In theory, this is a great idea. After all, cholesterol comes from 2 sources, why not create a drug that affects them both? This is exactly what Merck and Schering-Plough did in a joint venture using drugs that each company still had under patent.
Having created this drug, the pharmaceutical companies had to get the approval of the FDA to market it. Otherwise, they could not have aired those memorable ads. To earn FDA approval, a drug company has to provide data from a clinical trial showing the drug’s effectiveness. Vytorin was approved based on its ability to lower blood levels of LDL, the "bad cholesterol" that is associated with heart attacks and strokes. After FDA approval, the company launched another study called the ENHANCE study. This study was designed to show an effect on atherosclerosis ("hardening of the arteries"). It lasted just 2 years and enrolled 720 patients with a genetic disorder (familial hypercholesterolemia) that causes high cholesterol levels and heart attacks and strokes at a very young age. The study showed that Vytorin lowers cholesterol levels in these patients, but it did not detect a decrease in heart attacks or strokes.
Importantly, the study did not show that Vytorin was any better than Simvastatin alone.
There have been 2 drug company-sponsored trials since then: the SEAS trial (SEAS stands for Simvastatin and Ezetimibe in Aortic Stenosis) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial. Both studies were designed to test whether Vytorin reduces the risk of heart attacks and strokes better than Simvastatin alone. The results of the SEAS trial were released this week (The IMPROVE-IT trial is still ongoing). In a disappointment for the drug companies, Vytorin did not decrease the risk of progression of aortic stenosis (a narrowing of the valve leading from the heart into the aorta, the major artery that drains the heart) or on cardiovascular events in general.
Surprisingly, the patients taking Vytorin had an increased risk of cancer compared with patients taking a placebo.
What’s going on here? Does this new heart medicine not only not work, but also cause cancer?
The answer is probably not that simple.
When the data from all 3 trials are combined, there is no increase in the incidence of cancer in patients who take Vytorin. However, there was an increased risk of dying from cancer.
How could this happen?
Well, one possibility is that this is just a coincidence. The studies were not designed to detect a risk of getting or dying from cancer. So maybe it was a statistical fluke.
But it could be real. An editorial in the New England Journal accompanying the articles warns about this possibility. Ezetimibe inhibits the absorption of plant sterols from the diet, not just cholesterol. Epidemiologic studies have linked diets high in plant sterols to a lower incidence of cancer. Laboratory animals (mice and rats) fed a diet high in plant sterols show modest resistance to chemical carcinogens and to tumors grown from injected human cancer cells. Plant sterols have a number of inhibitory effects on human cancer cells grown in the lab. These findings could provide the basis for a plausible biological explanation for the results in the SEAS study.
I wrote this piece for two main reasons: one reason is that I think this case (and the fiasco surrounding Vioxx) is an important reminder not to be so eager to take a new drug just because it’s new and has a cute ad. FDA approval is no guarantee that a drug is safe, and some relatively rare but certainly very significant side effects only become noticed during what is called post-marketing surveillance. The other reason is as a teaser for my upcoming, first ever book review: Reasonable Rx: Solving the Drug Price Crisis, by Finkelstein and Temin.
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This topic was also covered extensively by one of my friends in another blog. Read her posts here and here.