Exenatide Alters Motor Network Activity in Parkinson Disease, Though Clinical Impact Remains Limited

A recently presented placebo-controlled trial revealed that exenatide, an FDA-approved glucagon-like peptide 1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes, led to distinct effects on mediating brain metabolic networks associated with both motor and cognitive declines in Parkinson disease (PD). Despite this, the therapy’s effects on patients with PD did not translate to any clinical benefit, consistent with a previously published large-scale study.¹

In this double-blind, placebo-controlled trial, 59 patients with PD received either exenatide or placebo weekly for 18 months, followed by a 3-month washout. Over the pooled 21-month period, results using mixed-effects ANCOVA models showed significant between-group differences in changes of PD-related motor expression (P = .001) across all 3 timepoints.

Presented at the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, results revealed a significant interaction effect at 9 months between the treatment groups (P = .01), with PD-related motor metabolic pattern expression decreased in only the exenatide group. A similar interaction effect was observed for PD-related cognitive progression expression at 9 months (P <.05), but not over the 21-month total period.

The study authors, which included Per Svenningsson, MD, PhD, a professor of neurology at the Karolinska University Hospital, noted that despite the effects on brain metabolite networks, treatment with exenatide did not result in between-group differences on MDS Unified Parkinson’s Disease Rating Scale-Part III scores. Of note, this was true for both the ON and OFF medication states. In addition, the study also found distinct responses in plasma-derived inflammatory and metabolic markers among exenatide-treated patients relative to placebo.

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Over the years, there have been a number of studies testing exenatide in PD, with mixed results reported across various settings. A 2017, double-blind, placebo-controlled trial of 62 patients with the disease showed that the GLP-1 receptor agonist (RA) led to positive effects in OFF-medication scores in PD, which were sustained over a long-term period. After 60 weeks of treatment, OFF-medication scores on Part III of the MDS-UPDRS had improved by 1.0 points (95% CI, –2.6 to 0.7) in the exenatide group and worsened by 2.1 points (95% CI, –0.6 to 4.8) in the placebo group, leading to an adjusted mean difference of –3.5 points (95% CI, –6.7 to –0.3; P = .0318).²

Earlier this year, a study published in The Lancet aimed to confirm previous positive results, testing whether exenatide could be beneficial in a larger, multicenter setting. This phase 3 study, a double-blind, parallel-group, placebo-controlled trial spanning 6 research hospitals in the U.K., included 194 patients with PD who were assigned to subcutaneous exenatide at 2 mg (n = 97) or placebo (n = 97) for a 96-week period.³

Overall, results from that study supported the safety of exenatide in PD, but did not find any evidence to support the medication as a disease-modifying treatment. After 96 weeks of treatment, MDS-UPDRS Part 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 effect, 0.92; 95% CI, –1.56 to 3.39; P = .47). Of note, the number of serious adverse events was comparable between the exenatide group (n = 9; 9%) relative to those on placebo (n = 11; 11%).

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REFERENCES
1. Markaki I, Tang CC, Papathoma PE, et al. Effect of Exenatide on Disease Progression in Early Parkinson’s Disease–A Randomized, Placebo Controlled, Single-center Trial in Sweden. Presented at: 2025 MDS Congress. October 5-10, Honolulu, Hawaii. ABSTRACT S443
2. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664-1675. doi:10.1016/S0140-6736(17)31585-4
3. Vijiaratnam N, Girges C, Auld G, 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, multicenter, double-blind, parallel-group, randomized, placebo-controlled trial. The Lancet. 2025;405:10479. doi:10.1016/S0140-6736(24)02808-3