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GLP-1, Parkinson’s Disease, and Neuroprotection
Author: David G. Standaert, M.D., Ph.D. https://orcid.org/0000-0003-2921-8348Author Info & Affiliations
Published April 3, 2024
N Engl J Med 2024;390:1233-1234
DOI: 10.1056/NEJMe2401743
VOL. 390 NO. 13

https://www.nejm.org/doi/full/10.1056/NEJMe2401743

… In this issue of the Journal, Meissner et al. report on a trial of lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist used to treat diabetes mellitus.3 Diabetes is a risk factor for Parkinson’s disease,4 and treatment of diabetes with GLP-1 receptor agonists is associated with a reduction of more than 50% in the risk of new-onset Parkinson’s disease.5 GLP-1 receptor agonists are also protective in animal models of Parkinson’s disease.6 Although a variety of physiological effects are observed in response to GLP-1 receptor activation, a consistent finding is reduced inflammation in the brain, a process that is central to the pathophysiology of Parkinson’s disease in humans.7

In the current trial, investigators studied participants with early clinical Parkinson’s disease. All were already receiving treatment for Parkinson’s disease symptoms with levodopa or other drugs. Participants were randomly assigned to either lixisenatide or placebo. After 12 months, the lixisenatide group had essentially no change in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, but the placebo group had worsening of Parkinson’s disease symptoms (an increase of 3.04 points on the MDS-UPDRS part III, on which higher scores indicate greater motor disability). Taken at face value, these data suggest that lixisenatide completely prevented worsening of symptoms over the 12-month period, but this is probably an overly optimistic view. All the MDS-UPDRS scales, including part III, are composites with many components, and improvement in one feature may offset worsening of another. In addition, both trial groups may have benefited simply from participating in a clinical trial.8 Still, the difference between the two trial groups appears genuine and supports an effect of lixisenatide on the symptoms, and potentially the course, of Parkinson’s disease.

The trial participants did encounter adverse effects of treatment. The trialists set out to administer lixisenatide at the highest dose currently approved for diabetes but found that 36% of the participants had unacceptable side effects at that dose. Even with dose reduction, adverse effects of the treatment were common, with nausea reported in 46% of the participants and vomiting in 13% in the lixisenatide group (as compared with 12% and 3%, respectively, in the placebo group). The incidence of side effects may be a barrier to wider use of lixisenatide for Parkinson’s disease, and further exploration of lower doses and other mitigation approaches would be valuable…

… Producing a convincing demonstration of a disease-modifying, neuroprotective effect in Parkinson’s disease is a difficult task. So far, technical measures such as imaging have not proven useful in tracking disease progression, and the focus has remained on assessing clinical signs and symptoms. In the current trial, the difference in scores on the MDS-UPDRS after 12 months of treatment with lixisenatide was statistically significant but small. The importance of this finding is not the magnitude of the change but what it portends. Indeed, the primary concern of most patients with Parkinson’s disease is not their present condition — it is the fear of progression of the disease. If a three-point improvement in score on the MDS-UPDRS is the most that can be achieved with lixisenatide, then the value of treatment with the drug may be limited (especially in view of the adverse effects). On the other hand, if the benefit of lixisenatide is cumulative, adding another three points each year over a period of 5 to 10 years or more, then this could be a truly transformative treatment. The next step is clearly trials of longer duration to see whether GLP-1 receptor agonists can live up to Dr. Parkinson’s prediction.