Diabetes drugs test a new side effect: slowing down symptoms of Parkinson’s
A clinical trial shows the neuroprotective effect of lixisenatide, a GLP-1 receptor agonist. Its use during a year prevented patients from getting worse, in what has been described as limited but promising benefits
On April 26, at a special news event in Science magazine, two scientists specializing in GLP-1 receptor agonists answered questions from journalists via videoconference. Most queries were about diabetes and obesity. These drugs have revolutionized the treatment of these two epidemics, changing the relationship that society has with hunger, diet and food. While facing supply problems due to their enormous demand, these drugs are showing some interesting side effects. “In recent years we have seen that it affects diseases such as Alzheimer’s and Parkinson’s,” said Lotte Bjerre Knudsen, chief scientific advisor in research and early development at the Danish company Novo Nordisk, the maker of Ozempic. “Everything is hypothetical, but it is important to highlight that it is progressing and that is very positive.”
A recent clinical trial, published in The New England Journal of Medicine, confirms this idea. This research points out how Parkinson’s patients treated with lixisenatide, a diabetes drug, maintained their motor abilities without major changes for a year.
“We started investigating thanks to the clues that epidemiology had been leaving us,” explains Olivier Rascol, a neurologist at the University of Toulouse and lead author of the research, in a video call. Patients with type 2 diabetes have a higher risk of developing Parkinson’s than the rest of the population. It is a trend that has been pointed out in different studies. “On the other hand, we saw that diabetic patients who were treated with this type of medication, GLP-1, had a lower risk of developing Parkinson’s than those who received other antidiabetic medications,” explains the author. So they started investigating.
The study began in 2014 with 156 patients who were recruited in the initial stages of the disease. Half were given lixisenatide for 12 months. The rest received a placebo. After that time, they found that this last group had developed more serious symptoms of Parkinson’s by three points (on a scale that measures how well people can perform tasks such as talking, eating and walking). Those who had been treated with lixisenatide remained stable.
These three points of difference are relevant, but not dramatic. “It is a small change,” assesses Álvaro Sánchez Ferro, a neurologist at the 12 de Octubre Hospital in Madrid, Spain and Coordinator of the Movement Disorders Study Group of the Spanish Society of Neurology. “It would be minimally perceptible to the human eye. The five-point change is what we establish to say that something has had a more or less substantial effect.” The interesting thing, points out Dr. Sánchez Ferro, who was not involved in the study, is the verification of this neuroprotective effect. And the revolutionary thing would be to check if this difference of three points continues to increase over the years.
“It’s the million-dollar question… No, it’s the 10-million-euro question,” quips Wassilios Meissner, a professor of neurology at the University Hospital of Bordeaux. Meissner, who participated in the study, is cautious. “That’s what we hope, but we have to prove it. If in the end the maximum effect is three points after 10 years of treatment, then we can conclude that it is not worth it. But if it increases to five or 10 points… that would make a clear difference and would be of tremendous help.”
The relevant thing about this treatment is not only what it achieves, but how it does it: by tackling the problem at its roots. “Parkinson’s is a neurodegenerative disease, there are different areas of the brain that become damaged, that lose neurons,” explains Dr. Sánchez Ferro. “This affects many areas, but especially the nigrostriatal pathway, which is related to motor control.” The disease kills the cells that produce dopamine, and this is reflected in the person’s movements, which become increasingly slower and uncoordinated. Until now, medications such as levodopa, which has been used against Parkinson’s since the 1960s, artificially increased dopamine production.
“What GLP1 agonists do is completely different,” says Professor Rascol. “They protect the neurons that produce dopamine from dying. In other words, it’s like you have a swimming pool and you’re losing water in it. There are two ways to deal with the problem: either you add water to the pool to maintain the level (and this is what the levodopa is doing) or you try to find where the leak is and where the water is escaping. This is what we are achieving with lixisenatide.” In any case, the expert emphasizes, it should be noted that this treatment could stop or slow down the loss of neurons, but in no case recover those that have been lost. The effects of Parkinson’s are irreversible.
But how can a drug designed for diabetes have a neuroprotective effect on the brain? “We know that insulin receptors also exist in the brain,” says Meissner. “They are crucial for regulating glucose levels in the blood and in different organs. But they are also involved in the survival of neurons.” When a person has Parkinson’s, these receptors begin to fail. “In these regions we see abnormalities reminiscent of insulin resistance. Abnormalities that resemble those that occur with diabetes.”
GLP-1 agonists not only act in the intestine, they also act in the brain. Lixisenatide is one of the first generation drugs in this family, one of those that has the greatest effect at the neuronal level. “In diabetes it is no longer used, it is a drug that has already died because it was injected once a day and its results were not as optimal as with the weekly ones,” says Cristóbal Morales, an endocrinologist at the Virgen de la Macarena and Vithas hospitals ( both in Seville, Spain) and member of the Spanish Society for the Study of Obesity. “But its neuroprotective effects are very good.” Morales points out how this is something that began to be suspected years ago. “In large clinical trials, many quality of life questionnaires are done, and we began to realize that markers of cognitive impairment improved with this medicine.” This study, the first to directly relate Parkinson’s and lixisenatide, is a first step to demonstrate what different studies have been suggesting. But there is a long way to go.
Work is already underway. GLP-1 receptor agonists have been shown to not only reduce inflammation of the liver, kidneys, and heart. The drugs even appear to reduce inflammation in the brain, giving scientists hope that these compounds could be used to treat not only Parkinson’s, but other neurodegenerative diseases such as Alzheimer’s. Both are characterized by brain inflammation. In a recent review, published in the scientific journal Nature, more than 20 clinical trials are listed in which the drugs are being explored as therapies for both diseases.
For now, what is clear is the relationship between two very different diseases, but which could have a common solution. “It is important to seek treatments,” says the neurologist Sánchez Ferro. “But also talk about how to avoid Parkinson’s. And in this case we must emphasize the importance of physical exercise. It has been shown that sport protects at a neuronal level.”
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