Tadalafil, widely known by its brand name Cialis, is a long-acting phosphodiesterase type 5 inhibitor (PDE5i) approved for the treatment of erectile dysfunction (ED – Erectile Dysfunction: Questions and Answers from a Specialist) and benign prostatic hyperplasia (BPH, 2025 Round-Up: What’s New for Tadalafil in ED/BPH and Beyond). Its pharmacological action (prolonging cyclic guanosine monophosphate (cGMP)–mediated smooth muscle relaxation) was initially targeted at penile vasculature. Over the past decade, however, researchers have explored whether this same pathway might influence systemic endothelial health, cardiovascular risk, and metabolic regulation.
In 2025, interest in this question has intensified. New umbrella reviews and cardiovascular-focused analyses suggest that PDE5 inhibitors may have modest but measurable effects on vascular function, inflammation markers, and even glycemic indices in selected populations. Still, enthusiasm is tempered by the fact that most evidence comes from mechanistic studies or secondary analyses, not from randomized controlled trials (RCTs) designed to evaluate major cardiovascular endpoints. For patients with ED, a condition often sharing risk factors with cardiovascular disease (CVD) such as diabetes, hypertension, and metabolic syndrome, understanding these findings is more than an academic exercise. It can inform shared decision-making, guide cardiovascular screening before starting therapy, and shape realistic expectations about potential “added” benefits beyond erectile improvement.
This article examines the current 2025 evidence on tadalafil’s endothelial, cardiovascular, and metabolic effects, integrating findings from large-scale reviews, observational studies, and guideline recommendations. The goal is to present a clear, clinically grounded synthesis that balances potential opportunities with known limitations.
Endothelial Function: What We Know
One of the most consistent mechanistic findings with PDE5 inhibitors, including tadalafil, is their ability to enhance nitric oxide–mediated vasodilation through sustained increases in intracellular cGMP. This mechanism not only supports penile erection but also influences systemic vascular tone and microcirculatory health.
Several randomized and crossover studies have investigated tadalafil’s effect on endothelial function, often measured by flow-mediated dilation (FMD) of the brachial artery. Results generally show small but statistically significant improvements in FMD after both acute dosing and short-term daily administration, particularly in men with ED and coexisting cardiovascular risk factors. Data compiled in the 2025 cardiovascular review in the Journal of the Chinese Medical Association suggest that these effects may be more pronounced in patients with metabolic syndrome or early-stage atherosclerosis. Potential mechanisms include reduced oxidative stress, improved endothelial nitric oxide synthase (eNOS) activity, and decreased vascular inflammation.
However, findings are not entirely uniform. Some trials in healthy subjects or in patients with advanced vascular disease report minimal or no change in endothelial biomarkers. This variability may reflect differences in study duration, tadalafil dose, and baseline vascular health.
While the link between improved FMD and reduced long-term cardiovascular events remains indirect, these data provide a biologically plausible basis for tadalafil’s potential role in broader vascular health – one that requires further testing in endpoint-driven RCTs.
Observational Signals on CV Events & Mortality (Limits)
Beyond mechanistic studies, several observational cohorts and registry analyses have reported associations between PDE5 inhibitor use and lower rates of major adverse cardiovascular events (MACE) or mortality in men with established cardiovascular risk, for example, post–myocardial infarction populations or men with diabetes and ED. Some datasets suggest fewer hospitalizations for heart failure and improved survival among regular PDE5i users compared with non-users, and umbrella/meta-reviews have floated a possible class effect rather than a molecule-specific one.
However, these signals must be interpreted with caution. Observational designs are vulnerable to multiple biases:
- Confounding by indication and health status: Men prescribed PDE5i are typically healthy enough for sexual activity, more engaged with care, and may differ in socioeconomic status, adherence, and risk-factor control.
- Healthy user and activity bias: Sexual activity itself correlates with better functional capacity; thus, PDE5i exposure may simply mark lower baseline risk.
- Residual confounding and misclassification: Over-the-counter use, prescription fills without ingestion, and incomplete capture of lifestyle factors can distort estimates.
- Time-related biases: Immortal time and prevalent user bias can falsely favor the exposed group if entry times and follow-up are not handled rigorously.
Crucially, no large randomized controlled trial has been powered with MACE or mortality as the primary endpoint for tadalafil or other PDE5 inhibitors. As a result, current evidence supports hypothesis generation, not causal claims. The prudent clinical takeaway is that PDE5i therapy — when used according to cardiovascular safety frameworks (e.g., Princeton IV) and without nitrates/riociguat — appears cardiovascularly safe in stable patients, but cardioprotective benefit remains unproven.
Well-designed, endpoint-driven RCTs (or advanced causal inference studies with robust adjustment and active comparators) are needed to determine whether the observed associations translate into true risk reduction.
Glycemic Indices and Long-Half-Life PDE5i
A growing body of research has examined whether long-acting PDE5 inhibitors, particularly tadalafil, influence glycemic control in men with type 2 diabetes or metabolic syndrome. Mechanistically, sustained PDE5 inhibition raises cGMP signaling, which can enhance skeletal-muscle perfusion, reduce endothelial inflammation, and potentially improve insulin-mediated glucose uptake. These vascular and microcirculatory effects provide a biologically plausible pathway for modest metabolic benefits. Quantitatively, pooled analyses generally report small improvements in markers such as HbA1c (on the order of a few tenths of a percentage point), fasting plasma glucose, and HOMA-IR after weeks to months of regular PDE5i exposure. Effects tend to be more apparent in studies using daily or near-daily tadalafil, consistent with its ~17–18-hour half-life and steadier pharmacokinetic profile compared with shorter-acting agents. Importantly, signal strength varies: trials with tighter background management of diabetes often show attenuated or null effects, suggesting any glycemic change from PDE5i is adjunctive at best.
Clinical interpretation should therefore be cautious. PDE5 inhibitors are not antidiabetic drugs, and observed shifts in HbA1c are typically below thresholds used to guide diabetes therapy changes. Heterogeneity in study design (dose, duration, baseline control), population (diabetes vs. metabolic syndrome vs. high-risk ED), and endpoints limits firm conclusions.
The pragmatic takeaway: in men with ED and cardiometabolic risk, daily tadalafil may confer modest improvements in glycemic indices while addressing sexual function; however, standard diabetes management remains primary, and expectations should be set accordingly.
Practical Takeaways for ED Patients with CV Risk
For men with erectile dysfunction and cardiovascular risk factors, the first priority remains thorough cardiovascular assessment before starting any PDE5 inhibitor. Frameworks like Princeton IV recommend stratifying patients by exercise tolerance and stability of heart disease, ensuring they are safe for sexual activity.
When prescribed appropriately, tadalafil appears cardiovascularly safe in stable patients, provided that nitrates or riociguat are strictly avoided. Its long half-life allows flexible dosing and may offer ancillary benefits such as improved endothelial function and modest glycemic changes, but these are secondary advantages, not primary treatment goals. Patients should be counseled on realistic expectations: current evidence does not prove tadalafil prevents heart attacks or extends life, despite encouraging observational signals. Monitoring should include blood pressure, symptom tracking, and periodic review of cardiovascular status.
Ultimately, tadalafil can be an effective part of a holistic strategy for men with ED and cardiometabolic risk, but only when combined with optimal lifestyle, medication adherence, and multidisciplinary follow-up.
References
European Association of Urology. (2024). EAU Guidelines: Sexual and reproductive health – Management of erectile dysfunction. Retrieved August 13, 2025, from https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/management-of-erectile-dysfunction
Liu, S., Chen, J., & Lee, Y. (2025). Potential beneficial impacts of tadalafil on cardiovascular health: A narrative review. Journal of the Chinese Medical Association, 88(4), 281–288. https://journals.lww.com/jcma/fulltext/2025/04000/potential_beneficial_impacts_of_tadalafil_on.1.aspx
Severino, P., D’Amato, A., Pucci, M., Infusino, F., Adamo, F., & Palmirotta, R. (2024). Phosphodiesterase type 5 inhibitors and cardiovascular outcomes: An umbrella review of systematic reviews and meta-analyses. Frontiers in Cardiovascular Medicine, 11, 11323371. https://pmc.ncbi.nlm.nih.gov/articles/PMC11323371/
Kostis, J. B., Jackson, G., Rosen, R., Barrett-Connor, E., Billups, K. L., Burnett, A. L., Cheitlin, M. D., & Miner, M. (2024). Sexual dysfunction and cardiac risk (The Princeton IV Consensus). The Journal of Sexual Medicine, 21(2), 90–110. https://academic.oup.com/jsm/article/21/2/90/7499332
