Are GLP-1 diabetes drugs like Ozempic coming for Parkinson’s disease?
By Michael S. Okun
Picture from an article about GLP-1 at https://cureparkinsons.org.uk/2022/02/diabetes-dual-agonist-drugs-for-parkinsons/ as part of a terrific recent story by Cure Parkinson in the UK.
The New England Journal of Medicine’s recent publication of a randomized study of a GLP-1 agonist originally designed for diabetes, but applied to Parkinson's disease, has led to a flurry of excitement and to a mountain of questions. Should I rush out and get a prescription for a GLP-1 diabetes drug? Will it help my Parkinson’s motor or non-motor symptoms, and if so which ones? Will it slow disease progression? In this month’s parkinsonsecrets.com blog, I will address all of these questions, and more.
Authors of the NEJM Lixisenatide study for Parkinson’s disease.
What was this Lixisenatide study all about?
The study was a French multi-center effort. The drug tested was called Lixisenatide, which is a glucagon-like peptide-1 receptor agonist, designed primarily for use in diabetes. Agonists tickle and stimulate receptors in the brain, and this drug stimulates a glucose-dependent insulin release from the pancreas.
Shang and colleagues in the Journal of Movement Disorders show in this diagram where one GLP-1 (Exenatide) stimulates the GLP-1 receptor and al of the downstream potential effects. Though this picture shows Exenatide, the general thought is that most drugs in this class manifest a similar mechanism of action.
The trial was double-blinded, meaning neither the investigators nor the persons with Parkinson’s were made aware of who was actually receiving an active drug (rather than a placebo/inactive drug). The question the authors asked was simple. Would this diabetes drug slow the progression of motor disability?
Did the authors limit the types of persons with Parkinson’s disease who were allowed to enroll in the trial?
The study design for the NEJM study on Lixisenatide.
The enrollment was limited to persons with Parkinson's disease who were ‘on’ dopaminergic Parkinson’s medications. Participants were not allowed to have been diagnosed or to have manifested symptoms for more than a total of three years.
How was the drug administered in this trial? In a pill or by injection?
Persons with Parkinson’s disease were randomly and equally assigned to a daily subcutaneous shot of Lixisenatide or to a shot of a placebo. The study was conducted over a one year period. Following this period, all persons enrolled in the trial stopped the drug (or the placebo) for two months, in what was referred to as a ‘washout period.’
What would have been considered a positive result for this trial?
A summary of the results from the Lixisenatide versus placebo groups.
Every major clinical trial in medicine must, prior to the enrollment of the first person into a study, declare what will constitute a positive trial. The investigators thus pre-select what is referred to as a primary outcome. The primary outcome for this study was a change from baseline of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III compared to what was measured at 12 months after the trial was initated. The persons in the trial were ‘on’ their dopaminergic medications at the time the primary outcome for this particular trial. This was in contrast to some other GLP-1 Parkinson’s studies.
A change in 3.25 units on the motor scale was considered as ‘constituting a clinically important difference’ for the study. Applying a clinically meaningful number or difference helps to prevent trials from being declared positive based solely on statistical significance; even if not impactful in real-world practice. The authors thus hoped ‘their GLP-1 agonist Lixisenatide’ would reach this threshold.
There were 78 subjects randomized to receive the diabetes drug Lixisenatide and 78 randomized to a placebo.
The authors of the study concluded that the “GLP-1 receptor agonist lixisenatide had a three-point beneficial effect, as compared with placebo, in the change over a 12-month period from a baseline value of approximately 15 points on a 132-point scale measuring motor disability.”
The active arm improved −0.04 points in the lixisenatide group and worsened 3.04 points in the placebo group. For the scientists reading the blog, the difference was 3.08 (95% confidence interval, 0.86 to 5.30; P = 0.007). This result was thus considered a statistically positive investigation, however the results did not reach the threshold to constitute clinically meaningful study.
When interpreting studies, both clinicians and scientists will opine as to whether the outcome of this study was clinically meaningful. The idea of using a metric such as the clinically meaningful change can be applied to assess whether the outcome is not only statistically relevant, but would be meaningful to a person with a particular disease. The changes following Lixisenatide therapy in Parkinson’s disease were ‘slightly less’ than the clinically meaningful threshold.
There will certainly be many arguments among experts as to whether this study met a minimum threshold for neuroprotection, and my personal opinion is a cautious MAYBE. One note is that the assessment of neuroprotection does not have a specific associated metric, so it is largely based on the interpretation of scientists and clinicians.
Why did the investigators ‘wash out’ the drug for 2 months after the primary outcome?
When you ‘stop’ a drug for a period of time and then attempt to re-measure the outcome, this may give you a glimpse or a clue as to whether the drug delayed disease progression. Interestingly, after a 2 month washout period for Lixisenatide, the scores in the off-dopaminergic state were 17.7 in the active drug arm and 20.6 in the placebo arm. Lower scores on this scale are better, thus the authors considered this data as potential evidence of slowing of disease progression.
Though there was a ‘3-point between-group difference in motor score favoring active treatment,’ the authors commented ‘that the result was not adjusted for multiple factors, and thus no conclusions could be drawn.’
What were the most common side effects?
A summary of the adverse events from the Lixisenatide NEJM study.
The most common side effects associated with Lixisenatide in this study were nausea in 46% and vomiting in 13%.
Gut related adverse effects manifested in more than half of the people receiving Lixisenatide. The authors commented that in some cases, the dose had to be ‘decreased from 20 μg per day to 10 μg per day,’ due to side effects. Weight loss was more commonly encountered in those taking Lixisenatide.
Should you ask your doctor to prescribe Lixisenatide or a GLP1 agonist diabetes drug for your Parkinson’s disease?
My view is NO. Why? Here are 8 potential reasons why not to prescribe Lixisenatide: 1- this is only one small study and only one dose was tested, 2- Lixisenatide is not currently available at pharmacies, 3- the weight loss associated with this GLP-1 is not desirable in many cases of Parkinson’s disease where weight loss is an issue, 4- non-motor outcomes did not change as in other trials, and this will need to be better explained. 5- other GLP-1 trials in Parkinson’s have been statistically negative or the results unclear, 6- the study was conducted in only ‘very early Parkinson’s cases,’ 7- the data, if replicable, may not be generalizable to all GLP-1 agonist drugs or to all subtypes of Parkinson’s, and 8- the drug Lixisenatide requires a DAILY injection.
Not only do I believe you should not rush to your doctor to request a prescription for a GLP-1 agonist drug, but I also recommend you avoid the urge to creatively acquire Lixisenatide or another GLP-1 drug. We have been down this road many times with potential therapies for Parkinson’s disease including leukemia drugs, cough syrups, lithium and more. The data for this one is just not quite there. More importantly, the weight loss associated with GLP-1’s is not a welcome symptom in a disease were slowly progressive ‘wasting’ is common concern.
Interestingly, Lixisenatide has been recently discontinued. The current available information on Lixisenatide is that it was tested and it is safe for diabetes, however it was removed from the market as a result of a ‘business decision.’
In April 2024 the NY Times featured this headline about an Ozempic relative slowing Parkinson’s disease.
Why are we interested in GLP-1 diabetes drugs for Parkinson’s disease?
Patrik Brundin and colleagues in 2018 published a nice article in Nature Medicine on GLP-1 agonists possibly functioning as ‘fire prevention’ for the brain.
There are several reasons which make GLP-1 agonists an attractive option for Parkinson’s disease.
• Dopamine therapies have not been shown to prevent disease progression.
• There is an increased risk of Parkinson’s disease among those with diabetes.
• Insulin resistance is common in Parkinson’s disease and it seems to be associated with α-synuclein containing Lewy Bodies.
• Drugs which increase GLP-1 levels are associated with a decreased prevalence of Parkinson’s disease.
• GLP-1 receptor agonists have been shown to be protective in some animal models of Parkinson’s.
• Some experts have postulated that GLP-1 receptors could be protective against cytokine-mediated apoptosis (cell death) and may also stimulate neurogenesis (cell life).
• GLP-1’s may possibly enhance synaptic dopamine levels.
In a follow-up editorial to the New England Journal of Medicine Study, David Standaert MD PhD from the University of Alabama commented that, “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.”
Have there been other trials of GLP-1 drugs in Parkinson’s disease besides Lixisenatide?
Picture from the Lancet article by Tom Foltynie and colleagues of exenatide, another GLP-1 tested in Parkinson’s disease. The authors concluded that “Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain.”
Yes. There are several GLP-1 receptor agonists which have been studied as potential treatments and potential disease modifiers for Parkinson’s disease.
• Exenatide improved motor function when participants when without dopaminergic medications.
• NLY01 which is a pegylated analogue of exenatide showed no improvements when withoit dopaminergic therapy.
• Liraglutide and Semaglutide are listed on clinicaltrials.gov as also conducting trials associated with Parkinson’s disease and there are others in various stages of animal and human testing.
Why did investigators choose Lixisenatide?
It is impossible to know for sure why they chose this particular compound, among all the diabetes drugs in this class of medications. They did however comment in their New England Journal of Medicine article that the ‘affinity of lixisenatide for the GLP-1 receptor was up to four times greater than that of human GLP-1…and there have been neuroprotective actions shown in animal models of Alzheimer’s disease.’ Together, I suspect these were likely strong rationales driving their choice of the use of Lixisenatide.
Sloan and colleagues show graphically in their paper several diseases beyond diabetes which GLP-1 may be important.
Take home messages
The Lixisenatide study was a carefully conducted and well constructed investigation. The results were certainly encouraging, however let's not rush to the drug store counter. Let’s build on what we have learned and accept that the drug fell ‘a little short’ of the clinically meaningful difference. Additionally, in the area of disease modification it looked interesting and we should continue to study it.
The larger treatment effect reported by the authors, which manifested in trial participants younger than age 60, will need to be further investigated. Is it possible we are missing a ‘treatment effect’ of Lixisenatide because of the heterogeneity present in most Parkinson’s groups recruited for clinical trials?
It would be terrific if future studies could test more than one dose of Lixisenatide and would also include imaging biomarkers (i.e. imaging). These biomarkers could possibly be used to monitor and document disease progression.
Finally, let’s consider ad augusta per angusta – to glory through narrow spaces, by continuing to follow the data with GLP-1 diabetes drugs. I say, let the data leads us to enlightenment. I agree with Dr. Standaert’s view that, “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.”
Michael Okun is the author of the blog on Lixisenatide for Parkinson’s disease and the co-editor of the parrkinsonsecrets.com bog.
Indu Subramanian is a co-editor of the parkinsonsecrets.com blog.
Jonny Acheson is the parkinsonsecrets.com artist and also is a physician and a person with Parkinson’s.
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