A recent study suggests that certain drugs commonly used to treat enlarged prostate may also decrease the risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.
Medscape reports that this observational finding may seem surprising, but it mirrors previous work by the University of Iowa Health Care team that links the drugs to a protective effect in another neurodegenerative condition, Parkinson’s disease, the researchers said.
They found that older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.
“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” said study investigator Jacob Simmering, PhD, of the University of Iowa said.
“If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”
The findings were published online in Neurology, the journal of the American Academy of Neurology.
Increasing ATP neuroprotective?
In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s.
In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1) which increases the availability of adenosine triphosphate (ATP).
There have been case reports of PD being linked to mutations affecting PGK1, and researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to ageing and synuclein aggregation.
To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.
Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrolment in the claims databases.
After following claimants for an average of three years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10 000 people per year.
During the follow-up period, 1 286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10 000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10 000 people per year.
After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).
“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesised mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.
Study limitations include excluding women from the study, so the findings cannot be generalised to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.
However, Simmering and his colleagues are excited by the potential of these drugs, which are already FDA approved, inexpensive, and have been used safely for decades.
Study details
Association of Terazosin, Doxazosin, or Alfuzosin Use and Risk of Dementia With Lewy Bodies in Men
Alexander Hart, Georgina Aldridge, Qiang Zhang, Nandakumar Narayanan, Jacob Simmering.
Published in Neurology on 23 June 2024
Abstract
Background and Objectives
Terazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are α-1 adrenergic receptor antagonists that also bind to and activate a key adenosine triphosphate (ATP)–producing enzyme in glycolysis. It is hypothesised that the increase in energy availability in the brain may slow or prevent neurodegeneration, potentially by reducing the accumulation of alpha-synuclein. Recent work has suggested a potentially neuroprotective effect of the use of Tz/Dz/Az in Parkinson disease in both animal and human studies. We investigated the neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB).
Methods
We used a new-user active comparator design in the Merative Marketscan database to identify men with no history of DLB who were newly started on Tz/Dz/Az or 2 comparator medications. Our comparator medications were other drugs commonly used to treat benign prostatic hyperplasia that do not increase ATP: the α-1 adrenergic receptor antagonist tamsulosin or 5α-reductase inhibitor (5ARI). We matched the cohorts on propensity scores and duration of follow-up. We followed up the matched cohorts forward to estimate the hazard of developing DLB using Cox proportional hazards regression.
Results
Men who were newly started on Tz/Dz/Az had a lower hazard of developing DLB than matched men taking tamsulosin (n = 242,716, 728,256 person-years, hazard ratio [HR] 0.60, 95% CI 0.50–0.71) or 5ARI (n = 130,872, 399,316 person-years, HR 0.73, 95% CI 0.57–0.93). while the hazard in men taking tamsulosin was similar to that of men taking 5ARI (n = 159,596, 482,280 person-years, HR 1.17, 95% CI 0.96–1.42). These results were robust to several sensitivity analyses.
Discussion
We find an association in men who are taking Tz/Dz/Az and a lower hazard of DLB compared with similar men taking other medications. When combined with the literature of Tz/Dz/Az on Parkinson disease, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. A future randomised trial is required to assess these associations for causality.
Medscape article – Prostate Meds Tied to Reduced Risk for Lewy Body Dementia (Open access)
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