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GLP-1 receptor agonists in multiple sclerosis: a systematic review of preclinical and clinical evidence
Mobeen Sajjad1, Ahsan Sajjad2, Rida Amer3
1Saad Hospital and Cardiac Care Centre, Daska, Punjab, Pakistan.
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.
Insights
Glucagon-like peptide-1 receptor agonists show promise in multiple sclerosis preclinical models by reducing inflammation and protecting nerves. Human studies indicate metabolic benefits without neurological harm, warranting further clinical trials.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease.
- Glucagon-like peptide-1 receptor agonists (GLP-1RAs) possess anti-inflammatory and neuroprotective properties.
- Existing evidence on GLP-1RAs in MS lacks formal synthesis.
Purpose of the Study:
- To systematically review and synthesize evidence on the efficacy and safety of GLP-1RAs in multiple sclerosis.
- To evaluate the impact of GLP-1RAs in both preclinical MS models and human studies.
Main Methods:
- A PROSPERO-registered systematic review adhering to PRISMA 2020 guidelines.
- Searches of PubMed/MEDLINE, Scopus, and Google Scholar for studies on GLP-1RAs in MS patients and EAE/cuprizone models.
- Risk of bias assessment using SYRCLE and Newcastle-Ottawa Scale, followed by narrative synthesis.
Main Results:
- GLP-1RAs consistently reduced EAE model severity via mechanisms like AMPK/SIRT1 activation and microglial deactivation.
- Human studies linked GLP-1RA use to BMI reduction and vitamin D increase, with no significant changes in EDSS or relapse rates.
- Pharmacovigilance data suggested inverse reporting odds ratios for semaglutide, dulaglutide, and liraglutide; Mendelian randomization found no causal link to MS susceptibility.
Conclusions:
- GLP-1RAs exhibit consistent preclinical neuroprotective effects through multiple mechanisms.
- Human evidence suggests metabolic benefits without neurological detriment.
- Randomized controlled trials are essential to confirm these findings and explore therapeutic potential in MS.
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