Glucagon-like peptide-1 receptor agonists in movement disorders: From Parkinson's disease to the broader spectrum — Mechanisms, evidence, and future directions

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have emerged as potential neuroprotective agents in neurodegenerative disorders. GLP-1 signaling modulates key pathogenic pathways relevant to movement disorders, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with receptors widely expressed in motor-related brain regions. This narrative review aimed to summarize current mechanistic, preclinical, and clinical evidence regarding the role of GLP-1RAs across the spectrum of movement disorders. Methods A narrative review of the literature was conducted, including preclinical studies, randomized clinical trials, observational data, and pharmacovigilance analyses evaluating GLP-1RAs in movement disorders. Results Preclinical studies consistently demonstrate neuroprotective effects of GLP-1RAs, including preservation of dopaminergic neurons, reduction of α-synuclein aggregation, and improvement in motor function. Clinical evidence is most advanced in Parkinson's disease, where early randomized trials of exenatide and lixisenatide suggested modest motor benefits and possible disease-modifying effects. However, subsequent larger studies, including the phase III Exenatide-PD3 trial, failed to demonstrate significant clinical benefit. Preliminary signals have been reported in multiple system atrophy, whereas evidence in Huntington's disease, essential tremor, and other movement disorders remains largely preclinical. Conclusions GLP-1RAs represents a biologically plausible but as yet unproven disease-modifying strategy in movement disorders. Translational challenges, including pharmacologic heterogeneity, variability in central nervous system exposure, and clinical trial design limitations—must be addressed. Future research should focus on biomarker-guided patient selection, optimized CNS-penetrant agents, and rigorously designed clinical trials.