To assess whether exposure to GLP-1 receptor agonists is associated with differences in disease activity and neurological outcomes among patients with MS.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), widely used for diabetes and obesity, have emerging immunomodulatory and neuroprotective properties mediated through gut–brain axis signaling. Their potential relevance to multiple sclerosis (MS), a chronic immune-mediated demyelinating disease, remains incompletely characterized.

We conducted a retrospective observational cohort study using the TriNetX Research Network. Patients with MS were identified using a standardized, platform-validated ICD-10 coding protocol (G35) and compared based on exposure to GLP-1 receptor agonists (A10BJ). Demographics, metabolic comorbidities, and MS-related outcomes were evaluated after 1:1 propensity score matching by age and sex. Disease-modifying therapy use was not a criterion in cohort construction. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.

Among 339,092 patients with multiple sclerosis (MS), 14,300 were exposed to GLP-1 RAs and 335,867 were unexposed. GLP-1 RA users had higher mean body mass index (36.7 vs 29.0 kg/m²) and a greater prevalence of metabolic comorbidities, including type 2 diabetes (49% vs 4%) and obesity (58% vs 6%). The majority of GLP-1 RA users were female. GLP-1 RA exposure was associated with lower rates of acute steroid-treated relapses (2.33% vs 5.0%; risk ratio [RR] 2.14, 95% CI 1.89–2.44) and optic neuritis (1.53% vs 4.02%; RR 2.63, 95% CI 2.26–3.08) compared with non-users. Demyelinating events were also less frequent (3.58% vs 6.5%; RR 1.82, 95% CI 1.63–2.03). Lower rates of gait or mobility abnormalities (7.56% vs 12.76%), fatigue (8.3% vs 14.2%), and depression (18.1% vs 25.2%) were observed among GLP-1 RA–exposed patients.

GLP-1 receptor agonist exposure in MS was associated with reduced relapse activity, optic neuritis incidence, and demyelinating events.These findings suggest that GLP-1 RAs may be associated with neuroprotective and anti-inflammatory effects relevant to MS pathophysiology.