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GLP-1 RA Lixisenatide for Early-Stage Parkinson’s Disease
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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, randomized, 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 3 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 2-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 persons 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.
Additional Info
Disclosure statements are available on the authors' profiles:
Parkinson’s disease (PD) is managed with symptomatic therapies, but no therapies have high-quality evidence for disease modification or neuroprotection in clinical trials. Epidemiologic studies have suggested a link between type II diabetes mellitus and PD and mitigation of this risk with glucagon-like peptide 1 (GLP-1) agonists.1 Preclinical work has suggested that GLP-1 agonists slow PD progression through dampening of microgliosis induced by α-synuclein aggregation,2 which prevents astrocyte-mediated neurotoxicity.3 In fact, a phase II study of exenatide, a GLP-1 agonist based on extendin-4, showed a statistically significant difference between the placebo and treatment groups in motor progression, as measured by the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part III).4 There is substantial interest in GLP-1 agonists as potential disease-modifying agents for PD.
The current study is a phase II, multicenter, randomized, double-blind, parallel group, placebo-controlled clinical trial of the GLP-1 agonist lixisenatide. The study’s primary outcome was met in that the lixisenatide group showed no statistically significant change from baseline while the placebo group showed a 3.00-point worsening at 12 months and a 3.08-point difference between the placebo and lixisenatide groups (95% CI, 0.86–5.30).
Although this is exciting news, several issues should be considered in the interpretation of this result. The 3.08-point difference in the MDS-UPDRS part III score between the groups is smaller than the difference that is typically considered meaningful to patients,5 although that minimal clinically important difference was based on a cohort in which the mean MDS-UPDRS part III score was 41 at baseline. The current study’s cohort was much less affected (the mean MSD-UPDRS part III score was approximately 15), so a 3-point change is a substantially larger percentage of change from baseline and might be more meaningful to patients at this earlier stage. Additionally, the supplementary figure showing the curve of disease progression in each group suggests a difference in the slopes of decline that, if persistent, could lead to a larger effect size over time. Furthermore, exploratory analysis stratified by age younger than 60 years or 60 years or older followed the trend found with another recent GLP-1 agonist,6 NLY-01, where the magnitude of difference between the treatment groups was larger in patients younger than 60 years. The lack of difference between the treatment groups in any of the secondary measures fails to support the primary finding and, along with the observation in previous studies of a small improvement in motor scores,4 raises the possibility of a symptomatic motor effect from lixisenatide. However, the participants were re-examined after washing out from the study drug for 2 months, and a difference of 3 (95% CI, 0.1–5.8) points was maintained, making this less likely. Further, most secondary (MDS-UPDRS parts I, II, and IV) and exploratory (MoCA) outcomes were very low at baseline in this cohort with early PD, and a minimal change was even noted in the placebo group, making it very unlikely that any treatment-associated change would be detected in 12 months.
There are also practical issues to consider. Given the tendency for people with more advanced PD to lose weight and muscle mass, it is unclear whether the use of GLP-1 agonists in those with a longer disease duration than those in the current study would worsen wasting and add to frailty. Similarly, although hypoglycemia did not occur in the lixisenatide group, it is unclear whether this would be the case in patients at a more advanced stage. Tolerability is also a concern; although there was no difference between the treatment groups in the incidence of serious adverse effects, 59% of people in the lixisenatide group experienced nausea and/or vomiting compared with only 15% of people in the placebo group.
Although it is encouraging that this phase II study is in line with a prior study of exenatide and with the findings in the cohort younger than 60 years in the NLY-01 study,6 it has yet to be determined whether enrichment for patients with high microgliosis or other processes more amenable to GLP-1 agonist therapy would provide an even larger effect size. Nevertheless, this phase II study offers hope and justifies replication and, eventually, a phase III study. In light of the difference in the slopes of decline, it may be important to conduct a trial for more than 12 months to observe the full potential disease-modifying effects of GLP-1 agonist therapy.
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