Adjunctive Dulaglutide in Relapsing-Remitting Multiple Sclerosis: A Randomized Open-Label Proof-of-Concept Trial

Multiple sclerosis (MS) is an immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS) that leads to demyelination, axonal injury, and progressive disability. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been proposed as adjunctive therapy with potential neuroprotective properties. We evaluated the effects of GLP-1RA treatment on metabolic parameters, functional performance, and biomarkers of neurodegeneration in relapsing-remitting MS (RRMS).

In this prospective, randomized, open-label, single-center proof-of-concept study, 28 patients with RRMS receiving stable natalizumab treatment were randomized to adjunctive GLP-1RA (dulaglutide; 0.75 mg subcutaneously once weekly for 12 months; n = 15) or to a control group without adjunctive therapy (n = 13). Assessments were performed at baseline and 12 months. Primary outcomes included plasma neurofilament light chain (NfL) and brain magnetic resonance imaging (MRI) volumetry. Secondary outcomes included resting metabolic rate, functional performance (Timed 25-Foot Walk [T25FW] and 9-Hole Peg Test [9HPT]), cognitive performance (Symbol Digit Modalities Test [SDMT]), anthropometric and metabolic measures, and oral glucose tolerance test (OGTT)-derived insulin sensitivity indices.

Dulaglutide significantly reduced weight, body mass index (BMI), body fat, and visceral fat, and improved glucose tolerance (reduced glucose area under the curve [AUC]). No adverse events were recorded in either group; no discontinuations occurred. Exploratory analyses indicated trends toward improved walking speed (T25FW, group × time interaction: F_1,26 = 9.4, p = 0.005) and non-dominant hand manual dexterity (9HPT, F_1,26 = 4.7, p = 0.039) in the dulaglutide group. However, no significant between-group differences were observed in plasma NfL, brain MRI volumetric measures, or cognitive performance.

Adjunctive dulaglutide 0.75 mg weekly for 12 months improved metabolic parameters and showed exploratory signals of functional benefit, but did not modify plasma NfL or MRI volumetric measures in natalizumab-treated RRMS. Larger, adequately powered studies with higher-dose GLP-1RA regimens and longer follow-up are warranted.

The trial was registered in the EU Clinical Trials Register (EudraCT 2019-003001-94).