• Nirosen Vijiaratnam, Christine Girges, Grace Auld, Rachel McComish, Alexa King, Simon S Skene, Steve Hibbert, Alan Wong, Sabina Melander, Rachel Gibson, Helen Matthews, John Dickson, Camille Carroll, Abigail Patrick, Jemma Inches, Monty Silverdale, Bethan Blackledge, Jessica Whiston, Michele Hu, Jessica Welch, Gordon Duncan, Katie Power, Sarah Gallen, Jacqueline Kerr, K Ray Chaudhuri, Lucia Batzu, Silvia Rota, Edwin Jabbari, Huw Morris, Patricia Limousin, Nigel Greig, Yazhou Li, Vincenzo Libri, Sonia Gandhi, Dilan Athauda, Kashfia Chowdhury, and Tom Foltynie.
• Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, University College London, London, UK.
• Lancet. 2025 Feb 4.

BackgroundGLP-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.MethodsWe 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).FindingsBetween 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.InterpretationOur 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.FundingNational Institute for Health and Care Research and Cure Parkinson's.Copyright © 2025 Elsevier Ltd. All rights reserved.

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