A recently published article in The Journal of Sexual Medicine investigating the associations between phosphodiesterase-5 inhibitor (PDE-5i) use and major adverse cardiovascular events has piqued the interest of/sparked debate within the urology community.¹ The observational study, capturing a sizable population of over 23,000 patients receiving PDE-5i, found that major adverse cardiovascular events, a metric which incorporates cardiovascular mortality, hospitalization, stroke, coronary revascularization, heart failure, unstable angina, and overall mortality, was 13% lower with PDE-5i exposure. Impressively, overall mortality actually fell by 25%.¹ Interestingly, patients with higher exposure, based on dosage or length of prescription, demonstrated greater benefits from these drugs. The researchers performed further subanalyses to uncover possible effect modification, finding that patients with preexisting cardiovascular risk factors and type 2 diabetes mellitus experienced similar improvements. However, known coronary artery disease seemed to negate the benefits of PDE-5i. Hence, PDE5-i exposure may primarily offer preventive benefits.

Although this retrospective study certainly has limitations, the authors write that these findings confirm several earlier studies suggesting that PDE-5is offer impressive benefits for patients with erectile dysfunction surrounding several cardiovascular conditions. Yet this study goes beyond previous perspectives to demonstrate benefits over a longer time period and in a broader population, including men without preexisting cardiovascular risk factors.

Perhaps most interesting is that PDE5-is, traditionally viewed as treatments exclusively for erectile dysfunction, may be soon considered for indications outside the realm of urology, harkening back to their historical early days in angina research. Beyond cardiovascular disease, there are additional studies investigating their use in diabetes, chronic kidney disease, and Raynaud’s phenomenon. Specifically, literature suggests the potential for PDE-5is to reduce the metabolic, microvascular, and macrovascular complications associated with diabetes.² In chronic kidney disease, PDE-5is enhance NO-cGMP signaling leading to renal protective effects, potentially attributable to anti-inflammatory, antioxidant, and antiproliferative mechanisms. In Raynaud’s phenomenon, PDE-5is represent a viable approach to improving microcirculation through vasodilation and enhanced endothelial function.³ Through their effects on intracellular signaling, PDE-5is may also have benefit in patients with hematological, breast, colorectal, and prostate malignancies.⁴ Their role as immunomodulators suggests that further investigations would be advisable to consider their use in conjunction with novel checkpoint inhibitors.⁵

Importantly, though PDE-5is may share a core mechanism of action, individual compounds hold significant pharmacological differences, particularly in potency, selectivity, and duration of action. They also hold unique drug interactions or implications for other patient comorbidities. Hence, further studies are needed to clarify the best pharmacological options for various indications in a patient-specific manner. The uncertainty surrounding the safety profile of PDE-5is and the importance of careful patient selection are evidenced by a case series demonstrating drug-induced nonarteritic anterior ischemic neuropathy leading to painless visual loss in PDE-5i users. Thus, prior episodes of nonarteritic anterior ischemic neuropathy or hereditary eye disease should be regarded as contraindications for their use.^6,7 Although this is but one, low-powered finding, it invites caution in exploring the expansion of these drugs. Given the broad physiological effects of these drugs throughout the body, prospective controlled studies are becoming warranted as early signals of benefit and safety become clearer.

At this point, consistent retrospective signals have suggested that PDE-5is may improve men’s cardiovascular health, and early studies have proposed uses far outside this space as well. The most robust findings certainly surround cardiovascular indications, and as data continue to accumulate, there may be increasing support for organizing prospective randomized controlled trials which offer adequate power to further clarify the use of these drugs in improving patient care. This is an exciting time for pharmacology and urology as a mainstay drug offers potential in a variety of conditions that affect a wide swath of our population. Ultimately, prospective randomized clinical trials examining the cardioprotective role of PDE-5is are warranted.