Efficacy and Safety of Glucagon‐Like Peptide 1 Receptor Agonists in Parkinson Disease: A Systematic Review and Meta‐Analysis

ABSTRACT Background Parkinson's disease (PD) is a progressive neurodegenerative disorder with no currently approved disease‐modifying treatments. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), originally used in type 2 diabetes, have demonstrated neuroprotective and anti‐inflammatory effects in preclinical PD models. This systematic review and meta‐analysis evaluated the efficacy and safety of GLP‐1RAs in patients with PD. Methods A systematic search of MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov was conducted through July 2025 for randomized controlled trials (RCTs) comparing GLP‐1RAs to placebo in PD. Primary outcomes included MDS‐UPDRS Part III (motor examination) both on and off medication. Secondary outcomes included MDS‐UPDRS Parts I, II, IV, PDQ‐39, NMSS, and adverse effects. Data were pooled using a random‐effects model with results reported as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). Results Five RCTs involving 708 participants were included. No statistically significant differences were found in MDS‐UPDRS Part III scores off medication (MD: –2.00, 95% CI: –4.12 to 0.11, p = 0.06) or on medication (MD: –1.40, 95% CI: –3.42 to 0.62, p = 0.17). Secondary outcomes also showed no significant benefits with GLP‐1RA use. However, GLP‐1RAs were associated with increased gastrointestinal side effects, including nausea (RR: 2.09), vomiting (RR: 4.53), constipation (RR: 1.60), and weight loss (RR: 1.83). Conclusion Current evidence does not demonstrate a statistically significant overall benefit of GLP‐1RAs on efficacy outcomes in PD, while gastrointestinal adverse events are increased. More trials are needed to clarify their disease‐modifying potential.