Sildenafil (Viagra, Revatio) may be a candidate drug to prevent or treat Alzheimer's disease, new research suggested.
Across 6 years of follow-up, sildenafil users were 69% less likely to develop Alzheimer's disease than non-sildenafil users (HR 0.31, 95% CI 0.25-0.39, P<1 × 10-8), a large case-control analysis of insurance claims showed.
Sildenafil also emerged as a potential disease risk modifier in an analysis of drugs that might be repurposed for Alzheimer's, reported Feixiong Cheng, PhD, of the Cleveland Clinic Genomic Medicine Institute, and co-authors.
Moreover, the phosphodiesterase 5 inhibitor, which is approved to treat erectile dysfunction and pulmonary arterial hypertension, increased neurite growth and decreased phospho-tau expression in neuron models derived from induced pluripotent stem cells, Cheng and colleagues wrote in .
Understanding may uncover common underlying mechanisms and lead to drugs that could be repurposed for diseases like Alzheimer's, the researchers noted.
"Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer's than either by itself," Cheng said in a statement. "Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success."
The researchers integrated genetic and other data to determine which of over 1,600 FDA-approved drugs might be effective in treating Alzheimer's disease, zeroing in on drugs that targeted both amyloid and tau. As the investigators narrowed the list of candidates, they looked for drugs with ideal brain penetration, positive in vivo findings in Alzheimer's mouse models, and sufficient patient data.
"Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate," Cheng said.
The team then looked at diagnostic codes and pharmacy claims for 7.23 million people in the MarketScan Medicare Claims database from 2012 to 2017 to identify relationships between sildenafil and Alzheimer's disease in a case-control analysis.
To reduce the likelihood of confounding by indication, the researchers also evaluated four comparator drugs: losartan (Cozaar), an antihypertensive agent, metformin (Glucophage), a biguanide used to treat type 2 diabetes, diltiazem (Cartia), an antihypertensive and calcium channel blocker, and glimepiride (Amaryl), a sulfonylurea used to treat type 2 diabetes. Of the four comparators, and currently are in clinical trials for Alzheimer's disease.
Sildenafil showed a 55% reduced risk of Alzheimer's compared with losartan, 63% compared with metformin, 65% compared with diltiazem, and 64% compared with glimepiride, after adjusting for age, sex, race, and disease comorbidities.
Across all comparator drug groups, people with coronary artery disease, hypertension, and type 2 diabetes had reduced likelihood of Alzheimer's disease. The results remained consistent when people with these comorbidities were excluded.
The researchers further tested sildenafil in a model based on human microglia cells and neurons derived from induced pluripotent stem cells from Alzheimer's patients and found the drug increased neurite growth and decreased p-tau 181 expression.
"There is to date that suggests sildenafil treatment is associated with increased neurogenesis and decreased inflammation, but more research is needed," noted Claire Sexton, DPhil, of the Alzheimer's Association in Chicago, who wasn't involved with the study.
"More than ever before, Alzheimer's researchers understand that a variety of approaches will be needed -- most likely used in combination -- for effective treatment of the disease," Sexton told 鶹ý.
"Scientists are more extensively testing the potential benefits of drugs approved for other diseases for the treatment of dementia," she pointed out. "Repurposing existing drugs for new uses can speed up the research process. Since scientists are building on previous research, much is already known about the drugs' potential side effects, it may take less time for the drugs to be tested, and the clinical trials may be less expensive."
A subgroup analysis showed sildenafil was linked to a decreased risk of Alzheimer's across all comparator drugs for men, but only compared with diltiazem for women. This may be because there were not enough women to power a study for statistical significance since sildenafil is prescribed primarily to men, Cheng and co-authors noted.
The study has other limitations, the team acknowledged. Potential literature bias and data incompleteness may have influenced the network analysis. In addition, Alzheimer's disease was defined using ICD codes, which may be inaccurate.
"The association between sildenafil use and decreased incidence of Alzheimer's disease does not establish causality, which will require a randomized controlled trial," the researchers added.
Disclosures
This work was primarily supported by the National Institute on Aging and Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center. It was supported in part by the Brockman Foundation, Allen Initiative in Brain Health and Cognitive Impairment, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, the Louis Stokes VA Medical Center and the Alzheimer's Disease Drug Discovery Foundation.
Cheng had no disclosures. One co-author disclosed relationships with Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, BioXcel, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Third Rock, United Neuroscience, ADAMAS, MedAvante, and Bioasis; other co-authors declared no competing interests.
Primary Source
Nature Aging
Fang J, et al "Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease" Nat Aging 2021; DOI: 10.1038/s43587-021-00138-z.