MARSHFIELD – A drug already used safely to treat Parkinson’s disease, restless leg syndrome and other movement disorders also could delay or prevent the most common cause of blindness affecting more than 9 million older Americans – age-related macular degeneration (AMD).
Researchers have discovered that patients who take the drug L-DOPA are significantly less likely to develop AMD, and if they do get AMD it’s at a significantly older age, according to the study published online Nov. 4 in the American Journal of Medicine. The retrospective study was led by researchers at Marshfield Clinic Research Foundation, University of Arizona, Medical College of Wisconsin, University of Miami, Essentia Health, Stanford University and University of Southern California.
“Research points to this as a pathway to regulate and prevent this most common cause of blindness in adults,” said Murray Brilliant, Ph.D., director, Marshfield Clinic Research Foundation Center for Human Genetics, Marshfield, Wisconsin. “Imagine telling patients we potentially have medication that will allow them to see and continue enjoying life, their family and perform every day activities as they age. That is very powerful.”
AMD, the No. 1 cause of legal blindness in adults over 60, is a progressive eye condition affecting as many as one in three adults. The disease attacks the macula of the eye, where the sharpest central vision occurs, causing central blindness. This vision is used to drive, read, recognize faces and perform daily tasks. AMD spares the peripheral vision, leaving dim images or black holes at the center of vision.
L-DOPA is a natural by-product of pigmentation and is made in a layer of cells in the back of the eye that functions to promote health and survival of retinal tissues. Researchers asked the question if people taking L-DOPA as a medicine are protected from AMD.
“The obvious question was if the L-DOPA no longer produced was supplemented via pill form, does it have the potential to serve as a preventive medicine against AMD,” Brilliant said. “We need more research, but this first step is promising.”
Albinism research leads to hope
This work grew out of research using albino mouse models. Mice, as well as humans who have albinism or lack of pigmentation, have profound vision loss and changes in the eye structure , especially the macula, the oval-shaped area near the center of the retina associated with a person’s ability to see clearly.
Race and ocular pigmentation are known risk factors for developing AMD, indicating darker pigmentation may protect from the disease as it occurs much, much more frequently in the white population than black or Hispanic populations. This led to the hypothesis that those with darker pigmentation may have greater L-DOPA signaling in the RPE.
To test this, researchers examined health records of 37,000 Marshfield Clinic patients looking for those with AMD, those taking L-DOPA and those with both L-DOPA and AMD. They then determined the age patients developed AMD.
According to national statistics, the average age at which individuals are given L-DOPA is 67; the average age of AMD diagnosis is 71. In those people who got L-DOPA before being diagnosed with AMD, their AMD diagnosis occurred eight years later than those without L-DOPA.
These provocative results were then confirmed in a much larger data set of 87 million patients where similar results were observed and the study expanded to include prevention and delay of “wet” AMD, the most devastating form of the disease.
In all the groups examined, data suggests L-DOPA may prevent or delay AMD.
“This study suggests an intriguing link between patients taking L-DOPA and a lower incidence and delayed onset of AMD,” said Paul A. Sieving, M.D., Ph.D., director of the National Eye Institute. “Showing that L-DOPA causes this protective effect will require further investigation, but if confirmed, could lead to new drugs or combination therapies for AMD that target DOPA-responsive cells in the retina.”
The next step in this research is to perform a clinical trial to determine the ability of this drug to prevent AMD.
“Results suggest a new path forward in our fight against AMD that may even include a strategy to prevent those at risk of the disease from ever developing it,” said Brian McKay, Ph.D., associate professor, Department of Ophthalmology and Vision Science, University of Arizona. “In the end, L-DOPA may not be the drug that ends the disease but the pathway identified is likely to be a key observation as the search for a cure continues.”
This research, titled “Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration,” was supported by National Center for Advancing Translational Sciences, National Human Genome Research Institute, Research to Prevent Blindness, Bright Focus Foundation, The Edward N. & Della L. Thome Memorial Foundation, Wisconsin Genomics Initiative, National Eye Institute, Marshfield Clinic and University of Arizona.
Marshfield Clinic provides patient care, research and education with more than 50 locations in northern, central and western Wisconsin, making it one of the largest comprehensive medical systems in the United States.
This release explains results from a review of health records of thousands of patients with age-related macular degeneration (AMD) who also had taken the drug levodopa (L-DOPA). Researchers questioned whether the drug might slow or prevent the onset of this disease. They found an association between delayed onset of AMD in seniors who took L-DOPA. These patients were diagnosed with AMD up to eight years later than those not taking the drug. The release is mostly cautious about presenting the association but omitted some information we consider crucial, namely costs, alternative therapies, the absolute size of the benefit observed, and full disclosure on a significant conflict of interest.
Age-related macular degeneration (AMD) is a serious illness affecting millions of the elderly. It is the number one cause of blindness among older people and robs them of their central vision, leaving only peripheral vision in most cases. This impairment severely affects their quality of life. The discovery of an association between the drug levodopa (L-DOPA) and AMD through a large data search may lead to better understanding of how AMD starts if a future randomized trial validates the hypothesis. If an existing drug is shown to be effective against AMD, it could save both time and expense in bringing a therapy to patients in need.
While the release is relatively cautious, it fails to mention the costs of its suggested treatment in any way. One assumes from the release that patients would be taking L-DOPA for a considerable length of time, which could represent a substantial expense. L-DOPA has been prescribed for patients with Parkinson’s disease and other maladies for years and offering an estimate of yearly costs of the drug should have been easy, and would have helped readers gauge the value of this research in terms of patient care. Levodopa is generally prescribed in combination with another drug or drugs but the treatment cost of L-DOPA alone is several thousand dollars annually.
The release states that, based on the evaluation of a 37,000 clinic records of patients who took L-DOPA and noting those from the group that also developed AMD, that there appears to be a correlation between patients’ taking of L-DOPA and their later development of AMD. It states that those taking the drug tend to develop the disease eight years later than those who don’t. The release also suggests that in addition to delaying onset of the disease, the drug may also prevent it, although it is less clear in that claim. However, these numbers only portray relative risk rather than absolute risk and the number needed to treat (NNT). The numbers of people who developed AMD was relatively small, making it likely that the NNT would be very large (very many need to be treated in order to prevent or delay one case of blindness). Because the statistics used do not give readers a complete sense of the benefits attributable to to L-DOPA, we’ll rule this Not Satisfactory.
At no point does the release mention any harmful effects from taking L-DOPA. And while patients might arguably be willing to face greater risks in order to retain their eyesight, it doesn’t excuse the release for omitting relevant details. L-DOPA has been given to patients for years and the list of possible side effects — both physical and mental — is considerable. Patients reading stories or releases touting the possible treatment use of new drugs deserve to know the full story including possible negative effects of the drug’s use.
To its credit, the release explains early — in the second paragraph — that the research is a retrospective study of patient records. This informs knowledgeable readers of the inherent limitations of retrospective studies but readers not familiar with research may not understand that retrospective studies cannot show causality, that one thing leads to another. We’ll give them a grudging satisfactory in this category but with a caution about the overall message of the release — that L-DOPA can delay or prevent AMD. It may very well do so, but this kind of study cannot prove that. But again, transparency is offered when the authors of the study are quoted saying that this research justifies the performance of future randomized clinical trials specifically looking at the benefits and any additional risks of long term L-Dopa for prevention or delay of AMD.
While it describes the prevalence of AMD, the release doesn’t commit disease mongering.
The release identifies the funding sources of this research but does not alert readers to the conflict of interest disclosure found in the published results. While the lead author has not yet received income from the drug application, he is the patent holder. “Dr. McKay is an inventor on an approved patent for the use of L-DOPA to treat or delay AMD,” according to the published paper. Just because he hasn’t received royalties yet doesn’t mean he or his institution will never accept royalties if and when L-DOPA is approved for treating AMD. The release should have called attention to this.
No alternatives are mentioned. While there is no known effective cure for AMD, there are treatments available to slow the progression of the disease or prevent severe vision loss including drug injection, laser therapy and vitamin supplementation.
L-DOPA is readily available to patients now and the story makes this clear.
The idea that an established drug might be effective against a disease other than what it was intended to treat is novel enough to justify a release touting the findings of an acceptable study. And the release makes clear that this study was prompted by earlier studies in mouse models that supported a role for L-DOPA in AMD.
We’ll give the benefit of the doubt here because the release does not use overtly unjustifiable language. But the use of words such as “prevention” implies causation, which this study was incapable of showing. A better way to phrase this might be to say “There is an association between taking L-Dopa and having AMD start at a later age.”