Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson's disease, new research suggests.
Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson's disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which doesn't affect glycolysis.
"If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists," Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa in Iowa City, told Medscape Medical News.
There are few reliable neuroprotective treatments for Parkinson's disease, he said. "We can manage some of the symptoms, but we can't stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson's disease," Simmering said.
The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators note. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they write.
The findings were published online February 1 in JAMA Neurology.
The major risk factor for Parkinson's disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson's, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors write.
Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.
In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson's than patients receiving tamsulosin. To do that, they used healthcare utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.
The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson's within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.
They looked at patient outcomes beginning at one year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.
The investigators used propensity score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson's disease.
They identified 52,365 propensity score-matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.
Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson's vs those who took tamsulosin (hazard ratio [HR], 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson's than those who took tamsulosin (HR, 0.63).
In both cohorts, the risk for Parkinson’s among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and in the Truven (HR, 0.46) cohorts, vs tamsulosin.
Differences in case definitions, which may reflect how Parkinson's disease was managed, complicate comparisons between the Danish and Truven cohorts, said Simmering. Another challenge is the source of the data.
"The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans," he told Medscape Medical News. "This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn't contribute data, we would lose them."
The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.
The results support the hypothesis that increasing energy in cells slows disease progression, Simmering added. "There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson's disease. Right now, we don't have anything to offer people at elevated risk of Parkinson's disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson's disease, we would have something truly protective to offer these patients."
Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at University of Cincinnati Academic Health Center, Cincinnati, Ohio, was cautious. "These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect," Espay told Medscape Medical News. "Hence, there is no feasible or warranted change in practice as a result of this study."
Pathogenic mechanisms are heterogeneous among patients with Parkinson's disease, Espay added. "We will need to understand who among the large biological universe of Parkinson's patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention."
Parkinson's is not one disease, but a group of disorders with unique biological abnormalities, said Espay. "We know so much about 'Parkinson's disease' and next to nothing about the biology of individuals with Parkinson's disease."
This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.
The University of Iowa contributed funds for this study. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Espay has disclosed no relevant financial relationships.
JAMA Neurol. Published online February 1, 2021. Full text
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