Study finds erectile dysfunction drugs linked to lower Alzheimer's risk

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Feb 12 2024

In a recent study published in Neurology, researchers evaluated the effect of phosphodiesterase-5 inhibitor (PDE5I) initiation compared to non-use and Alzheimer's disease (AD) development risk among males suffering from erectile dysfunction (ED).

Background

AD is the most prevalent form of dementia and a leading cause of mortality. Interventions that can delay or prevent AD development are critical to promoting healthy aging and continue to garner scientific interest. Animal studies have highlighted the neuroprotective benefits of repurposing PDE5 inhibitors as medications for AD risk reduction; however, evidence among humans is inconclusive.

About the study

In the present population-based cohort study, researchers explored the potential repurposing benefits of phosphodiesterase type 5 inhibitors against AD.

The team analyzed the IQVIA Medical Research Data (IMRDA) United Kingdom (The Health Improvement Network) data to identify men aged 40 years and above diagnosed with ED from 1^st January 2000 to 31^st  March 2017 and prescribed PEDE5Is (tadalafil, sildenafil, avanafil, or vardenafil). They included men with new-onset ED and no PDE5I prescriptions (non-exposed or non-users) in the comparator group.

The team excluded individuals with prior histories of cognitive impairment, dementia, confusion, and prescriptions for phosphodiesterase type 5 inhibition and dementia symptoms. They also excluded individuals contraindicated for PDE5I use, such as those prescribed nicorandil or nitrate-based medications in the previous three months.

The researchers identified new-onset AD using diagnostic codes. To reduce immortal-time-type bias, they considered PDE5I initiation to be time-varying. They followed the study participants until AD diagnosis, death, transfer from their general physician (GP) practice, the last date of GP data availability, or study period termination (31^st March 2018), whichever occurred first.

The team estimated propensity scores (PS) using logistic regressions and performed Cox proportional hazards modeling to determine the hazard ratios (HR) of new-onset Alzheimer’s disease, comparing phosphodiesterase type 5 inhibitor initiation and non-usage. They adjusted for potential confounders using the inverse probability of treatment weighting (IPTW) approach. Study covariates included age, body mass index (BMI), blood pressure, comorbidities, medications, calendar year, alcohol intake, smoking habits, and Townsend deprivation scores.

The researchers performed secondary analyses to explore the relationship between Alzheimer’s disease and the number of phosphodiesterase type 5 inhibitor prescriptions. They also performed sensitivity analyses, including delay (lag) periods of one year and three years after ED diagnosis to address prodromal AD.

Results

In total, the team identified 413,858 males with new-onset erectile dysfunction during the study period; however, they included only 269,725 eligible males for analysis, of whom 1,119 were diagnosed with Alzheimer’s disease over a five-year follow-up (median). The mean participant age at ED diagnosis was 59 years. Among PDE5I-exposed individuals, 749 developed Alzheimer’s disease, a crude incident rate of 8.10 per 10,000 person-years at risk (PYAR). Among the non-exposed, 370 males developed AD, a crude incident rate of 9.7 per 10,000 person-years at risk.

The team observed an adjusted hazard ratio of 0.8 for phosphodiesterase type 5 inhibitor initiation compared to non-usage. The associated AD risks were reduced among individuals with more than 20 PDE5I prescriptions (hazard ratio, 0.6 for 21 to 50 drug prescriptions) and those with more than 50 PDE5I prescriptions (hazard ratio, 0.7). However, there was no evidence of lowered AD risk among individuals issued with one, two, ten, or twenty prescriptions compared to non-users.

Sensitivity analysis considering a lag period of one year yielded similar results (HR, 0.8); however, the findings differed considering three years of lag (HR, 0.9). Subgroup analysis findings indicated lowered AD risk among individuals who initiated sildenafil (adjusted HR, 0.8), with similar effect estimates among those using vardenafil and tadalafil but lacking robust evidence for lowered risk compared to non-users. The team also observed lower AD risk among PDE5I users compared to non-users among study participants with diabetes and hypertension and individuals aged 70 years and older.

Conclusion

Overall, the study findings showed that phosphodiesterase type 5 inhibitor initiation among males with erectile dysfunction was related to a lower Alzheimer’s disease risk, especially among those frequently prescribed PDE5I medications. The discrepancies between the primary findings and sensitivity analysis results highlight the importance of determining the optimum lag period. Randomized clinical trials, including males and females, and exploring different phosphodiesterase type 5 inhibitor dosages could validate the results and improve the generalizability of the study findings.