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.
Level 2 - randomized trial
Phase 3 multicentre, double-blind, parallel-group, randomised placebo-controlled trial
PubMed 39919773 · doi:10.1016/S0140-6736(24)02808-3
What was done
A phase 3, multicentre, double-blind, parallel-group, randomised placebo-controlled trial across six UK research hospitals evaluated whether the GLP-1 receptor agonist exenatide slows progression in Parkinson's disease. Eligible participants were 25–80 years of age, Hoehn and Yahr stage ≤2.5 on dopaminergic treatment, and on stable dopaminergic therapy for at least 4 weeks. A total of 194 participants were randomly assigned (1:1) to extended-release subcutaneous exenatide 2 mg weekly (n=97) or matched placebo (n=97) for 96 weeks. The primary outcome was the change in MDS-UPDRS Part III motor score in the OFF-medication state at 96 weeks, analyzed by intention-to-treat using linear mixed models.
What was found
Among participants with at least one follow-up visit (92 exenatide, 96 placebo), MDS-UPDRS Part III OFF-medication scores worsened by a mean of 5.7 points (SD 11.2) in the exenatide group and 4.5 points (SD 11.4) in the placebo group at 96 weeks. The adjusted coefficient for the effect of exenatide was 0.92 (95% CI -1.56 to 3.39; p=0.47). Serious adverse events occurred in 9 (9%) participants receiving exenatide and 11 (11%) receiving placebo.
Why it matters
Despite supportive preclinical models and earlier small clinical trials suggesting neuroprotective potential for GLP-1 receptor agonists, this phase 3 trial shows no disease-modifying benefit from weekly exenatide over 96 weeks in mild-to-moderate Parkinson's disease.
Limits
The study tested only one dosing regimen of extended-release exenatide (2 mg once weekly) and was limited to UK patients with mild-to-moderate disease (Hoehn and Yahr ≤2.5). Central nervous system target engagement was not established within the trial abstract, and findings cannot necessarily be generalized to other GLP-1 receptor agonists with different pharmacokinetics or central penetration profiles.
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