GLP-1 Drugs Like Ozempic Face a New Test: Multiple Sclerosis

The blockbuster drugs behind Ozempic and Wegovy are now being scrutinized for an entirely different purpose: treating multiple sclerosis. A new narrative review published in Annals of Clinical and Translational Neurology examines what happens when the world’s most talked-about weight-loss and diabetes medications meet one of neurology’s most complex autoimmune diseases, and the answer is a mixture of early reassurance, genuine biological intrigue, and unresolved safety questions.

Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, mimic the action of GLP-1, an incretin hormone synthesized primarily by intestinal L cells and brainstem neurons. Released when undigested nutrients enter the small intestine, GLP-1 signaling through the vagus nerve and central nervous system delays gastric emptying, improves satiety, and promotes glucose-dependent insulin release—the so-called ileal brake. Exenatide, modeled on exendin-4, a peptide isolated from Gila monster venom that resists degradation by the enzyme DPP-4, became the first FDA-approved GLP-1RA in 2005. That synthetic success inspired a generation of more potent, long-acting, CNS-penetrant agonists, including semaglutide, liraglutide, dulaglutide, lixisenatide, and the dual GLP-1/GIP agonist tirzepatide. Their popularity has been explosive: an estimated one in eight Americans has now tried a GLP-1RA.

Why would neurologists care? Because obesity and MS are deeply entangled. In the multi-center MS PATHS cohort, 42 percent of newly diagnosed people with MS in the United States were obese, and in a separate prospective cohort of 130 patients with at least moderate disability, 56 percent had a waist circumference consistent with abdominal obesity. A population-based case-control study of 3,249 people in the Swedish MS registry found that obesity at baseline is associated with faster disease progression—measured by time to an Expanded Disability Status Scale score of 3 or 4—more frequent T2 hyperintense demyelinating lesions on MRI, worse quality of life, and higher risk of cognitive worsening. The German National MS registry corroborated many of these findings, and Norwegian anthropometric data showed that high body mass index between ages 14 and 24 consistently increased MS susceptibility later in life in both sexes. Proposed mechanisms range from adipose tissue dysregulation and decreased vitamin D bioavailability to altered estrogen signaling, amplified Epstein–Barr virus immune responses, and gut microbiota dysbiosis.

Beyond weight loss, GLP-1RAs now carry FDA approvals for a remarkable list of comorbidities common in MS. Type 2 diabetes affects about 5 percent of people with MS, and poor glycemic control exacerbates the cognitive impairment that typically presents later in life. Tirzepatide became the first FDA-approved medication for obstructive sleep apnea in 2024, a condition that shares fatigue and cognitive deficits with MS; a Phase III trial showed it reduced apnea frequency, hypoxic burden, blood pressure, and fatigue. Semaglutide was approved in 2024 to reduce life-threatening cardiovascular events in adults with obesity or overweight—even without diabetes—and in 2025 for metabolic-associated steatohepatitis with moderate-to-advanced fibrosis, after a Phase III trial demonstrated improved resolution of steatohepatitis and reduced liver fibrosis. Semaglutide also reduced major kidney disease events in an international randomized trial in type 2 diabetes, relevant because people with MS face kidney complications from neurogenic bladder and, rarely, from treatments such as alemtuzumab. Emerging indications include alcohol use disorder, where semaglutide reduced heavy drinking days in patients with comorbid obesity, and knee osteoarthritis, where the STEP 9 trial of 407 participants found significant reductions in both body weight and pain.

The first MS-specific data come from small retrospective cohorts, and they are cautiously encouraging. In one single-center study of 49 adults with MS taking semaglutide or tirzepatide for an average of 24.2 months, average weight loss was 0.47 kilograms per month—roughly half the rate documented in the original Phase III semaglutide obesity trial, likely reflecting confounding factors such as steroid use. Still, the drugs worked. Twenty-nine percent of patients reported gastrointestinal side effects, but only 6 percent discontinued due to intolerability. MS disease activity fell within an expected range: one clinical relapse and four patients with new subclinical MRI lesions, in a cohort where 24 percent were not taking a disease-modifying therapy. A second retrospective study of 60 people with MS added a metabolic twist: after GLP-1RA initiation, average body mass index decreased while serum 25-hydroxy-vitamin D levels rose, without progression in EDSS scores or timed 25-foot walk duration. Lower vitamin D has been linked to increased relapse risk and new T2 lesions, so the increase in bioavailability is potentially meaningful.

Prescribing considerations are far from trivial. Cost is a major barrier: the 2024 KFF Health Tracking Poll found that more than half of adults who have taken GLP-1RAs say the cost was difficult to afford, and a NARCOMS survey of 4,181 people with MS found that although 40 percent had an indication, only 14.6 percent had ever taken a GLP-1RA. Sarcopenia is an emerging concern, since skeletal muscle possesses GLP-1 receptors and one-fifth of people with MS already have sarcopenia, associated with severe fatigue and inability to exercise. The lean-mass fraction of weight loss varies dramatically by drug: 45.2 percent in the STEP-1 semaglutide trial versus 25.7 percent in the SURMOUNT-1 tirzepatide study. Perhaps the most eye-catching safety signal is nonarteritic anterior ischemic optic neuropathy, or NAION. A retrospective study from the Massachusetts Eye and Ear Infirmary of 16,827 overweight or obese patients found NAION incidence of 6.7 percent in the semaglutide-treated group versus 0.8 percent in the non-treated group, though subsequent studies found a far more modest increase, with one meta-analysis reporting an absolute NAION risk of 0.09 percent. Causality is unconfirmed, but people with MS share vascular risk factors for NAION—diabetes, cardiovascular disease, sleep apnea—and are already vulnerable to visual loss from optic neuritis, making any ophthalmic complication especially problematic.

The deeper biological question is whether GLP-1RAs could be neuroprotective in MS itself. GLP-1 receptors are present in the central nervous system, particularly in brain areas essential for cognition, and GLP-1RA administration reduces inflammatory markers such as C-reactive protein, tumor necrosis factor alpha, and various interleukins, commonly through the NF-kB signaling pathway. In experimental autoimmune encephalomyelitis, the mouse model of relapsing-remitting MS, the results are striking. EAE markedly downregulates GLP-1 and GLP-1R, but GLP-1RA administration rescues GLP-1R signaling, improving clinical symptoms, maintaining CNS organ weight, reducing spinal cord damage, and attenuating myelin staining loss. Exendin-4 reduced pro-inflammatory cytokine expression in EAE-activated microglia via NF-kB; liraglutide delayed EAE onset and reduced severity by upregulating Nrf2 and the mitochondrial antioxidant MnSOD while reducing the neurodegenerative marker amyloid precursor protein; semaglutide increased CREB/BDNF/MBP markers of myelination while reducing NF-kB and TNF-alpha, acting through PI3K/Akt pathways.

Yet the myelin story is contradictory. A cuprizone-induced mouse model of acute demyelination suggested liraglutide restored myelinated nerve staining, improved behavior and brain weight, elevated p-AMPK/SIRT1 levels and Olig2 protein expression, and decreased microgliosis. But a subsequent study challenged these findings by identifying that the anorexigenic effect of GLP-1RAs confounds the amount of cuprizone the mice actually ingest. By controlling for cuprizone and adding a myelin-specific immune response, that study found the experimental brain-penetrant agonist NLY01 had no effect on demyelination or remyelination in the setting of inflammatory barriers specific to MS. The Parkinson’s disease experience offers a sobering parallel: NLY01 prevented microglial-mediated conversion of astrocytes to a neurotoxic phenotype in mouse models, and lixisenatide slowed motor disability progression in a Phase II trial, but a clinical trial of NLY01 at 2.5 and 5.0 milligrams showed no improvement in Parkinson’s motor or non-motor features. Whether GLP-1RAs truly cross the blood-brain barrier at clinically meaningful levels remains an unresolved research gap.

Two ongoing trials may settle the question for MS. At Northwestern University in Chicago, an actively enrolling study is investigating long-term outcomes of people with MS co-treated with ocrelizumab and a GLP-1RA, following patients for 72 weeks with patient-reported outcome measures, clinical assessments, and disease biomarkers. At Johns Hopkins University in Baltimore, a nearly two-year study will administer NLY01—the novel brain-penetrant agonist that showed promise in Parkinson’s trials—and measure change in normalized brain parenchymal volume on MRI to evaluate possible neuroprotection directly. The review’s authors also speculate that GLP-1RAs could complement statins, which reduced whole-brain atrophy by 43 percent annually in a randomized trial of 140 people with secondary progressive MS but could not modulate inflammatory markers—precisely where GLP-1RAs excel.

For now, the verdict is measured. Early observational data are reassuring on safety and tolerability, and effective treatment of comorbidities may itself carry disease-modifying potential in MS, given that at least 15 percent of people are clinically obese at diagnosis and weight loss improves outcomes. By pharmacologically inducing weight loss that dietary and exercise interventions struggle to achieve in patients burdened by fatigue, imbalance, and motor weakness, GLP-1RAs may help people with MS return to regular aerobic activity, with secondary benefits for mood and energy. But available evidence does not yet establish disease-modifying efficacy, and prospective randomized controlled trials are needed before the class can claim a role in the MS treatment regimen itself. As the multi-billion-dollar GLP-1 industry continues its expansion, the MS community is watching closely—because the next chapter of the Ozempic story may be written in the brain.

Subject of Research: Neurology

Article Title: Glucagon‐Like Peptide‐1 Receptor Agonists in Multiple Sclerosis: A Topical Narrative Review

Article References: Chang, A. Y., & Mateen, F. J. (2026). Glucagon‐Like Peptide‐1 Receptor Agonists in Multiple Sclerosis: A Topical Narrative Review. Annals of Clinical and Translational Neurology, Article acn3.70547. https://doi.org/10.1002/acn3.70547

Image Credits: AI Generated

DOI: 10.1002/acn3.70547

Keywords: GLP-1 receptor agonists, multiple sclerosis, semaglutide, tirzepatide, obesity, neuroprotection, experimental autoimmune encephalomyelitis, optic neuropathy, comorbidities, clinical trials, inflammation, disease-modifying therapy