Glucagon-like peptide-1 receptor agonists and the risk of Parkinson's disease in patients with type 2 diabetes: a systematic review and meta-analysis of large-scale real-world data.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet effective disease-modifying therapies remain elusive. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes mellitus (T2DM), have shown neuroprotective potential in preclinical studies. However, real-world evidence on the association between GLP-1RAs use and PD risk remains inconsistent and has not been systematically synthesized. This systematic review and meta-analysis aimed to evaluate this association using large-scale real-world data. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science from database inception to March 18, 2026, for cohort and case-control studies exploring the association between GLP-1RA exposure and PD risk among patients with T2DM. Study selection, data extraction, and methodological quality assessment were independently conducted by two reviewers. All meta-analyses were performed using Stata 15.0 software. Results: A total of six studies were included, involving 452,763 participants. The meta-analysis revealed that GLP-1RA exposure was significantly associated with a reduced risk of PD in patients with T2DM (HR = 0.68, 95%CI (0.54,0.85), P = 0.001). Subgroup analyses demonstrated that compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, and other hypoglycemic drugs, GLP-1RAs were linked to a lower risk of incident PD (DPP-4 inhibitors: HR = 0.60, 95%CI (0.43,0.83), P = 0.001; Metformin: HR = 0.83, 95%CI (0.73,0.95), P = 0.006; Other: HR = 0.73, 95%CI (0.60,0.87), P = 0.002). Conclusions: This meta-analysis based on large-scale real-world data indicates that GLP-1RA exposure is associated with a lower risk of PD in patients with T2DM, with robust and consistent results across diverse comparator groups. These findings support the hypothesis that GLP-1RAs may confer neuroprotective properties, a finding that merits further rigorous investigation. Nevertheless, given the inherent limitations inherent to observational study designs and the possibility of residual confounding in the included studies, the present results should be regarded as preliminary and hypothesis-generating rather than conclusive. Future large-scale prospective cohort studies with standardized methodologies, as well as well-designed randomized controlled trials, are warranted to validate these findings and clarify whether the observed inverse association reflects a causal neuroprotective effect of GLP-1RAs.