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GLP-1 receptor agonists in Parkinson’s disease

GLP-1 receptor agonists—first used for type 2 diabetes—show pre-clinical and epidemiological hints of neuroprotection in Parkinson’s disease (PD). Early phase-2 trials of exenatide and lixisenatide modestly improved motor scores, but a recent phase-3 exenatide study failed to slow disease progression. As of May 2025, no GLP-1 therapy has proven disease-modifying in PD, though several trials are still under way.

Glucagon-like peptide-1 (GLP-1) receptor agonists were initially developed for type 2 diabetes mellitus (T2DM), in which they enhance insulin secretion, suppress appetite, and deliver sustained glycemic control. Preclinical studies suggest these agents may also protect neurons by reducing injury, dampening neuro-inflammation, and improving neuronal glucose metabolism (1). Supporting this possibility, two large epidemiological studies in people with T2DM reported a lower incidence of Parkinson’s disease (PD) among those using GLP-1 receptor agonists.

Clinical evidence, however, is mixed (2). An open-label study published in 2013 showed that 12 months of exenatide improved motor scores, and the benefit remained a year after discontinuation. A subsequent double-blind, randomized, placebo-controlled phase-2 trial reported a 3.5-point advantage on the MDS-UPDRS part III after 48 weeks of exenatide, an effect that persisted through the wash-out period. Likewise, a one-year phase-2 trial of another GLP-1 agonist, lixisenatide, outperformed placebo, while a study of pegylated exenatide showed no overall benefit—aside from a significant reduction in motor scores in participants younger than 60 years.

Despite these encouraging early results, a recent large phase-3 trial of exenatide failed to show meaningful slowing of PD progression (3). As of May 2025, no phase-3 study has demonstrated disease-modifying efficacy for GLP-1-based therapy in PD. Ongoing trials (e.g., NCT03659682) and follow-up analyses of lixisenatide’s phase-2 data will clarify the picture. For now, whether GLP-1-targeted treatments can truly provide neuroprotection in PD remains an important—yet unanswered—question.

Key Points:

  • GLP-1 receptor agonists, developed for type 2 diabetes, showed neuroprotective effects in preclinical models and have been associated with a lower incidence of Parkinson’s disease (PD) in epidemiological studies.
  • Phase-2 trials of some GLP-1 agonists produced modest but lasting improvements in motor scores; however, a recent phase-3 exenatide trial failed to demonstrate a slowing of PD progression.
  • As of May 2025, no GLP-1-based therapy has proven to have disease-modifying efficacy in PD.
  • Future trials will clarify whether GLP-1 agonists can offer neuroprotection

References:

  1. Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res. 2022 Dec;186:106550.
  2. Albuquerque MB, Nunes LEDB, Oliveira Maldonado JV, Melo Ferreira DG, Margato MM, Rabelo LV, et al. GLP-1 receptor agonists for Parkinson's disease: An updated meta-analysis. Parkinsonism Relat Disord. 2025 Jan;130:107220.
  3. Vijiaratnam N, Girges C, Auld G, McComish R, King A, Skene SS, 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, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial. Lancet. 2025 Feb 22;405(10479):627-636

Co-authors:
Alberto Imarisio, University of Pavia, Department of Molecular Medicine, Pavia, Italy

Publish on behalf of the Scientific Panel on Movement disorders

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