PDE5 Inhibitors (Viagra, Cialis) Show Promise in Reducing Heart Disease Risk: New Study

In recent years, the treatment of erectile dysfunction (ED) has undergone a significant transformation with the use of oral phosphodiesterase type 5 inhibitors (PDE-5is). These medications, known for their efficacy in managing ED, have also shown promise in benefiting cardiovascular health Erectile dysfunction (ED) and cardiovascular disease (CVD) are common conditions, often sharing overlapping risk factors and pathophysiology. PDE5 inhibitors (PDE5i) are the first-line medication for ED, but concerns exist regarding their interaction with nitrates used for CVD treatment. This summary delves into the complex relationship between PDE5i, ED, and CVD, exploring potential benefits and risks in men with both conditions.

• Vascular Impact: PDE-5 inhibitors extend beyond local vasodilation, improving overall endothelial function throughout the vascular system by enhancing nitric oxide (NO)-mediated vasodilation. This has sparked interest in their role in cardiovascular health, particularly for those with risk factors like type 2 diabetes (T2DM) and coronary artery disease (CAD).

• Reducing Cardiac Risk: Studies focusing on men with T2DM or CAD have shown a positive link between chronic PDE-5i use and a decrease in acute myocardial infarction rates.

• Major Findings: A retrospective observational study in a large US claims database revealed significant benefits of PDE-5 inhibitors in men with ED, including a 13% reduction in major adverse cardiovascular events (MACE), a 25% decrease in total mortality, and an impressive 39% drop in cardiovascular mortality.

• Reductions in MACE: These benefits were primarily seen in specific cardiovascular conditions, such as coronary revascularisation, heart failure, unstable angina, and cardiovascular mortality, extending even to men with CAD risk factors.

• Strengths and Future Prospects: The study underscores the need for well-designed, prospective randomized trials to solidify these findings. Future research might explore the broader impact of PDE-5is on cardiovascular health in a wider population.

• Limitations: The study's retrospective nature and potential confounding variables raise the need for further research to establish causation and address potential biases.

PDE-5 Inhibitors and Systemic Vasodilation

The systemic influence of PDE-5 inhibition is nothing short of remarkable, as it enhances NO-mediated vasodilation and overall endothelial function. This phenomenon is not confined to the genitalia but extends to the vasculature of all body systems. It's an eye-opening revelation that patients with conditions linked to endothelial dysfunction, including coronary artery disease (CAD) and risk factors for atherosclerosis such as type 2 diabetes mellitus (T2DM), may reap the benefits of PDE-5i therapy. This revelation has spurred a closer examination of PDE-5is' potential role in cardiovascular health.

Understanding the Link between PDE5 Inhibitors and Cardiovascular Health

Numerous studies have delved into the relationship between chronic PDE-5i use and the reduction of cardiac risk. These studies have primarily focused on men with T2DM or known CAD, shedding light on the potential of PDE-5is to mitigate cardiovascular events. Notably, the rate of hospitalization for acute myocardial infarction has shown a steady decline over the past two decades. In the context of evolving therapies with cardioprotective effects, it becomes imperative to assess the recent and widespread population of men with ED to understand the effects of chronic PDE-5i use on their cardiovascular health.

Co-possession of PDE5i and nitrates: While co-exposure to PDE5i and nitrates can lead to potentially dangerous hypotension, studies suggest co-possession of these medications may not necessarily translate to increased cardiovascular risk. A large real-world study found no significant difference in cardiovascular outcomes between men with ED taking both compared to those taking nitrates alone. However, co-use remains generally contraindicated due to the potential for severe adverse events.

PDE5i and cardiovascular implications: Research reveals several promising aspects of PDE5i beyond treating ED. Studies suggest these medications:

• Improved endothelial function: Endothelial dysfunction plays a crucial role in both ED and CVD. PDE5i may improve endothelial function, potentially benefiting cardiovascular health.

• Decrease cardiovascular events: In men with a history of myocardial infarction, PDE5i treatment seems to reduce the risk of future cardiovascular events. This suggests a potential protective effect against CVD progression.

• Increase treatment adherence: In patients with ED and concomitant CVD, PDE5i may improve adherence to CVD treatment regimens, potentially slowing disease progression.

• Reduced Afterload: PDE-5is may reduce the afterload on the heart, which can result in less oxygen demand and potentially protect the heart during ischemic events.

• Arterial Stiffness Reduction: It's suggested that PDE-5is may reduce arterial stiffness, contributing to overall cardiovascular health.

• Antiplatelet Effects: Some research points to the potential antiplatelet effects of PDE-5is, which could reduce the risk of clot-related cardiovascular events.

Prescriber rationales and managing co-possession: Despite the contraindication, some cases warrant careful co-prescription of PDE5i and nitrates. Physicians often engage in detailed discussions with patients regarding the risks and potential benefits of co-use in specific situations. A qualitative analysis of patient records revealed that, in many cases, physicians warned patients about the risks and provided instructions on safely managing the potential interaction.

Scientific Validation

A study published in the Journal of Sexual Medicine investigated whether co-prescribing PDE5i (medication for erectile dysfunction) and nitrates (medication for heart conditions) in men increases cardiovascular risks. (2)

Key findings:

• Co-possession of medications (having both prescriptions) seems not to increase cardiovascular risks compared to having only nitrates.

• Physicians often discuss the risks of co-using these medications with their patients.

• It's still recommended to avoid co-exposure of PDE5i and nitrates due to potential hypotension, but co-possession might be manageable in specific situations.

Limitations:

• The study looked at prescription records, not actual medication use.

• Retrospective analysis so causality cannot be confirmed.

Overall, this study suggests that co-possession of PDE5i and nitrates may not be as dangerous as previously thought, but caution and careful management are still necessary. More research is needed to fully understand the risks and benefits of co-use in different patient groups.

The primary objective of another comprehensive study published in the Journal of Sexual Medicine was to investigate the effect of PDE-5i exposure on the incidence of major adverse cardiovascular events (MACE) and overall mortality in men with ED, encompassing relevant subpopulations. (3)

This study adopted a retrospective observational cohort design, utilizing patient data from an extensive medical and pharmacy claims database. Male patients aged 18 or older with at least one diagnosis of ED between January 1, 2006, and October 31, 2020, were identified. The exposed group comprised men who filled one or more prescriptions for approved PDE-5is (sildenafil, vardenafil, tadalafil, or avanafil) following their ED diagnosis within the patient identification period (from January 1, 2007, to October 31, 2020). Importantly, this group had no PDE-5i claims in the baseline period (12 months preceding the index date), with the first claim date of PDE-5i serving as their index date.

Reductions in MACE and Mortality

The reductions in MACE observed in the study were primarily driven by decreases in specific cardiovascular conditions, including coronary revascularization, heart failure, unstable angina, and cardiovascular mortality. Notably, these benefits were also extended to men without known coronary artery disease (CAD) but with risk factors for CAD. In the main study cohort, it was observed that men with the highest quartile of PDE-5i exposure enjoyed even greater reductions in MACE, with a staggering 55% lower incidence as well as a 49% reduction in overall mortality compared to the lowest quartile of PDE-5i use. The most extensive exposures to PDE-5is were also associated with significantly greater reductions in myocardial infarction and stroke compared to lower exposures. However, in subgroups of men with ED and type 2 diabetes (T2DM) or known CAD, the study found mixed results. While there was a lower incidence of MACE in the T2DM subgroup, no significant reduction in MACE was observed in men with known CAD. It's important to note that the sample sizes for these subgroups were relatively limited compared to the main study population.

Strengths of the Current Study

The strength of this study lies in its ability to confirm and extend the findings of recent studies that investigated the effects of PDE-5is in various subpopulations of men with ED. These subpopulations included those with T2DM, known CAD, and even rheumatoid arthritis., Furthermore, the study expands upon previous research by demonstrating that the benefits of PDE-5 extend to a large, general population of men with ED in the United States. The associations between PDE-5is and reduced MACE and mortality were shown to persist long-term. Kaplan-Meier curves suggest a widening gap in outcomes between exposed and unexposed groups over time. The results also indicated a dose-response effect, with the highest exposure levels of PDE-5 associated with the most substantial reductions in MACE and mortality. This dose-response observation aligns with previous research on men with known CAD. The findings are consistent with studies that have shown the safety of combining PDE-5is with antihypertensive medications. Notably, there was no increase in cardiovascular events when patients received both PDE-5is and nitrates. In conclusion, this study highlights the potential cardioprotective effects of PDE-5 inhibitors in men with ED and, by extension, men with cardiovascular risk factors. The reductions in MACE and mortality are noteworthy and underscore the need for further research. A prospective, randomized, placebo-controlled trial could provide more conclusive evidence regarding the benefits of PDE-5is in this context.

Key Points:

1. PDE5i may benefit cardiovascular health: Beyond treating ED, PDE5 inhibitors like sildenafil (Viagra) may improve endothelial function, reduce cardiovascular events, and even protect against heart damage.

2. Reduced MACE and mortality in the large study: A study of men with ED found those taking PDE5is had lower rates of major adverse cardiovascular events (MACE) and overall mortality compared to those who didn't.

3. Benefits extended to high-risk groups: Men with ED and risk factors like diabetes or coronary artery disease also saw reductions in MACE with PDE5i use.

4. The dose-response effect observed: Higher doses of PDE5i were associated with even greater reductions in MACE and mortality, suggesting a potential dose-dependent benefit.

5. More research needed: While promising, these findings are based on observational studies. Future randomized controlled trials are crucial to confirm the cardiovascular benefits of PDE5i.

Conclusion:

The relationship between PDE5i, ED, and CVD is complex and multifaceted. While co-exposure of PDE5i and nitrates should be avoided, co-possession of these medications may not necessarily increase cardiovascular risk in carefully managed situations. PDE5i may even offer some potential benefits for cardiovascular health in specific populations. Further research is crucial to provide definitive answers and guide clinical practice in this complex area.

Reference Articles

1 .Maas, R, Rodionov, R. Phosphodiesterase-5 Inhibitors and Survival in Men With Coronary Artery Disease∗. J Am Coll Cardiol. 2021 Mar, 77 (12) 1551–1553. https://doi.org/10.1016/j.jacc.2021.02.021

2.Nunes, A. P., Seeger, J. D., Stewart, A., Gupta, A., & McGraw, T. (2021). Cardiovascular Outcome Risks in Patients With Erectile Dysfunction Co-Prescribed a Phosphodiesterase Type 5 Inhibitor (PDE5i) and a Nitrate: A Retrospective Observational Study Using Electronic Health Record Data in the United States. The journal of sexual medicine, 18(9), 1511–1523.https://doi.org/10.1016/j.jsxm.2021.06.010

3 .Robert A Kloner, Eric Stanek, Christopher L Crowe, Mukul Singhal, Rebecca S Pepe, Julia Bradsher, Raymond C Rosen, Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data, The Journal of Sexual Medicine, Volume 20, Issue 1, January 2023, Pages 38–48, https://doi.org/10.1093/jsxmed/qdac005

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