Objective: To evaluate the efficacy and safety of GLP-1 receptor agonists in Parkinson’s disease (PD) by adding new 2025 randomized controlled trial (RCT) data, and assessing their impact on motor and non-motor symptoms.

Background: The emergence of GLP-1 receptor agonists as potential neuroprotective therapies for PD due to their role in decreasing inflammation and promoting neuronal survival. Earlier meta-analyses have led to contradictory results, mainly due to the small sample sizes and heterogeneity involved in the studies. In light of recently published RCTs, we conducted an updated systematic review meta-analysis to evaluate their therapeutic potential in PD.

Method: A comprehensive search was performed using PubMed, EMBASE, and Cochrane Library to find eligible RCTs comparing GLP-1 receptor agonists (exenatide, lixisenatide, liraglutide, and NLY01) to placebo. A change in the movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III motor scores was the main outcome. Secondary outcomes were MDS-UPDRS Part II, PDQ-39 (quality of life), Non-Motor Symptoms Scale (NMSS), and safety assessment. Cochrane ROB2 tool was used to asses risk of bias. Fixed effects model was chosen to maintain statistical stability and avoid effect size inflation due to elevated heterogeneity (I*> 60%) that sensitivity analysis did not resolve.

Results: Six RCTs with 763 patients met the inclusion criteria, including one newly published 2025 RCT. GLP-1 receptor agonists significantly improved MDS-UPDRS Part III (on-medication) scores (MD: -1.40; 95% CI: -2.70, -0.09; P = 0.04). However, no significant effect was found in MDS-UPDRS Part III (off-medication) (MD: -0.80; P = 0.17), MDS-UPDRS Part II (MD: -0.25; P = 0.41), PDQ-39 (MD: -0.67; P = 0.26), or NMSS scores (MD: 0.11; P = 0.94). High heterogeneity remained unresolved despite sensitivity analysis.

Conclusion: Motor symptoms have been improved by GLP-1 receptor agonist in PD according to this updated meta-analysis, especially when the patients are on medication, though the overall effectiveness remains variable. The constancy of high heterogeneity points to the need for standardized trial designs and larger, rigorously controlled studies.

MDS-UPDRS part III (Off-medication state)

MDS-UPDRS part III (On-medication state)

MDS-UPDRS part II – On-medication state

Change in PDQ 39

Change from baseline NMSS score

References: [1] N. Vijiaratnam et al., “Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson’s disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial,” Lancet, vol. 405, no. 10479, Feb. 2025, doi: 10.1016/S0140-6736(24)02808-3.
[2] W. G. Meissner et al., “Trial of Lixisenatide in Early Parkinson’s Disease,” N Engl J Med, vol. 390, no. 13, pp. 1176–1185, Apr. 2024, doi: 10.1056/NEJMOA2312323.
[3] A. McGarry et al., “Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson’s disease: a randomised, double-blind, placebo-controlled trial,” Lancet Neurol, vol. 23, no. 1, pp. 37–45, Jan. 2024, doi: 10.1016/S1474-4422(23)00378-2.
[4] D. Athauda et al., “Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial,” Lancet, vol. 390, no. 10103, pp. 1664–1675, Oct. 2017, doi: 10.1016/S0140-6736(17)31585-4.
[5] I. Aviles-Olmos et al., “Exenatide and the treatment of patients with Parkinson’s disease,” J Clin Invest, vol. 123, no. 6, pp. 2730–2736, Jun. 2013, doi: 10.1172/JCI68295.
[6] E. Hogg et al., “A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson’s Disease,” SSRN Electronic Journal, Sep. 2022, doi: 10.2139/SSRN.4212371.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glucagon-like-peptide-1-glp-1-receptor-agonists-for-parkinsons-disease-an-updated-systematic-review-and-meta-analysis/