A Case-control Study of Phosphodiesterase-5 Inhibitor Use and Alzheimer’s Disease and Related Dementias Among Male and Female Patients Aged 65 Years
David S. Henry, Richard G. Pellegrino
Abstract
Background
Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer’s disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.
Methods
We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old.
Results
Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.
Introduction
There are currently only six FDA-approved therapies to treat Alzheimer’s disease (AD): cholinesterase inhibitors (donepezil, galantamine, and rivastigmine), an n-methyl-D-aspartate receptor antagonist (memantine), and two anti-amyloid antibodies (aducanumab and lecanemab) [1–3]. However, clinical studies of the cholinesterase inhibitors and memantine have demonstrated, at best, only modest statistical benefits in cognition, which may not translate to meaningful benefits for patients and caregivers in daily life [4, 5]. Additionally, these drugs can have numerous dose-dependent side effects, limiting their tolerability [6, 7]. The antibody therapies were approved by the FDA via an expedited pathway based on limited data demonstrating their benefit, which has received extensive criticism [8–13]. Lecanemab later received full approval by the FDA after the randomized, controlled, phase three Clarity AD trial, which demonstrated an average benefit of only 0.45 points versus placebo on the Clinical Dementia Rating–Sum of Boxes scale, which rates dementia from 0 (normal) to 18 (severe dementia), after 18 months among patients with early AD [10, 14, 15]. The magnitude of this benefit may not be clinically perceptible to patients and caregivers [16].
Methods
We used an unmatched case-control design to evaluate the association between history of PDE5i (sildenafil and tadalafil) use and ADRD. All patients included in the study were identified from the Epic electronic medical record database of Baptist Health, a large integrated health system in Arkansas, USA, which includes medical records for more than 1.4 million patients across the health system. All patients included in this study had at least one outpatient provider encounter between 1 January 2018 and 31 December 2022. Due to limitations in the data analysis platform we used, patients were at least 65 years old at the time of data tabulation (January 2023 to March 2023), which accounts for minor variability in the aggregate patient counts. Additionally, inclusion in this study was restricted to patients with at least one FDA-approved chronic indication for PDE5i (ED, BPH, or pHTN), and throughout the study, we restricted each analysis by PDE5i indication in order to minimize confounding by indication. WCG IRB issued a waiver of HIPAA authorization for this study (Protocol No.: II-001). Only aggregate data were obtained during this study, and no protected health information was used.
Results
We began by evaluating whether the odds of PDE5i exposure is different for patients with ADRD versus controls without ADRD among populations with each chronic FDA-approved indication for PDE5i: ED, BPH, and pHTN. Demographic and clinical characteristics of all patients over 65, stratified by exposure and outcome, are summarized in Table 1. For ED, BPH, and pHTN, the odds of exposure to PDE5i are significantly less among patients with ADRD versus controls without ADRD. The same is true for ERA exposure in pHTN (Table 2).
Discussion
We undertook the present study to reconcile the diametrically opposed conclusions of Fang et al. and Desai et al. regarding the protective effect of PDE5i on AD risk and to determine whether further observational studies and/or clinical trials to evaluate this association are warranted. We began by repeating the main epidemiologic investigations from those studies. Similar to the protective effect of PDE5i reported by Fang et al., we observed lower odds of PDE5i use in patients with AD and ADRD than in controls without ADRD among populations with ED, BPH, and pHTN. Congruent with the results of Desai et al., we observed similar odds ratios of PDE5i use and ADRD and ERA use and ADRD, among patients with pHTN. A major difference between the study of Desai et al. and our study is that their study classified patients taking ERA as the unexposed (control) group, while we classified patients without a history of use of the drug in question (PDE5i or ERA) as the unexposed group. Based on this comparison, they concluded that PDE5i do not decrease the risk of ADRD. An alternate explanation of their data could be that both PDE5i and ERA similarly reduce the risk of ADRD in patients with pHTN when compared with patients with untreated pHTN. Our data support the latter interpretation.
Acknowledgments
We are grateful to Lesa Gann for assistance with the IRB submission, to Karen Smith for technical assistance with SlicerDicer, and to Dr. Rachael Pellegrino for thoughtfully critiquing the manuscript.
Citation: Henry DS, Pellegrino RG (2023) A case-control study of phosphodiesterase-5 inhibitor use and Alzheimer’s disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial. PLoS ONE 18(10): e0292863. https://doi.org/10.1371/journal.pone.0292863
Editor: Israel Silman, Weizmann Institute of Science, ISRAEL
Received: May 23, 2023; Accepted: October 2, 2023; Published: October 18, 2023
Copyright: © 2023 Henry, Pellegrino. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interest exists.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0292863#abstract0
