Lixisenatide: An anti-diabetic drug with promising potential for Early Parkinson’s Disease

Type 2 diabetes is a disease characterized by insulin resistance due to reduced β cell function¹. Insulin is a hormone that regulates glucose uptake into the cell through the activation of signaling pathways². Pharmacological treatment of Type 2 diabetes aims to control glycemia and increase insulin sensitivity.

There has been an interesting rise in the number of anti-diabetic drugs that have been shown to have neuroprotective effects in mouse models. Some of these drugs are metformin, GLP-1 receptor agonists, 3 PPARγ agonists, 5 bromocriptine, sulfonylureas, and SGLT-2 inhibitors³. Currently there are clinical trials assessing these drugs for the use of treatment in neurodegenerative diseases. On April 4th of this year, the results of a clinical trial evaluating an anti-diabetic drug Lixisenatide as treatment for Parkinson’s disease were published by French Clinical Research Network (F-CRIN) for Parkinson’s Disease and Movement Disorders. These results were published in the article “Trial of Lixisenatide in Early Parkinson’s Disease” in The New England Journal of Medicine.

Lixisenatide is a GLP-1 (Glucagon-Like peptide-1) receptor agonist. GLP-1 is a hormone that is an insulin stimulator and inhibits glucagon secretion by binding to the GLP-1 receptor⁴. The GLP-1 receptor is a desirable pharmacological target for increasing insulin sensitivity in diabetes. Interestingly, GLP-1 receptor agonists have also shown the potential to be used as treatment for Parkinson’s disease. This brings up an interesting question about GLP-1 receptor agonists:

How does Lixisenatide a GLP-1 receptor agonist alleviate the symptoms or halt disease progression in Parkinson’s disease?

GLP-1 Receptor Agonists and Parkinson’s Disease

Parkinson’s Disease is characterized by the aggregation of an intracellular protein, α-synuclein (also known as Lewy bodies) and dopaminergic neuronal loss that begins in substantia nigra region of the brain⁵. Eventually as the disease progresses, Lewy bodies and neuronal loss becomes more widespread. Clinical symptoms of Parkinson disease are defined by bradykinesia (slow movement), rigidity, or rest tremor⁵. Current treatment for Parkinson’s disease is focused on targeting the regulators involved in dopaminergic transmission⁵. But an issue with the current treatments is that they are not effective in preventing disease progression⁶. As a result, new and more effective Parkinson’s treatments are being sought or developed.

So where do anti-diabetic drugs come into the picture for Parkinson’s treatment?

There is an increased risk of developing Parkinson’s disease among those diagnosed with Type 2 diabetes. In some studies, there was lower risk of developing Parkinson’s Disease associated with diabetic patients that took GLP-1 receptor agonists⁷. Also, a clinical pilot trial of GLP-1R agonist, exenatide, showed an improvement in motor function in patients⁸. Lixisenatide is a GLP-1 receptor agonist with potential to be used as treatment for Parkinson’s Disease. This is due to its successes improving motor impairment in the mouse model of Parkinson’s Disease⁸. In the protocol for “Trial of Lixisenatide in Early Parkinson’s Disease,” the reasons above were provided as justification for the clinical trial evaluating an anti-diabetic drug Lixisenatide as treatment for Parkinson’s disease.

Methodology of Trial of Lixisenatide in Early Parkinson’s Disease

The clinical trial enrolled participants aged 40 to 75 years old who were diagnosed with Parkinson’s disease based on the U.K Brain Bank Criteria within the past three years. U.K Brain Bank Criteria is used to diagnose Parkinson’s disease based on the presentation of bradykinesia and tremors/rigidity. A total of 156 patients were selected for this trial, and the trial was conducted for 1 year.

The patients were treated for one month with a dopaminergic medication regimen to establish a baseline for the trial. Patients were randomly placed into a control group that receive the placebo or the experimental group that received Lixisenatide. The participants in the trial received a dopaminergic medication regimen though the whole trial. The initial dose of the placebo and Lixisenatide was 10 µg for 2 weeks. Dosage was increased to 20 µg for both the placebo and Lixisenatide.

Participants had to attend clinic visits at the beginning of the trial, day 15, and every other month. In these visits, participants were evaluated for the progression of Parkinson’s Disease using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal cognitive assessment, and Parkinson’s Disease Questionnaire summary index. Adverse effects were also evaluated at each visit. 2 months after the 12-month trial had concluded, participants were evaluated to confirm that the results collected in the trial were due to Lixisenatide and not due to other treatment. This was referred as the “washout” period as participants were not receiving the placebo or Lixisenatide. The goal of assessing all these parameters was to determine the efficacy of Lixisenatide treatment.

Does Lixisenatide improve motor function or prevent cognitive decline in Parkinson’s’ Disease patients?

Results of Trial of Lixisenatide in Early Parkinson’s Disease.

Participants in the Lixisenatide group had notable change in the MDS-UPDRS part 3 score compared to the placebo group. This scale consists of 4 parts that each measure distinct functions affected by Parkinson’s disease. Part 3 measures motor function, and the higher score in this scale shows severe motor function deficits. In the placebo group, the mean increase of the score was 3.04 while in the Lixisenatide group there was a decrease of 0.04. The most common side effect was nausea, and only 6% of the side effects were considered. This suggests that Lixisenatide is well tolerated in patients with Parkinson’s disease.

Overall, the results from this trial are promising. Lixisenatide improves motor impairment and side effects are minimal. But there are some limitations to this clinical trial. The most obvious one being that the participants have early Parkinson’s disease, which makes it unclear if Lixisenatide is effective at treating late Parkinson’s Disease. Another drawback is the duration of the trial, which was only 1 year, raising the question is Lixisenatide is effective in the long run? These issues were acknowledged by authors of “Trial of Lixisenatide in Early Parkinson’s Disease” and the authors stated that “Larger and longer trials are needed to determine the effect and safety of this agent in the treatment of Parkinson’s disease.”

I look forward to future clinical trials that further examine the efficiency of Lixisenatide and other anti-diabetic drugs in neurodegenerative disease. This is an interesting and promising trend of anti-diabetic drugs being repurposed for treatment of neurodegenerative diseases.

Reference

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8. Cai H-Y, Hölscher C, Yue X-H, et al. Lixisenatide rescues spatial memory and synaptic plasticity from amyloid β proteininduced impairments in rats. Neuroscience 2014;277:6-13