GLP-1s in Neurodegenerative Disease: Hope or Halt?

Medscape

30-06-2025

This transcript has been edited for clarity.
Indu Subramanian, MD: Hi. Welcome, everyone, to Medscape. It's with great excitement that I present today a friend and colleague, Lorraine Kalia. Professor Kalia is a senior scientist at the Krembil Research Institute in Toronto, and she's also a neurologist at the University of Toronto.
She's been prolific. We use her graphics many times in our slide decks. She's a great clinician and scientist, bringing you today some knowledge about clinical trials. We're excited to talk about a very hot topic, the GLP drugs.
I am Dr Indu Subramanian. I'm based at UCLA. Welcome, Lorraine.
Lorraine V. Kalia, MD, PhD: Hi, Indu. Thanks for having me.
Why Try GLP-1 RAs in Neurodegenerative Disease?
Subramanian: I was excited to read your commentary in The Lancet about the GLP-1 trials. Perhaps we could start with your thoughts and maybe a brief introduction about GLP-1 drugs and where they fit into neurodegenerative disease and Parkinson's, specifically.
Kalia: I'm sure that the audience is aware of GLP-1 receptor agonists, as they've been such a hot topic with respect to treating diabetes and probably more so around treatment for obesity. They've been heavily investigated for increasing number of indications around those areas, including sleep apnea, osteoarthritis of the knees, cardiovascular disease, and in the field of neurogenerative disease, which is obviously near and dear to our hearts.
They've been heavily investigated with the idea that there might be a component of insulin resistance that leads people to be at risk for neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, and that maybe repurposing these drugs for neurogenerative diseases would have some benefit.
From the laboratory side, there have been tests of some of these GLP-1 receptor agonists in Parkinson's disease models that show that if you give them peripherally to animals, you can reduce the neurodegeneration of dopaminergic neurons.
Importantly, there are also some epidemiologic studies that suggest if people have been treated with a GLP-1 receptor agonist, they're less likely to develop Parkinson's disease.With all of these different lines of evidence, there have been now a good number of clinical trials testing the hypothesis that treatment with a GLP-1 receptor agonist will slow the progression of Parkinson's disease.
Subramanian: I think it's an exciting group to look at because we don't have to do many of the safety studies in general because we are basically repurposing a drug that's already out there. Maybe you could briefly summarize the studies and what they've shown to date.
Exenatide Study
Kalia: There have been a number of studies running up to this phase 3 trial of exenatide that was relatively recently published in The Lancet . Similar to the preclinical and the epidemiology work, there was a large amount of signal there that suggested some benefits.
A phase 2 trial using exenatide in individuals with moderate Parkinson's disease on dopaminergic therapies showed that there was a slower progression or an increase in the number of points on their motor scores. A study using lixisenatide, which is another GLP-1 receptor agonist,also showed something similar. I, along with many others in the field, was really anticipating what the results of this phase 3 trial were going to show.
It was a big study — approximately 200 participants and multicenter — which was different from the phase 2 trials, which tended to be single center. I think it was five or six UK sites. It was long for a Parkinson's disease trial at almost 2 years, solike a 96-week trial, which I think is important when we think about a slowly progressive disease. We can ask questions as to whether or not some of our earlier trials, which didn't capture any differences, was because we didn't wait long enough. This was, I'd say, a pretty good trial in terms of length.
The primary outcome for this was the same primary outcome that they saw benefit with in the phase 2 trial,so learning from the phase 2 trial and hoping that that would translate to the phase 3 trial, which was basically motor scores in the off state because all of thepatients who were enrolled were on a dopaminergic therapy.
Unlike the phase 2 trial, there was no difference between the placebo control group and the group that received exenatide.One could ask, was that the right measure? We always have discussions around whether or not our outcome measures are sensitive enough or was that the right one.
All of the secondary outcome measures — so all of the other measures, including the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score, Montreal Cognitive Assessment (MoCA) score, quality of life scores, and how muchdopaminergic therapies had to be changed over the course of the trial — were absolutely identical between the two groups. There was no signal in any of the secondary or exploratory outcomes, so really negative across the board.
Subramanian: I think the patients have been really hungry to see the results of this trial. I don't know about you, but I think everyone and their mother is on a GLP drug, it seems like. People have been trying to use some of these even off-label and acquire them and get themmade in compounding pharmacies.
Patient Guidance
Kalia: I think that's a great point that you bring up that I thought was useful for discussion also. If patients come to you and ask to be put on a GLP-1 receptor agonist, even though there's no indication for it, then my answer — especially now with a negative trial — would be that there's really no indication to do that, especially in the context of no benefit and potential for side effects.
Subramanian: Let's talk about the side effects, because I think one of the things that I've been really interested in is weight loss in Parkinson's. We've been doing some work on women, especially Asian women like you and me, who may have lower body mass and end up getting dyskinetic and sometimes getting into the cycle of losing weight and getting very frail.Sometimes, bone fractures, fall risk, and other issues can come up. Maybe we could talk a little bit about your sense of that.
Kalia: Everyone's concern around the GLP-1 receptor agonists in a Parkinson's disease population where you don't want people losing weight, per se, was if that's going to be the side effect of these drugs, it's going to increase frailty. At least in this trial with exenatide, the extended-release version in the phase 3 trial, there wasn't as much weight loss as had been seen in prior studies.
One could wonder if maybe that was then an indicator of insufficient dosing. That's just speculation. I guess, as expected, for anyone who's familiar with the side effects around GLP-1 receptor agonists, there were gastrointestinal (GI) side effects, so GI upset and diarrhea, and then nonspecific things.
Overall, if we were to look at the silver lining, the trial demonstrated, as did the phase 2 trial, that exenatide can be well tolerated in a Parkinson's disease population. Whether that's the case for all GLP-1 receptor agonists is not known. Perhaps for some that are much more efficacious at weight loss, we will still probably need to be cautious as to that kind of side effect or that effect that people want in a non-Parkinson's disease population, and how that might have negative ramifications in a Parkinson's disease population.
The 'Lessebo' Effect
Subramanian: We do have to weigh the risks and the benefits, and I don't personally see an indication at the moment either. You brought up also, a point about lessebo. Maybe we could talk about lessebo. What is that?
Kalia: I brought that up, again, entirely as speculation. It was related to the amount of weight loss seen in this trial that was not as much as anticipated. Obviously, participants in these clinical trials are very likely going to knowsomething, if not a lot, about GLP-1 receptor agonists.
Knowing that they're in a placebo-controlled trial and knowing that they might be on placebo vs exenatide, if they weren't actually experiencing weight loss, they may have assumed,and so then the effects that come with a placebo effect are absent.
That's entirely speculation on my part to try to explain why maybe the differences seen in this trial were not as obvious as they had been in the previous phase 2 trial.
Subramanian: There's so much to consider and so much complexity. Thank you so much, Lorraine, for joining us today. It's been a pleasure to talk about this rather complex area and get your insights.
Kalia: Thanks for having me. It was a great chat.