5-ARIs Not Linked to Risk of Dementia Over the Long Term

Men taking 5α-reductase inhibitors (5-ARIs), commonly used for androgenic alopecia and benign prostatic hyperplasia (BPH), should be aware of possible adverse psychological effects, researchers warned.

In a register-based cohort study of over 2.2 million Swedish men, an increased risk for depression was seen in those taking finasteride (Proscar, Propecia; HR 1.61, 95% CI 1.48-1.75) or dutasteride (Avodart; HR 1.68, 95% CI 1.43-1.96) compared with unexposed men, reported Miguel Garcia-Argibay, PhD, of Örebro University in Sweden, and colleagues in JAMA Network Open.

Finasteride and dutasteride were also initially associated with an increased risk for:

• All-cause dementia: HR 1.22, 95% CI 1.17-1.28 and HR 1.10, 95% CI 1.01-1.20, respectively
• Alzheimer's disease: HR 1.20, 95% CI 1.10-1.31 and HR 1.28, 95% CI 1.09-1.50
• Vascular dementia: HR 1.44, 95% CI 1.30-1.58 and HR 1.31, 95% CI 1.08-1.59

However, when the group tracked these associations over time, they found that men exposed to finasteride only saw an elevated all-cause dementia risk during the first 48 months of treatment, with the risk becoming nonsignificant after 4 years of exposure, while the link with dutasteride was only significant in the 13 to 48 months after starting treatment.

Similarly, the association with Alzheimer's disease and vascular dementia also became nonsignificant by 48 months.

Unlike with dementia risk, the risk for depression remained significant at all follow-up timepoints.

Completed suicide was the only outcome measured that wasn't significantly tied with the treatments at any timepoint.

"The take-home message from this research is that 5-ARIs do not seem to be associated with an increased risk for dementia or suicide," Garcia-Argibay told MedPage Today. "Our results should reassure healthcare professionals about the safety of 5-ARIs in relation to these outcomes."

"However, 5-ARIs seem to be associated with depression," he added. "It is therefore important for clinicians to be aware of this potential side effect when prescribing these medications and to monitor patients closely for signs of depression."

Garcia-Argibay noted that it was a relief to find that the risk for dementia did not persist over time.

"The possibility that 5-ARIs ... could increase the risk of developing dementia is biologically plausible," he explained. The way they work is by selectively inhibiting the enzyme 5α-reductase, which is involved in the conversion of testosterone to the androgen metabolite 5α-dihydrotestosterone expressed in tissues like the prostate and hair follicles. But because 5-ARIs reduce androgen levels, these agents were thought to possibly increase the risk for adverse cognitive outcomes.

"Given the marked rise in BPH risk with age, the common use of 5-ARIs to treat it, and the scarcity of research on the potential association with dementia, this research seemed important," he added.

In their paper, the researchers explained that the initial increased risk of dementia followed by a decrease over time may be reflective of surveillance bias, since patients with BPH were likely undergoing more screening by their clinicians.

Data for this study came from multiple Swedish national registers from July 2005 through December 2018. A total of 2,236,876 men ages 50 to 90 were included: 70,645 exposed to finasteride, 8,582 to dutasteride, and 1,837,474 who were unexposed.

Median age at the start of follow-up was 55, and median age at treatment initiation was 73.

More men on finasteride or dutasteride also had type 2 diabetes and hypertension and were on a beta-blocker compared with those who were unexposed.

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