Double the Benefit: GLP-1 Receptor Agonists for Parkinson's Disease

Since the first GLP-1 receptor agonist drug was approved by the FDA in 2005, GLP-1 receptor agonists have risen to fame as a class of drugs approved for the treatment of Type 2 Diabetes. They work by mimicking the effects of the gut hormone glucagon-like peptide-1 (GLP-1), helping regulate blood sugar levels. However, researchers believe they might also have neuroprotective effects and are exploring their potential use in treating Parkinson’s disease (PD). This could be a significant step forward in the treatment of PD – the second most common neurodegenerative disease.

Some studies suggest that there is a connection between Parkinson’s disease and dysregulated insulin signalling and that insulin resistance might play a role in dopamine degeneration. Moreover, abnormal glucose metabolism has been observed in various brain regions of Parkinson’s patients, which has been linked to the progression of their motor symptoms. Notably, individuals with Type 2 Diabetes have been found to have an increased risk of developing Parkinson’s.

Lixisenatide and exenatide are examples of GLP-1 receptor agonists being tested in Parkinson's patients. These drugs have shown the potential to slow the progression of motor disability caused by Parkinson’s, offering a glimmer of hope for managing this progressive disease.

Research published in NEJM unveils new potential for this class of drugs. The LIXIPARK study group, based in France, has published results from a clinical trial that provides further evidence of the connection between Parkinson’s and GLP-1 receptor agonists. They recruited participants whose Parkinson's had been diagnosed for less than three years and showed no motor complications. The trial participants were then split into two groups: one group was given Parkinson’s medication and a placebo, and the other was given Parkinson’s medication plus a daily lixisenatide injection for one year.

Through each stage of the study, the participants' motor symptoms were scored on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, a disease severity scale. After 12 months, the results revealed that those who received lixisenatide had reduced progression of motor disability compared to the group that received the placebo.

How does it work?

Due to the complex etiology of Parkinson’s disease, the exact mechanism of action is not clearly understood. However, in vivo and in vitro studies have shown that GLP-1 RAs impact several pathways involved in the development of Parkinson's disease. These include protein misfolding and aggregation, defects in the ubiquitin-proteasome system and aggregation, inflammation, impaired oxidative stress, and mitochondrial dysfunction.

In addition, GLP-1 receptors are expressed not only in the gastrointestinal tract and kidneys but also in the brain regions affected by Parkinson’s, such as the basal ganglia and substantia nigra, making them a promising therapeutic target for the disease. Data from several studies have demonstrated a connection between the ability of GLP-1 receptor agonist drugs, including liraglutide and semaglutide, to cross the blood-brain barrier and their neuroprotective effects.

Further evidence from animal models of PD and preclinical studies has demonstrated that this class of drugs can restore dopamine levels, prevent dopamine loss, reduce neuronal degeneration, and improve both motor and non-motor symptoms of PD.

It's important to note that while the initial research is promising, more studies are needed to fully understand the effectiveness and long-term impact of GLP-1 receptor agonists in treating Parkinson's disease. However, this new avenue of investigation offers a chance to improve the lives of Parkinson’s patients and potentially slow the progression of this debilitating disease.