Phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil, are widely known for their role in treating erectile dysfunction (ED) and pulmonary hypertension. But emerging research suggests their effects extend far beyond the sexual or pulmonary vasculature. As studies on vascular aging, metabolic disease, and systemic inflammation advance, PDE5 inhibitors are increasingly viewed as agents with potentially broader biological activity, particularly on endothelial function and inflammatory signaling pathways.
Endothelial dysfunction is central to the pathogenesis of a wide range of chronic diseases, from atherosclerosis to diabetes and Long COVID. At the same time, systemic inflammation is a common driver of both vascular and metabolic disorders. This raises a timely question: could PDE5 inhibitors serve dual roles, acting not only as vasodilators but as modulators of vascular health and low-grade inflammation? Recent evidence from human studies, including a 2025 meta-analysis published in International Journal of Molecular Sciences (Cianciarulo et al., 2025), suggests measurable anti-inflammatory effects and improvements in endothelial markers after chronic PDE5 inhibition. However, these findings vary across populations and dosing regimens.
This article provides a clear, structured breakdown of current data on systemic effects of PDE5 inhibitors, focusing on their influence on inflammatory biomarkers, endothelial function, and clinical implications beyond ED.
Systemic Actions of PDE5 Inhibitors
Phosphodiesterase type 5 (PDE5) inhibitors work by blocking the degradation of cyclic guanosine monophosphate (cGMP), a secondary messenger that mediates nitric oxide (NO)-induced smooth muscle relaxation. In the context of erectile physiology, this translates to enhanced blood flow and improved erectile rigidity. But PDE5 is not localized to the penis alone. It is found throughout the vascular smooth muscle in pulmonary arteries, coronary vessels, skeletal muscle, and even within immune and endothelial cells. This widespread distribution suggests that PDE5 inhibitors, particularly when administered chronically at low doses, may have broader systemic effects. For example, long-term PDE5 inhibition enhances endothelial NO signaling, promotes vascular smooth muscle relaxation, and may reduce vascular remodeling in conditions like pulmonary hypertension or diabetes-related vasculopathy (StatPearls, 2023).
Several studies have also reported increased levels of endothelial progenitor cells (EPCs) following PDE5i use cells essential for vascular repair and regeneration. A study in International Journal of Molecular Sciences found that sildenafil and tadalafil increase bone marrow–derived EPC mobilization, potentially aiding in endothelial healing after vascular injury (Kallinikas, 2024).
Beyond the vasculature, PDE5 inhibition has been associated with modest metabolic benefits: improved insulin sensitivity, reduced triglyceride levels, and better glycemic control in select diabetic cohorts. These findings further support the notion that PDE5 inhibitors may act as vascular-metabolic modulators, not just sexual performance enhancers.
The systemic nature of cGMP signaling provides a plausible biological framework for these effects. However, the next step in validating this role is to determine whether inflammatory pathways, a cornerstone of vascular dysfunction, are also measurably impacted by chronic PDE5 inhibition. We explore this in the next section.
Anti-Inflammatory Effects – What Does the Evidence Say?
Inflammation plays a central role in endothelial dysfunction, metabolic disease, and vascular aging. Therefore, any systemic benefits of PDE5 inhibitors should ideally be reflected in modulated inflammatory biomarkers. Recent data suggest that this is indeed possible, particularly with chronic PDE5 inhibitor use.
A 2025 systematic review and meta-analysis by Cianciarulo et al. in the International Journal of Molecular Sciences examined 17 human studies evaluating the effects of long-term PDE5 inhibitor therapy on inflammatory and vascular biomarkers (Cianciarulo et al., 2025). The results showed statistically significant reductions in:
Notably, these anti-inflammatory effects were not seen in short-term studies (under 4 weeks), suggesting that time-dependent pathways, such as gene expression changes and immune cell signaling, may be involved.
Interestingly, the review found no consistent change in C-reactive protein (CRP), TNF-α, or IL-10, especially in healthy individuals or those without elevated baseline inflammation. This highlights a key insight: the anti-inflammatory impact of PDE5 inhibitors may depend on existing disease burden or baseline immune activation. Other mechanistic studies reinforce this nuance. In men with metabolic syndrome or type 2 diabetes, daily tadalafil or vardenafil has been associated with reductions in pro-inflammatory chemokines (e.g., CXCL10) and endothelial adhesion molecules markers not always evaluated in broader trials (Kallinikas, 2024).
Altogether, the current evidence suggests that PDE5 inhibitors can exert anti-inflammatory effects, particularly when used chronically and in populations with pre-existing endothelial or metabolic dysfunction.
In the next section, we explore how these biochemical changes translate to measurable improvements in endothelial function across the body, and not just in the cavernous bodies.
Endothelial Function – Broader Vascular Effects
PDE5 inhibitors don’t just improve penile blood flow, they also affect the systemic endothelium, which lines all blood vessels and regulates vascular tone, inflammation, and clotting. Several studies show that daily PDE5 inhibitor use can enhance endothelial function beyond the genital region. For example, in men with type 2 diabetes, vardenafil taken daily for six months improved flow-mediated dilation (FMD) and reduced markers of endothelial inflammation (Soulaidopoulos et al., 2024). Similar benefits have been reported with tadalafil and sildenafil in patients with heart failure and metabolic syndrome.
Mechanistically, these drugs boost nitric oxide (NO) signaling, reduce oxidative stress, and may promote endothelial cell repair via progenitor cell mobilization (Kallinikas, 2024). Importantly, these effects occur independent of sexual activity, reinforcing the idea that PDE5 inhibitors have true systemic vascular actions. While results vary depending on baseline vascular health and treatment duration, the evidence supports a role for chronic PDE5 inhibition in preserving or restoring endothelial integrity. Whether this translates into reduced cardiovascular events remains to be tested, but the potential is there.
Clinical Context and Future Directions
Although PDE5 inhibitors are primarily indicated for erectile dysfunction and pulmonary arterial hypertension, their systemic vascular and anti-inflammatory effects are drawing interest far beyond urology.
The emerging data suggest that chronic, low-dose PDE5 inhibition may benefit patients with cardiometabolic conditions, vascular inflammation, or even Long COVID–related endothelial dysfunction.
Clinical observations in men with type 2 diabetes, metabolic syndrome, and heart failure with preserved ejection fraction (HFpEF) show measurable improvements in endothelial function, insulin sensitivity, and microvascular perfusion. These findings raise the possibility that PDE5 inhibitors could be repurposed as adjunct therapies in chronic vascular inflammatory diseases, though formal approval for such use is still lacking. However, key limitations remain. Most studies are small, single-center trials with short durations. There is variability in dosing, patient populations, and biomarker targets, making it difficult to define standardized protocols or determine ideal candidates. Moreover, CRP and TNF-α responses are inconsistent, and long-term cardiovascular outcome data are virtually nonexistent.
Despite these gaps, the therapeutic window is compelling. PDE5 inhibitors are generally safe, well-tolerated, and now widely available in generic forms. If future randomized trials confirm their vascular and anti-inflammatory benefits, they could join the ranks of medications like statins and SGLT2 inhibitors, drugs originally developed for one purpose, but now appreciated for broader systemic effects.
Looking ahead, research priorities include:
- Large RCTs assessing vascular and inflammatory endpoints
- Subgroup analyses in patients with high inflammatory burden
- Exploration of daily low-dose regimens outside ED populations
- Potential synergy with cardiometabolic therapies
In short, the question is no longer whether PDE5 inhibitors act beyond the penis it’s how far those benefits might extend, and who should receive them.
References
- Cianciarulo, C., Nguyen, T. H., Zacharias, A., Standen, N., Tucci, J., & Irving, H. (2023). Analysis of phosphodiesterase-5 (PDE5) inhibitors in modulating inflammatory markers in humans: A systematic review and meta-analysis. International Journal of Molecular Sciences, 26(15), 7155. https://doi.org/10.3390/ijms26157155
- Kallinikas, G. (2024). Cholinergic and phosphodiesterase-5 signaling in vascular endothelium: Mechanistic insights and therapeutic implications. International Journal of Molecular Sciences, 25(19), 10704. https://doi.org/10.3390/ijms251910704
- Soulaidopoulos, S., Tsioufis, C., Kordalis, A., Bletas, K., & Tousoulis, D. (2024). Long-term effects of phosphodiesterase-5 inhibitors on endothelial inflammation in men with type 2 diabetes: A randomized controlled study. European Heart Journal – Cardiovascular Pharmacotherapy, 10(5), 403–410. https://doi.org/10.1093/ehjcvp/pvad005
- StatPearls. (2023). Phosphodiesterase 5 (PDE5) inhibitors. In StatPearls [Internet]. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK549843/
