ORCID
- Camille Carroll: 0000-0001-7472-953X
Abstract
Background: GLP-1 receptor agonists have neurotrophic properties in in-vitro and in-vivo models of Parkinson's disease and results of epidemiological studies and small randomised trials have suggested possible benefits for risk and progression of Parkinson's disease. We aimed to establish whether the GLP-1 receptor agonist, exenatide, could slow the rate of progression of Parkinson's disease. Methods: We did a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial at six research hospitals in the UK. Participants were aged 25–80 years with a diagnosis of Parkinson's disease, were at Hoehn and Yahr stage 2·5 or less when on dopaminergic treatment, and were on dopaminergic treatment for at least 4 weeks before enrolment. Participants were randomly assigned (1:1) using a web-based system with minimisation according to Hoehn and Yahr stage and study site to receive extended-release exenatide 2 mg by subcutaneous pen injection once per week over 96 weeks, or visually identical placebo. All participants and all research team members at study sites were masked to randomisation allocation. The primary outcome was the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, off dopaminergic medication at 96 weeks, analysed in the intention-to-treat population using a linear mixed modelling approach. This study is registered with ISRCTN (14552789), EudraCT (2018-003028-35), and ClinicalTrials.gov (NCT04232969). Findings: Between Jan 23, 2020, and April 23, 2022, 215 participants were screened for eligibility, of whom 194 were randomly assigned to exenatide (n=97) or placebo (n=97). 56 (29%) participants were female and 138 (71%) were male. 92 participants in the exenatide group and 96 in the placebo group had at least one follow-up visit and were included in analyses. At 96 weeks, MDS-UPDRS III OFF-medication scores had increased (worsened) by a mean of 5·7 points (SD 11·2) in the exenatide group, and by 4·5 points (SD 11·4) points in the placebo group (adjusted coefficient for the effect of exenatide 0·92 [95% CI –1·56 to 3·39]; p=0·47). Nine (9%) participants in the exenatide group had at least one serious adverse event compared with 11 (11%) in the placebo group. Interpretation: Our findings suggest that exenatide is safe and well tolerated. We found no evidence to support exenatide as a disease-modifying treatment for people with Parkinson's disease. Studies with agents that show better target engagement or in specific subgroups of patients are needed to establish whether there is any support for the use of GLP-1 receptor agonists for Parkinson's disease. Funding: National Institute for Health and Care Research and Cure Parkinson's.
DOI Link
Publication Date
2025-02-04
Publication Title
Lancet
Volume
405
Issue
10479
ISSN
0140-6736
Acceptance Date
2025-01-01
Deposit Date
2025-02-18
Funding
Funding for the study was provided by the National Institute for Health and Care Research (NIHR; Efficacy and Mechanism Evaluation scheme number 16/167/19) with imaging (DaT\u2013SPECT) funding by Cure Parkinson's. AstraZeneca provided the investigational medical product (exenatide) but were not involved in the design of the trial, analysis of data, or writing of the manuscript. This study was sponsored and coordinated by University College London (UCL) Comprehensive Clinical Trials Unit. Trial operations were supported by the NIHR University College London Hospitals (UCLH) Clinical Research Facility/Leonard Wolfson Experimental Neurology Centre and the NIHR UCLH/UCL Biomedical Research Centre at the UCL Institute of Neurology and the UCLH National Hospital for Neurology and Neurosurgery (London, UK). NV was supported by the Janet Owens Bequest. The analysis of exenatide concentrations was partly supported by the Intramural Research Program of the US National Institutes of Health's National Institute on Aging. This research was conducted with support from AstraZeneca UK. We are grateful to staff in pharmacies across trial sites who ensured accurate trial dispensing and laboratories who ensured safe handling and storage of trial research specimens. Exenatide and matched placebo packaging, labelling, storage, and distribution were performed at Royal Free London NHS Foundation Trust and WGK Clinical Group. We are grateful to members of our trial steering committee: Carl Clarke, Caroline Williams-Gray, Clive Bartram, Helen Matthews, Victoria Cornelius, and Zia Mursaleen. We are grateful to members of our independent data monitoring committee: David Burn, Lorna Aucott, Roger Barker, Oliver Bandmann, and Andrew Embleton-Thirsk. Most of all, we thank the people with Parkinson's disease and their families who participated in the trial, and who contributed to its design and conduct.
Additional Links
https://linkinghub.elsevier.com/retrieve/pii/S0140673624028083
First Page
627
Last Page
636
Recommended Citation
Vijiaratnam, N., Girges, C., Auld, G., McComish, R., King, A., Skene, S., Hibbert, S., Wong, A., Melander, S., Gibson, R., Matthews, H., Dickson, J., Carroll, C., Patrick, A., Inches, J., Silverdale, M., Blackledge, B., Whiston, J., Hu, M., Welch, J., Duncan, G., Power, K., Gallen, S., Kerr, J., Chaudhuri, K., Batzu, L., Rota, S., Jabbari, E., Morris, H., & Limousin, P. (2025) '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, 405(10479), pp. 627-636. Available at: 10.1016/S0140-6736(24)02808-3
