Efficacy and safety of glucagon-like peptide-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis of randomized placebo-controlled clinical trials.

BACKGROUND: Converging lines of preclinical evidence support the neuroprotective properties of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Parkinson's disease (PD). Nevertheless, results from randomized-controlled clinical trials (RCTs) remain conflicting. OBJECTIVES: To assess the safety and efficacy of GLP-1 RAs in PD. DESIGN: Systematic review and meta-analysis of randomized placebo-controlled clinical trials. DATA SOURCES AND METHODS: A systematic search of MEDLINE and Scopus databases was conducted on October 7, 2025, for randomized placebo-controlled clinical trials investigating GLP-1 RAs in adults with PD. Risk of bias was evaluated using the Cochrane Collaboration risk-of-bias (RoB2) tool. RESULTS: Four RCTs comprising 667 PD patients (377 receiving GLP-1 RAs) were included. Between baseline and end-of-treatment, no differences were observed in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score change between GLP-1 RA- and placebo-treated patients in either off-medication (standardized mean difference (SMD): -0.16; 95% CI: -0.64 to 0.32;  = 0.52) or on-medication states (SMD: -0.13; 95% confidence interval (CI): -0.51 to 0.25;  = 0.49). No significant differences were uncovered in other MDS-UPDRS subscores, Non-Motor Symptoms Scale, Montreal Cognitive Assessment, or Parkinson's Disease Questionnaire scores. The risk of serious adverse events and odds of treatment discontinuation were similar between groups, but GLP-1 RAs were associated with an increased risk of weight loss compared to placebo (risk ratio: 1.44; 95% CI: 1.04-1.99;  = 0.03). CONCLUSION: GLP-1 RAs were not associated with improvements in motor or non-motor domains of PD. However, robust preclinical evidence and promising findings in select subpopulations warrant further RCTs to evaluate their neuroprotective potential, prioritizing long-acting and brain-penetrant agents that effectively engage central GLP-1 circuits for PD treatment. REGISTRATION: The pre-specified protocol of the present systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration ID: CRD420251008703).