Multiple sclerosis (MS) patients exposed to a GLP-1 receptor agonist had lower rates of relapse activity and steroid use, reduced incidence of optic neuritis, and fewer demyelinating events compared with those who didn’t use these agents, a large real-world study in the U.S. showed.
Over 12 years, use of GLP-1 drugs was associated with lower rates of acute steroid-treated relapses (1.85% vs 4.84%, relative risk [RR] 2.62, 95% CI 2.28-3.03) and optic neuritis (1.46% vs 2.56%, RR 1.78, 95% CI 1.48-2.09), reported Mahsa Khayat-Khoei, MD, of the University of California Riverside, at MSToronto2026, the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Demyelinating events were also lower in MS patients who used GLP-1 drugs (3.48% vs 7.01%, RR 2.01, 95% CI 1.80-2.25) over 12 years, as were gait abnormalities (10.46% vs 16.15%, RR 1.54, 95% CI 1.44-1.65), fatigue (11.87% vs 17.55%, RR 1.48, 95% CI 1.38-1.58), and depression (19.34% vs 26.38%, RR 1.36, 95% CI 1.28-1.45; all P<0.00001).
Patterns were similar in a B-cell therapy subgroup of MS patients treated with ocrelizumab (Ocrevus), with the greatest relative risk reduction in acute steroid-treated relapses (RR 5.52, 95% CI 3.75-8.13) and optic neuritis (RR 2.37, 95% CI 1.56-3.61). This analysis had a 10-year observation window, reflecting ocrelizumab’s availability since 2017.
GLP-1 agents, approved for diabetes, obesity, and other indications, may modulate neuroinflammation and neuronal survival through the gut-brain axis, Khayat-Khoei noted.
“There are studies in the literature — animal models of Alzheimer’s disease, Parkinson’s, multiple sclerosis, and stroke — looking at GLP-1 receptor agonists and how they can maybe contribute to reduced neuroinflammation,” she said. Their role in MS and neurodegenerative diseases, however, is unclear.
GLP-1 receptor agonists may be a promising therapeutic strategy in several neurologic disorders, observed Paul Edison, MD, PhD, of Imperial College London, who wasn’t involved with the study.
“Beyond diabetes and weight loss, they influence insulin signaling, mitochondrial resilience, vascular function, and neuroinflammation, providing a credible biological basis for neurological investigation,” he told MedPage Today. “The presented data in multiple sclerosis are encouraging: in a large cohort, GLP-1 receptor agonist exposure was associated with fewer relapses, optic neuritis episodes, demyelinating events, and gait abnormalities.”
Although the GLP-1 agent semaglutide (Rybelsus) did not slow Alzheimer’s progression in the EVOKE clinical trials, “the failure of oral semaglutide to improve clinical outcomes in Alzheimer’s disease should not close the field,” Edison emphasized.
“Different GLP-1 analogues may vary in molecular structure, distribution, receptor engagement, and central or peripheral actions,” he pointed out.
In the ELAD trial, for example, liraglutide (Saxenda, Victoza) demonstrated some beneficial effects on cognitive performance and brain volume in people with mild Alzheimer’s dementia. Exenatide (Byetta, Bydureon) has been studied in Parkinson’s disease, showing positive effects in a phase II study that were not sustained in a phase III trial.
NLY01, a pegylated analogue of exenatide, is now being tested in the TAG-MS trial to see whether it can lessen brain and retinal atrophy by reducing inflammation in people with progressive MS. Preclinical research suggested that NLY01 may reduce inflammation and disease severity in an MS mouse model.
In their analysis, Khayat-Khoei and co-authors used the TriNetX research network to identify MS patients in the U.S. using ICD-10 codes, comparing patients exposed to GLP-1 agonists with unexposed controls.
The cohort included 339,092 MS patients, and 14,300 were exposed to GLP-1 drugs. Most exposed patients (82%) were women. The B-cell therapy subgroup analysis included 30,934 MS patients treated with ocrelizumab; of these, 1,953 were exposed to GLP-1 drugs.
Overall, patients in the GLP-1 agonist group had higher mean body mass index (36.7 vs 29.0) and higher rates of type 2 diabetes (49% vs 4%) and obesity (58% vs 6%).
Outcomes were assessed after propensity-score matching. “We did propensity-score matching to make sure the data were matched by age, sex, and comorbidities,” Khayat-Khoei said. “The patients who received GLP-1s should have had either diabetes, or be obese, or have sleep apnea.”
Analyses spanning 21 years showed similar findings as the 12-year outcomes, Khayat-Khoei noted.
“These findings support further investigations of the potential anti-inflammatory and neuroprotective properties of GLP-1 receptor agonists,” she said. “Prospective studies are needed to determine whether GLP-1 receptor agonists have disease-modifying or neuroprotective effects in MS.”
