2 Diabetes: Evidence From a Large Real-World Emulated Trial

Background: Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder. Emerging evidence suggests sodium–glucose cotransporter-2 inhibitors (SGLT2is) exert anti-inflammatory effects; however, their association with MS risk remains unclear. This study compared the risk of incident MS and neurological autoimmune diseases in patients with type 2 diabetes (T2D) initiating SGLT2is versus dipeptidyl peptidase-4 inhibitors (DPP-4is). Methods: We conducted a multicenter cohort study using the TriNetX U.S. Collaborative Network (2015–2024), emulating a target trial. Adults with T2D newly initiating SGLT2is or DPP-4is were propensity score-matched (1:1). The primary outcome was incident MS. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. Findings: After matching, 205,704 patients were included per group. SGLT2i users had 137 MS cases (0.067%) versus 230 in DPP-4i users (0.112%). Initiation of SGLT2is was associated with a significantly lower risk of incident MS compared with DPP-4is (HR 0.78; 95% CI 0.63–0.97). Kaplan–Meier analyses showed a lower cumulative incidence of MS with SGLT2is (log-rank p = 0.025). The inverse association was consistent across key subgroups, particularly among women, patients <65 years, those with or without obesity, and individuals with well-controlled glycemia. Results were robust across sensitivity analyses, including extended lag periods and varying follow-up durations. No significant differences were observed for most secondary neurological autoimmune outcomes. Interpretation: In this large emulated target trial, SGLT2i use was associated with a significantly lower risk of incident MS compared with DPP-4i use among patients with T2D. These findings suggest a potential protective association and warrant confirmation in prospective studies to elucidate underlying biological mechanisms.