Objective: To evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists in patients with Parkinson’s disease (PD) through an updated systematic review and meta-analysis incorporating recent phase 3 randomized evidence.

Background: Drug repurposing has gained increasing attention in PD research. GLP-1RAs, commonly used for the treatment of type 2 diabetes mellitus, have demonstrated neuroprotective properties in experimental models and early clinical studies. However, recent large randomized trials have produced conflicting findings regarding their clinical benefit in PD.

Method: A systematic search of PubMed, Scopus, Web of Science, Cochrane Central, and Google Scholar was conducted from inception to February 2026. Randomized controlled trials evaluating GLP-1RAs in PD were included. Outcomes were extracted as mean change from baseline. Variance measures were standardized by converting standard errors and confidence intervals to standard deviations when necessary. Random-effects meta-analysis was performed to calculate pooled mean differences (MD) with 95% confidence intervals (CI). Outcomes included motor function (MDS-UPDRS), quality of life (PDQ-39), and non-motor symptoms.

Results: Five randomized controlled trials involving 708 patients evaluating exenatide, lixisenatide, and NLY01 were included. For the primary outcome, motor function in the OFF-medication state (MDS-UPDRS Part III), the pooled random-effects estimate showed no significant improvement with GLP-1RAs compared with placebo (MD −2.07, 95% CI −5.59 to 1.44; I²=66%). Similarly, pooled analyses of ON-state motor scores, activities of daily living (MDS-UPDRS Part II), non-motor symptoms, and quality of life (PDQ-39) demonstrated no significant differences between groups. Across studies, GLP-1RAs were associated with higher rates of gastrointestinal adverse events, particularly nausea and vomiting.

Conclusion: This updated meta-analysis incorporating phase 3 evidence does not demonstrate a significant clinical benefit of GLP-1RAs on motor or non-motor outcomes in patients with Parkinson’s disease. Despite promising preclinical neuroprotective mechanisms, current clinical evidence does not support routine use of these agents for disease modification in PD. Future research should focus on identifying responsive patient subgroups and agents with improved central nervous system penetration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-and-safety-of-glp-1-receptor-agonists-in-parkinsons-disease-a-meta-analysis-integrating-the-96-week-phase-3-exenatide-trial-results/