Did you know that there is a link between Parkinson’s disease and diabetes? Well, there is: people with diabetes are ~40% more likely to be diagnosed with Parkinson’s disease than non-diabetics. A large number of people are living with both conditions simultaneously, and there are also many people with Parkinson’s without diabetes who have some level of insulin resistance or decreased glucose tolerance.
This association between the two conditions led some in the field to wonder if perhaps diabetes medications would be useful for treating Parkinson’s, including potentially slowing the progression of disease. One class of diabetes drug that has generated a lot of interest over the last decade is a class of drugs known as GLP-1R agonists (basically, drugs that look a bit like the hormone glucagon, which enhances insulin secretion, and bind to the same receptor on cells, thereby activating it). You may have heard of one GLP-1R agonist, semaglutide, which is commercially known as Ozempic. This diabetes drug has a side effect of weight loss, leading to it becoming the epicentre of a recent weight-loss craze. Another one you might have heard of is exenatide (commercial name Bydureon), which is currently being trialled in a phase 3 trial at six UK hospitals with results expected later this year. Our good friends at Cure Parkinson’s in the UK, together with the Van Andel Institute in the US, have been steering this line of research for over a decade now, since prioritizing exenatide for testing in people with Parkinson’s was back in 2012 at the first ever international Linked Clinical Trials meeting held in Grand Rapid, Michigan. The present phase 3 trial is expected to build on the promising results delivered from a phase 2 trial in 2017.
Different GLP-1R agonists have slightly different properties, including in terms of their ability to cross the blood–brain barrier and act in the brain—something a drug for Parkinson’s would need to be able to demonstrate. While the research into exenatide for Parkinson’s progresses, a phase 2 trial of the GLP-1R agonist liraglutide was completed in late 2022 showing a potential impact on non-motor symptoms and aspects of daily living in people with Parkinson’s. Another GLP-1R agonist that has recently been investigated in people with Parkinson’s is lixisenatide, and the results of a phase 2 study conducted in France (called the LixiPark trial) were reported in the New England Journal of Medicine earlier this month.
This trial assessed 156 people with early-stage Parkinson’s (within 3 years of diagnosis) who received either daily lixisenatide (injected subcutaneously) or placebo for a period of 12 months (78 in each group). Their other Parkinson’s medications were kept stable for the duration of the study. The trial was primarily designed to assess changes in motor symptoms (specifically, the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] part III, which has a range from 0 to 132 (with higher scores indicating greater motor disability). Unsurprisingly, the motor symptoms in patients who were in the placebo group worsened over the 12-month period; excitingly though, in those in the lixisenatide group, the motor symptoms were slightly improved, resulting in a significant difference between the two groups at 12 months. There were, however, some gastrointestinal side effects that occurred more often in patients in the lixisenatide group, namely, nausea, vomiting, and reflux.
More research is needed, as is often the case, particularly larger and longer studies; however, these results bring us one step closer to potential disease-modifying therapies for Parkinson’s. Across the class of GLP-1R agonists, we are getting closer to the level of evidence needed for approval for use in people with Parkinson’s. Although clinicians certainly need to be mindful of the risks and side effects, including gastrointestinal effects with some and weight loss with others (not ideal for patients who may already be frail and at risk of falls), the results of the current phase 3 exenatide trial will be awaited with cautious optimism, while further studies of liraglutide and lixisenatide will no doubt be in the planning. Hats off to the team at Cure Parkinson’s and the Van Andel Institute for committing to funding this line of inquiry!
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