Objective: Evaluate the efficacy and safety of Glucagon-like peptide-1 (GLP-1) agonists on Parkinson’s disease (PD).

Background: The idea of ​​repositioning drugs used to treat PD has gained significant attention in recent years. Given the unsafety of current PD treatment protocols (1), repositioning drugs may provide good alternatives for PD and reduce research costs and time in developing new treatment strategies (2). One of the repositioned drugs is GLP-1 agonists, a type 2 diabetes mellitus drug.

Method: A literature search conducted through PubMed, Scopus and Web of Science to identify RCTs assessing GLP-1 agonists on PD. Two reviewers conducted screening and data extraction independently. Screening was conducted on two levels: 1. Title and abstract screening and 2. Full text screening. Quality assessment was performed using RoB-2 tool. The included studies were pooled in a meta-analysis model using mean difference for continuous outcomes and risk ratios for categorical outcomes with 95% confidence interval. A random-effect model was used. Sensitivity analysis was performed.

Results: Of the 883 articles retrieved for title and abstract screening, 32 articles were eligible for full text screening and Six papers were included in data extraction and meta-analysis. Four studies were assessing exenatide (3–6), One assessing Lixisenatide (7) and One pre-printed study assessing Liraglutide (8). The primary outcome was the change in the MDS-UPDRS III during OFF-medication state. The overall mean difference between the GLP-1 agonists group and control group did not favor either of them (MD= -1.34, 95%CI [-3.90 to 1.23], P=0.31). MDS-UPDRS III ON-medication, I, II, II, IV were evaluated and did not show any significant differences between the two groups (fig.2). GLP-1 agonists showed a significant risk for nausea (RR=2.19, P= <0.00001), vomiting (RR=4.61, P=0.0002), constipation (RR=1.63, P=0.004), and weight loss (RR=1.81, P=0.006) in PD patients (fig.3). For fear from conflicting information between pre-printed studies and future published forms (9), we conducted a sensitivity analysis excluding Hogg et al. study , where the results did not differ significantly from the main analysis (fig.4,5).

Conclusion: GLP-1 agonists did not show any significant improvement in the motor function, quality of life or cognition in PD. Further studies with specified protocols and PD groups should be considered.

Fig.1 Quality assessment of included studies.

Fig.2 Efficacy outcomes.

Fig.3 Adverse events.

Fig.4 Sensitivity analysis of efficacy outcomes.

Fig.5 Sensitivity analysis of Adverse events.

References: 1. Murakami H, Shiraishi T, Umehara T, Omoto S, Iguchi Y. Recent Advances in Drug Therapy for Parkinson’s Disease. Intern Med. 2023 Jan 1;62(1):33–42.
2. Hernández-Parra H, Cortés H, Avalos-Fuentes JA, Del Prado-Audelo M, Florán B, Leyva-Gómez G, et al. Repositioning of drugs for Parkinson’s disease and pharmaceutical nanotechnology tools for their optimization. J Nanobiotechnology. 2022 Sep 15;20:413.
3. McGarry A, Rosanbalm S, Leinonen M, Olanow CW, To D, Bell A, et al. Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2024 Jan 1;23(1):37–45.
4. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. The Lancet. 2017 Oct 7;390(10103):1664–75.
5. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013 Jun 3;123(6):2730–6.
6. Vijiaratnam N, Girges C, Auld G, McComish R, King A, Skene SS, 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. The Lancet [Internet]. 2025 Feb 4 [cited 2025 Feb 9];0(0). Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02808-3/fulltext
7. Meissner WG, Remy P, Giordana C, Maltête D, Derkinderen P, Houéto JL, et al. Trial of Lixisenatide in Early Parkinson’s Disease. N Engl J Med. 2024 Apr 3;390(13):1176–85.
8. Hogg E, Wu T, Bresee C, Wertheimer J, Malatt C, Tan E, et al. A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson’s Disease [Internet]. Rochester, NY: Social Science Research Network; 2022 [cited 2024 Dec 23]. Available from: https://papers.ssrn.com/abstract=4212371
9. Brietzke E, Gomes FA, Gerchman F, Freire RCR. Should systematic reviews and meta-analyses include data from preprints? Trends Psychiatry Psychother. 2023 Apr 14;45:e20210324.

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