Examining shared pathways of cardiovascular disease and erectile dysfunction

By Naveed Saleh, MD, MS | Medically reviewed by Yasmine S. Ali, MD, MSCI, FACC, FACP

Published March 14, 2024

Key Takeaways

PDE5 inhibitors are commonly used in patients with cardiovascular disease (CVD).
PDE5 inhibitors may curb the risk of CVD in patients with diabetes, although such benefits have not been consistently demonstrated in those with congestive heart failure, myocardial infarction, or ventricular arrhythmia.
The use of PDE5 inhibitors in patients taking nitrates raises concerns among experts and is still considered a contraindication, despite limited evidence of no increased CVD risk in patients co-administered both drugs.

Cardiovascular disease (CVD) and erectile dysfunction (ED) share many common underpinnings, likely due to endothelial dysfunction present in both pathologies. In fact, phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil (Viagra) and tadalafil (Cialis), were originally administered to investigate their treatment potential for hypertension and angina.^[]

The unexpected (and, at the time, revolutionary) side effect of causing the erection of the penis is primarily why millions of patients today are prescribed PDE5 inhibitors. However, many patients with heart disease are also prescribed PDE5 inhibitors, given their efficacy in managing pulmonary hypertension and reducing mortality following major cardiovascular events, among other uses.

Although preclinical studies examining the impact of PDE5 inhibitors on ischemia-reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity have indicated a clinical role of this class of drugs, such findings did not always translate to the bedside. The use of PDE5 inhibitors in patients with heart disease is thus an area of active interest that requires further exploration.

PDE5 inhibitors and the heart

Authors of a review article in Cardiovascular Drugs and Therapy write that “chronic administration of PDE5 inhibitors has shown promising results in reducing adverse cardiac outcomes, especially in those with underlying risk factors such as diabetes. However, these findings have not translated consistently as treatment for patients with congestive heart failure, myocardial infarction, or ventricular arrhythmia.”^[] They note that reports convincingly showing that PDE5 inhibitors have potential as cardiovascular therapy are still infrequent.

One trial suggested that PDE5 inhibition decreases the risk of overall mortality in patients with diabetes who had a history of myocardial infarction. A non-randomized trial showed that PDE5 inhibitors could decrease the risk of major adverse cardiac events (MACE) in patients with coronary artery disease, diabetes, and ED.

Such studies, however, had methodological limitations and lacked specifics on PDE5 use in the relevant study samples.

Various preclinical and clinical studies have examined the effects of PDE5 inhibitors on the arterial endothelium, which is damaged by hyperglycemia.

“Based on a possible link between painful neuropathy and insufficient NO synthesis under diabetic conditions, PDE5 inhibitors have been tested for prevention of diabetic neuropathy and vasculopathy,” write authors in Pharmacology & Therapeutics.^[]

The authors cited a clinical study demonstrating improvements in flow-mediated dilation (FMD), which is representative of NO-mediated endothelial function, with chronic and daily administration of 25 mg sildenafil in patients with type 2 diabetes (T2D).

Interestingly, similar studies have shown that PDE5 inhibitors decrease albuminuria and glycated hemoglobin levels as well, possibly promoting further clinical benefit.

In summarizing, the authors write that “chronic daily sildenafil or tadalafil treatment could exert prolonged beneficial effects on endothelial dysfunction in patients with T2D and such a benefit of chronic tadalafil dosing may last for more than 2 weeks after the discontinuation of treatment.”

There may be several reasons why preclinical research findings do not translate to clinical use. As mentioned in Cardiovascular Drugs and Therapy, this could be related to the in-vitro PDE5 inhibitor dosages being used and the relevance of the animal models. Translating the ischemia-reperfusion animal model presents some known challenges. In addition, the studies may represent variable use of different PDE5 inhibitors, which can have differences in their respective pharmacokinetics.

It’s also possible that the reportedly limited effect of PDE5 inhibitors on the endovascular system may be partially due to conflicting data from clinical studies involving patients with heart disease who expressed a varying degree of upregulated PDE5.

On the other hand, Princeton Consensus Guidelines point to evidence that PDE5 inhibitors are cardioprotective. Recent retrospective reports indicate lower MACE, CV death, and overall mortality risk, as determined by levels of inhibitor exposure.^[]

PDE5 inhibitors for pulmonary arterial hypertension

A mechanism by which PDE5 inhibitors effectively treat pulmonary hypertension is by preservation of cyclic guanosine monophosphate in the nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling pathway. This action results in vasodilation.

As explained by authors of a meta-analysis published in Cureus, the aim of using PDE5 inhibitors in patients with pulmonary hypertension is to promote exercise tolerance and good quality of life, and to decrease the risk of death.^[] This treatment is also meant to maintain right ventricular function by using supplemental oxygen and targeting the etiology.

Nitric oxide mediates vascular tone regulation and blocks nitric oxide synthase, resulting in less vasoconstriction in patients with heart failure vs those with normal pulmonary vascular resistance.

The meta-analysis indicated that PDE5 inhibitors improved peripheral arterial pressure, 6-minute walking distance, and cardiac index in patients with pulmonary hypertension.

The problem with nitrates

The American Heart Association recommends that PDE5 inhibitors not be given in conjunction with nitrates, unless the nitrates were taken at least 24 hours prior to the use of fast-acting PDE5 inhibitors and 48 hours before the use of slow-acting PDE5 inhibitors.^[]

Nevertheless, results of at least two studies suggest that nitrate use doesn’t lead to adverse cardiac events in individuals using PDE5 inhibitors.

In a retrospective study (n=3167), patients for whom there was prescription data for both PDE5 inhibitors and nitrates experienced no increase in hypotension or CV adverse outcomes vs patients with a prescription for nitrates alone.

In the study, only 27% of patients with accurate documentation (n=252) were warned of the risks of co-administration.

Danish researchers published the results of a population-based study conducted between 2000 and 2018.^[] The use of PDE5 inhibitors increased 20-fold among patients with ischemic heart disease who were taking nitrates, but no significant association between the use of these medications and CV adverse events could be identified.

A commentary on this study from the American College of Cardiology notes that there is little data to support the American Heart Association guideline, “but the results of the study may reflect the patient withholding the long-acting nitrate on the morning of or day prior to using the PDE5 inhibitor.”

The commentary added: “There are data accumulating that suggest use of PDE5 inhibitors may reduce CV event rates in [ischemic heart disease]. It is time for a randomized clinical trial.”

OTC use

The Princeton Consensus Guidelines identify the use of PDE5 inhibitors as an absolute contraindication in patients taking nitrates.

Accordingly, they warn that if PDE5 inhibitors were to become available OTC, the coadministration of these drugs could result in adverse CV events, despite any warnings, labeling, or other safeguards put in place. Moreover, younger, recreational users may abuse PDE5 inhibitors and experience adverse events.

Further market research is needed to determine whether making PDE5 inhibitors OTC would sate the desire of consumers for effective ED treatments and thereby dissuade them from seeking sexual performance-enhancing dietary supplements, some of which may pose the danger of containing undeclared PDE5 inhibitors.

Prescribing PDE5 inhibitors

According to the Princeton Consensus Guidelines, managing patients with ED begins with taking a patient history. Once ED is verified and the patient requests treatment, they must be classified as low risk, intermediate or indeterminable risk, or high risk of developing a cardiac event associated with sexual activity. This risk is based on the patient’s exercise ability and may require a stress test. If the patient has good exercise tolerance without evidence of ischemia, is low risk, and is not taking nitrates (or riociguat), then treatment with PDE5 inhibitors can be initiated. If the patient is taking nitrates or riociguat, then the use of PDE5 inhibitors is contraindicated.

During the most recent Princeton Consensus Conference in 2023, experts recognized that many patients may be prescribed nitrates but neither use them nor need them (eg, if they have undergone revascularization by percutaneous coronary intervention or coronary artery bypass surgery and are free of angina or evidence of myocardial ischemia).

Advice to the HCP was as follows:

“A decision should be made by the HCPs whether nitrates are necessary or whether they may be stopped, or whether other antianginal agents may be substituted. If nitrates are not necessary, then consideration should be given to stopping them and trying PDE5 inhibitors to treat ED, a new concept added since [the third Princeton Consensus Conference]. However, if it is deemed that nitrates are indeed necessary, then other non PDE5 inhibitors should be considered to treat ED. Patients who are deemed high risk for cardiac events with sexual activity or who develop ischemia during a stress test, especially at a low level of exercise, should be referred to a cardiologist for additional care.”

What this means for you

Cardiologists should carefully evaluate their patients with ED. Patients with good exercise tolerance and no evidence of ischemia, who are at low risk of cardiac events with sexual activity, and who are not taking nitrates (or riociguat) are safe candidates for PDE5 inhibitors.