New life for old heart drug

A decades-old lipid-lowering drug withdrawn from use in the West may have been abandoned for the wrong reasons, according to a new study that included clinicians at the Translational Research Center for Medical Innovation (TRI)¹.

Originally developed as an antioxidant compound to prevent the degradation of tire rubber, probucol was soon found to have potent cholesterol-lowering potential.

However, in addition to reducing blood levels of low-density lipoprotein cholesterol (LDL-C), commonly perceived to be ‘bad’ cholesterol, probucol also reduced its ‘good’ counterpart, high-density lipoprotein cholesterol (HDL-C). In some patients, it also increased the QT interval, a feature of the heart’s electrical signals, an increase of which has been associated with dangerous arrhythmia in patients.

So when statins, which neither impact good cholesterol levels nor heart beats, hit the market in the late 1980s, many of the world’s lipidologists and cardiologists turned away from probucol.

But Professor Shizuya Yamashita, head of the Laboratory of Cardiovascular Lipidology and Atherosclerosis at Osaka University Graduate School of Medicine and director of the Rinku General Medical Center in Osaka, considered that it was important to gather more evidence on the drug’s efficacy. With support from several pharmaceutical companies, he has sought over many years to better understand probucol’s cholesterol-lowering power.

In his latest study, Yamashita, with colleagues from the TRI and elsewhere across Japan, tracked the fate of nearly 900 individuals with coronary heart disease and high levels of dangerous LDL cholesterol. All the trial participants received statins or some other conventional lipid-lowering agents, while half additionally received probucol.

After more than 3 years, the difference between the numbers of patients in the two groups who experienced some kind of blood vessel–related complications was not large enough to be statistically significant. Meanwhile, both good and bad cholesterols were significantly reduced in the probucol group. And while the QT interval increased, there was no difference in the reported incidences of arrhythmia. “Therefore, QT prolongation by probucol may not enhance the occurrence of lethal ventricular arrhythmias,” the authors wrote, and “the reduction of serum HDL-C by probucol may not be harmful.”

Yamashita believes that these findings warrant further investigation in a trial involving a larger number of patients and that large randomized controlled trials are needed to demonstrate the merits of probucol treatment in combination with other lipid-lowering medicines in treating heart disease. But given the totality of the evidence gathered to date, “we strongly believe that the clinicians in Western countries abandoned probucol too soon,” he says.

1.  Yamashita, S. et al. Probucol trial for secondary prevention of atherosclerotic events in patients with coronary heart disease (PROSPECTIVE). Journal of Atherosclerosis and Thrombosis, advance online publication, 24 April 2020| article