GLP-1 receptor agonists in multiple sclerosis: a systematic review of preclinical and clinical evidence.
GLP-1RAs show potential for metabolic benefits in MS patients, but no significant changes in neurological outcomes were observed. Further randomized controlled trials are necessary to clarify these findings.
Where it sits
this study against the rest of the dulaglutide corpusSummary and findings
This systematic review assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in multiple sclerosis (MS) patients and preclinical models. It included 15 studies, with findings indicating that GLP-1RAs were associated with BMI reduction and vitamin D augmentation in humans, but no changes in EDSS or relapse rates. The review highlights the need for randomized controlled trials to further investigate these findings.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
Background
This paper addresses the potential role of GLP-1 receptor agonists in the management of multiple sclerosis (MS), a chronic immune-mediated demyelinating disease. Prior to this review, there was no formal synthesis of evidence regarding the effects of GLP-1RAs in MS. Given the reported anti-inflammatory and neuroprotective properties of GLP-1RAs in preclinical models, this study aims to clarify their impact on MS patients.
Methods
The study employed a systematic review design, registered with PROSPERO (CRD420261385854), following PRISMA 2020 guidelines. A systematic search of PubMed/MEDLINE and Scopus was conducted up to June 12, 2026, with Google Scholar used for supplementary grey literature. Eligible studies included those examining GLP-1RAs in confirmed MS patients, EAE animal models, or case reports, with risk of bias assessed using SYRCLE and the Newcastle-Ottawa Scale.
Results
Fifteen studies met the inclusion criteria, comprising eight preclinical animal studies (six EAE, two cuprizone models), four human observational studies, and three narrative-context studies. The primary finding indicated that GLP-1RAs were associated with a 7.4% ever-use rate in a NARCOMS survey (n=4181). In human studies, GLP-1RA use was associated with BMI reduction and vitamin D augmentation without changes in EDSS or relapse rate.
Interpretation
The findings suggest that while GLP-1RAs may offer metabolic benefits in MS patients, the lack of significant changes in neurological outcomes raises questions about clinical relevance. The high risk of bias in most preclinical studies and the moderate to high risk in human studies limit the conclusions that can be drawn. This review underscores the necessity for randomized controlled trials to better understand the implications of GLP-1RA use in MS.
Key findings
- 7.4% ever-use of GLP-1RAs reported in a NARCOMS survey, n=4181.
- BMI reduction and vitamin D augmentation observed in two cohorts, n=109, without change in EDSS or relapse rate.
- Inverse reporting odds ratios for semaglutide (ROR 0.238), dulaglutide (ROR 0.165), and liraglutide (ROR 0.161).
- Most preclinical studies were assessed as high risk of bias.
- Human studies were assessed as moderate to high risk of bias.
Limitations
- Most preclinical studies assessed as high risk of bias.
- Human studies assessed as moderate to high risk of bias.
- No randomized controlled trials reported.