GLP-1 receptor agonists in multiple sclerosis: a systematic review of preclinical and clinical evidence.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) demonstrate anti-inflammatory and neuroprotective properties in preclinical models. No formal synthesis of this evidence existed prior to this review. METHODS: We conducted a PROSPERO-registered systematic review (CRD420261385854) following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus were systematically searched to June 12, 2026. Google Scholar was used as a supplementary source for grey literature. Studies examining GLP-1RAs in confirmed MS patients, EAE animal models, or case reports were eligible. Risk of bias was assessed using SYRCLE (preclinical) and Newcastle-Ottawa Scale (human studies). Narrative synthesis followed SWiM guidelines. RESULTS: Fifteen studies met inclusion criteria: eight preclinical animal studies (six EAE, two cuprizone models), four human observational studies, and three narrative-context studies. GLP-1RAs consistently reduced clinical severity in EAE models through multiple mechanisms (AMPK/SIRT1 activation, NLRP3 suppression, Th1/Th17 modulation, microglial deactivation). In humans, GLP-1RA use was associated with BMI reduction and vitamin D augmentation without change in EDSS or relapse rate (two cohorts; n = 109). A NARCOMS survey (n = 4181) documented 7.4% ever-use. Pharmacovigilance showed inverse reporting odds ratios with semaglutide (ROR 0.238), dulaglutide (ROR 0.165), and liraglutide (ROR 0.161). Mendelian randomization found no causal association between GLP-1R activation and MS susceptibility. Most preclinical studies were high risk of bias; human studies moderate to high. CONCLUSION: GLP-1RAs demonstrate consistent preclinical efficacy through diverse neuroprotective mechanisms. Human evidence shows metabolic benefit without neurological harm. Randomized controlled trials are urgently needed. This is the first registered, PRISMA-compliant synthesis of GLP-1RA evidence in MS.