Researchers say findings that diabetes drug lixisenatide may slow the progression of Parkinson’s disease could be a major step forward, and provide hope for the millions of sufferers around the world.
Although there is no cure for the condition, in recent years, glucagon-like peptide 1 receptor agonists (or GLP-1R agonists) have caused a ripple of hope, with one such drug, the type 2 diabetes medication called exenatide, found to help slow the progression of motor symptoms in a small group of people with Parkinson’s.
Now researchers say another such drug, a type 2 diabetes medication called lixisenatide, appears to do the same, supporting the theory that Parkinson’s could be associated with insulin resistance in the brain.
Professor Wassilios Meissner, of University Hospital of Bordeaux, France, a principal investigator of the study, said the results were exciting.
“We have to stay cautious about the interpretation and about applicability at the current stage, but it is really a very, very clear and strong signal we have never seen except (in the) exenatide trial,” he told The Guardian.
GLP-1R agonists shot to fame for their use in managing type 2 diabetes and aiding weight loss, with semaglutide and liraglutide among the best-known drugs.
However, unlike exenatide and lixisenatide, these do not easily cross into the brain, making them less likely candidates for use in treating Parkinson’s.
Writing in The New England Journal of Medicine, the French researchers report that they randomly split 156 people – who had recently been diagnosed with Parkinson’s – into two equal-sized groups.
While both groups took their usual Parkinson’s medication, one group was given an additional daily injection of lixisenatide, while the other was given a placebo.
Before, during and after the study, participants underwent an examination of their motor symptoms and were scored on a disease-severity scale.
The results reveal that after 12 months, those given lixisenatide showed essentially no progression of motor problems, while those given the placebo showed worsening symptoms, dropping around three points on the 132-point assessment scale – a modest difference, yet thought to be clinically meaningful.
The difference remained two months after the trial stopped and other Parkinson’s medications were halted overnight.
That, the researchers say, suggests lixisenatide does not just reduce symptoms but protects the brain against the loss of neurons.
However, there was a drawback, with about half of the participants receiving lixisenatide reporting nausea and 13% reporting vomiting.
The researchers add that further work is now needed to unpick whether lixisenatide does indeed slow disease progression itself, whether the benefits persist over time or even increase if the drugs are given for longer, the best dose and whether the drug would offer benefits to people at other stages of Parkinson’s.
Heather Mortiboys, a professor of cellular neuroscience and metabolism at the University of Sheffield, who was not involved in the work, said the findings paved the way for larger phase 3 clinical trials.
“The new clinical trial results for lixisenatide showing a significant reduction in motor symptom progression compared with placebo group represent a really promising step forward in our research fight to get new drugs to the clinic for Parkinson’s,” she said.
Study details
Trial of Lixisenatide in Early Parkinson’s Disease
Wassilios Meissner, Philippe Remy, Mathieu Anheim, et al.
Published in The New England Journal of Medicine on 3 April 2024
Abstract
Background
Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson’s disease.
Methods
In this phase 2, double-blind, randomised, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson’s disease. Participants in whom Parkinson’s disease was diagnosed less than three years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications, were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a two-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent.
Results
A total of 156 people were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by −0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P=0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%.
Conclusions
In participants with early Parkinson’s disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson’s disease.
The NEJM article – Trial of Lixisenatide in Early Parkinson’s Disease (Open access)
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