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? Then a second study came out in the Lancet that contradicted the NEJM findings. What should you do?
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 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 the study, declare what will constitute a positive trial. The investigators 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 initiated. The persons in the trial were ‘on’ their dopaminergic medications at the time the primary (most important) outcome. 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 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, when 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 considered a statistically positive investigation, however the results did not reach the threshold to constitute a ‘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 (preventing brain cells from dying), and my personal opinion would be “a cautious MAYBE.” The assessment of neuroprotection does not in general have a specific accepted and associated metric (way to measure it), so neuroprotection 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 are better, thus the authors considered this data as “potential evidence” supporting 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 iwere 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 from the market. 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 either with or without 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.
What did the recent randomized study published in the Lancet on Exenatide for Parkinson’s disease?
A recent randomized study just published in the Lancet in 2025 evaluated 194 folks randomly assigned to Exenatide (n=97) or placebo (n=97). At a 96 week followup, the OFF- dopamine medication scores actually worsened by 5.7 points in the Exenatide group, and 4.5 points in the placebo group. It was safe and well tolerated, however not effective at slowing Parkinson’s disease.
Why was one study (Lixisanatide) positive and one study (Exenatide) negative for Parkinson’s?
We do not know the answer to this question. Here is a nice comparison table and some nuggets to think about. Differences in trial duration, drug exposure, target engagement and outcome sensitivityall may have factored in.
A few other nuggets:
Exenatide may cross the blood-brain barrier more effectively than lixisenatide.
-Lixisenatide is short-acting and might have limited CNS exposure, especially at standard doses.
In neurodegeneration, brain penetration is everything. Peripheral effects alone may not be enough.
Lixisenatide's dosing may not have reached a therapeutic CNS level.
If patients in the lixisenatide study were further along in Parkinson’s, it could have blunted a possible observable benefit.
Slight differences in endpoints, assessment tools, and statistical power could have shifted results.
Exenatide is a synthetic version of exendin-4 (from Gila monster saliva), which has unique receptor binding and unique stability properties.
Lixisenatide is more modified and short-acting, designed for glucose control—not necessarily optimized for neuroprotection.
Even though lixisenatide and exenatide are both GLP-1R agonists, they differ in brain penetration, duration of action, and pharmacologic properties — which likely explains the discrepancy in Parkinson’s trial outcomes.
The Lixisenatide study was a carefully conducted and well constructed investigation. The results were encouraging, however let's not rush to the drug store counter, especially considering the negative Exenatide study results. Let’s build on what we have learned and accept that both drusg fell ‘a little short’ of a clinically meaningful difference.
The larger treatment effect reported by the authors of the Lixisenatide study (that 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 (in other words Parkinson’s is not one disease and we may have recruited a few different subtypes and this watered down the potential effects)?
It would be terrific if future studies could test multiple doses of these or similar drugs and include 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.
Dr Okun is the author of this blog that appears on PDPlan.org and on parkinsonsecrets.com. He is co-author of 14 books and most recently the Parkinson’s Plan and Ending Parkinson’s.
Jonny Acheson is the parkinsonsecrets.com artist and also is a physician and a person with Parkinson’s.
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