GLP-1 Receptor Agonists Show Consistent Preclinical Efficacy in Multiple Sclerosis Models, Human Data Suggest Metabolic Benefit Without Neurological Harm

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system, leading to progressive neurological disability. Current treatments primarily target immune modulation, but there remains a significant unmet need for neuroprotective and neuroregenerative therapies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), known for their metabolic benefits in type 2 diabetes, have also demonstrated promising anti-inflammatory and neuroprotective properties in various preclinical models. Prior to this work, a comprehensive synthesis of GLP-1RA evidence specifically for MS was lacking, hindering translation.

This PROSPERO-registered systematic review (CRD420261385854) followed PRISMA 2020 guidelines, searching PubMed/MEDLINE and Scopus up to June 12, 2026, with Google Scholar for grey literature. Studies examining GLP-1RAs in confirmed MS patients, experimental autoimmune encephalomyelitis (EAE) animal models, or case reports were eligible. Risk of bias was assessed using SYRCLE for preclinical studies and the Newcastle-Ottawa Scale for human studies. A narrative synthesis was conducted following SWiM guidelines to integrate findings across diverse study types.

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, including AMPK/SIRT1 activation, NLRP3 suppression, Th1/Th17 modulation, and microglial deactivation. In human studies (n=109 across two cohorts), GLP-1RA use was associated with BMI reduction and vitamin D augmentation without any observed change in EDSS scores or relapse rates. A large NARCOMS survey (n=4181) documented 7.4% ever-use of GLP-1RAs among MS patients. Pharmacovigilance data showed inverse reporting odds ratios (RORs) for MS with semaglutide (ROR 0.238), dulaglutide (ROR 0.165), and liraglutide (ROR 0.161), suggesting a potential protective signal or at least no increased risk. Mendelian randomization analysis found no causal association between GLP-1R activation and MS susceptibility. Most preclinical studies were deemed high risk of bias, while human studies were moderate to high risk.

GLP-1RAs consistently reduced clinical severity in EAE models through diverse neuroprotective and anti-inflammatory mechanisms.