This systematic review and network meta-analysis of five RCTs (n=708) found dose-specific ON-state motor improvements with some GLP-1 receptor agonists (notably exenatide 20 μg/day and lixisenatide 20 μg/day) but overall heterogeneous results and limited evidence for broader clinical benefit.

Moderately high translational value because GLP-1RAs are an already available, mechanism-plausible repurposing class that showed clinically meaningful motor effects in some trials, supporting larger, longer, biomarker-informed trials despite current heterogeneity and tolerability issues.

BACKGROUND: Current therapies for Parkinson’s disease lack proven disease-modifying effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), developed for type 2 diabetes, have shown potential neuroprotective properties. Their comparative efficacy in Parkinson’s disease remains unclear. METHODS: A systematic search (inception–February 2026) identified randomized controlled trials evaluating GLP-1RAs in Parkinson’s disease. Pairwise and frequentist random-effects network meta-analyses were performed. The primary outcome was MDS-UPDRS Part III (ON state). RESULTS: Five trials (n = 708) were included. Pairwise meta-analysis showed no significant overall improvement in MDS-UPDRS Part III (MD –2.00; 95% CI –5.46 to 1.46; I² = 80.5%). Network meta-analysis demonstrated significant ON-state motor improvement with Exenatide 20 µg/day (MD –9.80; 95% CI –14.47 to –5.13) and Lixisenatide 20 µg/day (MD –3.08; 95% CI –5.31 to –0.85). No significant effects were observed for MDS-UPDRS Part III (OFF-state) or other domains (Parts I, II, and IV; ON-state). NLY01 at 5 mg/week improved PDQ-39, while NMSS showed dose-dependent divergence. Gastrointestinal adverse events were more frequent with GLP-1RAs. CONCLUSION: GLP-1 receptor agonists may provide dose-specific motor benefits in Parkinson’s disease, but evidence for broader clinical improvement is limited. Larger, longer-duration trials are needed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10072-026-08929-1.