From diabetes to dopamine: Evaluating the disease-modifying potential of GLP-1 receptor agonists in Parkinson's disease. A systematic review and meta-analysis of placebo-controlled trials.

BACKGROUND: While current therapies address symptom management, there is an unmet need for disease-modifying treatments in Parkinson's disease (PD). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for diabetes, have shown neuroprotective properties. AIM: To assess the disease-modifying potential and safety of GLP-1 RAs in PD. METHODS: We followed Cochrane Handbook. We included all randomized controlled trials (RCTs) evaluating GLP-1 RAs in PD that were identified through comprehensive database searches through March 2025. Cochrane's risk-of-bias tool was used to assess the RCTs' quality. A random-effects model was used to calculate mean differences (MDs) and risk ratios (RRs) with their confidence intervals (CIs) and analyze them using R. RESULTS: Our meta-analysis of four placebo-controlled RCTs found that GLP-1 RAs demonstrated a statistically significant overall improvement in ON-medication motor scores (MDS-UPDRS Part III: MD -0.75, 95% CI [-1.50, -0.0009]; P = 0.04). However, this benefit was not consistently observed at individual follow-up time points. In contrast, the pooled analysis for OFF-medication motor scores showed no significant overall improvement (MD -1.39; P = 0.16), despite considerable heterogeneity; only the 60-week follow-up showed a significant benefit (MD -3.0; P = 0.005). No significant differences were found for health-related quality of life (PDQ-39), other MDS-UPDRS domains (Part I, Part II, or Part IV), or Levodopa equivalent daily dose. GLP-1 RAs were associated with significantly higher rates of gastrointestinal adverse events (loss of appetite, nausea, vomiting, dyspepsia, gastroesophageal reflux) and weight loss. CONCLUSIONS: Current evidence does not sufficiently support the routine use of GLP-1 RAs for motor improvement in PD.