Recently, there have been some question as to whether or not Vytorin is effective in reducing the risk of cholesterol-related heart disease. Now, another concern has been raised that Vytorin can increase the risk of getting cancer.
This week the New England Journal of Medicine has published two research papers and an editorial that provide the first detailed glimpse into the controversy. Unfortunately, the evidence isn’t sufficient in my opinion to provide a clear yes or no answer as to whether the increased risk of cancer is real.
Vytorin is a drug that has been widely advertised to reduce cholesterol. If you are like me, you have seen hundreds of these advertisements. The drug itself is actually a combination of two medicines. One, simvistatin, is a widely used typical cholesterol lowering medicine that has been around for years. The other drug in the combo is ezetimibe which works through a different mechanism to lower cholesterol. Its use has not been as long or as widespread. Through the rest of this blog I will simply refer to the drugs by their trade name Vytorin.
We have substantial experience with simvistatin and have no evidence that it increases the risk of cancer. As noted, we simply don’t have as much experience with the other drug component of Vytorin although there has been no evidence reported to date of an increased cancer risk.
The first NEJM article was a report of a study called “SEAS” that looked at whether or not Vytorin decreased the risk of serious progression of stenosis (or thickening) of the aortic valve, which is located on the left side of the heart. When aortic stenosis becomes severe it can lead to congestive heart failure and increase the risk of death. Treatment in its advanced stages requires surgery.
I am not going to get into details about the science behind the trial, other than to say that some of the same factors that increase the risk of coronary artery disease may also be associated with an increased risk of aortic stenosis. The theory was that if you reverse those factors you may be able to reduce the severity and progression of aortic stenosis.
Bottom line, in a clinical trial conducted in Europe in 1873 patients, there was no real benefit found relative to reducing the progression and impact of aortic stenosis. I should note that the people who participated in the trial were not usual “high cholesterol” candidates that would usually be treated with Vytorin.
Median patient follow-up in this trial was about 52 months. That means half the patients were followed for less than that period of time, and half longer than 52 months.
Although Vytorin didn’t improve the course of aortic stenosis, the investigators did find that there was a significant increased risk of developing cancer for those taking Vytorin. 105 patients treated with Vytorin were diagnosed with cancer after starting the medicine, compared to 70 patients in the placebo or untreated arm of the study. That’s an increased risk of about 50%, which is certainly substantial and a cause for concern.
There was no specific cancer that had an increased rate compared to other cancers. The numbers of cancers were distributed basically across the board among many different types.
As to cancer deaths, there was an increase in the risk of death from cancer in the Vytorin treated group, but this difference was not significant (although it did approach what we call statistical significance). In looking at the number of deaths, the curves did not begin to separate until about three years after starting Vytorin. That means that the cancers in the Vytorin treated group started pretty quickly after patients started taking the drug.
As a result of these findings, a group of highly regarded researchers were asked to take a look at the issue. Those researchers were then given access to information from two other ongoing clinical trials of Vytorin. Their objective was to find out whether the same increase in cancer was seen in these other two trials.
The report of that research was the second article in the NEJM. The scientists pointed out that when you have many clinical trials you inevitably will get a result that raises concerns but ultimately on further investigation turns out to be a false alarm.
When the researchers looked at all the data from the additional trials, they found no evidence of an increased incidence of cancer. But they didn’t stop there.
They pointed out that when something causes cancer it “would be expected to produce an increasing relative risk over time.” In simpler terms, the longer the exposure to the drug, the more the risk would increase. No such trend was seen in the Vytorin trials.
They also noted that about half of the increased risk of cancer in the original SEAS trial was seen within two years after the participants started Vytorin. And, after three years of taking Vytorin, there was in fact no increased incidence of cancer from that point onwards. That was clearly not the case in the two “new” trials. There was no such early increase in cancer risk observed.
There was a slight increase in the number of cancer deaths in the new trials that were analyzed, but for other reasons the authors did not consider that a significant finding.
The researchers in the second paper wrote:
“On the basis of chance alone, many conventionally significant associations….of particular drugs with particular outcomes will arise that misleadingly suggest an unexpected benefit or hazard…Against this background, trial results…that indicate an unexpected hazard should generally be treated not as good evidence of a hazard but merely as a finding that generates a hypothesis that should be tested by means of statistically independent evidence, preferably based on much larger numbers of relevant outcomes.
“(In the two additional trials that were analyzed) there was no significant excess incidence of cancer, either overall or at any particular site, and there was no suggestion of an emerging rend with longer treatment and follow-up periods. Epidemiologic knowledge about chemical causes of cancer in humans suggests that a large proportional increase in the incidence of several types of solid tumor over a small fraction of the human life span is implausible.”
“The currently available results do not provide credible evidence of any adverse effect on cancer (by Vytorin).”
What did the New England Journal of Medicine have to say about this controversy in their editorial?
They said the issue was uncertain:
“Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution. Whether the increased mortality risk is due solely to the play of chance is uncertain…Physicians and patients are unfortunately left for now with uncertainty about the efficacy and safety of the drug.”
What should you do?
I can’t tell you whether or not Vytorin actually increases your risk of cancer. A 50% increase in the risk of cancer so soon after starting a medication is certainly a concern.
However, that increase isn’t supported by larger studies (although the duration of patient follow-up in those studies are much shorter than in the aortic stenosis study).
From my perspective, such a rapid increase in the numbers of cancers so soon after starting a drug is something that I find difficult to accept as biologically believable. The absence of an increasing trend in the risk of cancer—that is a continuing and enlarging increase over time—is something else that I consider important to note.
But when all the rhetoric is over, and you are sitting there with your doctor who has prescribed or wants to prescribe Vytorin, it would be prudent to have a discussion of the benefits and risks of the drug. The most important question is whether in your particular case Vytorin offers a real advantage over other cholesterol-lowering drugs which do not have such a cancer-risk cloud hanging over them.
My colleague Eric Jacobs is an expert in these types of drugs and their impact on cancer. Here is what he had to say on behalf of the American Cancer Society:
“The possibility that (Vytorin) may increase risk of cancer death cannot be entirely ruled out. Within the next few years, studies that are already underway will likely settle this question. In the meantime, people prescribed (Vytorin)…can discuss its risks and benefits with their health care provider.”
I consider that prudent advice. Why beg the issue if you don’t have to? We certainly have enough other things to worry about.