Exenatide Does Not Slow Parkinson’s Progression in Largest Trial Yet
STUDY: Vijiaratnam N et al, Lancet 2025;405:627–636, PMID: 39909066
STUDY TYPE: Phase 3, randomized, double-blind, placebo-controlled trial
FUNDING: Industry (AstraZeneca); National Institute for Health and Care Research; Cure Parkinson’s
Background
The GLP-1 agonist exenatide improved movements in Parkinson’s disease in two earlier trials, with sustained benefits after stopping the med – implying a disease modifying effect. GLP-1 receptor agonists also reduce Parkinson’s risk in diabetic populations. A similar med, lixisenatide, also showed promise. But this phase 3 trial disappoints.
The Study
194 adults with moderate-severity Parkinson’s disease (and no diabetes) were randomized to weekly subcutaneous exenatide 2 mg or placebo for 96 weeks at six UK hospitals. Primary outcome: change in MDS-UPDRS Part III score assessed off dopaminergic medication at 96 weeks.
Exenatide did not slow motor progression. Off-medication scores worsened by 5.7 points in the exenatide group versus 4.5 points in placebo (adjusted difference 0.92, 95% CI −1.56 to 3.39, p = 0.47) — if anything, a small numerical disadvantage for exenatide. No secondary outcome favored treatment: non-motor symptoms, cognition, quality of life, dopamine transporter imaging; nor did it change the need for other Parkinson’s treatment (levodopa). They also looked at younger patients (under 60), but again no benefit.
Exenatide was well tolerated; GI side effects and modest weight loss were more common in the active group.
Practice Implications
This is a clean negative. The trial was adequately powered, double-blind, and two years long — three times longer than the phase 2 trials that generated the original signal.
The discordance with earlier results is striking and unexplained. Perhaps it is that the medication doesn’t reach the brain (only about 1% of plasma exenatide reaches the cerebral spinal fluid).
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
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