In the 1990s, the Pfizer cardiovascular (CV) research group in the UK was looking for new drugs to treat cardiovascular disease. This group had already scored some major successes in this area most notably with Norvasc (amlodipine) which became the premier calcium channel blocker for the treatment of hypertension. In the course of their work, the UK scientists explored blockade of a specific enzyme, phosphodiesterase-5 (PDE-5). Their early work demonstrated that blocking PDE-5 in animals enhanced blood flow to a variety of organs and that an inhibitor of PDE-5 could be of value in treating CV conditions such as angina and heart failure.
The team was able to find a novel, potent PDE-5 inhibitor, UK-92,480, and they rapidly advanced this compound to the clinic. The initial trials in volunteers were disappointing. UK-92,480 had a minimal acute impact on important CV parameters such as blood pressure, heart rate, cardiac output and blood flow. The program was almost discontinued – not a rare occurrence. A promising hypothesis can initially be exciting but then fails when actually tested with a compound in humans. However, in this case an important observation was made in male volunteers who were dosed with 50mg of UK-92,480 daily over a week. They were getting more erections – a finding that wasn’t far-fetched. UK-92,480 was designed as a drug to enhance blood flow. However, the enhanced blood flow was occurring in a different organ than had been anticipated – the penis. Suddenly, the prospects for UK-92,480 changed dramatically. It had the potential to be the first oral drug to treat erectile dysfunction (ED).
The rest of the story is well known. Pfizer began a major development program for sildenafil, the generic name given to UK-92,480. In many ways, this was uncharted territory. No one had developed an oral drug to treat ED. Pfizer consulted with the FDA to put together a plan to demonstrate the safety and efficacy of sildenafil. For example, working with the FDA, Pfizer developed the “International Index of Erectile Function”, a tool that has become the gold standard for evaluating ED drugs. Pfizer went on to conduct clinical trials involving thousands of patients and the drug was, in fact, safe and effective. On March 27, 1998, sildenafil was approved by the FDA for the treatment of ED. This drug was trademarked by Pfizer as Viagra and was sold as the now famous diamond-shaped blue pill.
While the focus of Viagra (sildenafil) was on ED, it turns out that this drug was also found to be useful in treating a lung disease – pulmonary arterial hypertension (PAH). In PAH, the arteries of the lung are constricted and the heart has to work harder to pump blood through the lungs. This increased work can eventually lead to heart failure. Since PDE-5 is found throughout the pulmonary vasculature and, given that sildenafil blocks this enzyme, it was thought that it could also be used to treat PAH. Sure enough, clinical trials showed that this PDE-5 inhibitor improved exercise capacity, functional capacity and hemodynamics in PAH patients, leading to a second FDA approval for sildenafil for this condition. For PAH, sildenafil is sold under the trademark Revatio.
Over the years scientists have speculated that PDE-5 inhibitors (PDE-5is) like sildenafil could have long-term benefits in treating CV disease – the original motivation for the Pfizer scientists to begin this research. Now, a new study from the University of Southern California (USC) provides evidence that this could indeed be the case. The USC investigators sought to determine whether PDE-5is reduce the incidence of major adverse cardiovascular events (MACE) defined as CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure and unstable angina. They carried out a retrospective observational cohort study in a large US claims database in men with one or more diagnoses of ED without prior MACE within one year from January 1, 2006 to October 31, 2020. The analysis compared 23,816 men who had been exposed to PDE-5is vs. 48,682 men with no exposure to PDE-5is. Their average age was 52.