Early Parkinson Disease and the Potential Therapeutic Role of Lixisenatide

Parkinson disease (PD) is a neurodegenerative disorder primarily affecting motor function, leading to movement difficulties, balance disorders, and memory deterioration.¹ Emerging research suggests that the progression of PD may be linked to brain insulin resistance, prompting scientists to explore the therapeutic potential of drugs like lixisenatide (Adlyxin; Sanofi).²

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Currently, no approved treatments can alter the course of Parkinson's disease. Available therapies focus on symptom management and enhancing the quality of life.¹ However, intense research is underway to find treatments that could slow disease progression, protect neurons, or reverse the pathological processes behind PD.

Among these areas of research is the intriguing relationship between type 2 diabetes (T2D) and PD. Epidemiological studies have indicated that individuals with T2D are at a higher risk of developing PD, possibly due to shared pathways such as insulin resistance, chronic inflammation, and oxidative stress. Of particular interest is the use of glucagon-like peptide-1 (GLP-1) receptor agonists in reducing this risk. Initially developed for diabetes, GLP-1 receptor agonists such as lixisenatide have shown neuroprotective properties in preclinical studies.³

In 2016, the FDA approved lixisenatide for the treatment of T2D, offering a once-daily subcutaneous injection to help control blood sugar. However, in 2023, Sanofi discontinued its marketing for this indication due to business reasons rather than issues with efficacy or safety.⁴

GLP-1 receptor agonists mimic the effects of the incretin hormone GLP-1, enhancing insulin secretion in response to glucose. It is now being studied for potential neurological benefits, particularly in PD. Lixisenatide is part of a group of GLP-1 receptor agonists under investigation for neurodegenerative diseases. This 44-amino acid peptide shares similarities with exenatide, another drug in the same class, but has demonstrated superior ability to cross the blood-brain barrier compared with liraglutide and semaglutide.⁵ Given its potential neuroprotective properties, lixisenatide holds promise as a therapeutic agent beyond diabetes, but its role in treating conditions like PD remains under exploration.⁶

A randomized, double-blind, placebo-controlled study published in The New England Journal of Medicine investigated the use of lixisenatide in patients with early-stage PD. The trial included participants who had been diagnosed with PD within the past 3 years and were on stable treatment regimens. The primary outcome, measured using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3, demonstrated a statistically significant difference favoring lixisenatide in slowing motor disability over 12 months. However, the clinical significance of this difference, with a modest −0.04-point change in the lixisenatide group versus a 3.04-point increase in the placebo group, requires further investigation. Notably, nausea and vomiting were reported in nearly half of the participants receiving lixisenatide, which could affect adherence in future trials.⁶

These results are promising, particularly because they represent the second clinical trial of a GLP-1 receptor agonist showing potential benefits for PD motor symptoms. The first drug in this class to show similar promise was exenatide, currently in phase 3 clinical trials. Research has also shown that individuals with both T2D and PD often experience faster symptom progression, suggesting a potential overlap in disease mechanisms. Moreover, it has been reported that individuals with diabetes treated with GLP-1 receptor agonists have a reduced risk of developing PD.⁶

Although the findings are encouraging, more extensive and long-term studies are needed to fully understand the efficacy and safety of lixisenatide as a neuroprotective agent in PD. Future research should also focus on elucidating the mechanisms behind its neuroprotective effects, which could open new therapeutic avenues. Although the current study provides valuable insights into the potential of lixisenatide in treating PD, further investigation is warranted to determine its long-term benefits and clinical viability.

REFERENCES

1. Parkinson’s Disease. National Institute of Neurological Disorders and Stroke. Updated September 4, 2024. Accessed October 10, 2024. https://www.ninds.nih.gov/health-information/disorders/parkinsons-disease

2. Lopez-Ojeda W, Hurley RA. Glucagon-like peptide 1: an introduction and possible implications for neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2024;36(2):A4-86. doi:10.1176/appi.neuropsych.20230226

3. Kalinderi K, Papliagkas V, Fidani L. GLP-1 receptor agonists: a new treatment in Parkinson’s disease. Int J Mol Sci. 2024;25(7):3812. doi:10.3390/ijms25073812

4. Ernst D. Diabetes Treatment Adlyxin Will No Longer Be Available in the US. Medical Professionals Reference. February 6, 2023. Accessed October 10, 2024. https://www.empr.com/home/news/diabetes-treatment-adlyxin-will-no-longer-be-available-in-the-us/

5. Leon N, LaCoursiere R, Yarosh D, Patel RS. Lixisenatide (Adlyxin): a once-daily incretin mimetic injection for type-2 diabetes. P T. 2017;42(11):676-711.

6. Meissner WG, Remy P, Giordana C, et al. Trial of lixisenatide in early Parkinson’s disease. N Engl J Med. 2024;390(13):1176-1185. doi:10.1056/NEJMoa2312323