GLP-1 Drugs for Parkinson’s Disease
It’s important to first point out that there are no disease-modifying interventions for Parkinson’s disease. All current treatments are for symptoms but nothing has yet been validated to stop or slow progression of the disease. In the New England Journal of Medicine
a double-blind randomized trial of 156 participants with early Parkinson’s disease were assigned to lixisenatide or placebo. Lixisentaide is a GLP-1 drug that was approved in the United States in 2016 and discontinued by its manufacturer (Sanofi) in 2023. The drug or matching placebo were given for 12 months and the primary endpoint, as shown below, was a motor score used by neurologists (Movement Disorder Scale-Unified Parkinson’s Disease Rating Scale) MDS-UPDRS Part III). The GLP-1 drug participants had no progression of motor symptoms (-0.04), and the 3.04 worsening in the placebo group (difference between the two arms=3.08) is just short of what is considered clinically meaningful (3.5).
This is not the first randomized trial reporting benefit of GLP-1 drugs for Parkinson’s.
In 2013, a single-blind trial of 45 patients with exenatide showed significant statistical benefit but the motor score difference was 2.7 points.
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n 2017, a small single-center randomized trial of 62 participants, but with longer follow-up, found benefit with exenatide given once weekly (see graph below). It concluded: "There is a strong indication that GLP-1 receptor agonists may have a useful role in future treatment of Parkinson's disease."
Of note, both trials had a washout period after the drug treatment ended and the benefit for motor symptoms persisted.
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key point made into accompanying editorial for the new trial is that the >3-point benefit may accrue further over time: “The importance of this finding is not the magnitude of the change but what it portends….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 trill transformative treatment.”
There are 2 other important considerations. Lixisenatide and exenatide are much weaker GLP-1 drugs compared with semaglutide, tirzepatide and several others that are in clinical trials
as shown below for weight loss. The extent of weight loss likely also reflects the potency of anti-inflammatory effect, and biomarkers indicative of reduced inflammation have been shown to precede wight loss in multiple trials of this drug class.
Also, we know that these drugs do not cross the blood brain barrier. As Daniel Drucker explained in the companion podcast, that isn’t necessary to achieve the GLP-1 mediated suppression of inflammation in the brain. There’s the gut-brain axis and enteric nervous system to relay signals, talk to the brain. As Drucker pointed out to me: “ We know that GLP-1 is not getting directly to those neurons, but it's activating pathways that turn on those neurons. And so, there's probably a very intricate set of pathways that sense the GLP-1 and the accessible neurons and then transmit those signals deeper into the brain.”
So the new study provides some optimism for Parkinson’s disease. The GLP-1 drug mediated suppression of brain inflammation may turn out to be yet another key use case. Note there are 2 large randomized trials of semaglutide for Alzheimer’s disease expected to report out in 2026.
erictopol.substack.com
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